NO321361B1 - Cyclo-carbamate derivatives, their use as a medicament, a pharmaceutical preparation, and the use of the derivatives for the manufacture of medicaments. - Google Patents

Description

The present invention relates to compounds which are antagonists for the progesterone receptor, a pharmaceutical preparation and use of the compounds.

Intracellular receptors, IRs, form a class of structurally related gene regulators known as "ligand-dependent transcription factors" (R.M. Evans, "Science", 240,889, 1988). The steroid receptor family is a subset of the IR family which includes progesterone receptors, PR, estrogen receptors, ER, androgen receptors, AR, glucocorticoid receptors, GR, and mineralocorticoid receptors, MR.

The natural hormone, or ligand, for FR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been prepared and also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion and binds to the IR, requiring a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to DNA, the complex modulates the production of mRNA and protein encoded by this gene.

A compound that binds to an IR and mimics the action of the natural hormone is called an agonist, while a compound that inhibits the action of the hormone is an antagonist.

PR antagonists can be used for contraception. In this context, they can be administered alone (Ulmann et al., "Ann. N.Y. Acad. Sei.", 261,248, 1995), in combination with a PR agonist (Kekkonen et al., "Fertility and Sterility", 60,610,1993 ) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 Al, 4 July 1996).

PR antagonists may also be useful for the treatment of hormone-dependent breast cancer (Horwitz et al., "Horm. Cancer", 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeciks) as well as uterine and ovarian cancer. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy et al., "J.

Clin. A toilet. Metab.", 76, 513, 1993) and endometriosis (Kettel et al., "Fertility and Sterility", 56, 402, 1991).

PR antagonists may also be useful in hormone replacement therapy for postmenopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5,719,136).

PR antagonists such as mifepristone and onapristone have been shown to be effective in a model of hormone-dependent prostate cancer, which may indicate their utility in treating this condition in men (Michna et al., "Ann. N.Y. Acad. Sei.", 761,224, 1995).

The compounds according to the invention have been shown to act as competitive inhibitors for progesterone binding to PR and act as antagonists in functional models, either/or in vitro and in vivo. These compounds can be used for contraception, for the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer as well as for post-menopausal hormone replacement therapy.

Compounds according to the known technique are described by Jones et al. (US 5,688,810) in the form of the PR antagonist dihydroquinoline 1.

Jones et al. have described the enoleter 2 (US 5,693,646) as a PR ligand:

Jones et al. have described compound 3 (US 5,696,127) as a PR ligand:

Zhi et al. have described the lactones 4, 5 and 6 as PR antagonists ("J. Med. Chem.", 41, 291, 1998).

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

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

Perlman et al. have described the vitamin D analogs 9 as a PR ligand ("Tet. Letters", 35,2295,1994).

Hamann et al. have described the PR antagonist 10 ("Ann. N.Y. Acad. Sei.", 761,383, 1995).

Chen et al. have described the PR antagonist 11 (Chen et al., "POI-37", 16. Int. Cong. Het. Chem., Montana, 1997).

Kurihari et al. have described PR ligand 12 ("J. Antibiotics", 50, 360, 1997).

Narr et al. (DE 3633861, CA 109:22973) claimed imidazobenzoxazinones, for example A, as cardotonics; benzoxazin-2-ones such as brofoxine (B) as active as anxiolytics have been reported by Hartmann et al. ('Troe. West. Pharmacol. Soc.', 21, 51-55

(1978)). In the later, a number of patents (eg Young et al. WO 95/20389; Christ et al. WO 98/14436) have claimed quinazolin-2-ones and benzoxazin-2-ones, for example compounds C1 and C2 as inhibitors of HIV reverse transcriptase: The compounds according to the invention contain a pendant aromatic substituent. The aromatic substituents are found to be essential for the resulting compounds active as progesterone receptor modulators and have wide structural diversity which may consist of aryl, substituted aryl, heteroaryl or substituted heteroaryl groups.

Description of the invention

The present invention provides compounds of formula (I)

there:

R<1> and R<2> independently are substituents selected from the group H, optionally substituted C 1-6 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 3-scycloalkyl, aryl and a heterocyclic group;

or R<1> and R<2> are fused to form:

a carbon-based 3- to 8-membered saturated spirocyclic ring;

R<3> is H, optionally substituted C1-6 alkyl or COR<c>;

R<c> is substituted aryl or substituted C 1-6 alkoxy;

R 4 is H, halogen, OH, C 1-6 alkyl or C 1-6 alkoxy;

R<5> is selected from the group comprising (i) and (ii):

(i) a substituted benzene ring containing the substituents X, Y and Z as shown below:

there:

X is selected from the group comprising halogen, CN, OH, optionally substituted C 1-3 alkyl, optionally substituted C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 perfluoroalkyl, NO 2 , C 1-3 perfluoroalkyl, a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms, COR<D>, SO 2 NH 2 or NR<E>COR<D>; RD is H, C 1-3 alkyl, aryl and C 1-3 alkoxy; R<E>erH; Y and Z are independently substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1-6 alkoxy, C 1-6 alkyl and C 1-3 perfluoroalkyl; or (ii) a 5- or 6-membered ring with 1,2 or 3 heteroatoms selected from the group O, S, SO, SO2 and NR<6> and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , amino, optionally substituted CM alkyl, SO 2 NH 2 and COR<F>;

provided that when R<5> is the 5-membered ring with two NR<6> heteroatoms, R<1> and R<2> are not both H; and

provided that when R<5> is a 5-membered ring with one NR<6->heteroatom and where R<5> is attached in the 2-position of the ring, there is no CN substituent in the 5-position of the ring;

R is H;

R<6> is absent, H, C1-3 alkyl, O or C(0)C1-4 alkoxy,

provided that when R<5> the benzene ring (i) is substituted with one or two substituents or it

5- or 6-membered ring, (ii) with 1, 2 or 3 heteroatoms in the ring selected from O, S and NR<6>, and R<1> is alkenyl or alkynyl, R<2> is not optionally substituted alkyl , cycloalkyl, alkenyl or alkynyl; or if R<2> is alkenyl, or alkynyl, R<1> is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl;

with the proviso that when R<5> the benzene ring (i) is substituted with one or two substituents or the 5- or 6-membered ring (ii) with 1,2 or 3 heteroatoms in the ring selected from

file")

the group consisting of O, S and NR , and R is alkenyl, R is not cycloalkyl, or if R<2> is optionally substituted alkyl, R<1> is not cycloalkyl;

where:

said aryl group is phenyl;

said heterocyclic group is selected from the group consisting of thienyl, thiophene, pyrrole, thiazole, furyl, pyridinyl, thiadiazole, tetrazole, pyrazinyl and pyrimidinyl;

said substituted alkyl and substituted alkynyl groups have one to three substituents selected from the group consisting of halogen, CN, OH, C1-6 alkoxy, silyl and phenyl;

said substituted aryl has one to four substituents selected from the group consisting of C1-6 alkoxy and C1-6 alkylamino;

or a pharmaceutically acceptable salt thereof.

Preferred compounds according to the invention are those of formula (I)

there:

R<1> and R<2> are independent substituents selected from H, optionally substituted C1-6 alkyl, C2-6 alkenyl, optionally substituted C2-6 alkynyl, C3-8 cycloalkyl, aryl and a heterocyclic group;

or R<1> and R<2> are fused to form a carbon-based 3- to 8-membered saturated spirocyclic ring;

R<3> is H, optionally substituted C1-6 alkyl or COR<c>;

R<c> is substituted aryl or C 10 carboxy;

R<4> is H, halogen, C1-6 alkyl or C1-6 alkoxy;

R<5> is (i) or (ii):

(i) a substituted benzene ring containing the substituents X, Y and Z as shown below:

there:

X is selected from the group comprising halogen, CN, optionally substituted C 1-4 alkyl, C 1-3 alkoxy, NO 2 , C 1-3 perfluoroalkyl, a 5-membered heterocyclic ring in the ring containing 1 to 3 heteroatoms, COR<D> and NR<E>COR <D>; RD is H, C 1-6 alkyl, aryl or C 1-6 alkoxy; R<E>erH; Y and Z are independently substituents selected from the group consisting of H, halogen, CN, NO 2 , CMalkoxy and C 1 -alkyl; or (ii) a 5- or 6-membered ring with 1, 2 or 3 heteroatoms in the ring selected from the group consisting of O, S, SO, SO2 and NR<6> and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , amino and C 1-6 alkyl;

provided that when R<5> is the 5-membered ring with two NR<6> heteroatoms, R<1> and R<2> are not both H; and

provided that when R<5> is a 5-membered ring with one NR<6->heteroatom and where R<5> is attached in the 2-position of the ring, there is no CN substituent in the 5-position of the ring;

R<6> is either C 1-3 alkyl;

provided that when R<5> the benzene ring is (i) substituted with one or two substituents or the 5- or 6-membered ring, (ii) with 1,2 or 3 heteroatoms in the ring selected from O, S and NR6, and R <1> is alkenyl or alkynyl, R<2> is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl; or if R<2> is alkenyl, or alkynyl, R<1> is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl; or

with the proviso that when R<5> the benzene ring (i) is substituted with one or two substituents or the 5- or 6-membered ring (ii) with 1, 2 or 3 heteroatoms in the ring chosen from

file 9

the group consisting of O, S and NR, and R is optionally substituted alkyl, is R

not cycloalkyl, or if R<2> is optionally substituted alkyl, R<1> is not cycloalkyl;

where:

said aryl group is phenyl;

said heterocyclic group is selected from the group consisting of thienyl, thiophene, pyrrole, thiazole, furyl, pyridinyl, pyrazinyl, pyrimidinyl, thiadiazole and tetrazole;

said substituted alkyl and substituted alkynyl groups have one to three substituents selected from the group consisting of halogen, CN, OH, C1-6 alkoxy, silyl and phenyl;

said substituted aryl has one to four substituents selected from the group consisting of C 1-6 alkoxy and C 1-6 alkylamino;

a pharmaceutically acceptable salt thereof.

Other preferred compounds are those of formula (I)

there

12 12 R = R and selected from the group consisting of optionally substituted C1-3alk.yl, or R and R are fused to form a carbon-based 3- to 6-membered spirocyclic ring;

R 3 is H, optionally substituted C 1-6 alkyl or COR<c>;

R<c>is C 1-4 alkoxy;

R<4 > is H, halogen, C 1-6 alkyl or C 1-6 alkoxy;

R<5> is selected from the group consisting of a), b) and c):

a) a substituted benzene ring with the formula shown below:

there

X is halogen CN, C 1-3 alkoxy, C 1-3 alkyl, NO 2 , C 1-3 perfluoroalkyl or a 5-membered heterocyclic ring in the ring containing 1 to 3 heteroatoms;

Y is H, halogen, CN, NO 2 , C 1-3 alkoxy or C 1-3 alkyl;

b) 5-membered ring with the structure:

there:

U is O, Seller NR<6>;

X' is selected from halogen, CN, NO 2 and C 1-3 alkyl;

Y' is selected from the group consisting of H and C-1 alkyl; and

c) a 6-membered ring with the structure:

there:

X<1> is N or CX<2>;

X 2 is halogen, CN or NO 2 ;

R<6 > is H, C 1 -C 1 alkyl or C 1 -C 2 alkyl;

where:

said substituted alkyl, has one to three substituents selected from the group consisting of halogen, CN, OH, C1-6 alkoxy, silyl and phenyl;

said substituted aryl has one to four substituents selected from the group consisting of C 1-6 alkoxy and C 1-6 alkylamino;

said aryl group is phenyl;

said heterocyclic group is selected from the group consisting of thienyl, thiophene, pyrrole, thiazole, furyl, pyridinyl, pyrazinyl, pyrimidinyl, thiadiazole and tetrazole;

or a pharmaceutically acceptable salt thereof.

Further preferred compounds are those of formula (I):

there

R<1> = R2 and selected from the group consisting of optionally substituted Cualkyl, or R<1> and R<2> are fused to form a carbon-based 3- to 6-membered saturated spirocyclic ring;

R 3 is H, optionally substituted C 1-6 alkyl or COR<c>;

R 1 -C 1-4 alkoxy;

R<4> is H, halogen or C1-6 alkoxy;

R<5> is a 6-membered ring with the structure:

where

X 1 is N;

or a pharmaceutically acceptable salt thereof.

The compounds according to the invention may contain an asymmetric carbon atom and some of the compounds according to the invention may contain one or more centers of asymmetry and thus give rise to optical isomers and diastereomers. While shown without regard to the stereochemistry of formula (I), the invention includes such optical isomers and diastereomers as well as the racemic and resolved, enantiomerically pure R- and S-stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.

The term "alkyl" is used herein to refer to both straight and branched, saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms such as 1 to 8 carbon atoms and preferably 1 to 6 carbon atoms; "alkenyl" is intended to include both straight and branched alkyl groups with at least one carbon-carbon double bond and e.g. 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms; "alkynyl" is intended to cover both straight and branched alkyl groups with at least one carbon-carbon triple bond and e.g. 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms.

The terms "substituted alkyl", "substituted alkenyl" and "substituted alkynyl" refer unless otherwise specified to alkyl, alkenyl and alkynyl as described above with from 1 to 3 substituents selected from the group comprising halogen, CN, OH, NO2, amino,

aryl, heterocycle, substituted aryl, substituted heterocycle, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio. These substituents may be attached to any carbon in the alkyl, alkenyl or alkynyl group provided that the bond constitutes a stable chemical moiety.

The term "aryl" is used here to refer to an aromatic system which can be a single ring or several aromatic rings fused or linked together so that at least part of the fused or linked rings form the conjugated aromatic system. The aryl groups include, unless otherwise specified, but are not limited to phenyl, naphthyl, biphenyl or anthryl, tetrahydronaphthyl or phenanthryl.

The term "substituted aryl" unless otherwise specified, refers to aryl as just defined with from 1 to 4 substituents from the group comprising CN, OH, NO2, amino,

alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio.

The term "heterocycle", unless otherwise specified, is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated, and which consists of carbon atoms and with from 1 to 4 heteroatoms selected from the group consisting of N, O and S atoms. The N and S atoms can be oxidized. The heterocyclic ring also includes any multicyclic ring in which any one of the defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached to 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" unless otherwise specified, is used herein to describe a heterocycle as defined above with from 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl , substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino or arylthio. The term "alkoxy" is used here to refer to the OR group, where R is alkyl or substituted alkyl. The term "aryloxy" is used herein to refer to the OR group, where R is aryl or substituted aryl. The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is alkyl or substituted alkyl. The term "alkylcarboxy" is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. The term "aminoalkyl" refers to both secondary and tertiary amines in which alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms which may be the same or different, are attached to the nitrogen atom. The term "halogen" refers to Cl, Br, F or I.

The compounds according to the invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric, sulfuric, nitric or phosphoric acid, or possibly organic acids such as acetic, oxalic, succinic and maleic acids. Other salts are salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "prodrug" precursors, which, when administered in such form, convert the active moiety in vivo.

The present invention includes pharmaceutical preparations comprising one or more compounds according to the invention and a pharmaceutically acceptable carrier or an emollient. The invention is used in methods of treatment comprising administering to a mammal a pharmaceutically effective amount of one or more compounds as described above as antagonists of the progesterone receptor.

The present invention comprises the compounds according to the invention for use as a medicament for administration to a mammal.

Furthermore, the present invention comprises the use of a compound according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for administration to a mammal, wherein an effective amount induces contraception.

The invention also relates to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for administration to a mammal, where the compound treats hormone-dependent neoplastic diseases in the mammal.

The invention further relates to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for administration to mammals, where the compound synchronizes estrus in the mammal.

The present invention further comprises the use of a compound selected from the group

6-(3-chlorophenyl)-4-methyl-4-propyn-1 -yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4 -ethynyl-4-methyl-1,4-dihydro-benzo[d] [1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-cyclopropyl-4-propyn-1 -yl-1, 4-dihydro-benzo[d] [ 1,3]oxazin-2-one, and

6-(3-Chlorophenyl)-4,4-dipropyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one or a pharmaceutically acceptable salt, for the manufacture of a medicament for administration to a mammal, wherein an effective amount of said compound induces contraception.

In addition, the invention relates to the use of a compound selected from the group 6-(3-chlorophenyl)-4-methyl-4-propyn-1 -yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2- one, 6-(3-chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-cyclopropyl -4-propyn-1 -yl-1,4-dihydro-benzo[d][ 1,3]oxazin-2-one, and

6-(3-Chlorophenyl)-4,4-dipropyn-1 -yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one or a pharmaceutically acceptable salt, for the manufacture of a medicament for administration to a mammal, wherein the compound treats hormone-dependent neoplastic diseases in the mammal.

The present invention also includes the use of a compound selected from the group consisting of

6-(3-chlorophenyl)-4-methyl-4-propyn-l-yl-1,4-dihydro-benzo[d][l,3]oxazin-2-one, 6-(3-chlorophenyl)-4 -ethynyl-4-methyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-cyclopropyl-4-propyn-1 -yl-1, 4-dihydro-benzo[d] [ 1,3]oxazin-2-one, and

6-(3-Chlorophenyl)-4,4-dipropyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one or a pharmaceutically acceptable salt for the preparation of a medicament for administration to a mammal, wherein the compound synchronizes estrus in the mammal.

In addition, the present invention relates to the use of a compound according to the invention or said acceptable salt in the preparation of a drug for administration to a mammal by hormone replacement therapy. The progesterone receptor antagonists according to the invention, used alone or in combination, can be used in methods for contraception and therapy and/or prevention of benign and malignant neoplastic diseases. Specific uses for the compounds and pharmaceutical preparations according to the invention include therapy and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors. Additional uses of the present progesterone receptor antagonists include synchronization of estrus in cattle.

When the compounds are used for the above areas, they can be combined with one or more pharmaceutically acceptable carriers or excipients, for example solvents, diluents and the like, and can be administered orally in forms such as tablets, capsules, dispersible powders, granules or suspensions containing for example from 0.05 to 5% suspending agent, syrups containing for example from around 10 to 50% sugar and elixirs containing for example from 20 to 50% ethanol and the like, or in the form of sterile, injectable solutions or suspensions containing from 0, 05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may for example contain from about 25 to about 90% of the active ingredient in combination with the carrier, usually between about 5 and 60% by weight.

The effective dose of active ingredient used may vary depending on the compound used, the mode of administration and the severity of the condition being treated. However, generally satisfactory results are obtained when the compounds of the invention are administered at a daily dose of from about 0.5 to about 500 mg/kg animal body weight, preferably given in individual doses 2 to 4 times daily, or in a sustained release form. For most large animals the total daily dose is from about 1 to 100 mg and preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in thorough admixture with solid or liquid pharmaceutically acceptable carriers. The dosage regimen can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be reduced proportionally as indicated by the therapeutic situation.

These active compounds can be administered orally and intravenously, intramuscularly or subcutaneously. Solid carriers are starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers are sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oil, depending on the nature of the active ingredient and the special form of administration. Emulsifiers that are usually used in the manufacture of pharmaceutical preparations can be advantageously included, for example flavourings, colourings, preservatives and antioxidants, for example vitamin E, ascorbic acid, BHT and BUA.

The preferred pharmaceutical preparations from a manufacturing and administration point of view are solid preparations and in particular tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds 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 salt can be prepared in water, suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent microorganism growth.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that light syringe use is available. It must be stable under manufacturing and storage conditions and must protect against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersing medium, for example water, ethanol (for example glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oil.

The compounds according to the invention can be prepared by following the schemes given below.

As shown in scheme I, the compounds according to the invention are generally prepared by using the appropriate coupling reaction as the final step. An appropriately substituted ortho-aminobenzoic acid or its derivatives such as the ethyl ester (X = Br, I, Cl, or a latent coupling precursor such as an alkoxy group which can be converted into an OTf group suitable in the coupling reaction) was treated with a suitable organometallic reagent, e.g. a Grignard reagent, in suitable non-protic solvents including but not limited to THF or ether to thereby afford the ortho-aminocarbinol 2 under an inert atmosphere such as argon or nitrogen at -78°C to room temperature. Ring closure of the carbinol 10 to benzoxazin-2-ones 3 is generally carried out using a condensing agent such as carbonyldiimidazole, phosgene, dimethyl carbonate or diethyl carbonate in a suitable, non-protic solvent such as THF at temperatures in the range of room temperature to 65°C. The arylation of the benzoxazin-2-ones 3 to obtain 4 can be accomplished by various coupling reactions including Suzuki or Stille reactions. These reactions are usually carried out in the presence of transition metal catalysts, for example palladium or nickel complexes often with phosphino ligands, for example PI13P, l,r-bis(diphenylphosphino)ferrocene, l,2-bis(diphenylphosphino)ethane or palladium salt such as palladium acetate. Under these catalytic conditions, a suitable substituted nucleophilic reagent, for example arylboronic acid, arylstannane or arylzinc compound, is coupled with the benzoxazinones 3 to obtain 4. If a base is needed in this reaction, commonly used bases include without limitation sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate , potassium acetate or cesium fluoride. The solvents usually used in these reactions are benzene, DMF, isopropanol, toluene, ethanol, DME, ether, acetone or a mixture of any of these solvents and water. The coupling reaction is usually carried out under an inert atmosphere such as nitrogen or argon at a temperature in the range of room temperature to the boiling point of the solvent or solvent system or mixture.

The benzoxazinones 3 can be converted to a nucleophile such as boric acid which can be coupled with a suitable electrophile, for example aryl bromide or aryl iodide, to give 4, using the coupling reaction conditions as described above. The transformation of 3 to 5 can be accomplished by treating 3 with an organometallic reagent, for example n-BuLi, in a non-protic solvent such as THF or ether, followed by quenching the reaction solution with a suitable electrophile such as trimethyl borate, triisopropyl borate, bishexyl -step reagent or zinc chloride at temperatures from -78°C to reflux temperature under an inert atmosphere such as argon or nitrogen.

Scheme Ia illustrates an alternative approach leading to the benzoxazinones 3. Thus, a suitable aniline 1 is protected with a suitable alkoxycarbonyl protecting group, including but not limited to allyloxycarbonyl, t-butoxycarbonyl, benzoxycarbonyl, ethoxycarbonyl or methoxycarbonyl in a suitable solvent such as THF or acetonitrile, with or without the presence of a base, either as a catalyst or as an acid scavenger. The protected aniline is then treated with a suitable organometallic reagent such as an organolithium reagent or a Grignard reagent in the same manner as to prepare compound 2 to give the carbinol 6. The treatment of 6 with a suitable base such as potassium t-butoxide, n- butyllithium, potassium hydroxide in a suitable solvent such as toluene, THF or alcohol under an inert atmosphere such as nitrogen or argon at temperatures in the range of room temperature to the boiling point of the relevant solvent to give the benzoxazinones 3. Scheme II describes the procedures for preparing benzoxazinones with two different substituents in 4 position. The Weinreb amide 8 can be prepared from a suitable substituted isatoic anhydride 7 by treatment with N-,O-dimethylhydroxylamine hydrochloride salt in a protic solvent such as ethanol or isopropanol under reflux under an inert atmosphere such as argon or nitrogen. Coupling of the amide 8 with an aryl electrophile such as arylboronic acid or arylstannane to give 9 can be accomplished using a typical coupling reaction such as a Suzuki or Stille coupling procedure in the same manner as described for the preparation of the benzoxazinones 4. Treatment of the Weinreb amide 9 with organometallics compounds, for example alkyllithium, alkynyllithium, aryllithium or their Grignard counterpart in a non-protic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen, at -78°C to room temperature, gives the amino ketone 10. Conversion of the ketone 10 to the carbinol 11 can be accomplished by treating 10 with an organometallic reagent such as an alkyl, alkynyl or aryl Grignard compound in a non-protic solvent such as THF or ether, under an inert atmosphere such as argon or nitrogen at -78°C to room temperature . Conversion of the ketone 10 to the carbinol 11 can also be carried out by reduction of the ketone group in 10 to the carbinol part in 11 using a suitable reducing agent such as lithium aluminum hydride, sodium borohydride in a suitable solvent such as THF, ether or aqueous alcohol under an inert atmosphere in the temperature range 0 °C to the boiling point of the solvent. Cyclization of the carbinol 11 to give the compounds according to the invention can be carried out with condensing agents such as carbonyldiimidazole, phosgene, dimethyl carbonate or diethyl carbonate in a suitable non-protic solvent such as THF at temperatures in the range of room temperature to 65°C.

Alternatively, the ortho-amine ketone 10 can be prepared by treating the ortho-amino-benzonitrile 14 with an organometallic compound, for example an organolithium compound 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 of -78°C to room temperature as shown in Scheme III. The benzonitrile 14 can be easily prepared from a suitable substituted benzonitrile such as bromobenzonitrile 13 using a suitable coupling reaction such as a Stille or Suzuki protocol carried out in the same manner as described for the preparation of the Weinreb amide 9.

Scheme IV suggests an approach for the preparation of benzoxazinones with a lower perfluoroalkyl substituent in the 4-position, for example where R 1 is a trifluoromethyl group. A suitable substituted chloroaniline 15 was protected with a suitable protecting reagent such as pivaloyl chloride or di-tert-butyl pyrocarbonate to give the protected aniline 16 in a suitable solvent such as acetonitrile, acetone, THF, methylene chloride or a mixture of solvents such as methylene chloride and water under a inert atmosphere such as argon or nitrogen, at temperatures in the range 0°C to 70°C. A suitable base such as sodium carbonate, sodium bicarbonate or potassium carbonate may be required when the reaction gives an acid as a by-product, for example hydrochloric acid. Treatment of 16 with a suitable alkyllithium such as n-butyllithium or s-butyllithium, followed by reaction of low-perfluorocarboxy derivatives, for example trifluoroacetyl chloride, l-(trifluoroacetyl)-imidazole or ethyl trifluoroacetate in a non-protic solvent, for example ether or THF, under an inert atmosphere such as argon or nitrogen and at -78°C to ambient temperature, they give protected ortho-aminoketones. Subsequent removal of the protecting group can be accomplished by reacting protected amino ketones with a suitable acid such as TF A, 3N aqueous hydrochloric acid solution in a suitable solvent such as methylene chloride or water at 0°C to the boiling point of the solvent to give the ortho-amino ketone 17. The Preparation of the 6-chloro-benzoxazinones 19 from 17 can be carried out in the same way as described for the synthesis of benzoxazinone 12 from ketone 10. Coupling of 19 with an aryl group to give compounds according to the invention 12 as shown in scheme IV can be carried out with the aid of a nickel complex -catalyzed coupling reaction. The palladium catalysts do not prove to be effective catalysts in this coupling process. The coupling reaction of 19 with a suitable arylboronic acid can be carried out 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. The solvents usually used in this reaction are dioxane or THF. The coupling reaction is generally carried out under an inert atmosphere such as nitrogen or argon at temperatures in the range of ambient temperature to 95°C.

As shown in Scheme V, compounds 6 or 12 can be further derivatized at the 1-position via numerous approaches leading to a variety of novel cyclocarbamate derivatives including 1-alkyl-, 1-substituted alkyl-, 1-carbonyl-, 1-substituted carbonyl- , 1-carboxy-, 1-substituted carboxy derivs. For example, alkyl or substituted alkyl derivatives 20 can be formed 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, followed by the addition of a suitable electrophile such as alkyl or substituted alkyl -bromide, -iodide or triflate. Such a transformation of 12 or 6 in the 1-position can also be carried out using two-phase conditions as indicated in scheme V, where the alkylation is carried out using a two-phase catalyst such as tributylammonium bromide in a suitable solvent such as acetonitrile. Another example of this type of modification is without limitation that indicated in Scheme V, where heating 12 or 6 with triethyl orthoformate gives 1-substituted derivatives of compound 12 or 6.

The acylation or carboxylation of compound 12 or 6 in the 1-position to give compound 21 can be readily accomplished by treating 12 or 6 with a suitable acylating or carboxylating reagent such as di-t-butyldicarbonate in the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen. The amination at the 1-position of compound 12 or 6 to give 22 can be carried out using a suitable aminating agent such as chloramine in the presence of a suitable base such as sodium hydroxide in a suitable solvent such as THF or diethyl ether, according to literature procedures (see Metlesics et al . in "J. Org. Chem.", 30, 1311 (1965)).

The following examples 1-4 describe the production of precursors to the compounds according to the present invention.

EXAMPLE 1

2-(2-amino-5-bromophenyl)propan-2-ol

A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in 200 mL of dry THF was warmed to -78°C under nitrogen with a solution of methylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reaction mixture was slowly warmed to room temperature, stirred for 48 hours under nitrogen and then poured into 300 ml of cold aqueous 0.5N hydrochloric acid solution. The mixture was neutralized with 1N aqueous sodium hydroxide solution and 300 ml of ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted with 3 x 100 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgSO 4 . After removal of the solvent under vacuum, the residue was purified by silica gel flash chromatography with hexane:ethyl acetate 3:2 to give 2-(2-amino-5-bromophenyl)propan-2-ol as an off-white solid (6 g, 57%) with melting point 62-63°C.

1 H-NMR (CDCl 3 ) δ 7.19 (d, 1H, J = 2.3 Hz), 7.12 (dd, 1H, J = 8.4 Hz), 6.51 (d, 1H, J =

8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H).

EXAMPLE 2

6-brom-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) in 150 ml of dry THF was added l,r-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction mixture was heated to 50°C overnight. The solvent was removed under vacuum and the residue dissolved in 100 ml of ethyl acetate. The solution was washed with 2 x 40 mL 1N aqueous hydrochloric acid solution, 20 mL brine and dried over MgSO 4 . After removal of the solvent under vacuum, 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtained as a white solid (20 g, 100%) with melting point 199-200°C.

1H-NMR (DMSO-dé) δ 10.32 (s, 1H, D 2 O exchangeable), 7.48 (d, 1H, J = 2.1 Hz), 7.43 (dd,

1H, J = 8.5, 2.1 Hz), 6.84 (d, 1H, J = 8.4 Hz), 1.61 (s, 6H).

EXAMPLE 3

6-iodo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

This product was prepared from 2-amino-5-iodobenzoic acid by following the procedures of Examples 1 and 2 as a white solid, mp 196-197°C.

1H-NMR (DMSO-de): 10.30 (s, 1H, D 2 O exchangeable), 7.58 (m, 2H), 6.71 (d, 1H, J = 8.4

Hz), 1.58 (s, 6H);

MS (EI) m/z: 326 ([M+Na]<+>, 100%).

Analysis for CiqHioIN02:

EXAMPLE 4

(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro- benzo[d][l,3]oxazin-2-one (2 g, 7.8 mmol) in 60 ml of anhydrous THF is added a solution of n-BuLi in hexane (10M, 2.4 ml, 24 mmol) at - 78°C under nitrogen. After stirring at -78°C for 30 minutes, a slurry is obtained which is treated with triisopropyl borate (6.5 ml, 28 mmol). The reaction medium is slowly heated to ambient temperature and quenched with 60 ml IN aqueous hydrochloric acid solution. 100 ml of ethyl acetate was added and the organic layer separated, after which the aqueous layer was extracted with 3 x 60 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgSO 4 . The solvent was removed in vacuo and the residue purified by silica gel flash chromatography with ethyl acetate:hexane 2:1 to give (1,4-dihydro-4,4-dimethyl-2-oxo -2H-3,1-benzoxazin-6-yl)boric acid as a white solid (1.4 g, 81%) mp 249-250°C.

<J>H-NMR (DMSO-d6) δ 10.21 (s, 1H, D20 exchangeable), 7.90-7.95 (br s, 2H, D20 exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J = 7.8 Hz), 1.61 (s, 6H);

MS (ESI) m/z 222 ([M+H]<+>, 87%).

EXAMPLE 5

6-(3-chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

(Procedure A)

A mixture of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one (1.5 g, 5.9 mmol), 3-chlorophenylboronic acid (1 .83 g, 11.7 mmol), tetrakis(triphenylphosphine)-palladium(0)

(0.35 g, 0.3 mmol) and sodium carbonate (2.48 g, 23.4 mmol) in a mixture of 40 mL DME and 10 mL water was degassed to remove oxygen and then heated to 85°C under a nitrogen blanket for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with 20 ml of saturated aqueous ammonium chloride solution. 50 ml of ethyl acetate was added and the organic layer separated. The aqueous layer was extracted with 3 x 15 ml ethyl acetate. The combined organic layers were washed with brine and dried over MgSCv. The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography with hexane:ethyl acetate 2:1 to afford 6-(3-chlorophenyl)-4,4-dimethyl- 1,4-dihydro-benzo[d][1,3]oxazin-2-one as a yellowish solid (1.4 g, 82%) mp 158-159°C.

1H-NMR (DMSO-dfi) δ 10.31 (s, 1H, D 2 O exchangeable), 7.75 (s, 1H), 7.61 (m, 3H), 7.46 (t,

1H, J = 7.9 Hz), 7.39 (dd, 1H, J = 7.0,1.1 Hz), 6.96 (d, 1H, J = 8.6 Hz), 1.68 ( s, 6H);

Analysis for Ci6H,4ClNO20,lH2O:

EXAMPLE 6

6-(3-Methoxyphenyl)-4,4-dimethyl]-1,4-dihydro-beZo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 6-bromo-4, 4-Dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-methoxyphenylboronic acid as a yellow solid with melting point 164-165°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 7.56 (m, 2H), 7.36 (t, 1H, J = 7.89 Hz), 7.20 (m,

2H), 6.96 (d, 1H, J = 8.88 Hz), 6.91 (dd, 1H, J = 8.13,2.35 Hz), 3.8 (s,

3H), 1,7(s,6H);

MS (ESI) m/z 284 ([M+Hf, 30%);

Analysis for C17H17NO3:

EXAMPLE 7

6-(2-Chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 6-bromo-4,4 -dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 2-chlorophenylboronic acid as a white solid with melting point 181-182°C.

MS (ESI) m/z 288 ([M+H]<+>, 70%);

Analysis for Ci6Hi4ClN03:

EXAMPLE 8

6-(4-Chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 6-bromo-4, 4-dimethyl 1-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one and 4-chlorophenylboronic acid as a white solid with melting point 255-257°C.

1H-NMR (DMSO-d 6 ) δ 10.3 (s, 1H), 7.7 (d, 2H, J = 8.52 Hz), 7.55 (m, 2H), 7.5 (d, 2H,

J = 8.52 Hz), 6.96 (d, 1H, J = 8.52 Hz), 1.7 (s, 6H);

MS (ESI) m/z 288 ([M+H]<+>, 70%);

Analysis for Ci6Hi4ClN02:

EXAMPLE 9

6-(3-Chlorophenyl)-4-methyl-1,4-dihydro-benzo [d] [1,3]oxazin-2-one To a solution of 1-(4-amino-3'-chloro-biphenyl -3-yl)-ethanone (see example 35, 0.15 g, 0.61 mmol) in anhydrous methanol was added sodium borohydride (0.07 g, 1.03 mmol) at room temperature under nitrogen. After 15 minutes, the reaction mixture was treated with ice water. 30 ml of ethyl acetate was then added, the organic layer separated and the aqueous layer extracted with 3 x 20 ml of ethyl acetate. The combined organic layers were washed with 10 ml of brine and dried over MgSO4 After removal of the solvent, the resulting residue was crystallized from toluene to give 1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanol as a white solid (0.087 g, 58%).

1H-NMR (DMSO-de) δ 7.55 (t, 1H, J = 1.4 Hz), 7.50 (d, 1H, J = 7.8 Hz), 7.44 (d, 1H, J

= 2.1 Hz), 7.39 (t, 1H, J = 8.2 Hz), 7.31-7.21 (m, 2H), 6.68 (d, 1H, J = 8.1 Hz ), 5.25 (s, 2H), 5.20 (m, 1H), 4.83 (m, 1H), 1.35 (d, 3H, J = 8.8

Hz),

MS (ESI) m/z 247 (M<+>).

A mixture of 1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanol (0.03 g, 0.13 mmol) and triphosgene (0.01 g, 0.04 mmol) in 3 mL dry THF was stirred under a blanket of nitrogen for 10 min. The solvent was removed to give 6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid (0.031 g, 91%) with melting point 155-156°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 7.72 (m, 1H), 7.62 (m, 2H), 7.56 (m, 1H), 7.47 ( t,

1H, J = 8.00 Hz), 7.39 (d, 1H, J = 8.0 Hz), 6.98 (d, 1H, J = 8.0 Hz), 5.50

(q, 1H, J = 6.82 Hz), 1.6 (d, 3H, J = 6.82 Hz);

MS (APCI) m/z 274 ([M+H]<+>, 100%).

EXAMPLE 10

6-(3-Chlorophenyl)-4-ethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to the procedure of Example 9 from 1-(4-amino- 3'-chloro-biphenyl-3-yl)-propanol and triphosgene as a white solid with melting point 146-148°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 7.70 (m, 1H), 7.60 (m, 3H), 7.47 (t, 1H, J = 8.22

Hz), 7.39 (d, 1H, J = 8.28 Hz), 6.97 (d, 1H, J = 8.22 Hz), 5.4 (t, 1H, J =

10.9 Hz), 1.9 (m, 2H), 0.97 (t, 3H, J = 7.68 Hz);

MS (ESI) m/z 286 ([M-H]", 100%).

EXAMPLE 11

6-(3-Chlorophenyl)-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to the procedure of Example 9 from 1-(4-amino- 3'-chloro-biphenyl-3-yl)-benzyl alcohol and triphosgene as a whitish solid with a melting point of 177-178°C.

1H-NMR (DMSO-d 6 ) δ 10.5 (s, 1H), 7.68 (dd, 1H, J = 8.7, 1.7 Hz), 7.62 (t, 1H, J = 1 ,74

Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04 (d, 1H, J = 8.7 Hz), 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

(Procedure B)

A mixture of (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid (2.22 g, 10 mmol), 3-bromobenzonitrile (2.18 g, 12 mmol), tetrakis(triphenylphosphine)palladium(0)

(0.6 g, 0.52 mmol) and sodium carbonate (2.2 g, 21 mmol) in 70 mL DME and 15 mL water were degassed to remove oxygen and then heated to 85 °C under a blanket of nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and quenched with 20 ml of saturated aqueous ammonium chloride solution. 100 ml of ethyl acetate was added and the organic layer separated. The aqueous layer was extracted with 3 x 30 ml of ethyl acetate. The

combined organic layers were washed with brine and dried over MgSCv The solvent was removed in vacuo and the residue purified by silica gel flash chromatography with 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 as an off-white solid (0.7 g, 25%) mp 236-237°C.

1H-NMR (DMSO-de) δ 10.34 (s, 1H, D 2 O exchangeable), 8.21 (s, 1H), 8.02 (d, 1H, J = 8.1

Hz), 7.79 (d, 1H, J =7.7 Hz), 7.60-7.70 (m, 3H), 6.98 (d, 1H, J =8.2 Hz), 1, 71 (p, 6H);

Analysis for CnHi^Qz-O.lIkO:

EXAMPLE 13

4,4-dimethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one Prepared from 6-iodo-4,4-dimethyl-1,4-dihydro- benzo[d][l,3]oxazin-2-one and 3-nitrophenylboronic acid according to procedure A, as a yellowish solid, mp 244-245°C.

1H-NMR (DMSO-de) 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 = 8.1 Hz), 1.68 (s, 6H);

MS (ES) m/z 297 ([M-H]\ 100%);

Analysis for C16H14N2O4:

EXAMPLE 14 6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Prepared from (1,4-dihydro-4 ,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1,3-dibromo-5-fluorobenzene according to procedure B as a white solid, mp 182-183°C. 1 H-NMR (DMSO-de) δ 10.36 (s, 1H, D 2 O exchangeable), 7.78 (s, 1H), 7.58-7.65 (m, 3H),

7.49 (dd, 1H, J = 8.3, 1.8 Hz), 6.96 (d, 1H, J = 8.5 Hz), 1.69 (s, 6H); <19>F-NMR (DMSO-de) δ -112.46 (m, 1F);

MS (Cl) m/z 352 ([M+H]<+>, 78%), 350 ([M+H]<+>, 75%);

Analysis for Ci6Hi3BrFN02:

EXAMPLE 15

3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile A mixture of 6-(3-bromo- 5-fluorophenyl)-4,4-dimethyl-2H-benzo[d][l,3]oxazin-2-one (1 g, 2.8 mmol), zinc cyanide (0.2 g, 1.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmol) in 20 mL dry DMF was degassed to remove oxygen and then heated to 85°C under nitrogen for 6V2 h. The reaction solution was cooled to room temperature and poured into 100 ml of cold saturated aqueous ammonium chloride solution. A white precipitate appeared and this was collected on a filter. The white solid was washed with 3 x 20 ml of distilled water and dissolved in a mixture of 10 ml of ethyl acetate and 10 ml of methanol. The solution was placed on a pad of silica gel and eluted with ethyl acetate: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 obtained as a white solid (0.7 g, 84%) with melting point 253-254°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H, D 2 O exchangeable), 8.13 (s, 1H), 7.92 (m, 1H), 7.82 (m,

1H), 7.73 (m, 2H), 6.98 (d, 1H, J = 8.2 Hz), 1.68 (s, 6H);

<19>F-NMR (DMSO-de) δ -112.25 (m, 1F);

MS (EI) m/z 296(M<+>.65%);

Analysis for C17H13FN2O2:

EXAMPLE 16

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-nicotinonitrile The compound was prepared from (1,4-dihydro-4 ,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 3-bromo-5-cyanopyridine according to procedure B as a whitish solid, m.p. 290-291°C.

1H-NMR (DMSO-de) δ 10.41 (s, 1H, D 2 O exchangeable), 9.21 (d, 1H, J = 2.2 Hz), 8.97 (d,

1H, J = 1.7 Hz), 8.68 (t, 1H, J = 2.1 Hz), 7.76 (m, 2H), 7.01 (d, 1H, J =

8.2 Hz), 1.70 (s.6H);

MS (ESI) m/z 278 (M-H, 96%);

Analysis for Ci6Hi3N3Q2-0.2H2O:

EXAMPLE 17

4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

The compound was prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 4-bromo-2-thiophenecarbonitrile according to procedure B as a yellowish solid with melting point 230-231°C (decomp.).

1H-NMR (CDCl 3 ) δ 8.32 (s, 1H, D 2 O exchangeable), 7.83 (d, 1H J = 1.5 Hz), 7.61 (d, 1H, J

= 1.4 Hz), 7.43 (dd, 1H, J = 8.2,1.9 Hz), 7.29 (d, 1H, J = 1.8 Hz), 6.85

(d, 1H, J = 8.2 Hz), 1.78 (s, 6H);

MS (EI) m/z 283 (M-H, 100%);

Analysis for Ci5H12N2O2S 0.2H2O:

EXAMPLE 18

5-Bromo-2-thiophenecarbonitrile

A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), 500 mL pyridine, and 500 mL ethanol was heated under nitrogen to reflux for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under vacuum to give an oil. The crude product was triturated twice with ice water and the resulting solid collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper(H)acetate monohydrate (4.2 g, 21 mmol) in 1.4 L of acetonitrile was heated to reflux for 3 hours. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The solution was washed with 2 x 30 ml of 5% aqueous sulfuric acid, 2 x 30 ml of water, 20 ml of saline and then dried over MgSO 4 . The solvent was removed under vacuum and the residue dissolved in a minimal amount of chloroform and allowed to crystallize. The crystals obtained were collected on a filter and the filtrate was concentrated and purified by chromatography over silica gel with chloroform to give the title compound as an off-white solid (31.5 g combined, 58%).

IR (film) cm-<1> 2200;

<!>H-NMR (CDCl 3 ) δ 7.39-7.38 (d, 1H, J = 4.1 Hz), 7.10 (d, 1H, J = 4.0 Hz);

MS (EI) m/z 1872 (M<+>, 100%).

EXAMPLE 19

5-Bromo-4-methyl-2-thiophenecarboxaldehyde

To a solution of diethylamine (28 g, 0.383 mol) in 400 mL of anhydrous THF was added a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol) in hexane. The solution was then stirred at -40°C under nitrogen for 30 minutes, cooled to -78°C and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in 450 mL of anhydrous THF. The reaction solution was stirred at -78°C for 30 minutes and treated with 100 ml of anhydrous DMF. The mixture was allowed to warm to ambient temperature and quenched with 11 IN aqueous hydrochloric acid solution. The product was extracted with 3 x 450 ml of ethyl acetate. The extracts were washed with water, brine and dried over MgSO 4 . After removal of the solvent under vacuum, the title compound was obtained as an off-white solid (46 g, 88.3%). A sample of the product was crystallized from hexane and gave a melting point of 63-65°C.

IR(KBr) 1654 cm-<1>;

1H-NMR (CDCl 3 ) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H);

MS (EI) m/z 204/206^.

Analysis for CeftBrOS:

EXAMPLE 20

5-Bromo-4-methyl-2-thiophenecarbonitrile

The compound is prepared from 5-bromo-4-methyl-2-thiophenecarboxaldehyde using the procedure in Example 18, as a white solid with a melting point of 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%);

Analysis for C6H4BrNS:

EXAMPLE 21

5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile

Prepared according to procedure B from 5-bromo-2-thiophenecarbonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as an off-white solid with melting point 264-266°C.

1 H-NMR (DMSO-d 6 ) δ 10.3 (s, 1H), 7.97 (d, 1H, J = 7.9 Hz), 7.60-7.66 (m, 3H), 6, 96

(d, 1H, J = 8.1 Hz), 1.65 (s, 6H);

MS (APCI) m/z 285 (M+H)<+>, 302 ((M+HN4)<+>;

Analysis for C15H12N2O2S:

EXAMPLE 22

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-benzo[d][1,3]oxazin-6-yl)-4-methyl-thiophenyl-2-carbonitrile

The compound was prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 5-bromo-4-methyl-2- thiophene carbonitrile as a whitish solid with a melting point of 195°C-200°C.

1H-NMR (DMSO-de) δ 10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01 (d, 1H, J =

8.8 Hz), 2.28 (s, 3H), 1.64 (s, 6H);

MS (APCI) m/z 299 [M+H]<+>;

Analysis for C16H14N2O2S:

EXAMPLE 23

4-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)furan-2-carbonitrile

The compound was prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 4-bromo-2-furancarbonitrile as an off-white solid with melting point 255-256°C.

1H-NMR (DMSO-d 6 ) δ 10.32 (s, 1H, D 2 O exchangeable), 8.57 (s, 1H), 8.15 (s, 1H), 7.61 (s,

1H), 7.55 (dd, 1H, J = 8.3, 1.5 Hz), 6.92 (d, 1H, J = 8.2 Hz), 1.65 (s, 6H); MS (ESI) m/z 269 (M+H, 72%);

Analysis for C15H12N2O3:

EXAMPLE 24

4,4-diethyl-6-(3-nitrophenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 4,4-diethyl-6-iodo -1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-nitrophenylboronic acid as a whitish solid with a melting point of 193-194°C. 1 H-NMR (CDCl3) δ 9.19 (s, 1H, D20 exchangeable), 8.38 (t, 1H, J = 1.9 Hz), 8.20 (m, 1H), 7.83 (m , 1H), 7.61 (t, 1H, J = 8.0 Hz), 7.50 (dd, 1H, J = 8.2,2.0 Hz), 7.23 (d, 1H, J = 1.7 Hz), 6.99 (d, 1H, J = 8.3 Hz), 2.09 (q, 4H, J = 7.4 Hz),

0.96 (t, 6H, J = 8.3 Hz);

MS (EI) m/z 325 ([M-H]-, 100%);

Analysis for Ci8Hi8N2O40.3H2O:

EXAMPLE 25

6-(3-Chlorophenyl)-4,4-diethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 4,4-diethyl-6-iodo -1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-chlorophenylboronic acid as a white solid with a melting point of 150-151°C.

1H-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 = 1.5 Hz), 6.89 (d, 1H, J = 8.2 Hz), 2.03 (m, 4H), 0.94 (t, 6H, J

= 7.4 Hz);

MS (EI) m/z 315(M<+>.53%);

Analysis for Ci8Hi8ClN02:

EXAMPLE 26

1-(2-amino-5-bromophenyl)cyclohexanol

The compound was prepared according to the procedure of Example 1 from 2-amino-5-bromo-benzoic acid and the Grignard reagent prepared from 1,5-dibromopentane, as a clear oil.

1H-NMR (DMSO-d6) δ 7.07 (d, 1H, J = 2.3 Hz), 7.03 (dd, 1H, J = 8.4,2.4 Hz), 6.55 ( d,

1H, J = 8.6 Hz), 5.49 (s, 2H, D20 exchangeable), 5.00 (s, 1H, D20 exchangeable), 2.01 (d, 2H, J = 1.8 Hz), 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)-oii The compound was prepared according to the procedure of Example 2 from 1-(2-amino-5-bromo- phenyl)cyclohexanol and carbonyldiimidazole as a whitish solid with a melting point of 208-210°C.

1H-NMR (DMSO-de) δ 10.26 (s, 1H), 7.45 (d, 1H, J = 2.2 Hz), 7.39 (dd, 1H, J = 8.2,2 ,2

Hz), 6.81 (d, 1H, J = 8.3 Hz), 1.90-1.97 (m, 2H), 1.80-1.85 (m, 5H),

1.25-1.35 (m, 1H);

MS (APCI) m/z 296 ([M+H]<+>, 68%).

EXAMPLE 28

Spiro-(4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid The compound was prepared according to Example 4 from 6-bromo-spiro[4H- 3,1-benzoxazin-4,r-cyclohexan-2(1H)-one as a whitish solid with melting point 223-225°C.

1H-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 = 8.0,1.1 Hz), 6.81 (d, 1H, J = 7.9 Hz), 1.96 (s,

1H), 1.93 (s, 1H), 1.57-1.88 (m, 7H), 1.24-1.34 (m, 1H);

MS (ESI) m/z 262 (M+H)<+>.

EXAMPLE 29

6-(3-Chlorophenyl)-spiro[4H-3,1-benzoxazin-4,1'-cyclohexan-2(1H)-one The compound was prepared according to procedure A from 6-bromo-spiro[4H-3 ,1-benzoxazine-4, 1'-cyclohexane]-2(1H)-one and 3-chlorophenylboronic acid as a whitish solid with a melting point of 165-168°C.

1H-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 = 4.2 Hz), 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-benzoxazin-4,1'-cyclopentane]-2-(1H)-one The compound was prepared according to Examples 26 and 27 from 2-amino-5-bromo-benzoic acid and Grignard reagent prepared from 1,4-dibromobutane as a whitish solid with melting point 180-185°C. 1 H-NMR (DMSO-d6) δ 10.29 (s, 1H, D20 exchangeable) 7.45 (d, 1H, J = 2.2 Hz), 7.41 (dd, 1H, J = 8.1 , 2.1 Hz), 6.82 (d, 1H, J= 8.0 Hz), 1.96-2.09 (m, 4H), 1.76-1.87 (m, 4H);

MS (EI) m/z 281 (M<+>.98%);

Analysis for Ci2H,2BrN02:

EXAMPLE 31

6-(3-Chlorophenyl)-spiro-[4H-3,1-benzoxazin-4,1'-cyclopentane]-2(1H)-one The compound was prepared according to procedure A from 6-bromo-spiro-[4H -3,1-benzoxazin-4,1'-cyclopentan]-2(1H)-one and 3-chlorophenylboronic acid as a whitish solid with a melting point of 140-145°C.

1H-NMR (DMSO-de) δ 10.27 (s, 1H), 7.75 (t, 1H, J = 1.8 Hz), 7.53-7.63 (m, 3H), 7, 44

(t, 1H, J = 7.9 Hz), 7.36 (m, 1H), 6.95 (d, 1H, J = 8.6 Hz), 2.09-2.15 (m,

4H), 1.81-1.89 (m, 4H);

MS (ESI) m/z 314 [M+H] + ;

Analysis for Ci8Hi6ClN02:

EXAMPLE 32

6-(3-nitrophenyl)-spiro[4H-3,1-benzoxazin-4,1'-cyclohexane]-2(1H)-one The compound was prepared according to procedure A from 6-bromo-spiro[4H-3 ,1-benzoxazin-4,1'-cyclohexane]-2-(1H)-one and 3-nitrophenylboronic acid as a whitish solid with a melting point of 245-246°C.

1H-NMR (CDCl 3 ) δ 8.39 (t, 1H, J = 1.9 Hz), 8.20 (dd, 1H, J = 8.2, 1.4 Hz), 8.11 (s, 1H,

D20 exchangeable), 7.86 (d, 1H, J = 8.0 Hz), 7.62 (t, 1H, J = 8.1 Hz), 7.50 (dd, 1H, J = 8.2, 1.9 Hz), 7.39 (d, 1H, J = 1.8 Hz), 6.93 (d, 1H, J = 8.2

Hz), 2.25 (d, 2H, J = 12.7 Hz), 1.60-1.99 (m, 7H), 1.31-1.42 (m, 1H); MS (EI) m/z 337 ([M-H]-, 100%);

Analysis for Ci9Hi8N2O40.35H2O:

EXAMPLE 33

2-amino-5-bromo-N-methoxy-N-methylbenzamide

A solution of 5-bromoisotonic anhydride (20 g, 74 mmol) in 100 ml ethanol and 10 ml water at ambient temperature under nitrogen. The reaction mixture was heated to reflux for 3 hours. The solvent was removed under vacuum and the residue dissolved in 100 ml ethyl acetate, washed with 2 x 20 ml 1N aqueous sodium hydroxide solution, 30 ml brine and dried over MgSO 4 . After removal of the solvent, the residue was purified by silica gel flash chromatography with hexane-rethyl acetate 3:1 to give 2-amino-5-bromo-N-methoxy-N-methylbenzamide as an off-white solid (13 g, 68%) mp 80-81°C .

1 H-NMR (CDCl 3 ) δ 7.49 (d, 1H, J = 2.1 Hz), 7.26 (dd, 1H, J = 8.3, 2.0 Hz), 6.59 (d, 1H,

J = 8.4 Hz), 4.69 (br, 2H), 3.58 (s, 3H), 3.34 (s, 3H);

Analysis for C9HnBrN202:

EXAMPLE 34

4-amino-3'-chloro-biphenyl-3-carbonitrile

The compound was prepared according to procedure A from 2-amino-5-bromobenzonitrile and 3-chlorophenylboronic acid as a whitish solid, mp 118-119°C.

1H-NMR (DMSO-d6) δ 7.80 (d, 1H, J = 2.3 Hz), 7.65-7.72 (m, 2H), 7.57 (d, 1H, J = 8 ,0

Hz), 7.42 (t, 1H, J = 7.9 Hz), 7.31 (m, 1H), 6.87 (d, 1H, J = 8.7 Hz), 6.29 (br, 2H);

Analysis for C13H9CIN2:

EXAMPLE 35

1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanone

A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenylboronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphIn)palladium(0) ( 1.73 g, 1.5 mmol) and sodium carbonate (7.63 g, 72 mmol) in 150 mL DME and 30 mL water were degassed to remove the oxygen and heated to 85°C under nitrogen for 3 h. The reaction mixture was cooled to room temperature and treated with 30 ml of brine and 100 ml of ethyl acetate. The organic layer was separated and the aqueous layer extracted with 3 x 40 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgScu. After removal of the solvent, the residue was purified by flash chromatography over silica gel with hexane:ethyl acetate 1:1 to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added dropwise a solution of methyllithium in ether (1.4 M, 28.6 ml, 40 ml) at -78°C under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with 50 ml of saturated aqueous ammonium chloride solution at -78°C. 100 ml of ethyl acetate was added, the organic layer was prepared and the aqueous layer was extracted with 3 x 20 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgSO 4 . After removal of the solvent, the residue was purified by flash chromatography over silica gel with hexamethyl acetate 2:1 to give 1-(4-amino-3'-chlorobiphenyl-3-yl)-ethanone as a yellow solid (2 g, 47%) m.p. 89-90°C.

1H-NMR (CDCl 3 ) δ 7.89 (d, 1H, J = 2.0 Hz), 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%);

Analysis for C14H12CINO:

EXAMPLE 36

4-allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

(Procedure C)

To a solution of 1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanone (0.2 g, 0.82 mmol) in 10 mL of anhydrous THF was added a solution of allyl magnesium bromide in ether ( 1.0M, 3 mL, 3 mmol) at 0°C under nitrogen. The reaction solution was slowly warmed to ambient temperature and stirred under nitrogen for 1 hour. 10 ml of saturated aqueous ammonium chloride solution was added, followed by 50 ml of ethyl acetate. The organic layer was separated and the aqueous layer extracted with 3 x 10 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by flash chromatography over silica gel with hexane-rethyl acetate 3:1 to give an amino-carbinol intermediate which was used without further purification.

To a solution of the above amino carbinol in anhydrous THF was added CDI (0.38 g, 2.3 mmol) at ambient temperature under nitrogen. The reaction solution was heated to 55°C for 12 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue purified by flash chromatography over silica gel with hexane ethyl acetate 2:1 to give 4-allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][l, 3]oxazin-2-one as a whitish solid (130 mg from two steps, 52%) mp 128-129°C.

1 H-NMR (CDCl 3 ) δ 8.68 (s, 1H, D 2 O exchangeable), 7.50 (s, 1H), 7.44 (dd, 1H, J = 8.2, 1.9

Hz), 7.31-7.40 (m, 3H), 7.25 (d, 1H, J = 1.6 Hz), 6.92 (d, 1H, J = 8.2 Hz),

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%);

Analysis for Ci8Hi6ClN02:

EXAMPLE 37

6-(3-Chlorophenyl)-4-methyl-4-propyn-l-yl-1,4-dihydro-benzo[d][l,3]oxazin-2-one Prepared from 1-(4-amino-3 '-chloro-biphenyl-3-yl)-ethanone and propynylmagnesium bromide followed by treatment with CDI according to procedure C, as a white solid, m.p. 184-185°C.

1H-NMR (CDCU) δ 8.18 (s, 1H, D 2 O exchangeable), 7.53 (t, 1H, J = 1.7 Hz), 7.49 (s, 1H),

7.31-7.48 (m, 4H), 6.92 (d, 1H, J = 8.1 Hz), 2.02 (s, 3H), 1.87 (s, 3H); MS (ESI) m/z 304 ([M-H]\ 100%);

Analysis for Ci8H,4ClN02:

EXAMPLE 38

6-(3-chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzo [d] [1,3]oxazin-2-one Prepared from 1-(4-amino-3'-chloro- biphenyl-3-yl)-ethanone (0.2 g, 0.82 mmol) and ethynyl magnesium bromide followed by treatment with CDI according to procedure C, as an off-white solid, m.p. 185-186°C.

1H-NMR (CDCl 3 ) δ 8.18 (s, 1H, D 2 O exchangeable), 7.53 (t, 1H, J = 1.7 Hz), 7.49 (s, 1H),

7.31-7.48 (m, 4H), 6.92 (d, 1H, J = 8.1 Hz), 2.81 (s, 1H), 1.87 (s, 3H); MS (ESI) m/z 304 ([M-H]-, 100%);

Analysis for Ci7Hi2ClN02:

EXAMPLE 39

6-(3-Chlorophenyl)-4-methyl-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Prepared from 1-(4-amino-3'-chloro- biphenyl-3-yl)-ethanone (0.2 g, 0.82 mmol) and phenyl magnesium bromide followed by treatment with CDI according to procedure C, as a white solid, mp 179-180°C.

1 H-NMR (CDCl 3 ) δ 8.27 (s, 1H, D 2 O exchangeable), 7.51-7.57 (m, 2H), 7.28-7.45 (m, 9H),

6.92 (d, 1H, J = 8.4 Hz), 2.12 (s, 3H);

MS (ESI) m/z 348 ([M-H]-, 100%);

Analysis for C2iHi6ClN02:

EXAMPLE 40

4-benzyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo [d] [1,3]oxazin-2-one A mixture of 1-(4-amino-3'-chloro -biphenyl-3-yl)-1-benzyl-ethanol (prepared using 1-(4-amino-3'-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to procedure C, (.14 g . :hexane to give 4-benzyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as a whitish solid with melting point 187-188°C.

1H-NMR (DMSO-d 6 ) δ 10.1 (s, 1H), 7.70 (t, 1H, J = 2.3 Hz), 7.6 (d, 1H, J = 8.0 Hz) ,

7.58-7.53 (m, 2H), 7.46 (t, 1H, J = 8.0 Hz), 7.38 (d, 1H, J = 8.0 Hz), 7.22-7 .17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J = 9.14 Hz), 3.24 (d,

1H, J = 14.3 Hz), 3.06 (d, 1H, J = 14.3 Hz), 1.68 (s, 3H);

MS (ESI) m/z 364 ([M+H]<+>, 100%);

Analysis for C22H18CINO2:

EXAMPLE 41

6-(3-Chlorophenyl)-4-cyclopropyl-4-methyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one To a solution of cyclopropylmagnesium bromide in anhydrous THF (prepared using cyclopropyl bromide and magnesium metal, 70 mmol) at 51°C, 4-amino-3'-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 room temperature and quenched with 100 mL of 1N aqueous HCl solution. 100 ml of ethyl acetate was added and the aqueous layer extracted with 3 x 40 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgSCv The solvent was removed and the residue purified on a silica gel column with hexane:ethyl acetate 20:1 to give (4-amino-3'-chloro-biphenyl-3-yl)-cyclopropyl -methanone.

1H-NMR (hydrogen chloride salt, DMSO-d6) δ 8.30 (d, 1H, J = 2.1 Hz), 7.76 (t, 1H, J = 1.7

Hz), 7.68-7.63 (m, 2H), 7.43 (t, 1H, J = 7.9 Hz), 7.32 (m, 1H), 6.88 (d,

1H, J = 8.7 Hz), 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 10 ml of anhydrous THF at -78°C was added a solution of methylmagnesium bromide (3.0M in diethyl ether, 2.5 mL, 7.5 mmol) under nitrogen. The reaction mixture was slowly warmed to room temperature, stirred under nitrogen for 12 hours and quenched with 20 ml of a saturated aqueous ammonium chloride solution. 50 ml of ethyl acetate was added, the organic layer separated and dried over MgSO4 After removal of the solvent, the residue was purified by silica gel chromatography with hexane:ethyl acetate 7:1 to give 1-(4-amino-3'-chloro-biphenyl-3-yl )-1-cyclopropyl-ethanol as a yellow oil.

MS (EI) m/z 287/289 (M4).

The title compound was prepared from 1-(4-amino-3'-chloro-biphenyl-3-yl)-1-cyclopropyl-ethanol and 1,1'-carbonyldiimidazole according to procedure C as a whitish solid, mp 158-159° C.

1H-NMR (DMSO-d 6 ) δ 10.3 (s, 1H), 7.74 (t, 1H, J = 1.71 Hz), 7.67-7.57 (m, 3H), 7, 47

(t, 1H, J = 7.88 Hz), 7.39 (d, 1H, J = 8.1 Hz), 6.95 (d, 1H, J = 8.12 Hz),

1.7 (s, 3H), 1.45 (m, 1H), 0.48 (m, 2H), 0.28 (m, 2H);

MS (APCI) m/z 314 ([M+H]<+>, 100%);

Analysis for Ci8Hi6ClN02:

EXAMPLE 42

6-(3-chlorophenyl)-4-cyclopropyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

1-(4-amino-3'-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol was prepared from (4-amino-3'-chloro-biphenyl-3-yl)-1- cyclopropylmethanone and propynylmagnesium bromide according to Example 41.

A mixture of 1-(4-amino-3'-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl methanol (0.02 g, 0.064 mmol) and 1,1'-carbonyldiimidazole (0.016 g, 0.096 mmol) in 10 ml dry

The THF was stirred under a blanket of nitrogen for 10 minutes. After the reaction was complete, THF was removed and the residue purified by flash chromatography over silica gel with 40% ethyl acetate:hexane to give 6-(3-chlorophenyl)-4-cyclopropyl-4-prop-1-ynyl-1,4-dihydro-benzo[ d][1,3]oxazin-2-one (0.014 g, 56%) as a pale yellow solid, mp 178-179°C.

1H-NMR (DMSO-d 6 ) δ 10.6 (s, 1H), 7.68 (m, 2H), 7.64 (bs, 1H), 7.59 (d, 1H, J = 7.72

Hz), 7.49 (t, 1H, J = 7.82 Hz), 7.42 (d, 1H, J = 7.95 Hz), 7.02 (d, 1H, J = 8 Hz), 1 .86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H);

MS (ESI) m/z 336 ([M-H]-, 100%).

EXAMPLE 43

6-(3-chlorophenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one 4-amino-3'-chloro-biphenyl-3-yl) -dicyclopropyl methanol with a melting point of 90-92°C; MS ((+)ESI) m/z 314 (M+H)<+>, was prepared from (4-amino-3'-chloro-biphenyl-3-yl)-cyclopropyl-methanone and cyclopropylmagnesium bromide according to Example 41 .

The title compound was prepared according to Example 41 from (4-amino-3'-chloro-biphenyl-3-yl)-dicyclopropyl-methanol and 1,1'-carbonyldiimidazole as a yellow solid with a melting point of 198-200°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 7.72 (bs, 1H), 7.67 (bs, 1H), 7.62 (m, 2H), 7.48 ( t,

1H, J = 7.88 Hz), 7.40 (d, 1H, J = 8.04 Hz), 6.94 (d, 1H, J = 8.27 Hz),

1.55 (m, 2H), 0.5 (m, 2H), 0.5 (m, 6H), 0.28 (m, 2H);

MS (EI) m/z 339(M<+>.40%);

Analysis for C2oHi8ClN02:

EXAMPLE 44

6-(3-chlorophenyl)-4,4-dipropyn-1-yl-1,4-dihydrobenzo[d][1,3]oxazin-2-one Following the procedure of Example 41, (4-amino-3 '-chloro-biphenyl-3-yl)-propynyl-methanone with melting point 112-114°C; MS ((+) ESI) m/z 270/272 (M+H)<+>, 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 as a yellow solid m.p. 151°C (decomp.).

1H-NMR (DMSO-de) δ 10.8 (s, 1H), 7.71 (dd, 1H, J = 8.52, 1.94 Hz), 7.69 (m, 2H),

7.61 (d, 1H, J = 7.64 Hz), 7.50 (t, 1H, J = 7.85 Hz), 7.43 (d, 1H, J = 7.99

Hz), 7.06 (d, 1H, J = 8.23 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 To a solution of 6-(3-bromo-5 -fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one (0.34 g, 0.99 mmol) in 10 ml of dry DMF was nitrogen and at room temperature sodium hydride (80 mg, 2.0 mmol) was added in one portion. The mixture was stirred at ambient temperature for 30 minutes, treated with 1 ml (excess) iodomethane and stirred for 2 hours. To the reaction mixture was added 30 ml of cold, saturated ammonium chloride solution and the resulting white precipitate was collected on a filter, washed with distilled water and the title compound was obtained as a white solid (0.31, 87%) with melting point 1578-158° C.

1H-NMR (DMSO-d 6 ) δ 7.83 (s, 1H), 7.76 (dd, 1H, J = 8.5, 2.0 Hz), 7.67 (m, 2H), 7, 53

(dt, 1H, J = 8.3,1.9 Hz), 7.18 (d, 1H, J = 8.5 Hz), 3.33 (s, 3H), 1.67 (s,

6H);

<19>F-NMR (DMSO-de) δ -111.01 (m, 1F);

MS (APCI) m/z 364 ([M+H]<+>, 96%), 366 ([M+H]<+>, 100%).

EXAMPLE 46

1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone

To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (6.7 g, 30 mmol) in 100 ml of anhydrous THF was added dropwise under nitrogen and at 0°C a solution of n-BuLi (2 .5M, 30 ml, 70 mmol) in hexane. After the addition, the solution was stirred at 0°C for 40 minutes and treated with a solution of 1-(trifluoroacetyl)imidazole (9 mL, 78 mmol) in 10 mL of anhydrous THF. The reaction mixture was warmed to ambient temperature and held there for 18 hours. To the reaction solution was added 50 ml of saturated aqueous ammonium chloride solution, followed by 100 ml of ethyl acetate. The organic layer was separated and the solvent removed under vacuum. The obtained residue was suspended in 50 ml of 3N aqueous hydrochloric acid solution and heated to reflux overnight. The reaction solution was cooled to room temperature and treated with a cold ammonium hydroxide solution to a pH above 8. The reaction mixture was extracted with 3 x 50 ml ethyl acetate and the organic layers washed with brine and dried over MgSO 4 . After removal of the solvent, the residue was purified by flash chromatography over silica gel with hexane:ethyl acetate 4:1 to give the title compound as a yellow solid (1 g, 15%) mp 93-94°C.

1 H-NMR (CDCl ) δ 7.70 (m, 1H), 7.33 (dd, 1H, J = 9.0, 2.3 Hz), 6.70 (d, 1H, J = 9.1

Hz), 6.45 (bs, 2H);

MS (ESI) m/z 222 (M-H, 100%), 224 (M-H, 33%).

EXAMPLE 47

6-Chloro-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared from 1-(2-amino-5-chlorophenyl)-2, 2,2-trifluoroethanano by addition of methylmagnesium bromide, followed by treatment of the resulting carbinol with 1,1'-carbonyldiimidazole according to the procedure of Example 2, as a white solid, m.p. 216-216°C.

1H-NMR (DMSO-de) δ 10.91 (bs, 1H, D 2 O exchangeable), 7.64 (d, 1H, J = 1.6 Hz), 7.49

(dd, 1H, J = 8.6,2.3 Hz), 6.95 (d, 1H, J = 8.6 Hz), 1.91 (s, 3H); <19>F-NMR (DMSO-de) δ 82.0 (s, 1F);

MS (EI) m/z 264 ([M-H]-, 100%), 266 ([M-H]-, 33%);

Analysis for C10H7CIF3NO2:

EXAMPLE 48

6-(3-Methoxyphenyl)-4-methyl-4-trifluoromethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one A mixture of 6-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) in anhydrous dioxane were placed under a blanket of nitrogen to remove oxygen and heated to 95°C under nitrogen for 48 hours. An additional portion of 3-methoxyphenylboronic acid (0.13 g, 0.9 mmol) and nickel(II)(diphenylphosphino)ferrocenyl dichloride (52 mg, 0.076 mmol) was added and the reaction heated to 95°C under nitrogen for 48 h. The reaction mixture was cooled to room temperature. 30 ml of saturated aqueous ammonium chloride solution and 50 ml of ethyl acetate were added. The organic layer was separated and the aqueous layer extracted with 3 x 20 ml of ethyl acetate. The combined organic layers were washed with brine and dried over MgSO 4 - After removal of the solvent, the residue was purified by flash chromatography over silica gel with hexane:ethyl acetate 4:1 to give the title compound as a white solid (50 mg, 20%) with melting point 178-179°C.

1H-NMR (DMSO-d 6 ) δ 10.85 (bs, 1H, D 2 O exchangeable), 7.73 (m, 2H), 7.38 (t, 1H, J = 7.9

Hz), 7.23 (d, 1H, J = 7.7 Hz), 7.19 (d, 1H, J = 1.9 Hz), 7.02 (d, 1H, J = 8.2 Hz) , 6.94 (dd, 1H, J = 8.2, 2.4 Hz), 3.88 (s, 3H), 1.98 (s, 3H);

<19>F-NMR (DMSO-d 6 ) δ -81.88 (s, 1F);

Analysis for C17H14F3NO3:

EXAMPLE 49

7-(3-Methoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one A mixture of 7-chloro-4,4-dimethylbenzoxazin-2-one (0.197 g, 0.93 mmol), 3-methoxyphenylboronic acid (0.21 g, 1.4 mmol), Ni(dppf)Cl2 (0.095 g, 0.14 mmol) and potassium phosphate (0.59 g, 2.79 mmol) in 10 ml dioxane was placed under a blanket of nitrogen for 15 minutes at 50°C and then heated to 95°C for 48 hours. The reaction mixture was cooled to room temperature and 100 ml of ethyl acetate was added. The organic substances were washed twice with 30 ml of aqueous ammonium chloride, once with 30 ml of saline and dried over magnesium sulfate. The residue was purified via flash chromatography over silica gel with 40% ethyl acetate hexane to give 7-(3-methoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one ( 0.090 g, 35%) as a clear oil. The oil was triturated with 25 ml of ether to give a white solid, mp 167-168°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 7.42-7.28 (m, 3H), 7.14 (d, 1H, J = 8.11 Hz), 7, 11

(bs, 2H), 6.96 (dd, 1H, J = 8.11 Hz), 3.56 (s, 3H), 1.52 (s, 6H);

MS (EI) m/z 283 ([M+H]<+>, 90%);

Analysis for C17H17NO3:

EXAMPLE 50

6-(3-acetylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one 3-(4,4-dimethyl-2-oxo-1,4 -dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile (0.25 g, 0.9 mmol) was dissolved in 10 mL THF and cooled to 0 °C. To this solution was added methylmagnesium bromide (3.0M in ether, 1.8 mL, 5.4) and the reaction mixture was heated to reflux under nitrogen. After the reaction was complete, the reaction mixture was quenched with 1N aqueous HCl solution after cooling to room temperature. The mixture

was extracted with 100 ml ethyl acetate, dried over MgSO4 and concentrated. Purification of the residue obtained by silica gel chromatography with 50% ethyl acetate:hexane gave 6-(3-acetyl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid (0.031 g, 12%) mp 178-179°C.

1H-NMR (CDCl 3 ) δ 8.15 (t, 1H, J = 1.71 Hz), 8.04 (s, 1H), 7.95 (dt, 1H, J = 8.85, 1.13

Hz), 7.76 (dt, 1H, J = 7.90, 1.43 Hz), 7.57 (t, 1H, J = 7.72 Hz), 7.52 (dd, 1H, J = 8 ,28.2.11 Hz), 7.39 (d, 1H, J = 1.81 Hz), 6.93 (d, 1H, J = 8.19

Hz), 2.69 (s, 3H), 1.81 (s, 6H);

MS (EI) m/z 295 ([M+H]<+>, 40%).

EXAMPLE 51

6-(3-benzoylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to the procedure of Example 50 from 3-(4, 4-Dimethyl-2-oxo-1,4-dihydro-benzo[d] [ 1,3]oxazin-6-yl)benzonitrile and phenylmagnesium bromide as a white solid with melting point 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 = 8.06 Hz), 1.67 (s, 6H);

MS (EI) m/z 357 ([M+H]<+>, 40%);

Analysis for C23H19NO3:

EXAMPLE 52

4,4-dimethyl-6- [3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydro-benzo [d] [1,3]oxazin-2-one A mixture of 3- (4,4-Dimethyl-2-oxo-1,4-dihydro-benzo[d][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) in 20 mL of dioxane were heated to reflux under a blanket of nitrogen. After the reaction was complete, the dioxane was removed, the organic substances taken up in 100 ml of ethyl acetate and washed with 100 ml of NaHCC>3. The aqueous layer was acidified with 1N aqueous HCl and extracted with 100 mL of ethyl acetate. The organic layer was dried over MgSO4 and concentrated. Crystallization from 20 ml of ether gave 4,4-dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a pale yellow solid (0.23 g, 26%) m.p. 238-240°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.3 (bs, 1H), 8.02 (d, 1H, J = 7.66 Hz), 7.9 (d, 1H,

J = 7.91 Hz), 7.72-7.65 (m, 3H), 7.03 (d, 1H, J = 8.75 Hz), 1.70 (s, 6H); MS (ESI) m/z 320 ([M-H]-, 100%);

Analysis for C17H15N5O2:

EXAMPLE 53

4-(4,4-Dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-2-carbonitrile

(4,4-Dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid was prepared according to Examples 1, 2 and 4 from 2-amino-5-bromobenzoic acid as a white solid with a melting point of 240-242°C.

1H-NMR (DMSO-de) δ 10.13 (s, 1H), 8.01 (s, 2H), 7.85 (s, 1H), 7.64 (d, 1H, J = 7.9

Hz), 6.77 (d, 1H, J = 7.9 Hz), 1.38 (m, 2H), 0.52 (m, 2H), 0.39 (m, 4H), 0.22 ( m, 2H).

The title compound was prepared according to procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 4-bromo-2-thiophenecarbonitrile as a white solid with melting point 244-245°C.

1H-NMR (DMSO-de) δ 10.25 (s, 1H), 8.49 (d, 1H, J = 0.87 Hz), 8.33 (s, 1H), 7.74 (d,

1H, J = 1.44 Hz), 7.67 (dd, 1H, J = 8.28, 1.54 Hz), 6.90 (d, 1H, J = 8.28 Hz), 1.53 ( m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H);

MS (ESI) m/z 335 ([M-H]-, 100%);

Analysis for C19H16N2O2S:

EXAMPLE 54

6-(3-bromo-5-fluorophenyl)-4,4-dicyclopropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from (4,4- dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1,3-dibromo-5-fluorobenzene as a white solid with a melting point of 228-229°C.

1 H-NMR CDMSO-d6) 8 10.3 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, 1H, J = 8.32,1.74 Hz) , 7.60 (d, 1H, J = 10.36 Hz), 7.51 (d, 1H, J = 8.3 Hz), 6.93 (d, 1H, J

8.31 Hz), 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.30-0.28 (m, 2H); MS (APCI) m/z 402/404 ([M-H]\ 100%);

Analysis for C2oHi7BrFN02:

EXAMPLE 55

3-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-6-fluoro-benzonitrile

A mixture of 6-(3-bromo-5-fluorophenyl)-4,4-dicyclopropyl-1,4-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(O) (0.07 g, 0.06 mmol) in 20 mL DMF were placed under a blanket of nitrogen in 15 minutes at 50°C and then heated to 85°C for 1 hour. After cooling to room temperature, the mixture was poured into 100 ml of NH 4 Cl and extracted with 3 x 50 ml of ethyl acetate. The organic layers were washed with brine, dried over MgSO 4 and concentrated. The resulting clear oil was triturated with 30 mL of ether to give a white solid. Recrystallization of the solid from ethyl acetate gave 3-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-6-fluorobenzonitrile (0.016 g, 46%) with melting point 250-252°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H, J = 10.54 Hz), 7.81-7, 79

(m, 2H), 7.73 (dd, 1H, J = 8.3, 1.59 Hz), 6.94 (d, 1H, J = 8.34 Hz), 1.59

(m, 2H), 0.58-0.42 (m, 6H), 0.30-0.28 (m, 2H);

MS (ESI) m/z 347 ([M-H]-, 100%);

Analysis for C2iHi7FN202:

EXAMPLE 56

6-(3-bromo-5-methylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from (4, 4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 3,5-dibromotoluene as a white solid with melting point 231-233°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 7.66 (s, 1H), 7.58-7.56 (m, 2H), 7.50 (s, 1H), 7.37

(s, 1H), 6.95 (d, 1H, J = 8.67 Hz), 2.37 (s, 3H), 1.67 (s, 6H);

MS (ESI) m/z 344/346 ([M-H]-, 100%);

Analysis for Ci7H,6BrlN02:

EXAMPLE 57

6-(3-bromo-5-trifluoromethoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one

The compound was prepared according to procedure B from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1,3-dibromo-5-trifluoromethoxybenzene as a white solid with a melting point of 214-216°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97

(d, 1H, J = 8.0 Hz), 1.68 (s, 6H);

MS (ESI) m/z 414 ([M-H]-, 100%);

Analysis for Ci7Hi3BrF3N03:

EXAMPLE 58

3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methylbenzonitrile

The compound was prepared according to the procedure in Example 55 from 6-(3-bromo-5-methylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid with a melting point of 256-258°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.67-7.62 (Åm, 3H),

6.97 (d, 1H, J = 8.11 Hz), 2.42 (s, 3H), 1.68 (s, 6H);

MS (APCI) m/z 293 ([M+H]<+>, 100%);

Analysis for C18H16N2O2:

EXAMPLE 59

3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-trifluoro-methoxybenzonitrile

The compound was prepared according to the procedure in Example 55 from 6-(3-bromo-5-trifluoromethoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a white solid with a melting point of 227-228°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H, 7.97 (s, 1H), 7.75-7 ,72

(m, 3H), 6.99 (d, 1H, J = 8.11 Hz), 1.7 (s, 6H);

MS (APCI) m/z 363 ([M+H]<+>, 80%);

Analysis for C18H13F3N2O3:

EXAMPLE 60

6-(3,5-difluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one The compound was prepared according to procedure B from (4,4- dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1-bromo-3,5-difluorobenzene as a white solid with a melting point of 218-219°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 7.67-7.65 (m, 2H), 7.49 (d, 2H, J = 7.73 Hz), 7, 19

(t, 1H, J = 9.29 Hz), 6.96 (d, 1H, J = 8.88 Hz), 1.7 (s, 6H);

MS (APCI) m/z 290 ([M+H]<+>, 100%);

Analysis for C16H13F2NO2:

EXAMPLE 61

6-(3,3-Dichlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 6-bromo-4 ,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3,5-dichlorophenylbromic acid as a white solid with melting point 245-246°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 7.77 (m, 2H), 7.67-7.64 (m, 2H), 7.56 (bs, 1H),

6.96 (d, 1H, J = 7.98 Hz), 1.7 (s, 6H);

MS (EI) m/z 321 ([M+H]<+>, 40%);

Analysis for C16H13CI2NO2:

EXAMPLE 62

6-(3,5-bis-trifluoromethylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure A from 6-bromo -4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and bis-trifluoromethylphenylboronic acid as a white solid with a melting point of 258-260°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.35 (s, 2H), 8.05 (s, 1H), 7.79-7.76 (m, 2H), 7.01

(d, 1H, J = 8.01 Hz), 1.7 (s, 6H);

MS (ESI) m/z 390 ([M+H]<+>, 20%);

Analysis for C18H13F6NO2:

EXAMPLE 63

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxybenzonitrile

A mixture of (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-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(O) (1.1 g, 0.95 mmol), sodium carbonate (4.0 g, 38.0 mmol) and lithium bromide (5 g, 57 mmol) in 50 ml DME and 25 ml water was placed under a nitrogen blanket for 15 minutes at 50°C and then the whole was heated to 85°C for 1 hour. The reaction mixture was cooled to room temperature and 100 ml of ethyl acetate was added. The organic layers were washed twice with 100 ml of aqueous ammonium chloride and once with 100 ml of brine, dried over magnesium sulfate and concentrated. Purification by chromatography over silica gel with 40% ethyl acetate:hexane gave 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5 -methoxybenzonitrile as a white solid (0.69 g, 53%) mp 254-255°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 7.84 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (bs, 1H), 7.4

(bs, 1H), 6.99 (d, 1H, J = 7.94 Hz), 3.88 (s, 3H), 1.67 (s, 6H);

MS (EI) m/z 308 ([M+H]<+>, 30%);

Analysis for C18H16N2O3:

EXAMPLE 64

6-(3-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one The title compound was prepared according to procedure A from 6-bromo-4,4 -dimethyl-l,4-dihydro-benzo[d][l,3]oxazin-2-one and l-bromo-3-fluorobenzene as a pale yellow solid with melting point 181-182°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 7.62-7.44 (m, 5H), 7.16 (t, 1H, J = 2.22 Hz), 6, 97

(d, 1H, J = 8.83), 1.67 (s, 6H);

MS (EI) m/z 271 ([M+H] + , 40%);

Analysis for C16H14FNO2:

EXAMPLE 65

6-(3-Chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The title compound was prepared according to procedure A from 6-bromo -4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one and l-bromo-3-chloro-4-fluorobenzene as a white solid with a melting point of 211-212°C .

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 7.92 (dd, 1H, J = 7.13,2.19 Hz), 7.71-7.66 (m,

1H), 7.60-7.57 (m, 2H), 7.49 (t, 1H, J = 8.95 Hz), 6.96 (d, 1H, J = 8.01 Hz), 1, 67 (p, 6H);

MS (EI) m/z 305 ([M+H]<+>, 20%);

Analysis for Ci6Hi3ClFN02:

EXAMPLE 66

3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile

A mixture of 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 50 ml of triethyl orthoformate were heated to 160°C for 12 hours. Excess triethyl orthoformate was removed under vacuum and purification by silica gel chromatography with 20% ethyl acetate:hexane gave 3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-(hhydro-2H-benzo[d][l, 3]oxazin-6-yl)-5-fluoro-benzonitrile (0.116 g, 33%) as a white solid, mp 123-124°C.

1H-NMR (DMSO-d 6 ) δ 7.97 (d, 1H, J = 8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H),

7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H),

1.77 (s, 6H), 1.27 (t, 6H, J = 7.05 Hz);

MS (ESI) m/z 295 ([M-H]', 100%, lower MW ion consistency with loss of diethyl acetal);

Analysis for C22H23FN2O4:

EXAMPLE 67

3-Fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]-oxazin-6-yl)-benzonitrile

A solution of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.150 g, 0.51 mmol) in 5 mL DMF was treated at room temperature with sodium hydride (0.061 g, 1.53 mmol). The mixture was stirred for 30 min and treated with chloromethyl methyl ether (0.062 g, 7.7 mmol). After the reaction was complete, the reaction mixture was quenched with 25 ml of water and extracted with 3 x 30 ml of ethyl acetate, dried over MgSO 4 and concentrated. The residue was purified by silica gel chromatography with 25% ethyl acetate:hexane to give 3-fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][l, 3]oxazin-6-yl)-benzonitrile as a white solid (0.11 g, 65%) mp 169-171°C.

1H-NMR (DMSO-d 6 ) δ 8.17 (bs, 1H), 8.03 (dt, J = 10.4, 2.13 Hz), 7.85-7.77 (m, 3H),

7.31 (d, 1H, J = 8.49 Hz), 5.33 (s, 2H), 3.35 (s, 3H), 1.7 (s, 6H);

MS (APCI) m/z 341 ([M+H]<+>, 50%);

Analysis for C19H17FN2O3:

EXAMPLE 68

Phosphoric acid 6-(3-cyano-5-fluorophenyl)-4,4-dimethyl-4H-benzo[d][l,3]oxazin-2-yl ester diethyl ether

To a solution of 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) in 5 ml of DMF 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). After the reaction was complete, the reaction solution was quenched with 25 ml of water and the product extracted with 2 x 50 ml of ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 25% ethyl acetate:hexane to give phosphoric acid-6-(3-cyano-5-fluorophenyl)-4,4-dimethyl-4H-benzo[d][1,3]oxazin-2-yl -ester diethyl ether as a white solid (0.064 g, 18%) m.p. 196-198°C.

1H-NMR (DMSO-de) δ 8.19 (bs, 1H), 8.05 (d, 1H, J = 10.4 Hz), 7.9-7.8 (m, 3H), 7, 51

(d, 1H, J = 8.41 Hz), 4.33-4.41 (m, 4H), 1.76 (s, 6H), 1.27 (t, 6H, J =

7.05 Hz);

MS (APCI) m/z 433 ([M+H]<+>, 80%);

Analysis for C21H22FN2O5P:

EXAMPLE 69

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-fluorobenzonitrile The compound was prepared according to procedure B from ( 1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 5-bromo-2-fluorobenzonitrile as a white solid with a melting point of 229-230°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.15 (dd, 1H, J = 7.39,2.12 Hz), 7.95-7.89 (m,

1H), 7.59-7.48 (m, 3H), 6.99 (d, 1H, J = 8.1 Hz), 1.7 (s, 6H);

MS (APCI) m/z 297 ([M+H]<+>, 100%);

Analysis for C17H13FN2O2:

EXAMPLE 70

8-fluoro-4,4-dimethyl-dihydro-benzo[d][l,3]oxazin-2-one

N-(tert-butoxycarbonylamino)-3-fluorobenzoic acid (Takagishi et al., "Synlett", 4,360-362 (1992); mp 159-161°C) was deprotected using trifluoroacetic acid to give o-aminobenzoic acid which was treated with methylmagnesium bromide to give o-amino-dimethylcarbinol. The O-aminodimethylcarbinol (2.23 g, 13.2 mmol) was treated with 1,1'-carbonyldiimidazole (2.8 g, 17.2 mmol) in 20 mL of THF at 50°C for 12 h. After the reaction was complete, it was cooled to room temperature and 100 ml of ethyl acetate was added. The organic layer was washed with 2 x 25 ml of 10% aqueous HCl solution, dried over MgSO 4 and concentrated. The residue was purified via silica gel chromatography with 10% ethyl acetate:hexane to give 8-fluoro-4,4-dimethyl-dihydro-benzo[d][l,3]oxazin-2-one as a white solid (1.3 g, 50%) with melting point 127-128°C.

1H-NMR (DMSO-de) 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%);

Analysis for C10H10FNO2:

EXAMPLE 71

6-(3-chloro-4-fluorophenyl)-8-fluoro-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one To a solution of 8-fluoro- 4,4-dimethyl-dihydro-benzo[d][l,3]oxazin-2-one (0.15 g, 0.77 mmol) in 5 ml of acetic acid was added dropwise a solution of bromine (0.37 g , 2.31 mmol) in 5 ml of acetic acid under nitrogen at room temperature. After stirring for 10 minutes, the mixture was concentrated and the residue obtained was purified on a silica gel column with hexane:ethyl acetate 4:1 to obtain 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][l,3 ]-oxazine as an off-white solid (0.176 g, 84%) which was used in the next step without further purification.

A mixture of 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][l,3]oxazin-2-one (0.176 g, 0.64 mmol), 4-fluoro-3-chlorophenylboronic acid (0.15 g, 0.84 mmol), tetrakis(triphenylphosphine)-palladium(O) (0.04 g, 0.032 mmol) and sodium carbonate (0.20 g, 1.92 mmol) in 10 mL DME and 5 mL water was placed under a nitrogen blanket for 15 minutes at 50°C and then heated to 85°C for 1 hour. The reaction mixture was cooled to room temperature and 100 ml of ethyl acetate was added. The organic layer was washed twice with 100 ml of aqueous ammonium chloride and once with 100 ml of brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography with 25% ethyl acetate:hexane to give 6-(3-chloro-4-fluorophenyl)-8-fluoro-4,4-dimethyl-1,4-dihydro-benzo[d][l,3 ]oxazin-2-one as a white solid (0.13 g, 66%) mp 246-248°C.

1H-NMR (DMSO-de) δ 10.5 (s, 1H), 8.00 (dd, 1H, J = .09, 2.32 Hz), 7.78-7.73 (m, 1H) ,

7.62 (dd, 1H, J = 11.86, 1.77 Hz), 7.7 (t, 2H, J = 9 Hz), 1.7 (s, 6H);

MS (APCI) m/z 324 ([M+H]<+>, 100%);

Analysis for CieH^M^O^O:

EXAMPLE 72

6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from (1,4-dihydro- 4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 1,3 dibromobenzene as a white solid with a melting point of 174-175°C.

1H-NMR (DMSO-de) δ 10.35 (s, 1H), 7.99 (bs, 1H), 7.68 (d, 1H, J = 7.5 Hz), 7.6-7, 51

(m, 3H), 7.4 (t, 1H, J = 7.5 Hz), 6.97 (d, 1H, J = 8.57 Hz), 1.64 (s, 6H); MS (EI) m/z 331 ([M+], 60%), 333 [M4], 60%);

Analysis for Ci6Hi4BrN02:

EXAMPLE 73

4,4-dimethyl-6-(3-trimethylsilanylethynylphenyl)-1,4-benzo[d][1,3]oxazin-2-one A mixture of 6-(3-bromophenyl)-4,4-dimethyl-1 ,4-dihydro-benzo[d][l,3]oxazine (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine)palladium(0)

(0.17 g, 0.24 mmol) and copper(I) iodide (0.05 g, 28 mmol) in 20 mL of triethylamine were heated under nitrogen at 80°C for 3 h. The reaction mixture was cooled to room temperature and the solvent removed. The residue was taken up in 50 ml of ethyl acetate and washed with 3 x 20 ml of 1N aqueous HCl and 20 ml of saline. The organic layer was separated and dried over MgSO4. After removal of the solvent, the residue was purified by silica gel chromatography with hexane:ethyl acetate 3:1 to give the title compound as a white solid (0.77 g, 92%) mp 240-242°C.

1 H-NMR (DMSO-de) 6 10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7 ,40

(m, 2H), 6.96 (d, 1H, J = 7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H);

MS (EI) m/z 349 ([M4], 50%);

Analysis for C2iH23NO2Si0.2EtPAc:

EXAMPLE 74

6-(3-ethynylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazine A mixture of 4,4-dimethyl-6-(3-trimethylsilanylethynylphenyl)-1,4 -dihydro-benzo[d]-[l,3]oxazin-2-one (0.7 g, 2 mmol) and potassium carbonate (2 g, excess) in anhydrous methanol were stirred at room temperature under nitrogen for 4 h. The mixture was treated with 100 ml of ice water and extracted with 2 x 80 ml of ethyl acetate. The organic layers were washed with brine and dried over MgSO 4 . The solvent was removed and the title compound obtained as an off-white solid (0.4 g, 72%) mp 171-172°C.

1H-NMR (DMSO-de) 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 = 7.98 Hz), 4.25 (s, 1H), 1.67 (s,

6H);

MS (EI) m/z 277 ([M<+>], 100%).

Analysis for d 8Hi5NO20,2EtOAc:

EXAMPLE 75

3-[3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)phenyl]-propynenitrile

To a stirred solution of 9 ml of DMSO, 3 ml of acetonitrile and 0.5 ml of water was added at room temperature and under nitrogen copper (I) cyanide (0.193 g, 2.2 mmol), sodium iodide (11 mg, 0.072 mmol ) and 6-(3-ethynylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]-oxazin-2-one (0.2 g, 0.72 mmol). Chlorotrimethylsilane was then added dropwise to this mixture. After the addition, the mixture was heated to 50°C for 72 hours. The reaction mixture was then cooled to room temperature and treated with 50 ml of 0.5N aqueous cold HCl solution. The precipitate obtained was collected on a filter and washed with water. The solid was purified on a silica gel column with hexane:ethyl acetate 2:1 to give the title compound as an off-white solid (10 mg, 4.6%) mp 212-213°C.

1H-NMR (CHCU-de) 6 7.96 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H, J = 7.8 Hz), 7.60 (d, 1H, J

= 7.69 Hz), 7.51 (d, 1H, J = 7.77 Hz), 7.45 (dd, 1H, J = 8.67, 2.21 Hz),

7.31 (d, 1H, J = 1.55 Hz), 6.91 (d, 1H, J = 8.19 Hz), 1.8 (s, 6H);

MS (EI) m/z 302 ([M1"], 30%).

EXAMPLE 76

6-(3-Fluoro-5-nitrophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Prepared according to procedure B from (1,4- dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 1-bromo-3-fluoro-5-nitrobenzene as a yellow solid with melting point 260-261°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 8.37 (bs, 1H), 8.14-8.05 (m, 2H), 7.77-7.74 (m ,

2H), 7.01 (d, 1H, J = 7.94 Hz), 1.7 (s, 6H);

MS (ESI) m/z 315 ([M-H-]', 100%);

Analysis for C16H13FN2O4:

EXAMPLE 77

6-(3-Chloro-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Prepared according to procedure B from (1,4- dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 1-bromo-3-chloro-5-fluorobenzene as a white solid with a melting point of 193-194°C.

1H-NMR (DMSO-de) 6 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 = 8.72 Hz), 1.7 (s, 6H);

MS (APCI) m/z 306 ([M+H]<+>, 100%);

Analysis for CieHi3ClFN02:

EXAMPLE 78

3-chloro-5-(4,4-dimethyl-2-oxo-1,4-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile Prepared according to procedure B from (1,4 -dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 1-bromo-3-chlorobenzonitrile as a white solid with a melting point of 256-257°C.

1H-NMR (DMSO-de) 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 = 8.09 Hz), 1.7 (s, 6H);

MS (ESI) m/z 311 ([M-H]-, 100%);

Analysis for C17H13CIN2O2:

EXAMPLE 79

6-(3,5-dinitrophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one Prepared according to procedure B from (1,4-dihydro- 4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 1-bromo-3,5-dinitrobenzene as a yellow solid with melting point 297-298°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.88 (d, 2H, J = 1.98 Hz), 8.78 (bs, 1H), 7.78-7, 82

(m, 2H), 7.04 (d, 1H, J = 8.23 Hz), 1.7 (s, 6H);

MS (APCI) m/z 343 ([M-H]', 100%);

Analysis for C16H13N3O6:

EXAMPLE 80

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1^loxazin-6-yl)-isophthalonitrile Prepared according to procedure B from (1,4-dihydro- 4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and 5-bromoisotphalonitrile as a white solid with melting point 288-289°C.

<l>H-NMR (DMSO-de) 6 10.4 (s, 1H), 8.58 (s, 2H), 8.40 (d, 1H, J = 0.77 Hz), 7.80- 7.75

(m, 2H), 6.99 (d, 1H, J = 8.2 Hz), 1.7 (s, 6H);

MS (EI) m/z 303([M<*>],20%);

Analysis for Ci8Hi3N3O2-1.65H2O:

EXAMPLE 81

4,4-Dimethyl-6-(3-thiazol-2-yl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one A mixture of 6-(3-bromophenyl) -4,4-Dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.25 g, 0.75 mmol), tri-n-butyl-thiazol-2-yl step (0.5 g, 1.3 mmol) in 5 mL DMF was degassed to remove oxygen and then heated under nitrogen to 90 °C for 3 h. The reaction mixture was cooled to room temperature and treated with 70 ml of ice water. 100 ml of ethyl acetate was added and the organic layer separated, washed with brine and dried over MgSO*. After removal of the solvent, the residue was purified on a silica gel column with hexamethyl acetate 1:1 to give the title compound as a white solid (60 mg, 23%) mp 223-224°C.

1H-NMR (DMSO-d 6 ) δ 10.4 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 7.94 (bs, 1H), 7.67- 7.61

(m, 4H), 7.53 (t, 1H, J = 7.68 Hz), 7.00 (d, 1H, J = 8.81 Hz), 1.7 (s, 6H); MS (APCI) m/z 337 ([M+Hf, 100%);

Analysis for Ci9Hi6N2O2S0.25H2O:

EXAMPLE 82

6-(3-Fluoro-5-methoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Prepared according to procedure B from (1,4- dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 3-bromo-5-fluoroanisole as a white solid with melting point 181-182°C.

<!>H-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 = 8.89 Hz), 6.80 (dt, 1H, J = 10.95, 2.12 Hz), 3.8 (s, 3H), 1.7 (s,

6H);

MS (ESI) m/z 302 ([M+H]<+>, 100%);

Analysis for Ci7Hi6FNO30,lH2O:

EXAMPLE 83

6-(3-fluoro-5-trifluoromethylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one Prepared according to procedure B from (1,4- dihydro-4,4-dimethyl-1-oxo-2H-benzoxin-6-yl)boric acid and l-bromo-3-fluoro-5-trifluoromethylbenzene as a white solid with a melting point of 207-208°C.

1 H-NMR (DMSO-de) δ 10.4 (s, 1H), 7.94-7.9 (m, 2H), 7.73-7.7 (m, 2H), 7.63 (d , 1H, J

= 8.58 Hz), 6.99 (d, 1H, J = 8.68 Hz), 1.7 (s, 6H);

MS (EI) m/z 339 ([M + ], 60%);

Analysis for C17H13F4NO2:

EXAMPLE 84

6-(5-Bromo-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one Prepared according to procedure B from (l, 4-dihydro-4,4-dimethyl-1-oxo-2H-benzoxin-6-yl)boric acid and 3,5-dibromopyridine as a white solid with a melting point of 211-212°C.

"H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.92 (d, 1H, J = 1.9 Hz), 8.66 (d, 1H, J = 2.09 Hz) ,

8.40 (t, 1H, J = 2.02 Hz), 7.72-7.68 (m, 2H), 6.99 (d, 1H, J = 8.1 Hz), 1.7

(p, 6H);

MS (APCI) m/z 333 ([M+H]<+>, 100%), 335 [M+H]<+>, 100%);

Analysis for CisHi3BrN2O2:

EXAMPLE 85

6-(5-bromo-1-oxy-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one A mixture of 6-( 5-bromopyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.34 g, 1 mmol), 5 mL of 30%- of hydrogen peroxide in 5 ml of acetic acid was heated to 60°C for 3 hours. The reaction mixture was cooled to room temperature and neutralized by the addition of a 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 (0.35 g, 100%) mp 157-159°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.99 (s, 1H), 7.73- 7.69

(m, 2H), 6.97 (d, 1H, J = 8.18 Hz), 1.7 (s, 6H);

MS (APCI) m/z 349 ([M+H]<+>, 100%), 351 ([M+H]<+>, 100%),

Analysis for Ci5Hi3BrN2O3-2.5H20:

EXAMPLE 86

6-(3-cyano-5-fluorophenyl)-4,4-dimethyl-2-oxo-4H-benzo[d][1,3]oxazine-1-carboxyl tert-butyl ester

A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile (0.3 g, ~ 1 mmol), di-tert-butyl dicarbonate (0.33 g, 1.5 mmol) and 50 mg of DMAP in anhydrous acetonitrile were stirred at room temperature under nitrogen for 4 min. The reaction mixture was washed with 1N aqueous HCl, brine and dried over MgSO 4 . After removal of the solvent, the title compound was obtained as a white solid (0.25 g, 63%) mp 139-140°C. •H-NMR (CDCl3-de) 8 7.66-7.63 (m, 2H), 7.53-7.48 (m, 2H), 7.38-7.35 (m, 2H), 1 .79 (s,6H), 1.62 (s,9H);

MS (APCI) m/z 289 ([M-H]\ 100%);

Analysis for C22H21FN2O4:

EXAMPLE 87

5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile

Prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and l-bromo-2-fluorobenzonitrile as a white solid with melting point 255-256°C. •H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.30 (dd, 1H, J = 6.15, 2.41 Hz), 8.12-8.07 (m, 1H ), 7.76-7.58 (m, 3H), 6.97 (d, 1H, J = 8.22 Hz), 1.7 (s, 6H;

MS (APCI) m/z 297 ([M+H]<+>, 100%);

Analysis for CnHnFlS^-O.l^O:

EXAMPLE 88

4-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-2-carbonitrile

8-Fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid was prepared from 6-bromo-8-fluoro-4,4-dimethyl- dihydro-benzo[d][l,3]oxazin-2-one using the procedure of Example 4.

The title compound was prepared according to procedure B from 8-fluoro-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boronic acid and 4-bromo-2- the cyanothiophene as a white solid with a melting point of 250-251°C.

1H-NMR (DMSO-de) δ 10.5 (s, 1H), 8.54 (d, 1H, J = 1.42 Hz), 8.43 (d, 1H, J = 1.35

Hz), 7.69 (dd, 1H, J = 11.71,1.54 Hz), 7.58 (bs, 1H), 1.7 (s, 6H);

MS (EI) m/z 302 ([M<+>], 50%);

Analysis for Ci5HiiFN2O2S0.45H2O:

EXAMPLE 89

3-fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile

The compound was prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-bwnzoxin-6-yl)boric acid and 5-bromo-3-fluorobenzonitrile as a white solid with melting point 256-257°C.

1H-NMR (DMSO-d6) δ 10.5 (s, 1H), 8.20 (bs, 1H), 8.06 (dt, 1H, J = 10.48, 2.16 Hz),

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)-thiophene-3-carbonitrile

The compound was prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 2-bromo-4-thiophenecarbonitrile as an off-white solid with melting point 255-260°C.

1H-NMR (DMSO-de) δ 10.36 (s, 1H), 8.48 (d, 1H, J = 1.1 Hz), 7.88-7.87 (d, 1H, J = 1 ,3

Hz), 7.63 (d, 1H, J = 1.9 Hz), 7.56-7.54 (dd, 1H, J = 8.0, 2.0 Hz), 6.93 (d,

1H, J = 8.1 Hz), 1.64 (s.6H);

MS (ESI) m/z 283 (M-H).

EXAMPLE 91

2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile

The compound was prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxin-6-yl)boric acid and 2-bromo-3-thiophenebenzonitrile as an off-white solid with melting point 200-202°C.

1H-NMR (DMSO-d 6 ) δ 10.49 (s, 1H), 87.75 (m, 1H), 7.63 (d, 1H, J = 2.2 Hz), 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 (M-H)-.

EXAMPLE 92

6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one A mixture of 5-[ 3-Bromophenyl]-[1,3,4]oxathiazol-2-one (21.25 g, 82.3 mmol), ethyl cyanoformate (32.5 mL, 329 mmol) in 500 mL in o-xylene was heated to 150°C for 60 hours. After the solvent was removed from the reaction mixture, the product was recrystallized from ethanol to give 3-[3-bromophenyl]-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester as white crystals (17.5 g, 68%) with melting point 87-90°C.

1H-NMR (CDCl 3 ) δ 8.53 (t, 1H, J = 1.76 Hz), 8.28 (dt, 1H, J = 5.4, 1.2 Hz), 7.62 (dq,

1H, J = 5.1, 1.0 Hz), 7.36 (t, 1H, J = 7.9 Hz), 4.55 (q, 2H, J = 7.1 Hz),

1.48(t,3H,J = 7.1Hz);

MS ((+)APCI) [M+H]<+> @ m/z 313/315;

Analysis for CiiH9BrN202S:

A mixture of 3-[3-bromophenyl]-[1,2,4]thiadiazole-5-carboxylic acid.ethyl ester (16.8 g, 53.5 mmol), sodium hydroxide (2.4 g, 58.8 mmol) 120 ml of distilled water and 20 ml of ethanol were heated to 100°C for 2 hours. The reaction mixture was cooled to room temperature. 5.1 mL of concentrated hydrochloric acid was added and the reaction mixture reheated to 100°C for 3 hours. The solution was cooled to room temperature and extracted with 3 x 150 ml of diethyl ether. The combined organic layers were washed with 3 x 100 mL of distilled water and dried over MgSO 4 . After the solvent was removed, 3-[3-bromophenyl]-[1,2,4]thiadiazole was obtained as white needles (12.7 g, 99%) mp 69-71°C.

1H-NMR (CDCl 3 ) δ 9.89 (s, 1H), 8.52 (t, 1H, J = 1.8 Hz), 8.28 (dt, 1H, J = 5.2,1.3 Hz),

7.61 (dq, 1H, J = 4.9, 1.1 Hz), 7.35 (t, 1H, J = 7.9 Hz);

MS ((+)APCI) [M+H]<+> @ m/z 241/243;

Analysis for C8H5BrN2S:

According to procedure B, (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzo[d][1,3]-oxazin-6-yl)boronic acid was coupled with 3- [3-bromophenyl]-[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 whitish solid (0.5 g, 35%) mp 214-216°C.

1H-NMR (DMSO-de) δ 10.40 (s, 1H), 10.36 (s, 1H), 8.49 (s, 1H), 8.23 (d, 1H, J = 7.7

Hz), 7.83 (d, 1H, J = 7.9 Hz), 7.66-7.61 (m, 3H), 7.02 (t, 1H, J = 4.4 Hz),

1.70 (s, 6H);

MS ((+)APCI) [M+H]<+> @ m/z 338.

EXAMPLE 93

6-(3-Fluoro-5-thiophen-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one and 3-thiophenboronic acid as a brownish-orange solid with melting point 200-203°C.

1H-NMR (CDCl 3 ) δ 8.62 (s, 1H), 7.53 (q, 1H, J = 1.4 Hz), 7.50 (d, 1H, J = 1.5 Hz), 7 ,49

(d, 1H, J = 2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, J = 1.8 Hz), 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

(p. 6H):

MS ((-)APCI) [M-H]- @ m/z 352;

Analysis for C20HieFNO2S0.50H2O:

EXAMPLE 94

2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester

A solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one (0.87 g, 3.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (96 mg, 0.08 mmol) in 40 mL toluene was stirred under a stream of nitrogen for 25 min. To the solution were successively added 1-t-butoxycarbonylpyrrole-2-boronic acid (1.4 g, 7.0 mmol) in 10 ml of absolute ethanol and potassium carbonate (0.94 g, 7.0 mmol) in 10 ml of water. The mixture was heated to 80°C for 16 hours and allowed to cool to room temperature. The reaction mixture was poured into 100 mL saturated aqueous sodium bicarbonate solution and extracted with 3 x 100 mL ethyl acetate. The organic layers were combined, washed with 100 ml water and 50 ml brine and dried over magnesium sulfate. The solution was filtered, concentrated under vacuum and the residue purified by flash column chromatography on silica gel with 30% ethyl acetate:hexane to give the title compound as an off-white powder (0.7 g, 62%) mp 176°C.

1 H-NMR (CDCl 3 ) δ 1.40 (s, 9H), 1.73 (s, 6H), 6.17 (dd, 1H, J = 1.8, 3.3 Hz), 6.22 ( dd,

1H, J = 3.3, 3.3 Hz), 6.77 (d, 1H, J = 8.1 Hz), 7.13 (d, 1H, J = 1.8 Hz), 7.23 ( dd, 1H, J = 1.8, 8.1 Hz), 7.33 (dd, 1H, J = 1.8, 3.3 Hz), 7.69 (bs,

1H);

MS ((-)-ESI) m/z 341 [M-H]';

Analysis for C19H22N2O4:

EXAMPLE 95

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

To a solution of 2-(4,4-dimethyl-2-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 25 ml of acetonitrile and 1 ml of dichloromethane, silver nitrate (0.37 g, 2.1 mmol) was added at room temperature. After 5 minutes, acetyl chloride (0.15 mL, 2.0 mmol) in 3 mL of acetonitrile was added and the solution stirred for 2 hours. The reaction mixture was poured into 50 ml of water and extracted with 2 x 50 ml of ethyl ether. The organic layer was combined, washed with 30 ml of brine and dried over magnesium sulfate. The solution was filtered, concentrated under vacuum and the residue purified by flash column chromatography on silica gel with 30% ethyl acetate:hexane to give a yellow oil which crystallized from 5% ethyl acetate:hexane to give the title compound as a pale yellow powder (350 mg, 45%) with melting point 125°C.

1H-NMR (CDCl 3 ) δ 1.47 (s, 9H), 1.75 (s, 6H), 6.26 (D, lh, j = 4.2 Hz), 6.87 (d, 1H, J =

8.1 Hz), 7.19 (d, 1H, J = 4.2 Hz), 7.34 (d, 1H, J = 2 Hz), 7.4 (dd, 1H, J =

1.8, 8.1 Hz), 8.17 (bs, 1H).

MS ((+)APCI) 388 [M+H]<+>;

Analysis for C19H21N3O6:

EXAMPLE 96

4,4-Dimethyl-6-(5-nitro-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one 2-(4,4- dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1J3]oxazin-6-yl)-5-nitro-pyrrole-1-carboxylic acid.tert-butyl ester (0.7 g, 1.8 mmol) was placed in a 25 mL round bottom flask with a rubber septum and equipped with a nitrogen inlet and a needle to allow gas escape. A vigorous stream of nitrogen was maintained while the flask was placed in an oil bath and heated to 180°C. After 10 minutes at this temperature, the flask was removed from the oil bath and set aside to cool to room temperature. The brown residue was washed into a larger flask with dichloromethane ethyl acetate and absorbed on a small amount of silica gel. Purification by flash column chromatography on silica gel with 60% ethyl acetate:hexane gave the title compound as a brown powder (200 mg, 40%) m.p. 265°C (decomp.).

<!>H-NMR (DMSO-de) 6 1.65 (s, 6H), 6.81 (d, 1H, J = 4.4 Hz), 6.90 (d, 1H, J = 8.6 Hz),

7.25 (d, 1H, J = 4.2 Hz), 7.79 (dd, 1H, J = 2, 8.3 Hz), 7.91 (d, 1H, J = 2

Hz), 10.37 (s, 1H), 13.17 (bs, 1H);

MS ((-)-ESI) m/z 286 [M-H]-;

Analysis for C14H13N3O4:

EXAMPLE 97 4,4-Dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one 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 in a 25 mL round flask with a rubber septum and equipped with a nitrogen inlet and a needle to allow gas escape. A vigorous stream of nitrogen was maintained while the flask was placed in an oil bath and heated to 180°C. After 10 minutes at this temperature, the flask was removed from the oil bath and set aside to cool to room temperature. The brown residue was washed into a larger flask with dichloromethane ethyl acetate and absorbed on a small amount of silica gel. Purification by flash column chromatography on silica gel with 60% ethyl acetate hexane gave the title compound as a green solid (2 g, 80%) m.p. 202°C (decomp.): 1 H-NMR (CDCl 3 ) 6 1.75 (s, 6H, 6, 30 (m, 1H), 6.45 (m, 1H), 6.85 (d, 1H, J = 8.5 Hz),

6.86 (m, 1H), 7.24 (d, 1H, J = 2 Hz), 7.33 (dd, 1H, J = 2, 8.4 Hz), 8.44 (bs, 1H), 8.66 (s, 1H);

MS ((+)-APCI) m/z 243 [M+H]<+>;

Analysis for C14H14N2O2:

EXAMPLE 98 4,4-Dimethyl-6-(1-methyl-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one To a mixture of 4, 4-Dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one (1.5 g, 6.2 mmol) in 20 mL dimethylformamide, potassium carbonate (4.28 g, 31 mmol) and a solution of methyl iodide (1.16 ml, 19 mmol) in 5 ml of dimethylformamide were added one after the other at room temperature. After one hour, the reaction mixture was boiled. The reaction mixture was cooled to room temperature, poured into 50 ml of water and extracted with 2 x 50 ml of ethyl ether. The organic layers were combined, washed with 30 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by flash column chromatography on silica gel with 40% ethyl acetate:hexane gave the title compound as an off-white powder (0.5 g, 31%) mp 230°C.

1H-NMR (CDCl 3 ) δ 1.71 (s, 6H), 3.42 (s, 3H), 6.31 (dd, 1H, J = 2.9, 5.9 Hz), 6.47 ( m,

1H), 6.88 (m, 1H), 6.94 (d, 1H, J = 8.6 Hz), 7.26 (d, 1H, J = 2.2 Hz), 7.41

(dd, 1H, J = 2.2, 8.6 Hz), 8.43 (bs, 1H);

MS ((-)-ESI) m/z 255 [M-H]-;

Analysis for C15H16N2O2:

EXAMPLE 99

4,4-Dimethyl-6-(1-methyl-5-nitro-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one

To a solution of 4,4-dimethyl-6-(1-methyl-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d]-[1,3]oxazin-2-one (0, 3 g, 1.2 mmol) in 20 ml of acetonitrile was added silver nitrate (0.21 g, 1.26 mmol). The solution was cooled to -78°C and treated with a solution of acetyl chloride (0.08 mL, 1.2 mmol) in 1 mL of acetonitrile. The reaction mixture was allowed to warm to room temperature. After one hour, the reaction mixture was poured into 50 ml of water and extracted with 2 x 50 ml of ethyl ether. The organic layers were combined, washed with 30 ml of brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by flash column chromatography on silica gel with 40% ethyl acetate:hexane gave the title compound (5 mg, 1%) as a yellow solid, mp 180-185°C.

<l>H-NMR (CDCh) 6 1.75 (s, 6H), 3.45 (s, 3H), 6.57 (dd, 1H, J = 2.9,4.3 Hz), 7, 04 (d,

1H, J = 8.5 Hz), 7.22 (dd, 1H, J = 2.5,4.3 Hz), 7.36 (d, 1H, J = 2.1 Hz),

7.56 (dd, 1H, J = 2.1, 8.5 Hz), 9.67 (bs, 1H);

MS ((+)-APCI) m/z 302 [M+Hf.

EXAMPLE 100

5-Bromo-4-ethylthiophene-2-carboxaldehyde

Prepared in the same manner as in Example 19 from 2-bromo-3-ethylthiophene.

1H-NMR (DMSO-de) δ 9.82 (s, 1H, 7.81 (s, 1H), 2.5 (q, 2H, J = 7.4 Hz), 1.15 (t, 3H , J =

7.5 Hz).

EXAMPLE 101

5-Bromo-4-ethylthiophene-2-carbonitrile

Prepared in the same manner as in Example 18 from 5-bromo-4-ethylthiophene-2-carboxaldehyde.

IR(KBr) 2221 cm'<1>;

1H-NMR (DMSO-de) δ 7.87 (s, 1H), 2.55 (q, 2H, J = 7.3 Hz), 1.18 (t, 3H, J = 7.6 Hz) ;

MS (EI) m/z 215/217 (M<+>).

EXAMPLE 102

5-Bromo-4-n-propylthiophene-2-carboxaldehyde

Prepared in the same manner as in Example 19 from 2-bromo-3-n-propylthiophene.

1H-NMR (DMSO-d6) δ 9.82 (s, 1H), 2.6-2.5 (m, 2H), 1.65-1.51 (m, 2H), 1.0 (t, 3H, J =

4.7 Hz).

EXAMPLE 103

5-Bromo-4-n-propylthiophenecarbonitrile

Prepared in the same manner as in Example 18 from 5-bromo-4-n-propylthiophene-2-carboxaldehyde. 1 H-NMR (DMSO-d6) δ 7.87 (s, 1H), 2.5 (t, 2H, J = 5.2 Hz), 1.64-1.5 (m, 2H), 1, 91 (t, 3H, J = 5.1 Hz).

MS (EI) m/z 229-231 (M1”).

EXAMPLE 104

5-bromo-4-n-butylthiophenecarboxaldehyde

Prepared in the same manner as in Example 19 from 2-bromo-3-n-butylthiophene.

IR(KBr) 1660 cm1; 1 H-NMR (DMSO-d6) δ 9.78 (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 = 5.2 Hz).

MS (EI) m/z 246 (M<*>).

EXAMPLE 105

5-Bromo-4-n-butylthiophenecarbonitrile

Prepared in the same manner as in Example 18 from 5-bromo-4-n-butylthiophenecarboxaldehyde.

1 H-NMR (DMSO-d 6 ) δ 7.87 (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 = 5.3 Hz).

MS (EI) m/z 243 (M1”).

EXAMPLE 106

3-(1,2-dihydro-2-oxospiro[4H-3,1-benzoxazin-4,1-cyclohexane]-6-yl)-benzonitrile Prepared according to procedure B from spiro-(4,r-cyclohexane- 1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 3-bromobenzonitrile as a golden powder with melting point 245-247°C.

1H-NMR (DMSO-de) δ 10.31 (s, 1H), 8.21 (s, 1H), 8.02 (d, 1H, J = 8.0 Hz), 7.78 (d,

1H, J = 7.7 Hz), 7.68-7.61 (m, 3H), 6.97 (d, 1H, J = 8.2 Hz), 1.98-1.96

(m, 4H), 1.75-1.64 (m, 5H), 1.40-1.32 (m, 1H).

MS (EI) m/z 318 [M<*>];

Analysis for C2oH18N202-<1>/2H20:

EXAMPLE 107

3-(1,2-dihydro-2-oxospiro[4H-3,1-benzoxazin-4,1-cyclohexane]-6-yl)-5-fluoro-benzonitrile

Prepared according to procedure B from spiro-(4,1'-cytohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-fluorobenzonitrile as a white powder with melting point 250-253°C.

IR(KBr) 2220 cm<1>;

1H-NMR (DMSO-de) δ 10.34 (s, 1H), 8.13 (s, 1H), 8.0 (d, 1H, J = 10.6 Hz), 7.80-7, 7

(m, 3H), 6.98-6.95 (d, 1H, J = 8.1 Hz), 1.99-1.97 (m, 4H), 1.76-1.65 (m,

6H), 1.37-1.33 (m, 1H).

MS (EI) m/z 336 (M<+>);

Analysis for C20H17FN2O2H2O:

EXAMPLE 108

4-(1,2-dihydro-2-oxospiro[4H-3,1-benzoxazin-4,1-cyclohexane]-6-yl)-2-thiophene-carbonitrile

Prepared according to procedure B from spiro-(4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-cyanothiophene as white crystals with melting point 230-232°C.

IR(KBr) 2220 cm<1>;

1H-NMR (DMSO-de) 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 = 8.2 Hz), 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)<+>.

Analysis for C18H16N2O2S I/4H2O:

EXAMPLE 109

5-(1,2-dihydro-2-oxospiro[4H-3,1-benzoxazin-4,1-cyclohexane]-6-yl)-thiophene-carbonitrile

Prepared according to procedure B from spiro-(4,r-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 2-bromo-5-cyanothiophene as a golden powder with melting point 243-245°C.

1H-NMR (DMSO-de) δ 10.41 (s, 1H), 7.98-7.97 (d, 1H, J = 3.9 Hz), 7.67-7.60 (m, 3H ),

6.97-6.94 (d, 1H, J = 8.3 Hz), 1.98-1.92 (m, 4H), 1.74-1.64 (m, 5H),

1.45-1.21 (m, 1H);

MS (EI) m/z 324 (M+);

Analysis for CigHie^OzS-^O:

EXAMPLE 110

5-(1,2-dihydro-2-oxospiro[4H-3,1-benzoxazin-4,1-cyclohexane]-6-yl)-4-methyl-2-thiophenecarbonitrile

Prepared according to procedure B from spiro-(4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 2-bromo-3-methyl-5 -cyanothiophene as a white powder with a melting point of 200-203°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 7.85 (s, 1H), 7.43-7.40 (m, 2H), 7.0 (d, 1H, J = 8.8

Hz), 2.27 (s, 3H), 2.00-1.62 (m, 9H), 1.42-1.23 (m, 1H).

MS (EI) m/z 338 (M<+>).

Analysis for C19H18N2O2S:

EXAMPLE 111

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-ethyl-thiophene-2-carbonitrile

Prepared according to procedure B from spiro-(4,r-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 2-bromo-3-ethyl-5- the cyanothiophene as white crystals with a melting point of 160-162°C.

1H-NMR (DMSO-de) δ 10.46 (s, 1H), 7.96 (s, 1H), 7.40-7.38 (m, 2H), 7.02-6.99 (d , 1H,

J = 8.8 Hz), 2.61 (q, 2H, J = 7.5 Hz), 1.64 (s, 6H), 1.16 (t, 3H, J = 7.6

Hz).

MS ((+)-APCI) m/z 313 [M+H]<+>;

Analysis for Ci7Hi6N202S-1/4H20:

EXAMPLE 112

5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-propyl-thiophene-2-carbonitrile

Prepared according to procedure B from spiro-(4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 2-bromo-3-n-propyl -5-thiophenecarbonitrile as white crystals with melting point 160-162°C.

IR (KBr) 2220 cm<1>;

1H-NMR (DMSO-de) δ 10.47 (s, 1H), 7.93 (s, 1H), 7.38-7.36 (m, 2H), 7.01 (d, 1H, J =

8.7 Hz), 2.59-2.48 (m, 2H), 1.64-1.51 (m, 2H), 0.85 (t, 3H, J = 7.3 Hz). MS (-ESI) m/z 325 [M-H]-;

Analysis for Ci8Hi8N202S-3/4H20:

EXAMPLE 113

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-n-butyl-thiophene-2-carbonitrile

Prepared according to procedure B from spiro-(4,1'-cyclohexane-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 2-bromo-3-n-butyl -5-thiophenecarbonitrile as white crystals with melting point 167-168°C.

1H-NMR (DMSO-de) δ 10.46 (s, 1H), 7.93 (s, 1H), 7.38-7.36 (m, 2H), 7.01 (d, 1H, J =

8.7 Hz), 2.59 (t, 2H, J = 8.1 Hz), 1.63 (s, 6H), 1.58-1.51 (m, 2H), 1.48-1, 17 (m, 2H), 0.82 (t, 3H, J = 7.4 Hz).

MS (-ESI) m/z 339 [M-H]-;

Analysis for C19H20N2O2S4/4H2O:

EXAMPLE 114 6-(4-cyano-3-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one A solution of 4-cyano-3-fluoro -bromobenzene (0.6 g, 3.0 mmol) and 0.2 g of tetrakis-(triphenylphosphine)palladium(O) in 20 mL of ethylene glycol dimethyl ether were stirred under N 2 for 20 min. To this mixture was then added (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid (1.0 g, 4.5 mmol) and sodium carbonate (1.1 g, 10.6 mmol) in 5 ml of water. The solution was refluxed for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with 3 x 50 mL EtOAc. The combined extracts were washed with water, brine, dried over MgSO 4 and evaporated. The residue was purified by column chromatography over SiO 2 in EtOAc:hexane 1:2 to give the title compound (0.05 g, 6%) as an off-white solid, mp 272-275°C. 1 H-NMR (DMSO-de) δ 10.4 (s, 1H), 8.0 (t, 1H, J = 7.7 Hz), 7.9 (dd, 1H, J = 10.3,1 ,3 Hz), 7.8 (dd, 1H, J = 6.8,1.4 Hz), 7.7 (m, 2H), 6.9 (d, 1H, J = 8.9 Hz),

1.7 (s, 6H);

MS (EI) m/z 296 (M<*>).

EXAMPLE 115

6-(4-Fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from (1,4-dihydro- 4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1-bromo-4-fluorobenzene as whitish crystals with melting point 232-233°C.

1H-NMR (DMSO-de) 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).

EXAMPLE 116

6-(3,4-difluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from (1,4- dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1-bromo-3,4-difluorobenzene as whitish crystals with a melting point of 207-208°C.

1H-NMR (DMSO-d 6 ) δ 10.35 (s, 1H), 7.79 (m, 1H), 7.40-7.63 (m, 4H), 6.95 (d, 1H, J =

8.9 Hz), 1.62 (s, 6H).

EXAMPLE 117

6-(2-Fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from (1,4-dihydro- 4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 1-bromo-2-fluorobenzene as whitish crystals with melting point 164-165°C.

1H-NMR (DMSO-de) δ 10.33 (s, 1H), 7.56 (m, 1H), 7.25-7.45 (m, 4H), 6.98 (d, 1H, J =

8.7 Hz), 1.64 (s,6H).

EXAMPLE 118

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)phenylacetonitrile The compound was prepared from 3-bromophenylacetonitrile and (1,4- dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid with a melting point of 188-190°C.

1H-NMR (DMSO-de) δ 10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, J = 8.00

Hz), 7.33 (d, 1H, J = 7.57 Hz), 6.99 (d, 1H, J = 8.81 Hz), 4.09 (s, 2H),

1.67 (s, 6H);

MS m/z 291 (M-H);

Analysis for Ci8Hi6N2O20,3H2O:

EXAMPLE 119

5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile

The title compound was prepared according to procedure B from 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)boric acid (1.8 g, 8.18 mmol) as a white solid (0.39 g , 1.45 mmol, 17%) with melting point 257-260°C.

1H-NMR (DMSO-de) δ 10.48 (s, 1H), 7.73-7.70 (m, 3H), 7.19 (d, 1H, J = 3.8 Hz), 6, 98

(d, 1H, J = 8.9 Hz), 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-fluorobenzonitrile A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in 5 mL dry methanol was treated under nitrogen with trimethylotroformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), then heated under reflux. After 16 hours, the mixture was evaporated and the residue partitioned between water and Et 2 O. The organic layer was washed with saturated sodium bicarbonate solution, water, brine, dried over MgSO4 and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%).

1 H-NMR (CDCl 3 ) δ 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J = 8.0.1, 0

Hz), 3.94 (s, 3H);

MS (EI) m/z 232 (M<4>).

A solution of the latter compound (3.077 g, 13.2 mmol) in 80 mL of dry toluene was treated at -78°C under nitrogen with di-iso-butylaluminum hydride in toluene (1M, 15.7 mL, 15.7 mmol ). After 1 hour at -78°C, the reaction mixture was quenched with 16 ml of 3M aqueous HCl. The mixture was warmed to room temperature and partitioned between EtOAc:H 2 O, after which the aqueous layer was re-extracted with EtOAc and the combined organic layers washed with water, dried over MgScu and evaporated to give 3-bromo-2-fluorobenzaldehyde (2.63 g , 12.9 mmol, 98%) which was used without further purification.

1 H-NMR (CDCl 3 ) δ 10.35 (s, 1H), 7.82 (m, 2H), 7.18 (t, 7.8 Hz).

A mixture of the latter compound (2.63 g, 12.9 mmol), hydroxylamine hydrochloride (1.0 g, 14 mmol) and potassium acetate (1.37 g, 14 mmol) was placed in 60 mL of ethanol: H 2 O 8:2 and the mixture was heated under reflux. After 30 minutes, the mixture was cooled, evaporated and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4 and evaporated to give 3-bromo-2-fluorobenz-aldoxime which was used without further characterization.

A solution of the latter compound (0.75 g, 3.43 mmol) and 0.2 g of tetrakis-(triphenylphosphine)palladium(O) was stirred in 30 mL of dimethoxyethane at room temperature under nitrogen. After 15 minutes, (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid (1.1 g, 5.0 mmol) and 1.35 sodium carbonate in 10 ml of water added and the mixture heated under reflux. After 16 hours, the mixture was cooled, partitioned between water and EtOAc, after which the organic layer was washed with saturated sodium carbonate solution, brine, dried over MgSO 4 and evaporated. The residue was then dissolved in 50 ml of acetonitrile, treated with 0.2 g of copper acetate and heated under reflux. After 16 hours, the mixture was cooled and evaporated. The residue was partitioned between water and EtOAc, the organic layer washed with dilute 1N sulfuric acid, water, brine, dried over MgSO 4 and evaporated. The residue was then subjected to column chromatography over SiO 2 with EtOAc:hexane by gradient elution and then crystallized from EtOAc:hexane to give the title compound (0.176 g, 0.59 mmol, 17%) as a white solid, mp 192-198°C.

1 H-NMR (CDCl 3 ) δ 9.15 (s, 1H), 7.69-7.58 (m, 2H), 7.42-7.31 (m, 3H), 6.99 (d, 1H ), J

= 8.2 Hz), 1.78 (s, 6H);

MS ((+)-ESI) 297 [M+H]<+>.

EXAMPLE 121 - PHARMACOLOGY

The compounds according to the invention were tested in the relevant assay as described below and their potency lies within the range of 0.01 nM to 5 µM in the in vitro assays and 0.001 to 300 mg/kg in the in vivo assays.

A. In vitro biology

The in vitro biology is determined by

(1) competitive radioligand binding: Use of the A form of the human progesterone receptor with progesterone as radioligand; (2) co-transfection assay yielding functional activity expressed as agonist EC 50 and antagonist IC 50 values; (3) A T47D cell proliferation which is an additional functional assay that also provides agonist and antagonist data; and' (4) T47D cell alkaline phosphatase assay which is an additional functional assay that also provides agonist and antagonist data.

1. hPR binding assay

This analysis is carried out according to C. Pathirana, R.B. Stein, T.S. Berger, W. Fenical, T. Ianiro, D.E. Mais, A. Torres, M.E. Glodman, "Nonsteroidal human progesterone receptor modulators from the marine alga cymoplia barbata", "J. Steroid Biochem. Mol. Biol.", 1992,41, 733-738.

2. PRE-luciferase analysis in CV-1 cells

The object of this assay is to determine the progestational and anti-progestational potency of a compound based on its effect on the PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. Materials and methods used in the analysis are as follows.

a. Medium:

The growth medium was as follows: DMEM (Bio Whittaker) containing 10% (vol/vol) fetal bovine 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). The experimental medium was as follows: DMEM (Bio Whittaker), phenol red-free, containing 10%

(vol/vol) charcoal-stripped fetal bovine 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).

b. Cell culture, transfection, treatment and luciferase assay

Stock CV-1 cells are maintained in growth medium. Co-transfection occurs using 1.2 x IO<7 > cells, 5 mg of pLEM plasmid with hPR-B inserted at the Sphl and BamHl sites, 10 mg of pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg of sonicated calf thymus DNA as carrier DNA in 250 ml. The electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II. After electroporation, the cells are resuspended in growth medium and plated in 96-well plates at 40,000 cells/well in 200 ul. After overnight incubation, the medium is changed to test medium. The cells are then treated with reference or test compounds in test medium. The compounds are tested for antiprogestational activity in the presence of 3 nM progesterone. 24 hours after treatment, the medium is discarded, the cells are washed three times with D-PBS (GIBCO, BRL). 50 µl of cell lysis buffer (Promega, Madison, WI) is added to each well and the plates are shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity is measured using luciferase reagents from Promega.

c. Analysis of results:

Each treatment consists of at least 4 replicates. Log-transformed data are used for analysis of variance and non-linear dose-response curve fitting for both the agonist and antagonist models. Huber weighting is used to reduce the effect of extraneous factors. The EC50 or ICso values are calculated from the retransformed values. JMP programs (SAS Institute, Inc.) are used for both one-way analysis of variance and non-linear response analyses.

d. Reference connections:

Progesterone and trimegestone are the reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50 or ICso values are calculated.

Progestational activity: Compounds that exert PRE-luciferase activity significantly (p < 0.05) compared to the vehicle control are considered active.

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

EC50: Concentration of a compound that gives half-maximal increase of PRE-lucife race activity (default-nM) with SE.

IC50: Concentration of a compound that produces half-maximal reduction in 3nM progestin-induced PRE-luciferase activity (default-nM) with SE.

3. T47D cell proliferation assay

The purpose of this analysis is the determination of the progestational and antiprogestational potency using a cell proliferation assay in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured. Material and methods used in this analysis are as follows.

a. Growth medium:

DMEM:F12 (1) (GIBCO, BRL) supplemented with 10% (vol/vol) fetal bovine serum (non-heat inactivated), 100 U/ml penicillin, 100 mg/ml streptomycin and 2 mm GlutaMax (GIBCO, BRL).

b. Treatment medium:

Minimum essential medium (MEM) (#51299.038GIBCO, BRL) phenol red-free supplemented with 0.5% charcoal-stripped fetal bovine serum, 100 U/ml penicillin, 200 mg/ml streptomycin and 2 mM GlutaMax (GIBCO, BRL).

c. Cell culture

T47D stock cells are maintained in growth medium. For the BrdU incorporation assay, the cells are plated in 96-well plates (Falcon, Becton Dicikinson Labware) at 10,000 cells/well in growth medium. After overnight incubation, the medium is changed to treatment medium and the cells are cultured for a further 24 hours before treatment. The 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 run in full dose response curves. The final concentration of vehicle is 0.1%. In control wells, the cells only receive vehicle. Antiprogestins are treated in the presence of 0.03 nM trimegestone, the reference progestin agonist. 24 hours after treatment, the medium and the cells labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) in treatment medium for 4 hours are discarded.

d. Cell proliferation assay

At the end of BrdU labeling, the medium is removed and BrdU incorporation is measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to the manufacturer's instructions. Briefly, the cells are fixed in an ethanolic fixative for 30 minutes, followed by incubation in a blocking buffer for 30 minutes to reduce the 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'-tetramethyl-benzimide (TMB) substrate for 10-20 minutes depending on the potency of the tested compounds.

Then 25 µl IM sulfuric acid is added to each well to stop the color reaction and optical density is read in a plate reader at 450 nm within 5 minutes.

e. Analysis of results:

Square-root transformed data are used for analysis of variance and non-linear dose-response curve fitting bpde for agonist and antagonist modes. Huber weighting is used to reduce the effects of extraneous factors. EC50 or ICso values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and nonlinear dose-response analyzes in both single-dose and dose-response studies.

f. Reference connections:

Trimegestone and medroxyprogesterone acetate (MPA) are the reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50 or ICso values are calculated.

4. T47D- cell alkaline phosphatase assay

The purpose of this assay is to identify progestins or antiprogestins by determining a compound's effect on alkaline phosphatase activity in T47D cells. Material and methods used in this analysis are as follows.

a. Culture medium:

DMEM:F 12 (1:1) (GIBCO, BRL) supplemented with 5% (vol/vol) charcoal-stripped fetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100 µg/ml streptomycin and 2 mM GlutaMax ( GIBCO, BRL).

b. Alkaline phosphatase buffer assay:

I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100

II. 0.1 M Tris-HCl, pH 9.8, containing 4 mM p-nitrophenyl phosphate (Sigma).

c. Cell culture and treatment:

Deep-frozen T47D cells were thawed in a 37°C water bath and diluted to 280,000 cells/ml in culture medium. To each well in a 96-well plate (Falcon, Becton Dickinson Labware) was added 180 µl of diluted cell suspension. 20 µl of reference or test compounds, diluted in the culture medium, were then added to each well. When testing for progestin antagonist activity, reference antiprogestins or test compounds were added in the presence of 1 nM progesterone. The cells were incubated at 37°C in a 5% CO 2 /humidified atmosphere for 24 hours.

d. Alkaline phosphatase enzyme assay:

At the end of the treatment, the medium was removed from the plate and 50 µl of assay buffer I was added to each well. The plates were shaken on a titer plate shaker for 15 minutes. Then 150 µl of assay buffer II was added to each well. Optical density measurements were carried out at 5 minute intervals for 30 minutes at a test wavelength of 405 nM.

e. Analysis of results: Analysis of dose-response data

For reference and test compounds, a dose-response curve is generated for dose (X-axis) versus rate of enzyme reaction (slope (Y-axis). Square-root-transformed data is used for analysis of variance and non-linear dose-response curve fitting for both agonist- and antagonist mode. Huber weighting is used to weight down the effects of outliers. EC50 or IC50 values are calculated from "transformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and nonlinear dose-response analyzes both in single-dose and dose-response studies.

f. Reference connections:

Progesterone and trimegestone are the reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50 and IC50 values are calculated.

B. In vivo biology

The primary in vivo assay is the rat decidualization model that can be used to determine progestational effects of both agonists and antagonists. The secondary in vivo assay is the rat ovulation inhibition model which is under development and therefore the protocol is not available.

1. Rat ductualization assay

The purpose of this procedure is to evaluate the effect of progestins and antiprogestins on rat uterine decidualization and to compare the relative potencies of different test compounds. Material and methods used in this analysis are as follows.

a. Methods:

The test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle). Stock solutions of the test compounds in oil ("Mazola") are then prepared by heating (~80°C) the mixture to evaporate ethanol. Test compounds are then diluted with 100% corn oil or 10% ethanol in corn oil before treating the animals. No difference in decidual response was found when these two vehicles were compared.

b. Dvr (RACUC protocol no. 5002)

Ovariectomized mature female Sprague-Dawley rats (~60 days old with body weight 230 g) are obtained from Taconic (Taconic Farms, NY) after surgery. Ovariectomy is carried out at least 10 days before treatment to reduce circulating sex steroids. The animals are housed under 12-hour light/dark cycles and given standard rat chow and water ad libitum.

c. Processing

The rats are weighed and randomly assigned to groups of 4 or 5 before treatment. The test compounds in 0.2 ml vehicle are administered by subcutaneous injection at the nape of the neck or by forced gavage using 0.5 ml. The animals are treated once a day for 7 days. For testing antiprogestins, the animals are given the test compounds and an EC50 dose of progesterone (5.6 mg/kg) during the first three days of treatment. After decidual stimulation, the animals continue to receive progesterone until necropsy 4 days later.

d. Dosage

The doses are prepared based on average mg/kg group body weight. In all studies, a control group that only received vehicle is included. The determination of the dose-response curves is carried out using doses in half-log increments (eg 0.1, 0.3, 1.0, 3.0 mg/kg).

e. Decidual induction

About. 24 hours after the third injection, decidualization is induced in one of the uterine horns by scraping the antimesometrial luminal epithelium with a blunt 21 G needle. The contralateral horn is not scratched and serves as a non-stimulated control. About. 24 hours after the last treatment, the rats are killed by asphyxiation and the body weight is measured. Uterus is removed and trimmed for fat. Decidualization (D-horn) and control (C-horn) uterine horns are weighed separately.

f. Analysis of results:

The increase in weight of the decidualized uterine horn is calculated by D-horn:C-horn and logarithmic transformation is used to maximize normality and homogeneity of variance. The Huber-M estimator is used to weight down the outlying transformed observations for both the dose-response curve fitting and the one-way analysis of variance. JMP software (SAS Institute, Inc.) is used for both one-way ANOVA and for non-linear dose-response analyses.

g. Referral links

All progestin reference compounds were run in full dose-response curves and the EC50 for uterine weight was calculated.

Concentration: The compound concentration in the analysis (default mg/kg

body weight).

Mode of administration: The way in which the compound is administered to the animals. Body weight: Mean total animal body weight (default kg).

D-horn: Wet weight of decidualized uterine horn (default mg).

C horn: Wet weight of control uterine horn (default mg).

Decidual response: [D-C)/C] x 100%

Progestational activity: Compounds that induce decidualization significantly (p<0.05) compared to the vehicle control are considered

active.

Antiprogestational activity: Compounds that reduce EC50 progesterone induced

decidualization significantly (p<0.05).

EC50 for uterine weight: Concentration of compound that gives a half-maximal increase of

decidual response (default mg/kg).

IC50 for uterine weight: Concentration of compounds giving half-maximal reduction

in EC50 progesterone-induced decidual response (default mg/kg).

EXAMPLE 122

6-(3-Methoxyphenyl)spiro[4H-3,1-benzoxazin-4,1-cyclobutane]-2(1H)-one A solution of Boc-protected 4-chloroaniline (1.15 g, 5 mmol) in anhydrous THF was treated at -78°C under a nitrogen blanket with t-butyllithium (7.4 mL, 12.5 mmol). The reaction solution was then slowly warmed to -20°C, stirred for 1 V h and treated with cyclobutanone (1 ml, 13.4 mmol). The mixture was warmed to room temperature and quenched with 30 ml of saline, after which 10 ml of IN aqueous hydrogen chloride solution was added. Ethyl acetate was added and the organic layer separated and dried over MgSO 4 . After removal of the solvent, the residue was purified by flash column chromatography with hexane:ethyl acetate 3:1 to give the alcohol used in the next step without further purification.

To a solution of the above product in ethanol was added 2 g of potassium hydroxide. The reaction mixture was stirred at room temperature for 18 hours, followed by the addition of 20 mL of brine and 20 mL of cold 1N aqueous hydrogen chloride solution. The precipitate was collected on a filter and washed with water to give 6-chlorospiro[4H-3,1-benzoxazin-4,1-cyclobutane]-2(1H)-one as a white solid (0.13 g, 12% for two steps) with melting point 183-184°C.

MS (ESI) m/z 222 ([M-H]').

A mixture of 6-chlorospiro[4H-3,1-benzoxazin-4,1-cyclobutane]-2(1H)-one (0.1 g, 0.45 mmol), 3-methoxyphenylboronic acid (0.1 g, 0 .66 mmol), [l,r-bis(diphenylphosphine)ferrocene]-dichloronickel(H) (50 mg, 0.073 mmol), potassium phosphate (0.35 g, 1.7 mmol) in 5 mL dioxane was degassed to remove oxygen and then heated to 85°C under a nitrogen blanket for 72 hours. The reaction mixture was allowed to cool to room temperature. 30 ml of ethyl acetate and 20 ml of saline were added. The organic layer was separated and dried over MgSCv After removal of the solvent, the residue was purified by column chromatography with hexane:ethyl acetate 3:1 to give 6-(3-methoxyphenyl)spiro[4H-3,1-benzoxazine-4,1-cyclo -butan]-2(1H)-one as a white solid (18 mg, 14%) mp 145-146°C.

1H-NMR (DMSO-d 6 ) δ 8.04 (s, 1H), 7.69 (d, 1H, J = 1.6 Hz), 7.59 (dd, 1H, J = 2.2 Hz) ,

6.99 (d, 1H, J = 8.2 Hz), 6.92 (dd, 1H, J = 8.0,2.4 Hz), 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-one For a mixture of 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, 1.2 mmol) in 5 ml of acetic acid, bromine (0.04 ml, 0.78 mmol) was added at room temperature and under nitrogen. The reaction mixture was stirred for 20 hours and poured into 30 ml of ice water. The precipitate was collected on a filter and washed with 3 x 5 mL water to give 8-bromo-6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one as a whitish solid (0.18 g, 72%) mp 194-195°C.

1 H-NMR (DMSO-de) δ 9.77 (s, 1H), 8.02 (dd, 1H, J = 7.10,1.81 Hz), 7.92 (s, 1H), 7, 77

(m, 1H), 7.66 (s, 1H), 7.47-7.53 (m, 1H), 1.71 (s, 6H);

MS (ESI) m/z 384, 386 [M-H]".

EXAMPLE 124

3-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile

The compound was prepared according to the above procedure from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.5 g, 1.7 mmol) as a whitish solid (0.48 g, 75%) m.p. 216-217°C.

1H-NMR (DMSO-d 6 ) δ 9.78 (s, 1H), 8.18 (t, 1H, J = 1.6 Hz), 8.02-8.08 (m, 2H), 7, 81

(m, 1H), 7.75 (d, 1H, J = 1.8 Hz), 1.66 (s, 6H);

MS (ESI) m/z 373, 375 [M-H]-.

EXAMPLE 125

5-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile

The compound was prepared according to the above procedure from 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorobenzonitrile (0.2 g, 0.67 mmol) as a whitish solid (0.18 g, 72%) with melting point 235-236°C.

1H-NMR (DMSO-d 6 ) δ 9.78 (s, 1H), 8.38 (dd, 1H, J = 6.1, 2.4 Hz), 8.14-8.20 (m, 1H ),

7.98 (d, 1H, J = 1.9 Hz), 7.71 (d, 1H, J = 1.8 Hz), 7.62 (t, 1H, J = 9.1 Hz), 1, 69 (p, 6H).

MS (ESI) m/z 373, 375 [M-H]-.

EXAMPLE 126

6-(3-bromophenyl)-1,4,4-trimethyl-2H-3,1-benzoxazin-2-one

To a solution of 6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1 g, 3.0 mmol) in anhydrous DMF was added at room temperature and sodium hydride (60% in mineral oil, 0.24 g, 6.0 mmol) was placed under a blanket of nitrogen. After stirring for 20 minutes, the reaction solution was treated with iodomethane and stirred for VA hour. The mixture was poured into 40 ml of saturated, aqueous ammonium sulfate solution and 40 ml of ethyl acetate was added. The organic layer was separated, dried over MgSO4 and evaporated to give 6-(3-bromophenyl)-1,4,4-trimethyl-2H-3,1-benzoxazin-2-one as an off-white solid (0, 75 g, 72%) with melting point 142-143°C.

1H-NMR (DMSO-ds) δ 7.93 (s, 1H), 7.71 (m, 1H), 7.65 (s, 1H), 7.55 (d, 1H, J = 8.0

Hz), 7.42 (t, 1H, J = 7.7 Hz), 7.18 (d, 1H, J = 8.4 Hz), 3.35 (s, 3H), 1.67

(p, 6H);

MS (ESI) m/z 368, 370 [M+Na]<+>.

EXAMPLE 127

6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one 4-amino-3'-fluoro[1,r-biphenyl]-3-carbonitrile was prepared from 3-fluorophenylboronic acid and 2-amino-5-bromobenzonitrile according to procedure A. A solution of 4-amino-3'-fluoro[l,r-biphenyl]-3-carbonitrile (6.65 g, 31.3 mmol ) in 100 mL anhydrous THF was treated dropwise and at room temperature under nitrogen with methylmagnesium bromide (3.OM in ether, 21 mL, 63 mmol). After addition, the reaction mixture was heated to gentle reflux for 1 V hour, cooled to room temperature and treated with 30 ml of aqueous 3N hydrogen chloride solution. The mixture was heated to reflux for 3 hours, cooled to ambient temperature and adjusted to pH 5-6 by addition of saturated aqueous sodium carbonate solution. 100 ml of ethyl acetate was added, the organic layer separated and the aqueous layer extracted with 3 x 50 ml of ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography with hexane:ethyl acetate 3:1 to give 1-(4-amino-3'-fluoro[1,r-biphenyl]-3-yl)ethanone (3.1 g, 43%) m.p. 156-157°C.

A solution of 1-(4-amino-3'-fluoro[1,r-biphenyl]-3-yl)ethanone (3 g, 13 mmol) in 60 mL of anhydrous methanol was treated at room temperature and under nitrogen with sodium borohydride portionwise manner. After addition, the reaction mixture was stirred for 4 hours, treated with 50 ml of saturated aqueous ammonium sulfate solution and 100 ml of ethyl acetate. The organic layer was separated, dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography with hexane:ethyl acetate 3:1 to give 1-(4-amino-3'-fluoro-[1,1'-biphenyl]-3-yl)ethanol as a white solid (2 g, 67 %) with melting point 136-137°C.

A mixture of the above alcohol (0.2 g, 0.87 mmol) and triphosgene in anhydrous THF was stirred at room temperature under nitrogen. After 15 minutes, the mixture was treated with 30 ml of saturated aqueous sodium bicarbonate solution and 40 ml of ethyl acetate. The organic layer was separated, dried over MgSO4 and evaporated to give 6-(3-fluorophenyl)-4-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid ( 018 g, 81%) with melting point 160-161°C.

1H-NMR (DMSO-de) 6 10.31 (s, 1H), 7.62 (dd, 1H, J = 8.2,1.9 Hz), 7.57 (s, 1H), 7, 44-7.53 (m, 3H), 7.13-7.20 (m, 1H), 6.97 (d, 1H, J = 8.2 Hz), 5.57 (q, 1H, J

= 6.6 Hz), 1.63 (d, 3H, J = 6.6 Hz).

MS (ESI) m/z 256 [M-H]-.

EXAMPLE 128

3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluoro-benzonitrile

To a solution of 2-amino-3-methoxybenzoic acid (5g, 30 mmol) in 100 ml of anhydrous THF was added methylmagnesium bromide (3.0M in THF, 50 ml, 150 mmol) at ambient temperature and under a blanket of nitrogen. The reaction mixture was heated to 50°C for 18 hours, cooled to room temperature and treated with 50 ml of saturated aqueous ammonium chloride solution. 100 ml of ethyl acetate was added and the organic layer separated, dried over MgSO 4 and evaporated. The residue was dissolved in 100 mL of THF and treated at ambient temperature under nitrogen with 1,1-carbonyldiimidazole (5.4 g, 33 mmol). After 24 hours, the mixture was quenched with 30 ml of 1N aqueous hydrogen chloride solution. 100 ml of ethyl acetate was added, the organic layer separated, dried over MgSO 4 and evaporated. The residue was purified by silica gel column chromatography with 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%.2-one as a white solid (3.5 g, 56%

MS (ESI) m/z 208 [M+H]<+>.

To a mixture of 8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (2.1 g, 10.1 mmol), sodium acetate (1.5 g, 18 mmol) in 30 ml of acetic acid was added bromine (0.62 ml, 12 mmol) at ambient temperature. After 30 minutes, the solution was treated with 50 ml of concentrated ammonium hydroxide solution. The precipitate was collected on a filter and washed with 2 x 20 mL water to give 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]<+>.

A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolate) diboron (1.6 g, 6.3 mmol, potassium acetate (1.5 g, 15.3 mmol) and [l,r-bis(diphenylphosphine)ferrocene]palladium(n)chloride (1:1 complex with methylene chloride, 0 .5 g, 0.6 mmol) in 30 mL DMF was subjected to a positive stream of nitrogen to remove oxygen and then heated to 85 °C under a blanket of nitrogen for 18 h. The reaction mixture was allowed to cool to ambient temperature, treated with 3 -bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [l,r-bis(diphenylphosphine)-ferrocene]palladium(II) chloride (1:1 complex with methylene chloride, 0.5 g, 0, 6 mmol) and sodium carbonate (2 g, 19 mmol) in 10 mL of water. The resulting solution was heated to 85°C for 3 h under a blanket of nitrogen, cooled to room temperature, and treated with 50 mL of brine. 100 mL of ethyl acetate was added , the organic layer separated, dried over MgSO4 and evaporated The residue was purified by flash silica gel column chromatography with 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 as a white solid (0.6 g, 33%) with melting point 252-253°C.

1H-NMR (DMSO-d 6 ) δ 9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J = 10.6 Hz), 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 [M-H]'.

EXAMPLE 129

3-(4,4-dimethyl-8-hydroxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluoro-benzonitrile

A mixture of 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.1 g, 0, 31 mmol), lithium iodide (0.3 g, 2.24 mmol) in 2,4,6-colidine was heated to reflux under nitrogen for 5 h. The solvent was removed under vacuum and the residue taken up in a mixture of 10 ml of saline and 30 ml of ethyl acetate. The organic layer was separated, dried over MgSO 4 and evaporated. The resulting residue was purified by silica gel column chromatography with hexane:ethyl acetate 1:1 to give the title compound as white plates (0.03 mg, 31%) mp 197-198°C.

1 H-NMR (DMSO-de) 8 10.16 (s, 1H), 9.55 (s, 1H, 8.01 (s, 1H), 7.79-7.87 (m, 2H), 7 ,20

(s, 1H), 7.08 (d, 1H, J = 1.0 Hz), 1.65 (s, 6H).

MS (ESI) m/z 311 [M-H]".

EXAMPLE 130

6-(2,3-difluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one The compound was prepared according to procedure B from (1,4- dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and 2,3-difluorobenzyl triflate as a yellow solid with melting point 166-167°C.

1H-NMR (DMSO-de) δ 10.4 (s, 1H), 7.5-7.2 (m, 5H), 7.0 (m, 1H), 1.7 (s, 6H);

MS (EI) m/z 289 ([M+H]<4>);

Analysis for C16H13F2NO2:

EXAMPLE 131

3-(1-ethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-6-fluoro-benzonitrile

The compound was prepared according to Example 125 from 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile as a white solid with a melting point of 154-155°C.

1 H-NMR (DMSO-d6) δ 8.17 (s, 1H), 8.03 (d, 1H, J = 10.5 Hz), 7.84-7.77 (m, 3H), 7, 27 (d, 1H, J = 8.54 Hz), 3.97 (q, 2H, J = 6.89 Hz), 1.67 (s, 6H), 1.21 (t, 3H, J

= 6.95 Hz);

MS (EI) m/z 324 ([M+H]<+>);

Analysis for Ci9HnFN2O2:

EXAMPLE 132

[6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile

The compound was prepared according to procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and (6-bromo-2-pyridyl)acetonitrile ("J. Org. Chem.", 1988, 53, 786-790) as a whitish solid with a melting point of 210-212.5°C.

1H-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 = 7.1 Hz), 7.89-7.96 (m, 2H), 8.00-8.05 (m, 2H), 10.42 (s, 1H);

MS (ESI) m/z 292 [M-H]-;

Analysis for C17H15N3O2:

EXAMPLE 133

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxaziri-6-yl)-5-fluorophenyl-acetonitrile

To a solution of 3-bromo-5-fluorobenzaldehyde (22.25 g, 0.11 mol) in methanol was added NaBEU (2.07 g, 0.055 mol) at room temperature and stirred at room temperature for 2 hours. The reaction mixture 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 obtained as a colorless oil (14.6 g, 65%).

1H-NMR (DMSO-d 6 ) δ 4.50 (m, 2H), 5.44 (t, 3H, J = 5.93 Hz), 7.16 (dd, 1H, J = 1.09,

8.79 Hz), 7.36 (s, 1H), 7.38 (dd, 1H, J = 2.99, 6.15 Hz);

Analysis for CyHeB^FO:

To a solution of 3-bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 mol) in 15 mL of CH 2 Cl 2 was added 12.4 mL of 1.0 M PBr 3 (3.33 g, 0.0123 mol) in CH 2 Cl 2 , stirred for 3 h, diluted with 100 mL ether, washed with 3 x 50 mL H 2 O, dried over MgSO 4 and concentrated. Purification was carried out by column chromatography using 1:9 ethyl acetate:hexane as the elution solvent system. 3-Bromo-5-fluorobenzyl bromide was obtained as a white crystalline material with a melting point of 41-43°C.

1H-NMR (DMSO-d 6 ) δ 4.69 (s, 2H), 7.52 (d, 1H, J = 1.76 Hz), 7.54 (d, 1H, J = 1.91

Hz), 7.56 (s, 1H);

MS (EI) m/z 266 (M<+>);

Analysis for CvHsB^F:

To a solution of 3-bromo-5-fluorobenzyl bromide (3.2 g, 0.0112 mol) in 20 mL of 1,4-dioxane was added a solution of KCN (0.82 g, 0.013 mol) in 5 mL of H2O and 5 mL of EtOH and the whole was refluxed for 2 hours. After extraction with ether, the whole was washed with salt solution, dried over MgSCv and concentrated. Column chromatography was carried out using hexane:ethyl acetate 19:1. 3-bromo-5-fluorophenylacetonitrile was obtained as a colorless oil. 1 H-NMR (DMSO-de) δ 4.15 (s, 2H), 7.29 (d, 1H, J = 9.37 Hz), 7.47 (s, 1H), 7.55 (d,

1H, J = 8.45 Hz);

MS (EI) m/z 213 (M<4>);

Analysis for C8H5BrFN:

The title compound was prepared according to procedure B from 3-bromo-5-fluorophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid and a white solid was obtained which was recrystallized from ethanol ether, with a melting point of 218-220°C.

1H-NMR (DMSO-de) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98 (d, 1H, J = 8.92 Hz), 7.18 (d,

1H, J = 9.26), 7.52-7.62 (m, 3H), 10.37 (s, 1H);

MS (EI) m/z 309 (M-H)-;

Analysis for C in gH 15FN2O2:

EXAMPLE 134

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-fluorophenyl-acetonitrile

To a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mol) in 150 mL CCI 4 was added 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. The CCl 4 was removed under reduced pressure and the residue was dissolved dilute in ether, washed three times with brine, dried over MgSO 4 and concentrated. Chromatography with hexane gave 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below.

5-Bromo-2-fluorobenzyl bromide (8.0 g, 0.03 mol) was dissolved in 60 mL of 1,4-dioxane and added to a solution of KCN (2.04 g, 0.031 mol) in 20 mL of H2O and 20 ml of ethanol. The resulting mixture was heated under reflux for 5 hours. After cooling to room temperature, the product was extracted with 200 ml of ether, washed with brine, dried over MgSO 4 and concentrated. Crystallization took place from ethylene hexane and one obtained

5-Bromo-2-fluorophenylacetonitrile as a white crystalline material (5.6 g, 88%) mp 55-58°C.

1H-NMR (DMSO-de) δ 4.07 (s, 2H), 7.29 (t, 1H, = 9.23 Hz), 7.60-7.69 (m, 2H);

MS (EI) m/z 2132 (M4);

Analysis for C8H5Br2FN:

The title compound was prepared from 5-bromo-2-fluorophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid, mp 184- 187°C.

1H-NMR (DMSO-de) δ 1.67 (s, 6H), 4.11 (s, 2H), 6.98 (d, 1H, J = 8.92 Hz), 7.36 (t, 1H,

J = 9.13 Hz), 7.54 (d, 2H, J = 7.91 Hz), 7.67-7.75 (m, 2H), 10.37 (s, 1H); MS (EI) m/z 309 (M-H)-;

Analysis for C18H15FN2O2:

EXAMPLE 135

4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluorophenylacetonitrile

The compound was prepared according to procedure B from 4-bromo-2-fluorophenylacetonitrile (US 4,895,862) and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazine-6- yl)boric acid as a gray solid with a melting point of 253-256°C.

1H-NMR (DMSO-de) 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 (ESI) m/z 309 [M-H]";

Analysis for Ci8Hi5N2FO2 0.15H2O:

EXAMPLE 136

2-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)phenylacetonitrile The compound was prepared according to procedure B from 2-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid, m.p. 176-179°C.

1H-NMR (DMSO-de) 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/z 293 [M+H]<+>;

Analysis for C18H16N2O2:

EXAMPLE 137

N-[4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluorophenyl]-acetamide

The compound was prepared according to procedure B from 4'-bromo-2'-fluoroacetanilide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a whitish solid with a melting point of 245-247°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 9.79 (s, 1H), 7.95 (t, 1H, J = 8.4 Hz), 7.56-7, 63 (m,

3H), 7.47 (dd, 1H, J = 1.64, 8.47 Hz), 6.95 (d, 1H, J = 8.9 Hz), 2.1 (s,

3H), 1.67 (s, 6H);

MS (APCI) m/z 329 [M+H]<+>;

Analysis for C18H17N2FO3:

EXAMPLE 138

6-(3-fluoro-4-methoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one The compound was prepared according to procedure B from 4-bromo -2-fluoroanisole and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid with a melting point of 210-211°C.

1H-NMR (DMSO-de) δ 10.27 (s, 1H), 7.52-7.60 (m, 3H), 7.45 (d, 1H, J = 8.6 Hz), 7, 22

(t, 1H; J = 8.9 Hz), 6.94 (d, 1H, J = 8.8 Hz), 3.87 (s, 3H), 1.66 (s, 6H); MS m/z 300 [M-H]-;

Analysis for C17H16FNO3:

EXAMPLE 139

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)phenylacetonitrile The compound was prepared according to procedure B from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid with a melting point of 188-190°C.

1H-NMR (DMSO-de) δ 10.33 (s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H, J = 8.00

Hz), 7.33 (d, 1H, J = 7.57 Hz), 6.99 (d, 1H, J = 8.81 Hz), 4.09 (s, 2H),

1.67 (s, 6H);

MS m/z 291 (M-H);

Analysis for Ci8Hi6N2O2-2.0.3H2O:

EXAMPLE 140

3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzenesulfonamide The compound was prepared according to procedure B from 3-bromobenzenesulfonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid, m.p. 242-244T (decomp.).

1H-NMR (DMSO-de) δ 10.28 (s, broad 1H), 8.07 (s, 1H), 7.9 (d, 1H, J = 7.80 Hz), 7.78

(d, 1H, J = 7.86 Hz), 7.64 (t, 1H, J = 7.79 Hz), 7.59 (m, 2H), 7.42 (s, wide

2H), 7.02 (d, 1H, J = 8.86 Hz), 1.68 (s, 6H);

MS m/z 331 (M+H);

Analysis for Ci6Hi6N204S:

EXAMPLE 141

5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-sulfonamide

The compound was prepared according to procedure B from 5-bromothiophene-2-sulfonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as a white solid with melting point 258-260°C.

1H-NMR (DMSO-d 6 ) δ 10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (d, 1H, J = 3.9

Hz), 7.48 (d, 1H, J = 8.16 Hz), 6.95 (d, 1H, J = 8.16), 1.66 (s, 6H); MS m/z 337 (M-H);

Analysis for C14H14N2O4 S:

EXAMPLE 142

6-(6-aminopyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one The compound was prepared according to procedure B from 2-amino -5-bromopyridine and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boric acid as white crystals with melting point 257-259°C.

1H-NMR (DMSO-d6) δ 10.20 (s, 1H), 8.22 (d, 1H, J = 2.38 Hz), 77.69, 7.66 (dd, 1H, J =

2.5, 2.5 Hz), 7.42 (m, 2H), 6.89 (d, 1H, J = 8.8 Hz), 6.49 (d, 1H, J = 8.64

Hz), 6.02 (s, 2H), 1.64 (s, 6H);

MS m/z 269 (M<4>);

Analysis for Ci5H15N3O2-1,7H2O:

EXAMPLE 143

6-(5-diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d][l,3]oxazin-2-one The compound was prepared according to procedure B from 4 ,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-boronic acid and 3-bromo-5-diethoxymethylfuran as a brown gum.

1H-NMR (DMSO-d 6 ) δ 10.2 (s, 1H), 8.12 (s, 1H), 7.54-7.49 (m, 2H), 6.93-6.88 (m ,

2H), 5.56 (s, 1H), 3.60-3.38 (m, 4H), 1.67 (s, 6H), 1.2-1.14 (m, 6H); MS (ESI) m/z 344 [M-H]';

Analysis for C19H23NO3 V2H2O:

EXAMPLE 144

4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde

A solution of 6-(5-diethoxymethyl-furan-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d]-[1,3]oxazin-2-one (1.1 g, 3 mmol) was stirred in 20 ml THF and 2 ml 2N HCl for 1 hour. The crystalline product was filtered and dried (0.52 g, 69%) and had a melting point of 262-263°C.

1H-NMR (DMSO-de) δ 10.3 (s, 1H), 9.65 (s, 1H), 8.59 (s, 1H), 8.04 (s, 1H), 7.65- 7.64

(d, 1H, J = 1.5 Hz), 7.61-7.60 (d, 1H, J = 1.8 Hz), 7.59-7.58 (d, 1H, J =

1.8 Hz), 6.94-6.91 (d, 1H, J = 8.2 Hz), 1.65 (s, 6H);

MS (ESI) m/z 270 [M-H]".

EXAMPLE 145

4-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)-2-furancarboxaldehyde oxime

A mixture of 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) were heated to reflux in 25 mL of 80% ethanol for 2 hours. The title compound crystallized from the cooled reaction mixture as golden crystals (1.5 g, 52.4%) mp 236-238°C.

1H-NMR (DMSO-de) δ 11.97 (s, 1H), 10.26 (s, 1H), 8.2 (s, 1H), 7.63 (s, 1H), 7.56- 7.52

(m, 3H), 6.91-6.88 (d, 1H, J = 8.1 Hz), 1.66 (s, 6H): MS (ESI) m/z 285 [M-H]";

Analysis for C15H14N2O4:

Claims (24)

1. Compound, characterized by the formula: there: R<1> and R<2> independently are substituents selected from the group H, optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, aryl and a heterocyclic group; or R and R are fused to form: a carbon-based 3- to 8-membered saturated spirocyclic ring; R<3> is H, optionally substituted C1-6 alkyl or COR<c>; R<c> is substituted aryl or substituted C 1-6 alkoxy; R<4> is H, halogen, OH, C1-6 alkyl or C1-6 alkoxy; R<5> is selected from the group comprising (i) and (ii): (i) a substituted benzene ring containing the substituents X, Y and Z as shown below: where: X is selected from the group comprising halogen, CN, OH, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 perfluoroalkyl, NO 2 , C 1-3 perfluoroalkyl, a 5- or 6-membered heterocyclic ring containing 1 to 3 heteroatoms, COR<D>, SO 2 NH 2 or NR<E>COR<D>; RD is H, C 1-3 alkyl, aryl and C 1-3 alkoxy; R<E>erH; Y and Z are independently substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1-4 alkoxy, C 1-3 alkyl and C 1-3 perfluoroalkyl; or (ii) a 5- or 6-membered ring with 1, 2 or 3 heteroatoms selected from the group O, S, SO, SO2 and NR<6> and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, amino, optionally substituted CMalkyl, SO2NH2 and COR<F>; provided that when R<5> is the 5-membered ring with two NR<6> heteroatoms, R<1> and R<2> are not both H; and provided that when R<5> is a 5-membered ring with one NR<6->heteroatom and where R<5> is attached in the 2-position of the ring, there is no CN substituent in the 5-position of the ring; R is H; R<6> is absent, H, C 1 -C 1 alkyl, O or C(O)C 1 -C 6 -alkyloxy, provided that when R<5> the benzene ring (i) is substituted with one or two substituents or the 5- or 6-membered ring, (ii) with 1, 2 or 3 heteroatoms in the ring selected from O, S and NR<6>, and R<1> is alkenyl or alkynyl, R<2> is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl; or if R is alkenyl, or alkynyl, R is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl; with the proviso that when R<5> the benzene ring (i) is substituted with one or two substituents or the 5- or 6-membered ring (ii) with 1, 2 or 3 heteroatoms in the ring selected from the group consisting of O, S and NR<6>, and R<1> is alkenyl, R<2> is not cycloalkyl, or if R2 is optionally substituted alkyl, R<1> is not cycloalkyl; where: said aryl group is phenyl; said heterocyclic group is selected from the group consisting of thienyl, thiophene, pyrrole, thiazole, furyl, pyridinyl, thiadiazole, tetrazole, pyrazinyl and pyrimidinyl; said substituted alkyl and substituted alkynyl groups have one to three substituents selected from the group consisting of halogen, CN, OH, C1-6 alkoxy, silyl and phenyl; said substituted aryl has one to four substituents selected from the group consisting of C 1-6 alkoxy and C 1-6 alkylamino; or a pharmaceutically acceptable salt thereof. 2. Compound, characterized by the formula: there R<1> and R<2> are independent substituents selected from H, optionally substituted C1-6 alkyl, C2-6 alkenyl, optionally substituted C2-6 alkynyl, C3-8 cycloalkyl, aryl and a heterocyclic group; or R 1 and R are fused to form a carbon-based 3- to 8-membered saturated spirocyclic ring; R<3> is H, optionally substituted C in .6alkyl or COR<c>; R<c> is substituted aryl or C 1-6 alkoxy; R<4> is H, halogen, C1-6 alkyl or C1-6 alkoxy; R<5> is (i) or (ii): (i) a substituted benzene ring containing the substituents X, Y and Z as shown below: there X is selected from the group consisting of halogen, CN, optionally substituted C1-3alkyl, C1-3alkyl, NO2, C1-3perfluoroalkyl, a 5-membered heterocyclic ring in the ring containing 1 to 3 heteroatoms, CORD and NR<E>COR<D> ; RD is H, C 1-3 alkyl, aryl or C 1-3 alkoxy; R<E>erH; Y and Z are independently substituents selected from the group consisting of H, halogen, CN, NO 2 , decyloxy and C 1-6 alkyl; or (ii) a 5- or 6-membered ring with 1,2 or 3 heteroatoms in the ring selected from the group consisting of O, S, SO, SO2 and NR<6> and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , amino and C 1-3 alkyl; provided that when R<5> is the 5-membered ring with two NR<6> heteroatoms, R<1> and R<2> are not both H; and provided that when R<5> is a 5-membered ring with one NR<6->heteroatom and where R5 is attached in the 2-position of the ring, there is no CN substituent in the 5-position of the ring; R<6> is either C 1-3 alkyl; provided that when R<5> the benzene ring is (i) substituted with one or two substituents or the 5- or 6-membered ring, (ii) with 1,2 or 3 heteroatoms in the ring selected from O, S and NR<6> , and R<1> is alkenyl or alkynyl, R<2> is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl; or if R is alkenyl, or alkynyl, R is not optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl; or with the proviso that when R<5> the benzene ring (i) is substituted with one or two substituents or the 5- or 6-membered ring (ii) with 1,2 or 3 heteroatoms in the ring selected from the group consisting of O, S and NR<6>, and R<1> is optionally substituted alkyl, R<2> is not cycloalkyl, or if R<2> is optionally substituted alkyl, R<1> is not cycloalkyl; where: said aryl group is phenyl; said heterocyclic group is selected from the group consisting of thienyl, thiophene, pyrrole, thiazole, furyl, pyridinyl, pyrazinyl, pyrimidinyl, thiadiazole and tetrazole; said substituted alkyl and substituted alkynyl groups have one to three substituents selected from the group consisting of halogen, CN, OH, C 1-6 alkoxy, silyl and phenyl; said substituted aryl has one to four substituents selected from the group consisting of C 1-6 alkoxy and C 1-6 alkylamino; a pharmaceutically acceptable salt thereof. 3. Compound, characterized by the formula: there R 1 = R and selected from the group consisting of optionally substituted Cualkyl, or R 1 and R 0 are fused to form a carbon-based 3- to 6-membered spirocyclic ring; R 3 is H, optionally substituted C 1-6 alkyl or COR<c>; R<c>is t-4 alkoxy; R<4> is H, halogen, C 1-6 alkyl or C 1-6 alkoxy; R<5> is selected from the group consisting of a), b) and c): a) a substituted benzene ring with the formula shown below: there X is halogen CN, C 1-3 alkoxy, C 1-3 alkyl, NO 2 , C 1-3 perfluoroalkyl or a 5-membered heterocyclic ring in the ring containing 1 to 3 heteroatoms; Y is H, halogen, CN, NO 2 , C 1-4 alkoxy or C 1-4 alkyl; b) 5-membered ring with the structure: where: U is O, Seller NR<6>; X' is selected from halogen, CN, NO 2 and C 1-3 alkyl; Y' is selected from the group consisting of H and C 1-6 alkyl; and c) a 6-membered ring with the structure: where:X<1> is N or CX<2>; X 2 is halogen, CN or NO 2 ; R<6> is H, C1-3 alkyl or C1-4-CO2 alkyl; where: said substituted alkyl, has one to three substituents selected from the group consisting of halogen, CN, OH, C1-6 alkoxy, silyl and phenyl; said substituted aryl has one to four substituents selected from the group consisting of C 1-6 alkoxy and C 1-6 alkylamino; said aryl group is phenyl; said heterocyclic group is selected from the group consisting of thienyl, thiophene, pyrrole, thiazole, furyl, pyridinyl, pyrazinyl, pyrimidinyl, thiadiazole and tetrazole; or a pharmaceutically acceptable salt thereof. 4. Compound, characterized by the formula: where 19 19 R = R and selected from the group consisting of optionally substituted C 1-6 alkyl, or R and R are fused to form a carbon-based 3- to 6-membered saturated spirocyclic ring; R<3> is H, optionally substituted C1-6 alkyl or COR<c>; C 1-6 alkoxy; R<4> is H, halogen or C1-6 alkoxy; R<5> is a 6-membered ring with the structure: where X 1 is N; or a pharmaceutically acceptable salt thereof. 5. Compound according to any one of claims 1 to 2, characterized in that R<1> is H, optionally substituted C1-6 alkyl, C3-8 cycloalkyl, aryl or a heterocyclic group; R<c> is H, optionally substituted C 1-6 alkyl or aryl; R<4> is H, halogen, C1-6 alkyl or C1-6 alkoxy; R<5> is a) or b): a) the substituted benzene ring, where: X is selected from the group comprising halogen, CN, optionally substituted C 1-3 alkyl, C 1-3 alkoxy, NO 2 , Cuperfluoroalkyl, 5-membered heterocyclic ring as in the ring contains 1 to 3 heteroatoms, CORD and NRECORD; Y and Z independently are substituents selected from H, halogen, CN, NO 2 , C 1-4 alkoxy, C 1-4 alkyl; or b) the 5- or 6-membered ring, where said one or two independent substituents are selected from the group H, halogen, CN, NO 2 , amino and C 1-6 alkyl. 6. Compound according to any one of claims 1 to 3, characterized in that 19 1 R = R and is selected from the group consisting of optionally substituted C 1-4 alkyl or R and R<2> are fused to form the carbon-based 3- to 6-membered saturated spirocyclic rings; R<3> is H, optionally substituted C1-6 alkyl or COR<c>; R<c>erC 1-3 alkoxy; R<4 > is H, halogen, C 1-6 alkyl or C 1-6 alkoxy; R<5> is selected from the group consisting of a), b) and c): a) the substituted benzene ring with the formula: where: X is halogen, CN, C1-3 alkoxy, C1-3 alkyl, NO2, C1-3 perfluoroalkyl or a 5-membered heterocyclic ring containing 1 to 3 heteroatoms in the ring; and Y is H, halogen, CN, NO 2 , C 1-3 alkoxy and C 1-3 alkyl; b) the 5-membered ring with the structure: where: U is O, Seller NR<6>; X' is selected from the group consisting of halogen, CN, NO 2 and C 1-3 alkyl; Y' is selected from the group consisting of H and Cualkyl; or R<6> is either C 1-3 alkyl; c) the 6-membered ring with the structure: where: X<1> is CX<2>; X<2> is halogen, CN or NO 2 ; or a pharmaceutically acceptable salt thereof. 7. Compound according to any one of claims 1 to 3, characterized in that R<1> = R<2> and is CH3 or R<1> and R<2> are fused to form the carbon-based 6-membered saturated spirocyclic ring; R<3> is H, optionally substituted Qalkyl or COR<c>; R is C 1-6 alkoxy; R<4 > is H, halogen or C 1-6 alkyl; R<5> is the substituted benzene ring with the formula: there: X is selected from the group halogen, CN, C 1 alkoxy, NO 2 or the 5-membered heterocyclic ring where the heterocyclic ring is 2-thiazole; and Y is H or halogen. 8. Compound according to any one of claims 1 to 3, characterized in that R<1> = R<2> and is CH3 or R<1> and R2 are fused to form the carbon-based 6-membered saturated spirocyclic ring; R<3> is H, optionally substituted C 1 alkyl or COR<c>; R c is C 1-3 alkoxy; R<4> is H, halogen or Cualkyl; R<5> is the 5-membered ring with the structure: there: U is O,S or NH, X' is halogen, CN or NO 2 , provided that when U is NH, X' is not CN; Y' is H or C 1-3 alkyl; or a pharmaceutically acceptable salt thereof. 9. Compound according to any one of claims 1 to 3 and 7 to 8, characterized in that R<5> is selected from the group consisting of: 10. Compound, characterized in that it is selected from the group consisting of 6-(3-chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-Methoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one; 6-(2-chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(4-chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one; 6-(3-Chlorophenyl)-4-ethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-chlorophenyl)-4-phenyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile; 4,4-dimethyl-6-(3-nitrophenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile; 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [1,3]oxazin-6-yl)-nicotinnitrile; 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-carbonitrile; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-methyl-thiophen-2- carbonitrile; 4-(4,4-Dimethyl-2-oxo-1,4-dimethyl-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile; 4,4-diethyl-6-(3-nitrophenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; or 6-(3-chlorophenyl)-4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-chlorophenyl)-spiro[4H,3,1-benzoxazin-4,1'-cyclohexan-2(1H)-one; 6-(3-chlorophenyl)-spiro[4H-3,1-benzoxazin-4,1'-cyclohexane]-2(1H)-one; 6-(3-nitrophenyl)-spiro[4H-3,1-benzoxazin-4,1'-cyclohexane]-2(1H)-one; 4-allyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-chlorophenyl)-4-methyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4-benzyl-6-(3-chlorophenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-chlorophenyl)-4-cyclopropyl-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-chlorophenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-bromo-5-fluorophenyl)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-acetylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-benzoylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4,4-dimethyl-6-[3-(1H-tetrazol-5-yl)-phenyl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophen-2- carbonitrile; 6-(3-bromo-5-fluorophenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(4,4-dicyclopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro- benzonitrile; 6-(3-bromo-5-methylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-bromo-5-trifluoromethoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methylbenzonitrile; 3 -(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo [d] [ 1,3 ]oxazin-6-yl)-5 -trifluoromethoxy- benzonitrile; 6-(3,5-difluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][ 1,3]oxazin-2-one; 6-(3,5-dichlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3,5-bis-trifluoromethylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxy- benzonitrile; 6-(3-fluorophenyl)-4,4-dimethyl-1,4-benzo[d][1,3]oxazin-2-one; 6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [1,3]oxazin-6-yl)-5- fluorobenzonitrile; 3-Fluoro-5-(1-methoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6- yl)-benzonitrile; phosphoric acid 6-(3-cyano-5-fluorophenyl)-4,4-dimethyl-4H-benzo[d][1,3]oxazin-2-yl-ester diethyl ether; 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-fluoro-benzonitrile; 6-(3-chloro-4-fluorophenyl)-8-fluoro-4,4-dimethyl-1,4-dihydro-benzo[d][ 1,3]oxazin-2-one; 6-(3-bromophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4,4-dimethyl-6-(3-trimethylsilanylethynyl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-ethynylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-[3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [ 1,3]oxazin-6-yl)-phenyl]propyn- nitrile; 6-(3-fluoro-5-nitrophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one; 6-(3-chloro-5-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-chloro-5-(4,4-dimethyl-2-oxo-1,4-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile; 6-(3,5-dinitrophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-isophthalonitrile; 4,4-dimethyl-6-(3-thiazol-2-yl-phenyl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-fluoro-5-methoxyphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-fluoro-5-trifluoromethylphenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(5-bromopyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one; 6-(5-bromo-1-oxy-pyridin-3-yl)-4,4-dimethyl-1,4-dihydro-benzo[d] [1,3]oxazin-2-one; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazm-6-yl)-2-fluoro-benzonitrile; 4-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophen-2- carbonitrile; 3-fluoro-5-(8-fluoro-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [ 1,3]oxazin-6-yl)- benzonitrile; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile; 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-3-carbonitrile; 6-(1,2,4-thiadiazol-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3-fluoro-5-thiophen-3-yl-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4,4-dimethyl-6-(5-nitro-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4,4-dimethyl-6-(1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4,4-dimethyl-6-(1-methyl-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 4,4-dimethyl-6-(1-methyl-5-nitro-1H-pyrrol-2-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(1,2-dihydro-2-oxospiro[4H,3,1-benzoxazin-4,1-cyclohexane]-6-yl)-benzonitrile; 3-(1,2-dihydro-2-oxospiro[4H,3,1-benzoxazin-4,1-cyclohexane]-6-yl)-5-fluoro-benzonitrile; 4-(1,2-dihydro-2-oxospiro[4H,3,1-benzoxazin-4,1-cyclohexane]-6-yl)-2-thiophenecarbonitrile; 5-(1,2-dihydro-2-oxospiro[4H,3,1-benzoxazin-4,1-cyclohexane]-6-yl)-2-thiophene- carbonitrile; 5-(1,2-dihydro-2-oxospiro[4H,3,1-benzoxazin-4,1-cyclohexane]-6-yl)-4-methyl-2- thiophene carbonitrile; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-ethylthiophen-2- carbonitrile; 5-(4,4-dimethyl-2-oxo-1,4-hydrocarbonitrile; 6-(4-cyano-3-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 6-(3,4-difluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one; 6-(2-fluorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)phenylacetonitrile; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile; 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbonitrile; 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile; 6-(3-cyano-5-fluorophenyl)-4,4-dimethyl-2-oxo-4H-benzo[d] [ 1,3]oxazin-1 - carboxylic acid.tert-butyl ester; 6-(2,3-difluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 3-( 1 -ethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [ 1,3]oxazin-6-yl)5-fluoro- benzonitrile, [6-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile, 3-(4,4-dimethyl-2 -oxo-1,4-dihydro-2H-[d][1,3]oxazin-6-yl)-5-fluoro-phenylacetonitrile, 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-4-fluoro-phenylacetonitrile, 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [ 1,3]oxazin-6-yl)-2-fluoro-phenylacetonitrile, 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-phenylacetonitrile, N-[4-(4,4-dimethyl -2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2-fluoro-phenyl]- acetamide, 6-(3-Fluoro-4-methoxy-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(6-amino-pyridin- 3 -yl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(5-diethoxymethyl-furan-3-yl)-4,4- dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde, 4,4-dimethyl-6 -(3-trimethylsilanylethynyl-phenyl)1,4-dihydro-benzo[d][1,3]oxazin-2-one, 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d] [ 1,3]oxazin-6-yl)benzenesulfonamide, 5-(4,4-dimethyl-2-oxo -1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-thiophene-2-sulfonamide and 4-(1,4-dihydro-4,4-dimethyl-2-oxo-2H-benzo-3,1-benzoxazin-6-yl)-2- furancarboxaldehyde oxime, or a pharmaceutically acceptable salt thereof. 11. Compound according to claim 3, characterized in that it is selected from the group consisting of 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl )-pyrrole-1-carboxylic acid tert-butyl ester, 2-(4,4-dimethoxy-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-nitro-pyrrole-1-carboxylic acid tert-butyl ester, 5 -(4,4-dimethyl-2-oxo-1,4-2H-benzo[d] [ 1,3]oxazin-6-yl)-4-n-butylthiophene-2-carbonitrile or a pharmaceutically acceptable salt thereof. 12. Compound according to any one of claims 1 to 3, characterized in that R<5> is selected from the group consisting of 3-chloro-4-fluorophenyl, 3,5-dichlorophenyl, 3-cyano-4-fluorophenyl, 3,4 -difluorophenyl, 3-cyano-5-chlorophenyl, 3-trifluoromethyl-5-fluorophenyl, 2-fluoro-3-cyanophenyl, 2-fluorophenyl, 3.4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-bromo-4-fluorophenyl, 3-chloro-4-bromophenyl and 3.5-dibromophenyl. 13. Compound according to any one of claims 1 to 3, characterized in that R<5> is 4-cyano-3-furanyl. 14. Pharmaceutical preparation, characterized in that it comprises a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or emollient. 15. A compound according to any one of claims 1 to 13 or a salt thereof for use as a medicament for administration to a mammal. 16. Use of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for administration to a mammal, wherein an effective amount induces contraception. 17. Use of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for administration to a mammal, wherein the compound treats hormone-dependent neoplastic diseases in the mammal. 18. Use according to claim 17 for the treatment of hormone-dependent neoplastic diseases selected from the group uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary and meningioma. 19. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for administration to a mammal, wherein the compound synchronizes oestrus in the mammal. 20. Use of a compound selected from the group 6-(3-Chlorophenyl)-4-methyl-4-propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-Chlorophenyl)-4 -ethynyl-4-methyl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-cyclopropyl-4-propyn-1 -yl-1, 4-dihydro-benzo[d] [ 1,3]oxazin-2-one, and 6-(3-Chlorophenyl)-4,4-dipropyn-1 -yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one or a pharmaceutically acceptable salt, for the manufacture of a medicament for administration to a mammal, wherein an effective amount of said compound induces contraception. 21. Use of a compound selected from the group of 6-(3-chlorophenyl)-4-methyl-4-propyn-1-yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-cyclopropyl-4 -propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, and 6-(3-Chlorophenyl)-4,4-dipropyn-1 -yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one or a pharmaceutically acceptable salt, for the manufacture of a medicament for administration to a mammal, wherein the compound treats hormone-dependent neoplastic diseases in the mammal. 22. Use according to claim 21, for the treatment of hormone-dependent neoplastic diseases selected from the group uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary and meningioma. 23. Use of a compound selected from the group consisting of 6-(3-chlorophenyl)-4-methyl-4-propyn-1-yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-ethynyl-4-methyl-1,4-dihydro-benzo [d] [ 1,3]oxazin-2-one, 6-(3-chlorophenyl)-4-cyclopropyl-4 -propyn-1-yl-1,4-dihydro-benzo[d][1,3]oxazin-2-one, and 6-(3-chlorophenyl)-4,4-dipropyn-1 -yl-1,4-dihydro-benzo[d] [ 1,3]oxazin-2-one or a pharmaceutically acceptable salt for the preparation of a medicament for administration to a mammal, wherein the compound synchronizes estrus in the mammal. 24. Use of a compound according to any one of claims 1 to 13, or said acceptable salt, in the manufacture of a medicament for administration to a mammal in hormone replacement therapy.