CYCLIC UREA AND CYCLIC AMIDE DERIVATIVES

Abstract: This invention provides compounds of formula (I) wherein: A, B and D are N or CH, with the proviso that A, B and D can not all be CH; R<1> and R<2> are independent substituents selected from H, COR<A>, NR<B>COR<A>, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or groups; or R<1> and R<2> are fused to form an optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring; R<A> is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R<B> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R<3> is H, OH, NH2, or optionally substituted alkyl, or alkenyl, or COR<C>; R<c> is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R<4> is a substituted benzene ring or a five or six membered ring with 1, 2 or 3 heteroatoms from the group including O, S, SO, SO2 or NR<5>; R<F> is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R<G> is H, alkyl, or substituted alkyl; R<5> is H or alkyl; Q is O, S, NR<6>, or CR<7>R<8>; R<6> is CN, SO2CF3, or optionally substituted alkyl, cycloalkyl, aryl, or heterocyclic ring; R<7> and R<8> are H, NO2, CN CO2R<9>, or optionally substituted alkyl, cycloalkyl, aryl, or heterocyclic; R<9> is C1 to C3 alkyl; or CR<7>R<8> form a six membered ring of structure (a): W is O or a chemical bond; or a pharmaceutically acceptable salt thereof, as well as their use and pharmaceutical compositions as agonists and antagonists of the progesterone receptor.

Description: CYCLIC UREA AND CYCLIC AMIDE DERIVATIVES Field of the Invention This invention relates to compounds which are agonists and antagonists of the progesterone receptor, their preparation and utility Background of the Invention Intracellular receptors (IR) form a class of structurally related gene regulators known as "hgand dependent transcription factors" (R M Evans, Science, 240, 889, 1988) The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) The natural hormone, or hgand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which 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 to create a receptor/kgand complex This complex binds to specific gene promoters present in the cell's DNA Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist PR agonists (natural and synthetic) are known to play an important role in the health of women PR agonists are used in birth control formulations, typically in the presence of an ER agonist ER agonists are used to treat the symptoms of menopause. but have been associated with a prohferative effect on the uterus that can lead to an increased risk of uterine cancers Co-administration of a PR agonist reduces or ablates PR antagonists may also be used in contraception In this context they may be administered alone (Ulmann. et al, Ann N Y Acad Sci . 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. July 4. 1996) PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm Cancer. 283, pub Birkhaeuser, Boston, Mass , ed Vedeckis) as well as uterine and ovarian cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy . et al, J Clin Endo Metab , 76. 513, 1993) and endometπosis (Kettel. et al. Fertility and Sterility, 56, 402, 1991) PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136) PR antagonists, such as mifepnstone and onapnstone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann N Y Acad Sci , 761, 224, 1995) The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists and/or antagonists in functional models, either/or in-vitro and in-vivo These compounds may be used for contraception, in the treatment of fibroids, endometπosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy Jones, et al (U S Patent No 5.688.810) describe the PR antagonist dihydroquinohne 1 1 Jones, et al. described the enol ether 2 (U.S Patent No 5,693,646) as a PR ligand Jones, et al, described compound 3 (U.S Patent No 5.696,127) as a PR ligand Zhi, et al, descπbed lactones 4, 5 and 6 as PR antagonists (J Med Chem . 41. 291. 1998) Zhi. et al, descπbed the ether 7 as a PR antagonist (J Med Chem , 41, 291. 1998) 7 Combs, et al . disclosed the amide 8 as a ligand for the PR (J Med Chem . 38, 4880. 1995) Perlman, et al , described the vitamin D analog 9 as a PR hgand (Tet Letters. 35. 2295. 1994) Hamann, et al, described the PR antagonist 10 {Ann N Y Acad Sci , 761, 383, 1995) 10 Chen, et al, descπbed the PR antagonist 11 (Chen, et al, POI-37, 16 th Int Cong Het Chem , Montana. 1997) 11 Kuπhari. et al . described the PR ligand 12 (J Antibiotics. 50, 360, 1997) 12 The patent by Christ et al (WO 9814436) claims cyclo amide such as compound A as inhibitors of HIV reverse transcriptase Other prior art includes pyπdazme cyclo amide such as compound B by Turck et al {Tetrahedron. 49(3). 599- 606 (1993) ) and compound such as C by Canonne et al (J heterocyclic Chem 26, 1 13(1989) ) No activity data were reported in Turck ' s and Canonne' publications B Regarding cyclic amides, Singh et al and Kumar et al (Singh et al J Med Chem 37(2), 248-254(1994), Kumar et al J Org Chem 57(25), 6995-6998(1992) ) disclose compounds such as D and E claimed as cAMP PDE III inhibitors Description of the invention This invention provides compounds of Formula I wherein A. B and D are N or CH. with the proviso that A, B and D can not all be CH. R 1 and R 2 are independent substituents selected from H, Ci to C 6 alkyl substituted Ci to C 6 alkyl. C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl. C to C 6 alkynyl. substituted C 2 to C alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A . or R 1 and R 2 are fused to form a spirocychc ring selected from a), b) or c), each spirocychc πng optionally substituted by from 1 to 3 Cι-C 3 alkyl groups a) a 3 to 8 membered spirocychc alkyl πng, b) a 3 to 8 membered spirocychc alkenyl πng, or c) an optionally substituted 3 to 8 membered heterocychc πng containing one to three heteroatoms from the group including O. S and N. the spirocychc rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine. Ci to C 6 alkyl. Ci to Cβ alkoxy . Ci to Cβ thioalkyl. -CF . -OH. - CN. NH 2 . -NH(Cι to C 6 alkyl), or -N(C, to C 6 alkyl) 2 . R A is H. Ci to C 3 alkyl. substituted Ci to G alkyl. aryl, substituted aryl. Ci to C 3 alkoxy . substituted Ci to C^ alkoxy. Ci to C^ aminoalkvl. or substituted Ci to Ci aminoalkyl. R B is H. Ci to C 3 alkyl. or substituted C, to C, alkyl. R 3 is H. OH. NH 2 . Ci to C 6 alkyl. substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl. substituted Ci to C 6 alkenyl. or COR c , R c is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl. Ci to C 3 alkoxy. substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl, or substituted Ci to C aminoalkyl, R 4 is a tπsubstituted benzene πng containing the substituents X, Y and Z as shown below X is taken from the group including halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl. Ci to C 3 alkoxy, substituted Cj to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, amino, Ci to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D , R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl, or substituted Ci to C 3 aminoalkyl, R E is H, Ci to C 3 alkyl, or substituted C] to C 3 alkyl, Y and Z are independent substituents taken from the group including H halogen. CN. NO 2 , Cj to C alkoxy, Ci to C^ alkyl, or Ci to C 3 thioalkoxy , or R 4 is a five or six membered πng with 1, 2, or 3 heteroatoms from the group including O, S, SO. SO 2 or NR 5 and containing one or two independent substituents from the group including H, halogen, CN. N0 2 and Cj to C 3 alkyl. Ci to C 3 alkoxy, Ci to C 3 aminoalkyl COR F , or NR G COR F . R F is H, Ci to C 3 alkyl substituted Ci to C 3 alkyl, aryl substituted aryl Ci to C 3 alkoxy . substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl. or substituted Q to C 3 aminoalkvl R G is H, Ci to C 3 alkyl or substituted d to C, alkyl R 5 is H or Ci to C 3 alkyl, e is from the group including CN, Ci to C 6 alkyl. substituted Ci to C 6 alkyl C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc. substituted heterocyclic, or SO 2 CF 3 , R 7 and R 8 are independent substituents from the group including H. Ci to C 6 alkyl. substituted Ci to C 6 alkyl, C-* to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl. aryl substituted aryl, heterocyclic, substituted heterocyc c, NO 2 , CN, or CO 2 R 9 , R 9 is C, to C 3 alkyl. or CR 7 R 8 form a six membered ring of the structure below W is O or a chemical bond When W is a chemical bond, it is understood that Formula I exists as Preferred compounds are those of Formula I I wherein A. B and D are N or CH. with the proviso that A, B and D can not all be CH. R 1 is H, Ci to C 6 alkyl, substituted Cj to C 6 alkyl. C 3 to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR A , or NR B COR A , R 2 is H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl. substituted C 2 to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl. substituted aryl, heterocychc, substituted heterocychc, COR A or NR B COR A , or R 1 and R 2 are fused to form the optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocychc rings described above, R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl Ci to C 3 alkoxy. substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl or substituted Ci to C, aminoalkyl R B is H, Ci to C 3 alkyl, or substituted C, to C 3 alkyl, R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted C, to C 6 alkyl. C to C 6 alkenyl substituted C λ to C 6 alkenyl, or COR c , R c is H. C] to C 4 alkyl, substituted Ci to C 4 alkyl aryl substituted aryl. Ci to C 4 alkoxy. substituted Ci to C 4 alkoxy, Ci to C aminoalky l or substituted Ci to C 4 aminoalkyl R 4 is a tπsubstituted benzene ring containing the substituents X. Y and Z as shown below X is selected from halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, Ci to C 3 aminoalkyl, substituted Ci to C 3 aminoalkyl, N0 2 . Ci to C3 perfluoroalkyl, a 5 membered heterocyclic ring containing 1 to 3 heteroatoms. COR D . OCOR D . or NR E COR D , R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl Ci to C 3 alkoxy, substituted Ci to C alkoxy, Ci to C 3 aminoalkyl or substituted Ci to C 3 aminoalkyl, R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl. Y and Z are independent substituents selected from H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy; or R 5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO. SO 2 or NR 5 and containing one or two independent substituents from the group including H. halogen, CN, NO 2 and Ci to C ? alkyl, or Ci to C 3 alkoxy, R 5 is H or Ci to C 3 alkyl Re is selected from CN. Ci to C 6 alkyl. substituted Ci to C 6 alkyl. C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl. aryl substituted aryl. heterocyclic. substituted heterocyclic. or S0 2 CF 3 . R 7 and R 8 are independent substituents selected from H, Ci to C 6 alk l substituted Ci to C 6 alkyl C 3 to C 8 cycloalkyl substituted C 3 to C 8 cycloalkyl. aryl substituted aryl. heterocyclic. substituted heterocyc c. N0 2 . or CN CO 2 R 9 . R 9 is Ci to C, alkyl. or CR 7 R 8 form a six membered πng of the structure below W is O or a chemical bond, or a pharmaceutically acceptable salt thereof Still, more preferred compounds are those of Formula I I wherein. A, B and D are N or CH, with the proviso that A, B and D cannot all be CH, R 1 = R 2 and are selected from the group of Ci to C 3 alkyl, substituted Ci to C 3 alkyl. or spirocychc alkyl constructed by fusing R 1 and R 2 to form a 3 to 6 membered spirocychc πng, R 3 is H. OH, NH 2 , Ci to C 6 alkyl. substituted Ci to C 6 alkyl. or COR c . R c is H, Ci to C 4 alkyl, or Ci to C alkoxy, R 4 is a disubstituted benzene ring containing the substituents X, and Y as shown below X is selected from the group of halogen, CN, Ci to C3 alkoxy, Ci to C 3 alkyl, NO 2 . Ci to C 3 perfluoroalkyl 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or Ci to C3 thioalkoxy. Y is a substituent on the 4' or 5'posιtιon from the group including H. halogen. CN. N0 2 , Ci to C 3 alkoxy. C λ to C 4 alkyl. or Ci to C 3 thioalkoxy, or R 4 is a five membered ring with the structure R 5 is H, or Ci to C 3 alkyl, or Ci to C 4 CO 2 alkyl, X ' is selected from halogen, CN, N0 2 , Ci to C 3 alkyl, or Ci to C3 alkoxy, Y' is selected from H and Ci to C 4 alkyl; or R 4 is a six membered ring with the structure X 2 is halogen, CN or N0 2 . Rg is selected from CN. Ci to C 6 alkyl. substituted C] to C 6 alkyl. d to C s cycloalkyl substituted C 3 to C 8 cycloalkyl aryl, substituted aryl heterocychc. substituted heterocvchc. or S0 CF 3 . R 7 and R 8 are independent substituents selected from H, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C to C 8 cycloalkyl, substituted to C 8 cycloalkyl. aryl, substituted aryl, heterocychc, substituted heterocyclic, NO 2 , CN, or CO 2 R 9 , R 9 is Ci to C 3 alkyl, or CR 7 R 8 form a six membered ring of the structure below or a pharmaceutically acceptable salt thereof Further preferred compounds include those of Formula I I wherein A, B and D are N or CH. with the proviso that A, B and D can not all be CH, R 1 = R 2 and are selected from CH3 and spirocychc alkyl constructed by fusing R 1 and R 2 to form a 6 membered spirocychc πng, R 3 is H, OH. NH 2 . CH 3 , substituted methyl or COR c . R c is H, Ci to C alkyl, or Ci to C 4 alkoxy. R 4 is a disubstituted benzene πng containing the substituents X and Y as shown below X is halogen, CN, methoxy, NO 2 , or 2-thιazole. Y is a substituent on the 4' or 5'posιtιon selected from H and F, or R 4 is a five membered ring of the structure X' is halogen, CN, or NO 2 ; Y' is H or Ci to C alkyl; Q is O, S, NR 6 . or CR 7 R 8 , Re is CN, Ci to C 6 alkyl. substituted Cj to C 6 alkyl, C to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl. heterocychc, substituted heterocychc. or S0 2 CF 3 , R 7 and R 8 are independent substituents selected from H, Ci to C 6 alkyl substituted Ci to Cβ alkyl, to C 8 cycloalkyl substituted to C 8 cycloalkyl. aryl substituted aryl. heterocyclic, substituted heterocyc c, N0 2 . or CN CO 2 R 9 . R 9 is Ci to alkyl or CR 7 R 8 form a six membered πng of the structure W is O or a chemical bond, or a pharmaceutically acceptable salt thereof Each of the generic and subgenenc groups of compounds descnbed above, as well as the methods of treatment and pharmaceutical compositions utilizing them, may be divided into two further subgenenc groups, one in which Q is oxygen and another in which Q is sulfur or NR 6 or CR 7 R 8 The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers While shown without respect to stereochemistry in Formula I, the present 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-cham saturated aliphatic hydrocarbon groups having one to eight carbon atoms, preferably one to six carbon atoms, "alkenyl" is intended to include both straight- and branched- cham alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms, "alkynyl" group is intended to cover both straight- and branched-chain alkyl group with at least one carbon-carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms The terms "substituted alkyl " . "substituted alkenyl", and "substituted alkynyl" refer to alkyl. alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN. OH. N0 2 . amino, aryl, heterocyclic. substituted aryl substituted heterocychc. alkoxy, aryloxy, substituted alkyloxv, alkylcarbony I alkylcarbox , alkylamino, arylthio These substituents may be attached to any carbon of alkyl, alkenyl or alkynyl group provided that the attachment constitutes a stable chemical moietv The term "aryl" is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system The aryl groups include but not limited to phenyl, naphthyl, biphenyl. anthryl tetrohydronaphthyl. phenanthryl The term "substituted aryl" refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, N0 2 , amino, alkyl, cycloalkyl. alkenyl, alkynyl alkoxy. aryloxy , substituted alkyloxy, alkylcarbonyl, alkylcarboxy . alkylamino, or arylthio The term "heterocyclic" is used herein to descπbe a stable 4- to 7-membered monocyc c or a stable multicyclic heterocyc c ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms The N and S atoms may be oxidized The heterocychc πng also includes any multicyclic πng in which any of above defined heterocyclic rings is fused to an aryl πng The heterocychc πng may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable Such heterocyclic groups include, for example, tetrahydrofuran. pipeπdinyl, piperazinyl 2-oxopιpeπdιnyl, azepinyl, pyrro dinyl, lmidazolyl, pyπdyl, pyrazinyl pyπmidinyl, pyπdazinyl. oxazolyl, isoxazolyl, morphohnyl. lndolyl quinolinyl. thienyl furyl, benzofuranyl. benzothienyl thiamorphohnyl. thiamorpholiny 1 sulfoxide. and lsoquinolinyl The term "substituted heterocyclic" is used herein to describe the heterocyclic lust defined having one to four substituents selected from the group which includes halogen. CN, OH, N0 2 . amino. alkyl. substituted alkyl, cycloalkyl alkenyl. substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy . alkylamino. or arylthio The term "alkoxy " is used herein to refer to the OR group, where R is alkyl or substituted alkyl The term " " aryloxy " is used herein to refer to 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 wherein the alkyl or substituted alkyl groups containing one to eight carbon atoms, which may be either same or different and the pomt of attachment is on the nitrogen atom 'Halogen" refers to Cl, Br, F, or I The compounds of the present invention can be used m the form of salts deπved 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 acid, sulfuπc acid, nitric acid, phosphoric acid and, as the case may be. such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo This invention includes pharmaceutical compositions and treatments which comprise administering to a mammal a pharmaceutically effective amount of one or more compounds as described above wherein Q is oxygen as antagonists of the progesterone receptor The invention further provides comparable methods and compositions which utilize one or more compounds herein wherein Q is S. NR 6 , or CR 7 R 8 as agonists of the progesterone receptor The progesterone receptor antagonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myometπal fibroids, endometπosis, benign prostatic hypertroph . carcinomas and adenocarcinomas of the endometπum, ovary . breast, colon, prostate, pituitary . meningioma and other hormone-dependent tumors Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock The progesterone receptor agonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometπum, ovary, breast. colon, prostate Additional uses of the invention include stimulation of food intake When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients. for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0 05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of steπle injectable solutions or suspensions containing from about 0 05 to 5% suspending agent in an lsotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the earner, more usually between about 5% and 60% by weight The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the seventy of the condition being treated However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0 5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a da . or in a sustained release form For most large mammals, the total daily dosage is from about 1 to 100 mg, 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 intimate admixture with a solid or liquid pharmaceutically acceptable earner This dosage regimen may be adjusted to provide the optimal therapeutic response For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropπate to the nature of the active ingredient and the particular form of administration desired Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules Oral administration of the compounds is preferred These active compounds may also be administered parenterally or lntrapeπtoneally Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms The pharmaceutical forms suitable for mjectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile mjectable solutions or dispersions In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e g . glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil The compounds of this invention can be prepared following the Schemes illustrated below As demonstrated in Scheme I, the compounds of this invention are generally prepared by employing the suitable coupling reaction as a final step An appropriately substituted ortho-amino acid or its derivatives such as ethyl ester (X = Br, I, Cl, or a latent coupling precursor such as alkoxy group which can be converted into OTf group suitable in the coupling reaction) is treated with a suitable organo metallic reagent, e g Gπgnard reagent, in appropriate nonprotic solvents which include but not limited to THF or ether to give ortho-amino carbinol 2 under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature Ring closure of carbinol 2 to yield oxazin- 2-ones 3 is commonly effected by a condensing agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 °C The arylation of oxazιn-2-ones 3 to yield 4 can be effected by various coupling reactions including Suzuki, Stille reactions etc These reactions are commonly performed in the presence of transition metallic catalyst, e g , palladium or nickel complex often with phosphino ligands. e g , Ph 3 P, l.l '-bιs(dιphenylphosphιno)ferrocene, 1,2- bιs(dιphenylphosphιno)ethane or palladium salt such as palladium acetate Under this catalytic condition, an appropriately substituted nucleophihc reagent, e g , aryl boronic acid, arylstannane. or aryl zinc compound, is coupled with oxazinones 3 to give compounds 4 If a base is needed in the reaction, the commonly used bases include but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, potassium acetate, or cesium fluoride The most commonly used solvents in these reactions include benzene. DMF. isopropanol. ethanol DME, ether, acetone or a mixture of any one of these solvent and water The coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95 °C Oxazinones 3 can be converted into a nucleophile such as boronic acid which can be coupled with an appropπate electrophile. e g . ary 1 bromide or aryl iodide, to yield 6 employing the coupling reaction condition as described above Scheme I RMgBr, THF, it, N 2 CDI, THF, 50 degrees C N 2 , n-BuLi, THF, B(OMe)3 -7 8 degrees C to rt, N 2 , awesson's reagent The transformation of 3 into 5 can be effected by treating 3 with an organo metallic reagent, e g . n-BuLi. in a nonprotic solvent such as THF or ether followed by quenching the reaction solution with a suitable electrophile such as tπmethyl borate. triisopropyl borate, bishexalkyl tin reagent, or zinc chloride at temperatures ranging from-78 °C to room temperature under an inert atmosphere such as argon or nitrogen Conversion of carbamate 6 to thiocarbamate 7 can be readily effected by treatment of 6 with a suitable sulfur reagent such as P S 5 or Lawesson's reagent in a suitable nonprotic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent Scheme II describes the procedures to prepare oxazinones bearing two different substituents at posιtιon-4 The Weinreb amide 9 can be prepared from an appropriately substituted isatoic anhydride when treated with N-, 0-dιmethylhydroxy 1- amine hydrochloride salt in a protic solvent such as ethanol or isopropanol at reflux under an inert atmosphere such as argon or nitrogen Coupling of amide 9 with an ary 1 electrophile such as aryl boronic acid or arylstannane to give 10 can be effected by employing a typical coupling reaction such as Suzuki. Stille coupling procedure in a similar fashion as described for the preparation of oxazinones 4 Treatment of Weinreb amide 10 with organo metallic compounds, e g , alkylhthium, alkynylhthium, arylhthium, or their Gπgnard counterpart in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78 ° to room temperature affords amino ketone 11. Conversion of ketone 11 to carbinol 12 can be effected by treatment of 10 with an organo metallic reagent such as alkyl, alkynyl, or aryl Gπgnard compound in a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature Conversion of ketone 11 to carbinol 12 can also be effected by reduction of ketone group of 11 to the carbinol moiets of 12 using an appropπate reducing reagent such as lithium aluminum hydride, sodium borohydπde in a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere in the temperature ranging from 0 °C to the boiling point of the solvent Ring closure of carbinol 12 to produce the compounds of this invention. 13. can be accomplished with condensing agents such as carbonyldiimidazole. phosgene, dimethylcarbonate. or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 °C Conversion of carbamate 13 to thiocarbamate 14 can be readilv effected by treatment of 13 with a suitable sulfur reagent such as P 2 S 5 or Lawesson ' s reagent m a suitable nonprotic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent. Scheme II Alternatively, ortho-amino ketone 11 can be prepared by treatment of ortho- amino nitrile 16 with an organo metallic compound such as organo lithium reagent or Gπngard reagent in a suitable solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at temperatures ranging from -78 °C to room temperature as illustrated in Scheme III Nitrile 16 can be readily prepared from an appropriately substituted nitrile such as bromobenzonitπle 15 using a suitable coupling reaction such as Stille or Suzuki protocol earned out in a similar fashion as descnbed for the preparation of the Weinreb amide 10 Scheme III 15 16 R 6 ι or R 6 MgX, 0 degrees C 11 The following non-limiting examples illustrate the compounds of the invention EXAMPLE 1 2-Amino-5-bromo-3-pyridine carboxylic acid To a solution of 2-amιno-nιcotιnιc acid (10 g. 72 5 mmol) in acetic acid (70 mL) was dropwise added bromine (9 8 mL. 79 8 mmol) at room temperature under nitrogen Upon completion of the reaction, the solvent was removed in vacuo the residue tπturated with ether and collected on a filter to give 2-amιno-5-bromo-3- pyπdine carboxylic acid as a yellow solid (15 7 g, 99%) mp 272 °C, (decomposed), X H-NMR (DMSO-de) 5 8 8-7 8 (bs. 2H), 8 44 (d. IH, J = 2 48 Hz), 8 34 (d, IH, J = 2 48 Hz), MS (El) m/z 216/218 ([M +] + , 100%) EXAMPLE 2 2-(2-Amino-5-bromo-pyridin-3-v-)-propan-2-ol To a solution of 2-amιno-5-bromo-3-pyπdιne carboxylic acid (5 g, 23 mmol) in THF (70 mL) at 0 °C was added methyl magnesium bromide (13 7 g, 115 mmol) under nitrogen After addition, the reaction mixture was heated at 65 °C for 12 hours, cooled to room temperature and quenched with saturated aqueous ammonium chloride The ethyl acetate was added and organic layer was separated, dned over sodium sulfate and concentrated The residue was purified via flash chromatography to give 2-(2-amιno-5-bromo-pyπdιn-3-yl)-propan-2-ol as a yellow solid (1 2 g, 23%) mp 107-108 °C, Η-NMR (DMSO-d 6 ) δ 7 89 (d, IH, J = 2 3 Hz), 7 40 (d. IH, J - 2 3 Hz), 6 28 (bs, 2H), 5 51 (s, IH), 1 4 (s, 6H), MS (APCI) m/z 231 ([M + H] + , 100%) EXAMPLE 3 6-Bromo-4,4 , -dimethvI-l,4-dihvdro-3-oxa-l,8-diaza-naphthalen-2-one A mixture of 2-(2-amιno-5-bromo-pyndιn-3-yι)-propan-2-ol (0 86 g, 3 7 mmol) and l N-carbonyldiimidazole (excess) in THF (10 mL) was heated at 35 °C overnight The reaction solution was cooled to room temperature, poured into ethyl acetate (200 mL), washed with 1 N HCl (2x50 mL), dried o\er sodium sulfate, and concentrated The residue was purified by a flash chromatography (silica gel. 25 % ethyl acetate/hexane) to afford 6-bromo-4,4'-dιmethyl-1.4-dιhydro-3-oxa-l,8-dιaza- naphthalen-2-one (0 9 g. 94%) as a white solid mp 251-252 °C. 'H-NMR (DMSO- de) δ 10 9 (s. IH), 8 32 (d, IH. J = 2 19 Hz). 8 0 (d. IH, J = 2 22 Hz). 1 6 (s. 6H), MS (El) m/z 256 ([M]\ 80%), Anal Calc For C 9 H 9 BrN 2 0 2 C. 42 05, H. 3 53, N, 10 90 Found C. 42 15. H. 3 65. N. 10 80 EXAMPLE 4 6-(3-Chloro-phenyl)-4,4-dimethv--l,4-dihvdro-3-oxa-l,8-diaza-naphth-ϋene-2- one A mixture of 6-bromo-4,4'-dιmethyl-l,4-dιhydro-3-oxa-l,8-dιaza-naphthalen- 2-one (0 1 g, 0 39 mmol), 3-chlorophenyl boronic acid (0 075 g, 0 47 mmol), tetrakιs(tπphenylphosphιne)-palladιum (0) (0 023 g. 0 02 mmol), and sodium carbonate (0 1 g. 0 94 mmol) in DME (8 mL) and water (5 mL) was subject to a blanket of nitrogen for 15 minutes at 50 °C and then was heated at 85 °C for 30 minutes The reaction was cooled to room temperature and ethyl acetate (100 mL) was added The organic layer washed with aqueous ammonium chlonde (2x50 mL) and with brine (50 mL), dπed over magnesium sulfate and concentrated The product was dissolved in dichloromethane and passed through a plug of magnesol The solvent was removed and the clear oil obtained tnturated with ether (25 mL) to give 6-(3- chloro-phenyl)-4,4-dιmethyl-l,4-dιhydro-3-oxa-l,8-dιaza-naphthalene-2-one as a white sohd (0 087 g, 80%) mp 214-215 °C, Η-NMR (DMSO-de) δ 10 9 (s, IH), 8 56 (d. IH, J = 2 35 Hz), 8 06 (d, IH. J = 2 35 Hz), 7 86 (t, IH, J = 2 35 Hz), 7 72 (td. IH, J = 9 4, 2 35 Hz), 7 54-7 44 (m, 2H), 1 69 (s, 6H), MS (ESI) m/z 289 ([M+H] + , 100%), Anal Calc For C 17 H 17 NO 3 C, 62 40, H. 4 54, N, 9 70 Found C. 60 53. H. 4 40, N. 9 21 EXAMPLE 5 6-Chloro-3-nitro-pyridine-2-carbonitrile A mixture of 2. 6-dιchloro-3-nιtropyπdme and cuprous cyanide in l-methyl-2- pyrrolidinone was quickly heated to 180 °C and maintained at that temperature for 15 minutes with vigorous stirring The mixture was cooled to -10 °C and the deep brown solution was poured into ice water ( 3 5 L) and stirred for 30 mm The flocculent brown precipitate was collected and washed with H2O After drying for about 1 5 h. the moist solid was extracted with boiling toluene (3x300 mL) The combined toluene extracts were washed with H2O. brine, and dned (MgSO_ι), concentrated The crude product was crystallized from EtOAc/hexane to afford the title compound mp 115- 117 °C. 1H NMR( DMSO-d 6 ) δ 8 16 (dd, IH, J = 8 7, 3 0 Hz), 8 82 (d, IH, J = 9 0 Hz), MS (El) m/z 183/185 (M+H) + , Anal Calc For C 6 H 2 ClN3θ 2 C, 39 26, H. 1 10, N, 22 89 Found C, 39 47, H, 1 38, N, 22 77 EXAMPLE 6 3-Amino-6-chloro-pyridine-2-carbonitrile To a solution of 2,6-dιchloro-3-nιtropyπdιne(4 8 g, 26 15 mmol) in MeOH (60 mL) and concentrated HCl (25 mL) was slowly added iron powder (5 12g, 91 53 mmol) After the completion of addition, the mixture was refluxed for 45 minutes and poured into 700 mL of H 2 O Filtration of the resulting slurry gave a dull yellow solid The filtrate was made basic with concentrated NH4OH, the resulting slurry was filtered and both the solid and the filtrates were extracted with ether The combined extracts were dned (MgSO_ι) and evaporated to give the title compound as a creamy solid (2 8g, 58%) mp 162-165 °C which was used in next step without further purification EXAMPLE 7 l-(3-Amino-6-chloro-pyridin-2-yl)-ethanone To a solution of 3-amιno- 6-chloro-pyπdιne-2-carbonιtπle (0 75g, 4 88 mmol) in anhydrous THF (25 mL) under nitrogen was added a solution of methylmagnesium bromide (3M in ether, 8 1 mL, 24 3 mmol) The reaction mixture was stirred for 30 minutes and then slowly quenched with H2O. and treated with 5N HCl solution The mixture was extracted with ethyl acetate (3x100 mL) and organic extracts were washed with brine, and dried (MgSO ) After removal of the solvent, the residue was purified by a chromatography using EtOAc/hexane mixture (1 3) as eluent to afford the title compound as a greenish crystalline solid (0 71g. 85%) mp 108-110 °C ^H NMR (DMSO-d 6 ) δ 2 51 (s. 3H), 7 28-7 39 ( m. 4H). MS(ESI) m/z 171/173 (M+H)\ Anal Calc For C 7 H 7 C1N 2 0 C. 49 28, H. 4 14, N. 16 14 Found C. 49 70, H, 4 03, N. 16 41 EXAMPLE 8 l-(3-Amino-6-chloro-pyridin-2-yl)-propan-2-ol To a solution of l-(3-amιno-6-chloro-pyπdιn-2-yl)-ethanone in anhydrous THF under N 2 was added a solution of methylmagnesium bromide (3N m ether) The resulting reaction mixture was stirred at room temperature for 4 h, then slowly quenched with H2O, treated with 0 5 N HCl and stirred for 30 minutes, diluted with ethyl acetate, washed with brine, dried (MgSO/i), concentrated, and chromatographed using a mixture of EtOAc/Hexane ( 3 5 6 5) to afford the title compound as a white crystals (0 45g, 82%) mp 118-121 °C 1H NMR(DMSO-d 6 ) δ 1 45(s, 6H). 3 35(s. IH), 5 51(s, IH), 5 68(s, IH), 7 02(s, IH), MS((+)APCI) m/z 187/189 (M+H) + , Anal Calc For C 8 H] ι ClN 2 O C, 51 48, H, 5 94, N, 15 01 Found C, 51 22, H, 5 99. N, 14 47 EXAMPLE 9 6-Chloro-4,4-dimethyl-l,4-dihydro-3-oxa-l,5-diaza-naphthalen-2-one To a solution of l-(3-amino-6-chloro-3-nitro-pvridin-2-yl)-propan-2-ol (0 3g. 1 67 mmol) in anhydrous THF (20 mL) was added a solution of 1.1 " - carbonyldnmidazole (0 68g. 4 12 mmol) in anhydrous THF (10 mL) The reaction mixture was heated under reflux for 3 h The reaction mixture was treated with 0 5N HCl. washed with brine. H2O. dried (MgSθ4), concentrated and crystallized from EtOAc/hexane to obtain the title compound as a white crystalline solid (0 2g. 56%) mp 175-178 °C 1H NMR( DMSO-d 6 ) δ 1 60 (s. 6H), 7 30 (d, 1H. J = 8 41 Hz). 7 41 (d, 1H, J = 8 41 Hz), 10 47 (s, IH). MS((+)APCI) m/z 213 (M+Hj , Anal Calc For C9H9CIN2O2 C, 50 84, H, 4 27, N, 13 17 Found C. 50 99, H, 4 28, N. 12 98 EXAMPLE 10 The compounds of this invention were tested in the relevant assay as described below and their potency are in 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 The selected example is example 4 Example 4, hPR CV-1, IC S o= 0.8 μM A In-vitro biology The in-vitro biology is determined by (1) competitive Radiohgand Binding using the A-form of the human progesterone receptor with progesterone as the radiohgand, (2) co-transfection assay, which provides functional activity expressed as agonist EC50 and Antagonist IC50 values, (3) a T47D cell proliferation, which is a further functional assay which also provides agonist and antagonist data, and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agonist and antagonist data 1. hPR Binding assay - This assay is carried out in accordance with Pathirana, C . Stein, R B , Berger. T S , Femcal. W , laniro. T . Mais. D E , Torres, A , Glodman, M E , Nonsteroidal human progesterone receptor modulators from the marine alga cymopha barbata. J Steroid Biochem Mol Biol . 1992, 41. 733-738 2. PRE-luciferase assay in CV-1 cells The object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids The matenals methods used in the assay are as follows a Medium The growth medium was as follows DMEM (BioWhittaker) containing 10% (v/v) fetal bovine serum (heat inactivated). 0 1 mM MEM non-essential amino acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) The experimental medium was as follows DMEM (BioWhittaker), phenol red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0 1 mM MEM non-essential amino acids, lOOU/ml penicillin, lOOmg/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 is done using 1 2x10 7 cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl and BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250 ml Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II After electroporation. cells are resuspended in growth medium and plated in 96-well plate at 40.000 cells/well in 200 μl Following overnight incubation, the medium is changed to experimental medium Cells are then treated with reference or test compounds in experimental medium Compounds are tested for antiprogestational actiMty in the presence of 3 nM progesterone Twenty-four hr after treatment, the medium is discarded cells are washed three times with D-PBS (GIBCO, BRL) Fiftv ul of cell lysis buffer (Promega. Madison, WI) is added to each well and the plates are shaken for 15 mm 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 nonlinear dose response curve fitting for both agomst and antagomst modes Huber weighting is used to downweight the effects of outhers EC 50 or IC 50 values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of vanance and non-linear response analyses d Reference Compounds Progesterone and tπmegestone are reference progestins and RU486 is the reference antiprogestm All reference compounds are run in full dose- response curves and the EC50 or IC 50 values are calculated Table 1. Estimated ECso, standard error (SE), and 95% confidence intervals (CI) for reference progestins from three individual studies EC50 95% CI Compound Exp (nM) SE lower upper Progesterone 1 0616 0026 0509 0746 2 0402 0019 0323 0501 3 0486 0028 0371 0637 Tπmegestone 1 00075 00002 00066 00085 2 00081 00003 00070 00094 3 00067 00003 00055 00082 Table 2. Estimated IC 50 , standard error (SE), and 95% confident interval (CI) for the antiprogestm, RU486 from three individual studies IC 50 95% CI Compound Exp (nM) SE lower upper RU486 0028 0002 0 019 0 042 0037 0002 0 029 0 048 0019 0001 0 013 0 027 Progestational activity Compounds that increase PRE-luciferase activity significantly (p<0 05) compared to vehicle control are considered active Antiprogestational activity Compounds that decrease 3 nM progesterone induced PRE-luciferase activity significantly (p<0 05) EC 5 o Concentration of a compound that gives half-maximal increase PRE- luciferase activity (default -nM) with SE IC 50 Concentration of a compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity (default-nM) with SE 3 T47D cell proliferation assay The objective of this assay is the determination of progestational and antiprogestational potency by using a cell proliferation assay in T47D cells A compound's effect on DNA synthesis in T47D cells is measured The materials and methods used in this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat- mactivated), lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Treatment medium. Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with 0 5% charcoal stripped fetal bovine serum. lOOU/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) c Cell culture Stock T47 D cells are maintained in growth medium For BrdU incorporation assay, cells are plated in 96-well plates (Falcon Beet on Dickinson Labware) at 10 000 cells/well in growth medium After overnight incubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment Stock compounds are dissolved in appropriate vehicle (100%) ethanol or 50% ethanol/50% DMSO), subsequently diluted in treatment medium and added to the cells Progestm and antiprogestm reference compounds are run in full dose-response curves The final concentration of vehicle is 0 1% In control wells, cells receive vehicle only Antiprogestins are tested m the presence of 0 03 nM tnmegestone, the reference progestin agomst Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights. IL) m treatment medium for 4 hr d Cell Proliferation Assay At the end of BrdU labeling, the medium is removed and BrdU mcorporation is measured using a cell proliferation ELISA kit (#RPN 250. Amersham Life Science) accordmg to manufacturer's mstructions Briefl , cells are fixed in an ethanol contammg fixative for 30 mm, followed by mcubation m a blocking buffer for 30 mm to reduce background Peroxidase-labeled anti-BrdU antibody is added to the wells and mcubated for 60 mm The cells are rinsed three times with PBS and mcubated with 3,3'5,5'-tetramethylbenzιdιne (TMB) substrate for 10-20 mm depending upon the potency of tested compounds Then 25 μl of 1 M sulfunc acid is added to each well to stop color reaction and optical density is read m a plate reader at 450 nm within 5 mm e Analysis of Results Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes Huber weighting is used to downweight the effects of outliers EC 50 or IC 50 values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of variance and non-linear dose response analyses m both single dose and dose response studies f Reference Compounds Tnmegestone and medroxyprogesterone acetate (MPA) are reference progestins and RU486 is the reference antiprogestm All reference compounds are run m full dose-response curves and the EC 5 0 or IC5 0 values are calculated Table 3. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for individual studies Compound Exp (nM) SE lower upper Tnmegestone 1 0017 0003 0007 0040 2 0014 0001 0011 0017 3 0019 0001 0016 0024 MPA 1 0019 0001 0013 0027 2 0017 0001 0011 0024 Table 4. Estimated IC 50 , standard error, and 95% confident interval for the antiprogestin, RU486 IC 50 95% CI Compound Exp (nM) SE lower upper RU486 1 0011 0001 0008 0014 2 0016 0001 0014 0020 3 0018 0001 0014 0022 EC 50 Concentration of a compound that gives half-maximal increase m BrdU mcorporation with SE IC50 Concentration of a compound that gives half-maximal decrease m 0 1 tnmegestone induced BrdU mcorporation with SE 4 T47D cell alkalme phosphatase assa*. The purpose of this assay is to identify progestms or antiprogestins determmmg a compound s effect on alkalme phosphatase m T47D cells The materials and methods used in this assay are as follo s a. Culture medium DMEM F12 (1 1) (GIBCO. BRL) supplemented with 5% (\ /\) charcoal stripped fetal bovme serum (not heat-mactn ated) lOOU/ml penicillin. 100 μg/ml streptomvcin. and 2 mM GlutaMax (GIBCO. BRL) b Alkalme phosphatase assay buffer I 0 1 M Tπs-HCl, pH 9 8. contammg 0 2% Triton X-100 II 0 1 M Tπs-HCl. pH 9 8 contammg 4 mM p-mtrophenyl phosphate (Sigma) c Cell Culture and Treatment Frozen T47D cells were thawed in a 37°C water bath and diluted to 280.000 cells/ml m culture medium To each well m a 96-well plate (Falcon, Becton Dickinson Labware), 180 μl of diluted cell suspension was added Twenty μl of reference or test compounds diluted m the culture medium was then added to each well When testing for progestm antagonist activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C in a 5% CO 2 /humιdιfied atmosphere for 24 hr d Alkalme Phosphatase Enzyme Assay At the end of treatment, the medium was removed from the plate and fifty μl of assay buffer I was added to each well The plates were shaken m a titer plate shaker for 15 mm Then 150 μl of assay buffer II was added to each well Optical density measurements were taken at 5 mm intervals for 30 mm at a test wavelength of 405 nM e. Analysis of Results Analysis of dose-response data For reference and test compounds, a dose response cuπ e is generated for dose (X-axis) vs the rate of reaction (slope) (Y-axis) Square root-transformed data are used for analysis of variance and nonlmear dose response cur\ e fitting for both agonist and antagonist modes Huber weightmg is used to downweight the effects of outliers EC50 or IC50 \alues are calculated from the retransformed values JMP software (SAS Institute. Inc ) is used for both one-way analysis of variance and non-linear dose response analyses m both single dose and dose response studies f Reference Compounds Progesterone and tnmegestone are reference progestms and RU486 is the reference antiprogestm All reference compounds are run m full dose response curves and the EC 50 or IC50 values are calculated Table 5. Estimated EC50 ? standard error (SE), and 95% confidence intervals (CI) for reference progestins from three independent experiments EC50 95% CI Compound Exp (nM) SE lower upper 'gesterone 1 0839 0030 0706 0996 2 0639 0006 0611 0669 3 1286 0029 1158 1429 negestone 1 0084 0002 0076 0091 2 0076 0001 0072 0080 3 0160 0004 0141 0181 Table 6. Estimated ICso > standard error, and 95% confident interval for the reference antiprogestm RU486 from three independent experiments IC 50 95% CI Compound Exp (nM) SE lower upper RU486 1 0103 0002 0092 0115 2 0120 0001 0115 0126 3 0094 0007 0066 0134 B. In-vivo Biology The pπmarv ln-vr o assay is the rat decidualization model, which be used to determine progestational effects of both agonists and antagonists The secondary m- vι\o assa\ is the rat ovulation inhibition model, which is under development, and hence the protocol is un-available 1 Rat decidualization assay The objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uteπne decidualization and compare the relative potencies of vanous test compounds The materials and methods used in this assay are as follows a Methods: Test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil (MazolaT ) are t en prepared by heating (~80 °C) the mixture to evaporate ethanol Test compounds are subsequently diluted with 100% corn oil or 10% ethanol m corn oil prior to the treatment of animals No difference m decidual response was found when these two vehicles were compared b Animals (RACUC protocol #5002) Ovaπectomized mature female Sprague-Dawley rats (~60-day old and 230g) are obtained from Taconic (Tacomc Farms, NY) following surgery Ovanectomy is performed at least 10 days pnor to treatment to reduce circulating sex steroids Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum c Treatment Rats are weighed and randomly assigned to groups of 4 or 5 before treatment Test compounds in 0 2 ml vehicle are administered by subcutaneous mjection m the nape of the neck or by gavage usmg 0 5 ml The animals are treated once daily for seven day s For testing antiprogestins. animals are given the test compounds and a EC50 dose of progesterone (5 6 mg/kg) during the first three day s of treatment Folio wmg decidual stimulation, animals contmue to receive progesterone until necropsy four days later d Dosing Doses are prepared based upon mg/kg mean group weight In all studies, a control group receiving vehicle is included Determination of dose-response curves is carried out using doses with half log increases (e g 0 1. 0 3. 1 0. 3 0 mg/kg ) e Decidual mduction Approximately 24 hr after the third mjection. decidualization is induced in one of the uterme horns by scratching the antimesometπal luminal epithelium with a blunt 21 G needle The contralateral horn is not scratched and serves as an unstimulated control Approximately 24 hr followmg the final treatment, rats are sacnficed by Cθ2 asphyxiation and body weight measured Uteri are removed and trimmed of fat Decidualized (D-horn) and control (C-horn) uterme horns are weighed separately f Analysis of Results The mcrease m weight of the decidualized uterme horn is calculated by D-horn/C-horn and loganthmic transformation is used to maximize normality and homogeneity of vanance The Huber M-estimator is used to down weight the outlymg transformed observations for both dose-response curve fitting and one-way analysis of vanance JMP software (SAS Institute, Inc ) is used for both oneway ANOVA and non-linear dose-response analyses g Reference Compounds All progestm reference compounds were run in full dose- response curves and the EC50 for uterme wet weight were calculated Table 7. Estimated EC 50 , standard error (SE), and 95% confidence intervals for individual studies Compound Exp (mg/kg, s c ) SE lower upper Progesterone 1 5 50 0 77 4 21 7 20 2 6 21 1 12 4 41 8 76 3-Ketodesogestrel 1 0 1 1 0 02 0 07 0 16 0 10 0 05 0 11 0 25 3 0 06 0 03 0 03 0 14 gestrel 1 0 08 0 03 0 04 0 16 2 0 12 0 02 0 09 0 17 3 0 09 0 02 0 06 0 13 4 0 09 0 02 0 06 0 14 1 0 42 0 03 0 29 0 60 2 0 39 0 05 0 22 0 67 3 0 39 0 04 0 25 0 61 Table 8. Estimated average EC 50 , standard error, and 95% confidence intervals for dose-response curves of 3 reference compounds EC50 95% CI Compound (mg/kg. s c ) SE lower upper Progesterone 5 62 0 62 4 55 7 00 3-Ketodesogestrel 0 10 0 02 0 07 0 14 Levonorgestrel 0 10 0 01 0 08 0 12 Table 9. Estimated IC 5 o, standard error, and 95% confident interval for the antiprogestin, RU 486 IC 50 95% CI Compound Exp (mg/kg. p o ) SE lower upper RU 486 1 0 21 0 07 0 05 0 96 2 0 14 0 02 0 08 0 27 Concentration Compound concentration in assay(default-mg/kg body weight) Route of admmistration Route the compound is admmistered to the animals Body weight Mean total animal body weight (default-kg) D-horn Wet weight of decidualized uterme horn (default-mg) C-horn Wet weight of control uteπne horn (default-mg) Decidual response f(D-C)/C]xl00% Progestational activity Compounds that mduce decidualization significantly (p<0 05) compared to vehicle control are considered active Antiprogestational activity Compounds that decrease EC 50 progesterone mduced decidualization significantly (p<0 05) EC50 for uterine weight Concentration of compound that gives half-maximal mcrease m decidual response (default-mg/kg) IC 50 for uterine weight Concentration of compound that gives half-maximal decrease m EC 50 progesterone mduced decidual response (default-mg/kg) All publications cited m this specification are mcorporated herem by reference herein While the mvention has been descnbed with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departmg from the spirit of the mvention Such modifications are mtended to fall within the scope of the appended claims

Claims: What is Claimed: wherem A. B and D are N or CH, with the proviso that A, B and D can not all be CH, R 1 and R 2 are mdependent substituents selected from H, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C 2 to C 6 alkenyl, substituted C 2 to Cβ alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR A . NR B COR A , or R 1 and R 2 are fused to form a spirocychc ring selected from a), b) or c), each spirocychc πng optionally substituted by from 1 to 3 Cι-C 3 alkyl groups a) a 3 to 8 membered spirocychc alkyl rmg, b) a 3 to 8 membered spirocychc alkenyl ring, or c) an optionally substituted 3 to 8 membered heterocyclic ring contammg one to three heteroatoms from the group mcludmg O. S and N. the spirocychc rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine. Ci to C 6 alkyl. C, to C 0 alkoxy, Ci to C 6 thioalkvl. -CF 3 . -OH. -CN. NH 2 , -NH(d to C 6 alkyl). or -N(C, to C 6 alkyl) 2 , R is H. Ci to C-, alkyl, substituted Ci to C^ alkyl. aryl. substituted aryl. Ci to &, alkox} . substituted Ci to C 3 alkoxy, C] to C 3 aminoalkyl. or substituted Ci to C-, amino alkλl. R B is H. Ci to C 3 alkyl. or substituted Ci to C3 alkyl. R 3 is H. OH. NH 2 , Ci to C 6 alkyl. substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl. substituted Ci to C 6 alkenyl, or COR c , R c is H, Ci to C alkyl, substituted Ci to C 3 alkyl, aryl. substituted aryl, Ci to C alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 aminoalkyl, or substituted Ci to C-, aminoalkyl. R 4 is a tπsubstituted benzene rmg containing the substituents X, Y and Z as shown below X is taken from the group mcludmg halogen, CN. Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy . substituted Cj to C 3 thioalkoxy, ammo, Ci to C3 ammoalkyl. substituted Ci to C-, aminoalkyl. N0 2 . Ci to C 3 perfluoroalkyl. 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms. COR D . OCOR D or NR E COR D . R D is H. Ci to C3 alkyl. substituted Ci to C3 alkyl, aryl. substituted aryl. d to C3 alkoxy. substituted Ci to C3 alkoxy . Ci to C3 aminoalky l. or substituted Ci to C. aminoalkyl, R E is H. Cj to C3 alk\l. or substituted Ci to C3 alkvl. Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN. N0 2 . Ci to C 3 alkoxy, Ci to C3 alkyl, or Ci to C thioalkoxy. or R 4 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, SO 2 or NR 5 and contammg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO 2 and Ci to C3 alkyl, Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, COR F , or NR G COR F , R F is H, Ci to C 3 alkyl. substituted Ci to C 3 alkyl, aryl. substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Cj to C 3 ammoalkyl, or substituted Ci to C 3 aminoalkyl, R G is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl, R 5 is H or Ci to C 3 alkyl, R δ is from the group including CN, Ci to C 6 alkyl, substituted Ci to C 6 alkyl. C 3 to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl. ary 1. substituted aryl, heterocychc. substituted heterocychc. or SO 2 CF 3 , R 7 and R 8 are mdependent substituents from the group mcludmg H. Ci to C 6 alkyl, substituted C \ to C 6 alkyl. C 3 to C 8 cycloalkyl. substituted C 3 to C 8 cycloalkyl aryl. substituted aryl, heterocyclic, substituted heterocyclic. N0 2 . or CN CO 2 R 9 . R 9 is Ci to C3 alkyl. or CR 7 R 8 form a six membered rmg of the structure below W is O or a chemical bond, or a pharmaceutically acceptable salt thereof A compound of Claim 1 having the formula I wherem A. B and D are N or CH. with the proviso that A. B and D can not all be CH. R 1 is H. Ci to C 6 alkyl. substituted Ci to C 6 alkyl. C 3 to C 8 cy cloalkyl. substituted C 3 to C cycloalkyl. aryl. substituted aryl. heterocychc. substituted heterocychc. COR\ or NR B COR A R 2 is H. Ci to C 6 alkyl, substituted Ci to C 6 alkyl. C 2 to Cβ alkenyl. substituted C 2 to C 6 alkenyl. C3 to C 8 cvcloalkyl. substituted C3 to C 8 cycloalkyl, aryl. substituted an 1. heterocychc. substituted heterocvchc. COR A . or NR B COR A . or R 1 and R 2 are fused to form the optionally substituted 3 to 8 membered spirocvchc alkyl. alkenyl or heterocyclic rmgs described above. R A is H. Ci to C3 alkyl, substituted Ci to C alkyl. aryl. substituted aryl, Ci to C 3 alkoxy . substituted C] to C 3 alkoxy , Ci to C 3 aminoalkyl, or substituted Ci to C3 aminoalkyl. R B is H. Ci to C alkyl. or substituted Ci to C 3 alkyl. R" is H, OH, NH 2 , C, to C 6 alkyl. substituted Ci to C 6 alkyl. C 3 to C 6 alkenyl substituted Ci to C 6 alkenyl, or COR c . R c is H. Ci to C alkyl, substituted Ci to C alkyl, aryl, substituted aryl, Ci to C 4 alkoxy, substituted Ci to C alkoxy, Ci to C 4 ammoalkyl, or substituted Ci to C 4 ammoalkyl, R 4 is a tπsubstituted benzene nng containing the substituents X. Y and Z as shown below X is selected from halogen. CN. C \ to C 3 alkyl. substituted Ci to C alkyl. Ci to C3 alkoxy . substituted Cj to C alkoxv Ci to C3 thioalkow substituted Ci to C3 thioalkoxy . Ci to C3 ammoalkyl. substituted Ci to C3 ammoalkyl. N0 2 Ci to C, perfluoroalkv l. a 5 membered heteroc\chc rmg contammg 1 to 3 heteroatoms COR D OCOR D . or NR E COR D R D is H. Cj to C 3 alkyl, substituted Ci to C3 alkyl. aryl, substituted aryl. Ci to C3 alkoxy . substituted Ci to C3 alkox> . Ci to C3 aminoalkyl. or substituted Ci to C-, aminoalkyl. R L is H. Cj to C 3 alkyl. or substituted Ci to C 3 alkyl. Y and Z are mdependent substituents selected from H. halogen. CN. N0 2 . C] to C alkox . Ci to C alkyl. or Cj to C 3 thioalkoxy . or R 5 is a five or six membered πng with 1, 2. or 3 heteroatoms from the group mcludmg O. S. SO, S0 2 or NR 5 and contammg one or two mdependent substituents from the group mcludmg H, halogen. CN. N0 2 and Ci to C3 alkyl, or Ci to C 3 alkox . R 5 is H or Ci to C 3 alkyl, Q is O, S, NR 6 , or CR 7 R 8 Re is selected from CN, Ci to C 6 alkyl. substituted Ci to C 6 alkyl, C 3 to C 8 cycloalky l. substituted C to C 8 cycloalkyl, aryl. substituted aryl. heterocychc. substituted heterocyclic. or SO 2 CF3. R ^ and R 8 are mdependent substituents selected from H, Ci to C alk l. substituted Ci to C 6 alkλ l. C3 to C 8 cycloalky l. substituted C to C 8 cycloalky l. ar l. substituted ar l. heterocvchc substituted heterocychc N0 2 . or CN C0 2 R 9 . R 9 ιs C, to Cτ al Λl. or CR 7 R b form a six membered ring of the structure below W is O or a chemical bond, or a pharmaceutically acceptable salt thereof 3 A compound of Claim 1 of the formula I wherem A. B and D are N or CH. with the proviso that A, B and D cannot all be CH. R 1 = R 2 and are selected from the group of Ci to C alkyl. substituted Ci to C~, alkyl. or spirocychc alkyl constructed by fusing R 1 and R 2 to form a 3 to 6 membered spirocychc nng. R ? is H. OH. NH 2 . Ci to C 6 alkyl, substituted Ci to C 6 alkyl, or COR c . R c is H, Ci to C alkyl. or Ci to C 4 alkox . R 4 is selected from a), b) or c) a) R 4 is a benzene rmg of the formula X is selected from the group of halogen, CN, Ci to C 3 alkoxy, Ci to C 3 alkyl. N0 2 . Ci to C 3 perfluoroalkyl, 5 membered heterocyc c rmg containing 1 to 3 heteroatoms. or Ci to C3 thioalkox . Y is a substituent on the 4' or 5 " position from the group mcludmg H, halogen. CN, N0 2 . C ! to C 3 alkoxy, Ci to C 4 alkyl, or Ci to C 3 thioalkoxy, or b) R is a five membered rmg of the structure R 5 is H. or Ci to C3 alkyl. or C, to C 4 C0 2 alky l. X is selected from halogen. CN N0 2 . Ci to C3 alkvl. or Ci to C alkox . is selected from H and Ci to C or c) R 4 is a six membered ring of the structure X 1 is N or CX 2 . X 2 is halogen, CN or N0 2 . Re is selected from CN, Ci to Cβ alkyl, substituted Ci to Cβ alkyl. C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl. aryl, substituted aryl, heterocychc, substituted heterocychc, or S0 CF 3 ; R 7 and R 8 are independent substituents selected from H, Ci to C alkyl, substituted Ci to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, N0 2 , CN, or C0 2 R 9 , R 9 is C, to C 3 alkyl; or CR 7 R 8 form a six membered ring of the structure below or a pharmaceutically acceptable salt thereof A compound of Claim 1 of the formula I wherem A. B and D are N or CH. with the proviso that A, B and D can not all be CH. R 1 = R 2 and are selected from CH 3 and spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 6 membered spirocychc ring, R 3 is H, OH, NH 2 , CH 3 , substituted methyl, or COR c , R c is H, Ci to C alkyl, or Ci to C 4 alkoxy, R 4 is a disubstituted benzene rmg contammg the substituents X and Y as shown below X is halogen. CN. methoxy . N0 2 . or 2-thιazole. Y is a substituent on the 4 or 5 " position selected from H or F. Re is CN. Ci to C 6 alkyl, substituted Ci to C 6 alkyl. C 3 to C 8 cycloalkyl, substituted C to C 8 cycloalkyl, aryl, substituted aryl. heterocyclic, substituted heterocychc, or S0 2 CF 3 , R 7 and R 8 are mdependent substituents selected from H, Ci to Cβ alkyl, substituted Ci to C 6 alkyl. C 3 to C 8 cycloalkyl, substituted C to C 8 cycloalkyl. aryl, substituted aryl, heterocychc. substituted heterocyclic. N0 2 . or CN C0 2 R 9 , R 9 is C, to C 3 alkyl, or CR 7 R 8 form a six membered ring of the structure W is O or a chemical bond, or a pharmaceuticalh acceptable salt thereof A compound of Claim 4 wherein R is the moiety or a pharmaceutically acceptable salt thereof A compound of Claim 1 of the formula I where A. B and D are N or CH. with the proviso that A, B and D can not all be CH, R 1 = R 2 and are selected from CH 3 and spirocychc alkyl constructed by fusing R 1 and R 2 to form a 6 membered spirocychc ring, R 3 is H, OH, NH 2 , CH 3 , substituted methyl, or COR c , R c is H, Ci to C 3 alkyl, or Ci to C 4 alkoxy, R 4 is a five membered rmg of the structure X ' is halogen. CN. or N0 2 . Q is O. S. NR 6 . or CR 7 R 8 . Re is CN, Ci to C 6 alkyl, substituted Ci to C 6 alkyl. C 3 to C 8 cycloalkyl, substituted C3 to C 8 cycloalkyl, aryl, substituted aryl. heterocychc, substituted heterocychc. or S0 2 CF 3 , R 7 and R 8 are mdependent substituents selected from H, Ci to C 6 alkyl. substituted Ci to Cβ alkyl. C to C 8 cycloalkyl. substituted C3 to C 8 cycloalkyl. aryl. substituted aryl, heterocyc c. substituted heterocyc c. N0 2 , or CN C0 2 R 9 . R 9 is Ci to C 3 alkyl, or CR 7 R 8 form a six membered πng of the structure W is O or a chemical bond, or a pharmaceutically acceptable salt thereof A compound of Claim 6 wherein R is a selected from and Y " is selected from H or Ci to C alkyl. or a pharmaceutically acceptable salt thereof 8 A compound of Claim 1 which is 6-(3-Chloro-phenyl)-4,4-dιmethyl- 1.4-dιhydro-3-oxa-l,8-dιaza-naphthalene-2-one or a pharmaceutically acceptable salt thereof 9 A pharmaceutical composition comprismg a pharmaceutically effective amount of a compound of Claim 1 and a pharmaceutically effective carrier or excipient 10 A method of mducmg contraception m a mammal, the method comprismg admimstenng to a mammal in need thereof a pharmaceutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof 11 A method of treatment or prevention of benign or malignant neoplastic disease in a mammal, the method compnsing admimstenng to a mammal m need thereof a compound of Claim 1 wherem Q is oxygen, or a pharmaceutically acceptable salt thereof 12 The method of Claim 9 wherem the benign or malignant neoplastic disease is selected from the group of uterme myometnal fibroids, endometπosis. benign prostatic hypertrophy, carcinomas or adeno carcinomas of the endometπum, ovary, breast, colon, prostate, pituitary . memngioma or other hormone-dependent tumors 13 A method of treatment or prevention m a mammal of carcinomas or adenocarcinomas of the endometπum ovary, breast, colon, or prostate, the method comprismg administering to a mammal m need thereof a compound of Claim 1 wherem Q is S. NR 6 . or CR 7 R 8 . or a pharmaceutically acceptable salt thereof

Inventors: EDWARDS JAMES P, FENSOME ANDREW, JONES TODD K, SANTILLI ARTHUR A, TEGLEY CHRISTOPHER M, TEREFENKO EUGENE A, VIET ANDREW Q, WROBEL JAY E, ZHANG PUWEN, ZHI LIN, EDWARDS, JAMES, P., FENSOME, ANDREW, JONES, TODD, K., SANTILLI, ARTHUR, A., TEGLEY, CHRISTOPHER, M., TEREFENKO, EUGENE, A., VIET, ANDREW, Q., WROBEL, JAY, E., ZHANG, PUWEN, ZHI, LIN
Applicants: AMERICAN HOME PROD, EDWARDS JAMES P, FENSOME ANDREW, JONES TODD K, LIGAND PHARM INC, SANTILLI ARTHUR A, TEGLEY CHRISTOPHER M, TEREFENKO EUGENE A, VIET ANDREW Q, WROBEL JAY E, ZHANG PUWEN, ZHI LIN, AMERICAN HOME PRODUCTS CORPORATION, EDWARDS, JAMES, P., FENSOME, ANDREW, JONES, TODD, K., LIGAND PHARMACEUTICALS, INC., SANTILLI, ARTHUR, A., TEGLEY, CHRISTOPHER, M., TEREFENKO, EUGENE, A., VIET, ANDREW, Q., WROBEL, JAY, E., ZHANG, PUWEN, ZHI, LIN
Application year: 2000
Main classification: C07D498
IPC codes: A61P15, C07D498