EP1175404A1

EP1175404A1 - Quinazolinone and benzoxazine derivatives as progesterone receptor modulators

Info

Publication number: EP1175404A1
Application number: EP00930288A
Authority: EP
Inventors: Puwen Zhang; Andrew Fensome; Eugene A. Terefenko; Lin Zhi; Todd K. Jones; James P. Edwards; Christopher M. Tegley; Jay E. Wrobel
Original assignee: Ligand Pharmaceuticals Inc; American Home Products Corp
Current assignee: Wyeth; Ligand Pharmaceuticals Inc
Priority date: 1999-05-04
Filing date: 2000-05-01
Publication date: 2002-01-30
Also published as: CA2371651A1; JP2003524626A; MXPA01011310A; HK1043991A1; AU4814000A

Abstract

This invention provides compounds which are agonists and antagonists of the progesterone receptor having general structure (I): wherein R?1 and R2¿ are independently selected from H, COR?A, or NRBCORA¿, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclic moieties; or R?1 and R2¿ are fused to form: 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic rings; RA is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl groups; RB is H, C¿1? to C3 alkyl or substituted C1 to C3 alkyl; R?3¿ is H, OH, NH¿2, COR?C or optionally substituted alkyl, alkenyl, or alkynyl; RC is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R4 is H, halogen, CN, NO¿2?, or optionally substituted alkyl, alkynyl, alkoxy, amino or aminoalkyl; R?5¿ is an optionally substituted benzene or five or six membered ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO¿2? or NR?6; R6¿ is H or C¿1? to C3 alkyl; G1 is O, NR7, or CR7R8; G2 is CO, CS, or CR7R8; provided that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8; R7 and R8 are H or an optionally substituted alkyl, aryl, or heterocyclic moiety; or pharmaceutically acceptable salt thereof, and methods using these compounds in mammals as agonists or antagonists of the progesterone receptor.

Description

OUINAZOLINONE AND BENZOXAZINE DERIVATIVES AS PROGESTERONE RECEPTOR MODULATORS

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 "ligand dependent transcnption 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 hgands 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/ligand 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 which inhibits the effect of the hormone is an antagonist PR agonists (natural and synthetic) are known to play an important role m 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 Nedeckis) as well as uterine and ovanan cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Chn Endo Metab , 76, 513, 1993) and endometnosis (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 mifepπstone 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)

Jones, et al, (U S Patent No 5,688,810) describe the PR antagonist dihydroquinoline 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, described lactones 4, 5 and 6 as PR antagonists (J Med Chem, 41, 291, 1998)

4 5 6

Zhi, et al, descπbed the ether 7 as a PR antagomst (J Med Chem , 41, 291,

1998)

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 (7et Letters, 5, 2295, 1994)

Hamann, et al, described the PR antagomst 10 (Ann N Y Acad Sci , 761, 383,

1995)

10

Chen, et al, described the PR antagomst 11 (Chen, et al, POI-37, 16^th Int Cong Het Chem , Montana, 1997)

11

Kurihaπ, et al , described the PR hgand 12 (J Antibiotics, 50, 360, 1997)

12

A number of publications reported the synthesis and utilities of benzo diazinones and benzoxazines However, none of examples in this hterature contained substituents necessary for the compounds to be active as progesterone receptor modulators Included in this hterature is the patent by Kubla et al (US 4666913) which claimed that the compound such as A and B could be used as cardiotomc agents Nmg et al. reported the synthesis of quinazolinones such as C

Other pπor art close to this invention is the hterature which disclosed the benzoxazines Among these publications, Gromachevskaya et al (Chem Heterocycl Compd (N Y ), 33(10), 1209-1214 (1998)) studied the bromination process of certain benzoxazines such as compound D Kobzina et al (U S Patent No 3,917,592) claimed that compounds such as E can be used as a herbicidal agent

Pflegel et al (Pharmazie, 37(10), 714-717(1982)) disclosed quιnazolιn-2- thiones such as compound F in their study of polarography of heterocychcs No activity of the compound F was mentioned

Description of the invention

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 antagomsts in functional models, either/or in-vitro and in-vivo These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovanan and prostate cancer, and post menopausal hormone replacement therapy

The compounds in the present invention contain a pendent aromatic substituent The aromatic substituents proved to be cπtical for the resultant compounds being active as progesterone receptor modulators and have broad structural diversity which may consists of aryl, substituted aryl, heteroaryl or substituted heteroaryl group

This invention provides compounds of Formula I having the structure

I wherein

R¹, R² are independent substituents selected from the group which includes H,

Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C to C₆ alkenyl, substituted C₂ to C₆ alkenyl,

C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocyclic, COR^A, or NR^BCOR^A, or R¹ and R² are fused to form a) an optionally substituted 3 to 8 membered spirocychc alkyl πng, b) an optionally substituted 3 to 8 membered spirocychc alkenyl, 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 C₆ alkyl, Ci to C₆ alkoxy, Ci to C₆ thioalkyl, -CF₃, -OH, - CN, NH₂, -NH(Cι to C₆ alkyl), or -N(G to C₆ alkyl)₂,

R^A is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, G to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ aminoalkyl, substituted Ci to C₃ aminoalkyl,

R^B is H, C_ to C₃ alkyl, substituted C. to C₃ alkyl, R³ is H, OH, NH₂, C, to C₆ alkyl, substituted C, to C₆ alkyl, C₃ to C₆ alkenyl, substituted G to C₆ alkenyl, alkynyl, or substituted alkynyl, COR^c,

R^c is H, G to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ aminoalkyl, substituted Ci to C₃ aminoalkyl, R⁴ is H, halogen, CN, N0₂, C, to C₆ alkyl, substituted C, to C₆ alkyl, alkynyl, or substituted alkynyl, Ci to C₆ alkoxy, substituted Ci to C₆ alkoxy, amino, Ci to C₆ ammoalkyl, substituted Ci to C₆ aminoalkyl,

R⁵ is a tπsubstituted benzene ring containing the substituents X, Y and Z as shown below,

X is taken from the group including halogen, CN, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, alkynyl, or substituted alkynyl, to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ thioalkoxy, substituted Ci to C₃ thioalkoxy, amino, Ci to C₃ aminoalkyl, substituted Ci to C₃ aminoalkyl. N0₂, Ci to C₃ perfluoroalkyl, 5 or 6 membered heterocychc πng containing 1 to 3 heteroatoms, COR^D, OCOR^D, or NR^ECOR^D,

R^D is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, G to C₃ alkoxy, substituted Ci to C₃ alkoxy, G to C₃ aminoalkyl, or substituted Ci to C₃ ammoalkyl,

R^E is H, Ci to C₃ alkyl, substituted C, to C₃ alkyl,

Y and Z are independent substituents taken from the group including H, halogen, CN, N0₂, amino, aminoalkyl, Ci to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkoxy, or

R⁵ is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, S0₂ or NR⁶ and containing one or two independent substituents from the group including H, halogen, CN, N0₂ amino, and Ci to C₃ alkyl, Ci to C₃ alkoxy, C, to C₃ aminoalkyl, COR^F, or NR^GCOR^F, R^F is H, Ci to C₃ alkyl, substituted C, to C₃ alkyl, aryl, substituted aryl, C, to

C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ aminoalkyl,

R^G is H, Ci to C₃ alkyl, or substituted Ci to C₃ alkyl,

R⁶ is H or Ci to C₃ alkyl,

provided that when Gi is O, G₂ is CR₇Rs. and Gi and G₂ cannot both be

R₇ and R₈ are independent substituents selected from H or an optionally substituted alkyl, aryl, or heterocychc moiety, or pharmaceutically acceptable salt thereof

Preferred compounds are those of Formula I

wherein

R¹ is H, Ci to C₆ alkyl, substituted G to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR^A, or NR^BCOR^A,

R² is H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR^A, or NR^BCOR^A, or R¹ and R² are fused to form an optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocyclic πng containing one to three heteroatoms from the group including O, S and N, as descπbed above,

R^A is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted G to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ ammoalkyl,

R^B is H, Ci to C₃ alkyl, or substituted G to C₃ alkyl,

R³ is H, OH, NH₂, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₃ to C₆ alkenyl, substituted Ci to C₆ alkenyl, alkynyl, or substituted alkynyl, COR^c,

R^c is H, Ci to C₄ alkyl, substituted Ci to C alkyl, aryl, substituted aryl, Ci to C alkoxy, substituted Ci to C₄ alkoxy, Ci to C₄ aminoalkyl, or substituted Ci to C₄ aminoalkyl,

R⁴ is H, halogen, CN, N0₂, C, to C₆ alkyl, substituted C. to C₆ alkyl, G to C₆ alkoxy, substituted Ci to C₆ alkoxy, ammo, Ci to Cβ ammoalkyl, substituted Ci to β ammoalkyl, R⁵ is a tπsubstituted benzene rmg containing the substituents X, Y and Z as shown below

X is selected from halogen, CN, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, Ci to

C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ thioalkoxy, substituted Ci to C₃ thioalkoxy, ammo, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, N0₂, Ci to C₃ perfluoroalkyl, 5 membered heterocychc ring contaimng 1 to 3 heteroatoms, COR^D, OCOR^D, or NR^ECOR^D, R^D is H, Ci to C₃ alkyl, substituted G to C₃ alkyl, aryl, substituted aryl, Ci to

C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted G to C₃ ammoalkyl,

R^E is H, Ci to C₃ alkyl, or substituted G to C₃ alkyl,

Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, N0₂, C, to C₃ alkoxy, G to C₃ alkyl, or C, to C₃ thioalkoxy, or

R⁵ is a five or six membered rmg with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, S0₂ or NR⁶ and contaimng one or two mdependent substituents from the group mcludmg H, halogen, CN, N0₂ ammo, and Ci to C₃ alkyl, C_ to C₃ alkoxy

R⁶ is H, or C, to C₃ alkyl

G₂ is CO, CS, or CR₇R₈ , with the proviso that when Gi is O, G₂ is CR₇Rs, and Gi and G₂ cannot both be CR₇Rs, wherem R₇ and R₈ are mdependent substituent selected from H, alkyl, substituted alkyl. aryl, substituted aryl, heterocychc, or substituted heterocychc or a pharmaceutically acceptable salt thereof

Still, more preferred compounds are those of Formula I

I wherem

R¹ = R² and are selected from G to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocychc alkyl constructed by fusmg R¹ and R² to form a 3 to 6 membered spirocychc πng,

R³ is H, OH, NH₂, C, to C₆ alkyl, substituted C, to C₆ alkyl, -COH, -CO(C, to C₄ alkyl) or -CO(G to C₄ alkoxy),

R⁴ is H, halogen, N0₂, Ci to C₃ alkyl, substituted G to C₃ alkyl, R⁵ is a disubstituted benzene rmg contaimng the substituents X, and Y as shown below

X is taken from the group mcludmg halogen, CN, G to C₃ alkoxy, G to C₃ alkyl, N0₂, Ci to C₃ perfluoroalkyl, 5 membered heterocychc πng contaimng 1 to 3 heteroatoms, Ci to C₃ thioalkoxy,

Y is a substituent on the 4' or 5' position from the group mcludmg H, halogen, CN. N0₂, Ci to C₃ alkoxy, C, to C₄ alkyl, C_ to C₃ thioalkoxy or

R⁵ is a five membered rmg with the structure shown below

R⁶ is H, or C, to C₃ alkyl, C, to C₄ C0₂alkyl, X' is from the group mcludmg halogen, CN, N0₂, Ci to C₃ alkyl and Ci to C₃ alkoxy,

Y' is from the group mcludmg H and Ci to C₄ alkyl or

R⁵ is a six membered rmg with the structure shown

X² is halogen, CN, alkoxy, or N0₂

provided that when Gi is O, G₂ is CR₇Rs, and Gi and G₂ cannot both be CR₇R₈, wherem R₇ and R₈ are mdependent substituents selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocychc, or substituted heterocychc, or pharmaceutically acceptable salt thereof

Still, even more prefeπed compounds are those of Formula I

I wherem

R¹ = R² and are selected from the group which mcludes CH₃ and spirocychc alkyl constructed by fusmg R¹ and R² to form a 6 membered spirocychc πng,

R³ is H, OH, NH₂, CH₃, substituted methyl, COR^c,

R^c is H, Ci to C₃ alkyl, C. to C₄ alkoxy,

R⁴ is H, halogen, C, to C₃ alkyl,

R⁵ is a disubstituted benzene πng contaimng the substituents X, and Y as shown below

X is taken from the group including halogen, CN, methoxy, N0 , 2-thιazole, Y is a substituent on the 4' or 5' position from the group mcludmg H and F, or

R⁵ is a five membered rmg with the structure shown below

U is O, S, or NH,

X' is from the group including halogen, CN, N0₂, Y' is from the group mcludmg H and Ci to C₄ alkyl G₂ is CO, CS, or CR₇R₈ provided that when Gi is O, G₂ is CR₇Rs, and Gi and G₂ cannot both be CR₇Rs,

R₇ and Rs are mdependent substituent selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocychc, or substituted heterocychc, and pharmaceutically acceptable salts thereof

The compounds of this mvention may contain an asymmetnc carbon atom and some of the compounds of this mvention may contain one or more asymmetnc centers and may thus give nse to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, the present mvention mcludes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomeπcally pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof It will be understood by one skilled m the art that the number of substituents listed for spirocychc or heterospirocychc rings formed by fusmg R, and R₂ will be determined by the size of the spirocychc πng

The term "alkyl" is used herem to refer to both straight- and branched-cham saturated aliphatic hydrocarbon groups having one to eight carbon atoms, "alkenyl" is mtended to mclude both straight- and branched-cham alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms, "alkynyl" group is mtended to cover both straight- and branched-cham alkyl group with at least one carbon-carbon tπple bond and two to eight carbon atoms

The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl" refer to alkyl, alkenyl, and alkynyl as just descπbed having one or more substituents from the group mcludmg halogen, CN, OH, N0₂, ammo, aryl, heterocychc, substituted aryl, substituted heterocychc, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety The term "aryl" is used herem to refer to an aromatic system which may be a smgle rmg or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rmgs forms the conjugated aromatic system The aryl groups mclude but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl

The term "substituted aryl" refers to aryl as just defined havmg one to four substituents from the group mcludmg halogen, CN, OH, N0₂, ammo, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio The term "heterocyclic" is used herem to describe a stable 4- to 7-membered monocychc or a stable multicychc heterocychc πng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group mcludmg N, O, and S atoms The N and S atoms may be oxidized The heterocychc πng also mcludes any multicychc πng m which any of above defined heterocychc rmgs 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 heterocychc groups mclude, for example, tetrahydrofuran, pipendinyl, piperazinyl, 2-oxopιpeπdmyl, azepmyl, pyπohdinyl, imidazolyl, pyπdyl, pyrazinyl, pyπmidmyl, pyπdazmyl, oxazolyl, isoxazolyl, morphohnyl, indolyl, qumolmyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorphohnyl, thiamorpholmyl sulfoxide, and isoquinolinyl

The term "substituted heterocychc" is used herem to descπbe the heterocychc just defined having one to four substituents selected from the group which mcludes halogen, CN. OH, N0₂, ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio The term "alkoxy" refers to the OR group, where R is alkyl or substituted alkyl The term "aryloxy" is used herem to mdicate the OR group, where R is aryl or substituted aryl The term "alkylcarbonyl" refers to the RCO group, where R is alkyl or substituted alkyl The term "alkylcarboxy" refers to the COOR group, where R is alkyl or substituted alkyl The term "ammoalkyl" refers to both secondary and tertiary amines wherem 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 mtrogen atom The term "halogen" refers to CI, Br, F, and I element

The compounds of this mvention can be prepared following the Schemes illustrated below Scheme I

R gBr, THF, rt, N₂

ArB(OH)₂, Pd(Ph₃P)₄, Na_C0₃ DME H₂O, N₂, 85 degrees C

R«COR₇, p-TSA, toulene

As demonstrated m Scheme I, the compounds of this mvention are generally prepared by employmg the suitable couphng reaction as a key step An appropπately substituted ortho-ammo benzoic acid or its deπvatives such as ethyl ester (X = Br, I, Cl, or a latent couphng precursor such as alkoxy group which can be converted mto OTf group suitable m the coupling reaction) was treated with a suitable organo metallic reagent, e g Gngnard reagent, m appropnate nonprotic solvents which mclude but are not limited to THF or ether to give ortho-ammo carbinol 2 under an inert atmosphere such as argon or mtrogen at -78 °C to room temperature The arylation of ammo carbinol 2 to yield 3 can be effected by vaπous couplmg reactions mcludmg Suzuki, Stille reactions These reactions are commonly performed in the presence of a transition metallic catalyst, e g , palladium or mckel complex often with phosphmo hgands, e g , Ph₃P, dppf, dppe or a catalyst such as palladium acetate Under this catalytic condition, an appropπately substituted nucleophihc reagent, e g , aryl boromc acid, arylstannane, or aryl zmc compound, is coupled with ammo carbinol 2 to give 3 If a base is needed m the reaction, the commonly used bases mclude but are not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, baπum carbonate, cesium fluonde, or potassium acetate The most commonly used solvents in these reactions mclude benzene, DMF, isopropanol, ethanol, DME, ether, acetone, or a mixture of above solvent and water The couphng reaction is generally executed under an inert atmosphere such as mtrogen or argon at temperatures ranging from room temperature to 95 °C The compounds of this mvention 4 can be effected by treatment of ammo carbinol 3 with an appropriate ketone m the presence of an suitable acid catalyst such as ?-toluenesulfomc acid m a suitable solvent such as toluene, benzene under an inert atmosphere such as argon or mtrogen at room temperature to reflux

Scheme II descπbes the procedure to prepare benzoxazines bearing two different substituents at posιtιon-4 The Weinreb amide 6 can be prepared from an appropπately substituted isatoic anhydπde 5 when treated with N-, O- dimethylhydroxyl-amme hydrochloπde salt m a protic solvent such as ethanol, or isopropanol at reflux under an inert atmosphere such as argon or mtrogen Couplmg of amide 6 with an aryl electrophile such as aryl boronic acid or arylstannane to give 7 can be effected by employmg a typical couphng reaction such as Suzuki, Stille coupling procedure m a similar fashion as descπbed for the preparation of compound 3 Treatment of Wemreb amide 7 with organo metallic compounds, e g , alkylhthium, alkynylhthium, arylhthium, or their Gngnard counterpart m a nonprotic solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at -78 ° to room temperature affords ammo ketone 8 Conversion of ketone 8 to carbmol 9 can be effected by treatment of 8 with an organo metallic reagent such as alkyl, alkynyl, or aryl Gngnard reagent m a nonprotic solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at -78 °C to room temperature Conversion of ketone 8 to carbmol 9 can also be effected by reduction of ketone group of 8 to the carbmol moiety of 9 using an appropnate reducmg reagent such as hthium aluminum hydπde, sodium borohydride m a suitable solvent such as THF, ether, or anhydrous alcohol under an mert atmosphere m the temperature ranging from 0 °C to the boiling pomt of the solvent Further conversion of 9 to the compounds of this mvention can be effected as descπbed m scheme I for the preparation of compound 4

EtOH, HO e e, HO, reflux

ArB(OH)₂, Pd(P ,P)₄, Na_Cα, DME H₂0, 85 degrees C, N₂

g i or R_j gX, THF, - 8 degrees C to rt

R₇ gX, -78 degrees C to it, N_ or reducing agent

Alternatively, ortho-amino ketone 8 can be prepared by treatment of ortho- amino benzonitrile 11 with an organo metalhc compound such as organo hthium reagent or Gngnard reagent in a suitable solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at temperatures ranging from -78 °C to room temperature as illustrated in Scheme III. Benzonitrile 11 can be readily prepared from an appropriately substituted benzonitrile such as bromobenzonitrile 10 using a suitable coupling reaction such as Stille or Suzuki protocol carried out in a similar fashion as described for the preparation of the Weinreb amide 7.

or Rβ gX,0 degrees C

Scheme IN illustrates the synthesis of 3,4-dιhydroquιnazohn-2-ones The substituted 2-amιno benzonitrile 11 is treated with an organo metalhc compound such as an organo hthium or Gngnard reagent m a nonprotic solvent such as THF or ether under an mert atmosphere such argon or nitrogen at -78 °C to room temperature to produce an imino intermediate which is reacted with a suitable carbonate such as diethyl carbonate or dimethyl carbonate in situ at 0 °C to 60 °C to give quιnazohn-2- ones 12 Protection of quιnazohn-2-ones 12 with a suitable protective group such as a /?αrø-methoxybenzyl moiety can be effected by treating 12 with a suitable base such as potassium hydπde, potassium t-butoxide, or sodium hydπde followed by addition of a protective reagent such as /røra-methoxybenzyl chlonde m an appropnate solvent such as DMF, or a mixture of solvents such as THF and DMF under an mert atmosphere such as mtrogen or argon at 0 °C to room temperature The Michael addition of a suitable organo metalhc compound such as organo lithium or Gngnard reagent to the protected qumazohn-2-ones 12 to give 13 can be accomphshed m the presence of a suitable Lewis acid such as magnesium tnflate in a nonprotic solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at 0 °C to room temperature

Removal of the protective group can be effected by treatmg 13 with a suitable deprotectmg reagent, e g for the αrα-methoxybenzyl protective group it can be removed by treatment of 13 with protic acid such as TFA or with Ceπc ammonium mtrate in a suitable solvent such as methylene chloπde at 0 °C to room temperature under an mert atmosphere such as argon or nitrogen Pπor to the removal of protective group, the alkylation of 3-nιtrogen can be achieved by treatmg 13 with an appropnate base such as sodium hydride, potassium hydride, or potassium t-butoxide m a suitable solvent such as DMF followed by quenching the reaction solution with an organo iodide or an organo tnflate such as lodomethane under an mert atmosphere such as argon or mtrogen at 0 °C to room temperature The compounds of the present mvention 14 can be prepared when the protective group is removed with a suitable reagent, e g for the ?αro-methoxybenzyl protective group it can be removed by treatment of 13 with protic acid such as TFA or with Cenc ammonium mtrate in a suitable solvent such as methylene chloπde at 0 °C to room temperature under an mert atmosphere such as argon or nitrogen

The conversion of compounds 14 to 3,4-dιhydroquιnazohn-2-thιones 15 can be accomphshed by treatment of 14 with a suitable sulfur reagent such as Lawesson's reagent m a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an mert atmosphere such as argon or mtrogen at reflux As illustrated m scheme N, the compounds 14 or 15 can be further deπvatized at position- 1 via numerous approaches leading to a vanety of the novel deπvatives mcludmg 1 -alkyl, substituted 1 -alkyl, 1-carbonyl, substituted 1-carbonyl, 1 -carboxy, substituted 1 -carboxy deπvatives For example, alkyl or substituted alkyl deπvatives

16 or 17 can be formed by treatment of carbamate 14 or 15 with a suitable base such as sodium hydride m a suitable solvent such as DMF under an mert atmosphere such as argon or nitrogen followed by addition of an appropnate electrophile such as alkyl or substituted alkyl bromide, iodide, or tnflate Such transformation of 14 or 15 to 16 or

17 at position- 1 can also be effected usmg biphasic condition as mdicated m scheme N m which alkylation is executed using a biphasic catalyst such as tπbutylammomum bromide in a suitable solvent such as acetonitrile A further example of such modification m position- 1 mcludes but not limited to the one depicted m scheme N m that heatmg of 14 or 15 with tnethyl orthoformate affords 1 -substituted deπvatives of compound 14 or 15

1 (X=0) 16 (X=0) 15 (X=S) 17 (X=S)

18 (X=θ)

19 (X=S)

20 (X=θ)

21 (X=S) The acylation or carboxylation of the compound 14 or 15 at position- 1 to give compound 18 or 19 can be readily effected by treatment of 14 or 15 with a suitable acylatmg or carboxylating reagent such as di-t-butyl dicarbonate m the presence of a suitable basic catalyst such as DMAP m a suitable solvent such as acetonitrile under an mert atmosphere such as argon or mtrogen The animation of position- 1 of compound 14 or 15 to give compounds 20 and 21 can be furnished using a suitable aminating reagent such as chloroamme m the presence of a suitable base such as sodium hydride in a suitable solvent such as THF or diethyl ether following the hterature procedure (Metlesics et al J Org Chem 30, 131 1(1965) ) According to scheme NI an appropnate aniline such as 4-bromoanιhne 22, is reacted m the presence of a base m a suitable nonprotic solvent with an acryloyl chlonde 23 to form the amide 24 The base is preferably a strong base such as sodium hydnde or sodium or potassium hexamethyldisilylamide, utilizing THF as the solvent under an mert atmosphere (mtrogen or argon) from 0°C up to the reflux temperature of the solvent

Scheme VI

27

Reaction of the amide 24 under strongly acidic conditions, sulfuπc acid, borontπfluoπde etherate, or preferably aluminum chloride either as a melt, or m an mert solvent (dichlorobenzenes) under an mert atmosphere (mtrogen or argon) from 0 °C up to the reflux temperature, of the solvent then provides the cyclic amide 25 Subsequent reaction of compound 25 with an aryl or heteroaryl boromc acid, boronic acid anhydπde or tnalkyl stannane then provides access to the desired biaryl compound 26 The reaction can be earned out m a solvent such as acetone, ethanol, benzene, toluene or THF. under an mert atmosphere (mtrogen or argon) from 0 °C up to the reflux temperature of the solvent, m the presence of a palladium catalyst such as tetrakιs(tπphenylphosphιne) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluonde or potassium phosphate

The conversion of compounds 26 to thioamide 27 can be accomplished by treatment of 26 with a suitable sulfur reagent such as Lawesson's reagent m a nonprotic solvent such as o-xylene, chlorobenzene, or toluene under an mert atmosphere such as argon or mtrogen at reflux

Scheme VII

30

29

31 According to scheme Nil, an appropnate cychc amide such as 25, is allowed to react with ΝaH m THF to form the amon species and then a benzyl hahde is added to convert the starting material to the Ν-protected amide product, 28 Reaction of 28 with an aryl boromc acid m the presence of a palladium catalyst such as tetrakιs(tπphenylphosphme)palladιum(0) or palladium acetate permits a couplmg of the two aromatic species to yield 29 The reaction is normally earned out under biphasic conditions That is, water is often employed along with an appropnate orgamc solvent, such as toluene or DMF The palladium catalyst is typically added last and the reaction mixture is refluxed m the presence of an mert gas such as mtrogen The product is treated with a Gngnard Reagent, an alkyl magnesium halide, m THF followed by the addition of ammonium chlonde solution to afford the enarmne deπvative 30 The reduction of the double bond m 30 and removal of the protectmg group can be accomphshed m a smgle step by catalytic reduction m a Parr Hydrogenation Apparatus usmg palladium on charcoal to form the target compound 31.

Scheme Nm

ΝaCΝBH,

35 3-Fluoro-5-(2,4,4-tπmethyl-l,2,3,4-hydro-qmohnyl)-benzomtπle (compound 35) can be prepared by Scheme NIII ,a process similar to Scheme Nil According to scheme VIII, compound 28 is allowed to react with a Gngnard reagent, an alkyl magnesium halide, m THF followed by the addition of ammonium chloπde solution to afford the enamine deπvative 32 Reduction of the double bond with sodium cyanoborohydπde affords the reduced denvative 33 Removal of the protectmg group with a strong acid such as tnflic or sulfuπc acid affords the deprotected compound 34 which can then be coupled with a suitably substituted phenylboromc acid m the presence of a palladium catalyst such as tetrakis(tnphenylphosphme)palladium(0) or palladium acetate permits a couplmg of the two aromatic species to yield 35 The reaction is normally carried out under biphasic conditions That is, water is often employed along with an appropnate orgamc solvent, such as toluene or DMF

The compounds of the present mvention can be used m the form of salts denved from pharmaceutically or physiologically acceptable acids or bases These salts mclude, but are not hmited to, the following salts with morgamc acids such as hydrochloπc acid, sulfuπc acid, mtπc acid, phosphoric acid and, as the case may be, such orgamc acids as acetic acid, oxalic acid, succinic acid, and maleic acid Other salts mclude salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium m the form of esters, carbamates and other conventional "pro-drug" forms, which, when admimstered m such form, convert to the active moiety in vivo

This mvention mcludes pharmaceutical compositions and treatments which compπse administering to a mammal a pharmaceutically effective amount of one or more compounds as descnbed above wherem G₂ is C=0 as antagomsts of the progesterone receptor The mvention further provides comparable methods and compositions which utilize one or more compounds herem wherem G₂ is C=S as agomsts of the progesterone receptor Moreover the mvention further provides comparable methods and compositions which utilize one or more compounds herem wherem G=0 and G₂ =CR₇CRs are agomsts of the progesterone receptor and when and are agomsts of the progesterone receptor

The progesterone receptor antagomsts of this mvention, used alone or m combmation, can be utilized m methods of contraception and the treatment and/or prevention of bemgn and malignant neoplastic disease Specific uses of the compounds and pharmaceutical compositions of mvention mclude the treatment and/or prevention of uterine myometπal fibroids, endometnosis, bemgn prostatic hypertrophy, carcinomas and adenocarcinomas of the endometπum, ovary, breast, colon, prostate, pituitary, memngioma and other hormone-dependent tumors Additional uses of the present progesterone receptor antagomsts mclude the synchromzation of the estrus m hvestock When used m contraception the progesterone receptor antagomsts of the current mvention may be used either alone m a continuous administration of between 1 and 500 mg per day, or alternatively used m a different regimen which would entail 2-4 days of treatment with the progesterone receptor antagomst after 21 days of a progestm, m this regimen between 0 1 and 500 mg daily doses of the progestm (e g levonorgestrel, tnmegestone, gestodene, norethistrone acetate, norgestimate or cyproterone acetate) would be followed by between 0 1 and 500 mg daily doses of the progesterone receptor antagomsts of the current mvention

The progesterone receptor antagomsts of this mvention, used alone or m combmation, can also be utihzed m methods of treatment and/or prevention of bemgn and malignant neoplastic disease Specific uses of the compounds and pharmaceutical compositions of mvention mclude the treatment and/or prevention of uterine myometnal fibroids, endometnosis, bemgn prostatic hypertrophy, carcinomas and adenocarcinomas of the endometnum, ovary, breast, colon, prostate, pituitary, memngioma and other hormone-dependent tumors Additional uses of the present progesterone receptor antagomsts mclude the synchronization of the estrus in hvestock The progesterone receptor agonists of this mvention, used alone or m combmation, can be utilized m methods of contraception and the treatment and/or prevention of dysfunctional bleedmg, uterme leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometπum, ovary, breast, colon, prostate Additional uses of the mvention mclude stimulation of food mtake

When used m contraception the progesterone receptor agomsts of the current mvention are preferably used m combmation or sequentially with an estrogen agomst (e g ethmyl estradiol) The prefeπed dose of the progesterone receptor agomst is between 0 01 and 500 mg per day When the compounds are employed for the above utilities, they may be combmed with one or more pharmaceutically acceptable earners or excipients, for example, solvents, diluents and the hke, and may be admimstered orally m such forms as tablets, capsules, dispersible powders, granules, or suspensions contaimng, for example, from about 0 05 to 5% of suspendmg agent, syrups contaimng, for example, from about 10 to 50% of sugar, and elixirs contaimng, for example, from about 20 to 50% ethanol, and the hke, or parenterally m the form of steπle injectable solutions or suspensions contaimng from about 0 05 to 5% suspendmg agent m an isotomc medium Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient m combmation with the earner, more usually between about 5% and 60% by weight

The effective dosage of active ingredient employed may vary dependmg on the particular compound employed, the mode of administration and the severity of the condition bemg treated However, m general, satisfactory results are obtained when the compounds of the mvention are admimstered at a daily dosage of from about 0 5 to about 500 mg/kg of animal body weight, preferably given m divided doses two to four times a day, or m a sustained release form For most large marnmals, 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 m intimate admixture with a solid or liquid pharmaceutically acceptable carrier This dosage regimen may be adjusted to provide the optimal therapeutic response For example, several divided doses may be admimstered daily or the dose may be proportionally reduced as mdicated by the exigencies of the therapeutic situation These active compounds may be admimstered orally as well as by mtravenous, intramuscular, or subcutaneous routes Sohd earners mclude starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolm, while liquid earners mclude sterile water, polyethylene glycols, non-iomc surfactants and edible oils such as corn, peanut and sesame oils, as are appropnate to the nature of the active ingredient and the particular form of admimstration desired Adjuvants customarily employed m the preparation of pharmaceutical compositions may be advantageously mcluded, 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 admimstration are sohd compositions, particularly tablets and hard- filled or hquid-filled capsules Oral admimstration of the compounds is prefeπed

These active compounds may also be admimstered parenterally or mtrapeπtoneally Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared m water suitably mixed with a surfactant such as hydroxypropylceUulose Dispersions can also be prepared m 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 injectable use mclude 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 steπle 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 contaminatmg action of microorganisms such as bacterial and fungi The carrier can be a solvent or dispersion medium contaimng, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil

The following non-hmitmg examples illustrate preparation of compounds of the mvention

EXAMPLE 1 l-f4-Amino-3'-chloro-biphenyl-3-yl)-ethanone

A mixture of 2-ammo-5-bromo-N-methoxy-N-methylbenzamιde (7 78g, 30 mmol), 3-chlorophenyl boromc acid (5 63g, 36 mmol), tetrakιs(tπphenylphosphme)palladιum (0) (1 73g, 1 5 mmol), and sodium carbonate (7 63 g, 72 mmol) m a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and was then heated at 85 °C under mtrogen for 3 hours The reaction mixture was cooled to room temperature and treated with bnne (30 mL) and ethyl acetate (100 mL) The orgamc layer was separated and aqueous layer was extracted with ethyl acetate (3x40 mL) The combmed organic layers were washed with bnne and dned with MgS0₄ After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane ethyl acetate/1 1) to give 5-(3- chlorophenyl)-N-methoxy-N-methylbenzamιde as a brown oil (5g, 57%) To a solution of this benzamide (5g, 17 2 mmol) m anhydrous THF was added m a dropwise fashion a solution of methylhthium m ether (1 4M, 28 6 mL, 40 mL) at -78 °C under mtrogen After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammomum chloride solution (50 mL) at -78 °C Ethyl acetate (100 mL) was added, the orgamc layer was separated, and the aqueous layer was extracted with ethyl acetate (3x20 mL) The combmed orgamc layers were washed (bnne) and dned (MgS0₄) After removal of solvent, the residue was purified by a flash chromatography (sihca gel, hexane ethyl acetate/2 1) to afford l-(4-amιno-3'- chloro-bιphenyl-3-yl)-ethanone as yellow solid (2g, 47%) mp 89-90 °C, Η-NMR (CDC1₃) δ 7 89 (d, IH, J= 2 0 Hz), 7 51 (m, 2H), 7 25-7 40 (m, 3H), 6 73 (d, IH, J = 8 6 Hz), 6 38 (br, 2H), 2 65 (s, 3H), MS (El) m/z 268([M+Na]⁺, 60%), Anal Calc For C_I4Hι₂ClNO C, 68 44, H, 4 92, N, 5 70 Found C, 68 40, H, 4 89, N, 5 61

EXAMPLE 2 l-(4-Amino-3'-chloro-biphenyl-3-yl)-dimethyl-methanol

To a solution of l-(4-ammo-3'-chloro-bιphenyl-3-yl)-ethanone ( 55g, 2 2 mmol) m anhydrous THF under mtrogen was added a solution of methyl magnesium bromide (3 0 M m diethyl ether, 1 mL, 3 mmol) at 0 °C The mixture was slowly warmed to room temperature and kept stirring under mtrogen for 18 hours The mixture was treated with 10 mL of saturated ammomum chloπde aqueous solution and ethyl acetate (50 mL) was added The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x15 mL) The combmed organic layers were washed with bnne (20 mL) and dned (MgS0₄) After removal of the solvent, the residue was punfied by a flash chromatography (sihca gel, hexane ethyl acetate/2 1) to afford the title compound as an off-white sohd 186-188 °C (HCl salt) Anal Calc For Cι₅Hι₇Cl₂NO C, 60 42, H, 5 75, N, 4 7 Found C, 60 51, H, 5 62, N, 4 56

EXAMPLE 3 6-(3-Chloro-phenyl)-2_<4,4-trimethyl-2-trifluoromethyl-l,4-dihvdro-2H- benzofdl f l,31oxazine

A mixture of (4-amιno-3 -chloro-bιphenyl-3-yl)-dιmethyl-methanol (0 25 g, 0 95 mmol), tnfluoromethylacetone (0 16 g, 1 43 mmol), and/.-toluenesulfonιc acid (0 01 g, 0 05 mmol) in dry toluene (5 mL) was stured under a blanket of mtrogen for 48 hours Upon completion of the reaction, the toluene was removed and the residue purified via flash chromatography (silica gel, 10% ethyl acetate/hexane) to give 6-(3- chloro-phenyl)-2,4,4-tnmethyl-2-tnfluorometh} 1- 1 ,4-dιhydro-2H-benzo[d] [1,3]- oxazme (0 22 g, 65%) as a clear oil The oil was dissolved m ether at -78 °C and then treated with a solution of IN HCl m ether to give the hydrochloπde salt of the title compound as a white solid ^]H-NMR (OMSO-d₆) δ 7 67 (bs, IH), 7 58 (d, IH, J = 7 88 Hz), 7 42 (m, 3H), 7 32 (d, IH, _/= 7 96 Hz), 6 84 (d, IH, J= 8 03 Hz), 1 52 (s, 3H), 1 5 (s, 6H), MS (APCI) m/z 354 ([M-H] , 100%), Anal Calc For Ci8H,₇ClF₃NO C, 55 12, H, 4 62, N, 3 57 Found C, 54 97, H, 4 59, N, 3 41

EXAMPLE 4 6-(3-Chloro-phenyl)-2,2,4,4-tetramethyI-l,4-dihvdro-2H-benzoldlfl,31oxazine

A mixture of (4-ammo-3 -chloro-bιphenyl-3-yl)-dιmethyl-methanol (0 46 g, 1 8 mmol), acetone (0 16 g, 2 7 mmol), and »-toluenesulfomc acid (0 017 g, 0 09 mmol) m dry toluene (6 mL) was heated at 33 °C under a blanket of mtrogen overnight Upon completion of the reaction, the toluene was removed and the compoimd purified via a flash chromatography (sihca gel, 15% ethyl acetate/hexane) to give 6-(3-chloro- phenyl)-2,2,4,4-tetramethyl-l,4-dιhydro-2H-benzo[d][l,3]oxazme (0 36 g, 68%) as a yellow oil The oil was dissolved m ether at -78 °C and then treated with a solution of IN HCl m ether to give the hydrochlonde salt of the title compound as a yellow sohd 'H-NMR DMSO-d₆) δ 7 70 (bs, IH), 7 61 (d, IH, J= 7 82 Hz), 7 52 (bs, IH), 7 44 (m, 2H), 7 33 (d, IH, J= 8 21 Hz), 6 87 (d, IH, J= 1 85 Hz), 1 5 (s, 6H), 1 4 (s, 6H), MS (ESI) m/z 302 ([M+H]⁺, 100%), Anal Calc For C,₈H₂oClNO C, 63 91, H, 6 26, N, 4 14 Found C, 64 08, H, 6 43, N, 4 14

EXAMPLE 5 6-(3-Nitro-phenyl)-2,2,4,-trimethyl-l,4-dihydro-2H-benzoldUl,31oxazine

Prepared from l-(4-amιno-3'-nιtro-bιphenyl-3-yl)-ethanol and acetone m the same fashion as that of Example 4 Yellow sohd mp 188-189 °C, Anal Calc For C₁₇H₁₈N₂0₃ 0 35 H₂0 C, 67 02, H, 6 19, N, 9 20 Found C, 66 7, H, 5 89, N, 9 03 EXAMPLE 6 4-Amino-3'-chloro-biphenyl-3-carbonitrile

A mixture of 2-ammo-5-bromobenzomtnle (lOg, 50 mmol), 3-chlorophenyl boromc acid (9 5g, 60 mmol), tetrakιs(tπphenylphosphme)-palladιum (0) (3 5g, 3 mmol), and sodium carbonate (13g, 120 mmol) m a mixture of DME and water (100 mL/25 mL) was degassed to remove the oxygen and then heated to 85 °C under a blanket of mtrogen for 5 hours The reaction mixture was cooled to ambient temperature and quenched with a saturated aqueous ammomum chlonde solution (80 mL) Ethyl acetate (200 mL) was added, the orgamc layer was separated, and the aqueous layer was extracted with ethyl acetate (3x40 mL) The combmed organic layers were washed with bnne and dned with MgS0₄ The solvent was removed in vacuo and the residue was purified by a sihca gel flash chromatography (hexane ethyl acetate/4 1) to afford 4-ammo-3'-chloro-bιphenyl-3-carbonιtnle as an off-white sohd (8g, 87%) mp 118-119 °C, Η-NMR (DMSO-a?₆) δ 7 80 (d, IH, J = 2 3 Hz), 7 65- 7 72 (m, 2H), 7 57 (d, IH, J= 8 0 Hz), 7 42 (t, IH, J= 7 9 Hz), 7 31 (m, IH), 6 87 (d, IH, J= 8 7 Hz), 6 29 (br, 2H), Anal Calc For C_I3H₉C_N₂ C, 68 28, H, 3 97, N, 12 25 Found C, 67 68, H, 4 06, N, 11 89

EXAMPLE 7

6-(3-Chlorophenyl)-4-cvcIopropyl-lH-αuinazolin-2-one

Prepared usmg a similar procedure as descπbed m the hterature (Tucker et al J Med Chem , 1994, 37, 2437-2444) To a solution of cyclopropylmagnesium bromide prepared from magnesium (0 9g, 37 mmol) and cyclopropyl bromide (3 2 mL, 40 mmol) m anhydrous THF was added at 50 °C under mtrogen a solution of 4-amιno- 3'-chloro-bιphenyl-3-carbomtπle (2 3g, 10 mmol) m anhydrous THF After addition, the reaction mixture was kept at 50 °C for 30 minutes under mtrogen and treated with dimethyl carbonate m a dropwise manner The reaction solution was stirred at 50 °C under mtrogen for 30 minutes and cooled to ambient temperature A saturated aqueous ammomum chloπde solution (30 mL) was added followed by addition of ethyl acetate (80 mL) The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x40 mL) The combmed orgamc layers were washed with bnne and dned with MgS0₄ After removal of the solvent, the residue was purified by a flash chromatography (sihca gel, methylene chloride methanol/25 1) to give 6-(3- chlorophenyl)-4-cyclopropyl-lH-qumazolm-2-one as a yellowish sohd (0 55g, 18%) mp 189-190 °C, Η-NMR DMSO-d₆) δ 11 71 (s, IH, D₂0 exchangeable), 8 56 (d, IH, J= 1 3 Hz), 8 09 (dd, IH, J- 8 6, 1 6 Hz), 7 92 (s, IH), 7 77 (d, IH, J= 7 7 Hz), 7 52 (t, IH, J= 7 9 Hz), 7 45 (d, IH, J= 8 1 Hz), 7 36 (d, IH, J = 8 6 Hz), 3 15 (m, IH), 1 20 (m, 4H), MS (CI) m/z 297 ([M+H]⁺, 100%), Anal Calc For C₁₇H₁₃C1N₂0 C, 69 98, H, 4 49, N, 9 23 Found C, 67 98, H, 4 46, N, 9 10

EXAMPLE 8 6-(3-Chlorophenyl)-4-cvclopropyl-l-(4-methoxybenzyl)-lH-quinazolin-2-one

To a suspension of 6-(3-chlorophenyl)-4-cyclopropyl-lH-qumazohn-2-one (0 5g, 1 68 mmol) m anhydrous DMF was added potassium hexamethylsilyl amide (0 45g, 2 1 mmol) at ambient temperature under mtrogen The reaction mixture was stirred at ambient temperature for 30 minutes, treated with -methoxy benzyl chloride (0 35 mL, 2 5 mmol), and heated at 55 °C for 5 hours The mixture was then cooled to room temperature and quenched with a saturated aqueous ammomum chlonde solution (10 mL) Methylene chloπde (50 mL) was added and orgamc layer was separated The aqueous layer was extracted with methylene chloπde (2x20 mL) and the combmed orgamc layers were washed with brme and dried (MgS0₄) After removal of solvent, the residue was separated on a flash chromatography (sihca gel, hexane ethyl acetate/1 1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-l-(4- methoxybenzyl)-lH-quιnazohn-2-one as an off-white sohd mp 173-174 °C, Η-NMR (DMSO-< ) δ 8 65 (d, IH, J= 1 8 Hz), 8 10 (dd, IH, J= 8 9, 1 8 Hz), 7 93 (d, IH, J = 1.6 Hz), 7.79 (d, IH, J= 7.6 Hz), 7.53 (d, 2H, J= 8.4 Hz), 7.46 (t, IH, J= 8.1 Hz), 7.21 (d, 2H, J= 8.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 5.41 (s, 2H), 3.73 (s, 3H), 3.18 (m, IH), 1.18-1.27 (m, 4H); MS (CI) m/z 417([M+H]⁺, 100%); Anal. Calc. For C₂₅H₂₁C1N₂0₂: C, 72.02, H, 5.08, N, 6.72. Found: C, 71.88, H, 4.91, N, 6.70. 6-(3-Chlorophenyl)-4-cyclopropyl-2-(4-methoxybenzyloxy)quinazoline was obtained as a side product, off-white sohd: mp 158-159 °C; Η-NMR (OM$>0-d₆) δ 8.75 (d, lH, J= 1.7 Hz), 8.26 (dd, 1H, J= 8.8, 1.8 Hz), 8.01 (s, IH), 7.84 (m, 2H), 7.56 (t, IH, J= 7.9 Hz), 7.45 (m, 3H), 6.96 (d, 2H, J= 8.6 Hz), 5.38 (s, 2H), 3.75 (s, 3H), 3.24 (m, IH), 1.25 (m, 4H); MS (CI) m/z 417([M+H]⁺, 100%); Anal. Calc. For C₂₅H₂₁C1N₂0₂: C, 72.02, H, 5.08, N, 6J2. Found: C, 72.19, H, 4.91, N, 6.65.

EXAMPLE 9 6-(3-Chloropheny0-4-cvclopropyl-4-methyl-3,4-dihvdro-lH- quinazolin-2-one To a solution of 6-(3-chlorophenyl)-4-cyclopropyl-l-(4-methoxybenzyl)-lH- quinazolin-2-one (0.25g, 0.6 mmol) in anhydrous ether was added, at ambient temperature under nitrogen, magnesium triflate (0.78g, 2.4 mmol). The mixture was stirred for 30 minutes and treated with a solution of methylmagnesium bromide in ether (3.0 M, 1.0 mL, 3.0 mmol). The reaction mixture was kept at room temperature under nitrogen for 3 hours and quenched with a mixture of a saturated aqueous ammonium chloride solution (10 mL) and IN aqueous HCl solution (5 mL). The mixture was stirred at room temperature for 20 minutes and ethyl acetate (40 mL) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine and dried (MgS0₄). The solvent was removed and a half portion of the residue was dissolved in TFA (3 mL) and was stirred under nitrogen at room temperature for 72 hours. The solution was poured onto ice-water and the white precipitate obtained was collected on a filter. The solid was washed with water and then purified by a flash chromatography (methylene chlonde methanol/25 1, silica gel) to give 6-(3- chlorophenyl)-4-cyclopropyl-4-methyl-3,4-dιhydro-lH-qumazolm-2-one as off- white sohd(40 mg, 43%) mp 125-127 °C, Η-NMR (OMSO-d₆) δ 9 21 (s, IH), 7 71 (s, IH), 7 61 (d, IH, J= 7 8 Hz), 7 55 (d, IH, J= 1 6 Hz), 7 47 (dd, IH, J= 8 3, 1 8 Hz), 7 45 (t, IH, J = 1 8 Hz), 7 36 (d, IH, J= 8 1 Hz), 6 84 (d, IH, J = 8 2 Hz), 6 79 (s, IH), 1 54 (s, 3H), 1 11 (m, IH), 0 42 (m, IH), 0 15-0 20 (m, 3H), MS (ESI) m/z 313([M+H]⁺, 100%)

EXAMPLE 10 6-(3-Chlorophenyl)-4-cvclopropyl-3,4-dimethyl-3,4-dihvdro-lH-quinazoϋn-2-one To a solution of half of the crude addition product from Example 9 m anhydrous DMF (5 mL) was added under mtrogen at room temperature sodium hydπde (25 mg, 0 63 mmol) The mixture was stiπed at ambient temperature for 30 minutes and treated with methyl iodide (0 5 mL, excess) After stirring for 3 5 hours, a mixture of saturated aqueous ammomum chlonde and IN HCl aqueous solution (10 mL/5 mL) was added to the reaction mixture Ethyl acetate (30 mL) was added and orgamc layer was separated The aqueous layer was extracted with ethyl acetate (3x10 mL) and the combmed orgamc layers were washed with bnne and dned (MgS0₄) The solvent was removed and residue was dissolved m a mixture of methylene chlonde and TFA (2 mL/2 mL) After stirring for 3 hours, the solution was poured onto ice-water and neutralized by addition of a saturated aqueous sodium bicarbonate solution The ethyl acetate (30 mL) was added and orgamc layer was separated The aqueous layer was extracted with ethyl acetate (3x10 mL) The combmed orgamc layers were washed with bnne and dried (MgS0 ) The solvent was removed in vacuo and the residue was purified by a flash chromatography (sihca gel, hexane ethyl acetate/1 1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-3,4-dimethyl-3,4-dihydro-lH-qumazohn-2- one as a white sohd (11 mg, 11% for three steps) mp 193-194 °C, Η-NMR (DMSO- d₆) δ 9 51 (s, IH), 7 68 (s, IH), 7 59 (d, IH, J - 8 0 Hz), 7 57 (d, IH, J= 1 6 Hz), 7 51 (dd, 1H, J = 8 3, 1 7 Hz), 7 46 (t, 1H, J= 7 8 Hz), 7 35 (d, 1H, J= 8 1 Hz), 6 87 (d, IH, J= 8 3 Hz), 3 02 (s, 3H), 1 51 (s, 3H), 1 25 (m, IH), 0 32-0 51 (m, 3H), 0 25 (m, IH), MS (CI) m/z 327 ([M+Hf, 100%) Anal Calc For C₁₉Hι₉ClN₂O 0 3 H₂0 C, 68 69, H, 5 95, N, 8 43 Found C, 68 69, H, 5 70, N, 8 18

EXAMPLE 11 6-(3-Chloro-phenyl)-4,4-dimethyl-3,4-dihvdro-lH-quinoIin-2-one

Sodium hydπde (1 16 g, ca 29 mmol, 60% in oil) was washed with hexane (x3) then placed in anhydrous THF (50 mL) under mtrogen To this slurry was then added dropwise a solution of 4-bromoamhne (5 0 g, 29 mmol) m dry THF (100 ml) After

0 5 h, the mixture was cooled to 0 °C and treated with a solution of 3,3- dimethylacryloyl chloπde m anhydrous THF (30 ml) After 4 h, the mixture was quenched with saturated aqueous ammomum chlonde solution, and extracted with diethyl ether The orgamc layer was washed with water, brme, dned (Na₂S0 ) and evaporated The residue was then crystallized from EtOAc/hexane to afford N-(3,3'- dιmethylacryoloyl)-4-bromoanιhne (3 36 g, 13 22 mmol, 46%) as a white solid Η NMR (CDC1₃) δ 7 42 (s, 4H), 7 06 (s, IH), 5 68 (s, IH), 2 21 (s, 3H), 1 09 (s, 3H), MS (El) m/z 253 [M⁺]

N-(3,3'-Dιmethylacryoloyl)-4-bromoamhne (4 0 g, 15 38 mmol) was heated under mtrogen to ca 130 - 140 °C causmg the solid to melt Alummum chlonde (3 07 g, 23 mmol) was added and heatmg contmued After 1 h, the mixture was cooled and quenched carefully with water and then extracted with dichloromethane (3x60 mL) The combmed organic layers were washed with water, dned (MgS0₄) and evaporated The residue was then subjected to column chromatography (Sι0₂, EtOAc/hexane gradient elution) to afford 6-bromo-4,4-dιmethyl-3,4-dιhydro-lH-quιnolιn-2-one (1 69g, 6 6 mmol, 47%) as a white solid Η-NMR (CDC1₃) δ 8 82 (s, IH), 7 39 (d, IH, J= 2 Hz), 7 29 (dd, IH, J= 8 3, 2 0 Hz), 6 71 (d, IH, J = 8 0 Hz), 2 47 (s, 2H),

1 32 (s, 6H) To a solution of the last cited compound (0 5 g, 1 96 mmol) m dimethoxyethane (15 mL) was added tetrakιs(tnphenylphosphιne)palladιum (0) (0 11 g, 0 09 mmol) under mtrogen After 15 mm , 3-chlorophenylboronιc acid (0 6 g, 3 9 mmol) was added followed by potassium carbonate (1 62 g, 11 7 mmol) m water (7 5 mL) After 1 5 h at reflux, the mixture was cooled, filtered, and extracted with EtOAc The organic layer was washed with water, dned (MgS0 ) and evaporated The residue was then subjected to column chromatography (Sι0₂, EtOAc hexane/3 1) and crystallized from dichloromethane/hexane to afford 6-(3-chloro-phenyl)-4,4- dιmethyl-3,4-dιhydro-lH-qumolm-2-one (0 21 g, 0 73 mmol, 37%) as a white sohd, mp 211 - 215 °C, ^!H-NMR (CDC1₃) δ 8 48 (s, IH), 7 53 (s, IH). 7 47 (d, IH, J= 2 0 Hz), 7 44 - 7 29 (m, 4H), 6 87 (IH, d, _/= 2 0 Hz), 2 54 (s, 2H), 1 39 (s, 6H), MS ((- )ES) m/z 284 [M-H]^"

EXAMPLE 12 - Pharmacology The compounds of this mvention were tested m the relevant assay as descnbed below and their potency are m the range of 0 01 nM to 5 μM m the in vitro assays and 0 001 to 300 mg/kg m the in vivo assays The selected examples are listed below

hPR CV-1

Compound Ri R₂ R₃

ICso (nM)

Me Me CI 10.0

CF₃ Me CI 50.0

Me H N0₂ 1675

R = H, hPR CV-1, ICso = 1075 nM hPR CV-1, ICso = 1075 nM R = Me, hPR CV-1, ICso = 580 nM A In-vitro biology

The m- vitro biology is determined by (1) competitive Radiohgand Bmdmg usmg 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 Antagomst IC50 values, (3) a T47D cell proliferation, which is a further functional assay which also provides agomst and antagomst data, and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agomst and antagomst data

1. hPR B dmg assay - This assay is earned out in accordance with Pathirana, C , Stem, R B , Berger, T S , Femcal, W , lamro, T , Mais, D E , Tones, 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 m CN-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 m CN-1 cells co-transfected with human PR and PRE-luciferase plasmids The materials methods used m the assay are as follows a Medium The growth medium was as follows DMEM (BioWhittaker) contaimng 10% (v/v) fetal bovme serum (heat mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml pemcilhn, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) The expenmental medium was as follows

DMEM (BioWhittaker), phenol red-free, contaimng 10% (v/v) charcoal-stπpped fetal bovme serum (heat-mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Cell culture, transfection. treatment, and luciferase assay

Stock CN-1 cells are maintained m growth medium Co-transfection is done usmg 1 2x10⁷ 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 somcated calf thymus DΝA as earner DΝA m 250 ml Electroporation is earned out at 260 N and 1,000 mF in a Biorad Gene Pulser II After electroporation, cells are resuspended m growth medium and plated m 96-well plate at 40,000 cells/well m 200 μl Following overnight mcubation, the medium is changed to expenmental mediu Cells are then treated with reference or test compounds m expenmental medium Compounds are tested for antiprogestational activity m 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) Fifty μl of cell lysis buffer (Promega, Madison, WI) is added to each well and the plates are shaken for 15 mm m a Titer Plate Shaker (Lab Lme Instrument, Inc ) Luciferase activity is measured usmg luciferase reagents from Promega c Analysis of Results

Each treatment consists of at least 4 replicates Log transformed data are used for analysis of vanance and nonlinear dose response curve fittmg for both agomst and antagomst modes Huber weightmg is used to downweight the effects of outhers EC₅₀ or IC₅₀ values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of vanance and non- near response analyses d 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 EC₅₀ or IC₅₀ values are calculated Table 2. Estimated EC50, 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 0.616 0.026 0.509 0.746

2 0.402 0.019 0.323 0.501

3 0.486 0.028 0.371 0.637

Tnmegestone 1 0.0075 0.0002 0.0066 0.0085

2 0.0081 0.0003 0.0070 0.0094

3 0.0067 0.0003 0.0055 0.0082

Table 3. Estimated ICso, standard error (SE), and 95% confident interval (CI) for the antiprogestin, RU486 from three individual studies

IC 50 95% CI

Compound Exp. (nM) SE lower upper

RU486 1 0.028 0.002 0.019 0.042

2 0.037 0.002 0.029 0.048 3 0.019 0.001 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)

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

IC₅₀: 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 usmg a cell proliferation assay m T47D cells A compound's effect on DNA synthesis m T47D cells is measured The materials and methods used this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovme serum (not heat- lnactivated), lOOU/ml pemcilhn, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Treatment medium Minimum Essential

Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with 05% charcoal stripped fetal bovme serum, lOOU/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) c Cell culture Stock T47 D cells are maintained m growth mediu For BrdU incorporation assay, cells are plated m 96-well plates (Falcon, Becton Dickinson Labware) at 10,000 cells/well m growth medium After overnight mcubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment Stock compounds are dissolved in appropnate vehicle (100% ethanol or 50% ethanol/50% DMSO), subsequently diluted m treatment medium and added to the cells Progestm and antiprogestm reference compounds are run m full dose-response curves The final concentration of vehicle is 0 1% In control wells, cells receive vehicle only Antiprogestms are tested m the presence of 0 03 nM tnmegestone, the reference progestm agomst Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arhngton Heights, IL) m treatment medium for 4 hr d Cell Proliferation Assay At the end of BrdU labehng, the medium is removed and BrdU mcorporation is measured usmg a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) accordmg to manufacturer's instructions Bnefly, cells are fixed m an ethanol contaimng fixative for 30 mm, followed by mcubation m a blockmg 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 sulfuπc 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 vanance and nonlinear dose response curve fittmg for both agomst and antagomst modes Huber weightmg is used to downweight the effects of outhers EC₅₀ or IC₅₀ values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of vanance and non-hnear dose response analyses m both smgle dose and dose response studies f Reference Compounds Tnmegestone and medroxyprogesterone acetate (MPA) are reference progestms and RU486 is the reference antiprogestm All reference compounds are run in full dose-response curves and the EC₅₀ or IC₅₀ values are calculated

Table 4. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for individual studies

Compound Exp (nM) SE lower upper

Tnmegestone 1 0 017 0 003 0 007 0 040

2 0 014 0 001 0 011 0 017

3 0 019 0 001 0 016 0 024

MPA 1 0 019 0 001 0 013 0 027

2 0 017 0 001 0 011 0 024

Table 5. Estimated ICso, standard error, and 95% confident interval for the antiprogestin, RU486

Compoimd Exp (nM) SE lower upper

RU486 1 0 011 0 001 0 008 0 014

2 0 016 0 001 0 014 0 020

3 0 018 0 001 0 014 0 022

EC₅₀ Concentration of a compound that gives half-maximal mcrease m BrdU incorporation with SE, IC50 Concentration of a compound that gives half-maximal decrease m 0 1 tnmegestone mduced BrdU incorporation with SE 4 T47D cell alkaline phosphatase assay

The purpose of this assay is to identify progestins or antiprogestins by determinmg a compound's effect on alkahne phosphatase activity m T47D cells The materials and methods used m this assay are as follows a Culture medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 5% (v/v) charcoal stnpped fetal bovme serum (not heat-mactivated). lOOU/ml pemcilhn, 100 μg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) b Alkaline phosphatase assay buffer I 0 1 M Tns-HCl, pH 9 8, contaimng 0 2% Tπton X-100

II 0 1 M Tns-HCl, pH 9 8 contaimng 4 mM p-mtrophenyl phosphate (Sigma) c Cell Culture and Treatment

Frozen T47D cells were thawed m 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 in the culture medium was then added to each well When testmg for progestm antagomst activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C m a 5% C0₂/humιdιfied atmosphere for 24 hr d Alkaline 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 mtervals 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 curve is generated for dose (X-axis) vs the rate of enzyme reaction (slope) (Y-axis) Square root-transformed data are used for analysis of vanance and nonlinear dose response curve fittmg for both agomst and antagomst modes Huber weightmg is used to downweight the effects of outliers EC₅₀ or IC₅₀ values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of variance and non-hnear dose response analyses m both smgle dose and dose response studies f Reference Compounds Progesterone and tnmegestone are reference progestins and RU486 is the reference antiprogestm All reference compounds are nm m full dose response curves and the EC₅₀ or IC₅o values are calculated

Table 6. 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 uooer

Progesterone 1 0 839 0 030 0 706 0 996

2 0 639 0 006 0 611 0 669

3 1 286 0 029 1 158 1 429

Tnmegestone 1 0 084 0 002 0 076 0 091

2 0 076 0 001 0 072 0 080

3 0 160 0 004 0 141 0 181

Table 7. Estimated IC50_. standard error, and 95% confident interval for the reference antiprogestin RU486 from three independent experiments

IC 50 95% CI

Compound Exp (nM) SE lower upper

RU486 1 0 103 0 002 0 092 0 115

2 0 120 0 001 0 115 0 126

3 0 094 0 007 0 066 0 134 B. In-vivo Biology

The primary m-vivo assay is the rat decidua zation model which may be used to determine progestational effects of both agomsts and antagomsts The secondary ln- vivo assay is the rat ovulation inhibition model which is under development and hence the protocol is un-available

1 Rat deciduahzation assay The objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uterine deciduahzation and compare the relative potencies of various test compounds The mateπals and methods used m this assay are as follows a Methods: Test compounds are dissolved m 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil (Mazda™¹) re then prepared by heatmg (-80 °C) the mixture to evaporate ethanol Test compounds are subsequently diluted with 100% corn oil or 10% ethanol m corn oil pπor to the treatment of ammals No difference m decidual response was found when these two vehicles were compared b Ammals (RACUC protocol #5002)

Ovaπectomized mature female Sprague-Dawley rats (~60-day old and 230g) are obtained from Tacomc (Taconic Farms, NY) following surgery Ovaπectomy is performed at least 10 days prior to treatment to reduce circulating sex steroids Ammals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitu c Treatment

Rats are weighed and randomly assigned to groups of 4 or 5 before treatment Test compounds m 0 2 ml vehicle are admimstered by subcutaneous mjection m the nape of the neck or by lavage usmg 0 5 ml The animals are treated once daily for seven days For testmg antiprogestins, ammals are given the test compounds and a EC50 dose of progesterone (5 6 mg/kg) dunng the first three days of treatment Folio wmg decidual stimulation, animals contmue to receive progesterone until necropsy four days later d Dosmg

Doses are prepared based upon mg/kg mean group body weight In all studies, a control group receiving vehicle is included Determmation of dose-response curves is earned out using doses with half log mcreases (e g 0 1, 0 3, 1 0, 3 0 mg/kg) e Decidual mduction

Approximately 24 hr after the third mjection, deciduahzation is mduced 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 following the final treatment, rats are sacrificed by C02 asphyxiation and body weight measured Uten are removed and trimmed of fat Deciduahzed (D-horn) and control (C-horn) uterme horns are weighed separately f Analysis of Results

The mcrease in weight of the deciduahzed uterme horn is calculated by D-horn/C-horn and logarithmic 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 fittmg and one-way analysis of vanance JMP software (SAS Institute, Inc ) is used for both oneway ANONA and non-hnear dose-response analyses g Reference Compounds

All progestm reference compounds were run m full dose- response curves and the EC50 for uterme wet weight were calculated Table 8. Estimated EC₅o, standard error (SE), and 95% confidence intervals for individual studies

Compoimd 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 11 0 02 0 07 0 16

2 0 10 0 05 0 11 0 25

3 0 06 0 03 0 03 0 14

Levonorgestrel 1 0 08 0 03 0 04 0 16

2 0 12 0 02 0 09 0 17

3 0 09 0 02 0 06 0 13

4 0 09 0 02 0 06 0 14

MPA 1 0 42 0 03 0 29 0 60

2 0 39 0 05 0 22 0 67

3 0 39 0 04 0 25 0 61

Table 9. Estimated average ECso, 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 10. Estimated ICso, standard error, and 95% confident interval for the antiprogestin, RU 486

Compoimd Exp (mg/kg. p 0 ) 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 m assay(default-mg/kg body weight) Route of admimstration Route the compound is admimstered to the animals

Body weight Mean total animal body weight (default-kg) D-horn Wet weight of deciduahzed uterme horn (default-mg) C-horn Wet weight of control uterme horn (default-mg) Decidual response [(D-C)/C]xl00% Progestational activity Compounds that mduce deciduahzation significantly

(p<0 05) compared to vehicle control are considered active

Antiprogestational activity Compounds that decrease EC50 progesterone mduced deciduahzation significantly (p<0 05)

EC₅₀ for uterme weight Concentration of compoimd that gives half-maximal mcrease m decidual response (default-mg/kg)

IC₅₀ for uterme weight Concentration of compound that gives half-maximal decrease m EC₅₀ progesterone mduced decidual response (default-mg/kg)

EXAMPLE 13

5-(2,4,4-Trimethyl-l,4-dihvdro-2H-3 -benzoxa_an-6-yl)thiophene-2-carbonitrile

A solution of 2-ammo-5-bromobenzoιc acid (lOg, 46 mmol) m dry THF (200 mL) was treated at -78 °C under mtrogen with a solution of methylmagnesium bromide m ether (3 0 M, 90 mL, 270 mmol) The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under mtrogen and then poured mto a cold 0 5 N aqueous hydrochloπde solution (300 mL) The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added The orgamc layer was separated and aqueous layer was extracted with ethyl acetate (3x100 mL) The combmed organic layers were washed with bnne and dned (MgS0₄) After removal of solvent in vacuo, the residue was puπfied by a sihca gel flash column chromatography(hexane ethyl acetate/3 2) to give 2-(2-amιno-5- bromophenyl)propan-2-ol as off-white solid (6g, 57%) mp 62-63 °C, Η-NMR (CDCls) δ 7 19 (d, IH, J= 2 3 Hz), 7 12 (dd, IH, J= 8 4, 2 3 Hz), 6 51 (d, IH, J = 8 4 Hz), 4 70 (s, 2H), 1 82 (s, IH), 1 65 (s, 6H)

To a solution of 2-(2-amιno-5-bromophenyl)propan-2-ol (27g, 125 mmol) m anhydrous toluene was added at ambient temperature under a blanket of mtrogen acetylaldehyde (10 5 mL, 187 mmol) After 10 minutes, the mixture was passed through a pad of sihca gel and filtrate was concentrated to yield 6-bromo-2,4,4- tπmethyl- l,4-dιhydro-2H-3,l-benzoxazme as off-white sohd (25g, 78%) ^]H-NMR (DMSO-a?₆) δ 7 22 (d, IH, J= 2 2 Hz), 7 08 (dd, IH, J= 8 6, 2 3 Hz), 6 51 (d, IH, J = 8 6 Hz), 6 36 (s, IH), 4 72 (m, IH), 1 45 (s, 3H), 1 40 (s, 3H), 1 25 (d, 3H, J= 5 5 Hz)

A mixture of 6-bromo-2,4,4-tπmethyl-l,4-dιhydro-2H-3,l-benzoxazme (3 6g, 14 mmol), bιs(pmacolato)dιboron (5 g, 19 7 mmol), potassium acetate (4g, 41 mmol), and [l, -bιs(dιphenylphosphmo)fenocene]palladιum (II) chloπde (1 1 complex with methylene chloπde, 0 4g, 0 5 mmol) m DMF (80 mL) was subject to a positive mtrogen flow to remove oxygen and then heated at 85 °C under a blanket of mtrogen for 18 hours The mixture was allowed to cool to ambient temperature, treated with 5-bromo-2-thιophenecarbonιtπle (4g, 21 mmol), [1,1 '- bιs(dιphenylphosphιno)ferrocene]palladιum (II) chloride (1 1 complex with methylene chlonde, 0 4g, 0 5 mmol), and aqueous sodium carbonate solution (2M, 35 mL, 70 mmol), and then heated at 85 °C under mtrogen for 3 hours The reaction mixture was allowed to cool to ambient temperature, bnne (100 mL) and ethyl acetate (150 mL) were added The orgamc layer was separated and aqueous layer was extracted with ethyl acetate (3x50 mL) The combmed orgamc layers were dned (MgS0₄) and concentrated The residue was purified by a flash silica gel column chromatography(THF hexane/1 4) to afford the title compoimd as an off-white solid (lg, 25%) mp 172-173 °C, Η-NMR (DMSC .) δ 7 88 (d, IH, J= 4 0 Hz), 7 47 (d, IH, J= 4 0 Hz), 7 43 (d, IH, J= 2 0 Hz), 7 32 (dd, 1H, J = 8 36, 2 4 Hz), 6 77 (s, IH), 6 60 (d, IH, J= 8 4 Hz), 4 83 (m, IH), 1 51 (s, 3H), 1 48 (s, 3H), 1 28 (d, 3H, J = 5 6 Hz), MS (ESI) m/z 283 [M-H]^"

EXAMPLE 14 3-Fluoro-5-(2,4,4-trimethyl-l,4-dihvdro-2H-3,l-benzoxaan-6-yl)benzonitrile

Prepared accordmg to the procedure for Example 13 from 6-bromo-2,4,4- tπmethyl- 1 ,4-dιhydro-2H-3, 1 -benzoxazine and 3-bomo-5-fluorobenzomtπle A white sohd mp 163-164 °C, Η-NMR (DMSO-< ) δ 8 02 (t, IH, J = 1 5 Hz), 7 87 (dt, IH, J = 10 6, 2 2 Hz), 7 65 (m, IH), 7 55 (d, IH, J= 2 2 Hz), 7 44 (dd, IH, J= 8 4, 2 2 Hz), 6 63 (d, IH, J = 8 4 Hz), 6 58 (s, IH), 4 82 (m, IH), 1 52 (s, 3H), 1 50 (s, 3H), 1 28 (d, 3H, J= 5 1 Hz), MS (ESI) m/z 295 [M-H]^"

EXAMPLE 15

4-(2,4,4-Trimethyl-l,4-dihvdro-2H-3,l-benzoxazin-6-yl)thiophene-2-carbonitrile

Prepared accordmg to the procedure for Example 13 from 6-bromo-2,4,4- tπmethyl-l,4-dιhydro-2H-3,l-benzoxazme and 4-bromo-2-thιophenecarbomtnle An off-white sohd mp 175-176 °C, Η-NMR (OMS -d₆) δ 8 39 (d, IH, J= 1 5 Hz), 8 13 (d, IH, J= 1 5 Hz), 7 47 (d, IH, J = 1 9 Hz), 7 36 (dd, IH, J = 8 4, 1 9 Hz), 6 59 (d, IH, J= 8 4 Hz), 6 41 (s, IH), 4 78 (m, IH), 1 51 (s, 3H), 1 47 (s, 3H), 1 28 (d, 3H, J = 5 4 Hz), MS (ESI) m/z 285 [M+H]⁺ EXAMPLE 16 4-Methyl-5-(2,4,4-trimethyl-l,4-dihvdro-2H-3,l-benzoxaan-6-yl)thiophene-2- carbonitrile

Prepared accordmg to the procedure for Example 13 from 6-bromo-2,4,4- tπmethyl-l,4-dιhydro-2H-3,l-benzoxazme and 5-bromo-4-methyl-2- thiophenecarbomtnle A yellowish sohd mp 145-146 °C, Η-NMR (OMSO-d₆) δ 7 79 (s, IH), 7 18 (d, IH, J= 2 0 Hz), 7 13 (dd, IH, J= 8 4, 2 0 Hz), 6 68 (s, IH), 6 54 (d, IH, J= 8 3 Hz), 4 83 (m, IH), 2 26 (s, 3H), 1 49 (s, 3H), 1 46 (s, 3H), 1 28 (d, 3H, J = 5 5 Hz), MS (ESI) m/z 299 [M+H]⁺

EXAMPLE 17 3-[(2R.4S)-2,4-Dimethyl-4-phenyl-l,4-dihvdro-2H-3.1-benzoxazin-6-yll-5- fluorobenzonitrile

To a solution of 2-ammo-4-bomobenzomtnle (5g, 25 mmol) m anhydrous THF, was added at 0 °C under mtrogen, phenyhnagnesium bromide (3 M m ether, 25 mL, 75 mmol) The mixture was allowed to warm to room temperature, stirred under mtrogen for 15 hours, and treated with 2N aqueous hydrogen chlonde solution (100 mL) The aqueous solution was heated to 50 °C for 3 hours, cooled to room temperature, and neutralized with a cold saturated sodium bicarbonate solution Ethyl acetate (100 mL) was added and the orgamc layer was separated and aqueous layer was extracted with ethyl acetate (3x40 mL) The combmed orgamc layers were dried (MgS0₄) and evaporated The residue was purified by a flash column chromatography(sιhca gel, hexane ethyl acetate/4 1) to yield (2-amιno-5- bromophenyl)(phenyl)methanone as a yellow crystal (2 13g, 31%) MS (ESI) m/z 276/278 [M+H]⁺

To a solution of (2-ammo-5-bromophenyl)(phenyl)methanone (lg, 3 6 mmol) m anhydrous THF (15 mL) was added at room temperature under mtrogen methylmagnesium bromide (3M m ether, 3 mL, 9 mmol) After 3 hours, the mixture was treated with a saturated aqueous ammomum sulfate solution (30 mL) and ethyl acetate (50 mL) The orgamc layer was separated, dned (MgS0 ), and evaporated The residue was then dissolved m anhydrous toluene and treated at ambient temperature under mtrogen with acetylaldehyde (2 mL) After 2 minutes, the solvent was removed and residue was purified by a column chromatography(sιhca gel, hexane ethyl acetate/4 1) to afford 6-bromo-2,4-dιmethyl-4-phenyl-l,4-dιhydro-2H- 3,1-benzoxazιne as a yellowish sohd (0 8g, 70%) MS (ESI) m/z 318/320 [M+H]⁺

A mixture of 6-bromo-2,4-dιmethyl-4-phenyl-l,4-dιhydro-2H-3,l-benzoxazme (0 6g, 1 9 mmol), 3-cyano-5-fluorobenzene boromc acid (0 45g, 2 7 mmol), tetrakιs(tnphenylphosphιne)palladιum (0) (02g, 0 17 mmol), sodium carbonate (0 6g, 5 7 mmol) m a mixture of DME and water (20/5 mL) was subject to a positive mtrogen flow to remove oxygen and then heated to 85 °C under a blanket of mtrogen for 2 hours The mixture was allowed to cool to ambient temperature Bnne (30 mL) and ethyl acetate (100 mL) were added The orgamc layer was separated and aqueous layer was extracted with ethyl acetate (3x30 mL) The combmed orgamc layers were dned (MgS0₄), and evaporated The residue was purified by a sihca gel column chromatography(hexane ethyl acetate/4 1) to afford the title compound as off- white sohd (0 09g, 13%) mpl28-129 °C, Η-NMR (DMSO-< ) δ 8 08 (s, IH), 7 91 (dt, 1H. J= 10 7, 1 9 Hz), 7 71 (d, IH, J = 2 0 Hz), 7 65 (m, IH), 7 57 (dd, 1H, J= 8 8, 2 4 Hz), 7 32-7 36 (m, 2H), 7 24-7 29 (m, 3H), 6 71 (d, IH, J= 1 6 Hz), 6 69 (d, IH, J= 8 3 Hz), 4 33 (m, IH), 1 84 (s, 3H), 1 24 (d, 3H, J = 5 5 Hz), MS (ESI) m/z 357 [M-H]^"

EXAMPLE 18 terr-Butyl 2-cvano-5-(2,4.4-trimethyl-l,4-dihvdro-2H-3,l-benzoxazin-6-ylVlH- pyrrole-1-carboxylate tert-Butyl-5-(2,4,4-tπmethyl- 1 ,4-dιhydro-2H-3.1 -benzoxazm-6-yl)- 1 H-pyrrole- 1 -carboxylate was prepared accordmg to the couphng procedure for Example 17 from 6-bromo-2,4,4-tnmethyl-l,4-dihydro-2H-3,l-benzoxazme and 1-t- butoxycarbonylpyπol-2-yl boromc acid To a solution of tert-butyl-5-(2,4,4-tπmethyl- l,4-dihydro-2H-3,l-benzoxazm-6-yl)-lH-pyrrole-l-carboxylate (lg, 2 9 mmol) m anhydrous THF (20 mL) was added at -78 °C under mtrogen chlorosulfonyl isocyanate (0 35 mL, 4 0 mmol) The mixture was kept stirring at -78 °C under nitrogen for 2 hours, treated with anhydrous DMF (5 mL), and allowed to warm to room temperature Aqueous ammomum sulfate solution (50 mL) and ethyl acetate (100 mL) was added and organic layer was separated, dned (MgS0₄), and evaporated The residue was purified by a silica gel column chromatography(hexane ethyl acetate/4 1) to afford the title compound as a white solid (0 019g, 1 78%) Η-NMR (DMSO-ύk) δ 7 48 (d, IH, J = 2 0 Hz), 7 36 (dd, IH, J= 8 3, 2 0 Hz), 7 32 (d, IH, J = 3 6 Hz), 7 14 (d, IH, J= 8 3 Hz), 6 46 (d, IH, J= 4 0 Hz), 5 35 (q, IH, J= 5 2 Hz), 1 58 (d, 3H, J= 5 6 Hz), 1 56 (s, 3H), 1 51 (s, 3H), 1 38 (s, 9H), MS (ESI) m/z 366 [M-H]

EXAMPLE 19 9H-Fluoren-9-ylmethyl-6-[l-(tert-butoxycarbonyl)-5-cvano-lH-pyrrol-2-yll- 2,4,4- trimethyl-2H-3,l-benzoxazine-l(4H)-carboxylate

A mixture oftert-butyl-5-(2,4,4-tπmethyl-l,4-dιhydro-2H-3,l-benzoxazm-6- yl)-lH-pyπole-l -carboxylate (1 7g, 4 96 mmol), 9-fluorenylmethyl chloroformate (1 92g, 7 5 mL), sodium carbonate (4g, 37 mmol) m dioxane (50 mL) and water (50 mL) was stirred at room temperature under a blanket of mtrogen for 6 hours Ethyl acetate (100 mL) was added and organic layer was separated, dned (MgS0₄), and evaporated The residue was puπfied by a sihca gel column chromatography(hexane ethyl acetate/6 1) to afford 9H-fluoren-9-ylmethyl-6-[l-(tert- butoxycarbonyl)- 1 H-pyrrol-2-yl] -2,4,4-tπmethyl-2H-3 , 1 -benzoxazine- 1 (4H)- carboxylate as a clean oil Usmg the procedure for Example 18, the title compound (0 8g, 65%) was prepared from 9H-fluoren-9-ylmethyl-6-[l-(tert-butoxycarbonyl)-lH-pyrrol-2-yl]- 2,4,4-tnmethyl-2H-3,l-benzoxazme-l(4H)-carboxylate (1 2g, 2 1 mmol) and chlorosulfonyl isocyanate (0 28 mL, 3 1 mmol) A white sohd mp 135-136 °C, Η- NMR (OMSO-d₆) δ 7 90 (t, 2H, J = 6 7 Hz), 7 64 (d, IH, J= 7 5 Hz), 7 59 (d, IH, J = 7 1 Hz), 7 40 (td, 2H, J= 7 2, 2 0 Hz), 7 31-7 34 (m, 3H), 7 29 (d, IH, J = 1 2 Hz), 7 04-7 09 (m, 2H), 6 44 (d, IH, J = 3 57 Hz), 5 30 (q, IH, J= 5 6 Hz), 4 86 (dd, IH, J= 10 7, 5 2 Hz), 4 64 (dd, IH, J = 10 8, 5 2 Hz), 4 33 (t, IH, J= 4 7 Hz) 1 50 (s, 3H), 1 30 (s, 9H), 1 20 (s, 3H), 1 03 (d, 3H, J= 5 6 Hz), MS (ESI) m/z 590 [M+H]⁺

EXAMPLE 20 5-(2,4,4-Trimethyl-l,4-dihydro-2H-3,l-benzoxazin-6-yl)-lH-pyrrole-2- carbonitrile

9H-Fluoren-9-ylmethyl-6-[l-(tert-butoxycarbonyl)-5-cyano-lH-pyrrol-2-yl]- 2,4,4-tnmethyl-2H-3,l-benzoxazme-l(4H)-carboxylate (0 5g, 0 84 mmol) was heated under a blanket of mtrogen at 160 °C until gas evolution ceased After coohng to room temperature, 9H-fluoren-9-ylmethyl-6-[5-cyano-lH-pynol-2-yl]-2,4,4-tnmethyl- 2H-3,l-benzoxazme-l(4H)-carboxylate was obtained as a white sohd (0 4g, 97%) A solution of 9H-fluoren-9-ylmethyl-6-[5-cyano-lH-pynol-2-yl]-2,4,4- tπmethyl-2H-3,l-benzoxazme-l(4H)-carboxylate (0 lg, 0 2 mmol) m 20% pipendine m DMF (5 mL) was stiπed at room temperature under mtrogen for 10 minutes The mixture was poured mto a saturated ammomum sulfate solution (30 mL) and extracted with diethyl ether (3x30 mL) The combmed orgamc layers were dned (MgS0₄) and evaporated The residue was punfied by a sihca gel column chromatography(hexane ethyl acetate/3 1) to afford the title compound as a white solid (0 03g, 56%) mp 201-202 °C, Η-NMR (OMSO-d₆) δ 12 27 (s, IH), 7 44 (d, IH, J = 2 1 Hz), 7 32 (dd, IH, J= 8 3, 1 1 Hz), 6 92 (dd, IH, J = 4 1, 2 6 Hz), 6 57 (d, IH, J = 8 3 Hz), 6 50 (dd, IH, J = 4 2, 2 6 Hz), 6 40 (s, IH), 4 77-4 80 ( , IH), 1 51 (s, 3H), 1 46 (s, 3H), 1 27 (d, 3H, J= 5 7 Hz), MS (ESI) m/z 266 [M-H]

EXAMPLE 21 9H-Fluoren-9-ylmethyl 6-(5-cvano-l-methyl-lH-pyrrol-2-vn-2.4.4-trimethyl-2H- '3,l-benzoxazine-l(4H)-carboxylate

A mixture of 9H-fluoren-9-ylmethyl-6-[5-cyano-lH-pyπol-2-yl]-2,4,4- tπmethyl-2H-3,l -benzoxazme- l(4H)-carboxylate (0 4g, 0 8 mmol) and potassium carbonate (1 5g) m anhydrous DMF was treated at ambient temperature under a blanket of mtrogen with lodomethane (1 5 mL, excess) The mixture was stirred for 30 minutes A saturated ammomum sulfate solution (50 mL) and ethyl acetate (50 mL) was added The orgamc layer was separated and aqueous layer was extracted with ethyl acetate (3x15 mL) The combmed orgamc layers were dried (MgS0₄), evaporated to yield the title compound as a white solid (0 35g, 87%) mp 63-64 °C, Η-NMR (DMSO- _.) δ 7 90 (m, 2H), 7 62 (d, IH, J = 7 7 Hz), 7 58 (d, IH, J = 1 7 Hz), 7 40 (m, 2H), 7 29-7 32 (m, 3H), 7 14 (dd, IH, J = 8 1, 1 9 Hz), 7 01-7 04 (m, 2H), 6 33 (d, \H, J = 4 3 Hz), 5 31 (q, IH, J= 5 8 Hz), 4 88 (dd, IH, J= 10 8, 5 0 Hz), 4 65 (dd, IH, J= 10 8, 4 6 Hz), 4 34 (t, IH, J= 4 6 Hz), 3 71 (s, 3H), 1 52 (s, 3H), 1 21 (s, 3H), 1 06 (d, 3H, J= 5 4 Hz), MS (ESI) m/z 504 [M+H]⁺

EXAMPLE 22 l-Methyl-5-(2.4.4-trimethyl-1.4-dihvdro-2H-3.1-benzoxazin-6-ylVlH-pyrrole-2- carbonitrile

Prepared accordmg to the procedure for Example 20 from 9H-fluoren-9- y nethyl 6-(5 -cyano- 1 -methyl- 1 H-pyrrol-2-yl)-2,4,4-tnmethyl-2H-'3, 1 -benzoxazine- l(4H)-carboxylate (0 3g, 0 6 mmol) and 20% pipendme m DMF A white sohd (0 07g, 42%) mp 195-196 °C, 'H-NMR DMSO-d₆) δ 7 16 (d, IH, J= 2 8 Hz), 7 08 (dd, IH, J = 8 1, 1 9 Hz). 6 98 (d, IH, J= 4 1 Hz), 6 63 (d, IH, J= 8 5 Hz), 6 61 (s, 1H), 6.20 (d, IH, J = 4.1Hz), 4.79-4.81 (m, IH), 3.67 (s, 3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.27 (d, 3H, J= 5.5 Hz); MS (ESI) m/z 282 [M+H]⁺.

EXAMPLE 23 5-(2-Methylspiro[4H-3,l-benzoxazine-4,l'-cvclopentanel-6-yl)-4 methyl-2- thiophenecarb onitrile

2-Methyl-6-bromospiro[4H-3,l-benzoxazine-4,r-cyclopentane] was prepared using the same procedure as for 6-bromo-2,4,4-trimethyl-l,4-dihydro-2H-3,l- benzoxazine in Example 13. The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,l-benzoxazine-4,r-cyclopentane] and 5-bromo-4- methyl-2-thiophenecarbonitrile. A yellowish sohd: mp 58-60 °C; 'H-NMR (DMSO- d₆) δ 7.79 (s, IH), 7.16 (d, IH, J = 1.9 Hz), 7.12 (dd, 1H, J = 8.4, 2.2 Hz), 6.66 (s, IH), 6.63 (d, IH, J= 8.4 Hz), 4.75 (m, IH), 2.26 (s, 3H), 2.14 (m, IH), 1.87 (m, IH), 1.4-1.7 (m, 6H), 1.32 (d, 3H, J= 5.5 Hz).

EXAMPLE 24 4-(2-Methylspiro[2H-3,l-benzoxazine-4,l'-cvclopentanel-6-yl)-2- thiophenecarbonitrile Prepared according to the procedure for Example 13 from 2-methyl-6- bromospiro[4H-3,l-benzoxazine-4, -cyclopentane] and 4-bromo-2- thiophenecarbonitrile. An off-white sohd: mp 103-104 °C.

EXAMPLE 25

5-(2-methylspirof2H-3,l-benzoxazine-4,l'-cvclohexanel-6-yl)-4-methvI-2- thiophenecarbonitrile

2-Methyl-6-bromospιro[2H-3,l-benzoxazme-4,l'-cyclohexane] was prepared usmg the same procedure as for 6-bromo-2,4,4-tπmethyl- 1 ,4-dιhydro-2H-3, 1 - benzoxazme m Example 13

The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospιro[4H-3,l-benzoxazme-4,r-cyclohexane] and 5-bromo-4- methyl-2-thιophenecarbonιtπle A brown sohd Η-NMR (OMSO-d₆) δ 7 78 (s, IH), 7 17 (d, IH, J = 1 8 Hz), 7 14 (dd, IH, J = 8 4, 2 2 Hz), 6 64 (s, IH), 6 63 (d, IH, J = 8 2 Hz), 4 74 (m, IH), 2 26 (s, 3H), 2 14 (m, IH), 1 87 (m, IH), 1 4-1 7 (m, 8H), 1 31 (d, 3H, J= 5 3 Hz), MS (ESI) m/z 337 [M-H]^"

EXAMPLE 26 4-(2-Methylspirof2H-3,l-benzoxazine-4,l'-cvclohexanel-6-yl)2- thiophenecarbonitrile

Prepared accordmg to the procedure for Example 13 from 2-methyl-6- bromospιro[4H-3,l-benzoxazme-4,l'-cyclohexane] and 4-bromo-2- thiophenecarbonitπle A brown sohd mp 111-112 °C, Η-NMR (DMSO- 4) δ 8 42 (s, IH), 8 14 (s, IH), 7 47 (s, IH), 7 35 (dd, IH, J = 8 3, 1 1 Hz), 6 58 (d, IH, J = 8 4 Hz), 6 38 (s, IH), 4 72 (m, IH), 1 92-2 16 (m, 2H), 1 35-1 75 (m, 8H), 1 31 (d, 3H, J = 5 3 Hz), MS (ESI) m/z 325 [M+H]⁺

EXAMPLE 27 6-(3-Fluorophenyl)-2,4,4-trimethyl-l,4-dihydro-2H-3,l-benzoxazine

Prepared accordmg to the couphng procedure for Example 17 from 3- fluorophenyl boromc acid and 6-bromo-2,4,4-tnmethyl-l,4-dιhydro-2H-3,l- benzoxazme A yellow solid mp 139-140°C, 'H-NMR (CDC1₃) δ 7 40-7 19 (m, 6H), 7 01-6 94 (m, IH), 6 72 (d, IH, J= 8 24 Hz), 4 90 (q, IH, J= 5 48 Hz), 1 62 (s, 3H), 1 59 (s, 3H), 1 46 (d, 3H, J= 5 5 Hz), MS (ES) m/z 272 ([M+H]⁺)

EXAMPLE 28 6-(3-Chlorophenyl)-2,4,4-trimethyl-l,4-dihvdro-2H-3,l-benzoxazine

Prepared accordmg to the couphng procedure for Example 17 from 3- chlorophenyl boronic acid and 6-bromo-2,4,4-tπmethyl-l,4-dιhydro-2H-3,l- benzoxazine A orange solid mp 144-146 °C, Η-NMR (CDC1₃) δ 7 50 (t, IH, J = 1 78 Hz), 7 40 (dt, IH, J= 7 61, 1 45 Hz), 7 33 (t, IH, J= 7 76 Hz), 7 29-7 22 (m, 4H) 6 72 (d, IH, J = 8 24 Hz), 4 90 (q, IH, J = 5 45 Hz), 1 62 (s, 3H), 1 59 (s, 3H), 1 4 6 (d, 3H, J= 5 5 Hz), MS (ES) m/z 288/290 ([M + H]⁺)

EXAMPLE 29 6-(3-Chloro-4-fluorophenyl)-2,4,4-trimethyl-l,4-dihvdro-2H-3,l-benzoxazine A mixture of 6-bromo-2,4,4-tπmethyl- 1 ,4-dιhydro-2H-3, 1 -benzoxazme (3 0 g,

11 7 mmol), 3-chloro-4-fluorobenzeneboromc acid (3 1 g, 17 6 mmol), tetrakιs(tnphenylphosphιne)palladιum (0) (0 67 g, 0 59 mmol), and sodium carbonate (3 72 g, 35 1 mmol) in DME (80 mL) and water (40 mL) was subject to a blanket of mtrogen flow for 15 minutes at 50°C and then was heated at 85°C under mtrogen for 1 hour The reaction was cooled to room temperature and ethyl acetate (200 mL) was added The orgamc layer was washed twice with aqueous ammomum chlonde (50 mL) and once with bnne (50 mL), dned over sodium sulfate and concentrated to a yellow solid The solid was triturated with ether (25 mL) and hexane (25 mL), collected on a filter, and dried to give 6-(3-chloro-4-fluorophenyι)-2,4,4-trιmethyl-l,4- dιhydro-2H-3,l -benzoxazme (1 87 g, 35%) as a yellow solid mp 173-175°C, ^]H- NMR (DMSO-rf₆) δ 7 79 (dd, IH, J = 6 84, 2 14 Hz), 7 60-7 57 (m, IH), 7 43-7 39 (m, 2H), 7 29 (dd, IH, J = 8 12, 2 14 Hz), 6 62 (d, IH, J= 8 54 Hz), 6 40 (s, IH), 4 79 (q, IH, J= 5 55 Hz), 1 53 (s, 3H), 1 48 (s, 3H), 1 28 (d, 3H, J= 5 55 Hz), MS (ES) m/z 306/308([M + H]⁺)

EXAMPLE 30 2-Fluoro-5-(2,4,4-trimethyl-l,4-dihydro-2H-3,l-benzoxazin-6-yl)benzonitrile

Prepared accordmg to the couphng procedure for Example 13 from 6-bromo- 2,4,4-tnmethyl-l,4-dιhydro-2H-3,l-benzoxazme and 5-bromo-2-fluorobenzomtnle A white sohd mp 184-186°C, 'H-NMR DMSO-d₆) δ 8 17 (dd, IH, J= 5 86, 3 42 Hz), 8 00-7 98 (m, IH), 7 52 (t, IH, J= 9 28 Hz), 7 45 (d, IH, J= 1 95 Hz). 7 34 (dd, IH, J= 8 30, 1 95 Hz), 6 63 (d, IH, J = 8 3 Hz), 6 45 (d, IH), 4 8 (q, IH, J= 5 37 Hz), 1 53 (s, 3H), 1 49 (s, 3H), 1 29 (d, 3H, J= 5 37 Hz), MS (ES) m/z 297 ([M + H]⁺)

EXAMPLE 31 4-(2,4,4-TrimethyI-l,4-dihvdro-2H-3,l-benzoxazin-6-vD-2-furonitrile Prepared usmg the couphng procedure for Example 13 from 6-bromo-2,4,4- tπmethyl- 1 ,4-dιhydro-2H-3 , 1 -benzoxazme and 4-bromo-2-cyanofuran A hght brown sohd mp 116-118 °C, 'H-NMR (DMSO-ύ?₆) δ 8 43 (s, IH), 8 06 (s, IH). 7 38 (d, IH, J= 1 98 Hz), 7 25 (dd, IH, J= 1 93, 1 98 Hz) 6 58 (d, IH, J = 7 93 Hz). 6 37 (s, IH), 4 77 (q, IH, J= 5 55 Hz), 1 50 (s, 3H), 1 46 (s, 3H), 1 27 (d, 3H, J= 5 55 Hz), MS (ES) m/z 269 ([M+H]⁺), Anal Calc For Cι₆H₁₆N₂0₂ C, 71 62, H, 6 01, N, 10 44 Found C, 71 55, H, 6 26, N, 10 17

EXAMPLE 32 3-[4,4-Dimethyl-2-(trifluoromethyl)-l,4-dihvdro-2H-3.,l-benzoxazin-6-yll-5- fluorobenzonitrile

A mixture of 2-(2-amιno-5-bromo-phenyl)-propan-2-ol (5 g, 21 7 mmol), tπfluoroacetaldehyde methyl hemiacetal (5 mL), and magnesium sulfate (10 g) m toluene (75 mL) was heated at 80°C under mtrogen After disappearance of the starting material, the reaction was filtered through a pad of sihca gel and the filtrate dned over sodium sulfate and concentrated to give 6-bromo-4,4-dιmethyl-2- (tnfluoromethyl)-l,4-dιhydro-2H-3,l-benzoxazιne as an amorphous sohd ^]H-NMR (DMSO-d₆) δ 7 31 (d, IH, J= 1 99 Hz), 7 19 (dd, IH, J= 8 73, 2 38 Hz), 6 88 (s IH), 6 74 (d, IH, J= 8 33 Hz), 5 32 (m, IH), 1 52 (s, 6H)

A mixture of 6-bromo-4,4-dιmethyl-2-(tπfluoromethyl)-l,4-dιhydro-2H-3,l- benzoxazine (0 5 g, 1 61 mmol), 3-cyano-5-fluorobenzeneboromc acid (0 39 g, 1 8 mmol), tetrakis(tnphenylphosphine)-palladium (0) (0 2 g, 0 161 mmol), and sodium carbonate (0 5 g, 4 83 mmol) in DME (50 mL) and water (25 mL) was subject to a blanket of mtrogen flow for 15 mmutes at 50°C and then was heated at 85°C under mtrogen for 1 hour The reaction mixture was cooled to room temperature and ethyl acetate (200 mL) was added The organic layer was washed twice with aqueous ammomum chloπde (20 mL) and once with bnne (20 mL), dned over sodium sulfate and concentrated to a yellow sohd Purification via flash column chromatography (sihca gel, 5% ethyl acetate/hexane) gave 3-[4,4-dιmethyl-2-(tπfluoromethyl)-l,4- dihydro-2H-3,l-benzoxazm-6-yl]-5-fluorobenzomtnle (0 396 g, 73%) as a white sohd mp 102-103°C, Η-NMR MSO-d₆) δ 8 07 (s, IH), 7 91 (d, IH, J= 10 7 Hz), 7 7 (d, IH, J= 10 7 Hz) 7 62 (d, IH, J= 1 98 Hz), 7 53 (dd, IH, J= 8 33, 1 98 Hz), 7 05 (s, IH), 6 87 (d, IH, J= 8 33 Hz), 5 39-5 37 (m, IH), 1 61 (s, 3H), 1 59 (s, 3H), MS (ES) m/z 349 ([M-H] )

EXAMPLE 33 4-f4,4-DimethvI-2-(trifluoromethyl)-l,4-dihvdro-2H-3.1-benzoxazin-6- yllthiophene-2-carbonitrile Prepared usmg the couphng procedure for Example 13 starting with 6-bromo-

4.4-dιmethyl-2-(tnfluoromethyl)- 1 ,4-dιhydro-2H-3, 1 -benzoxazme and 4-bromo-2- thiophenecarbonitπle A yellow solid Η-NMR (OMSO-d₆) δ 8 43 (s, IH), 8 19 (s, IH), 7 54 (d, IH, J= 1 98 Hz), 7 46 (dd,lH, J= 8 33, 1 98 Hz), 6 90 (s, IH), 6 83 (d, 1H, J= 8 33 Hz), 5 35 (d, IH, J= 3 57 Hz), 1 59 (s, 3H), 1 57 (s, 3H), MS (ES) m/z 337 ([M-H] )

EXAMPLE 34 4-[l-Acetyl-4,4-dimethyl-2-(trifluoromethyl)-1.4-dihvdro-2H-3.1-benzoxazin-6- yll thiophene-2-carbonitrile

4-[4,4-dιmethyl-2-(tπfluoromethyl)-l ,4-dιhydro-2H-3, l-benzoxazm-6- yl]thιophene-2-carbonιtπle (0 25 g, 0 74 mmol) was dissolved m DMF (10 mL), NaH (0 09 g, 2 22 mmol) was added and the mixture was stirred for 30 mmutes pπor to the addition of acetyl chloride (0 079 mL, 1 11 mmol) Upon disappearance of the startmg mateπal the reaction mixture was poured mto bnne (100 mL) and the product extracted with ether (150 mL), dried over sodium sulfate and concentrated The residue was purified by a flash column chromatography (sihca gel, 25 % ethyl acetate/hexane) to yield 4-[l-acetyl-4,4-dιmethyl-2-(tπfluoromethyl)-l,4-dιhydro-2H- 3,l-benzoxazm-6-yl]thιophene-2-carbomtnle (0 1 g, 36%) as an amorphous solid ^l - NMR (DMSO-.i₆) δ 8 58 (s, IH), 8 5 (s, IH), 7 83-7 80 (m, 2H), 7 64 (d, IH, J = 8 74 Hz), 6 42 (q, IH, J= 10 Hz), 2 24 (s, 3H), 1 73 (s, 3H), 1 42 (s, 3H)

EXAMPLE 35 (6(5-Cvanothien-3-yl)-4,4-dimethyl-2-(trifluoromethyl)-2H-3,l-benzoxazin- l(4H)-yl)methyl pivalate

4-[4,4-dιmethyl-2-(tnfluoromethyl)-l,4-dιhydro-2H-3,l-benzoxazm-6- yl]thιophene-2-carbomtnle (0 30 g, 0 89 mmol) was dissolved m DMF (10 mL), NaH (0 065 g, 2 7 mmol) was added and the was mixture stiπed for 30 mmutes prior to the addition of tert-butyl chloroacetate (0 19 mL, 1 3 mmol) Upon disappearance of the startmg material the reaction mixture was poured mto bnne (100 mL) and the product extracted with ether (150 mL), dned over sodium sulfate and concentrated Flash column chromatography (silica gel, 8% ethyl acetate/hexane) gave (6(5-cyanothιen-3- yl)-4,4-dιmethyl-2-(tπfluoromethyl)-2H-3,l-benzoxazm-l(4H)-yl)methylpιvalate

(0127 g, 32%) as an amorphous sohd Η-NMR (CDC1₃) δ 782 (s, IH), 758 (s, IH),

741 (dd, 1H,J=833, 198 Hz), 725 (d, lH,J=198Hz)710 (d, lH,J=833Hz), 679(d, lH,J=833Hz), 566 (d, 1H,J=119 Hz), 538 (d, 1H,J=119 Hz), 172 (s, 3H), 155(s, 3H), 118 (s, 9H)

EXAMPLE 36 3-Fluoro-5-(^"2,2,4,4-tetramethyl-l,4-dihydro-2H-3,l-benzoxazin-6-yl)benzonitrile

Prepared usmg the couphng procedure for Example 13 startmg with 6-bromo- 2,2,4,4-tetramethyl-l, 4-dιhydro-2H-3, 1-benzoxazme and 3-bromo-5- fluorobenzonitπle A white solid >H-NMR DMSO-d₆) δ 803 (s, IH), 787 (d, IH, J = 107 Hz), 765 (d, IH, J= 107 Hz), 757 (d, IH, J= 198 Hz) 745 (dd, IH, J =

833, 198 Hz), 665 (d, IH, J= 833 Hz), 642 (s, IH), 152 (s, 6H), 134 (s, 6H), MS(ES)m/z311([M+H]⁺)

EXAMPLE 37 4-(2,2,4,4-Tetramethyl-l,4-dihydro-2H-3,l-benzoxazin-6-yl)thiophene-2- carbonitrile

Prepared usmg the couphng procedure for Example 13 startmg with 6-bromo- 2,2,4,4-tetramethyl-l ,4-dιhydro-2H-3, 1-benzoxazme and 4-bromo-2-cyanothιophene An amorphous orange sohd Η-NMR (DMSO-< ) δ 84 (d, IH, J= 169 Hz), 814 (d, IH, J = 169 Hz), 749 (d, IH, J= 220 Hz), 738 (dd, IH, J= 843, 202 Hz), 661 (d, IH, J= 843 Hz), 626 (s, IH), 149 (s, 6H), 132 (s, 6H), MS (ES) m/z 299 ([M+H]⁺) EXAMPLE 38

5-14,4-Dimethyl-2-(trifluoromethyl)-l,4-dihydro-2H-3,l-benzoxazin-6-yll-4- methylthiophene-2-carbonitrile

Prepared accordmg to the couphng procedure for Example 13 from 6-bromo- 4,4-dιmethyl-2-(tnfluoromethyl)-l,4-dιhydro-2H-3, 1-benzoxazme and 5-bromo-4- methyl-2-thιophene-carbomtπle A yellowish sohd mp 97-98 °C, ^]H-NMR (DMSO- dg) δ 7 82 (s, IH), 7 26 (d, IH, J = 1 7 Hz), 7 21 (dd, IH, J= 8 1, 2 1 Hz), 7 16 (s, IH), 6 88 (d, IH, J = 8 1 Hz), 5 40 (m, IH), 2 27 (s, 3H), 1 56 (s, 3H), 1 55 (s, 3H), MS (ESI) m/z 351 [M-H]

EXAMPLE 39

6-(3-Chlorophenyl)-4,4-dimethyl-2-(trifluoromethyl)-l,4-dihvdro-2H-3,l- benzoxazine

Prepared accordmg to the couphng procedure for Example 17 from 6-bromo- 4,4-dimethyl-2-(tnfluoromethyl)-l,4-dihydro-2H-3, 1-benzoxazme and 3-chlorophenyl boromc acid A yellowish solid mp 108-109 °C, Η-NMR (DMSO-cie) δ 7 69 (t, IH, J = 1 7 Hz), 7 59 (d, IH, J = 7 8 Hz), 7 35-7 50 ( , 3H), 7 32 (dt, IH, J= 8 1, 1 1 Hz), 6 91 (s, IH), 6 87 (d, IH, J = 8 4 Hz), 5 35 (m, IH), 1 60 (s, 3H), 1 59 (s, 3H), MS (ESI) m/z 340 [M-H]

EXAMPLE 40

6-(3-Fluorophenyl)-4,4-dimethyl-3,4-dihvdroquinolin-2(lH)-one

Prepared by couphng 3-fluorophenylboromc acid with an equivalent amount of 6-bromo-4,4-dιmethyl-3,4-dιhydo-lH-quιnolιn-2-one usmg a catalytic amount of tetrakis(tnphenylphosphme)palladium(0) with overnight refluxmg m toluene contaimng an equivalent amount of potassium carbonate dissolved m water Work up m the usual manner followed by recrystalhzation from ethanol gave a gray sohd mp 190-192° C 'H-NMR (OMSO-d₆) δ 10 27 (s, IH), 7 57 (s, IH), 7 50 (m, 4H), 7 15 (m, IH), 6 95 (d, IH J= 8 2Hz), 2 39 (s, 2H), 1 29 (s, 6H), MS (APCI (-)) m/z 268 [M-H] Anal Calc For C₁₇H₁₆FNO 0 25 H₂0 C, 74 57, H, 6 07, N, 5 12 Found C, 74 86, H, 5 97, N 5 06

EXAMPLE 41 3-(4,4-Dimethyl-2-oxo-l,2.3,4-tetrahvdroαuinolin-6-yl)-5-fluorobenzonitrile 6-bromo-4,4-quιnolιn-2-one was allowed to couple with an equivalent of bιs(pιnacolato)dιboron m refluxmg DMF contaimng an equivalent of sodium carbonate dissolved m a minimal amount of water and a catalytic quantity of tetrakιs(tπphenylphosphme)palladιum(0) After refluxmg overnight an equivalent of 3- bromo-5-fluorobenzomtnle was added Another equivalent of sodium carbonate was then added, followed by an additional amount of the same catalyst After several hours of reflux, the reaction mixture was filtered and taken to dryness in vacuo The residue was extracted mto ethyl acetate and the solution was dned over magnesium sulfate, filtered and the filtrate was again roto-evaporated to give a solid residue Recrystalhzation from ethanol afforded the title compound as a gray solid mp 249- 250° C Η-NMR (DMSO-< ) δ 10 32.(s, IH), 8 09 (t, IH, J= 1 6Hz), 7 93 (d, IH, J = 12 7 Hz) 7 77, (d, IH, J= 8 1Hz), 7 70 (s, IH), 7 61(d, IH J= 8 9Hz), 6 95 (d, IH, J = 8 3Hz),2 40 (s, 2H), 1 30 (s, 6H), MS (APCI (-)) m/z 293 [M-H] Anal Calc For C₁₈H₁₅FN₂0 1 5H₂0 C, 67 28, H, 5 65, N, 8 72 Found C, 67 36, H, 4 90, N s8 44

EXAMPLE 42 3-(4,4-Dimethyl-2-oxo-l,2,3,4,-tetrahvdroquinolin-6-yl)benzonitrile

Prepared by couphng 3-cyanophenylboronιc acid with an equivalent amount of 6-bromo-4,4-dιmethyl-3,4-dιhydo-lH-quιnohn-2-one usmg a catalytic amount of tetrakιs(tπphenylphosphme)palladιum(0) as a catalyst with overnight refluxmg in toluene containing an equivalent amount of potassium carbonate dissolved m water in the usual manner followed by recrystalhzation from ethanol gave a gray solid mp 190 - 192 ° C, Η-NMR (DMSO-d₆) δ 10 29 (s,lH), 8 17 (s, IH), 8 00 (d,lH, J = 7 9 Hz), 7 77 (d, IH, J = 6 4Hz), 7 65 (m, 2H), 7 55 (d, IH, J = 8 2 Hz), 6 97 (d, IH, J = 8 3 Hz), 2 40 (s, 2H), 1 30 (s, 6H), MS (APCI (-)) m/z 275 [M-H]^" Anal Calc For Cι₈Hι₆N₂0 0 25H₂0 C, 75 77, H, 6 01, N, 9 82 Found C, 75 45, H, 5 65, N 9 20

EXAMPLE 43

6-(3-Chlorophenyl)-4,4-dimethyl-3,4-dihvdroquinoline-2(lH)- thione

Prepared by heatmg under reflux overnight a mixture of 6-(3-chlorophenyl)- 4,4-dιmethyl-3,4-dιhydroqumohne-2(lH)-one and an equal weight of phosphorus pentasulfide m pyndine was stirred Removal of the pyndine in vacuo followed by treatmg the residue with 6N hydrochloπc acid and recrystallization of the residue in ethanol gave the product as a yellow sohd mp 197 - 198° C Η-NMR DMSO-d₆) δ 12 34 (s, IH), 7 75 (m, IH), 7 64 (m, 2H), 7 57 (dd , IH J= 9 3 and 2 1 Hz), 7 48 (t, IH, J= 1 7 Hz), 7 41 (m, 1H),7 20 (d, IH, J= 8 3 Hz), 3 34 (s, 2H), 1 26 (s,6H), MS (APCI (-)) m/z 300 [M-H]^" Anal Calc For C,₇H₁₆C1NS C, 67 65, H, 5 34, N, 4 64 Found C, 67 77, H, 5 57, N 4 54

EXAMPLE 44 6-(3-Fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2(lH)-thione

Prepared by heatmg under reflux overnight a mixture of 6-(3-fluororophenyl)- 4.4-dιmethyl-3,4-d_hydroquιnohne-2(lH)-one and an equal weight of phosphorus pentasulfide was stirred m pyndine Workup as m the previous example gave a yellow sohd, mp 209-211° C Η-NMR (DMSO- ₆) δ 12 34 (s,lH), 7 65 (d,lH J=2 2 Hz ) 7 57 (dd ,1H J, = 8 24 J₂= 2 2Hz), 7 51(m,3H), 7 18(m,2H), 2 84(s,2H), 1 26(s,6H) MS m/z 284 [M-H]^" Anal Calc For C₁₇H₁₆F1NS C,71 55, H,5 65, N,4 91 Found C,71 18, H,5 59, N4 82 EXAMPLE 45

3-(4,4-Dimethyl-2-thioxo-l,2,3,4,-tetrahvdroquinolin-6-yl)benzonitrile

Prepared by heatmg under reflux overnight a stirred mixture of 3 -(4,4- dιmethyl-2-oxo-l,2,3,4,-tetrahydroqumohn-6-yl)benzomtπle and an equal weight of phosphorus pentasulfide m pyπdme and workup as m the previous example gave a yellow solid mp 220-223 ° C dec Η-NMR (OMSO-d₆) δ 12 35 (s, IH), 8 21 (s, IH), 8 10 (d, IH, J= 6 0 Hz), 7 80 (d, IH, J= 7 9Hz), 7 72 (s, IH), 7 65 (m, 2H), 7 21 (d, IH, J = 8 4 Hz), 2 85 (s, 2H), 1 27 (s, 6H), MS (APCI (-)) m/z 291 [M-H] Anal Calc For C_]8H,₆N₂S 3H₂0 C, 62 40, H, 6 40, N, 8 09 Found C, 62 12, H, 4 88, N 7 77

EXAMPLE 46 3-(4,4-Dimethyl-2-thioxo-l,2,3,4-tetrahvdroquinolin-6-yl)-5-fluorobenzonitrile Prepared by heatmg under reflux overnight a stirred mixture of 3-(4,4- dιmethyl-2-oxo-l,2,3,4-tetrahydroqumohn-6-yl)-5-fluorobenzomtπle and an equal weight of phosphorus pentasulfide in pyndine and workup as m the previous example gave a yellow solid mp 240-242° C dec , Η-NMR (DMSO-^) δ 12 37 (s, IH), 8 13 (s, IH), 7 98 (dt,lH, j= 10 4 and 5 4 Hz), 7 81 (d, IH, J = 8 4Hz), 7 7 (d, IH, J = 1 8Hz), 7 68 (dd, IH, j = 8 3 and 1 9 Hz), 7 22 (d, IH, J = 8 3Hz), 2 85 (s, 2H), 1 27 (s, 6H), MS m/z 309 [M-H]^" Anal Calc For C₁₈H_I5FN₂S 0 10 H₂0 C, 69 25, H, 4 91, N, 8 97 Found C, 69 15, H, 4 74, N 8 75

EXAMPLE 47 6-(3-Fluoro-phenyl)-2,4,4-trimethyl-l,2,3_.4-tetrahydro-quinoline

6-Bromo-l-(4-methoxy-benzyl)-4.4-dιmethyl-3.4-d_hvdro-lH-quj_nolm-2-one

To a solution of 6-bromo-4,4-drmethyl-3,4-dιhydro-lH-qumolm-2-one (0 5g, 1 97mmol) m THF (25mL) was added 60% NaH (0 12g, 2 95mmol) suspended m mineral oil The resulting reaction mixture was stirred at room temperature for 30 mm , 4-methoxybenzyl chloride (0 34g, 2 17) added, and heated under reflux for 20 h The reaction was cooled to room temperature then quenched slowly with water After extraction with ethyl acetate, the orgamc layer was dned (MgS0 ), evaporated and the residue purified by chromatography (Sι0₂ 3 7 ethyl acetate/hexane) The white crystalhne product was obtained (0 35g, 48%), mp 118-119 °C, 1H NMR (DMSO-^₆) δ 1 23 (s, 6H), 2 59 (s, 2H), 3 70 (s, 3H), 3 72 (s, IH), 4 41 (d, IH, J= 5 86Hz), 5 09 (s, IH), 6 87 (m, 2H), 7 01 (d, IH, J= 8 78Hz), 7 17 (d, IH, J= 8 98Hz), 7 23 (d, IH, J= 8 79), 7 34 (dd, IH, J= 6 59 and 2 2 Hz), 7 43( d, IH, J= 2 2Hz), MS (APCI (+)) [M+H]⁺ =374/376

6-(3-Fluoro-phenyl)-l-(4-methoxy-benzyl)-4.4-dιmethyl-3.4-dιhydro-lH-qumolm-2- one

A mixture of 6-Bromo-l-(4-methoxy-benzyl)-4,4-dιmethyl-3,4-dιhydro-lH- quιnolιn-2-one (2 9g, 7 75mmol) in ethylene glycol dimethyl ether (50mL), K₂C0₃ ( 1 18 g, 8 53mmol) m H₂0 (5 OmL), and a catalytic amount of tetrakistπphenylphosphine palladium was heated under reflux overnight After coohng to room temperature, the mixture was extracted with ethyl acetate and the orgamc phase was washed with NaHC0₃ solution, bnne, dned over MgS0₄, concentrated, and crystalhzed from ethanol to obtam the product as a white crystalhne matenal (1 8 g, 60%) mp 159 - 162 °C, Η NMR (DMSO-tf₆) δ 1 32 (s, 6H), 2 63 (s, 2H ), 3 70 (s. 3H), 5 15 (s, 2H), 6 89 (d, 2H, J= 11 72Hz), 7 14 ( , 2H), 7 22 (d, 2H, J= 8 8Hz), 7 53 (m, 4H), 7 60 (d, IH, J= 2 2Hz), MS (APCI (+)) [M+H]⁺ = 390 6-Bromo-l-(4-methoxy-benzyl)-2.4.4-trιmethyl-1.4-dιhvdro-qumolme To a solution of 6-(3-Fluoro-phenyl)-l-(4-methoxy-benzyl)-4,4-dιmethyl-3,4- dιhydro-lH-quιnohn-2-one (1 16g, 2 99mmol) m THF (15mL) at room temperature was added a solution of 1 4 M MeMgBr (2 6mL, 12 56mmol) and the resulting reaction mixture was stirred for 6h The solution was quenched with H₂0. extracted with EtOAc, treated with ammomum chloride solution, washed with bnne, dried over MgS0₄, and concentrated The product was purified by column chromatography using a 2 8 hexane/ethyl acetate mixture and used below

To a solution of 6-(3-Fluoro-phenyl)-l-(4-methoxy-benzyl)-2,4,4-tπmethyl- 1,2,3,4-tetrahydroqumohne (0 15g, 0 39mmol) in EtOH (35mL) was added 10%Pd/C and hydrogenated for 10 h at 40 psi The catalyst was removed by filtration through cehte and the product puπfied by chromatography A reddish liquid was obtained ^]H NMR (OMSO-d₆) δ 1 15 ( d, 3H, J= 6 73Hz), 1.21( s, 3H ), 1 34(m, 4H), 1 60( dd, IH, J, =10 1,J₂= 2 69, Hz), 3 40( m, IH), 5 95( s, IH), 6 55( d, IH, J= 8 08Hz), 7 01 ( m, IH), 7 21 (dd, IH, J. =5 78 J₂= 2 02 Hz), 7 35(m,4H), MS( FI Pos) [M+H]⁺ =270

Still other compounds, mcludmg 5-(2,4,4-Tnmethyl-l,2,3,4-tetrahydro- qumolm-6-yl)-lH-pyπole-2-carbomtnle, l-Methyl-5-(2,4,4-tnmethyl-l, 2,3,4- tetrahydro-qumolm-6-yl)-lH-pynole-2- carbomtπle , and 3-Fluoro-5-(2,4,4-tnmethyl- l,2,3,4-tetrahydro-qumolm-6-yl)-benzomtπle may be prepared usmg the methods descnbed above

All publications cited m this specification are incorporated herem by reference herem While the mvention has been descπbed with reference to a particularly prefened embodiment, it will be appreciated that modifications can be made without departing from the spiπt of the mvention Such modifications are mtended to fall within the scope of the appended claims

Claims

Wh at is Claimed:

1 A compound of the formula

I wherem

R¹, R² are mdependent substituents selected from the group which mcludes H, Ci to C₆ alkyl, substituted C. to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR^A, or NR^BCOR^A,

or R¹ and R² are fused to form a) an optionally substituted 3 to 8 membered spirocychc alkyl rmg, b) an optionally substituted 3 to 8 membered spirocychc alkenyl, or c) an optionally substituted 3 to 8 membered heterocychc rmg contaimng one to three heteroatoms from the group mcludmg O, S and N, the spirocychc rmgs of a), b) and c) bemg optionally substituted by from 1 to 4 groups selected from fluorine, C, to C₆ alkyl, C, to C₆ alkoxy, C, to C₆ thioalkyl, -CF₃, -OH, -CN, NH₂, -NH(C, to C₆ alkyl), or -N(C, to C₆ alkyl)₂,

R^A is H, Ci to C₃ alkyl, substituted C, to C₃ alkyl, aryl. substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, R^B is H, Ci to C₃ alkyl, substituted C. to C₃ alkyl,

R³ is H, OH, NH₂, Ci to C₆ alkyl, substituted C, to C₆ alkyl, C₃ to C₆ alkenyl, substituted Ci to C₆ alkenyl, alkynyl, or substituted alkynyl, COR^c,

R^c 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 ammoalkyl, substituted Ci to C₃ ammoalkyl,

R⁴ is H, halogen, CN, N0₂, C, to C₆ alkyl, substituted Ci to C₆ alkyl, alkynyl, or substituted alkynyl, Ci to Cβ alkoxy, substituted Ci to Cβ alkoxy, ammo, C to Cβ ammoalkyl, substituted d to C₆ ammoalkyl,

R⁵ is selected from a) or b)

a) R⁵ is a tπsubstituted benzene of the structure

X is taken from the group including halogen, CN, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, , alkynyl, or substituted alkynyl,Cι to C₃ alkoxy, substituted Ci to C₃ alkoxy, O to C₃ thioalkoxy, substituted C. to C₃ thioalkoxy, ammo, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, N0₂, Ci to C₃ perfluoroalkyl, 5 or 6 membered heterocychc πng containing 1 to 3 heteroatoms, COR^D, OCOR^D, or NR^ECOR^D, R^D is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ ammoalkyl,

R^E is H, Ci to C₃ alkyl, substituted C. to C₃ alkyl,

Y and Z are mdependent substituents taken from the group including H, halogen, CN, N0₂, ammo, ammoalkyl, Ci to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkoxy, or

b) R⁵ is a five or six membered πng with 1, 2, or 3 heteroatoms selected from O, S, SO, S0₂ or NR⁶ and contaimng one or two mdependent substituents selected from H, halogen, CN, N0₂ ammo, and Ci to C₃ alkyl, Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, COR^F, or NR^GCOR^F,

R^F is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ ammoalkyl,

R^G is H, Ci to C₃ alkyl, or substituted d to C₃ alkyl,

R⁶ is H or C, to C₃ alkyl,

G₂ is CO, CS, or CR₇R₈, provided that when G, is O, G₂ is CR₇R8, and Gi and G₂ cannot both be CR₇Rs, R₇ and R₈ are mdependently selected from H or an optionally substituted alkyl, aryl, or heterocychc moiety,

or pharmaceutically acceptable salt thereof

2 A compound of Claim 1 of Formula I:

I wherem

R¹ is H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocyclic, COR^A, or NR^BCOR^A,

R² is H, Ci to C₆ alkyl, substituted Ci to Cβ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocychc, COR^A, or NR^BCOR^A,

or

R¹ and R² are fused to form an optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocyclic rmg contaimng one to three heteroatoms from the group mcludmg O, S and N, the spirocychc alkyl, alkenyl or heterocychc rmgs bemg optionally substituted by from 1 to 4 groups selected from fluorine, Ci to C₆ alkyl, C. to C₆ alkoxy, C. to C₆ thioalkyl, -CF₃, -OH, -CN, NH₂, -NH(C, to C₆ alkyl), or -N(C, to C₆ alkyl)₂, R^A is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ ammoalkyl,

R^B is H, Ci to C₃ alkyl, or substituted d to C₃ alkyl,

R^c is H, Ci to C₄ alkyl, substituted Ci to C₄ alkyl, aryl, substituted aryl, Ci to C₄ alkoxy, substituted Ci to C₄ alkoxy, Ci to C₄ ammoalkyl, or substituted Ci to C₄ ammoalkyl,

R⁴ is H, halogen, CN, N0₂, C, to C₆ alkyl, substituted Ci to C₆ alkyl, C, to C₆ alkoxy, substituted Ci to C₆ alkoxy, ammo, Ci to C₆ ammoalkyl, substituted Ci to C₆ ammoalkyl,

a) R⁵ is a benzene rmg of the structure

X is selected from halogen, CN, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ thioalkoxy, substituted Ci to C thioalkoxy, amino, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, N0₂, Ci to C₃ perfluoroalkyl. 5 membered heterocychc rmg contaimng 1 to 3 heteroatoms, COR^D, OCOR^D, orNR^ECOR ,

R^D is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ ammoalkyl,

R^E is H, Ci to C₃ alkyl, or substituted Ci to C₃ alkyl,

Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, N0₂, C. to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkoxy, or b) R⁵ is a five or six membered πng with 1, 2, or 3 heteroatoms selected from the group of O, S, SO, S0₂ or NR⁶ and contaimng one or two mdependent substituents selected fromH, halogen, CN, N0₂ ammo, and Ci to C₃ alkyl, Ci to C₃ alkoxy,

R⁶ is H, or d to C₃ alkyl

G₂ is CO, CS, or CR₇Rs, provided that when G, is O, G₂ is CR₇Rg, and G, and G₂ cannot both be CR₇Rs,

R₇ and Rs are mdependently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, or substituted heterocychc,

or a pharmaceutically acceptable salt thereof A compound of Claim 1 havmg the formula

wherem

R¹ = R² and are selected from Ci to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocychc alkyl constructed by fusmg R¹ and R² to form a 3 to 6 membered spirocychc πng, the spirocychc ring bemg optionally substituted by from 1 to 4 groups selected from fluonne, Ci to C₆ alkyl, Ci to C₆ alkoxy, Ci to Cβ thioalkyl, -CF₃, -OH, - CN, NH₂, -NH(C, to C₆ alkyl), or -N(C. to C₆ alkyl)₂,

R³ is H, OH, NH₂, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, -COH, -CO(Cι to C₄ alkyl) or-CO(C, to C₄ alkoxy),

R⁴ is H, halogen, N0₂, Ci to C₃ alkyl, substituted Ci to C₃ alkyl,

X is taken from the group mcludmg halogen, CN, Ci to C₃ alkoxy, Ci to C₃ alkyl, N0₂, Ci to C₃ perfluoroalkyl, 5 membered heterocychc πng contaimng 1 to 3 heteroatoms, Ci to C₃ thioalkoxy,

Y is a substituent on the 4' or 5' position from the group mcludmg H, halogen, CN, N0₂, Ci to C₃ alkoxy, C, to C₄ alkyl, d to C₃ thioalkoxy

G₂ is CO, CS, or CR₇R₈; provided that when G, is O, G₂ is CR₇Rg, and G, and G₂ cannot both be CR₇Rs;

wherein R₇ and R₈ are independent substituents selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocychc, or substituted heterocychc;

or pharmaceutically acceptable salt thereof

4. A compound of Claim 3 wherein X is CN and Y is 5 '-fluoro; or a pharmaceutically acceptable salt thereof.

5. A compound of Claim 3 wherein U is S, X' is CN and Y' is H or -CH₃; or a pharmaceutically acceptable salt thereof.

6. A compound of Claim 1 having the formula:

wherein:

R¹ = R² and are selected from Ci to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocychc alkyl constructed by fusing R¹ and R² to form a 3 to 6 membered spirocychc nng, the spirocychc nng bemg optionally substituted by from 1 to 4 groups selected from fluonne, Ci to Cβ alkyl, Ci to C₆ alkoxy, Ci to Cβ thioalkyl, -CF₃, -OH, - CN, NH₂, -NH(Cι to C₆ alkyl), or -N(C, to C₆ alkyl)₂,

R³ is H, OH, NH₂, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, -COH, -CO(Cι to C₄ alkyl) or-CO(Cι to C₄ alkoxy),

R⁴ is H, halogen, N0₂, Ci to C₃ alkyl, substituted Ci to C₃ alkyl,

R⁶ is H, or Ci to C₃ alkyl, C, to C₄ C0₂alkyl,

X' is from the group mcludmg halogen, CN, N0₂, Ci to C₃ alkyl and Ci to C₃ alkoxy,

Y' is from the group mcludmg H and Ci to C alkyl,

G₂ is CO, CS, or CR₇Rs, provided that when G, is O, G₂ is CR₇R«, and Gi and G₂ cannot both be CR₇Rs,

wherem R₇ and R₈ are mdependent substituents selected from H, alkyl, substituted alkyl, aryl, substituted aryL heterocychc, or substituted heterocychc,

or pharmaceutically acceptable salt thereof

7. A compound of Claim 1 having the formula:

wherein:

R¹ = R² and are selected from Ci to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocychc alkyl constructed by fusing R¹ and R² to form a 3 to 6 membered spirocychc ring, the spirocychc rings of being optionally substituted by from 1 to 4 groups selected from fluorine, Ci to C₆ alkyl, Ci to C₆ alkoxy, Ci to Cβ thioalkyl, -CF₃, -OH, -CN, NH₂, -NH(Cι to C₆ alkyl), or -N(C, to Cβ alkyl)₂;

R³ is H, OH, NH₂, C, to C₆ alkyl, substituted Ci to C₆ alkyl, -COH, -CO(C, to C₄ alkyl) or-CO(C, to C alkoxy);

R⁴ is H, halogen, N0₂, C, to C₃ alkyl, substituted C. to C₃ alkyl;

X¹ is N or CX²

X² is halogen, CN, alkoxy, or N0₂,

G₂ is CO, CS, or CR₇Rs; provided that when Gi is O, G₂ is CR₇R«, and G_ and G₂ cannot both be CR₇Rg; wherem R₇ and R₈ are mdependent substituents selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heterocychc, or substituted heterocychc,

or pharmaceutically acceptable salt thereof

8 A compound of Claim 1 which is 6-(3-Chloro-phenyl)-2,4,4-tnmethyl- 2-tnfluoromethyl-l,4-dιhydro-2H-benzo[d][l,3]oxazme or a pharmaceutically acceptable salt thereof

9 A compound of Claim 1 which is 6-(3-Chloro-phenyl)-2,2,4,4- tetramethyl-l,4-d_hydro-2H-benzo[d][l,3]oxazme or a pharmaceutically acceptable salt thereof

10 A compound of Claim 1 which is 6-(3-Nιtro-phenyl)-2,2,4,-tnmethyl- l,4-dιhydro-2H-benzo[d][l,3]oxazιne or a pharmaceutically acceptable salt thereof

11 A compound of Claim 1 which is 4-Amιno-3 '-chloro-bιphenyl-3- carbonitπle or a pharmaceutically acceptable salt thereof

12 A compound of Claim 1 which is 6-(3-Chlorophenyl)-4-cyclopropyl- lH-quιnazohn-2-one or a pharmaceutically acceptable salt thereof

13 A compound of Claim 1 which is 6-(3-Chlorophenyl)-4-cyclopropyl-l- (4-methoxybenzyl)-lH-quιnazohn-2-one or a pharmaceutically acceptable salt thereof

14 A compound of Claim 1 which is 6-(3-Chlorophenyl)-4-cyclopropyl-4- methyl-3,4-dιhydro-lH-quιnazohn-2-one or a pharmaceutically acceptable salt thereof 15 A compound of Claim 1 which is 6-(3-Chlorophenyl)-4-cyclopropyl- 3,4-dιmethyl-3,4-dιhydro-lH-quιnazohn-2-one or a pharmaceutically acceptable salt thereof

16 A compound of Claim 1 which is 6-(3-Chloro-phenyl)-4,4-dιmethyl- 3,4-dιhydro-lH-qumolm-2-one or a pharmaceutically acceptable salt thereof

17 A pharmaceutical composition compnsmg a compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner or excipient

18 A method of mducmg contraception m a mammal, the method compnsmg administering to a mammal m need thereof a pharmaceutically effective amount of a compound of Claim 1 or a pharmaceutically effective amount thereof

19 A method of treatmg or preventing bemgn or malignant neoplastic disease m a mammal, the method compnsmg administering to a mammal m need thereof a pharmaceutically effective amount of a compound of Claim 1 wherem G₂ is C=0 or CR₇R₈, or a pharmaceutically acceptable salt thereof

20 The method of Claim 19 wherem the bemgn or malignant neoplastic disease is selected from uterme myometnal fibroids, endometnosis, bemgn prostatic hypertrophy, carcinomas and adenocarcinomas of the endometnum, ovary, breast, colon, prostate, pituitary, memngioma or other hormone-dependent tumors 21 A method of treatment or prevention m a mammal of carcinomas or adenocarcmomas of the endometπum, ovary, breast, colon, or prostate, the method compnsmg admimstermg to a mammal m need thereof a pharmaceutically effective amount of a compound of Claim 1 wherem G is C=S, or a pharmaceutically acceptable salt thereof