EP1185535A1

EP1185535A1 - Cyclocarbamate and cyclic amide derivatives

Info

Publication number: EP1185535A1
Application number: EP00928691A
Authority: EP
Inventors: Arthur A. Santilli; Andrew Q. Viet; Puwen Zhang; Andrew Fensome; Lin Zhi; Todd K. Jones; Christopher M. Tegley; Jay E. Wrobel; James P. Edwards
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: 2002-03-13
Also published as: AU4688800A; JP2002543205A; MXPA01011288A; CN1349538A; CA2371632A1

Abstract

This invention provides compounds of formula (I) wherein A and B are independent substituents selected from S, CH or N; provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B both equal N, one N may be optionally substituted with a C1 to C6 alkyl group; R1 and R2 are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkyl, C2 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, heterocyclic, substituted heterocyclic, COR?A, or NRBCORA; or R1 and R2¿ are fused to form optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring, the heterocyclic ring containing one to three heteroatoms selected from the group of O, S and N; or pharmaceutically useful salts thereof. The compounds of this invention are useful as agonists and antagonists of the progesterone receptor and in methods of inducing contraception and in the treatment or prevention of benign or malignant neoplastic diseases.

Description

CYCLOCARBAMATE AND CYCLIC AMIDE DERIVATIVES

Field of the Invention

This invention relates to compounds that act as agonists and antagonists of the progesterone receptor, their preparation, and utility

Background of the Invention

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

The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as gands 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 then translocates to the nucleus of the cell where it binds to a specific gene or genes present in the cell's DNA Once bound to a specific DNA sequence the complex modulates the production of the 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 in the health of women PR agonists are used in birth control formulations, typically in the presence of an ER agonist ER agonists are used to treat the symptoms of menopause, but have been associated with a prohferative effect on the uterus (in non- hysterectomized women) which can lead to an increased πsk of uteπne cancers Co- administration of a PR agonist reduces or ablates that risk 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 ovarian cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Clin Endo Metab , 76, 513, 1993) and endometπosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991)

PR antagonists may also be useful in hormone replacement therapy for post- menopausal patients m combination with a partial ER antagonist such as tamoxifen (US 5719136) PR antagonists such as Mifepπstone have also been shown to have bone sparing effects in rodents, and as such may be useful in the treatment of osteoporosis associated with the menopause (Barengolts, et al, Bone, 17, 21, 1995)

PR antagonists, such as mifepπstone and onapπstone, 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 Acαd Sci , 761, 224, 1995)

Jones, et αl, (U S Patent No 5.688,810) described 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).

Zhi, et al, described the ether 7 as a PR antagonist (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 , descπbed the vitamin D analog 9 as a PR ligand (Jet Letters, 35, 2295, 1994)

Hamann, etal, descπbed the PR antagonist 10 (Ann N Y Acad Sci , 761, 383,

10

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

11

Kurihaπ, et al , descπbed the PR ligand 12 (J Antibiotics, 50, 360, 1997)

12

Description of the invention

This invention provides compounds of Formula I

wherein

A and B are independent substituents selected from S, CH or N,

Provided that when A is S, B is CH or N, provided that and A and B cannot both be CH, and when A and B both equal N, one N may be optionally substituted with an Ci to Cβ alkyl group,

Ri and R₂ are independent substituents selected from the group of H, Ci to Cβ alkyl, substituted Ci to C₆ alkyl, C₂ to Cβ alkenyl, substituted C to C₆ alkenyl, C₂ to Cβ alkynyl, substituted C₂ to C6 alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^A, or NR^BCOR^A, or R¹ and R² are fused to form a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring, preferably a 3 to 6 membered spirocyclic alkyl ring, or b) an optionally substituted 3 to 8 membered spirocyclic alkenyl ring, preferably a 3 to 6 membered spirocyclic alkenyl ring, or c) an optionally substituted 3 to 8 membered spirocyclic ring containing one to three heteroatoms selected from O, S and N, preferably a 3 to 6 membered spirocyclic ring containing one to three heteroatoms,

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

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

R^c is HL, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ aminoalkyl, or substituted Ci to C aminoalkyl,

R⁴ is a tπsubstituted benzene πng 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 thioalkyl, substituted Ci to C₃ thioalkyl, Ci to C₃ aminoalkyl, substituted Ci to C₃ aminoalkyl, NO₂, Ci to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic πng contammg 1 to 3 heteroatoms, COR^D, OCOR^D, or NR^ECOR^D,

R^D is H, Ci to C 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 aminoalkyl,

R^E is H, Ci to C₃ alkyl, or substituted Ci to C₃ alkyl, Y and Z are independent independently selected from H, halogen. CN,

NO₂, Ci to C₃ alkoxy, d to C₃ alkyl, or Ci to C₃ thioalkyl, or

R⁴ is a five or six membered πng with 1, 2, or 3 heteroatoms from the group mcluding O S, SO, SO₂ or NR⁵ and contammg one or two independent substituents from the group mcluding H, halogen, CN, NO₂ and Ci to C₃ alkyl,

Ci to C₃ alkoxy, Ci to C₃ aminoalkyl, 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 Ci to C₃ alkyl, R⁵ is H, or Ci to C₃ alkyl,

R⁶ is from the group mcluding CN, Ci to Cβ alkyl, substituted Ci to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃, R⁷ and R⁸ are mdependent substituents from the group mcludmg H, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, or CN CO₂R⁹,

R⁹ is Ci to C₃ alkyl, or CR⁷R⁸ may comprise a six membered πng of the structure below

W is O or a chemical bond or a pharmaceutically acceptable salt thereof

Among the preferred compounds of this invention are those of Formula I wherein

A and B are mdependent substituents S, CH or N, provided that when A is S. B is CH or N, and when B is S, A is CH or N, and A and B cannot both be CH, and when A and B both equal N, one N may be optionally substituted with an Ci to Cβ alkyl group, R¹ is H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^A, or NR^BCOR^A,

R² is H, Ci to Ce alkyl, substituted d to Ce alkyl, C₂ to C₆ alkenyl, substituted C₂ to Cβ alkenyl, C₂ to Cβ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^A, or NR^BCOR^A, or R¹ and R² are fused to form a) an optionally substituted 3 to 8 membered spirocyclic alkyl πng, or b) an optionally substituted 3 to 8 membered spirocyclic alkenyl πng, or c) an optionally substituted 3 to 8 membered spirocyclic πng contammg one to three heteroatoms selected from the group of O, S and N,

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 aminoalkyl,

R^B is H, Ci to C₃ alkyl, or substituted d 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, or COR^c, 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 a tπsubstituted benzene πng containing the substituents X, Y and

Z as shown below

X is taken from the group including halogen, CN, Ci to C₃ alkyl, substituted d to C₃ alkyl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to

C₃ thioalkyl, substituted Ci to C₃ thioalkyl, to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, NO₂, Ci to C₃ perfluoro alkyl, 5-membered heterocyclic πng contammg 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 C 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 including

H, halogen, CN, NO₂, Ci to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkyl, or

R⁴ is a five or six membered πng with 1 , 2, or 3 heteroatoms from the group mcluding O, S, SO, SO₂ or NR⁵ and contammg one or two mdependent substituents from the group mcluding H, halogen, CN, NO₂ and Ci to C₃ alkyl, or Ci to C₃ alkoxy,

R⁵ is H or Ci to C₃ alkyl,

R⁶ is from the group including CN, Ci to G. alkyl, substituted Ci to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl. substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃,

R⁷ and R⁸ are independent substituents from the group including H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, or CN CO₂R⁹,

R⁹ is Ci to C₃ alkyl, or CR⁸R⁹ compnse a six membered ring as shown by the structure below W is O or a chemical bond or a pharmaceutically acceptable salt thereof

Further prefeπed compounds are those of Formula I wherein A and B are mdependent substituents from the group mcludmg S, CH or N, provided that when A is S, B is CH or N, and when B is S, A is CH or N, and A and B cannot both be CH,

R¹ = R² and are selected from the group which includes Ci to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocyclic alkyl constructed by fusmg R¹ and R² to form a 3 to 6 membered spirocyclic πng,

R³ is H, OH, NH₂, Ci to Ce alkyl, substituted Ci to C₆ alkyl, or COR^c, R^c is H, Ci to C₄ alkyl, or Ci to C₄ alkoxy,

R⁴ is a disubstituted benzene πng contammg the substituents X and Y as shown below

X is selected from the group includmg halogen, CN, Ci to C₃ alkoxy, Ci to C₃ alkyl, NO₂, Ci to C₃ perfluoroalkyl, 5 membered heterocyclic πng contammg 1 to 3 heteroatoms, or Ci to C₃ thioalkyl, Y is a substituent on the 4^' or 5' position selected from the group of H, halogen, CN, NO₂, Ci to C₃ alkox>, Ci to C₄ alkyl, or Ci to C₃ thioalkyl, or

R⁴ is a five membered πng with the structure shown below

R⁵ is H, or Ci to C₃ alkyl, or d to C₄ CO₂alkyl, X' is selected from halogen, CN, NO₂, Ci to C₃ alkyl or Ci to C₃ alkoxy,

Y' is H or Ci to C₄ alkyl, or

R⁴ is a six membered πng with the structure

X² is halogen, CN or NO₂ ,

R⁶ is selected from the group mcluding CN, Ci to C₆ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl. aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF ,

R⁷ and R⁸ are independent substituents selected from the group of H, Ci to C₆ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, or CN CO₂R⁹, R⁹ is Ci to C₃ alkyl, or CR⁷R⁸ comprise a six membered rmg of the structure

W is O or a chemical bond, or a pharmaceutically acceptable salt thereof

Each of the geneπc and subgeneπc groups of compounds herem may further be divided into two further subgroups, one m which Q is oxygen and another wherem Q is selected from S, NR⁶, or CR⁷R⁸

The compounds of this invention have been shown to bind to the PR and act as agonists and/or antagonists m functional models, either in-vitro and/or in-vivo These compounds may be used for contraception, m the treatment of fibroids, endometπosis, breast, uteπne, ovaπan and prostate cancer, osteoporosis and post menopausal hormone replacement therapy

The compounds m the present mvention contain a pendent aromatic substituent which may consist of aryl, substituted aryl, heteroaryl or substituted heteroaryl groups The compounds of this invention may contain an asymmetπc carbon atom and some of the compounds of this invention may contam one or more asymmetπc centers and may thus give πse to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, II, and III, the present invention includes 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

The term "alkyl" is used herein to refer to both straight- and branched-cham saturated aliphatic hydrocarbon groups having from one to 8 carbon atoms, preferably from 1 to 6 carbon atoms, "alkenyl" is mtended to include both straight- and branched-cham alkyl group having from 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, with at least one carbon-carbon double bond, "alkynyl" group is intended to cover both straight- and branched-cham alkyl group havmg from 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, with at least one carbon-carbon tπple bond

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, NO₂, ammo, aryl, heterocyclic, substituted aryl, substituted heterocyclic, 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 here to refer to an aromatic system which may be a smgle πng or multiple aromatic rings fused or linked together as such that at least one part of the fused or lmked rings forms the conjugated aromatic system The aryl groups mclude but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl The term "substituted aryl" refers to aryl as just defined having one or more substituents from the group mcludmg halogen, CN, OH, NO₂, ammo, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio

The term "heterocyclic" is used herem to descπbe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic πng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group includmg N, O, and S atoms The N and S atoms may be oxidized The heterocyclic rmg also mcludes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl πng The heterocyclic πng may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable Such heterocyclic groups mclude, for example, tetrahydrofuran, pipeπdmyl, piperazmyl. 2-oxopιpendιnyl, azepinyl, pyrrohdmyl, lmidazolyl, pyπdyl, pyrazmyl, pyπmidinyl, pyπdazmyl, oxazolyl, isoxazolyl, morpholinyl. indolyl, quinolmyl. thienyl, furyl, benzofuranyl, benzothienyl, thiamorphohnyl, thiamorpholmyl sulfoxide, and isoquinolinyl The term "substituted heterocyclic" is used herem to describe the heterocyclic just defined having one or more substituents selected from the group which mcludes halogen, CN, OH, NO₂, ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylammo, or arylthio The term "alkoxy" is used herem to refer to the OR group, where R is alkyl or substituted alkyl The term "aryloxy" is used herem to refer to the OR group, where R is aryl or substituted aryl The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is alkyl or substituted alkyl The term "alkylcarboxy" is used herein to refer to the COOR group, where R is alkyl or substituted alkyl The term "ammoalkyl" refers to both secondary and tertiary ammes wherem the alkyl or substituted alkyl groups may be either same or different and the pomt of attachment is on the nitrogen atom The term "thioalkyl" is used herem to refer to the SR group, where R is alkyl or substituted alkyl The term "halogen" refers to CI, Br, F, and I element The compounds of this mvention can be prepared following the Schemes illustrated below

CYCLOCARBAMATE DERIVATIVES

Processes for preparing thiophene cyclocarbamate derivatives

A. Methods for synthesizing the thiophene cyclocarbamate compounds depicted in Scheme 1 are described below

R₄CH₂CHO 1

S, CNCH₂C0₂Me, Et₃N (Gewald Reaction)

4 Scheme 1

Thus the ammo thiophene ester 2 was prepared accordmg to a literature procedure mvolvmg the Gewald reaction (see Comprehensive Heterocyclic Chemistry II A Review of the Literature 1982-1995 A R Katπtsky et al Nol 2 page 639), l e the reaction of a suitably substituted aromatic acetaldehyde with sulfur and methyl cyanoacetate in refluxmg methanol (Scheme 1) Reaction of the 2-ammo group with a suitable chloroformate or carbonate affords the protected amine 3 This can be accomplished by allowing 2 to react with a chloroformate or carbonate derivative such as methyl chloroformate, ethyl chloroformate, allyl chloroformate, 2-

(tπmethylsιlyl)ethyl chloroformate or di-tert-butyldicarbonate m a solvent such as benzene, toluene, xylene, dichloromethane, tetrahydrofuran or pyπdme The reaction can be earned out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylaminopyπdine, tnethylamine, pyπdme or di-isopropyl ethylamme Treatment of the protected ammo compound 3 with an organo-metallic reagent such as a Gπgnard reagent, an alkyl or aryl-zinc reagent, an alkyl or aryl lithium reagent m an inert solvent (tetrahydrofuran, diethylether) under an mert atmosphere (nitrogen or argon) at a suitable temperature from 0°C up to reflux temperature of the solvent will then provide the tertiary alcohol 4 Compound 4 may then be subjected to basic conditions to effect πng closure to give the cyclocarbamate denvative 5 Suitable conditions would mvolve treatment of 4 with a base such as potassium hydroxide m a solvent such as ethanol or potassium t-butoxide in a solvent such as tetrahydrofuran The reaction can be earned out m an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent

Scheme 2

Alternatively the carbamate protecting group present in 4 may be removed under conditions appropπate for its removal to afford 6 (Scheme 2) Subsequent rmg closure of 6 with a reagent such as phosgene, carbonyldnmidazole or dimethyl carbonate m an appropπate solvent (tetrahydrofuran, dichloromethane, benzene, etc ) also will provide access to 5

4 7

Scheme 3

Alternatively, compound 4 may be dehydrated to afford the isopropene derivative 7 (Scheme 3). Suitable conditions for the dehydration would be the use of a reagent such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane sulfonyl chloride or anhydride, in a solvent such as pyridine, tetrahydrofuran, dichloromethane or benzene. The reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylaminopyridine, triethylamine, pyridine or di-isopropyl ethylamine. Exposure of 7 to acidic conditions would then afford ring closure to give 5. Suitable conditions would be the use of an acid such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in a solvent such as dichloromethane, benzene, toluene or tetrahydrofuran. The reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent.

11

Scheme 4

An alternative route to 5 is shown m Scheme 4 Treatment of the previously descπbed compound 8 (M Sugiyama, T Sakamoto, K Tabata, K Endo, K Ito, M Kobayashi, H Fukiumi, Chem Pharm Bull , 37(8) 2091 (1989)) with an organo- metalhc reagent such as a Gπgnard reagent, an alkyl or aryl zinc reagent, an alkyl or aryl lithium reagent m an inert solvent (tetrahydrofuran, diethylether) under an inert atmosphere (nitrogen or argon) at a suitable temperature from 0° C up to reflux temperature of the solvent will then provide the tertiary alcohol 9 Compound 9 may then be subjected to basic conditions to effect πng closure to give the cyclocarbamate deπvative 10 Suitable conditions would mvolve treatment of 10 with a base such as potassium hydroxide m a solvent such as ethanol or potassium t-butoxide in a solvent such as tetrahydrofuran The reaction can be earned out m an mert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent Compound 10 may then be converted to the brommated deπvative 11 Suitable conditions would be treatment with bromine or N-bromosuccimmide in a solvent such as dichloromethane, tetrahydrofuran or acetic acid The reaction can be earned out in an mert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent m the presence of an additive such as silica gel Subsequent reaction of 11 with an aryl or heteroaryl boronic acid, boronic acid anhydride or tπalkyl starmane then provides access to the desired biaryl compound 5 The reaction can be carried out m a solvent such as acetone, ethanol, benzene, toluene or tetrahydrofuran, under an inert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent, m the presence of a palladium catalyst such as tetrakιs(tπphenylphosphιne)palladιum (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoride or potassium phosphate

Scheme 5

Alternatively, 10 (Scheme 5) may be treated at low temperature with a reagent such as an alkyl lithium or lithium amide m an mert solvent such as tetrahydrofuran, and then converted to a boronic acid 12 (M= B(OH)₂) under the action of tπmethyl or tπisopropyl borate, or mto a starmane via reaction with tπmethyltin chloπde or bιs(tnmethyltιn) Subsequent reaction of 12 with an aryl or heteroaryl bromide or iodide m the presence of a palladium catalyst such as tetrakιs(tnphenylphosphιne) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoπde or potassium phosphate, would then effect conversion into the desired thiophene cyclocarbamate 5

B Methods for synthesizing the thiophene cyclocarbamate compounds depicted m Scheme 6 are descπbed below

17 18

Scheme 6

The ammo thiophene compounds 15 (Scheme 6) are prepared accordmg to a literature procedure (Comprehensive Heterocyclic Chemistry II A Review of the Literature 1982-1995 A R Katnsky et al , Nol 2, page 639) which mvolves treating a suitably substituted aromatic methyl ketone 13 with phosphorus oxychloπde m Ν,Ν- dimethyl formamide to afford the chloro cyano olefin deπvative 14. Allowing 14 to react with methyl mercaptoacetate m methanol contammg sodium methoxide affords the key ammo thiophene carboxylate starting matenal Reaction of the 2-ammo group with a suitable chloroformate or carbonate affords the protected amine 16 This can be accomplished by allowing 15 to react with a chloroformate or carbonate deπvative such as methyl chloroformate, ethyl chloroformate, allyl chloroformate, 2- (tπmethylsιlyl)ethyl chloroformate or di-tert-butyldicarbonate in a solvent such as benzene, toluene, xylene, dichloromethane, tetrahydrofuran or pyπdine The reaction can be earned out under an mert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylammopyπdme, tnethylamine, pyπdine or di-isopropyl ethylamine Treatment of the protected ammo compound 16 with an organo-metalhc reagent such as a Gπgnard reagent, an alkyl or aryl-zmc reagent, an alkyl or aryl lithium reagent in an inert solvent (tetrahydrofuran, diethylether) under an mert atmosphere (nitrogen or argon) at a suitable temperature from 0° C up to reflux temperature of the solvent will then provide the tertiary alcohol 17 Compound 17 may then be subjected to basic conditions to effect πng closure to give the cyclocarbamate deπvative 18 Suitable conditions would mvolve treatment of 4 with a base such as potassium hydroxide m a solvent such as ethanol or potassium t-butoxide in tetrahydrofuran The reaction can be earned out m an mert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent

Scheme 7

Alternatively the carbamate protectmg group present in 17 may be removed under conditions appropπate for its removal to afford 19 (Scheme 7) Subsequent πng closure of 19 with a reagent such as phosgene, carbonyldiimidazole or dimethyl carbonate m an appropπate solvent (tetrahydrofuran, dichloromethane, benzene, etc ) also will provide access to 18

Scheme 8

Alternatively, compound 17 may be dehydrated to afford the isopropene derivative 20 (Scheme 8). Suitable conditions for the dehydration would be the use of a reagent such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane sulfonyl chloride or anhydride, in a solvent such as pyridine, tetrahydrofuran, dichloromethane or benzene. The reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent and may require the presence of a base such as 4- dimethylaminopyridine, triethylamine, pyridine or di-isopropyl ethylamine. Exposure of 20 to acidic conditions would then afford ring closure to give 18. Suitable conditions would be the use of an acid such as p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid in a solvent such as dichloromethane, benzene, toluene or tetrahydrofuran. The reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0°C up to the reflux temperature of the solvent.

24 18

Scheme 9

An alternative route to 18 is shown m Scheme 9 Treatment of the previously descπbed compound 21, as taught by H Fukiumi, M Sugiyama, T Sakamoto. Chem Pharm Bull , 37(5) 1197 (1989), with an organo-metalhc reagent such as a Gπgnard reagent, an alkyl or aryl zmc reagent, an alkyl or aryl lithium reagent m an mert solvent (tetrahydrofuran, diethylether) under an inert atmosphere (mtrogen or argon) at a suitable temperature from 0° C up to reflux temperature of the solvent will then provide the tertiary alcohol 22 Compound 22 may then be subjected to basic conditions to effect πng closure to give the cyclocarbamate denvative 23 Suitable conditions would mvolve treatment of 22 with a base such as potassium hydroxide in a solvent such as ethanol or potassium t-butoxide in tetrahydrofuran The reaction can be earned out m an inert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent Compound 23 may then be converted to the brommated deπvative 24 Suitable conditions would be treatment with bromine or N- bromosuccinimide in a solvent such as dichloromethane, tetrahydrofuran or acetic acid The reaction can be earned out m an mert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent m the presence of an additive such as silica gel Subsequent reaction of 24 with an aryl or heteroaryl boronic acid boronic acid anhydride or tπalkyl starmane then provides access to the desired biaryl compound 18 The reaction can be earned out in a solvent such as acetone, ethanol, benzene, toluene or tetrahydrofuran, under an inert atmosphere (nitrogen or argon) from 0° C up to the reflux temperature of the solvent, m the presence of a palladium catalyst such as tetrakιs(tnphenylphosphme)palladιum (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoπde or potassium phosphate

18

23 25 Scheme 10

Alternatively, 23 (Scheme 10) may be treated at low temperature with a reagent such as an alkyl lithium or lithium amide m an mert solvent such as tetrahydrofuran, and then converted to a boronic acid 25 (M= B(OH)₂) under the action of tnmethyl or tnisopropyl borate, or into a starmane via reaction with tnmethyltm chlonde or bιs(tnmethyltm) Subsequent reaction of 25 with an aryl or heteroaryl bromide or iodide m the presence of a palladium catalyst such as tetrakιs(tπphenylphosphme) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoride or potassium phosphate, would then effect conversion into the desired thiophene cyclocarbamate 18

C. Method for synthesizing the thiophene thiocyclocarbamate compounds 26 and 27 depicted in Scheme 11 are described below

26

18 27

Scheme 11

Thiophene thiocyclocarbamates 26 and 27 may be obtained directly by treating 5 and 18 respectively with phosphorus pentasulfide in refluxing pyridine. Alternatively 5 and 18 may be treated with Lawesson's reagent ([2,4-bis(4-methoxyphenyl)-l,3- dithia-2,4-diphosphetane-2,4-disulfide]) in refluxing pyridine to afford 26 and 27, respectively.

Process for making thiazole cyclocarbamate derivatives.

Methods for preparing the thiazole cyclocarbamate compounds are described below.

30 31

Scheme 12 Thus the thiazole 28 was prepared accordmg to a literature procedure, schemel2 by B Golankiewicz and P Januszczyk, Tetrahedron, 41 5989 (1985) Reaction of the amine 28 with a suitable chloroformate or carbonate then gives the protected amine 29 This may be accomplished by reacting compound 28 with a chloroformate or carbonate deπvative such as methylchloroformate, ethylchloroformate, allylchloroformate, 2-(tπmethylsιlyl)ethylchloroformate or di- tert-butyldicarbonate in a solvent such as dichloromethane, THF, benzene, xylene or pyndme The reaction can be earned out under an mert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent and may require the presence of a base such as 4-dιmethylamιnopyndιne, tπethylamme, pyndine or di- lsopropyl ethylamine Exposure of compound 29 to an organo-metalhc reagent such as a Gπgnard reagent, an alkyl or aryl-zmc reagent, an alkyl or aryl lithium reagent in an inert solvent (THF, diethyl ether) under an mert atmosphere (nitrogen or argon) at a suitable temperature from 0 °C up to the reflux temperature of the solvent will then provide the alcohol 30 Compound 30 may then be exposed to basic conditions to effect ring closure to give the cyclocarbamate deπvative 31 Suitable conditions would mvolve treatment of compound 30 with a base such as potassium hydroxide in a solvent such as ethanol The reaction can be carried out under an inert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent

Scheme 13

Alternatively the carbamate protecting group present m compound 30 may be removed under conditions appropπate for its removal to afford compound 32 as taught by T W Greene and P G M Wuts, Protective Groups m Organic Synthesis, second ed , Wiley-Interscience (1991) Subsequent πng closure of compound 32 with a reagent such as phosgene, carbonyl dnmidazole or dimethyl carbonate in an appropπate solvent (THF, dichloromethane, benzene, etc) will also provide access to compound 31

30

33 31

Scheme 14

Alternatively, if compound 30 is a tertiary alcohol then it may be dehydrated to afford the isopropene denvative 33, scheme 3 Suitable conditions for the dehydration would the use of a reagent such as acetic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethane sulfonyl chlonde or anhydπde, m a solvent such as pyπdine, THF, dichloromethane or benzene The reaction can be earned out under an mert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent and may require the presence of a base such as 4-dιmethylammopyπdιne, tπethylamme, pyπdine or di-isopropyl ethylamme Exposure of compound 33 to acidic conditions would then afford ring closure to give compound 31 Suitable conditions would be the use of an acid such as p- toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid m a solvent such as dichloromethane, benzene, toluene or THF and the reaction can be earned out under an mert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent

Scheme 15

Compound 31 may then be converted mto the bromide 34, scheme 15 Suitable conditions would be exposure to bromine or N-bromosuccmimide in a solvent such as dichloromethane, THF or acetic acid, the reaction can be earned out under an inert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent m the presence of an additive such as silica gel Subsequent reaction of compound 34 with an aryl or heteroaryl boronic acid, boronic acid anhydride or tπalkyl stannane then provides access to the desired biaryl compound 35 The reaction can be earned out in a solvent such as acetone, ethanol, benzene, toluene or THF, under an mert atmosphere (nitrogen or argon) from 0 °C up to the reflux temperature of the solvent, m the presence of a palladium catalyst such as tetrakιs(tnphenylphosphιne) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoπde or potassium phosphate

31

36 35

Scheme 16

Alternatively compound 31 may be treated at low temperature with a reagent such as an alkyl lithium or lithium amide m an mert solvent such as THF, and then converted into a boronic acid (M = B(OH)₂) 36 under the action of tπmethyl or tnisopropyl borate, or mto a stannane under the action of tnmethyltm chlonde or bιs(tnmethyltm), Scheme 16 Subsequent reaction with an aryl or heteroaryl bromide or iodide m the presence of a palladium catalyst such as tetrakιs(tnphenylphosphme) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluonde or potassium phosphate would then effect conversion mto the desired compound 35

AMIDE DERIVATIVES

Process for making amide thiophene derivatives.

A method for preparing thiophene derivatives is described below, scheme 17

/-— -_^ CX^ e ^ .COjMe ^/^C02^H

*<-A ^

( *- X ^~ s^ NH₂ ^s NHCO₂R ^& NHC0₂R

₃7 38 ₃9

Scheme 17

Thus the amine 37 is converted mto a carbamate, such as a tert-butyl carbamate as descnbed m scheme 1 for the preparation of compound 2 Hydrolysis of the ester 38 under basic conditions, for example lithium or sodium hydroxide in THF or methanol at room temperature then gives the acid 39 Conversion of the acid 39 mto the acid chloride 40 is accomplished under standard conditions, thionyl chlonde or oxalyl chloride either neat or in the presence of a solvent such as dichloromethane and an additive such as a catalytic amount of N,N-dιmethylformamιde Compound 40 is then reacted with diazomethane or tπmethylsilyldiazomethane m an mert solvent such as THF or dichloromethane, and the product diazoketone 41 is then rearranged in the presence of silver (I) oxide to afford the acid 42 Treatment of compound 42 under conditions that specifically remove the protecting carbamate functionality, for example acidic conditions, will then affect cyc zation to give compound 43 Reaction of compound 43 with an alkylatmg agent such as an alkyl iodide, bromide, tosylate or mesylate, or a bis-alkyl iodide, bromide, tosylate or mesylate, under basic conditions, for example butyl lithium in the presence of N,N,N,N-tetramethylene diamine m a solvent such as THF under an mert atmosphere (nitrogen or argon) at a temperature between -78 °C and the boilmg po t of the solvent, will then afford the alkylated deπvative 44

Process for making thiazole derivatives.

A method for preparing thiazole denvatives is descπbed below, scheme 18

29 45 46

47 48 49

50 51 52

53

Scheme 18

Hydrolysis of the ester 29 under basic conditions, for example lithium or sodium hydroxide in THF or methanol at room temperature then gives the acid 45 Conversion of the acid 45 into the acid chloride 46 is accomplished under standard conditions, for example thionyl chlonde or oxalyl chlonde either neat or m the presence of a solvent such as dichloromethane and an additive such as a catalytic amount of N,N-dιmethylformamιde Compound 46 is then reacted with diazomethane or tπmethylsilyldiazomethane in an inert solvent such as THF or dichloromethane, and the product diazoketone 47 is then reaπanged m the presence of silver (I) oxide to afford the acid 48 Treatment of compound 48 under conditions that specifically remove the protecting carbamate functionality, for example acidic conditions, will then affect cyclization to give the heterocycle 49 Reaction of compound 49 with an alkylating agent such as an alkyl iodide, bromide, tosylate or mesylate, or a bis-alkyl iodide, bromide, tosylate or mesylate, under basic conditions, for example butyl lithium m the presence of N,N,N,N-tetramethylene diamine m a solvent such as THF under an mert atmosphere (nitrogen or argon) at a temperature between -78 °C and the boiling pomt of the solvent, will then afford the alkylated heterocycle 50 Compound 50 may then be converted mto the bromide 51 Suitable conditions would be exposure to bromine or N-bromosuccmimide m a solvent such as dichloromethane, THF or acetic acid, the reaction can be carried out under an mert atmosphere (mtrogen or argon) from 0 °C up to the reflux temperature of the solvent m the presence of an additive such as silica gel Subsequent reaction of compound 51 with an aryl or heteroaryl boronic acid, boronic acid anhydride or tπalkyl stannane then provides access to the desired biaryl compound 52 The reaction can be earned out m a solvent such as acetone, ethanol, benzene, toluene or THF. under an inert 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(tπphenylphosphme) palladium (0) or palladium acetate and may require an additive such as sodium carbonate, cesium fluoride or potassium phosphate The thione deπvative, compound 53, may be obtained directly by treatmg 52 with phosphorus pentasulfide m refluxing pyπdme Alternatively 52 may be treated with Lawesson's reagent m refluxing pyridine to afford 53. The compounds of the present mvention can be used m the form of salts derived from pharmaceutically or physiologically acceptable acids or bases These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfunc acid, nitnc acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succimc 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 admmistered in 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 wherein Q is oxygen as antagonists of the progesterone receptor The mvention further provides comparable methods and compositions which utilize one or more compounds herein wherem Q is S, NR⁶, or CR⁷R⁸ as agonists of the progesterone receptor

The progesterone receptor antagonists of this invention, used alone or m combmation, can be utilized m methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease Specific uses of the compounds and pharmaceutical compositions of invention mclude the treatment and/or prevention of uteπne myometnal fibroids, endometnosis, benign prostatic hypertrophy, carcinomas and adenocarcinomas of the endometπum, ovary, breast, colon, prostate, pituitary, menmgioma and other hormone-dependent tumors Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus m livestock The progesterone receptor agonists of this invention, used alone or m combination, can be utilized m methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uteπne leiomyomata, endometπosis, polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometπum, ovary, breast, colon, prostate Additional uses of the invention include stimulation of food mtake This mvention also mcludes pharmaceutical compositions compπsmg one or more compounds of this mvention with a pharmaceutically acceptable earner or excipient When the compounds are employed for the above utilities, they may be combmed with one or more pharmaceutically acceptable caπiers or excipients, for example, solvents, diluents and the like, and may be admmistered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions contammg, for example, from about 0 05 to 5% of suspending agent, syrups contammg, for example, from about 10 to 50% of sugar, and elixirs contammg, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions contammg 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 adrmmstration and the seventy of the condition being treated However, m general, satisfactory results are obtained when the compounds of the invention are admmistered 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 mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg Dosage forms suitable for internal use comprise from about 0 5 to 500 mg of the active compound in mtimate admixture with a solid or liquid pharmaceutically acceptable earner This dosage regimen may be adjusted to provide the optimal therapeutic response For example, several divided doses may be admmistered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation

These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes Solid carriers include starch, lactose, dicalcium phosphate, microcrystal ne cellulose, sucrose and kaolm, while liquid earners mclude sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropπate to the nature of the active ingredient and the particular form of administration desired Adjuvents customarily employed m the preparation of pharmaceutical compositions may be advantageously mcluded, such as flavoring agents, coloπng agents, preserving agents, and antioxidants, for example, vitamm E, ascorbic acid, BHT and BHA

The prefeπed pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules Oral administration of the compounds is preferred These active compounds may also be administered parenterally or mtrapentoneally 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 hydroxypropylcellulose Dispersions can also be prepared m glycerol, liquid, polyethylene glycols and mixtures thereof in oils Under ordinary conditions of storage and use, these preparations contam a preservative to prevent the growth of microorganisms

The pharmaceutical forms suitable for injectable use mclude steπle aqueous solutions or dispersions and stenle powders for the extemporaneous preparation of sterile injectable solutions or dispersions In all cases, the form must be stenle and must be fluid to the extent that easy synnge ability exits It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi The carrier can be a solvent or dispersion medium contaimng, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil The following non-limiting examples are illustrative of exemplary compound

5. EXAMPLE 1

6-(3-chlorophenvπ-l,4-dihydro-4.4-dimethyl-2H-thieno[2.,3-dlH 1oxazine-2-one

2-(3-Chlorobenzyl)acetaldehyde

To a 25°C solution of 3-chlorostyrene in anhydrous CH₂C1₂ ( 10 Og, 72 15 mmol) was added a well-stined solution of Pb(OAc)₄ ( 35 2g, 79 4mmol) m tπfluoroacetic acid (150mL), dropwise The reaction was completed within 30 mm of the addition and after being stiπed for a further 30 mm, the mixture was poured mto water, extracted with ether (3X), the combmed organic layers were washed with saturated NaHCO₃ solution, water, dned (MgSO ), and concentrated to a volume of about 15 ml and immediately used for the following reaction described below

2-Amιno-5-(3-chloro-phenyl)-thιophene-3-carboxyhc acid methyl ester

To the crude aldehyde, prepared above, m methanol was added a mixture of sulfur ( 2 55g, 79 44mmol), methylcyanoacetate (7 88 g, 79 44 mmol), morphohne (6 92 g, 79 44) and the resultmg reaction mixture was refluxed for 16 hours The unreacted sulfur was filtered off and the filtrates were evaporated leaving behmd a black residue This residue was extracted with ether and washed with H₂O Crystallized from ether/hexane (1 5) to obtam white crystals (3 85g, 14 3mmol, 50%), mp 85-87° 1H NMR (DMSO-d₆) δ 3 75 (s, 3H), 7 18-7 27 (m, 1H), 7 31-7 42 (m, 3H), 7 53 (s, 1H), 7 62 (s, 1H), MS(+APCI) m/z268(M+H), Anal Calc For Ci₂Hi₀ClNO₂S C, 53 83, H, 3 76, N, 5 23 Found C, 53 57, H, 3 37, N, 5 00

2-Allyloxycarbonylamιno-5-(3-chloro-phenvπ-thιophene-3-carboxylιc acid methyl ester To a solution of 2-ammo-5-(3-chloro-phenyl)-thιophene-3-carboxylιc acid methyl ester (2g, 7 5 mmol) m anhydrous 1,2-dιchloroethane (50 mL) was added at room temperature under nitrogen allyl chloroformate (1 6 mL, 15 1 mmol) The reaction mixture was heated at reflux under nitrogen for 18 hours, cooled to room temperature, and treated with a saturated aqueous sodium bicarbonate solution (100 mL) The organic layer was separated and aqueous layer was extracted with methylene chloride (3x20 mL) The combmed organic layers were washed (brine) and dried (MgSO₄) After removal of the solvent, the residue was puπfied by a flash silica gel column (hexane ethyl acetate/7 1) to give the subtitled compound as an off- white solid (2 14g, 81%) ^XH-NMR (DMSO-d₆) δ 10 2 (s, IH), 7 73 (t, IH, J = 1 7 Hz), 7 66 (s, IH), 7 57 (dt, 1H, J = 7 7, 1 7 Hz), 7 41 (t, 1H, J= 7 7 Hz), 7 34 (dt, IH, J= 6 8, 1 6 Hz), 6 01 (m, IH), 5 41 (dd, 1H, J= 7 3, 1 6 Hz), 5 29 (dd, 1H, J= 10 5, 1 3 Hz), 4 74 (d, 2H, J = 5 5 Hz), 3 84 (s, 3H) Anal Calc For Cι₆Hι₄ClNO₄S C, 54 63, H, 4 01, N, 3 98 Found C, 54 56, H, 3 92, N, 3 89

To a solution of 2-allenoxycarbonylamιno-5-(3-chloro-phenyl)-thιophene-3- carboxy c acid methyl ester (0 lg, 0 28 mmol) in anhydrous THF was added a solution of methylmagnesium bromide (3 0 M in diethyl ether, 1 5 mL, 4 5 mmol) at room temperature under nitrogen After stirring at room temperature under mtrogen for 20 minutes, the reaction mixture was treated with brine (10 mL) followed by addition of an aqueous IN HC1 solution (5 mL) Ethyl acetate (20 mL) was added and organic layer was separated, washed with brine (5 mL) and dned over MgSO₄ After removal of the solvent, the residue was purified by a flash column (silica gel, hexane ethyl acetate/5 1) to give carbinol which was used in next step without further punfication and charactenzation

A mixture of above crude carbmol, potassium hydroxide (excess) in ethanol was stirred at room temperature under nitrogen overnight The reaction solution was then acidified by an addition of a cold aqueous IN HC1 solution Ethyl acetate (20 mL) was added and organic layer was separated, washed with bnne (5 mL) and dried (MgSO₄) After removal of the solvent, the residue was puπfied by a silica gel column (hexane ethyl acetate/2 1) to give the title compound as an off-white solid (16 mg, 19% for two steps) mp 149-150 °C, *H-NMR (DMSO-ύ ) δ 10 69 (s, IH), 7 64 (t. IH, J = 1 8 Hz), 7 49 (s, IH), 7 47 (dt, IH, J = 7 7, 1 4 Hz), 7 39 (t, IH, J= 7 8 Hz), 7 29 (dt, IH, J = 7 8, 1 3 Hz), 1 61 (s, 6H) MS (El) m/z 293/295 (M⁺) Anal Calc For Ci₄Hι₂ClNO₂S C, 57 24, H, 4 12, N, 4 77 Found C, 57 27, H, 4 25, N, 4 66 EXAMPLE 2 6-(3-chlorophenyl)-l,4-dihydro-4,4-dimethyl-2H-thieno[3,2-d] [l 3]oxazine-2-one

3-Chloro-3-(3-chloro-phenyl)-acrylomtnle

A solution of POCl₃ was slowly added to anhydrous DMF over a peπod of 20 mmutes and the temperature was mamtamed around 30°C 3'-Chloroacetophenone solution m anhydrous DMF was added to the above solution and the reaction temperature was allowed to rise to around 50°C Hydroxylamme HC1 was added to the reaction solution, portionwise, over 1 hour A volume of 500 mL of water was added to form precipitate, stiπed for 1 hour and precipitate was collected on a Buchner funnel, washed with H₂O, and dried to afford a yellow crystallme compound, mp 60-62°C *H NMR (DMSO-^e) δ 1 60(s, 6H), 7 30 (d, IH, J= 8 41Hz), 7 41(d, IH, J= 8 41Hz), 10 47 (s, IH), MS(+APCI)m/z 213(M+H), Anal Calc For C₉H₉ClN₂O₂ C, 50 84, H, 4 27, N, 13 17 Found C, 50 99, H, 4 28, N, 12 98

3-Amιno-5-(3-chloro-phenyl)-thιophene-2-carboxylιc acid methyl ester

Sodium pellets were slowly added to methanol solution to form NaOMe m situ, then methyl thioglycolate was added over a penod of 20 mmutes to the methanol solution A solution of 3-Chloro-3-(3-chloro-phenyl)-acrylonιtnle m methanol was added slowly and was brought to reflux for 1 hour The reaction mixture was cooled to room temperature and methanol was concentrated to 100 mL and 200 mL of water was added, stiπed for 30 mmutes and the yellow precipitate was collected and washed with water several times to yield a yellow crystallme compound, mp 92-95 °C ^lH NMR (OMSO-d₆) δ 1 60 (s, 6H), 7 30 (d, IH, J = 8 41Hz), 7 41(d, IH, J= 8 41Hz), 10 47 (s, IH), MS(+APCI)m/z 213(M+H), Anal Calc For C₉H₉ClN₂O₂ C, 50 84, H, 4 27, N, 13 17 Found C, 50 99, H, 4 28, N, 12 98

3-Allyloxycarbonylamιno-5-(3-chloro-phenyl)-thιophene-2-carboxylιc acid methyl ester

To a solution of 3-Ammo-5-(3-chloro-phenyl)-thιophene-2-carboxyhc acid methyl ester (15g, 56 Ommol) m toluene (200mL) was added a solution of allyl chloroformate (8 lOg, 67 2mmol) in toluene (5 OmL) and the resulting reaction solution was heated under reflux for 3 h Toluene was stnpped down and the crystals were collected and washed with ether/hexane to afford a yellow crystallme compound, mp 101-103°C *H NMR (OMSO-d₆) δ 3 85 (s, 3H), 4 68-4 71 (d, 2H, J = 5 46Hz), 5 26-5 30 (dd, IH, J= 1 35, 9 84Hz), 5 36-5 42 (dd, IH, J = 1 57,

15 68Hz), 5 96(m, 2H), 7 50-7 52 (m, 2H), 7 67-7 71 (m, IH), 7 79 (s, IH), 8 10 (s, IH), MS(+APCI) m/z 352(M+H), Anal Calc For Cι₆H₁₄ClNO₄S C, 54 63, H, 4 01, N, 3 97 Found C, 54 05, H, 4 17, N, 3 84

r5-(3-Chloro-phenyl^")-2-(l-hvdroxy-l-methyl-ethyl)-thιophen-3-yl]-carbamιc acid allyl ester

To a solution of 3-Allyloxycarbonylamιno-5-(3-chloro-phenyl)-thιophene-2- carboxyhc acid methyl ester (5 3g, 15 lmmol) m anhydrous THF (30mL) at room temperature was added a solution of 3 0M MeMgl in ether (20 lmL, 60 24mmol) After 30 mmutes, the reaction was slowly quenched with H₂O (lOmL), treated with saturated NH-.OH (lOOmL), extracted with ether (200mL), washed with bnne, dried (MgSO₄), concentrated, and chromatographed (hexane/ether, 1 4) mp 60-61 °C, ^!H NMR (OMSO-d₆) δ 1 52 (s, 6H), 4 59-4 61 (d, 2H, J= 5 35Hz), 5 22-5 36 (m, 2H), 5 91-6 04 (m, 2H), 7 33-7 67 (m, 5H), 8 89 (s, IH), MS(EI) m/z 351/353(M+H), Anal Calc For Cι₇Hι₈ClNO₃S C, 58 03, H, 5 16, N, 3 98 Found C, 58 17, H, 5 16, N, 3 97

6-(3-Chlorophenyl)-1.4-dιhvdro-4.4-dιmethyl-2H-thιeno[3.2-d1[1.31oxazιn-2-one

To a solution of [5-(3-Chloro-phenyl)-2-(l-hydroxy-l-methyl-ethyl)-thιophen- 3-yl]-carbamιc acid allyl ester ( 12g, 34mmol) in anhydrous THF (5 OmL) was added KO'Bu (0 076g, 0 068mmol) and stirred for 15 mmutes, quenched with H₂O, and m situ crystallization was earned out by adding minimal amount of MeOH to the solution The white crystals were collected on a Buchner funnel, mp 123-125°C ^:H NMR (DMSO- e) δ 1 64(s, 6H), 7 05(s, IH), 7 37-7 48(m, 2H), 7 53-7 56(s, IH), 7 67-7 68 (m,lH), 10 41(s, IH), MS(EI) m/z 293/295(M+H), Anal Calc For Cι₇Hι₈ClNO₃S C, 57 24, H, 4 12, N, 4 77 Found C, 56 93, H, 3 92, N, 4 97

Example 3 - Pharmacology The progestational activity of the current mvention was evaluated in the PRE-luciferase assay in CV-1 cells, descπbed below In-vitro potencies can be m the range 0 01nM-10,000nM In vivo potencies are anticipated to be m the range 1 mg/kg to 30 mg/kg

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 CV-1 cells co-transfected with human PR and PRE-luciferase plasrmds The mateπals methods used m the assay are as follows a Medium The growth medium was as follows DMEM (BioWhittaker) contammg 10% (v/v) fetal bovine serum (heat inactivated), 0 1 raM MEM non-essential ammo acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL) The expenmental medium was as follows DMEM (BioWhittaker), phenol red-free, contammg 10% (v/v) charcoal- stripped fetal bovine serum (heat-inactivated), 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 CV-1 cells are mamtamed m growth medium Co-transfection is done using 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 sonicated calf thymus DNA as carrier DNA in 250 ml Electroporation is earned out at 260 V and 1,000 mF m a Biorad Gene Pulser II After electroporation, cells are resuspended m growth medium and plated m 96-well plate at 40,000 cells/well in 200 μl Following overnight mcubation, the medium is changed to expenmental medium Cells are then treated with reference or test compounds m expenmental medium Compounds are tested for antiprogestational activity in the presence of 3 nM progesterone Twenty-four hr after treatment, the medium is discarded, cells are washed three times with D-PBS (GIBCO, BRL) 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, Ine ) Luciferase activity is measured using luciferase reagents from Promega c Analysis of Results

Each treatment consists of at least 4 replicates Log transformed data are used for analysis of vaπance and nonlinear dose response curve fitting for both agonist and antagonist modes Huber weighting is used to downweight the effects of outliers EC50 or IC50 values are calculated from the retransformed values JMP software (SAS Institute, Ine ) is used for both one-way analysis of vaπance and non-linear response analyses d Reference Compounds

Progesterone and tπmegestone are reference progestins and RU486 is the reference antiprogestin All reference compounds are run m full dose- response curves and the EC50 or IC50 values are calculated

Table 1. 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 0616 0026 0509 0746

2 0402 0019 0323 0501

3 0486 0028 0371 0637

Tnmegestone 1 00075 00002 00066 00085

2 00081 00003 00070 00094

3 00067 00003 00055 00082 Table 2. Estimated IC₅o, 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 0028 0002 0019 0042

2 0037 0002 0029 0048

3 0019 0001 0013 0027

Progestational activity Compounds that mcrease PRE-luciferase activity significantly (p<0 05) compared to vehicle control are considered active

Antiprogestational activity Compounds that decrease 3 nM progesterone mduced 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 mduced PRE-luciferase activity (default-nM) with SE

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

Claims

What is Claimed:

A compound of Formula I

wherem

A and B are mdependent substituents selected from S, CH or N, Provided that when A is S, B is CH or N, provided that and A and B cannot both be CH, and when A and B both equal N, one N may be optionally substituted with an Ci to C₆ alkyl group,

Ri and R₂ are mdependent substituents selected from the group of H, Ci to C_O alkyl, substituted Ci to Cβ alkyl, C₂ to Cβ alkenyl. substituted C₂ to Cβ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to Cβ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^Λ, or NR^BCOR^A, or R¹ and R² are fused to form a) an optionally substituted 3 to 8 membered spirocyclic alkyl rmg, or

b) an optionally substituted 3 to 8 membered spirocyclic alkenyl πng, or

c) an optionally substituted 3 to 8 membered spirocyclic rmg contammg one to three heteroatoms selected from the group of O, S and N, 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 Ci to C₃ alkyl,

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

R⁴ is a tπsubstituted benzene rmg contammg 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 thioalkyl, substituted Ci to C₃ thioalkyl, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, NO₂, Ci to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring contammg 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, or substituted Ci to C₃ alkyl, Y and Z are independently selected from H, halogen, CN, NO₂, Ci to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkyl,

or

R⁴ is a five or six membered πng with 1, 2, or 3 heteroatoms selected from O, S, SO, SO₂ or NR⁵, the five or six membered πngs bemg optionally substituted by one or two independent substituents selected from H, halogen, CN, NO₂ and Ci to C₃ alkyl, Ci to C₃ alkoxy, Ci to C₃ aminoalkyl, COR^F, or NR^GCOR^F,

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

R⁵ is H, or Ci to C₃ alkyl,

Q is O, S, NR⁶, or CR⁷R⁸,

R⁶ is from the group mcludmg CN, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃,

R⁷ and R⁸ are independent substituents from the group mcludmg H, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, or CN CO₂R⁹,

R⁹ is Ci to C₃ alkyl,

or CR⁷R⁸ may comprise a six membered rmg of the structure below W is O or a chemical bond or a pharmaceutically acceptable salt thereof

2 A compound of Claim 1 wherein

A and B are independent substituents S, CH or N, provided that when A is S, B is CH or N, and when B is S, A is CH or N, and

A and B cannot both be CH, and when A and B both equal N, one N may be optionally substituted with an Ci to Cβ alkyl group,

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

R² is H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to Cβ alkenyl, C₂ to Cβ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^A, or NR^BCOR^A, or R¹ and R² are fused to form a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring, or

b) an optionally substituted 3 to 8 membered spirocyclic alkenyl rmg, or

c) an optionally substituted 3 to 8 membered spirocyclic πng contammg one to three heteroatoms selected from the group of O, S and N, R^A 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, or substituted Ci to C₃ ammoalkyl,

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

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

R⁴ is a tnsubstituted benzene rmg contammg the substituents X, Y and Z as shown below

X is taken from the group mcludmg halogen, CN, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, Ci to C₃ alkoxy, substituted C_ to C₃ alkoxy, Ci to C₃ thioalkyl, substituted Ci to C₃ thioalkyl, Ci to C₃ ammoalkyl, substituted Ci to C₃ aminoalkyl, NO₂, Ci to C₃ perfluoroalkyl, 5-membered heterocyclic rmg contammg 1 to 3 heteroatoms, COR^D, OCOR^D, or NR^ECOR^D,

R^E is H, Ci to C₃ alkyl, or substituted d to C₃ alkyl, Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, NO₂, Ci to C₃ alkoxy, d to C₃ alkyl, or Ci to C₃ thioalkyl, or

R⁴ is a five or six membered πng with 1, 2, or 3 heteroatoms selected from O, S, SO, SO₂ or NR⁵ , the five or six membered πng being optionally substituted by one or two independent substituents selected from H, halogen, CN, NO₂ and Ci to C₃ alkyl, or Ci to C₃ alkoxy,

R⁵ is H or Ci to C₃ alkyl,

R⁶ is from the group mcludmg CN, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃,

R⁷ and R⁸ are independent substituents from the group mcludmg H, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, or CN CO₂R⁹,

R⁹ is Ci to C₃ alkyl,

or CR⁸R⁹ compnse a six membered πng as shown by the structure below

W is O or a chemical bond or a pharmaceutically acceptable salt thereof 3 A compound of Claim 1 wherem

A and B are mdependent substituents from the group mcludmg S, CH or N, provided that when A is S, B is CH or N, and when B is S, A is CH or N, and

A and B cannot both be CH,

R¹ = R² and are selected from the group which mcludes Ci to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocyclic alkyl constructed by fusmg R¹ and R² to form a 3 to 6 membered spirocyclic ring,

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

R^c is H, Ci to C₄ alkyl, or d to C₄ alkoxy,

R⁴ is a disubstituted benzene ring conta mg the substituents X and Y as shown below

X is selected from the group mcludmg halogen, CN, Ci to C₃ alkoxy, Ci to C₃ alkyl, NO₂, Ci to C₃ perfluoroalkyl, 5 membered heterocyclic πng contammg 1 to 3 heteroatoms, or Ci to C₃ thioalkyl,

Y is a substituent on the 4' or 5' position selected from the group of H, halogen, CN, NO₂, Ci to C₃ alkoxy, Ci to C₄ alkyl, or Ci to C₃ thioalkyl,

or

R⁴ is a five membered rmg with the structure shown below

R⁵ is H, or Ci to C₃ alkyl, or Ci to C₄ CO₂alkyl,

X' is selected from halogen, CN, NO₂, Ci to C₃ alkyl or Ci to C₃ alkoxy,

Y' is H or d to C₄ alkyl, or

R⁴ is a six membered πng with the structure

X¹ is N or CX², X² is halogen, CN or NO₂ ,

R⁶ is selected from the group mcludmg CN, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃,

R⁷ and R⁸ are mdependent substituents selected from the group of H, Ci to Cβ alkyl, substituted Ci to Cβ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, or CN CO₂R⁹, R⁹ is Ci to C₃ alkyl,

or CR⁷R⁸ comprise a six membered πng of the structure

W is O or a chemical bond, or a pharmaceutically acceptable salt thereof

4 A compound of Claim 3 wherem

R¹ = R² and are selected from the group which includes Ci to C₃ alkyl, substituted Ci to C₃ alkyl, or spirocyclic alkyl constructed by fusmg R¹ and R² to form a 3 to 6 membered spirocyclic rmg, and A, B, R³, R^c, R⁴, X, Y, U, R⁵, X', Y\ X¹, X², Q, R⁶, R⁷, R⁸ , R⁹ and W are as defined m Claim 3, or a pharmaceutically acceptable salt thereof

5 A compound of Claim 3 wherem

R¹ and R² are fused to form a 3 to 6 membered spirocyclic ring, and A, B, R³, R^c, R⁴, X, Y, U, R⁵, X', Y', X¹, X², Q, R⁶, R⁷, R⁸ , R⁹ and W are as defined in Claim 3, or a pharmaceutically acceptable salt thereof

A compound of the formula wherem

Ri and R₂ are independent substituents selected from the group of H, Ci to Cβ alkyl, substituted Ci to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to Cβ alkenyl, C₂ to Cβ alkynyl, substituted C₂ to Cβ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^A, or NR^BCOR^A, or R¹ and R² are fused to form a) a 3 to 6 membered spirocyclic alkyl πng, or

b) a 3 to 6 membered spirocyclic alkenyl πng,

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

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

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 thioalkyl, substituted Ci to C₃ thioalkyl, Ci to C₃ ammoalkyl, substituted Ci to C₃ aminoalkyl, NO₂, Ci to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic πng contammg 1 to 3 heteroatoms, COR^D, OCOR^D, orNR^ECOR^D,

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

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

Y and Z are mdependently selected from H, halogen, CN, NO₂, Ci to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkyl, or a pharmaceutically acceptable salt thereof

7 A compound of Claim 1 which is 6-(3-chlorophenyl)-l,4-dιhydro-4,4- dιmethyl-2H-thιeno[2,3-d][l,3]oxazιne-2-one, or a pharmaceutically acceptable salt thereof

8 A method of mducmg contraception m a mammal, the method comprismg admmistering to a mammal in need thereof a compound of Claim 1, or a pharmaceutically acceptable salt thereof

9 A method of treatment or prevention in a mammal of benign or malignant neoplastic disease the method compπsmg administering to a mammal in need thereof a compound of Claim 1, or a pharmaceutically acceptable salt thereof

10. The method of Claim 9 wherein the benign or malignant neoplastic disease is selected from uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas or adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma or other hormone-dependent tumors.

11. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier or excipient.