CYANOPYRROLES AS PROGESTERONE RECEPTOR AGONISTS

Abstract: This invention provides a progesterone receptor antagonist of formula (1) having the structure wherein T is O, S, or absent; R1, and R2 are each, independently, hydrogen, alkyl, substituted alkyl; or R1 and R2 are taken together to form a ring and together contain -CH2(CH2)nCH2-, -CH2CH2CMe2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or -CH2CH2NR7CH2CH2-; n=1-5; p=1-4; q=1-4; R3 is hydrogen, OH, NH2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR<A>; R<A> is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R4 is hydrogen, halogen, CN, NH2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R5 is hydrogen, alkyl, or substituted alkyl; R6 is hydrogen, alkyl, substituted alkyl, or COR<B>; R<B> is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R7 is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.

Description: CYAN0PYRR0LES AS PROGESTERONE RECEPTOR AGONISTS Background of the Invention Intracellular receptors (IR) form a class of structurally related gene regulators known as "hgand 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 ligands Once a hgand 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 that inhibits the effect of the hormone is an antagonist PR agonists (natural and synthetic) are known to play an important role in the health of women PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers Co-administration of a PR agonist reduces or ablates that nsk The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists in functional models, either/or in-vitro and in-vivo These compounds may be used for contraception, in the treatment of fibroids, endometπosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy Jones et al (US 5,688,810) is the PR antagonist dihydroquinoline A. Jones et al described the enol ether B (US 5,693,646) as a PR ligand. B Jones et al described compound C (US 5,696,127) as a PR hgand. Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 98). D E Zhi et al described the ether G as a PR antagonist (J Med Chem 41, 291, 1998) Combs et al disclosed the amide H as a hgand for the PR (J Med Chem 38, 4880, 1995) H Perlman et al described the vitamin D analog I as a PR hgand (Tetrahedron Lett 35, 2295, 1994) Hamann et al described the PR antagonist J (Ann N Y Acad Set 761, 383, 1995) Chen et al described the PR antagonist K (Chen et al, POI-37, 16 th Int Cong Het Chem , Montana, 1997) K Kuπhari et al described the PR hgand L (J Antibiotics 50, 360, 1997) Kuhla et al claimed the oxindole M as a cardiotonic (WO 86/03749) M Weber claimed the oxindole N for cardiovascular indications (WO 91/06545) N Fischer et al claim a preparation for making compounds which include the genenc structure O (US 5453516) O R = various Singh et al described the PDE III inhibitor P (J Med Chem 37, 248, 1994) Andreani et al descπbed the cytotoxic agent Q (Ada Pharn Nord 2, 407, 1990) Q Binder et al descπbed structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767) R Walsh (A H Robins) descπbed the oxindole S as an intermediate (US 4440785, US 4670566) RI = F, Cl. Br, alkyl, NH 2 R2 = alkyl, alkoxy, F, Cl, NH2, CF 3 Bohm et al claim the oxindole T as cardiovascular agents (WO 91/06545) Bohm et al include the geneπc structure U (WO 91/04974) U A Japanese patent contains the generic structure V (JP 63112584 A) Boar et al descπbed the dioxolane W as an intermediate for preparation of acetyl- cholmesterase inhibitors (WO 93/12085 Al) W Kende et al described methodology for preparing 3, 3 -substituted oxindoles, e g , X, that was utilized in the present invention (Synth Commun 12, 1, 1982) There are numerous literature reports that disclose a number of benzoxazιn-2- ones However, none of these examples in these patents contain substituents necessary for the compounds to be active as progesterone receptor modulators Among these publications, Narr et al (German Patent, DE 3633861, CA 109 22973) claimed that lmidazobenzoxazinones, e g Y, as cardotonics, Benzoxazin- 2-ones, such as brofoxine (Z), being active as an anxiolytic was reported by Hartmann et al (Proc West Pharmacol Soc 21, 51-55 (1978)), More recently, a number of patents (e g , Young et al WO95/20389, Chπst et al WO98/14436) claimed quιnazolιn-2-ones and benzoxazιn-2-ones such as compounds AA and BB as inhibitors of HIV reverse transcπptase AA BB DESCRIPTION OF THE INVENTION This invention provides progesterone receptor agonists of Formula 1 having the structure wherein T is O, S, or absent, Ri, and R 2 are each, independently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a ring and together contain -CH 2 (CH 2 ) n CH 2 - , -CH 2 CH2CMe 2 CH 2 CH 2 - , -0(CH 2 ) P CH 2 - , -0(CH 2 ) q O- , -CH 2 CH 2 OCH 2 CH 2 - , or -CH 2 CH 2 NR 7 CH 2 CH 2 -, n = l-5, P = 1-4, q = l-4 R 3 is hydrogen, OH, NH 2 , alkyl, substituted alkyl. alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl, R IS hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl, R5 is hydrogen, alkyl, or substituted alkyl, Re is hydrogen, alkyl, substituted alkyl, or COR B , R B is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl, R 7 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof, which are useful for contraception, in the treatment of fibroids, endometπosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy Prefeπed compounds of this mvention are those having the structure wherein T is O, or absent, Ri, and R 2 are each, independently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a ring and together contain -CH 2 (CH 2 ) n CH 2 - , 11 = 1-5, R 3 is hydrogen, R is hydrogen or halogen, R 5 is hydrogen or alkyl, R-5 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof The compounds of this invention may contain an asymmetπc carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give πse to optical isomers and diastereoisomers While shown without respect to stereochemistry in Formula 1, the present invention includes such optical isomers and diastereoisomers, 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-chain saturated aliphatic hydrocarbon groups having 1-6 carbon atoms, "alkenyl" includes both straight- and branched-chain alkyl group of 2-6 carbon atoms containing at least one carbon-carbon double bond, "alkynyl" group includes both straight- and branched-chain alkyl group of 2-6 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 containing one or more substituents from the group including halogen, CN, OH, N0 2 , 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 "thioalkyl" is used herein to refer to the SR group, where R is alkyl or substituted alkyl The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or substituted alkyl The term "aryloxy" is used herein to refer to the OR group, where R is aryl or substituted aryl The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is alkyl or substituted alkyl The term "alkylcarboxy " is used herein to refer to the COOR group, where R is alkyl or substituted alkyl This term is also refeπed to as alkoxycarbonyl The term "aminoalkyl" refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups may be either same or different and the point of attachment is on the nitrogen atom The term "halogen"ιs defined as Cl, Br, F, and I Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propiomc, lactic, citπc, tartaπc, succinic. fumaπc, aleic, malonic, mandehc, malic, phthalic, hydrochloπc, hydro bromic, phosphoric, nitric, sulfuπc, methanesulfonic, napthalenesulfonic, benzenesulfomc, toluenesulfomc, camphorsulfonic, and similarly known acceptable acids Salts may also be formed from inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, and organic bases, such as ammonium, mono-, di-, and tπmethylammonium, mono-, di- and tπethylammonium, mono-, di- and tπpropyl- ammonium (iso and normal), ethyldimethylammomum, benzyldimethylammomum, cyclohexylammonium, benzylammonium, dibenzylammonium, pipeπdinium, morpho- nium, pyπohdimum, piperazinium, 1-methylpιpeπdιnιum, 4-ethylmoφholιnιum, 1-ιso- propylpyπohdimum, 1,4-dιmethylpιperazιnιum, 1-n-butyl pipeπdinium, 2-methyl- pipeπdinium, l-ethyl-2-methylpιpeπdιmum, mono-, di- and tπethanolammomum, ethyl diethanolammomum, n-butylmonoethanolammomum, tπs(hydroxymethyl)methyl- ammomum, phenylmonoethanolammomum, and the like The compounds of this invention were be prepared according to the following schemes from commercially available starting mateπals or starting mateπals which can be prepared using hterature procedures These schemes show the preparation of representative compounds of this invention Scheme 1 According to scheme 1, commercially available oxindole 4 is treated with a strong organo-metal c base (e g , butyl lithium lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (e g THF, diethyl ether) under nitrogen at reduced temperature (ca -20°C) (Kende, et al, Synth Commun 12, 1, 1982) The resulting di-amon then is treated with excess electrophile such as an alkyl halide. preferably an iodide If Ri and R 2 are to be joined such as the product 5 contains a spirocycle at position 3, then the electrophile should be bi-functional, I e a duodide Subsequent bromination of 5 proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to afford the aryl bromide 6 The bromide 6 is reacted with a palladium salt (e g , tetrakis(tnphenylphoshine)palladium(0) or palladium acetate), in a suitable solvent (e g , THF, dimethoxyethane, acetone, ethanol or toluene) at room temperature under an inert atmosphere (argon, nitrogen) The mixture is then treated with pyπole 2-boronιc acid (Synthesis 613, 1991) and a base (potassium carbonate, tπethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions Treatment of the biaryl compound 7 with chlorosulfonyl lsocyanate followed by an excess of DMF at low temperature produces the protected cyanopyrrole 8 Removal of the tert-butyloxycarbonyl (BOC) protecting group via standard conditions (e g , TFA dichloromethane, aqueous NaOH, thermolysis) produces the required final product which is purified by standard means Scheme 2 As depicted in Scheme 2, an appropπately substituted ortho-amino benzoic acid, or deπvative (such as ethyl ester) 10 is treated with a suitable organometallic reagent, e g , Gπgnard reagent, in appropπate nonprotic solvents (e g , THF, ether, toluene) under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature to give ortho-amino carbinol 11 Ring closure of carbinol 11 to yield benzoxazιn-2-ones 12 is commonly effected by a condensing agent (e g , carbonyldnmidazole, phosgene, dimethylcarbonate, diethylcarbonate) in a suitable nonprotic solvent (e g , THF, ether, toluene) at temperatures in the range of room temperature to 65 °C The pyrrole ring is attached to this platform by employing a suitable coupling reaction (e g , Suzuki, Stille) to give the biaryl 13 These reactions are performed in the presence of suitable catalyst (e g , palladium or nickel complexes often with phosphino ligands, e g , Ph 3 P, dppf, dppe or palladium salts such as palladium acetate) and a base the commonly used bases include (but are not limited to) sodium bicarbonate, sodium carbonate, potassium phosphate, baπum carbonate, potassium acetate, or cesium fluoπde The most commonly used solvents in these reactions include benzene, DMF, isopropanol, ethanol, DME, ether, acetone or a mixture of any one of these solvent and water The coupling reaction generally is executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95 °C Treatment of the biaryl compound 13 with chlorosulfonyl isocyanate followed by an excess of DMF at low temperature produces the protected cyanopyπole 14 Removal of the tert-butyloxycarbonyl (BOC) protecting group via standard conditions (e g , TFA/dichloromethane, aqueous NaOH, thermolysis) produces the required final product 15 which is purified by standard means The compounds of this invention are progestational agonists, and are therefore useful as oral contraceptives (male and female), in hormone replacement therapy (particularly when combined with an estrogen), in the treatment of endometπosis, luteal phase defects, benign breast and prostatic diseases and prostatic, breast, ovarian, uterine and endometπal cancers The compounds of this invention can be used alone as a sole therapeutic agent or can be used in combination with other agents, such as other estrogens, progestins, or androgens The compounds of this invention can be formulated neat or with a pharmaceutical earner for administration, the proportion of which is determined by the solubihty and chemical nature of the compound, chosen route of administration and standard pharmacological practice The pharmaceutical earner may be solid or liquid A solid earner can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, g dants, compression aids, binders or tablet-disintegrating agents, it can also be an encapsulating material In powders, the earner is a finely divided solid which is in admixture with the finely divided active ingredient In tablets, the active ingredient is mixed with a earner having the necessary compression properties in suitable proportions and compacted in the shape and size desired The powders and tablets preferably contain up to 99% of the active ingredient Suitable solid earners include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrro dine, low melting waxes and ion exchange resins Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions The active ingredient can be dissolved or suspended m a pharmaceutically acceptable liquid earner such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats The liquid earner can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators Suitable examples of liquid earners for oral and parenteral administration include water (partially containing additives as above, e g cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydπc alcohols and polyhydπc alcohols, e g glycols) and their deπvatives, lethicins, and oils (e g fractionated coconut oil and arachis oil) For parenteral administration, the earner can also be an oily ester such as ethyl oleate and isopropyl myπstate Sterile liquid earners are useful in steπle liquid form compositions for parenteral administration The liquid earner for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, lntrapeπtoneal or subcutaneous injection Sterile solutions can also be administered intravenously The compounds of this invention can also be administered orally either in liquid or solid composition form The compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository For administration by lntranasal or lntrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin The earner may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices The creams and ointments may be viscous liquid or semisohd emulsions of either the oil-in-water or water-in-oil type Pastes compnsed of absorptive powders dispersed in petroleum or hydrophihc petroleum containing the active ingredient may also be suitable A vaπety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a earner, or a matrix containing the active ingredient Other occlusive devices are known in the hterature The dosage requirements vary with the particular compositions employed, the route of administration, the seventy of the symptoms presented and the particular subject being treated Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0 02 μg/kg - 750 μg/kg Treatment will generally be initiated with small dosages less than the optimum dose of the compound Thereafter the dosage is increased until the optimum effect under the circumstances is reached, precise dosages for oral, parenteral, nasal, or lntrabronchial administration will be determined by the administering physician based on expenence with the individual subject treated Preferably, the pharmaceutical composition is in unit dosage form, e g as tablets or capsules In such form, the composition is sub-divided in unit dose containing appropπate quantities of the active ingredient, the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropnate number of any such compositions in package form. The following provides the preparation of representative compounds of this invention Example 1 5-(4.4-Dιmethyl-2-oxo-1.4-dιhvdro-2H-benzo fdl IN31 oxazιn-6-vD-lH-pyrrole-2- carbonitπle A solution of 2-amιno-5-bromobenzoιc acid (lOg, 46 mmol) in dry THF (200 mL) was treated at -78 °C under nitrogen with a solution of methylmagnesium bromide in ether (3 0 M, 90 mL, 270 mmol) The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under nitrogen and then poured into a cold 0 5 N aqueous hydrochlonde solution (300 mL) The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added The organic layer was separated and aqueous layer was extracted with ethyl acetate (3x100 mL) The combined organic layers were washed with brine and dπed (MgSO 4 ) After removal of solvent in vacuo, the residue was purified by a silica gel flash chromatography (hexane ethyl acetate/3 2) to give 2-(2-amιno-5- bromophenyl)propan-2-ol as an off-white solid (6g, 57%) mp 62-63 °C, Η-NMR (CDC1 3 ) 5 7 19 (d, 1HN = 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 (18g, 78 mmol) in dry THF (150 mL) was added lN-carbonyldiimidazole (15 5g, 94 mmol) under nitrogen The reaction solution was heated at 50 °C overnight The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL) The solution was washed with IN aqueous hydrochlonde solution (2x40 mL), brine (20 mL), and dried with MgS0 After removal of the solvent in vacuo, 6-bromo-4,4-dιmethyl-l,4- dihydro-benzofdj '[ 1 , 3Joxazιn-2-one was obtained as a white solid (20 g, 100%) mp 199-200 °C, Η-NMR (DMSO-de) δ 10 32 (s, IH, D 2 0 exchangeable), 7 48 (d, IH, J = 2 1 Hz), 7 43 (dd. 1HN= 8 5, 2 1 Hz), 6 84 (d, 1H, J = 8 4 Hz), 1 61 (s, 6H) A solution of 6-bromo-4,4-dιmethyl-l,4-dιhydro-benzo[d][l,3]oxazιn-2-one (5 0 g, 20 mmol) and tetrakιs(tnphenylphosphιne)palladιum(0) (580 mg, 0 5 mmol) in toluene (200 mL) was stirred under a flow of nitrogen for 25 mm To the solution was added sequentially l-tert-butoxycarbonylpyπole-2-boronιc acid (8 24 g, 39 mmol) in absolute ethanol (50 mL) and potassium carbonate (5 39 g, 39 mmol) in water (50 mL) The mixture was heated to 80 °C for 16 h and allowed to cool The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3 x 200 mL) The organic layers were combined, washed with water (200 mL) and bnne (100 mL) and dried over magnesium sulfate The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) to give 2-(4, 4- dιmethyl-2-oxo-l,4-dιhydro-2H-benzo [d] [1,3] oxazιn-6-yl)-pyrrole-l-carboxylιc acid tert-butyl ester (4 0 g, 58%) as a tan solid, mp 172-173 °C To a solution of 2-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-benzo [d] [1,3] oxazιn-6-yl)-pyrrole-l-carboxyhc acid tert-butyl ester (2 0 g, 5 8 mmol) in THF (anhydrous, 50 mL) at -78 °C was added chlorosulfonyl isocyanate (0 66 mL, 6 7 mmol) After 90 min, DMF (9 mL, 116 mmol) was added and the reaction was allowed to warm to room temperature The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL) The organic layers were combined, washed with bnne (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo Puπfication via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave 2-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-benzo [d] [1,3] oxazιn-6-yl)-5-cyano-pyrrole-l-carboxylιc acid tert-butyl ester (1 1 g, 52%) as a white powder, mp 165-167 °C Η NMR -DMSO, 300 MHz) δ 1 36 (s, 9H). 1 61 (s, 6 H), 6 44 (d, 1 H, J = 3 7 Hz), 6 92 (d, 1 H, J= 8 2 Hz), 7 27-7 32 (m, 2 H), 7 36 ('d', 1 H, J= 1 5 Hz), 10 36 (s, 1 H) MS (El) m/z 367 [M] + 2-(4,4-Dιmethyl-2-oxo-l,4-dιhydro-2H-benzo [d] [1,3] oxazιn-6-yl)-5-cyano- pyπole-1-carboxyhc acid tert-butyl ester (1 g, 2 7 mmol) was placed in a 25 mL round bottomed flask stoppered with a rubber septum and equipped with a nitrogen inlet and a needle to allow gaseous outflow A vigorous flow of nitrogen was maintained as the flask was placed in an oil bath and heated to 160 °C After 20 min at this temperature, the flask was removed from the oil bath and allowed to cool The yellow residue was washed into a larger flask with dichloromethane/ethyl acetate and adsorbed onto a small amount of silica gel Punfication by flash column chromatography on silica gel (40% ethyl acetate/hexane) gave the title compound (340 mg, 47%) as a yellow powder, mp 241-242 °C Η NMR (d 6 -OMSO, 300 MHz) δ 1 65 (s, 6 H), 6 67 (d, 1 H, J= 3 9 Hz), 6 91 (d, 1 H, J = 8 3 Hz), 6 98 (d, 1 H, J= 3 9 Hz), 7 61 (dd, 1 H, J = 1 8, 8 3 Hz), 7 65 ('d', 1 H, J = 1 6 Hz), 10 32 (s, 1 H), 12 54 (bs, 1 H) MS (El) m/z 267 M + Anal Calfs For C,5H I3 N 3 O2 C, 67 41, H, 4 90, N, 15 72 Found C, 67 19, H, 4 96, N, 15 35 Example 2 5-(2'-Oxo-2 , .3 , -dιhydrospιro[cvclohexane-1.3'-[3H]ιndol]-5 , -yl-2-cvanopyπole A solution of oxindole (25 g, 0 19 mol) in anhydrous tetrahydrofuran (800 mL) was cooled to -20°C, then n-butylhthium (2 5M in hexanes, 152 mL, 0 38 mol) was added slowly followed by NN--V',-/V'-tetramethylethylenedιamιne (51 mL, 0 38 mol,) After 15 min 1,5-dιιodopentane (174 g, 0 54 mol) was added slowly and the mixture was allowed to warm to room temperature After stirring for 16 h saturated aqueous ammonium chlonde solution (1L) and EtOAc (1L) were added After 15 min the layers were separated and the aqueous phase was extracted EtOAc (x2) The combined organic layers were extracted with hydrochloric acid (IN), then washed with brine (500 mL), dried (MgS0 4 ), and concentrated to obtain an oil The oil was triturated with hexane (200 mL) and benzene (20 mL) The precipitate was collected and dned in vacuo to obtain spιro[cyclohexane-l,3 '-[3H]mdol]-2 '-(l ΗJone (26 3 g, 69 6%) as colorless crystals mp 110-114°C, : H NMR (DMSO-d 6 ) δ 1 67 (m, 10H), 6 84 (d, IH, J = 8 Hz) 6 94 (t. 1HN = 8 Hz), 7 17 (t, IH, J = 8 Hz), 7 44 (d, IH, J = 8 Hz), 10 3 (s, IH) To a solution of spιro[cyclohexane-l,3'-[3H]ιndol]-2' (l 'H)-one (17 6 g, 9 mmol) in acetic acid (300 mL) was added sodium acetate (8 0 g, 0 1 mol) and bromine (14 6 g, 91 mmol) with stirring After 30 mm at room temperature, the reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted twice with EtOAc The combmed organic layers were washed with water, dried (MgS0 4 ) and evaporated and the residue was tπturated with hexane The precipitate was collected, and dried in vacuo to obtain 5 '-bromospιro[cyclohexane-l,3 '-[3H] ιndol]-2 '(l 'H)-one (16 5 g, 67%) as off-white crystals mp 196 -199 °C, Η NMR (DMSO-ds) δ 1 62 (m, 10H), 6 8 (d, IH, J = 6 8 Hz), 7 36 (d, 1HN = 8 2, 1 8 Hz), 7 58 (dd, 1HN= 8 2, 1 8 Hz), 10 44 (s, IH) To a solution of 5'-bromo-spιro[cyclohexane-l,3'-ιndohn]-2'-one (3 4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere, was added tetrakis(tnphenylphospine)palladium(0) (70 mg, 5 mol%) After 15 min, 2-borono- lH-pyrrole-1-carboxyhc acid, 1-tert butyl ester (1 3 eq, 3 31 g, 15 6 mmol) and a solution of K 2 CO 3 (2 3 eq, 3 83 g, 27 6 mmol) m water (5 mL) were added sequentially The solution was heated to 80 °C for 3 h and allowed to cool The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2 x 100 mL) The organic layers were combmed, washed with bnne (150 mL) and dried over MgSO The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (elutmg with 30% EtOAc/hexane) to give 2-(l ',2'-dιhydro-2'-oxospιro[cyclohexane-l,3'-[3H]mdol]-5'-yl)-lH-pyrrole-l- carboxyhc acid, tert-butyl ester (3 4 g, 76%) as a white powder, mp 177 °C Η NMR (CDC1 3 , 300 MHz) δ 1 38 (s, 9 H), 1 59-1 93 (m, 10 H), 6 18 (m, 1 H), 6 23 (T, IH, 3 Hz), 6 91 (d, 1 H, J=8 Hz), 7 21 (d, 1 H, J=8 Hz), 7 34 (m, 1 H), 7 44 (s, 1 H), 8 33 (br s, 1 H, D 2 Oex) MS ((+)-APCI) m/z 367 [(M+H) + ] Anal Calcd for C 22 H 26 N 2 O 3 C, 72 11, H, 7 15, N, 7 64 Found C, 71 7, H, 7 16, N, 7 5 To a solution of 2-(r,2'-dιhydro-2'-oxospιro[cyclohexane-l,3'-[3H]ιndol]-5'- yl)-lH-pyπole-l-carboxyhc acid, tert-butyl ester (0 75 g, 2 mmol) in THF (anhydrous, 20 mL) at -78 °C was added chlorosulfonyl isocyanate (1 15 eq, 0 23 mL, 2 3 mmol) After 90 mm, DMF (20 eq, 3 6 mL, 46 mmol) was added and the reaction was allowed to warm to room temperature The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL) The organic layers were combmed, washed with bnne (50 mL), dned over magnesium sulfate, filtered and concentrated in vacuo Purification via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave 5-(2 '-oxo-2 ', 3 '-dιhydrospιro[cyclohexane-l,3 '-[3H]mdol]-5 '- yl-2-cyanopyrrole-l-carboxyhc acid, tert-butyl ester (0 5 g. 63%) as an oil which crystallized from acetone to give white crystals, mp 156 °C ] H NMR (<-i 6 -DMSO, 400 MHz) δ 1 32 (s, 9H), 1 50 (m, 3 H), 1 60-1 70 (m, 5 H), 1 75-1 85 (m, 2 H), 6 38 (d, 1 HN = 3 7 Hz), 6 87 (d, 1 H, J= 7 9 Hz), 7 18 (dd, 1 H, J= 1 5, 7 9 Hz), 7 27 (d, 1 H. J = 3 7 Hz), 7 48 (d, 1 H, J = 1 8 Hz), 10 42 (bs, 1 H) MS (El) m/z 391 (Nf) Anal Calcd for C 23 H 25 N 3 O 3 C, 70 57, H, 6 44, N, 10 73 Found C, 69 82, H, 6 46, N, 10 43 5-(2'-Oxo-2',3'-dιhydrospιro[cyclohexane-l,3'-[3H]mdol]-5'-yl-2- cyanopyπole-1-carbox lιc acid, tert-butyl ester (0 25 g, 0 8 mmol) was placed m a 5 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow A vigorous flow of nitrogen was maintained as the flask was placed m an oil bath and heated to 180 °C After 5 mm at this temperature, the flask was removed from the oil bath and allowed to cool The black residue was washed into a larger flask with acetone and adsorbed onto a small amount of silica gel Purification by flash column chromatography on silica gel (elutmg with 30%) EtOAc/hexane) gave the title compound (95 mg, 51 %) as a yellow oil which crystallized from dichloromethane to give a grey powder, mp 239 °C (dec) Η NMR (DMSO-rf 6 , 300 MHz) δ 1 40-1 90 (m, 10H), 6 60 (m, IH), 6 88 (d, IH, J=8 1 Hz), 6 95 (m, IH), 7 56 (dd, IH, J=\ 8, 8 1 Hz), 7 78 (d, IH, J=l 3 Hz), 10 42 (s, 1 H), 12 50 (s, 1 H) MS (El) m/z 291 (M + ) Anal Calcd for C 18 H 17 N 3 O, C, 74 20, H, 5 88, N, 14 42 Found C, 66 63, H, 5 52, N, 12 46 Example 3 2-(3,3-DimethvI-2-oxo-2,3-dihvdro-lH-indol-5-yl)-2-cvanopyrrole To a solution 2-(3,3-dιmethyl-2-oxo-2,3-dιhydro-lH-mdol-5-yl)-pyrrole-l- carboxyhc acid tert-butyl ester (0 39 g, 1 2 mmol) m THF (anhydrous, 9 mL) at -78 °C was added chlorosulfonyl isocyanate (1 15 eq, 0 12 mL, 1 4 mmol) After 120 mm, DMF (20 eq, 1 8 mL, 23 mmol) was added and the reaction was allowed to warm to room temperature The reaction mixture was poured into water (25 mL) and extracted with ethyl acetate (2 x 50 mL) The organic layers were combmed, washed with brme (50 mL), dned over magnesium sulfate, filtered and concentrated in vacuo Purification via flash column chromatography on silica gel (1 3 ethyl acetate/hexane) gave 2-(3, 3-dιmethyl-2-oxo-2, 3-dιhydro-lH-ιndol-5-yl)-2-cyanopyrrole-l-carboxylιc acid tert-butyl ester (0 21 g. 50%) as a white solid mp 158 6 ] H NMR (DMSO-<i 6 , 300 MHz) δ 1 27 (s, 6H), 1 33 (s, 9H), 6 40 (d, IH, J=3 8 Hz), 6 90 (d, IH. J=8 0 Hz), 7 19 (dd, IH, J=l 8, 8 0 Hz), 7 30 (d, IH, J=l 5 Hz), 10 50 (s, 1 H) MS m/z 350 (M-H) Calcd for C 19 H 22 N 2 O 3 C. 68 36, H, 6 02, N, 11 96 Found C, 66 79, H, 6 03, N, 11 02 2-(3,3-Dιmethyl-2-oxo-2,3-dιhydro-lH-mdol-5-yl)-pyπole-l-carboxylιc acid tert-butyl ester (0 18 g, 0 51 mmol) was placed m a 50 mL round bottomed flask stoppered with a rubber septum and equipped with a nitrogen mlet and a needle to allow gaseous outflow A vigorous flow of nitrogen was maintained as the flask was placed m an oil bath and heated to 160 °C After 10 mm at this temperature, the flask was removed from the oil bath and allowed to cool The black residue was washed mto a larger flask with acetone and adsorbed onto a small amount of flurosil Purification by flash column chromatography on silica gel (eluting with 1 3 acetone hexane) gave the title compound (118 mg, 92%) as a white solid mp 255 9-257 9 °C ] H NMR (DMSO- 6 , 300 MHz) δ 1 29 (s, 6H), 6 60 (m, IH), 6 89 (d, IH, J=8 0 Hz), 6 96 (m, IH), 7 55 (dd, IH, J=l 4, 8 1 Hz), 7 69 (bs, IH), 10 47 (s, 1 H), 12 48 (s, 1 H) MS m/z 250 (M-H) Calcd for C 20 H 21 N 3 O 3 C, 71 7, H, 5 21, N, 16 72 Found C, 71 16, H, 5 58, N, 16 09 Example 4 5-(2 , -Oxo-2 , .3'-dιhvdrospιro[cvclopentane-l,3 , -[3H1mdoll-5'-yl-2-cvanopyrrole A solution of 5'-bromospιro[cyclopentane-l,3'-[3H] ιndol]-2'(l 'H)-one (2 0 g, 7 5 mmol) and tetrakis(tnphenylphosphine)palladium(0) (430 mg, 0 3 mmol) m ethylene glycol dimethyl ether (50 mL) was stiπed under a flow of nitrogen for 15 mm To the solution was added sequentially l-t-butoxycarbonylpyrrole-2-boromc acid (2 1 g, 9 7 mmol) and potassium carbonate (2 4 g, 17 mmol) m water (10 mL) The mixture was heated to 80 °C for 3 h and allowed to cool The reaction mixture was poured mto water (50 mL) and extracted with ethyl acetate (3 x 50 mL) The organic layers were combmed, washed with bnne (30 mL) and dried over magnesium sulfate The solution was filtered and concentrated in vacuo Crystallization from 20% ethyl acetate/hexane gave 2-(l 2'-dιhydro-2'-oxospιro[cyclopentane-l , 3'-[3H]mdol]-5'-yl)- lH-pyrrole-1-carboxylιc acid, tert-butyl ester (2 2 g, 83%) as a white powder, mp 179-180 5 °C 'H NMR (DMSO-^, 400 MHz) δ 1 30 (s, 9H), 1 75-1 98 (m, 8 H), 6 16 (dd, 1 H, J = 1 8, 3 3 Hz), 6 22 ('t', 1 H, J = 3 3, 3 3 Hz), 6 79 (d, 1 H, J = 7 9 Hz), 7 08 (dd, 1 H, J= 1 8, 7 9 Hz), 7 14 ('d', 1 H, J = 1 5 Hz), 7 28 (άά, J= 1 9, 3 3 Hz),10 30 (s, 1 H) MS (El) m/z 352 [M + ] Anal Calcd for C 2 iH 24 N 2 O 3 C, 71 57, H, 6 86, N, 7 95 Found C, 71 08, H, 6 83, N, 7 74 To a solution of 2-(r,2'-dιhydro-2'-oxospιro[cyclohexane-l,3 , -[3H]mdol]-5'- yl)-lH-pyπole-l-carboxyhc acid, tert-butyl ester (2 2 g, 6 0 mmol) in THF (anhydrous, 25 mL) was added at -78 °C chlorosulfonyl isocyanate (0 63 mL, 7 0 mmol) After 90 mm, dimethylformamide (11 mL, 140 mmol) was added and the reaction was allowed to warm to room temperature The reaction mixture was poured mto water (50 mL) and extracted with ethyl acetate (2 x 50 mL) The organic layers were combmed, washed with bnne (50 mL), dned over magnesium sulfate, filtered and concentrated in vacuo Punfication via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave 5-(2 '-oxo-2 ', 3 '-dιhydrospιro[cyclopentane-l,3 '- [3H]mdol]-5 '-yl-2-cyanopyrrole-l-carboxylιc acid, tert-butyl ester (1 7 g, 75%) as white crystals, mp 167-169 °C Η NMR (DMSO-- 400 MHz) δ 1 34 (s, 9H), 1 75- 1 98 (m, 8 H), 6 39 (d, 1 H, J= 3 7 Hz), 6 84 (d, 1 H, J = 7 9 Hz), 7 17 (dd, 1 H, J = 1 8, 7 9 Hz), 7 28 (T, 2 H), 10 41 (s, 1 H) MS (ESI) m/z 376 [M-H] Anal Calcd for C 22 H 23 N 3 O 3 C, 70 01, H, 6 14, N, 11 13 Found C, 69 67, H, 6 38, N, 11 04 5-(2'-Oxo-2',3'-dιhydrospιro[cyclopentane-l,3'-[3H]ιndol]-5'-yl-2- cyanopyπole-1-carboxyhc acid, tert-butyl ester (1 g, 2 7 mmol) was placed m a 25 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow A vigorous flow of mtro gen was mamtamed as the flask was placed in an oil bath and heated to 165 °C After 20 mm at this temperature, the flask was removed from the oil bath and allowed to cool Crystallization from ethyl ether gave the title compound (600 mg, 79%) as a yellow powder, mp 285-286 °C ! H NMR (DMSO-rf 6 , 400 MHz) δ 1 75-2 03 ( , 8 H), 6 60 (dd, 1 H, J = 2 4, 3 7 Hz), 6 84 (d, 1 H, J = 8 1 Hz), 6 94 (dd, 1 H, J = 2 4, 3 7 Hz), 7 52 (dd, 1 H, J = 1 8, 8 1 Hz), 7 60 (d, 1 H, J = 1 8 Hz), 10 38 (s, 1 H), 12 45 (s, 1 H) MS (ESI) m/z 276 [M-H] " Anal Calcd For C 17 H 15 N 3 O C, 73 63, H, 5 45, N, 15 15 Found C, 73 24, H, 5 34, N, 14 96 Example 5 5-(4.4-Dιmethyl-2-oxo-1.4-dιhvdro-2H-3.1-benzoxazm-6-yl)-l-methyl-lH-pyrrole-2 carbonitnle To a solution of 5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazm-6-yl)- lH-pyπole-2-carbonιtπle (1 eq, 71 mg, 0 27 mmol) in dimethylformamide (0 5 mL) was added potassium carbonate (5 eq, 0 18 g, 0 1 35 mmol) After 10 mm , lodomethane (3 eq, 05 mL, 0 81 mmol) was added and the suspension was stured for 2h, poured mto water (5 mL) and extracted with ethyl acetate (3 x 5 mL) The layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combmed organic layer was washed with bnne, dned over MgS0 4 and purified by flash column chromatography on silica gel elutmg with 30% ethyl acetate/hexane to give 5-(4,4-dιmethyl-2-oxo- 1 ,4-dιhydro-2H-3 , 1 -benzoxazιn-6-yl)- 1 -methyl- 1H- pyπole-2-carbonιtπle (30 mg, 41%) as a white solid Η NMR (300 MHz, d 6 -DMSO) δ 1 64 (s, 6 H), 3 71 (s, 3 H), 6 33 (d, 1 H, J = 4 1 Hz), 6 98 (d, 1 H, J= 8 0 Hz), 7 03 (d, 1 H, J = 4 1 Hz), 7 39 ( , 2 H), 10 39 (s, 1 H) MS (APCI (-)) m/z 280 (M-H) Anal calcd for C16H15N302, C, 68 3, H, 5 37, N, 14 9 Found, C, 68 4, H, 5 51, N, 14 6 Example 6 General Method A 5-(4.4-Dιmethyl-2-oxo-1.4-dιhydro-2H-3.1-benzoxazm-6-yl)-l-ethyl-lH-pyrrole-2- carbonitπle To a solution of 5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazιn-6-yl)- lH-pyrrole-2-carbonιtπle (1 3 g, 5 mmol) in dimethylfoπnamide ( 25 ml) was added potassium carbonate (1 g, 7 5 mmol), and lodoethane (0 4 ml, 5 1 mmol), and the mixture was stirred at room temperature for 3 hours Ethylacetate and water were added, the ethylacetate layer was separated, dried over magnesium sulfate, and concentrated in vacuo The residue was recrystalhzed from ethylacetate/hexane to afford the title compound, mp 200-202 °C (0 4 g, 27%), 1H-NMR (DMSO-ds) δ 1 25 (t, J = 7 2 Hz, 3H), 1 64 (s, 6H), 4 07 (q, J = 7 2 Hz, 2H), 6 29 (d, J = 4 1 Hz, IH), 7 0 (d, J= 8 Hz, IH), 7 05 (d, J = 4 1 Hz, IH), 7 34 (m, 2H), 10 42 (s, IH) MS (ESI (-)) m/z 294 (M-H) " Example 7 5-(4.4-dιmethyl-2-oxo- 1.4-Dιhydro-2H-3.1 -benzoxazm-6-yl)- 1 -prop-2-ynyl- 1 H- pyrrole-2-carbonιtnle 5-(4,4-Dιmethyl-2-oxo-l,4,dιhydro-2H-3,l-benzoxazm-6-yl)-lH-pyrrol-2- carbomtπle (0 74 g, 2 8 mmol) and propargylbromide (0 5 g, 4 2 mmol) were reacted, accordmg to General Method A, to afford the title compound, mp 222-224 °C ( 0 13 g, 15% ) Η-NMR (DMSO-de) δ 1 65 (s, 6H), 3 64 (t, J = 2 3 Hz , IH), 4 85 (d, J = 2 3 Hz, 2H), 6 37 (d, J = 4 Hz, IH), 7 01 (d, J = 8 2 Hz, IH), 7 11 (d, J=4 Hz, IH), 7 43 (m, 2H), 10 45 (s, IH), MS (APCI (-)) m/z 304 (M-H) " Example 8 tert-butyl[2-cyano-5-(4.4-dιmethyl-2-oxo-1.4-dιhydro-2H-3.1-benzoxazm-6-yπ-lH- pyrrol- 1-yll acetate 5-(4,4-Dιmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazm-6-yl)-lH-pyrrol-2- carborutπle (5 4 g, 20 mmol) and tert-butylbromoacetate (4 64 g, 22 mmol) were reacted, accordmg to General Method A, to afford the title compound, mp 188-190 °C (3 g, 40 %) 'H-NMR (DMSO-d 6 ) δ 1 35 (s, 9H), 1 62 (s, 6H), 4 8 (s, 2H), 6 35 (d, J = 4 3 Hz, IH), 6 98 (d, J = 8 1 Hz. IH), 7 09 (ά, J = 4 3 Hz, IH), 7 26 (m, 2H), 10 42 (s, IH), MS (APCI (-)) m/z 380 (M-H) Example 9 [ 2-Cvano-5 -(4.4-dιmethyl-2-oxo- 1 ,4-dιhvdro-2H-3.1 -benzoxazιn-6-vD- 1 H-pyrrol- 1 - yl] acetic acid A solution of tert-butyl[2-cyano-5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l- benzoxazm-6-yl)-lH-pyrrol-l-yl]acetate (2 2 g, 5 8 mmol), and sodium hydroxide (1 6 g, 40 mmol) in ethanol (200 ml) was heated to reflux for 2 hours After coolmg to room temperature the mixture was acidified with diluted hydrochloric acid, and extracted with ethylacetate The ethylacetate solution was dned over magnesium sulfate, filtered, and concentrated m vacuo Recrystallization from ethylacetate/hexane afforded the title compound, mp 207 - 209 °C (1 2 g, 64 %), 'H-NMR (DMSO-de) δ 1 61 (s, 6H), 4 77 (s, 2H), 6 35 (d, J= 4 Hz, IH), 6 98 (d, J= 8 1 Hz, IH), 7 09 (d, J = 4 1 Hz, IH), 7 26 (m, 2H), 10 43 (s, IH), MS (APCI (-)) m/z 324 (M-H) Example 10 2-[ 2-cyano-5-( 4.4-dιmethyl-2-oxo-1.4-dιhydro-2H-3.1-benzoxazm-6-yl )-lH-pyπol- I-yl]-N-[ 2-(3-ethoxy-4-methoxyphenyl) ethyl ]acetamιde A solution of [2-cyano-5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l- benzoxazιn-6-yl )-lH-pyrrol-l-yl] acetic acid (0 6 g, 1 8 mmol), 3-ethoxy-4- methoxyphenylethylamine (0 36 g, 1 9 mmol), du-?o-propylethylamιne (0 26 g. 2 mmol), and O-(7-azabenzotπazol-l-yl)-N,N,N ,N'-tetramethyluromum hexafluorophosphate (0 7 g. 1 8 mmol) m dimethylformamide (20 ml) was stirred at room temperature for 20 hours The mixture was diluted with water and extracted with ethylacetate The ethylacetate solution was washed with bnne, dried over magnesium sulfate, and concentrated in vacuo The residue was recrystallized from ethanol to afford the title compound, mp 160-162 °C (0 2 g, 22 %) Η-NMR (DMSO-ds) δ 1 3 (t, J = 6 9 Hz, 3H), 1 59 (s, 6H), 2 61 (t, 2H, J = 7 Hz), 3 29 (q, J= 6 9 Hz, 2H), 3 71 (s, 3H), 3 97 (q, J = 6 9 Hz, 2H), 4 6 (s, 2H), 6 32 (d, J = 5 1 Hz. IH), 6 65 (dd, J= 7 6, 2 0 Hz, IH), 6 77 (d. J=2 3, IH), 6 83 (d, J=8 3 Hz, IH), 6 96 (d, J= 8 7 Hz, IH). 7 05 (d, J =4 1 Hz, IH), 7 26 (m, 2H), 8 3 (t, J = 6 Hz, IH), 10 42 (s, IH), MS (APCI (+)) m/z 503 (M+H) + Example 11 5-(4.4-Dιmethyl-2-oxo- 1.4-dιhvdro-2H-3.1 -benzoxazιne-6-vD- 1 -pentyl- lH-pyrrole-2- carbomtπle 5-(4,4-Dιmethyl-oxo- 1 ,4-dιhydro-2H-3 , 1 -benzoxazιne-6-yl)- lH-pyπole- carbomtπle (1 94 g, 7 3 mmol) was reacted, accordmg to General Method A, with 1- lodopentane (1 5 g, 7 6 mmol) to afford the title compound, mp 128-131 °C (0 2 g, 8%), 'H-NMR (DMSO-de) δ 0 73 (t, J = 1 3 Hz, 3H), 1 05 (m, 2H), 1 14 (m, 2H), 1 57 (m, 2H), 1 63 (s, 6H ), 4 04 (t, J= 7 5 Hz, 2H), 6 28 (d, J= 4 Hz, IH), 6 98 (d, J = 7 9 Hz, IH), 7 04 (d, J = 4 5 Hz, IH), 7 33 (dd, J=8 9, 2 0 Hz, IH), 7 37 (d, J = 2 2 Hz, IH), 10 41 (s, IH), MS (APCI (-)) m/z 336 (M-H) Example 12 5-(1.4.4-tnmethyl-2-oxo-1.4-dιhvdro-2H-3.1-benzoxazm-6-yl)-lH-pyrrole-2- carbonitπle tert-Butyl 2-cyano-5-( 1.4.4-tnmethyl-2-oxo-l .4-dιhydro-2H-3.1 -benzoxazιn-6-yl)- 1 H- pyπole- 1 -carboxylate To a solution of 2-(4,4-Dιmethyl-2-oxo-l,4-dιhydro-2H-benzo [d] [1,3] oxazιn-6-yl)-5-cyano-pyπole-l-carboxyhc acid tert-butyl ester (0 5 g, 1 4 mmol, 1 eq) m DMF (anhydrous, 25 mL) was added NaH (60% dispersion m oil, 65 mg, 1 6 mmol, 1 2 eq) at 0 °C After 15 mm, methyl iodide (0 25 mL, 4 1 mmol, 3 eq) was added and the reaction was allowed to warm to room temperature over night The reaction mixture was poured mto water (50 mL) and extracted with ethyl acetate (2 x 50 mL) The organic layers were combmed, washed with bnne (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the product (0 5 g, 94%) as an off- white solid, mp 143-145 °C Η NMR (300 MHz, c^-DMSO) δ 1 38 (s, 9 H), 1 62 (s, 6 H), 3 33 (s, 3 H), 6 48 (d, 1 , J = 3 8 Hz), 7 13 - 7 16 ('dd', 1 H), 7 33 (d, 1 H, J = 3 8 Hz), 7 40 - 7 43 (m, 2 H) MS (ESI (+)) [M+H] + = 382 Anal calcd for C 2 ,H 23 N 3 0 4 C, 66 13, H, 6 08, N, 11 02 Found C, 65 46, H, 6 16, N, 11 02 tert-Butyl 2-cyano-5-(l,4,4-tπmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazm-6- yl)-lH-pyrrole-l-carboxylate (180 mg, 0 47 mmol) was placed m a 25 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow A vigorous flow of nitrogen was mamtamed as the flask was placed m an oil bath and heated to 150 °C After 20 mm at this temperature, the flask was removed from the oil bath and allowed to cool To the solid was added acetone/dichloromethane The solid was filtered to give the product (100 mg, 76%) as an off-white solid, mp 256-7 °C (dec ) l H NMR (300 MHz, -4-DMSO) δ 1 65 (s, 6 H), 3 33 (s, 3 H), 6 74 (dd, 1 U, J= 2 6, 3 6 Hz), 7 00 (dd, 1 , J= 2 2, 3 8 Hz), 7 15 (d, 1 H, J = 8 5 Hz), 7 67 (d, 1 H, J = 1 9 Hz), 7 73 (dd, 1 H, J= 1 9, 8 5 Hz), 12 62 (s, 1 H) MS (ESI (+)) [M+H] + = 282 Anal calcd for C, 68 31, H, 5 37, N, 14 94 Found C, 67 87, H, 5 42, N, 14 75 Example 13 4-Bromo-5-(4.4-dιmethyl-2-oxo- 1.4-dιhydro-2H-3.1 -benzoxazιn-6-yl ' )- 1 -methyl- 1 H- pyπole-2-carborutnle To a solution of tert-butyl 6-(5-cyano-l-methyl-lH-pyπol-2-yl)-4,4-dιmethyl- 2-oxo-2H-3,l-benzoxazιne-l(4H)-carboxylate (1 eq, 1 94 g, 5 10 mmol) m THF (150 mL) at -78 °C was added N-bromosuccinimide (1 1 eq, 1 0 g, 5 61 mmol) The solution was allowed to warm and stir for 16 hours Pyndme (1 mL) was added and the mixture was poured mto water (150 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combmed organic layer was washed with bnne, dried over MgSO and concentrated in vacuo The product, tert- butyl 6-(3-bromo-5-cyano-l-methyl-lH-pyrrol-2-yl)-4, 4-dιmethyl-2-oxo-2H-3, 1- benzoxazιne-l(4H)-carboxylate was obtamed by crystalhzation from 20% ethyl acetate/hexane as a white crystalline solid Η NMR (300 MHz, -i 6 -DMSO) δ 1 56 (s, 9H), 1 71 (s, 6H), 3 65 (s, 3H), 7 30 (s, IH), 7 44 (d, IH, J=8 4Hz), 7 52 (d, IH, J=8 4Hz), 7 55 (s, IH) M/z (ESI (+)) 461 (M+H)~ Anal calcd for C 21 H 22 N 3 O 4 , C, 54 8, H, 4 82, N, 9 13 Found, C, 54 9, H, 4 86, N, 9 1 A solution of tert-butyl 6-(3-bromo-5-cyano-l-methyl-lH-pynol-2-\l)-4,4- dιmethyl-2-oxo-2H-3,l-benzoxazme-l(4H)-carboxylate (1 eq, 0 4 g, 0 87 mmol) m THF was added to a solution of sodium ethoxide (3 eq, 0 18 g, 2 6 mmol) m ethanol (10 mL) The solution was heated at 80 ° C for lh then cooled to room temperature and concentrated in vacuo The residue was dissolved in THF (10 mL) and 4N HCl (10 mL) was added After heatmg to 60 °C for 16h the solution was cooled, poured mto water and the layers were separated The aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layer was washed with bnne, dned over MgS0 and concentrated in vacuo The product, (4-bromo-5-(4,4-dιmethyl-2-oxo- l, 4-dιhydro-2H-3,l-benzoxazιn-6-yl)-l-methyl-lH-pyrrole-2-carbonιtrιle (0 17 g, 54%) was obtamed by crystallization from 20% ethyl acetate/hexane 'H NMR (300 MHz, < -DMSO) δ 1 64 (s, 6H), 3 62 (s, 3H), 7 02 (d, IH, J = 8 2Hz), 7 34 (s, IH), 7 35 (dd, 1H, J = 1 3, 8 2Hz), 7 40 (s, IH), 10 47 (s, IH) MS (ESI (-)) m/z 358/360 (M-H) Anal calcd for C, 6 H 14 N 3 O 2 Br, C, 53 4, H, 3 92, N, 11 7 Found, C, 52 6, H, 3 82, N, 11 2 Example 14 5-(4.4-Dιmethyl-2-oxo-1.4-dιhydro-2H-3.1-benzoxazm-6-yl)-1.4-dιmethyl-lH- pyrrole-2-carbonιtπle A solution of 4-bromo-5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazm- 6-yl)-l -methyl- lH-pyrrole-2-carbomtπle (70 mg, 0 2 mmol), PhCNPdCl(PPh 3 ) 2 (cat , 7 mg) and tetramethyltm (10 eq, 0 35 g, 2 mmol) in HMPA (3 mL) was heated to 110 °C for 5 days The solution was allowed to cool, poured mto water (20 mL) and extracted with ethyl acetate (3 x 5 mL) The combmed organic layer was washed with bnne, dried over MgSO and purified by flash column chromatography on silica gel elutmg with 30% ethyl acetate/hexane to give 5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H- 3,l-benzoxazm-6-yl)-l,4-dιmethyl-lH-pyrrole-2-carbonιtπle (36 mg, 63%) as a white solid ! H NMR (300 MHz, tt 6 -DMSO) δ 1 64 (s, 6H), 1 97 (s, 3H), 3 56 (s, 3H), 6 87 (s, IH), 7 00 (d, 2H, J=8 1Hz), 7 28 (dd, IH, J=8 1 1 6Hz), 7 32 (s, IH), 10 40 (s, IH). MS (ESI (-)) 294 (M-H) Anal calcd for C 17 H, 7 N 3 0 2 , C, 69 1, H, 5 8, N, 14 2 Found, C, 69 1, H, 5 72, N, 14 0 Example 15 tert-Butyl 5-cvano-2-(4.4-dιmethyl-2-oxo-1.4-dιhvdro-2H-3.1-benzoxazm-6-yl -3- nιtro-lH-pyrrole-1 -carboxylate To a solution of 2-(4,4-Dιmethyl-2-oxo-l,4-dιhydro-2H-benzo [d] [1,3] oxazιn-6-yl)-5-cyano-pyπole-l-carboxyhc acid tert-butyl ester (3 0 g, 8 2 mmol, 1 eq) m acetic anhydride (50 mL) was added Cu(N0 3 ) 2 « 2 5 H 2 0 (1 04 g, 4 5 mmol, 0 55 eq) After the reaction mixture stirred at room temperature for 24 h, it was poured mto saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (2 x 100 mL) The organic layers were combmed, washed with water (50 mL) and bnne (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo Purification by flash column chromatography (20% ethyl acetate/hexane) on silica gel gave the product as a yellow sohd (0 54 g, 16%) : H NMR (500 MHz, 6 -DMSO) δ 1 25 (s, 9 H), 1 60 (s, 6 H), 6 97 (d, 1 H, J = 8 2 Hz), 7 38 (dd, 1 H, J = 1 8, 8 2 Hz), 7 49 (d, 1 H, J = 1 8 Hz), 8 09 (s, 1 H), 10 47 (s, 1 H) MS (ESI (-)) [M-H] = 411 Anal calcd for C 20 H 2 oN 4 0 6 C, 58 25, H, 4 89, N, 13 59 Found C, 58 72, H, 5 14, N, 13 39 Example 16 4-Amιno-5-(4.4-dιmethyl-2-oxo- 1.4-dιhydro-2H-3.1 -benzoxazm-6-yl)- 1 H-pyπole-2- carbonitπle A solution of 4-nιtro-5-(4,4-dιmefhyl-2-oxo- 1 ,4-dιhydro-2H-3.1 -benzoxazιn-6- yl)-lH-pyπole-2-carbomtnle (0 4 g, 1 28 mmol) m ethanol water (5 1, 20 mL) was treated sequentially with zmc powder (2 5 wt, 1 0 g) and ammonium chloride (5 wt, 2 0 g) The suspension was heated at 80 °C or 30 mm. cooled to room temperature. poured mto water (30 mL) and extracted with ethyl acetate (3 x 15 mL) The combmed organic layer was washed with brme, dried over MgS0 4 and purified by flash column chromatography on silica gel elutmg with ethyl acetate to give 4-amιno- 5-(4, 4-dιmethyl-2-oxo-l,4-dιhydro-2H-3, l-benzoxazm-6-yl)-lH-pyrrole-2- carbonitrile (0 29 g, 80%) as a yellow sohd *H NMR (500 MHz, 6 -DMSO) δ 1 63 (s, 6H), 4 29 (s, 2H), 6 39 (s, IH), 6 89 (d, IH, J=8 1Hz), 7 49 (s, IH), 7 52 (dd, IH, J=8 1 and 2 3Hz), 10 25 (s, IH), 11 76 (s, IH) MS (ESI (-)) m/z 281 (M-H) " Anal calcd for C, 5 H 14 N 4 O 2 , C, 63 8, H, 5 00, N, 19 9 Found, C, 63 7, H, 5 10, N, 19 82 Example 17 5-(4.4-dιmethyl-2-oxo- 1.4-dιhydro-2H-3.1 -benzoxazιn-6-yl)-3-nιtro- lH-pyrrole-2- carbonitnle To 4,4-Dιmethyl-6-(5-cyano-lH-pyπol-2-yl)-l,4-dιhydobenzo [d][l,3]oxazm- 2-one (0 3 g, 1 2 mmol, 1 eq) m acetic anhydride (7 3 mL) was added Cu(NO 3 ) 2 »2 5 H 2 0 (0 15 g, 0 65 mmol, 0 55 eq) After the reaction mixture stiπed at room temperature for 2h, it was poured mto saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2 x 50 mL) The organic layers were combmed, washed with water (50 mL) and bnne (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo The residue crystallized from dichloromethane/acetone to give the product as a yellow sohd (48 mg, 13%) The filtrate (0 3 g) was placed aside Η NMR (300 MHz, -5-DMSO) δ 1 65 (s, 6 H), 6 94 (d, 1 H, J = 8 3 Hz), 7 51 (s, 1 H), 7 73(d, 1 H, J = 8 3 Hz), 7 78 (s, 1 H), 10 46 (s, 1 H), 13 84 (s, 1 H) MS (ESI (-)) [M-H] m/z 311 Anal calcd for C 15 H 12 N 4 O 4 C, 57 69, H, 3 87, N, 17 94 Found C, 57 91, H, 3 96, N, 17 41 Example 18 3-ammo-5-(4.4-dιmethyl-2-oxo-1.4-dιhvdro-2H-3.1-benzoxazm-6-yl)-lH-pyrrole-2- carbomtnle To 5-(4,4-dιmethyl-2-oxo-l ,4-dιhydro-2H-3, 1 -benzoxazιn-6-yl)-3-nιtro-lH- pyrrole-2-carbonιtπle (0 14 g, 0 45 mmol) m EtOH H 2 0 (5 1, 20 mL 4 mL) was added Zn powder (0 35 g, 5 3 mmol) and N-H 4 CI (0 70 g, 13 mmol) and the mixture was heated to 60 °C for 25 mm After coolmg to room temperature and stirring 24 h, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of cehte The filtrate was washed with water (50 mL) and brme (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo Purification by flash column chromatography (60% ethyl acetate/hexane) on silica gel gave the product as an orange foam (30 mg, 24 %) Η NMR (500 MHz, ^DMSO) δ 1 63 (s, 6 H), 5 01 (s, 2 H), 5 95 (d, 1 H, J = 2 9 Hz), 6 87 (d, 1 H, J = 8 3 Hz), 7 48 (dd, 1 H, J= 2 0, 8 3 Hz), 7 54 (d, 1 H, J= 2 0 Hz), 10 30 (s, 1 H), 11 17 (d, 1 H, J = 2 5 Hz) MS (ESI) [M-H] m/z 281 Example 19 5-(4.4-Dιmethyl-2-oxo-1.4-dιhvdro-2H-3.1-benzoxazm-6-yl)-1.3.4-tπmethyl-lH- pyπole-2-carbomtπle To a solution of 5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazm-6-yl)- l,4-dιmethyl-lH-pyπole-2-carbomtnle (1 eq, 0 15 g, 0 51 mmol) m THF (5 mL) at -78 °C was added N-bromosuccimmide (1 1 eq, 0 1 g, 0 56 mmol) The solution was allowed to warm and stir for 16 hours Pyndme (1 mL) was added and the mixture was poured mto water (15 mL), the layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combmed organic layer was washed with bnne, dned over MgS0 4 and concentrated m vacuo The product, 5-(4,4-dιmethyl-2-oxo- 1 ,4-dιhydro-2H-3, 1 -benzoxazιn-6-yl)-3 -bromo- 1 ,4-dιmethyl- 1 H-pyπole-2-carbonιtπle was obtamed by crystal zation from 20% ethyl acetate/hexane as a white crystallme sohd ! H NMR (300 MHz, ύk-DMSO) δ 1 64 (s, 6H), 1 93 (s, 3H), 3 57 (s, 3H), 7 01 (d, IH, J=8Hz), 7 31 (dd, IH, J=l 95, 8Hz), 7 35 (s, IH), 10 43 (s, IH) MS m/z (ESI (-)) 372/374 (M-H) Anal calcd for C I7 H 16 N 3 θ2, C, 54 6, H, 4 31, N, 11 2 Found, C, 54 8, H, 4 42, N, 11 1 A solution of 5-(4,4-dιmethyl-2-oxo-l,4-dιhydro-2H-3,l-benzoxazm-6-yl)-3- bromo-l,4-dιmethyl-lH-pyπole-2-carbomtπle (0 11 g, 0 29 mmol), PhCNPdCl(PPh 3 ) 2 (cat , 11 mg) and tetramethyltin (10 eq, 0 53 g, 2 9 mmol) m HMPA (3 mL) was heated to 110 °C for 5d The solution was allowed to cool, poured mto water (20 mL) and extracted with ethyl acetate (3 x 15 mL) The combmed organic layer was washed with bnne, dned over MgS0 and purified by flash column chromatography on silica gel elutmg with 30% ethyl acetate hexane to give 5-(4,4-dιmethyl-2-oxo-l,4-dιhydro- 2H-3,l-benzoxazm-6-yl)-l,3,4-tπmethyl-lH-pyrrole-2-carbonιtπle (77 mg, 85%) as a white solid ] H NMR (300 MHz, d 6 -OMSO) δ 1 63 (s, 6H), 1 87 (s, 3H), 2 49 (s, 3H), 3 50 (s, 3H), 6 99 (d, IH, J=8 2Hz), 7 25 (dd, IH, J=8 2, 1 4Hz), 7 29 (s, IH), 10 39 (s, IH) MS (ESI (-)) 308 (M-H) Anal calcd for C 18 H 19 N 3 O 4 , C, 69 9, H, 6 19, N, 13 6 Found, C, 68 8, H, 6 22, N, 12 9 Example 20 4-bromo-(4.4-dιmethyl-2-oxo-1.4-dιhydro-2H-3.1-benzoxazm-6-yl)-lH-pyπole-2- carbomtπle To 4,4-Dιmethyl-6-(5-cyano- 1 H-pyrrol-2-yl)- 1 ,4-dιhydobenzo [d] [ 1 , 3] oxazin- 2-one (0 625 g, 2 3 mmol, 1 eq) m THF (anhydrous, 60 mL) was added NBS (0 46 g, 2 5 mmol, 1 1 eq) at -78 °C After 1 h, the reaction was warmed to room temperature, poured mto water (100 mL) and extracted with ethyl acetate (2 x 100 mL) The organic layers were combmed, washed with aqueous 10 % sodium bisulfite solution (50 mL), water (50 mL) and bnne (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo Crystallization from 20% ethyl acetate/hexane gave the product (40 mg, 5%) as a white solid The filtrate (0 5 g) was placed aside : H NMR (300 MHz, d 6 -OMSO) δ 1 64 (s, 6 H), 6 98 (d, 1 H, J = 8 2 Hz), 7 19 (d, 1 H, J= 1 4 Hz), 7 57 (s, 1 H). 7 62 (dd, 1 H, J = 1 4, 8 3 Hz), 10 43 (s, 1 H), 12 91 (s, 1 H) MS (ESI) [M-H] m/z 344/346 Anal calcd for C 15 H 12 BrN 3 O 2 C, 52 04, H, 3 49, N, 12 14 Found C, 51 4, H, 3 57, N, 11 59 All publications cited m this specification are mcorporated herem by reference herem While the invention has been described with reference to a particularly prefeπed embodiment, it will be appreciated that modifications can be made without departing from the spirit of the mvention Such modifications are mtended to fall within the scope of the appended claims

Claims: WHAT IS CLAIMED IS 1 A compound formula 1 having the structure wherem T is O, S, or absent, Ri, and R 2 are each, independently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a πng and together contain -CH 2 (CH 2 ) n CH 2 - , -CH 2 CH 2 CMe 2 CH 2 CH 2 - , -0(CH 2 ) p CH 2 - , -0(CH 2 ) q O- , -CH 2 CH 2 OCH 2 CH 2 - , or -CH 2 CH 2 N R 7 CH 2 CH 2 -, n = l-5, p = l-4, q = l-4 R 3 is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, RΛ is hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 5 is hydrogen, alkyl, or substituted alkyl, Re is hydrogen, alkyl, substituted alkyl, or COR B , R B is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy. ammoalkyl. or substituted ammoalkyl. R 7 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof 2 The compound accordmg to claim 1 , wherem wherem T is O, or absent, Ri, and R 2 are each, mdependently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a ring and together contain -CH 2 (CH 2 ) n CH 2 - , n = l-5, R 3 is hydrogen, R 4 is hydrogen or halogen, R 5 is hydrogen or alkyl, Re is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof 3 The compound accordmg to claim 1, which is 5-(4,4-dιmethyl-2-oxo-l,4- dιhydro-2H-benzo [d] [1,3] oxazm-6-yl)-lH-pyπole-2-carbonιtnle or a pharmaceutically acceptable salt thereof 4 The compound of claim 1, which is 5-(2'-Oxo-2',3'-dιhydrospιro[cyclohexane- l,3'-[3H]ιndol]-5'-yl-2-cyanopyrrole or a pharmaceutically acceptable salt thereof 5 The compound of claim 1, which is 2-(3,3-dιmethyl-2-oxo-2,3-dιhydro-lH- mdol-5-yl)-2-cyanopyrrole or a pharmaceutically acceptable salt thereof. 6 The compound of claim 1, which is 5-(2'-Oxo-2',3'- dιhydrospιro[cyclopentane-l,3'-[3H]mdol]-5'-yl-2-cyanopyπole or a pharmaceutically acceptable salt thereof 6 A method of providmg progestational therapy to a mammal m need thereof which comprises administering a progestationally effective amount of compound formula 1 havmg the structure wherem T is O, S, or absent, Ri, and R 2 are each, mdependently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a ring and together contain -CH 2 (CH 2 ) n CH 2 - , -CH 2 CH 2 CMe 2 CH 2 CH 2 - , -O(CH 2 ) p CH 2 - , -O(CH 2 ) q O- , -CH 2 CH 2 OCH 2 CH 2 - , or -CH 2 CH 2 NR 7 CH 2 CH 2 -, n = l-5, p = l-4, q = l-4 R 3 is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R-i is hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 5 is hydrogen, alkyl, or substituted alkyl, Re is hydrogen, alkyl, substituted alkyl, or COR B , R B is hydrogen, alkyl, substituted alkyl. alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 7 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof, to said mammal 7 A method of treatmg or inhibiting breast, uterme, ovarian-, endometπal, or prostate cancer which compπses administering a compound formula 1 having the structure wherem T is O, S, or absent, Ri, and R 2 are each, mdependently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a rmg and together contain -CH 2 (CH 2 ) n CH 2 - , -CH 2 CH 2 CMe2CH2CH2- , -O(CH 2 ) P CH 2 - , -O(CH 2 ) q O- , -CH 2 CH 2 OCH 2 CH 2 - , n = l-5, P = 1-4, q = l-4 R 3 is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl. alkynyl, substituted alkynyl, or COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 4 is hydrogen, halogen, CN, NH , alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 5 is hydrogen, alkyl, or substituted alkyl, Re is hydrogen, alkyl, substituted alkyl, or COR B , R B is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 7 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof, to said mammal 8 A method of providing contraception m a mammal m need thereof, which comprises administermg an effective amount compound formula 1 havmg the structure wherem T is O, S, or absent, Ri, and R 2 are each, mdependently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a rmg and together contain -CH 2 (CH 2 ) n CH 2 - , -CH 2 CH 2 CMe 2 CH 2 CH 2 - , -0(CH 2 ) p CH 2 - , -0(CH 2 ) q O- , -CH 2 CH 2 OCH 2 CH 2 - , or -CH 2 CH 2 NR 7 CH 2 CH 2 -, n = l-5, P = 1- , q = l-4 R 3 is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R-i is hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 5 is hydrogen, alkyl, or substituted alkyl, Re is hydrogen, alkyl, substituted alkyl, or COR B , R B is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted aminoalkyl, R 7 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof, to said mammal 9 A pharmaceutical composition, which comprises a compound formula 1 havmg the structure wherem T is O, S, or absent, Ri, and R 2 are each, mdependently, hydrogen, alkyl, substituted alkyl, or Ri and R 2 are taken together form a ring and together contam -CH 2 (CH 2 ) n CH 2 - , -CH 2 CH 2 CMe2CH 2 CH 2 - , -0(CH 2 ) p CH 2 - , -0(CH 2 ) q O- , -CH 2 CH 2 OCH 2 CH 2 - , or -CH 2 CH 2 NR 7 CH 2 CH 2 -, n = l-5, P = 1-4, q = l-4 R 3 is hydrogen, OH, NH 2 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or COR A , R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 4 is hydrogen, halogen, CN, NH 2 , alkyl, substituted alkyl, alkoxy, substituted alkoxy, ammoalkyl, or substituted ammoalkyl, R 5 is hydrogen, alkyl, or substituted alkyl, Re is hydrogen, alkyl, substituted alkyl, or COR B ; R B is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R 7 is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof and a pharmaceutical earner.

Inventors: COLLINS MARK A, EDWARDS JAMES P, JONES TODD K, MACKNER VALERIE A, TEGLEY CHRISTOPHER M, WROBEL JAY E, ZHI LIN, COLLINS, MARK, A., EDWARDS, JAMES, P., JONES, TODD, K., MACKNER, VALERIE, A., TEGLEY, CHRISTOPHER, M., WROBEL, JAY, E., ZHI, LIN
Applicants: AMERICAN HOME PROD, COLLINS MARK A, EDWARDS JAMES P, JONES TODD K, LIGAND PHARM INC, MACKNER VALERIE A, TEGLEY CHRISTOPHER M, WROBEL JAY E, ZHI LIN, AMERICAN HOME PRODUCTS CORPORATION, COLLINS, MARK, A., EDWARDS, JAMES, P., JONES, TODD, K., LIGAND PHARMACEUTICALS, INC., MACKNER, VALERIE, A., TEGLEY, CHRISTOPHER, M., WROBEL, JAY, E., ZHI, LIN
Application year: 2000
Main classification: C07D413
IPC codes: A61P15, C07D403, C07D413