US 2007 OO66637A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0066637 A1 Zhang et al. (43) Pub. Date: Mar. 22, 2007

(54) S-ARYL-NDAN-1-ONE OXIMES AND (57) ABSTRACT ANALOGS USEFUL AS PROGESTERONE RECEPTOR MODULATORS (75) Inventors: Puwen Zhang, Audubon, PA (US); Compounds of formula I, wherein R-R and n are defined Jeffrey Curtis Kern, Gilbertsville, PA herein, and pharmaceutical compositions and kits containing (US); Eugene Anthony Terefenko, these compounds are provided. Center Valley, PA (US); Eugene John Trybulski, Huntingdon Valley, PA (US) Correspondence Address: HOWSON AND HOWSON CATHY A. KODROFF SUTE 210 SO1 OFFICE CENTER DRIVE FT WASHINGTON, PA 19034 (US) (73) Assignee: Wyeth, Madison, NJ (US) (21) Appl. No.: 11/522,688 Also provided are methods of inducing contraception, pro (22) Filed: Sep. 18, 2006 viding hormone replacement therapy, treating cycle-related Related U.S. Application Data symptoms, or treating or preventing benign or malignant neoplastic disease using the compounds of formula I or (60) Provisional application No. 60/718.408, filed on Sep. formula II, wherein R-Rs, Rio, and R are defined herein. 19, 2005.

Publication Classification II (51) Int. C. A6 IK 3/4745 (2006.01) A6 IK 3/403 (2006.01) C07D 209/54 (2006.01) C07D 209/96 (2006.01) (52) U.S. Cl...... 514/278: 514/409; 514/640; 546/15: 548/408: 564/257 US 2007/0066637 A1 Mar. 22, 2007

5-ARYL-NDAN-1-ONE OXIMES AND ANALOGS 0010 PR antagonists, such as mifepristone and onapris USEFUL AS PROGESTERONE RECEPTOR tone, have been shown to be effective in a model of hormone MODULATORS dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al. Ann. CROSS-REFERENCE TO RELATED N.Y. Acad. Sci., 761, 224, 1995). APPLICATIONS 0001) This application claims the benefit under 35 USC SUMMARY OF THE INVENTION 119(e) of prior U.S. Provisional Patent Application No. 0011. In one aspect, a compound of formula I is provided, 60/718.408, filed Sep. 19, 2005. where R-R and n are defined below. BACKGROUND OF THE INVENTION 0002 This invention relates to agonists and antagonists

of the progesterone receptor, their preparation and utility. 0003 Intracellular receptors (IR) form a class of struc turally related gene regulators known as “ligand dependent transcription factors' (Mangelsdorf, D. J. etc. Cell, 83, 835, 1995). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid R. R. receptor (GR), and mineralocorticoid receptor (MR). 0004 The natural hormone, or ligand, for the PR is the 0012. In another aspect, a compound is provided selected steroid progesterone, but synthetic compounds, such as from among 5-(1E)-1-(hydroxyimino)-3-methyl-2,3-dihy medroxyprogesterone acetate or levonorgestrel, have been dro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; made which also serve as PR ligands. Once a ligand is 5-(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-in present in the fluid Surrounding a cell, it passes through the den-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; 5-(1E)-1- membrane via passive diffusion, and binds to the IR to create (hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H a receptor/ligand complex. This complex binds to specific pyrrole-2-carbonitrile; (1E)-5-(3,5-dimethylisoxazol-4-yl)- gene promoters present in the cell's DNA. Once bound to 3.3-dimethylindan-1-one oxime; and a pharmaceutically the DNA the complex modulates the production of mRNA acceptable salt thereof. and the protein encoded by that gene. 0013 In a further aspect, methods of inducing contracep 0005. A compound that binds to an IR and mimics the tion, providing hormone replacement therapy, treating action of the natural hormone is termed an agonist, whilst a cycle-related symptoms, or treating or preventing benign or compound which inhibits the effect of the hormone is an malignant neoplastic disease are provided using compounds antagonist. of formula I. 0006 PR agonists (natural and synthetic) are known to 0014. In yet another aspect, methods of inducing contra play an important role in the health of women. PR agonists ception, providing hormone replacement therapy, treating are used in birth control formulations, either along or in the cycle-related symptoms, or treating or preventing benign or presence of an ER agonist. ER agonists are used to treat the malignant neoplastic disease are provided using compounds symptoms of menopause, but have been associated with a of formula II, wherein R-Rs, Rio, and R are defined proliferative effect on the uterus which can lead to an below: increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk. 0007 PR antagonists may also be used in contraception. II 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 antago nist such as tamoxifen (U.S. Pat. No. 5,719,136). 0008 PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al. Horm. Cancer, 283, 1996, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antago 0015. Other aspects and advantages will be readily appar nists may also be useful for the treatment of non-malignant ent from the following detailed description of the invention. chronic conditions such as uterine fibroids (Murphy, et al., J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Ket DETAILED DESCRIPTION OF THE tel, et al., Fertility and Sterility, 56, 402, 1991). INVENTION 0009 PR antagonists may also be useful in hormone 0016 Novel progesterone receptor (PR) modulators and replacement therapy for post menopausal patients in com uses of the same in treating a variety of conditions are bination with a partial ER antagonist Such as tamoxifen provided. The novel compounds have been shown to act as (U.S. Pat. No. 5,719,136). competitive inhibitors of progesterone binding to the PR and US 2007/0066637 A1 Mar. 22, 2007

act as PR modulators in functional models. These PR to C alkyl, CF, CFCF, or C to C cycloalkyl, or R and modulators are thereby effective as PR agonists or PR R are fused to form a carbon-based 3 to 6 membered antagonists. saturated spirocyclic ring; R is H. halogen, CN, OH, or 0017. As used herein, the terms “anti-progestational NO; Rs is H. alkyl, or perfluoroalkyl; and R. R. Rs, and agent”, “anti-progestin' and “progesterone receptor antago Rare, independently, H or F. nist are understood to be synonymous. Similarly, proges 0023. In still a further embodiment, a compound of tin”, “progestational agent, and “progesterone receptor formula I is provided, wherein R is 1-methyl-2-cyanopyr agonist are understood to refer to compounds of the same role. activity. 0024. In another embodiment, a compound of formula I 0018 Compounds of formula I are provided: is provided, wherein R is 3,5-dimethylisoxazole. 0025. In a further embodiment, a compound of formula I is provided, wherein R is of the structure:

wherein, U is O, S, or NR: R is H, C, to C alkyl, or wherein, R and Rare, independently, selected from among CORD, RD is C to C alkyl; X is selected from among H. halogen, C to C alkyl, CF, CFCF, C2 to Calkenyl, halogen, CN, NO, C to C alkyl, and C to C alkoxy; and C. to C alkynyl, C. to Cs cycloalkyl, aryl, Substituted aryl, Y" is selected from among H and C to C alkyl. heteroaryl, and substituted heteroaryl; provided both of R and R2 are not H; or R and R2 are fused to form (a), (b), or 0026. In yet another embodiment, a compound of for (c): (a) a carbon-based 3 to 6 membered saturated spirocy mula I is provided, wherein R is of the structure: clic ring; (b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from among O, S, SO, SO, and NR; whereinrings (a)-(c) are optionally substituted by 1 to 3 substituents selected from among F, Cl, and C to C alkyl; R is a 5 or 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from among O, S, SO, SO, and NR wherein, X is N or CX; and X is halogen, CN, C, to C, and substituted with 0 to 3 substituents selected from among alkoxy, or NO. H, halogen, CN, NO, OH, amino, C to C alkyl, C to C. 0027. In yet a further embodiment, a compound of for alkoxy, C to C alkylamino, C=NOR, CORP, and NR mula I is provided selected from among 5-(1E)-1-(hydroxy CORP: R is absent, H, C, to C alkyl, substituted C, to Ca imino)-3-methyl-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H alkyl, CN, or CORP; RP is H, C, to C, alkyl, C to Calkoxy, pyrrole-2-carbonitrile; 5-(1E)-1-(hydroxyimino)-3.3- or C to C alkylamino; R is H, halogen, CN, OH, NO, dimethyl-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H alkoxy, or lower alkyl; Rs is H or lower alkyl; R. R. Rs. pyrrole-2-carbonitrile; 5-(1E)-1-(hydroxyimino)-2,3- and Ro are, independently, H. F. or C to C lower alkyl; in dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2- is 0 or 1; or a pharmaceutically acceptable salt thereof. carbonitrile; and (1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3- 0019. In one embodiment, a compound of formula I is dimethylindan-1-one oxime. provided, wherein R and Rare, independently, H or C to 0028. In still another embodiment, a compound of for C alkyl, R is a 5 membered heteroaryl ring containing in mula I is provided which is 5-(5E)-5-(hydroxyimino)-5,6, its backbone 1 NR heteroatom; R is C, to C alkyl; R is 7,8-tetrahydronaphthalen-2-yl)-1-methyl-1H-pyrrole-2-car H; and Rs is H or C to C alkoxy. bonitrile. 0020. In another embodiment, a compound of formula I 0029. The term “alkyl is used herein to refer to both is provided, wherein Rs is H. straight- and branched-chain Saturated aliphatic hydrocar 0021. In a further embodiment, embodiment, a com bon groups having 1 to about 8 carbon atoms, and desirably pound of formula I is provided, wherein R and R2 are, 1 to about 6 carbon atoms (i.e., C, C, C, C, Cs or C). independently, H or C to C alkyl; R is a 5 membered Similarly, the term “lower alkyl is used herein to refer to heteroayl ring containing in its backbone 1 NR heteroatom alkyl groups as just described, but having 1 to about 3 carbon and substituted with 1 CN group; R is C, to C alkyl; R is atoms. Unless otherwise specified, the alkyl groups are not H; and Rs is H or C to C alkoxy. substituted. 0022. In yet another embodiment, a compound of for 0030) The term “cycloalkyl is used herein to an alkyl mula I is provided, wherein R and Rare, independently, C group as just described, but cyclic in structure and having 3 US 2007/0066637 A1 Mar. 22, 2007

to about 8 carbon atoms. In one embodiment, a cycloalkyl can contain about 3 to about 50 carbon atoms, including all group has 3 to about 8 carbon atoms. In another embodi combinations and Subcombinations of ranges and specific ment, a cycloalkyl group has about 3 to about 6 carbon numbers of carbon atoms therein. In another embodiment, a atoms (i.e., C. C. Cs or C). heteroaryl group can contain about 4 to about 10 carbons. Non-limiting examples of heteroaryl groups include, for 0031) The term “alkenyl is used herein to refer to both example, pyrrolyl, furyl, pyridyl, 1,2,4-thiadiazolyl pyrim straight- and branched-chain alkyl groups having one or idyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, more carbon-carbon double bonds and containing about 3 to pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, about 8 carbon atoms. In one embodiment, the term alkenyl isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, ben refers to an alkyl group having 1 or 2 carbon-carbon double Zimidazolyl, and isoxazolyl. bonds. In a further embodiment, an alkenyl group has about 2 to about 8 carbon atoms. In another embodiment, an 0038. The term “substituted heteroaryl” refers to an het alkenyl group has about 2 to about 6 carbon atoms. Unless eroaryl group which is substituted with one or more sub otherwise specified, the alkenyl groups are not substituted. stituents including halogen, CN, OH, NO, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy. 0032) The term “alkynyl is used herein to refer to both straight- and branched-chain alkyl groups having one or 0.039 The term “heterocyclic” as used herein refers to a more carbon-carbon triple bond and having about 3 to about stable 4- to 7-membered monocyclic or multicyclic hetero 8 carbon atoms. In one embodiment, the term alkynyl refers cyclic ring which is Saturated or partially unsaturated. The to an alkyl group having 1 or 2 carbon-carbon triple bonds heterocyclic ring has in its backbone carbon atoms and one and having about 3 to about 6 carbon atoms. Unless other or more heteroatoms including nitrogen, oxygen, and Sulfur wise specified, the alkynyl groups are not Substituted. atoms. Desirably, the heterocyclic ring has 1 to about 4 heteroatoms in the backbone of the ring. When the hetero 0033. The terms “substituted alkyl”, “substituted alk cyclic ring contains nitrogen or Sulfur atoms in the backbone enyl', 'substituted alkynyl', and “substituted cycloalkyl of the ring, the nitrogen or Sulfur atoms can be oxidized. The refer to alkyl, alkenyl, alkynyl, and cycloalkyl groups, term "heterocyclic' also refers to multicyclic rings in which respectively, having one or more substituents including, a heterocyclic ring is fused to an aryl ring. The heterocyclic without limitation, halogen, CN, OH, NO, amino, aryl, ring can be attached to the aryl ring through a heteroatom or heterocyclic, substituted aryl, substituted heterocyclic, carbon atom provided the resultant heterocyclic ring struc alkoxy, aryloxy, Substituted alkoxy, alkylcarbonyl, alkylcar ture is chemically stable. boxy, alkylamino, or arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, alkynyl or 0040 A variety of heterocyclic groups are known in the cycloalkyl group provided that the attachment constitutes a art and include, without limitation, oxygen-containing rings, stable chemical moiety. nitrogen-containing rings, Sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing 0034. The term “acyl as used herein refers to a carbonyl rings, and combinations thereof. The heterocyclic groups are Substituent, i.e., a C(O)(R) group where R is a straight- or selected from, but not limited to, furyl, tetrahydrofuranyl, branched-chain hydrocarbon group including, without limi pyranyl, pyronyl, dioxinyl, pyrrolyl pyrazolyl, imidazolyl, tation, alkyl, alkenyl, and alkynyl groups. In one embodi triazolyl pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, ment, the R groups have 1 to about 8 carbon atoms, and in pyrimidinyl, pyrazinyl, piperazinyl, azepinyl, triazinyl, pyr a further embodiment 1 to about 6 carbon atoms. The term rolidinyl, azepinyl, oxathiolyl, oxazolyl, thiazolyl, oxadiaz “substituted acyl refers to an acyl group which is substi olyl, oXatriazolyl, dioxazolyl, Oxathiazolyl, oxathiolyl, tuted with 1 or more groups including halogen, CN, OH, and oxazinyl, oxathiazinyl, morpholinyl, thiamorpholinyl, thia NO. morpholinyl Sulfoxide, oxepinyl, thiepinyl, diazepinyl, ben 0035. The term “aryl as used herein refers to an aromatic Zofuranyl, thionapthene, indolyl, benazazolyl, purindinyl, system which can include a single ring or multiple aromatic pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, rings fused or linked together where at least one part of the anthranillyl, benzopyranyl, quinolinyl, isoquinolinyl, benzo fused or linked rings forms the conjugated aromatic system. diazonyl, napthylridinyl, benzothienyl, pyridopyridinyl, The aryl groups include, but are not limited to, phenyl, benzoxazinyl, Xanthenyl, acridinyl, and purinyl rings. naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenan 0041. The term “substituted heterocyclic” as used herein thryl, indene, benzonaphthyl, fluorenyl, and carbazolyl. refers to a heterocyclic group having one or more substitu Desirably, the aryl group is an optionally Substituted phenyl ents including halogen, CN, OH, NO, amino, alkyl, group. cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylcarbonyl, 0036) The term “substituted aryl refers to an aryl group alkylcarboxy, alkylamino, and arylthio, which groups can be which is substituted with one or more substituents including optionally substituted. Desirably, a substituted heterocyclic halogen, CN, OH, NO, amino, alkyl, cycloalkyl, alkenyl, group has 1 to 4 substituents. alkynyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alky 0042. The term “arylthio” as used herein refers to the lamino, and arylthio, which groups can be optionally Sub S(aryl) group, where the point of attachment is through the stituted. Desirably, a substituted aryl group is substituted Sulfur-atom and the aryl group can be optionally Substituted. with 1 to about 4 substituents. 0043. The term “alkoxy” as used herein refers to the 0037. The term “heteroaryl,” as used herein, refers to an O(alkyl) group, where the point of attachment is through the optionally Substituted, mono-, di-, tri-, or other multicyclic oxygen-atom and the alkyl group is optionally Substituted. aromatic ring system that includes at least one, and desirably 0044) The term “thioalkoxy” as used herein refers to the from 1 to about 4 heteroatom ring members including Sulfur, S(alkyl) group, where the point of attachment is through the oxygen and nitrogen. In one embodiment, a heteroaryl group Sulfur-atom and the alkyl group is optionally Substituted. US 2007/0066637 A1 Mar. 22, 2007

0045. The term “aryloxy” as used herein refers to the 0055. The compounds discussed herein also encompass O(aryl) group, where the point of attachment is through the “metabolites” which are unique products formed by pro oxygen-atom and the aryl group is optionally Substituted. cessing the compounds described herein by the cell or 0046) The term “alkylcarbonyl as used herein refers to subject. Desirably, metabolites are formed in vivo. the C(O)(alkyl) group, where the point of attachment is 0056. The compounds described herein are readily pre through the carbon-atom of the carbonyl moiety and the pared by one of skill in the art according to the following alkyl group is optionally Substituted. schemes from commercially available starting materials or 0047. The term “alkylcarboxy” as used herein refers to starting materials which can be prepared using literature the C(O)O(alkyl) group, where the point of attachment is procedures. These schemes show the preparation of repre through the carbon-atom of the carboxy moiety and the alkyl sentative compounds. Variations on these methods, or other group is optionally Substituted. methods known in the art, can be readily performed by one 0.048. The term “alkylamino” as used herein refers to of skill in the art given the information provided herein. both secondary and tertiary amines where the point of attachment is through the nitrogen-atom and the alkyl groups are optionally Substituted. The alkyl groups can be Scheme I the same or different. R6 R2 0049. The term “halogen” as used herein refers to Cl, Br, X 21 F, or I groups. SAS Y Li or BrMg R 0050. The compounds described herein encompass tau y tomeric forms of the structures provided herein character ized by the bioactivity of the drawn structures. Further, the O compounds described herein can be used in the form of salts 1 derived from pharmaceutically or physiologically accept X 21 R6 able acids, bases, alkali metals and alkaline earth metals. 0051 Pharmaceutically acceptable salts can be formed Sás N1. Lewis acid, heat from organic and inorganic acids including, for example, R4 acetic, propionic, lactic, citric, tartaric, succinic, fumaric, O R maleic, malonic, mandelic, malic, phthalic, hydrochloric, 2 hydrobromic, phosphoric, nitric, Sulfuric, methanesulfonic, R R2 napthalenesulfonic, benzenesulfonic, toluenesulfonic, cam phorsulfonic, and similarly known acceptable acids. Salts *n-1s may also be formed from inorganic bases, desirably alkali R6 metal salts including, for example, Sodium, lithium, or A-4 potassium, and organic bases, such as ammonium salts, R4 O mono-, di-, and trimethylammonium, mono-, di- and triethy lammonium, mono-, di- and tripropyl-ammonium (iso and 3 normal), ethyldimethylammonium, benzyldimethylammo nium, cyclohexylammonium, benzylammonium, dibenzy lammonium, piperidinium, morpholinium, pyrrolidinium, Riotopic reaction piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, R R2 R R2 1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n- R3 N NHORs R3 N butyl piperidinium, 2-methyl-piperidinium, 1-ethyl-2-meth R6 R6 ylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, 41 K A4 tris(hydroxymethyl)methyl-ammonium, phenylmonoetha NNOR R4 O nolammonium, and the like. 5 4 0.052 Physiologically acceptable alkali salts and alkaline earth metal salts can include, without limitation, Sodium, 0057. As illustrated in Scheme I, access to ketones 2 can potassium, calcium and magnesium salts in the form of be achieved by reaction of an appropriately substituted esters, and carbamates. benzoic acid or its derivatives such as Weinreb amides 1 0053. These salts, as well as other compounds described with a suitable organo lithium or Grignard reagent. The herein can be in the form of esters, carbamates and other reaction can be executed in an aprotic solvent including but conventional “pro-drug forms, which, when administered not limited to tetrahydrofuran (THF) or diethyl ether at a in Such form, convert to the active moiety in vivo. In one suitable temperature ranging from -78° C. to room tem embodiment, the prodrugs are esters. See, e.g., B. Testa and perature under a blanket of inert atmosphere such as nitro J. Caldwell, “Prodrugs Revisited: The “Ad Hoc' Approach gen or argon. To prevent the formation of carbinol side as a Complement to Ligand Design, Medicinal Research products, a reversing quenching procedure (pouring the Reviews, 16(3):233-241, ed., John Wiley & Sons (1996). reaction mixture to a diluted aqueous acidic solution Such as 0054 As described herein, the compounds described hydrogen chloride solution) is preferred. An alternative way herein and/or salts, prodrugs or tautomers thereof, are deliv to work up the reaction included but not limited to an ered in regimens therapeutic or prophylactic purposes, as addition of trialkylsilyl chloride or equivalent to the reaction described herein. before quenching the reaction mixture with a diluted aque US 2007/0066637 A1 Mar. 22, 2007

ous acidic solution. Cyclization of ketones 2 to afford 0058 Alternatively, indanones as well as their six-mem indanones 3 can be effected with a suitable Lewis acid such ber ring analogs, 3,4-dihydro-2H-naphthalen-1-ones 7, can as polyphosphoric acid (PPA) and aluminum chloride in an be furnished from appropriately substituted 3-phenyl-propi aprotic solvent such as chlorobenzene, Xylene, the onic acids or 4-phenyl-butyric acids 6 as depicted in scheme Dowtherm R A reagent, and nitrobenzene at the temperature II. Preferably, acids 6 are activated by converted into their ranging from room temperature to refluxing of Solvent. corresponding carbonyl chloride or anhydrides by reacting Formation of 5-aryl indanones 4 can be achieved by a with a suitable agent Such as thionyl chloride or oxalyl number of coupling reactions including Suzuki or Stille chloride. The activated intermediates can be then in situ protocols. These reactions are commonly performed in the presence of a transition metallic catalyst, e.g., palladium or cyclized to form 7 using a Friedel-Crafts acylation protocol nickel complex often with phosphino ligands, e.g., triph by addition of an appropriate Lewis acid Such aluminum enylphosphine (Ph-P), 1,1'-bis(diphenylphosphino)fer chloride or tin chloride in a suitable solvent such as benzene, rocene (dppf), or 1.2-bis(diphenylphosphino)ethane (dppe). chlorobenzene, and nitrobenzene at the temperature ranging Under this catalytic condition, an appropriately substituted from room temperature to refluxing of the solvent used. aryl nucleophilic reagent, e.g., aryl boronic acid, arylstan Formation of 5-aryl indanones or 6-aryl 3,4-dihydro-2H nane, or aryl Zinc compound, can be coupled with 3 to naphthalen-1-ones 8, the key intermediates led to the com produce 5-aryl indanones 4. The commonly used bases in pounds 5, can be readily effected using typical aforemen the reaction include but not limited to sodium bicarbonate, tioned coupling procedures as illustrated in Scheme I. Sodium carbonate, potassium phosphate, barium carbonate, cesium fluoride, and potassium acetate. The most commonly used solvents in these reactions include benzene, toluene, Scheme III dimethylformamide (DMF), isopropanol, ethanol, R R2 dimethoxyethane (DME), and ether. The coupling reaction is X generally executed under an inert atmosphere such as nitro N gen or argon attemperatures ranging from room temperature n oxidation to 95°C. In the case when an appropriate aryl nucleophilic A-4 reagent is not available, the 5-halogen of 3 can be converted R4 to the borate or Stannane, which can be coupled with an 9 appropriate aryl halide Such as aryl bromide or aryl iodide using any coupling reaction described above to yield com pounds 4. Conversion of ketones 4 to the compounds, 5, can be readily achieved by treating 4 with a suitable hydroxy lamine reagent such as hydroxylamine hydrogen chloride R R2 salt in an appropriate solvent such as ethanol and water at the X N temperature ranging from ambient temperature to the reflux n ing temperature of the solvent. A4 R4 O Scheme II 7 R R2 OH X 21 O Lewis Acid 0059 Indanones or 3,4-dihydro-2H-naphthalen-1-ones 7 He can also be prepared via oxidation of appropriately substi Sás tuted indans or 1.2.3,4-tetrahydro-naphthalenes 9 using a R4 Suitable oxidant such as chromium (VI) oxide or manganese 6 (IV) oxide in a suitable solvent such as water and acetic acid R R2 as depicted in scheme III. Conversion of 7 to 8, the key X intermediates to the compounds described herein, can be N R3B(OH)2 readily effected via the aforementioned coupling protocols. n ----coupling reaction A-4 0060 Acyclic 1-(4-substituted-phenyl)-alkanones 11 can R4 be furnished from reaction of an appropriately substituted O benzoic acid or its suitable derivative such as Weinreb amide 7 10 with a suitable organo lithium or Grignard reagent as R R2 illustrated in scheme IV and this transformation can be R3 N executed aforementioned for the preparation of ketones 2 in n scheme I. Followed the same coupling procedures as A4 described in Scheme I, the key ketone intermediates 12, can R4 be furnished by reacting ketones 11 with an appropriate aryl O nucleophilic reagent such as aryl boronic acid following 8 aforementioned coupling protocol in scheme I. Followed the n = 1, 2 same procedure aforementioned in Scheme I, the compounds 13 can be effected from ketones 12 by treatment of 12 with a suitable hydroxylamine reagent. US 2007/0066637 A1 Mar. 22, 2007

glycols, non-ionic Surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of Scheme IV the active ingredient and the particular form of administra tion desired. Adjuvants customarily employed in the prepa X 21 R ration of pharmaceutical compositions may be advanta RiLi or RMgX geously included. Such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, R4SS-N-1 ascorbic acid, butylated hydroxytoluene (BHT) and butylat O edhydroxyanisole (BHA). 10 0065. When formulated for oral delivery, the compound X 21 R described herein can be in the form of a tablet, capsule, R3B(OH)2 caplet, gel tab, dispersible powders, granules, or Suspen Sás R HeCoupling raction sions. In one embodiment, the compound can be combined R4 with suspending agents, including about 0.05 to about 5% of O Suspending agent, syrups containing, for example, about 10 11 to about 50% of Sugar, and/or elixirs containing, for R3 R2 example, about 20 to about 50% ethanol, and the like. N 0066. The compounds described herein may also be NHOR administered parenterally or intraperitoneally. Solutions or A 21 R S Suspensions of the compounds described herein as a free base or pharmacologically acceptable salt can be prepared in O water Suitably mixed with a Surfactant such as hydroxypro 12 pylcellulose. Dispersions can also be prepared in glycerol, R3 R2 liquid, polyethylene glycols and mixtures thereof in oils. In one embodiment, the Solutions or Suspensions containing a r compound described herein can contain about 0.05 to about A. 21 R 5% suspending agent in an isotonic medium. Such pharma R4 ceutical preparations may contain, for example, about 25 to N about 90% of the compound in combination with the carrier. OR Desirably, the pharmaceutical preparation contains about 13 5% and 60% by weight of the compound. 0067. The pharmaceutical forms suitable for injectable 0061 Also included are pharmaceutical compositions use include sterile aqueous solutions or dispersions and containing one or more compounds described herein and a sterile powders for the extemporaneous preparation of sterile pharmaceutically acceptable carrier or excipient. Also injectable solutions or dispersions. In all cases, the form included are methods of treatment which include adminis must be sterile and must be fluid to the extent that easy tering to a mammal a pharmaceutically effective amount of syringe ability exits. It must be stable under conditions of one or more compounds as described as progesterone recep manufacture and storage and must be preserved against the tor modulators. contaminating action of microorganisms such as bacterial 0062) The compounds described herein may be combined and fungi. The carrier can be a solvent or dispersion medium with one or more pharmaceutically acceptable carriers or containing, for example, water, ethanol (e.g., glycerol, pro excipients, for example, Solvents, diluents and the like. pylene glycol and liquid polyethylene glycol), Suitable mix Suitably, the compounds described herein are formulated for tures thereof, and vegetable oil. delivery to a subject by any suitable route including, e.g., 0068 The compounds described herein may also be transdermal, mucosal (intranasal, buccal, vaginal), oral, administered via a vaginal ring. Suitably, use of the vaginal parenteral, among others. A variety of Suitable delivery ring is timed to cycle to which the compound is being devices can be utilized and include, without limitation, administered, including a 28-day cycle. However, the vagi tablets, caplets, capsules, gel tabs, dispersible powders, nal ring can be inserted for longer or shorter periods of time. granules, Suspensions, injectable solutions, transdermal See, U.S. Pat. Nos. 5,972,372: 6,126,958; and 6,125,850, patches, topical creams or gels, and Vaginal rings, among which are hereby incorporated by reference, for formula others. tions of the vaginal ring that can be used. 0063. One particularly desirable pharmaceutical compo 0069. The compound described herein can also be deliv sition, from the standpoint of ease of preparation and admin ered via a transdermal patch. Suitably, use of the patch is istration, are solid compositions, particularly tablets and timed to the length of the cycle, including a 28 day cycle. hard-filled or liquid-filled capsules. Oral administration of However, the patch can remain in place for longer or shorter the compounds is most desirable. periods of time. 0064. The compounds described herein may be adminis 0070 These compounds can be utilized in methods of tered orally as well as by intravenous, intramuscular, or contraception, hormone replacement therapy, the treatment Subcutaneous routes. Solid carriers include starch, lactose, and/or prevention of benign and malignant neoplastic dis dicalcium phosphate, microcrystalline cellulose, Sucrose and ease including uterine myometrial fibroids, endometriosis, kaolin. Liquid carriers include sterile water, polyethylene benign prostatic hypertrophy; carcinomas and adenocarci US 2007/0066637 A1 Mar. 22, 2007

nomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors, and the treatment of cycle related symptoms, dys menorrheal, dysfunctional uterine bleeding, symptoms of premenstrual syndrome and premenstrual dysphoric disor der, and for inducing amenorrhea. Additional uses of the present progesterone receptor modulators include the Syn chronization of estrus in livestock. In one embodiment, the neoplastic disease is hormone-dependent. 0071. The term “cycle-related symptoms” as used herein refers to psychological and physical symptoms associated with a woman's menstrual cycle arising in the luteal phase wherein, R and Rare, independently, selected from among of the menstrual cycle. It has been reported that most women H. halogen, C to C alkyl, CF, CFCF, C2 to Calkenyl, report experiencing cycle-related symptoms. The symptoms C. to C alkynyl, C. to Cs cycloalkyl, aryl, Substituted aryl, generally disappear after the onset of menstruation, and the heteroaryl, and substituted heteroaryl; or RandR are fused patient is free from symptoms during the rest of the follicular to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered phase. The cyclical nature of the symptom variations is saturated spirocyclic ring; (b) a carbon-based 3 to 6 mem characteristic of cycle-related symptoms. bered spirocyclic ring having in its backbone one or more carbon-carbon double bonds; or (c) a carbon-based 3 to 6 0072 Cycle-related symptoms occur in about 95% of membered spirocyclic ring having in its backbone 1 to 3 women who experience Some physical or mood changes heteroatoms selected from among O, S, SO, SO, and NR; with their menstrual cycles. Only about one-third of those wherein rings (a)-(c) are optionally substituted by 1 to 3 women experiences moderate to severe cycle-related Symp Substituents selected from among F, Cl, and C to C alkyl; R is aryl, substituted aryl, or a 5 or 6 membered heteroayl toms. Women vary in the number, type, severity, and pattern ring containing in its backbone 1 to 3 heteroatoms selected of symptoms before menstruation. One thing common to all from among O, S, SO, SO, and NR and substituted with 0 the types of cyclic-related symptoms is the decrease or to 3 substituents selected from among H, halogen, CN, NO, elimination of the symptoms in the two weeks after men OH, amino, C to C alkyl, C to C alkoxy, C to C. struation up to ovulation. alkylamino, C=NOR, CORP, and NRCORP: R is absent, H, C to Calkyl, substituted C to C alkyl, CN, or 0073. The term “cycle-related symptoms’ refers to psy CORP; RP is H, C, to C, alkyl, C, to C, alkoxy, or C to C, chological symptoms (for example, mood change, irritabil alkylamino; R is H, halogen, CN, OH, NO, alkoxy, or ity, anxiety, lack of concentration, or decrease in sexual lower alkyl; Rs is H or lower alkyl, R. R. Rs, and Ro are, desire) and physical symptoms (for example, dysmenorrhea, independently, H, F, or C to C. lower alkyl; n is 0 or 1; or breast tenderness, bloating, fatigue, or food cravings) asso a pharmaceutically acceptable salt thereof. ciated with a woman’s menstrual cycle. Cycle-related Symp 0077. In one embodiment, the compound of formula I toms occur after ovulation but before menses and usually utilized in the method is selected from among 5-(1E)-1- terminate at the start of the menstrual period or shortly (hydroxyimino)-3-methyl-2,3-dihydro-1H-inden-5-yl)-1- thereafter. Cycle-related symptoms include, but are not methyl-1H-pyrrole-2-carbonitrile; 5-(1E)-1-(hydroxy limited to, dysmenorrhea and moderate to severe cycle imino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)-1-methyl related symptoms. 1H-pyrrole-2-carbonitrile, 5-(1E)-1-(hydroxyimino)-2,3- dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2- 0074. When utilized for these purposes, the compounds carbonitrile; (1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3- of formulas I or II can be administered in combination with dimethylindan-1-one oxime; 3-(1E)-1-(hydroxyimino)-2,3- other agents, as well as in combination with each other. Such dihydro-1H-inden-5-ylbenzonitrile; 4-(1E)-1- agents include, without limitation, progestins, anti (hydroxyimino)-2,3-dihydro-1H-inden-5-ylbenzonitrile; progestins, estrogens, among others. Progestins can include, 3-fluoro-5-(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihy without limitation, tanaproget, levonorgestrel, norgestrel, dro-1H-inden-5-ylbenzonitrile; (1E)-5-(4-acetylphenyl)-3, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, 3-dimethylindan-1-one oxime; (1E)-5-(3-acetylphenyl)-3,3- norethindrone acetate, norgestimate, osaterone, cyproterone dimethylindan-1-one oxime; (1E)-5-(2-acetylphenyl)-3,3- acetate, trimegestone, dienogest, drospirenone, nomegestrol, dimethylindan-1-one oxime: 4-(1E)-1-(hydroxyimino)-3.3- (17-deacetyl)norgestimate. Estrogens can include, without dimethyl-2,3-dihydro-1H-inden-5-ylbenzonitrile; 3-(1E)- limitation, ethinyl estradiol. 1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5- ylbenzonitrile; (1E)-5-(4-chlorophenyl)-3,3- 0075. In one embodiment, a patient or subject being dimethylindan-1-one oxime; (1E)-3.3-dimethyl-5-(4- treated is a mammalian Subject and typically a female. methylphenyl)indan-1-one Oxime; (1E)-5-(4- Desirably, the subject is a human. However, as used herein, methoxyphenyl)-3,3-dimethylindan-1-one oxime; (1E)-5- a female can include non-human mammals, e.g., cattle or (3-chlorophenyl)-3,3-dimethylindan-1-one oxime; 1E)-3.3- livestock, horses, pigs, domestic animals, etc. dimethyl-5-(3-methylphenyl)indan-1-one oxime; (1E)-5-(3- methoxyphenyl)-3,3-dimethylindan-1-one oxime; (1E)-5- 0.076 Methods of inducing contraception, providing hor (3,5-dichlorophenyl)-3,3-dimethylindan-1-one oxime; (1E)- mone replacement therapy, or treating cycle-related Symp 5-(2-chlorophenyl)-3,3-dimethylindan-1-one oxime; (1E)- toms are provided, including administering to a mammal in 5-(3,4-dichlorophenyl)-3,3-dimethylindan-1-one oxime; need thereof a pharmaceutically effective amount of a com (1E)-5-(2,3-dichlorophenyl)-3,3-dimethylindan-1-one pound of the structure: oxime; (1E)-5-(2,5-dichlorophenyl)-3,3-dimethylindan-1- US 2007/0066637 A1 Mar. 22, 2007 one oxime; (1E)-5-(2,4-dichlorophenyl)-3,3-dimethylindan 0081. In one embodiment, when performing the method 1-one oxime: (1E)-3,3-dimethyl-5-phenylindan-1-one using the compound of formula II, Ro and R are, inde oxime: (1E)-5-(3-chloro-4-fluorophenyl)-3,3-dimethylin pendently, H or C to C alkyl; R is a 5 membered heteroayl dan-1-one oxime; (1E)-3,3-dimethyl-5-3-(trifluorometh ring containing in its backbone 1 NR heteroatom; R is C yl)phenylindan-1-one oxime: (1E)-3,3-dimethyl-5-4-(trif to C alkyl, R is H; and Rs is H or C to C alkoxy. luoromethyl)phenylindan-1-one Oxime; (1E)-5-4- (dimethylamino)phenyl-3.3-dimethylindan-1-one oxime; 0082 In another embodiment, when performing the (1E)-5-3-(dimethylamino)phenyl)-3,3-dimethylindan-1- methods using the compounds of formula I or II, Rs is H. one oxime; (1E)-5-(3,4-difluorophenyl)-3,3-dimethylindan 0083. In a further embodiment, when performing the 1-one oxime; and (1E)-5-3-(ethylsulfonyl)phenyl-3,3- method using the compound of formula II, Ro and Rare, dimethylindan-1-one oxime. independently, H or C to C alkyl; R is a 5 membered 0078. In another embodiment, the compound of formula heteroayl ring containing in its backbone 1 NR heteroatom I utilized in the method is selected from among 5-(5E)-5- and substituted with 1 CN group; R is C to C alkyl; R is (hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1-me H; and Rs is H or C to C alkoxy. thyl-1H-pyrrole-2-carbonitrile; (1E)-6-(3-chlorophenyl)-3, 4-dihydronaphthalen-1 (2H)-one Oxime; 3-(5E)-5- 0084. In still another embodiment, when performing the (hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl) methods using the compounds of formula I or II, R is a benzonitrile; (1E)-6-(3-chloro-4-fluorophenyl)-3,4- benzene ring containing 0 to 3 Substituents selected from dihydronaphthalen-1 (2H)-one Oxime; (1E)-6-(4- among halogen, CN, C to C alkyl, Substituted C to Ca chlorophenyl)-3,4-dihydronaphthalen-1 (2H)-one oxime; alkyl, C. to Calkenyl, Substituted C to Calkenyl, C. to C (1E)-6-3-(trifluoromethyl)phenyl-3,4-dihydronaphthalen alkynyl, substituted C to C alkynyl, C to C alkoxy, 1(2H)-one oxime; (1E)-6-(3-fluorophenyl)-3,4-dihy Substituted C to C alkoxy, C to C thioalkoxy, Substituted dronaphthalen-1 (2H)-one oxime; (1E)-6-(3,4-difluorophe C to C thioalkoxy, amino, C to C alkylamino, Substituted nyl)-3,4-dihydronaphthalen-1 (2H)-one oxime; (1E)-6-(3- C to C alkylamino, NO, C to C perfluoroalkyl, 5 or 6 methylphenyl)-3,4-dihydronaphthalen-1 (2H)-one oxime; membered heteroayl ring containing in its backbone 1 to 3 and (1E)-6-(3-methoxyphenyl)-3,4-dihydronaphthalen-1 heteroatoms, COR, OCOR, and NRPCOR. (2H)-one oxime. 0085. In yet a further embodiment, when performing the methods using the compounds of formula I or II, R is a 0079. In a further embodiment, when utilized in the method, R of compound I is 3-cyanophenyl, 4-cyanophe benzene ring of the structure: nyl, 3-chlorophenyl, 3-chloro-4-fluoro-phenyl, 3-trifluo romethylphenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-tolyl, 3-methoxyphenyl, 3-cyano-5-fluorophenyl, 4-acetylphenyl, 3-acetylphenyl, 2-acetylphenyl, 4-tolyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 2-chlorophenyl, 3,4- Pri dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, N phenyl, 4-trifluoromethylphenyl, 4-dimethylaminophenyl, 3-dimethylaminophenyl, or 3-ethylsulfonylphenyl. 0080 A method of inducing contraception, providing wherein, X is selected from among halogen, CN, C to Ca hormone replacement therapy, treating cycle-related Symp alkyl, substituted C to Calkyl, C. to Calkenyl, Substituted toms, and treating or preventing benign or malignant neo C. to C alkenyl, C. to C alkynyl. Substituted C to C plastic disease is provided including administering to a alkynyl, C to C alkoxy, Substituted C to C alkoxy, C to mammal in need thereof a pharmaceutically effective C. thioalkoxy, Substituted C to C thioalkoxy, amino, C to amount of a compound of formula II: C. alkylamino, Substituted C to C alkylamino, NO, C to C. perfluoroalkyl, 5 or 6 membered heteroayl ring contain ing in its backbone 1 to 3 heteroatoms, COR, OCOR, or II NRPCOR: Y and Z are independent substituents selected from among H. halogen, CN, NO, C to Calkoxy, C to Ca alkyl, and C to C thioalkoxy. 0086. In still another embodiment, when performing the methods using the compounds of formula I or II, R is of the Structure: wherein, R is aryl, substituted aryl, or a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 heteroatoms selected among O, S, SO, SO, and NR and substituted with 0 to 3 substituents selected from among H, halogen, CN, NO, OH, amino, C to C alkyl, C to C alkoxy, C to C. alkylamino, C=NOR, CORP, and NRCORP: R is H, halogen, CN, OH, NO, or alkoxy; Rs is H or lower alkyl: Ro and Rare, independently, H. F. or C to Clower alkyl; wherein, X is selected from among halogen, CN, C to C. or a pharmaceutically acceptable salt thereof. alkoxy, C to C, alkyl, NO, C, to C, perfluoroalkyl, 5 US 2007/0066637 A1 Mar. 22, 2007 membered heteroayl ring containing in its backbone 1 to 3 body weight, about 1 to about 400 mg/kg, about 5 to about heteroatoms, and C to C thioalkoxy; Y is selected from 300 mg/kg, about 10 to about 250 mg/kg, about 50 to about among H. halogen, CN, NO, C to Calkoxy, C to C alkyl, 200 mg/kg, or about 100 to 150 mg/kg. For most large and C to C thioalkoxy. mammals, the total daily dosage is from about 1 to 100 mg. 0087. In another embodiment, when performing the In one embodiment, the total daily dosage is from about 2 to methods using the compounds of formula I or II, R is 80 mg. This dosage regimen may be adjusted to provide the 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl, 3-chloro-4- optimal therapeutic response. For example, several divided fluoro-phenyl, 3-trifluoromethylphenyl, 3-fluorophenyl, 3,4- doses may be administered daily or the dose may be pro difluorophenyl, 3-tolyl, 3-methoxyphenyl, 3-cyano-5-fluo portionally reduced as indicated by the exigencies of the rophenyl, 4-acetylphenyl, 3-acetylphenyl, 2-acetylphenyl, therapeutic situation. 4-tolyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 2-chlorophe 0094. As previously noted, the compounds may be nyl, 3,4-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlo administered via a vaginal ring. Suitably, use of the vaginal rophenyl, phenyl, 4-trifluoromethylphenyl, 4-dimethylami ring is timed to the 28 day cycle. In one embodiment, the nophenyl, 3-dimethylaminophenyl, O ring is inserted into the vagina, and it remains in place for 3-ethylsulfonylphenyl. 3 weeks. During the fourth week, the vaginal ring is removed and menses occurs. The following week a new ring 0088. In still a further embodiment, when performing the is inserted to be worn another 3 weeks until it is time for the methods using the compounds of formula I or II, R is next period. In another embodiment, the vaginal ring is 1-methyl-2-cyano-pyrrole. inserted weekly, and is replaced for 3 consecutive weeks. 0089. In yet another embodiment, when performing the Then, following 1 week without the ring, a new ring is methods using the compounds of formula I or II, R is inserted to begin a new regimen. In yet another embodiment, 3,5-dimethylisoxazole. the vaginal ring is inserted for longer or shorter periods of time. 0090. In a further embodiment, when performing the methods using the compounds of formula I or II, R is a 5 0095. Further, the previously mentioned patch is applied or 6 membered heteroayl ring containing in its backbone 1 via a Suitable adhesive on the skin, where it remains in place to 3 heteroatoms selected from among O, S, SO, SO and for 1 week and is replaced weekly for a total period of 3 NR and substituted with 0 to 3 substituents selected from weeks. During the fourth week, no patch is applied and among H. halogen, CN, NO,OH, amino, C to C alkyl, C menses occurs. The following week a new patch is applied to C, alkoxy, C to C, alkylamino, C=NOR, CORP, and to be worn to begin a new regimen. In yet another embodi NRCORP: R is absent, H, C to C alkyl, substituted C. ment, the patch remains in place for longer, or shorter to Calkyl, CN, or CORD; RP is H, C to C, alkyl, C. to C, periods of time. alkoxy, or C to C alkylamino. 0096. When used for contraception, the method typically includes delivering a daily dosage unit containing a com 0091. In still another embodiment, when performing the pound for 28 consecutive days to a female of child-bearing methods using the compounds of formula I or II, R and R age. Desirably, the method includes delivering the com are, independently, C to C alkyl, CF, CFCF, or C to C. pound over a period of 21 to 27 consecutive days followed cycloalkyl; or R and R are fused to form a carbon-based 3 by 1 to 7 consecutive days in which no effective amount or to 6 membered saturated spirocyclic ring; R is H. halogen, no amount of the compound is delivered. Optionally, the CN, OH, or NO; R is H, alkyl, or perfluoroalkyl; and R. period of 1 to 7 days in which no effective amount of the R7, Rs, and Ro are, independently, H or F. compound is delivered to the subject can involve delivery of 0092. In yet another embodiment, when performing the a second phase of daily dosage units of 1 to 7 days of a methods, the compound is selected from among 4'-(E)- pharmaceutically acceptable placebo. Alternatively, during (hydroxyimino)methyl-1,1'-biphenyl-3-carbonitrile; 5-4- this “placebo period, no placebo is administered. (E)-N-hydroxyethanimidoylphenyl-1-methyl-1H-pyr 0097. In another embodiment, the method includes deliv role-2-carbonitrile; 5-4-(Z)-(hydroxyimino)methyl ering a compound described herein for 21 consecutive days phenyl-1-methyl-1H-pyrrole-2-carbonitrile; 4'-(E)- followed by 7 days in which no effective amount of the (hydroxyimino)methyl-1,1'-biphenyl-4-carbonitrile; 4'- compound is delivered. Optionally, during these 7 days, a (E)-(hydroxyimino)methyl-3-methyl-1,1'-biphenyl-3- second phase of 7 daily dosage units of an orally and carbonitrile; 4'-(E)-(hydroxyimino)methyl-3-methyl-1,1'- pharmaceutically acceptable placebo can be delivered. The biphenyl-4-carbonitrile; 5-4-(E)-(hydroxyimino)methyl compound may optionally be administered in combination 3-methylphenyl-1-methyl-1H-pyrrole-2-carbonitrile; 5-4- with a progestin, antiprogestin, estrogen, or combination (1E)-N-hydroxypropanimidoylphenyl-1-methyl-1H thereof. pyrrole-2-carbonitrile; 5-4-(1E)-N-hydroxy-2.2- 0098. In a further embodiment, the method includes dimethylpropanimidoylphenyl-1-methyl-1H-pyrrole-2- delivering a compound described herein for 23 consecutive carbonitrile; and 5-4-(1E)-N-methoxy-2.2- days followed by 5 days in which no effective amount of the dimethylpropanimidoylphenyl-1-methyl-1H-pyrrole-2- compound is delivered. Optionally, during these 5 days, a carbonitrile. second phase of 5 daily dosage units of an orally and 0093. The effective dosage of the compounds described pharmaceutically acceptable placebo can be delivered. The herein may vary depending on the particular compound compound may optionally be administered in combination employed, the mode of administration and the severity of the with a progestin, antiprogestin, estrogen, or combination condition being treated. However, in general, satisfactory thereof. results are obtained when the compounds are administered at 0099. In yet another embodiment, the method includes a daily dosage of about 0.5 to about 500 mg/kg of animal delivering a compound described herein for 25 consecutive US 2007/0066637 A1 Mar. 22, 2007

days followed by 3 days in which no effective amount of the C. to C alkynyl, C. to Cs cycloalkyl, aryl, Substituted aryl, compound is delivered. Optionally, during these 3 days, a heteroaryl, and substituted heteroaryl; provided both of R second phase of 3 daily dosage units of an orally and and R2 are not H; or R and R2 are fused to form (a), (b), or pharmaceutically acceptable placebo can be delivered. The (c): (a) a carbon-based 3 to 6 membered Saturated spirocy compound described herein may optionally be administered clic ring; (b) a carbon-based 3 to 6 membered spirocyclic in combination with a progestin, antiprogestin, estrogen, or ring having in its backbone one or more carbon-carbon combination thereof. double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms 0100. In still a further embodiment, the method includes selected from among O, S, SO, SO, and NR; whereinrings delivering a compound described herein for 27 consecutive (a)-(c) are optionally substituted by 1 to 3 substituents days followed by 1 day in which no effective amount of the selected from among F, Cl, and C to C alkyl; R is a 5 or compound is delivered. Optionally, a second phase of 1 daily 6 membered heteroayl ring containing in its backbone 1 to dosage unit of an orally and pharmaceutically acceptable 3 heteroatoms selected from among O, S, SO, SO, and NR placebo can be delivered. The compound may optionally be and substituted with 0 to 3 substituents selected from among administered in combination with a progestin, antiprogestin, H, halogen, CN, NO, OH, amino, C to C alkyl, C to C. estrogen, or combination thereof. alkoxy, C to C, alkylamino, C=NOR, CORP, and NR 0101. In another embodiment, a method of contraception CORP: R is absent, H, C, to C alkyl, substituted C to Ca includes administering to a female of child bearing age for is alkyl, CN, or CORD, RD is H. C. to C alkyl, C to C, 28 consecutive days: (a) a first phase of from 14 to 24 daily alkoxy, or C to C alkylamino; R is H. halogen, CN, OH, dosage units of a progestational agent equal in progesta NO, alkoxy, or lower alkyl; Rs is H or lower alkyl; R. R7, tional activity to about 35 to about 100 uglevonorgestrel; (b) Rs, and Ro are, independently, H. F. or C to C lower alkyl; a second phase of from 1 to 11 daily dosage units, at a daily n is 0 or 1; or (ii) a compound of formula II: dosage of from about 2 to 50 mg. of a compound of formula I, formula II, or combination thereof, and (c) optionally, a third phase of daily dosage units of an orally and pharma II ceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28. 0102) In yet a further embodiment, a method of contra ception includes administering to a female of child bearing age for 28 consecutive days: (a) a first phase of from 14 to 24 daily dosage units of a compound of formula I, formula wherein, R is aryl, substituted aryl, or a 5 or 6 membered II, or combination thereof; (b) a second phase of from 1 to heteroayl ring containing in its backbone 1 to 3 heteroatoms 11 daily dosage units of an antiprogestin; and (c) optionally, selected from among O, S, SO, SO, and NR and substituted a third phase of daily dosage units of an orally and phar with 0 to 3 substituents selected from among H, halogen, maceutically acceptable placebo for the remaining days of CN, NO, OH, amino, C to C alkyl, C to C alkoxy, C to the 28 consecutive days in which no antiprogestin, progestin C, alkylamino, C=NOR, CORP, and NRCORP; R is H, or estrogen is administered; wherein the total daily dosage halogen, CN, OH, NO, or alkoxy; Rs is H or lower alkyl: units of the first, second and third phases equals 28. Ro and Rare, independently, H. F. or C to Clower alkyl; 0103) In yet a further embodiment, a method of contra and (c) optionally, a third phase of daily dosage units of an ception is provided which includes administering to a female orally and pharmaceutically acceptable placebo for the of childbearing age for 28 consecutive days: (a) a first phase remaining days of the 28 consecutive days in which no of from 14 to 24 daily dosage units of a progestational agent antiprogestin, progestin or estrogen is administered; wherein equal in progestational activity to about 35 to about 100 ug the total daily dosage units of the first, second and third levonorgestrel; (b) a second phase of from 1 to 11 daily phases equals 28. dosage units, at a daily dosage of from about 2 to 50 mg. of 0104. Also included are kits or packages of pharmaceu a compound of (i) or (ii): (i) a compound of formula I: tical formulations designed for use in the regimens described herein. Suitably, the kits contain one or more PR antagonist compounds as described herein. 0105 Advantageously, for use in the kits, the compound is formulated for the desired delivery vehicle and route. For example, the compound can be formulated for oral delivery, parenteral delivery, vaginal ring, transdermal delivery, or mucosal delivery, as discussed in detail above. The kit is preferably a pack (e.g. a blister pack) containing daily doses arranged in the order in which they are to be taken. 0106. In each of the regimens and kits described herein, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each wherein R and Rare, independently, selected from among particular phase in which it is administered. It is also H, halogen, C to C alkyl, CF, CFCF, C to Calkenyl, understood that the daily dose units described are to be US 2007/0066637 A1 Mar. 22, 2007

administered in the order described, with the first phase followed in order by the optional phases, including any second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle. It is further preferred that each package or kit contain a pharmaceuti cally acceptable package having indicators for each day of the 28-day cycle. Such as a labeled blister package, dial dispenser, or other packages known in the art. 0107 These dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as wherein, R and Rare, independently, selected from among indicated by the exigencies of the therapeutic situation. In H. halogen, C to C alkyl, CF, CFCF, C2 to Calkenyl, the descriptions herein, reference to a daily dosage unit may C. to C alkynyl, C. to Cs cycloalkyl, aryl, Substituted aryl, also include divided units which are administered over the heteroaryl, and substituted heteroaryl; provided both of R course of each day of the cycle contemplated. and R2 are not H; or R and R2 are fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered Saturated spirocy 0108. In one embodiment, the kit is designed for daily clic ring; (b) a carbon-based 3 to 6 membered spirocyclic oral administration over a 28-day cycle, desirably for one ring having in its backbone one or more carbon-carbon oral administration per day, and organized so as to indicate double bonds; or (c) a carbon-based 3 to 6 membered a single oral formulation or combination of oral formula spirocyclic ring having in its backbone 1 to 3 heteroatoms tions to be taken on each day of the 28-day cycle. Desirably selected among O, is S, SO, SO, and NR; wherein rings each kit will include oral tablets to be taken on each the days (a)-(c) are optionally substituted by 1 to 3 substituents specified; desirably one oral tablet will contain each of the selected from among F, Cl, and C to C alkyl; R is a 5 or combined daily dosages indicated. For example, a kit can 6 membered heteroayl ring containing in its backbone 1 to contain 21 to 27 daily dosage units of an effective amount of the compound described herein and, optionally, 1 to 7 daily 3 heteroatoms selected from among O, S, SO, SO, and NR dosage units of a placebo and other appropriate components and substituted with 0 to 3 substituents selected from among H, halogen, CN, NO, OH, amino, C to C alkyl, C to C. including, e.g., instructions for use. alkoxy, C to C alkylamino, C=NOR, CORP, and NR 0109. In another embodiment, the kit is designed for CORP: R is absent, H. C. to C alkyl, substituted C to C. weekly or monthly administration via a vaginal ring over a alkyl, CN, or CORP. RP is H, C, to Calkyl, C, to Calkoxy, 28-day cycle. Suitably, Such a kit contains individual pack or C to C alkylamino; R is H, halogen, CN, OH, NO, aging for each of the vaginal rings, i.e. one to three, required alkoxy, or lower alkyl; Rs is H or lower alkyl, Re, R7, Rs. for a monthly cycle and other appropriate components, and Ro are, independently, H. F. or C to C lower alkyl; in including, e.g., instructions for use. is 0 or 1; or (ii) a compound of formula II: 0110. In a further embodiment, the kit is designed for weekly or monthly administration via a transdermal patch over a 28-day cycle. Suitably, such a kit contains individual II packaging for each of the patches, i.e. one to three, required for a monthly cycle and other appropriate components including, e.g., instructions for use. 0111. In still another embodiment, the kit is designed for parenteral delivery of a compound described herein. Such a kit is typically designed for delivery at home and may include needles, Syringes, and other appropriate packaging and instructions for use. wherein, R is aryl, substituted aryl, or a 5 or 6 membered 0112 In yet another embodiment, the kit contains a heteroayl ring containing in its backbone 1 to 3 heteroatoms compound described herein in a gel or cream formulation. selected from among O, S, SO, SO, and NR and substituted Optionally, the kit can include appropriate packaging such as with 0 to 3 substituents selected from among H, halogen, a tube or other container, an applicator, and/or instructions CN, NO, OH, amino, C to C, alkyl, C to C, alkoxy, C to for use. C, alkylamino, C=NOR, CORP, and NRCORP: R is H, halogen, CN, OH, NO, or alkoxy; Rs is H or lower alkyl: 0113. In a further embodiment, the kit includes (a) a first Ro and Rare, independently, H., F, or C to C. lower alkyl: phase of from 14 to 21 daily dosage units of a progestational and (c) a third phase of daily dosage units of an orally and agent equal in progestational activity to about 35 to about pharmaceutically acceptable placebo; wherein the total 150 lug levonorgestrel; (b) a second phase of from 1 to 11 number of the daily dosage units in the first phase, second daily dosage units of a compound of formula I or II, each phase and third phase equals 28. daily dosage unit containing said compound at a daily dosage of from about 2 to 50 mg, wherein said compound is 0114. The following examples are illustrative only and (i) or (ii): (i) a compound of formula I: are not intended to be a limitation. US 2007/0066637 A1 Mar. 22, 2007 12

EXAMPLES Example 3 Example 1 5-(1E)-1-(hydroxyimino)-3-methyl-2,3-dihydro-1H inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile 4'-(E)-(hydroxyimino)methyl-1,1'-biphenyl-3-car 0118. To a mixture of sodium chloride (1.23 g, 21.0 bonitrile mmol) and aluminum chloride (5.0 g, 38.2 mmol) at 130° C. 0115) To a stirred solution of 4-bromobenzaldehyde (3.0 was added 1-(4-bromophenyl)-4-chlorobutan-1-one (1.0 g, g, 16.2 mmol) in ethanol (100 mL) and water (25 mL) was 3.82 mmol) and the resulting mixture was heated to 180° C. added sodium acetate (1.7g, 21.0 mmol) and hydroxylamine for 20 minutes. The mixture was allowed to cool to room hydrochloride (1.4g, 19.5 mmol). The resulting mixture was temperature and quenched by portionwise addition to a cold heated to reflux for 2 hours. The solution was allowed to 1N HCl solution (150 mL). The mixture was extracted cool to room temperature, concentrated, and filtered to give several times with dichloromethane. The combined organic 4-bromobenzaldehyde oxime (3.02 g, 93%). 4-Bromoben layers were separated, dried over magnesium Sulfate, fil Zaldehyde oxime (0.25 g, 1.25 mmol) was added to a stirred tered, and concentrated to give 5-bromo-3-methyl-indan-1- solution of 3-cyanophenylboronic acid (0.28 g, 1.87 mmol) one (0.77 g., 89%). in glyme (13 mL). Sodium carbonate (0.39 g, 3.75 mmol) in 0119) 1-Methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-in water (2 mL) and tetrakis(triphenylphosphine)palladium (O) den-5-yl)-1H-pyrrole-2-carbonitrile as an orange solid (0.65 (0.07 g., 0.06 mmol) was added and the resulting solution g, 76%) was prepared from 5-bromo-3-methyl-indan-1-one was heated to reflux for 3 hours. The solution was cooled to and 1-methyl-2-cyanopyrrole according to the same cou room temperature and partitioned between a saturated pling procedure as described in example 2. MS (ES) m/z. ammonium chloride solution (100 mL) and ethyl acetate 251.2: Anal. Calcd for CHNO: C, 76.78; H, 5.64; N, (150 mL). The organic layer was separated, dried over 11.19. Found: C, 76.49; H, 5.49; N, 11.10. HRMS: calcd for magnesium sulfate, filtered, and concentrated. The residue CHNO+H", 251.1179; found (ESI, M+H"), 251.1179. was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4'-(E)-(hydroxy 0.120. The title compound was prepared from 1-methyl imino)methyl-1,1'-biphenyl-3-carbonitrile as a white solid 5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole (0.17 g. 61%). MS m/z 223; HRMS: calcd for CHNO+ 2-carbonitrile and hydroxylamine hydrochloride according H', 223.08659; found (ESI, M+H"), 223.087; Anal. Calcd to the procedure described in example 1. MS m/z. 266; for CHNO: C, 75.66; H, 4.54: N, 12.60. Found: C, HRMS: calcd for CHNO+H", 266.12879; found (ESI, 75.49; H, 4.98: N, 12.51. M+H"), 266.1299; Anal. Calcd for CHNO: C, 72.43: H, 5.70: N, 15.84. Found: C, 71.86; H, 6.31; N, 15.47. Example 2 Example 4 5-4-(1E)-N-hydroxyethanimidoylphenyl-1-me thyl-1H-pyrrole-2-carbonitrile 5-(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro 1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile 0116. To a stirred solution of 1-methyl-2-cyanopyrrole (1.6 g. 15 mmol) and triisopropylborate (7.0 mL, 30 mmol) 0121 To a stirred solution of 1-(4-hydroxyphenyl)-3- in THF (45 mL) at 0°C. was added lithiumdiisopropylamide methylbut-2-en-1-one (1.0 g, 5.67 mmol) in dichloroben (LDA 2.0 M in heptane/THF/ethylbenzene, 13.3 mL, 26.6 Zene (50 mL) was added aluminum chloride (1.97g, 14.74 mmol) in a dropwise fashion over 45 minutes. The resulting mmol). The mixture was heated to 150°C. for 4 hours. After solution was stirred at 0°C. for 1 hour. To the solution was cooled to room temperature, the reaction mixture was added 1-(4-bromophenyl)-ethanone (1.0 g, 5 mmol) dis poured over ice and extracted with dichloromethane (3x80 solved in glyme (45 mL), sodium carbonate (1.59 g, 15 mL). The organic layers were combined, dried over mag mmol) dissolved in water (9 mL), and tetrakis(triph nesium Sulfate, filtered, and concentrated. The residue was enylphosphine) palladium (O) (0.28 g., 0.25 mmol). The purified on a silica gel column (20% ethyl acetate in hexane) resulting solution was heated to reflux for 1.5 hours. The to give 5-hydroxy-3.3-dimethylindan-1-one as a tan Solid Solution was cooled to room temperature and partitioned (0.32 g, 32%). MS m/z 177. between a saturated ammonium chloride solution (50 mL) 0122) A solution of 5-hydroxy-3,3-dimethylindan-1-one and ethyl acetate (80 mL). The organic layer was separated, in anhydrous pyridine at 0° C. was treated with triflic dried over magnesium Sulfate, filtered, and concentrated. anhydride under an atmosphere of nitrogen. After comple The residue was purified on a silica gel column (20% ethyl tion of reaction indicated by thin layer chromatography, the acetate in hexane) and triturated with ether to give 5-(4- reaction Solution was poured onto a mixture of ice and 6N acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a yel aqueous HCl solution and extracted with diethyl ether. The low solid (0.62g, 55%). MS (ES) m/z 225.1; HRMS: calcd organic layers were combined, washed with Saturated aque for CHNO+H", 225.1022; found (ESI, M+H"), ous sodium bicarbonate solution, dried (MgSO4), and con 225.1039. centrated to afford trifluoro-methanesulfonic acid 3,3-dim 0117 The title compound was prepared from 5-(4- ethyl-1-oxo-indan-5-yl ester that was used in the next step acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile and without further purification. hydroxylamine hydrochloride Salt according to the proce 0123 5-(3.3-Dimethyl-1-oxo-2,3-dihydro-1H-inden-5- dure described in example 1. MS (ESI) m/z 240; HRMS: yl)-1-methyl-1H-pyrrole-2-carbonitrile was prepared from calcd for CHNO+H+, 240.11314; found (ESI, M+H" trifluoro-methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5- ), 240.1126. yl ester and 1-methyl-2-cyanopyrrole according to the same US 2007/0066637 A1 Mar. 22, 2007 coupling procedure as described in example 2. MS (ES) m/z. according to the procedure described in examples 1 and 2. 265.1. HRMS: calcd for CHNO+H", 265.13354; found MS m/z 226; HRMS: calcd for CHNO+H", 226.09749; (ESI, M+H"), 265.1332. found (ESI, M+H"), 226.0972; Anal. Calcd for 0.124. To a stirred mixture of 5-(3,3-dimethyl-1-oxo-2,3- CHNO: C, 69.32; H, 4.92: N, 18.65. Found: C, 69.20; dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile H, 5.44; N, 18.70. (0.07 g., 0.26 mmol) in ethanol (1.6 mL)/water (0.4 mL) was Example 9 added sodium acetate (0.03 g, 0.34 mmol) and hydroxy lamine hydrochloride (0.02 g, 0.32 mmol). The resulting 4'-(E)-(hydroxyimino)methyl-1,1'-biphenyl-4-car mixture was heated to reflux for 5 hours. The solution was bonitrile allowed to cool to room temperature, diluted with water, and filtered to give 5-(1E)-1-(hydroxyimino)-3.3-dimethyl-2,3- 0129. The title compound was prepared from 4-bro dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile mobenzaldehyde and 4-cyanophenylboronic acid according as a white solid (0.04g, 55%). MS (ES) m/z 280.1. HRMS: to the procedure described in example 1. MS m/Z 223: calcd for CHNO+H", 280.14444; found (ESI, M+H"), HRMS: calcd for CHNO+H", 223.08.659; found (ESI, 28O145. M+H"), 223.0866; Anal. Calcd for CHNO: C, 75.66: H, 4.54: N, 12.60. Found: C, 75.48; H, 4.56: N, 12.37. Example 5 Example 10 5-(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5- yl)-1-methyl-1H-pyrrole-2-carbonitrile 4'-(E)-(hydroxyimino)methyl-3-methyl-1,1'-biphe 0125 The title compound was prepared from 1-methyl nyl-3-carbonitrile 5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbo 0.130. The title compound was prepared from 4-bromo nitrile and hydroxylamine hydrochloride according to the 2-methylbenzaldehyde and 3-cyanophenyl boronic acid procedure described in example 1. MS (ESI) m/z 252: according to the procedure described in example 1. MS (ES) HRMS: calcd for CHNO+H", 252.11314; found (ESI, m/Z 237.1; HRMS: calcd for CHNO+H", 237.10224; M+H"), 252.1133 found (ESI, M+H"), 237.1018. Example 6 Example 11 3-(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5- 4'-(E)-(hydroxyimino)methyl-3-methyl-1,1'-biphe ylbenzonitrile nyl-4-carbonitrile 0126 To a stirred solution of 5-bromoindan-1-one oxime 0131 The title compound was prepared from 4-bromo (0.25 g, 1.10 mmol) in glyme (11 mL) was added 3-cy 2-methylbenzaldehyde and 4-cyanophenyl boronic acid anophenyl boronic acid (0.21 g, 1.44 mmol), Sodium car according to the procedure described in example 1. MS (ES) bonate (0.35 g, 3.30 mmol) dissolved in deionized (D.I.) m/Z 237.2; HRMS: calcd for CHNO+H", 237.10224; water (2 mL), and tetrakis(triphenylphosphine) palladium found (ESI, M+H"), 237.1028. (0) (0.06 g., 0.05 mmol). The resulting solution was heated to reflux for 2 hours. The solution was cooled to room Example 12 temperature and partitioned between ammonium chloride Solution (sat.) and ethyl acetate. The organic layer was dried 5-4-(E)-(hydroxyimino)methyl-3-methylphe over magnesium sulfate, filtered, and concentrated. The nyl)} -1-methyl-1H-pyrrole-2-carbonitrile residue was purified on a silica gel column (20% ethyl acetate/hexane) and triturated with ether to give 3-(1E)-1- 0.132. The title compound was prepared from 4-bromo (hydroxyimino)-2,3-dihydro-1H-inden-5-ylbenzonitrile as 2-methylbenzaldehyde and 1-methyl-1H-pyrrole-2-carboni a white solid (0.12 g, 43%). MS (ESI) m/z. 249; HRMS: trile according to the procedure described in examples 1 and calcd for CHNO+H", 249.10224; found (ESI, M+H"), 2. MS (ES) m/z 240.1; HRMS: calcd for CHNO+H", 249.1033. 240.11314; found (ESI, M+H"), 240.1134. Example 7 Example 13 4-(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5- 5-4-(1E)-N-hydroxypropanimidoylphenyl)-1- ylbenzonitrile methyl-1H-pyrrole-2-carbonitrile 0127. The title compound was prepared from 5-bromoin 0.133 The title compound was prepared from 1-(4-bro dan-1-one oxime and 4-cyanophenylboronic acid according mophenyl)-propan-1-one and 1-methyl-2-cyanopyrrole to the procedure described in example 6. MS (ESI) m/z, 249; according to the procedure as described in examples 1 and HRMS: calcd for CHNO+H", 249.10224; found (ESI, 2. MS (ESI) m/z 254; HRMS: calcd for CHNO+H", M+H"), 249. 1021. 254.12879; found (ESI, M+H"), 254.1295. Example 8 Example 14 5-4-(Z)-(hydroxyimino)methylphenyl-1-methyl (1E)-6-(3-chlorophenyl)-3,4-dihydronaphthalen 1H-pyrrole-2-carbonitrile 1(2H)-one oxime 0128. The title compound was prepared from 4-bro 0.134. The title compound was prepared from trifluoro mobenzaldehyde and 1-methyl-1H-pyrrole-2-carbonitrile methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen US 2007/0066637 A1 Mar. 22, 2007

2-yl ester and 3-chlorophenylboronic acid according to the Example 21 procedure as described in example 1. MS (ES) m/z 272.1; HRMS: calcd for CHCINO+H, 272.08367: found (ESI, (1E)-6-(3,4-difluorophenyl)-3,4-dihydronaphthalen M+H"), 272.0845. 1(2H)-one oxime 0.141. The title compound was prepared from trifluoro Example 15 methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen 2-yl ester and 3,4-difluorophenylboronic acid according to 5-(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaph the procedure as described in example 1. MS m/z 274. thalen-2-yl)-1-methyl-1H-pyrrole-2-carbonitrile Example 22 0135 The title compound was prepared from trifluoro methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen (1E)-6-(3-methylphenyl)-3,4-dihydronaphthalen 2-yl ester and 1-methyl-1H-pyrrole-2-carbonitrile according 1(2H)-one oxime to the procedure as described in examples 1 and 2. MS m/z. 0142. The title compound was prepared from trifluoro 266; HRMS: calcd for CHNO+H", 266.12879; found methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen (ESI, M+H"), 266.1284. 2-yl ester and 3-methylphenylboronic acid according to the procedure as described in example 1. MS (ESI) m/z 252. Example 16 Example 23 3-(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaph (1E)-6-(3-methoxyphenyl)-3,4-dihydronaphthalen thalen-2-ylbenzonitrile 1(2H)-one oxime 0136. The title compound was prepared from trifluoro 0.143. The title compound was prepared from trifluoro methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen 2-yl ester and 3-cyanophenylboronic acid according to the 2-yl ester and 3-methoxyphenyl boronic acid according to procedure as described in example 1. MS (ESI) m/z. 263. the procedure as described in example 1. MS (ES) m/z. 2681. Example 17 Example 24 (1E)-6-(3-chloro-4-fluorophenyl)-3,4-dihydronaph 5-4-(1E)-N-hydroxy-2,2-dimethylpropanimidoyl) thalen-1 (2H)-one oxime phenyl-1-methyl-1H-pyrrole-2-carbonitrile 0137 The title compound was prepared from trifluoro 0144. The title compound was prepared from 1-(4-bro methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen mophenyl)-2,2-dimethylpropan-1-one and 1-methyl-2-cy 2-yl ester and 3-chloro-4-fluorophenylboronic acid accord anopyrrole according to the procedure as described in ing to the procedure as described in example 1. MS m/z. 290. examples 1 and 2. MS m/z 282; HRMS: calcd for CHNO+H", 282.16009; found (ESI, M+H"), Example 18 282.1606. (1E)-6-(4-chlorophenyl)-3,4-dihydronaphthalen Example 25 1(2H)-one oxime 5-4-(1E)-N-methoxy-2,2-dimethylpropanimidoyl) phenyl-1-methyl-1H-pyrrole-2-carbonitrile 0138. The title compound was prepared from trifluoro methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen 0145 To a stirred solution of 5-4-(1E)-N-hydroxy-2.2- 2-yl ester and 4-chlorophenylboronic acid according to the dimethylpropanimidoyl-phenyl-1-methyl-1H-pyrrole-2- procedure as described in example 1. MS m/z 272. carbonitrile (0.212 g, 0.75 mmol) in THF (7 mL) was added sodium hydride (0.03 g. 60% in mineral oil, 0.75 mmol) at Example 19 0° C. After the mixture was stirred for 10 minutes, methyl iodide (0.8 mL, 1.28 mmol) was added and the resulting (1E)-6-3-(trifluoromethyl)phenyl-3,4-dihydronaph mixture was stirred overnight at room temperature. The thalen-1 (2H)-one oxime reaction mixture was then quenched with a saturated ammo nium chloride solution (20 mL), and extracted several times 0.139. The title compound was prepared from trifluoro with ethyl acetate (3x20 mL). The combined organic layers methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen were dried over magnesium sulfate and concentrated. The 2-yl ester and 3-(trifluoromethyl)phenyl boronic acid residue was purified by a silica gel column (5% ethyl acetate according to the procedure as described in example 1. MS in hexane) to afford 5-4-(1E)-N-methoxy-2,2-dimethyl m/Z. 306. propanimidoylphenyl-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (0.023 g, 10%). MS (ES) m/z 296.0; HRMS: Example 20 calcd for C.HNO+H", 296.17574; found (ESI, M+H"), 296.1753. (1E)-6-(3-fluorophenyl)-3,4-dihydronaphthalen 1(2H)-one oxime Example 26 0140. The title compound was prepared from trifluoro (1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylin methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen dan-1-one oxime 2-yl ester and 3-fluorophenylboronic acid according to the 0146 The title compound was prepared from trifluoro procedure as described in example 1. MS m/z 256. methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester US 2007/0066637 A1 Mar. 22, 2007 and 3,5-dimethylisoxazol-4-ylboronic acid according to the and 3-cyanophenylboronic acid according to the procedure procedure as described in example 1. MS (ES) m/z 271.1; as described in example 1. MS (ESI) m/z 277; HRMS: calcd HRMS: calcd for CHNO+H", 271.14410; found (ESI, for C.HNO+H", 277.13354; found (ESI, M+H"), M+H"), 271. 1442. 277.134. Example 27 Example 33 3-fluoro-5-(1E)-1-(hydroxyimino)-3,3-dimethyl-2, (1E)-5-(4-chlorophenyl)-3,3-dimethylindan-1-one 3-dihydro-1H-inden-5-ylbenzonitrile Oxime 0147 The title compound was prepared from trifluoro 0153. The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 3-fluoro-5-cyanophenyl boronic acid according to the and 4-chlorophenylboronic acid according to the procedure procedure as described in example 1. MS (ESI) m/z. 295; as described in example 1. MS m/z 286; HRMS: calcd for HRMS: calcd for C.HFNO+H", 295.12412; found (ESI, CHCINO+H", 286,09932; found (ESI, M+H"), M+H"), 295.1241. 286.10O3. Example 28 Example 34 (1E)-5-(4-acetylphenyl)-3,3-dimethylindan-1-one (1E)-3.3-dimethyl-5-(4-methylphenyl)indan-1-one Oxime Oxime 0148. The title compound was prepared from trifluoro 0154) The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 4-acetylphenylboronic acid according to the procedure and 4-methylphenylboronic acid according to the procedure as described in example 1. MS (ESI) m/z 294; HRMS: calcd as described in example 1. MS m/z. 266; HRMS: calcd for for CHNO+H", 294.14885; found (ESI, M+H"), C.HNO+H", 266.15394: found (ESI, M+H"), 2941493. 266.1553. Example 29 Example 35 (1E)-5-(3-acetylphenyl)-3,3-dimethylindan-1-one (1E)-5-(4-methoxyphenyl)-3,3-dimethylindan-1-one Oxime Oxime 014.9 The title compound was prepared from trifluoro 0.155 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 3-acetylphenylboronic acid according to the procedure and 4-methoxyphenylboronic acid according to the proce as described in example 1. MS (ESI) m/z 294; HRMS: calcd dure as described in example 1. MS m/z 282; HRMS: calcd for CHNO+H", 294.14885; found (ESI, M+H"), for C.HNO+H", 282.14885; found (ESI, M+H"), 2.94.1503. 282.1506. Example 30 Example 36 (1E)-5-(2-acetylphenyl)-3,3-dimethylindan-1-one (1E)-5-(3-chlorophenyl)-3,3-dimethylindan-1-one Oxime Oxime 0150. The title compound was prepared from trifluoro 0156 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 2-acetylphenylboronic acid according to the procedure and 3-chlorophenylboronic acid according to the procedure as described in example 1. MS (ESI) m/z 294; HRMS: calcd as described in example 1. MS m/z 286; HRMS: calcd for for CHNO+H", 294.14885; found (ESI, M+H"), CHCINO+H", 286,09932; found (ESI, M+H"), 2941498. 286.O993. Example 31 Example 37 4-(1E)-1-(hydroxyimino)-3.3-dimethyl-2,3-dihydro (1E)-3.3-dimethyl-5-(3-methylphenyl)indan-1-one 1H-inden-5-ylbenzonitrile Oxime 0151. The title compound was prepared from trifluoro 0157 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 4-cyanophenylboronic acid according to the procedure and 3-methylphenylboronic acid according to the procedure as described in example 1. MS (ESI) m/z 277; HRMS: calcd as described in example 1. MS m/z. 266; HRMS: calcd for for C.HNO+H", 277.13354; found (ESI, M+H"), C.HNO+H", 266.15394: found (ESI, M+H"), 277.1335. 266.1552. Example 32 Example 38 3-(1E)-1-(hydroxyimino)-3.3-dimethyl-2,3-dihydro (1E)-5-(3-methoxyphenyl)-3,3-dimethylindan-1-one 1H-inden-5-ylbenzonitrile Oxime 0152 The title compound was prepared from trifluoro 0158. The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester US 2007/0066637 A1 Mar. 22, 2007 and 3-methoxyphenylboronic acid according to the proce and 2,4-dichlorophenyl boronic acid according to the pro dure as described in example 1. MS m/z 282; HRMS: calcd cedure as described in example 1. MS (ES) m/z 320.0; for C.HNO+H", 282.14885; found (ESI, M+H"), HRMS: calcd for CHC1NO+H", 320,06034; found 282.15. (ESI, M+H), 320,0602. Example 39 Example 45 (1E)-5-(3,5-dichlorophenyl)-3,3-dimethylindan-1- (1E)-3.3-dimethyl-5-phenylindan-1-one oxime one oxime 0.165. The title compound was prepared from trifluoro 0159. The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and phenyl boronic acid according to the procedure as and 3.5-dichlorophenyl boronic acid according to the pro described in example 1. MS (ES) m/z 252.0; HRMS: calcd cedure as described in example 1. MS m/z 320; HRMS: for CH-NO+H", 252.13829; found (ESI, M+H"), calcd for CHC1NO+H", 320,06034; found (ESI, 252.1397. M+H), 320.0605. Example 46 Example 40 (1E)-5-(3-chloro-4-fluorophenyl)-3,3-dimethylin (1E)-5-(2-chlorophenyl)-3,3-dimethylindan-1-one dan-1-one oxime Oxime 0166 The title compound was prepared from trifluoro 0160 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 3-chloro-4-fluorophenyl boronic acid according to the and 2-chlorophenylboronic acid according to the procedure procedure as described in example 1. MS (ES) m/z. 304.0; as described in example 1. MS m/z 286; HRMS: calcd for CHCINO+H", 286.09932; found (ESI, M+H"), HRMS: calcd for CHCIFNO+H", 304.08990; found 286.O993. (ESI, M+H), 304.0901. Example 41 Example 47 (1E)-3.3-dimethyl-5-3-(trifluoromethyl)phenyl (1E)-5-(3,4-dichlorophenyl)-3,3-dimethylindan-1- indan-1-one oxime one oxime 0161 The title compound was prepared from trifluoro 0.167 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 3,4-dichlorophenyl boronic acid according to the pro and 3-(trifluoromethyl)phenylboronic acid according to the cedure as described in example 1. MS m/z 320; HRMS: procedure as described in example 1. MS (ES) m/z, 320.0; calcd for CHC1NO+H", 320,06034; found (ESI, HRMS: calcd for CHFNO+H",320.12567; found (ESI, M+H), 320.0597. M+H), 320.1261. Example 42 Example 48 (1E)-5-(2,3-dichlorophenyl)-3,3-dimethylindan-1- (1E)-3.3-dimethyl-5-4-(trifluoromethyl)phenyl one oxime indan-1-one oxime 0162 The title compound was prepared from trifluoro 0.168. The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 2,3-dichlorophenyl boronic acid according to the pro and 4-(trifluoromethyl)phenylboronic acid according to the cedure as described in example 1. MS m/z 320; HRMS: procedure as described in example 1. MS (ES) m/z, 320.0; calcd for CHC1NO+H", 320,06034; found (ESI, HRMS: calcd for CHFNO+H",320.12567; found (ESI, M+H), 320.0605. M+H), 320.1262. Example 43 Example 49 (1E)-5-(2,5-dichlorophenyl)-3,3-dimethylindan-1- (1E)-5-4-(dimethylamino)phenyl)-3,3-dimethylin one oxime dan-1-one oxime 0163 The title compound was prepared from trifluoro 0169. The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 2,5-dichlorophenyl boronic acid according to the pro and 4-(dimethylamino)phenylboronic acid according to the cedure as described in example 1. MS (ES) m/z. 319.9; procedure as described in example 1. MS (ES) m/z. 295.0: HRMS: calcd for CHCINO+H", 320,06034; found HRMS: calcd for CHNO+H", 295. 18049; found (ESI, (ESI, M+H), 320.0615. M+H"), 295,1815. Example 44 Example 50 (1E)-5-(2,4-dichlorophenyl)-3,3-dimethylindan-1- (1E)-5-3-(dimethylamino)phenyl)-3,3-dimethylin one oxime dan-1-one oxime 0164. The title compound was prepared from trifluoro 0170 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester US 2007/0066637 A1 Mar. 22, 2007 17 and 4-(dimethylamino)phenylboronic acid according to the procedure as described in example 1. MS (ES) m/z. 295.1; TABLE 1-continued HRMS: calcd for CHNO+H", 295. 18049; found (ESI, Potency of representative 5-aryl-indan-1-one oximes and M+H"), 295,182. analogs as PR modulators in progesterone induced T47D alkaline phosphatase assay. Example 51

(1E)-5-(3,4-difluorophenyl)-3,3-dimethylindan-1- NC one oxime y 0171 The title compound was prepared from trifluoro methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 3,4-difluorophenyl boronic acid according to the pro N YOH cedure as described in example 1. MS (ES) m/z 288.0: Example 15 HRMS: calcd for CHf FNO+H", 288.11945; found (ESI, M+H"), 288.1203. 21 RH R2 R Example 52 N (1E)-5-3-(ethylsulfonyl)phenyl-3,3-dimethylindan 1-one oxime N YOH 0172 The title compound was prepared from trifluoro Example 6, 7, 33–42 methanesulfonic acid 3.3-dimethyl-1-oxo-indan-5-yl ester and 3-(ethylsulfonyl)phenyl boronic acid according to the Example Alk. Phos. Alk. Phos. procedure as described in example 1. MS (ES) m/z 344.0; No. R R2 R ICso (nM) % inh (a) 3 M 3 Me H 65.0 HRMS: calcd for CH, NOS+H",344.13149; found (ESI, 6 H H 3-CN -3OOO M+H), 344. 1317. 7 H H 4-CN -1000 15 H H 32.6 33 Me Me 4-CI 1OO Example 53 34 Me Me 4-Me 68 35 Me Me 4-OMe 63 36 Me Me 3-CI 70 Pharmacology 37 Me Me 3-Me 65 38 Me Me 3-OMe 65 0173 The compounds of this invention were tested in the 39 Me Me 3-Cl, 5-Cl 30 relevant assay as described below and their potency are in 40 Me Me 2-CI 62 41 Me Me 3-Cl, 4-Cl 455.6 the range of 0.01 nM to 5 OM in the in vitro assays and 0.001 42 Me Me 2-C1, 3-Cl 1OO to 300 mg/kg in the in vivo assays. "Percent inhibition of the progesterone (1 nM) induced alkaline phos 0174 Table 1. Potency of representative 5-aryl-indan-1- phatase activity using 3 M of the test compound is measured. one oXimes and analogs as PR modulators in progesterone 0175 Percent inhibition of the progesterone (1 nM) induced T47D alkaline phosphatase assay. induced alkaline phosphatase activity using 3 uM of the test compound is measured. TABLE 1. (1) T47D Cell Proliferation Assay Potency of representative 5-aryl-indan-1-one oximes and 0176 (a) Objective: Determination of progestational and analogs as PR modulators in progesterone induced antiprogestational potency by using a cell proliferation assay T47D alkaline phosphatase assay. in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured. 0177) (b) Methods: NC 0.178 A. Reagents / 0179 (i) Growth medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat-inactivated), 100U/mL penicillin, 100 mg/mL OH streptomycin, and 2 mM GlutaMaxTM media (GIBCO, Example 3 BRL). 0180 (ii) Treatment medium: Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol US 2007/0066637 A1 Mar. 22, 2007 18

red-free supplemented with 0.5% charcoal stripped fetal bovine serum, 100U/mL penicillin, 200 mg/mL TABLE 2 streptomycin, and 2 mM GlutaMaxTM media (GIBCO, Estimated ECso, standard error (SE), and 95% confidence BRL). intervals (CI) for individual studies

0181 B. Cell Culture ECso 95% CI 0182 Stock T47 D cells are maintained in growth medium. For BrdU incorporation assay, cells are plated Compound Exp (nM) SE lower upper Trimegestone 1 O.O17 O.OO3 O.007 O.040 in 96-well plates (Falcon, Becton Dickinson Labware) 2 O.O14 O.OO1 O.O11 O.O17 at 10,000 cells/well in growth medium. After overnight 3 O.O19 O.OO1 O.O16 O.O24 incubation, the medium is changed to treatment MPA 1 O.O19 O.OO1 O.O13 O.O27 medium and cells are cultured for an additional 24 2 O.O17 O.OO1 O.O11 O.O24 hours before treatment. Stock compounds are dissolved in appropriate vehicle (100% ethanol or 50% ethanol/ 0189) 50% DMSO), subsequently diluted in treatment medium and added to the cells. Progestin and anti TABLE 3 progestin reference compounds are run in full dose response curves. The final concentration of vehicle is Estimated ICso standard error, and 95% confident interval for the 0.1%. In control wells, cells receive vehicle only. antiprogestin, RU486 Antiprogestins are tested in the presence of 0.03 nM ECso 95% CI trimegestone, the reference progestin agonist. Twenty Compound Exp (nM) SE lower upper four hours after treatment, the medium is discarded and RU486 1 O.O11 O.OO1 O.OO8 O.O14 cells are labeled with 10 mM BrdU (Amersham Life 2 O.O16 O.OO1 O.O14 O.O20 Science, Arlington Heights, Ill.) in treatment medium 3 O.O18 O.OO1 O.O14 O.O22 for 4 hours. ECso: Concentration of a compound that gives half-maximal increase in BrdU incorporation with SE; 0183 C. Cell Proliferation Assay ICso: Concentration of a compound that gives half-maximal decrease in 0.184 At the end of BrdU labeling, the medium is 0.1 trimegestone induced BrdU incorporation with SE removed and BrdU incorporation is measured using a (2) Rat Decidualization Assay cell proliferation ELISA kit (HRPN 250, Amersham Life Science) according to manufacturers instructions. 0.190 (a) Objective: This procedure is used to evaluate Briefly, cells are fixed in an ethanol containing fixative the effect of progestins and antiprogestins on rat uterine for 30 minutes, followed by incubation in a blocking decidualization and compare the relative potencies of vari buffer for 30 minutes to reduce background. Peroxi ous test compounds. dase-labeled anti-BrdU antibody is added to the wells 0191 (b) Methods and incubated for 60 minutes. The cells are rinsed three times with PBS and incubated with 3,3'5,5'-tetrameth 0.192 A. Reagents ylbenzidine (TMB) substrate for 10-20 minutes 0193 Test compounds are dissolved in 100% ethanol depending upon the potency of tested compounds. and mixed with corn oil (vehicle). Stock solutions of Then 25 DL of 1 M sulfuric acid is added to each well the test compounds in oil (the MazolaTM oil) are then to stop color reaction and optical density is read in a prepared by heating (~80° C.) the mixture to evaporate plate reader at 450 nm within 5 minutes. ethanol. Test compounds are Subsequently diluted with 100% corn oil or 10% ethanol in corn oil prior to the 0185. D. Analysis of Results treatment of animals. No difference in decidual 0186 Square root-transformed data are used for analy response is found when these two vehicles are com sis of variance and nonlinear dose response curve pared. fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. 0194 B. Animals (RACUC Protocol #5002) ECso or ICso values are calculated from the retrans 0.195 Ovariectomized mature female Sprague-Dawley formed values. JMP software (SAS Institute, Inc.) is rats (-60-day old and 230 g) are obtained from Taconic used for both one-way analysis of variance and non (Taconic Farms, N.Y.) following surgery. Ovariectomy linear dose response analyses in both single dose and dose response studies. is performed at least 10 days prior to treatment to reduce circulating sex steroids. Animals are housed 0187 E. Reference Compounds under 12 hours light/dark cycle and given standard rat 0188 Trimegestone and medroxyprogesterone acetate chow and water ad libitum. (MPA) were reference progestins and RU486 is the refer 0196) C. Treatment ence antiprogestin. All reference compounds were run in full dose-response curves and the ECso or ICso values were 0.197 Rats are weighed9. and randomlyy assignedgn to calculated. groups of 4 or 5 before treatment. Test compounds in US 2007/0066637 A1 Mar. 22, 2007

0.2 mL vehicle are administered by subcutaneous injec 0206 tion in the nape of the neck or by gavage using 0.5 mL. The animals are treated once daily for seven days. For TABLE 5 testing antiprogestins, animals are given the test com Estimated average ECso standard error, and 95% confidence pounds and an ECso dose of progesterone (5.6 mg/kg) intervals for dose-response curves of 3 reference compounds during the first three days of treatment. Following decidual stimulation, animals continue to receive ECso 95% CI progesterone until necropsy four days later. Compound (mg/kg, s.c.) SE lower upper 0198 D. Dosing Progesterone S.62 O.62 4.SS 7.OO 3-Ketodesogestrel O.10 O.O2 O.O7 O.14 0199 Doses are prepared based upon mg/kg mean Levonorgestrel O.10 O.O1 O.08 O.12 group body weight. In all studies, a control group receiving vehicle is included. Determination of dose response curves is carried out using doses with half log 0207 increases (e.g. 0.1, 0.3, 1.0, 3.0 mg/kg). TABLE 6 0200 E. Decidual Induction Estimated ICso standard error, and 95% confident interval for the 0201 Approximately 24 hours after the third injection, antiprogestin, RU486 decidualization is induced in one of the uterine horns by Scratching the antimesometrial luminal epithelium ICso 95% CI with a blunt 21 G needle. The contralateral horn is not Compound Exp. (mg/kg, p.o.) SE lower upper Scratched and serves as an unstimulated control. RU486 1 O.21 O.O7 O.OS O.96 Approximately 24 hours following the final treatment, 2 O.14 O.O2 O.08 0.27 rats are sacrificed by CO asphyxiation and body weight measured. Uteri are removed and trimmed of Concentration: Compound concentration in assay (default-mg/kg body fat. Decidualized (D-horn) and control (C-horn) uterine weight) horns are weighed separately. 0208 Route of administration: Route the compound is 0202 F. Analysis of Results administered to the animals 0209 Body weight: Mean total animal body weight 0203 The increase in weight of the decidualized uter (default-kg) ine horn is calculated by D-horn/C-horn and logarith 0210 D-horn: Wet weight of decidualized uterine horn mic transformation is used to maximize normality and (default-mg) homogeneity of variance. The Huber M-estimator is used to down weight the outlying transformed obser 0211 C-horn: Wet weight of control uterine horn Vations for both dose-response curve fitting and one (default-mg) way analysis of variance. JMP software (SAS Institute, 0212 DecidualC1CU3 respSOS (D-C)/C)x100%X O Inc.) is used for both one-way ANOVA and non-linear 0213 Progestational activity: Compounds that induce dose-response analyses. decidualization significantly (p<0.05) compared to vehicle control are considered active 0204 G. Reference Compounds 0214) Antiprogestational activity: Compounds that 0205 All progestin reference compounds are run in full decrease ECso progesterone induced decidualization signifi dose-response curves and the ECso for uterine wet weight is cantly (p<0.05) calculated. 0215 ECso for uterine weight: Concentration of com pound that gives half-maximal increase in decidual response TABLE 4 (default-mg/kg) Estimated ECso standard error (SE), and 95% confidence intervals 0216) ICs for uterine weight: Concentration of com for individual studies pound that gives half-maximal decrease in ECso progester one induced decidual response (default-mg/kg) ECso 95% CI (3) PRE-Luciferase Assay in CV-1 Cells Compound Exp (nM) SE lower upper 0217 (a) Objective: To determine a compound's proges Progesterone 1 5.50 O.77 4.21 7.20 tational or antiprogestational potency based on its effect on 2 6.21 1.12 4.41 8.76 PRE-luciferase reporter activity in CV-1 cells co-transfected 3-Ketodesogestrel 1 O.11 O.O2 O.O7 O16 with human PR and PRE-luciferase plasmids. 2 O.10 O.OS O.11 O.25 3 O.O6 O.O3 O.O3 O.14 0218 (b) Methods Levonorgestrel 1 O.08 O.O3 O.04 O16 2 O.12 O.O2 O.09 O.17 0219 A. Reagents 3 O.09 O.O2 O.O6 O.13 0220 (i) Culture medium: 4 O.09 O.O2 O.O6 O.14 MPA 1 O.42 O.O3 O.29 O60 0221) Growth medium: DMEM (BioWhittaker) 2 O.39 O.OS O.22 O.67 containing 10% (v/v) fetal bovine serum (heat inac 3 O.39 O.04 O.25 O.61 tivated), 0.1 mM MEM non-essential amino acids, 100U/mL penicillin, 100 mg/mL streptomycin, and 2 mM the GlutaMaxTM reagent (GIBCO, BRL). US 2007/0066637 A1 Mar. 22, 2007 20

0222 Experimental medium: DMEM (BioWhit 0229) taker), phenol red-free, containing 10% (v/v) char coal-stripped fetal bovine serum (heat-inactivated), TABLE 8 0.1 mM MEM non-essential amino acids, 100U/mL penicillin, 100 mg/mL streptomycin, and 2 mM the Estimated ICso standard error (SE), and 95% confident interval (CI) GlutaMaxTM reagent (GIBCO, BRL). for the antiprogestin, RU486 from three individual studies ICso 95% CI 0223 B. Cell Culture, Transfection, Treatment, and Luciferase Assay Compound Exp (nM) SE lower upper RU486 1 O.O28 O.OO2 O.O19 O.042 0224 Stock CV-1 cells are maintained in growth 2 O.O37 O.OO2 O.O29 O.048 medium. Co-transfection is done using 1.2x107 cells, 5 3 O.O19 O.OO1 O.O13 O.O27 mg plEM plasmid with hPR-B inserted at SphI and BamHI sites, 10 mg pGL3 plasmid with two PRES upstream of the luciferase sequence, and 50 mg Soni 0230 Progestational activity: Compounds that increase cated calf thymus DNA as carrier DNA in 250 mL. PRE-luciferase activity significantly (p<0.05) compared to Electroporation is carried out at 260 V and 1,000 m F in vehicle control are considered active. a Biorad Gene Pulser(R) II instrument. After electropo ration, cells are resuspended in growth medium and 0231 Antiprogestational activity: Compounds that plated in 96-well plate at 40,000 cells/well in 200 OL. decrease 3 nM progesterone induced PRE-luciferase activity Following overnight incubation, the medium is significantly (p<0.05). changed to experimental medium. Cells are then treated 0232 ECso: Concentration of a compound that gives with reference or test compounds in experimental half-maximal increase PRE-luciferase activity (default-nM) medium. Compounds are tested for antiprogestational with SE. activity in the presence of 3 nM progesterone. Twenty four hours after treatment, the medium is discarded and 0233 ICs: Concentration of a compound that gives cells are washed three times with D-PBS (GIBCO, half-maximal decrease in 3 nM progesterone induced PRE BRL). Fifty mL of cell lysis buffer (Promega, Madison, luciferase activity (default-nM) with SE. Wis.) is added to each well and the plates are shaken for (4) T47D Cell Alkaline Phosphatase Assay 15 minutes in a Titer Plate Shaker (Lab Line Instru ment, Inc.). Luciferase activity is measured using 0234 (i) Purpose: To identify progestins or antiprogestins luciferase reagents from Promega. by determining a compound's effect on alkaline phosphatase activity in T47D cells. 0225 C. Analysis of Results 0235 (ii) Methods 0226 Each treatment consists of at least 4 replicates. Log transformed data are used for analysis of variance 0236 A. Reagents and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used 0237 (i) Culture Medium: to downweight the effects of outliers. ECso or ICso 0238) DMEM:F12 (1:1) (GIBCO, BRL) supple values are calculated from the retransformed values. mented with 5% (v/v) charcoal stripped fetal bovine JMP software (SAS Institute, Inc.) is used for both serum (not heat-inactivated), 100U/mL penicillin, one-way analysis of variance and non-linear response 100 mg/mL streptomycin, and 2 mM the analyses. GlutaMaxTM reagent (GIBCO, BRL). 0227 D. Reference Compounds 0239 (ii) Alkaline phosphatase assay buffer: 0228 Progesterone and trimegestone are reference 0240 I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% progestins and RU486 is the reference antiprogestin. All the TritonTM X-100 reagent; reference compounds are run in full dose-response curves and the ECso or ICso values are calculated. 0241 II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl phosphate (Sigma). TABLE 7 0242 B. Cell Culture and Treatment Estimated ECso, standard error (SE), and 95% confidence intervals (CI) for reference progestins from three individual studies 0243 Frozen T47D cells were thawed in a 37°C. water bath and diluted to 280,000 cells/mL in culture Cso 95% CI medium. To each well in a 96-well plate (Falcon, Compound Exp (nM) SE lower upper Becton Dickinson Labware), 180 DL of diluted cell Progesterone 1 O616 O.O26 O.S.09 O.746 suspension was added. Twenty DL of reference or test 2 O4O2 O.019 O.323 OSO1 compounds diluted in the culture medium was then 3 O486 O.O28 O.371 O.637 added to each well. When testing for progestin antago Trimegestone 1 0.0075 O.OOO2 O.OO66 O.OO85 2 O.OO81 O.OOO3 O.OO70 O.OO94 nist activity, reference antiprogestins or test compounds 3 O.OO67 O.OOO3 0.0055 O.OO82 were added in the presence of 1 nM progesterone. The cells were incubated at 37°C. in a 5% CO/humidified atmosphere for 24 hours. US 2007/0066637 A1 Mar. 22, 2007 21

0244. Note: For high throughput screening, one con 0252 All publications cited in this specification are centration of each compound was tested at 0.3 mg/mL. incorporated herein by reference. While the invention has Based on an average molecular weight of 300 g/mol for been described with reference to particular embodiments, it the compounds in the library, the concentration was will be appreciated that modifications can be made without approximately 1 mM. Subsequently, active compounds departing from the spirit of the invention. Such modifica were tested in dose response assays to determine ECso tions are intended to fall within the scope of the appended or ICso. claims. 0245 C. Alkaline Phosphatase Enzyme Assay What is claimed is: 0246. At the end of treatment, the medium was 1. A compound of formula I: removed from the plate. Fifty DL of assay buffer I was added to each well. The plates were shaken in a titer plate shaker for 15 minutes. Then 150 DL of assay buffer II was added to each well. Optical density measurements were taken at 5 minute intervals for 30 minutes at a test wavelength of 405 nM. 0247 D. Analysis of Results—Analysis of Dose-Re sponse Data 0248 For reference and test compounds, a dose response curve was generated for dose (X-axis) vs. the rate of enzyme reaction (slope) (Y-axis). Square root transformed data were used for analysis of variance and wherein: nonlinear dose response curve fitting for both agonist R and R2 are, independently, selected from the group and antagonist modes. Huber weighting was used to consisting of H. halogen, C to C alkyl, CF, CFCF, downweight the effects of outliers. ECso or ICso values C. to Calkenyl, C. to C alkynyl, Cs to Cs cycloalkyl, were calculated from the retransformed values. JMP aryl, substituted aryl, heteroaryl, and substituted het software (SAS Institute, Inc.) was used for both one eroaryl; way analysis of variance and non-linear dose response analyses in both single dose and dose response studies. provided both of R and R are not H; or 0249 E. Reference Compounds R and R2 are fused to form (a), (b), or (c): 0250 Progesterone and trimegestone were reference (a) a carbon-based 3 to 6 membered saturated spirocy progestins and RU486 was the reference antiprogestin. All clic ring: reference compounds were run in full dose response curves (b) a carbon-based 3 to 6 membered spirocyclic ring and the ECso or ICso values were calculated. having in its backbone one or more carbon-carbon double bonds; or TABLE 9 (c) a carbon-based 3 to 6 membered spirocyclic ring Estimated ECso standard error (SE), and 95% confidence intervals having in its backbone 1 to 3 heteroatoms selected CI) for reference progestins from three independent experiments from the group consisting of O, S, SO, SO, and ECso 95% CI NRC: Compound Exp (nM) SE lower upper wherein rings (a)-(c) are optionally Substituted by 1 to 3 Substituents selected from the group consisting of Progesterone 1 O.839 O.O3O O.7O6 O.996 2 O.639 O.OO6 O.611 O669 F, Cl, and C to C alkyl: 3 1.286 O.O29 1.158 1.429 R is a 5 or 6 membered heteroayl ring containing in its Trimegestone 1 O.O84 O.OO2 O.O76 O.091 2 O.O76 O.OO1 O.O72 O.O8O backbone 1 to 3 heteroatoms selected from the group 3 O-160 O.004 O.141 O181 consisting of O, S, SO, SO, and NR and substituted with 0 to 3 substituents selected from the group con sisting of H, halogen, CN, NO, OH, amino, C to C. 0251) alkyl, C, to Calkoxy, C, to C, alkylamino, C=NOR, TABLE 10 CORP, and NRCCORP; Estimated ICso standard error, and 95% confident interval for the R is absent, H, C, to C alkyl, substituted C to Ca reference antiprogestin RU486 from three independent experiments alkyl, CN, or CORP. R is H, C, to C, alkyl, C, to C, alkoxy, or C to C, ICso 95% CI alkylamino; Compound Exp (nM) SE lower upper Ra is H, halogen, CN, OH, NO, alkoxy, or lower alkyl: RU486 1 O.103 O.OO2 O.092 O.115 2 O.12O O.OO1 O. 115 O.126 Rs is H or lower alkyl: 3 O.O94 0.007 O.066 O.134 R. R-7, Rs, and Ro are, independently, H. F. or C to C. lower alkyl: US 2007/0066637 A1 Mar. 22, 2007 22

n is 0 or 1; 10. The compound according to claim 1, wherein R is of or a pharmaceutically acceptable salt thereof. the structure: 2. The compound according to claim 1, wherein: R and R are, independently, H or C to C alkyl: R is a 5 membered heteroayl ring containing in its backbone 1 NR heteroatom; R is C, to C alkyl: wherein: R is H: Rs is H or C to C alkoxy. X is N or CX; and 3. The compound according to claim 2, wherein Rs is H. X is halogen, CN, C to C alkoxy, or NO. 4. The compound according to claim 1, wherein: 11. The compound according to claim 1 Selected from the group consisting of 5-(1E)-1-(hydroxyimino)-3-methyl-2, R and R2 are, independently, H or C to C alkyl, 3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carboni R is a 5 membered heteroayl ring containing in its trile, 5-(1E)-1-(hydroxyimino)-3.3-dimethyl-2,3-dihydro backbone 1 NR heteroatom and substituted with 1 CN 1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile; group; 5-(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-1- methyl-1H-pyrrole-2-carbonitrile; and (1E)-5-(3,5-dimeth R is C to C alkyl: ylisoxazol-4-yl)-3.3-dimethylindan-1-one oxime. R is H: 12. The compound according to claim 1 which is 5-(5E)- 5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl)-1- Rs is H or C to C alkoxy. methyl-1H-pyrrole-2-carbonitrile. 5. The compound according to claim 1, wherein: 13. A pharmaceutical composition comprising a com R and R are, independently, C to C alkyl, CF pound of claim 1, or a pharmaceutically acceptable salt CFCF, or C to Ce cycloalkyl, or thereof, and a pharmaceutically acceptable carrier or excipi ent. R and R are fused to form a carbon-based 3 to 6 14. A method of inducing contraception, providing hor membered saturated Spirocyclic ring; mone replacement therapy, treating cycle-related symptoms, and treating or preventing benign or malignant neoplastic R is H, halogen, CN, OH, or NO; disease comprising administering to a mammal in need Rs is H, alkyl, or perfluoroalkyl: thereof a pharmaceutically effective amount of a compound according to claim 1. R. R-7, Rs, and Ro are, independently, H or F. 15. A method of inducing contraception, providing hor 6. The compound according to claim 5, wherein R is mone replacement therapy, treating cycle-related symptoms, 1-methyl-2-cyanopyrrole. and treating or preventing benign or malignant neoplastic 7. The compound according to claim 1, wherein R is disease comprising administering to a mammal in need 1-methyl-2-cyano-pyrrole. thereof a pharmaceutically effective amount of a compound 8. The compound according to claim 1, wherein R is of formula II: 3,5-dimethylisoxazole. 9. The compound according to claim 1, wherein R is of the structure: II

Yi X 2. wherein: wherein: R is aryl, substituted aryl, or a 5 or 6 membered heteroay1 U is O, S, or NR; ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO and R is H, C to C alkyl, or CORP. NR and substituted with 0 to 3 substituents selected RP is C, to C alkyl; from the group consisting of H, halogen, CN, NO,OH, amino, C to C alkyl, C to C alkoxy, C to C. X" is selected from the group consisting of halogen, CN, alkylamino, C=NOR, CORP, and NRCORP. NO, C to C alkyl, and C to C alkoxy; and Ra is H, halogen, CN, OH, NO, or alkoxy; Y' is selected from the group consisting of H and C to Ca alkyl. Rs is H or lower alkyl: US 2007/0066637 A1 Mar. 22, 2007

Ro and R are, independently, H. F. or C to C lower (c) a carbon-based 3 to 6 membered spirocyclic ring alkyl: having in its backbone 1 to 3 heteroatoms selected or a pharmaceutically acceptable salt thereof. from the group consisting of O, S, SO, SO, and 16. The method according to claim 15, wherein: NRC: wherein rings (a)-(c) are optionally Substituted by 1 Ro and R are, independently, H or C to C alkyl; to 3 Substituents selected from the group consist R is a 5 membered heteroayl ring containing in its ing of F, Cl, and C to C alkyl; backbone 1 NR heteroatom; R is a 5 or 6 membered heteroayl ring containing in its R is C, to C alkyl: backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO, and NR and substituted R is H: with 0 to 3 substituents selected from the group Rs is H or C to C alkoxy. consisting of H, halogen, CN, NO, OH, amino, C 17. The method according to claim 15, wherein Rs is H. to C alkyl, C to C alkoxy, C to C alkylamino, 18. The method according to claim 15, wherein: C=NOR, CORP, and NRCORP. Ro and R are, independently, H or C to C alkyl; R is absent, H, C, to C alkyl, substituted C to C. R is a 5 membered heteroayl ring containing in its alkyl, CN, or CORP. backbone 1 NR heteroatom and substituted with 1 CN RP is H. C. to C, alkyl, C to C alkoxy, or C to C. group; alkylamino; R is C, to C alkyl: R is H, halogen, CN, OH, NO, alkoxy, or lower alkyl; R is H: Rs is H or lower alkyl; Rs is H or C to C alkoxy. 19. A method of contraception which comprises admin R. R. Rs, and Rare, independently, H., F, or C to C. istering to a female of child bearing age for 28 consecutive lower alkyl: days: n is 0 or 1; or (a) a first phase of from 14 to 24 daily dosage units of a (ii) a compound of formula II: progestational agent equal in progestational activity to about 35 to about 100 ug levonorgestrel; (b) a second phase of from 1 to 11 daily dosage units, at II a daily dosage of from about 2 to 50 mg. of a compound of (i) or (ii): (i) a compound of formula I:

wherein: R is aryl, substituted aryl, or a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO, and NR and substituted with 0 to 3 Substituents selected from the group consisting of H, halogen, CN, NO, OH, amino, C to C alkyl, C to C. alkoxy, C to C, alkylamino, C=NOR, CORP, wherein and NRCORP; R and R are, independently, selected from the group Ra is H, halogen, CN, OH, NO, or alkoxy; consisting of H, halogen, C to C alkyl, CF CFCF.C. to Calkenyl, C. to C alkynyl, C. to Cs Rs is H or lower alkyl: cycloalkyl, aryl, Substituted aryl, heteroaryl, and Ro and Rare, independently, H. F. or C to C lower substituted heteroaryl; alkyl; and provided both of R and R are not H; or (c) optionally, a third phase of daily dosage units of an R and R2 are fused to form (a), (b), or (c): orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no (a) a carbon-based 3 to 6 membered saturated spi antiprogestin, progestin or estrogen is administered; rocyclic ring; wherein the total daily dosage units of the first, second (b) a carbon-based 3 to 6 membered spirocyclic ring and third phases equals 28. having in its backbone one or more carbon-carbon 20. A pharmaceutically useful kit adapted for daily oral double bonds; or administration which comprises: US 2007/0066637 A1 Mar. 22, 2007 24

(a) a first phase of from 14 to 21 daily dosage units of a consisting of H, halogen, CN, NO, OH, amino, C progestational agent equal in progestational activity to to C alkyl, C to C alkoxy, C to C alkylamino, about 35 to about 150 lug levonorgestrel; C=NOR, CORP, and NRCORP. (b) a second phase of from 1 to 11 daily dosage units of R is absent, H, C, to C alkyl, substituted C to C. a compound of formula I or II, each daily dosage unit alkyl, CN, or CORP. containing said compound at a daily dosage of from RP is H, C, to C, alkyl, C, to C, alkoxy, or C to C, about 2 to 50 mg, wherein said compound is (i) or (ii): alkylamino; (i) a compound of formula I: Ra is H, halogen, CN, OH, NO, alkoxy, or lower alkyl; Rs is H or lower alkyl; R. R. Rs, and Rare, independently, H., F, or C to C. lower alkyl: n is 0 or 1; or (ii) a compound of formula II:

II

wherein R and R2 are, independently, selected from the group consisting of H, halogen, C to C alkyl, CF CFCF.C. to Calkenyl, C. to C alkynyl, C. to Cs cycloalkyl, aryl, Substituted aryl, heteroaryl, and substituted heteroaryl; wherein: provided both of R and R are not H; or R is aryl, substituted aryl, or a 5 or 6 membered heteroayl ring containing in its backbone 1 to 3 R and R2 are fused to form (a), (b), or (c): heteroatoms selected from the group consisting of O, (a) a carbon-based 3 to 6 membered saturated spi S, SO, SO, and NR and substituted with 0 to 3 rocyclic ring; Substituents selected from the group consisting of H, (b) a carbon-based 3 to 6 membered spirocyclic ring halogen, CN, NO, OH, amino, C to C alkyl, C to having in its backbone one or more carbon-carbon C. alkoxy, C to C, alkylamino, C=NOR, CORP, double bonds; or and NRCORP. Ra is H, halogen, CN, OH, NO, or alkoxy; (c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected Rs is H or lower alkyl: from the group consisting of O, S, SO, SO, and Ro and Rare, independently, H. F. or C to C lower NRC: alkyl; and wherein rings (a)-(c) are optionally Substituted by 1 (c) a third phase of daily dosage units of an orally and to 3 Substituents selected from the group consist pharmaceutically acceptable placebo, ing of F, Cl, and C to C alkyl, wherein the total number of the daily dosage units in R is a 5 or 6 membered heteroayl ring containing in its the first phase, second phase and third phase equals backbone 1 to 3 heteroatoms selected from the group 28. consisting of O, S, SO, SO, and NR and substituted with 0 to 3 substituents selected from the group