AU2012216403A1 - Pyridine imidazoles and aza-indoles as progesterone receptor modulators - Google Patents

Abstract

Abstract The present invention is directed to novel pyrimidine imidazoles and aza-indoles according to formulae (I) and (II), pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more estrogen receptors. The 5 compounds of the invention are useful in the treatment of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

Description

- 1 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ORIGINAL Name of Applicant: Janssen Pharmaceutica N.V. Actual Inventors: Weiqin Jiang and James J. Fiordeliso and Zhihua Sui Address for Service is: SHELSTON IP 60 Margaret Street Telephone No: (02) 9777 1111 SYDNEY NSW 2000 Facsimile No. (02) 9241 4666 CCN: 3710000352 Attorney Code: SW Invention Title: Pyridine imidazoles and aza-indoles as progesterone receptor modulators Details of Original Application No. 2005302707 dated 21 Oct 2005 The following statement is a full description of this invention, including the best method of performing it known to me/us: File: 54060AUP01 Pyridine Imidazoles and Aza-indoles as Progesterone Receptor Modulators FIELD OF THE INVENTION The present application is a divisional application of Australian Application No. 5 2005302707, which is incorporated in its entirety herein by reference. The present invention is directed to novel pyridine imidazoles and aza-indole derivatives, the pharmaceutical compositions containing them and their use in the treatment or prevention of disorders and diseases mediated by agonists and antagonists of the progesterone receptor. The clinical usage of these compounds are related to 10 hormonal contraception, the treatment and/or prevention of secondary dysmenorrhea, amenorrhea, dysfunctional uterine bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minication of side effects of cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake. 15 Background of the Invention Intracellular receptors are a class of structurally related proteins involved in the regulation of gene proteins. Steroid receptors are a subset of these receptors, including the progesterone receptors (PR), androgen receptors (AR), estrogen receptors (ER), glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Regulation of a 20 gene by such factors requires the intracellular receptor and a corresponding ligand which has the ability to selectively bind to the receptor in a way that affects gene transcription. Progesterone receptor modulators (progestagens) are known to play an important role in mammalian development and homeostasis. Progesterone is known to be required for mammary gland development, ovulation and the maintenance of pregnancy. 25 Currently, steroidal progestin agonists and antagonists are clinically approved for contraception, hormone replacement therapy (HRT) and therapeutic abortion. Moreover, there is good preclinical - laand clinical evidence for the value of progestin antagonists in treating endometriosis, uterine leiomyomata (fibroids), dysfunctional uterine bleeding and breast cancer. 5 The current steroidal progestagens have been proven to be quite safe and are well tolerated. Sometimes, however, side effects (e.g. breast tenderness, headaches, depression and weight gain) have been reported that are attributed to these steroidal progestagens, either alone or in combination with estrogenic compounds. 10 Steroidal ligands for one receptor often show cross-reactivity with other steroidal receptors. As an example, many progestagens also bind to glucocorticoid receptor. Non-steroidal progestagens have no molecular similarity with steroids and therefore one might also expect differences in 15 physicochemical properities, pharmacokinetic (PK) parameters, tissue distribution (e.g. CNS versus peripheral) and, more importantly,non-steroidal progestagens may show no/less cross-reactivity to other steroid receptors. Therefore, non-steroidal progestagens will likely emerge as major players in reproductive pharmacology in the foreseeable future. 20 It was known that progesterone receptor existed as two isoforms, full length progesterone receptor isoform (PR-B) and its shorter counterpart (PR A). Recently, extensive studies have been implemented on the progesterone receptor knockout mouse (PRKO, lacking both the A- and B-forms of the 25 receptors), the mouse knockoutting specifically for the PR-A isoform (PRAKO) and the PR-B isoform (PRBKO). Different phenotypes were discovered for PRKO, PRAKO and PRBKO in physiology studies in terms of fertility, ovulation uterine receptivity, uterine proliferation, proliferation of mammary gland, sexual receptivity in female mice, sexual activity in male mice and infanticide 30 tendencies in male mice. These findings provided great challenge for synthetic 2 chemists to construct not only selective progesterone receptor modulator (SPRM), but also PR-A or PR-B selective progesterone receptor modulator. 5 Summary of the Invention The present invention provides novel pyridine imidazoles and aza-indole derivatives of the formula (1) or (1l): R R1R ~N 2, 132 R3- O R- N N (I) (R4 10 wherein

R

1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl or heteroaryl-alkyl; wherein the cycloalkyl, aralkyl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, 15 S(alkyl), S02(alkyl), NO 2 , CN, C0 2 H, -ORc, -SO 2 -NRDRE, -NRDRE, NRD-S0 2 RF, -(alkyl)0-4-C(O)NR DR E, (alkyl)0.4-NR D-C(0)-R F, -(alkyl)0-4-(Q)0-1-(alkyl)0-4 NRDRE, wherein Rc is selected from the group consisting of alkyl, cycloalkyl, 20 cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), S0 2 (alkyl), NO 2 , CN, 25 C0 2 H, RC, -SO 2 -NRDRE, NRDRE, NR DSO 2 -RF, -(alkyI)0.4-C(O)-NRDRE, -(alkyl)o 4 -NR DC(O)-RF, -(alkyl)0- 4 -(Q)0- 1 -(alkyI)0.

4 -NR RE wherein Q is selected from the group consisting of 0, S, NH, N(alkyl) and -CH=CH-; 3 wherein RD and RE are each independently selected from the group consisting of hydrogen and alkyl; alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 4 to 8 membered ring 5 selected from the group consisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 10 wherein RF is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected 15 from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R

3 is selected from the group consisting of halogen, CF 3 , hydroxy, Rc, nitro, cyano, S0 2 (alkyl), -C(O)RG, -C(O)ORG, -OC(O)R 0 , -OC(O)ORG _ 20 OC(O)N(RG) 2 , -N(RG)C(O)RG, -OSi(RG)3 -ORG, -SO 2

N(RG)

2 , -O-(alkyl) 1

.

4 C(O)RG, -O-(alkyl)1.

4 -C(O)ORG, aryl and heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, - OC(O) alkyl or -C(O)O-alkyl; 25 wherein each RG is independently selected from hydrogen, alkyl, aryl, aralkyl; wherein the alkyl, aryl or aralkyl group is optionally substituted with one or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, - OC(O)-alkyl or -C(O)O-alkyl; 30 alternatively two RG groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group; wherein the 4 heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 5 R 4 is selected from the group consisting of hydrogen, acetyl, S0 2 (alkyl), alkyl, cycloalkyl, aralkyl or heteroaryl-alkyl; wherein the cycloalkyl, aralkyl or heteroaryl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), S0 2 (alkyl), NO 2 , CN, CO 2 H, -ORc, -SO 2 NRDRE, -NRDRE, NRD-SO 2 RF, _ 10 (alkyl)0.

4 -C(O)NR RE, (alkyl) 0

.

4 -NR -C(O)-R F, -(alkyl)0-4-(Q)0--(alkyl)0.

4 -NRD RE wherein RO is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, 15 heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-akyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), S0 2 (alkyl), NO 2 , CN,

CO

2 H, Rc, -SO 2 NR DRE, NRD R E, NRD-SO 2 RF, -(alkyl)0.

4 -C(O)-NRDRE, -(alkyl)0. 4 -NR -C(O)-RF, -(alkyl)0- 4 -(Q)00.-(alkyl)0.

4 -NR DRE 20 wherein Q is selected from the group consisting of 0, S, NH, N(alkyl) and -CH=CH-; wherein RD and RE are each independently selected from the group 25 consisting of hydrogen and alkyl; alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 4 to 8 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, 30 carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 5 wherein RF is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is 5 optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; or a pharmaceutically acceptable salt thereof. 10 The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formulal and 2, the present invention includes such optical isomers and diastereomersl 15 as well as the racemic and resolved, enantiomerically pure S and R stereoisomersa dn pharmaceutically acceptable salts thereof. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. 20 An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier. 25 Exemplifying the invention are methods of treating a disorder mediated by one or more progesterone receptors in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. 30 6 Illustrating the invention is a method of contraception comprising administering to a subject in need thereof co-therapy with a therapeutically effective amount of a compound of formula (1) with an estrogen or estrogen antagonist. 5 Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) dysfunctional bleeding, (b) endometriosis, (c) uterine leiomyomata, (d) secondary amenorrhea, (e) polycystic ovary syndrome, (f) carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, (g) 10 minication of side effects of cyclid menstrual bleeding and for (h) contraception and i) stimulation of food intake in a subject in need thereof. Detailed Description of the Invention 15 The present invention is further directed to a compound of formula (I) or (II):

R

1 R

R

3

-

O Ra 0 NN N (I) (R4 wherein R 1 , R 2 , R 3 and R 4 are as herein defined, useful for the 20 treatment of disorders mediated by an progesterone receptor. More particularly, the compounds of the present invention are useful for the treatment and prevention of disorders mediated by the progesterone-A and progesterone-B receptors. More preferably, the compounds of the present invention are tissue selective progesterone receptor modulators. 25 The compounds of the present invention are useful in the treatment of disorders associated with the depletion of progesterone, hormone sensitive cancers and hyperplasia, endometriosis, uterine fibroids, osteoarthritis and as 7 contraceptive agents, alone or in combination with a estrogen or a partial estrogen antagonist. The compounds of the present invention are useful in the treatment of 5 disorders associated with the depletion of progesterone, secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minication of side effects of cyclid menstrual bleeding. and as contraceptive agents, alone or in 10 combination with a estrogen or restrogen antagonist. In an embodiment of the present invention R 1 , R 2 are both methyl groups. In another embodiment of the present invention R1, R 2 are connected 15 by -(CH 2

)

4 - to form a 5-membered spiro ring. In another embodiment of the present invention R 1 , R 2 are connected by -(CH 2

)

5 - to form a 6-membered spiro ring. In an embodiment of the present invention R 3 is selected from halogen, 20 CN, CF 3 , NO 2 or S0 2 (alkyl) group. In another embodiment of the present invention R 3 is selected from aryl, heteroaryl groups, wherein aryl or heteroaryl groups are mono-, di-, or tri-substituted by halogen, NO 2 , CF 3 , CN, O(alkyl). In an embodiment of the present invention R4 is selected from hydrogen, 25 acetyl or S0 2 (alkyl), lower alkyl, aralkyl, heteroarylalkyl. For use in medicine, the salts of the compounds of this invention refer to 30 non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of compounds according to this invention or of their 8 pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, 5 fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; 10 and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, 15 citrate, dihydrochloride, acetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, 20 nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. The present invention includes within its scope prodrugs of the 25 compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a 30 compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional 9 procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. As used herein, the term "progestogen antagonist" shall include mifepristone, 5 J-867 (Jenapharm / TAP Pharmaceuticals), J-956 (Jenapharm / TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638 (Organon), ORG-31806 (Organon), onapristone and PRA248 (Wyeth). As used herein, unless otherwise noted, "halogen" shall mean chlorine, 0 bromine, fluorine and iodine. As used herein, unless otherwise noted, the term "alkyl" whether used alone or as part of a substituent group, include straight and branched chain compositions of one to eight carbon atoms. For example, alkyl radicals include 5 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, "lower" when used with alkyl means a carbon chain composition of 1-4 carbon atoms. Similarly, the group "-(alkyl)og-", whether alone or as part of a large substituent group, shall me the absence of an alkyl group or the presence of an alkyl group comprising one to four carbon 0 atoms. Suitable examples include, but are not limited to -CH 2 -, -CH 2

CH

2 -, CH 2 CH(CH 3 )-, CH 2

CH

2

CH

2 -, -CH 2

CH(CH

3

)CH

2 -, CH 2

CH

2

CH

2

CH

2 -, and the like. As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For 25 example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. As used herein, unless otherwise noted, "aryl" shall refer to unsubstituted carbocyclic aromatic groups such as phenyl, naphthyl, and the like. As used herein, unless otherwise noted, "aralkyl" shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. Suitable 30 examples include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and the like. 10 As used herein, unless otherwise noted, the term "cycloalkyl" shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. 5 As used herein, unless otherwise noted, the term "cycloalkyl-alkyl" shall mean any lower alkyl group substituted with a cycloalkyl group. Suitable examples include, but are not limited to cyclohexyl-methyl, cyclopentyl-methyl, cyclohexyl-ethyl, and the like. 0 As used herein, unless otherwise noted, the terms "acyloxy" shall mean a radical group of the formula -O-C(O)-R where R is alkyl, aryl or aralkyl, wherein the alkyl, aryl or aralkyl is optionally substituted. As used herein, the term "carboxylate" shall mean a radical group of the formula -C(O)O-R where R is alkyl, aryl or aralkyl, wherein the alkyl, aryl or aralkyl is optionally substituted. 15 As used herein, unless otherwise noted, "heteroaryl" shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the ?0 group consisting of 0, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of 0, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that 25 the result is a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, 30 benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like. 11 As used herein, unless otherwise noted, the term "heteroaryl-alkyl" shall mean any lower alkyl group substituted with a heteroaryl group. Suitable examples include, but are not limited to pyridyl-methyl, isoquinolinyl-methyl, 5 thiazolyl-ethyl, furyl-ethyl, and the like. As used herein, the term "heterocycloalkyl" shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally 10 containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting 15 of 0, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, 20 piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3 dihydrobenzofuryl, and the like. As used herein, unless otherwise noted, the term "heterocycloalkyl-alkyl" shall mean any lower alkyl group substituted with a heterocycloalkyl group. 25 Suitable examples include, but are not limited to piperidinyl-methyl, piperazinyl methyl, piperazinyl-ethyl, morpholinyl-methyl, and the like. When a particular group is "substituted" (e.g., cycloalkyl, aryl, heteroaryl, heterocycloalkyl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most 30 preferably from one to two substituents, independently selected from the list of substituents. Additionally when aralkyl, heteroaryl-alkyl, heterocycloalkyl-alkyl or 12 cycloalkyl-alkyl group is substituted, the substituent(s) may be on any portion of the group (i.e. the substituent(s) may be on the aryl, heteroaryl, heterocycloalkyl, cycloalkyl or the alkyl portion of the group.) With reference to substituents, the term "independently" means that when 5 more than one of such substituents is possible, such substituents may be the same or different from each other. Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent 10 functionality toward the point of attachment. Thus, for example, a "phenylC

C

6 alkylaminocarbonylC-C 6 alkyl" substituent refers to a group of the formula 0 aly / \ Crlkyalk - -C6~ alkyA N ,.CC6ak"O H 15 Abbreviations used in the specification, particularly the Schemes and Examples, are as follows Ac Acetyl group (-C(O)-CH 3 ) DCM Dichloromethane DMF Dimethyl formamide ERT Estrogen replacement therapy Et ethyl (i.e. -CH 2

CH

3 ) EtOAc Ethyl acetate FBS Fetal bovine serum HPLC High pressure liquid chromatography HRT Hormone replacement therapy MeOH Methanol Ph Phenyl TEA or Et 3 N Triethylamine 13 THF Tetrahydrofuran TsOH Toluene sulfonic acid The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. 5 The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation 10 of the symptoms of the disease or disorder being treated. Wherein the present invention directed to co-therapy comprising administration of one or more compound(s) of formula I and a progestogen or progestogen antagonist, "therapeutically effective amount" shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or 15 medicinal response. For example, the therapeutically effective amount of co therapy comprising administration of a compound of formula I and progestogen would be the amount of the compound of formula I and the amount of the progestogen that when taken together or sequentially have a combined effect that is therapeutically effective. Further, it will be recognized by one skilled in the art 20 that in the case of co-therapy with a therapeutically effective amount, as in the example above, the amount of the compound of formula I and/or the amount of the progestogen or progestogen antagonist individually may or may not be therapeutically effective. 25 As used herein, the term "co-therapy" shall mean treatment of a subject in need thereof by administering one or more compounds of formula I with a progestogen or progestogen antagonist, wherein the compound(s) of formula I and progestogen or progestogen antagonist are administered by any suitable 14 means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Where the compound(s) of formula I and the progestogen or progestogen antagonist are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same 5 or different. The compound(s) of formula I and the progestogen or progestogen antagonist may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and rectal. Compounds may also be administered directly to the D nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal arnd / or peri-spinal routes of administration by delivery via intracranial or intravertebral needles and / or catheters with or without pump devices. The compou nd(s) of formula I and the progestogen or progestogen antagonist may be administered 5 according to simultaneous or alternating regimens, at the sarne or different times during the course of the therapy, concurrently in divided or single forms. As used herein, the term "composition" is intended to e ncompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified 0 ingredients in the specified amounts. One skilled in the art will recognize that it may be necessary and/or desirable to protect one or more of the R 3 and/or R 4 groups at any of the steps within the process described above. This may be accomplished using known protecting groups and know protection and de-protection reagents and 25 conditions, for example such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. 30 Compounds of formula (1) may be prepared according to the process outlined in Scheme (1). 15

~NH-

2 0 NH 2 acetone X O -N + .JxrB (lii) V) r

I-R

1

-R

2 -I R 1 Ior R 2 1 NaOEt X (VI) (V) EtOH N (VII) Scheme 1 More particularly, a suitably substituted compound of formula (II), wherein X is halogen, CN, CF 3 , NO 2 , or S0 2 (alkyl), a known compound or compound prepared by known methods, is reacted with a compound of formula (ll), a known compound, in an organic solvent such as acetone, THF, 1,4 ) dioxane, ethyl ether and the like, at a temperature in the range of about 0 LC to about 30 LC, to yield the corresponding compound of formula (IV). The cyclization of compound IV and alkyl iodide (V) or alkyl diiodide (VI) can be affected under the organic base such as NaOMe, NaOEt, KOtBu, NaOtBu and the like or inorganic base, such as NaOH, KOH, Na 2

CO

3 , NaHCO 3 , K 2 CO3, 5 Cs 2

CO

3 , KF and the like; in the presence of organic solvent, such as MeOH, EtOH, iPrOH, tBuOH at a temperature in the range of about 0 2C to 100 9C, to yield the corresponding compound of formula (VII). xO + R 3

B(OH)

2 Pd(O) or Pd(II) R 3 2 '~~ N base N when X = Br (Vill) (VII) 0 Scheme 11 16 Preferably, compound of formula (VII), wherein X is Br or I, a compound made from Scheme 1, can react further with aryl or heteroaryl boronic acid of formula R 3

B(OH)

2 , a known compound or a compound prepared from known methods, under the palladium (0) or palladium (+2) catalysts, such as Pd(PPh 3

)

4 , Pd(OAc) 2 with PPh 3 , PdCl 2 (PPh 3

)

2 , or PdCl 2 (dppf) 2 and the like, in the presence of inorganic base, such as K 2

CO

3 , Na 2

CO

3 , KOAc, K 3 P0 4 , NaOAc, Cs 2

CO

3 , and the like, in the organic solvent such as 1,4-dioxane, THF, toluene, with small amount of water; at a temperature in the range of 0 to 125 QC, to yield the corresponding compound of formula (VIII). R1 R2

R

3

R

1 1 and R 2 1, 1-(R 1

-R

2 )-I R 3 2 0 0 N N base NN (X) (XI) Scheme Ill Preferably, compound of formula (X), a known compound prepared 5 according to the procedure described in W02003/082868, was deprotonated under an organic base, such as nBuLi, LDA, NaHMDS and the like, in the aprotice solvent such as THF, ether, or hexane at a temperature in the range of -78 QC to -40 2 C; the anion was then reacted with iodide of formula R 1 1 or R 2 1 or diiodide of formula 1-(R-R 2 )-I to generate the compound of forrnula (XI). ?0 Table 1 R, Ra 20 25 17 ex. # R 1 , R 2 R3 MF 1-C3 Spirocyclohexane Br C 1 2

H

13 BrN 2 0 3 Spirocyclohexane 3-CI-phenyl C, 8

H

1 7

CIN

2 0 1-Cl Dimethyl Br CsH 9 BrN 2 0 2 Dimethyl 3-CI-phenyl C 1 5

H

1 aCIN 2 0 4 Dimethyl 3-CN-phenyl C 1 6

H

13 N30 5 Dimethyl Cl C9H9CIN20 6 Spirocyclohexyl Cl Cl 2H1 3CIN20 7 Dimethyl 3,5-di-F-phenyl C15H12F2N20 8 Dimethyl 3-NO 2 -phenyl C15H13N303 9 Dimethyl 3-CF 3 -phenyl C16H13F3N20 10 Dimethyl 2,4-di-F-phenyl C15H12F2N20 11 Dimethyl 3,5-di-CF 3 -phenyl C17H12F6N20 12 Dimethyl 3-MeO-phenyl C16H16N202 13 Dimethyl 3-F-phenyl C15H13FN20 14 Dimethyl 2-CI-phenyl C15H13CIN20 1-C2 spirocyclopentane Br C1 Hi 1 BrN20 15 spirocyclohexane 3-F-phenyl C18H17FN20 16 spirocyclohexane 3-MeO-phenyl C19H20N202 17 spirocyclohexane 3,5-di-CFa-phenyl C20H16F6N20 18 spirocyclohexane 3-NO2-phenyl C18H17N303 19 spirocyclohexane 3-CF 3 -phenyl C19H17F3N20 20 spirocyclohexane 3-CN-phenyl C19H17N30' 21 spirocyclohexane 3,5-di-F-phenyl C18H16F2N20 22 spirocyclohexane 3,4-di-Cl-phenyl C18H16Cl2N20 23 spirocyclohexane 2,4-di-F-phenyl C18H16F2N20 24 spirocyclopentane 3-CI-phenyl C17H15CIN20 25 spirocyclopentane 3-CN-phenyl C18H15N30 26 spirocyclopentane 3-F-phenyl C17H15FN20 27 spirocyclopentane 3-NO 2 -phenyl C17H15N303 28 spirocyclopentane 3, 4-di-CI-phenyl C17H14Cl2N20 29 spirocyclopentane 3,5-di-CF 3 -phenyl C19H14F6N20 30 spirocyclopentane 3-Ci-4-F-phenyl C17H14CIFN20 Table 2 18 R1 R3 R20 1 0 N Nq H (I) Ex. # R 1 , R 2

R

3 MF 31 Spirocyclohexane 3-F-phenyl C23H 21

FN

2 0 3 S 32 Dimethyl 3-F-phenyl C23H 21

CIN

2 0 3 S It is intended that the definition of any substituent or variable at a 5 particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth D herein. It is further intended that when m is >1, the corresponding R 4 substituents may be the same or different. The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with 15 inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "pro-drug" forms, which, 20 when administered in such form, convert to the active moiety in vivo. This invention includes pharmaceutical compositions comprising one or more compounds of this invention, preferably in combination with one or more pharmaceutically acceptable carriers and/or excipients. The invention also includes methods of contraception and methods of treating or preventing 19 maladies associated with the progesterone receptor, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more compounds as described above wherein R is alkyl, aryl, heteroary or alkylaryl groupl. 5 The progesterone receptor antagonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myometrial fibroids, endometriosis, 10 genign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-depent tumors. Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock. When used in contraception the progesterone receptor antagonists of 15 the durrent invention may be used either alone in a continuous administration of between 0.1 and 500 mg per day, or alternatively used in a different regimen which would entail 2-4 days of treatment with the progesterone receptor antagonist after 21 days of a progestin. In this regimen between 0.1 and 500 mg daily doses of the progestin (e.g. levonorgestrel, trimegestone, gestodene, 20 norethistrone acetate, norgestimate or cyproterone acetate) would be followed by between 0.1 and 500 mg daily doses of the progesterone receptor antagonists of the current invention. The progesterone receptor agonists of this invention, used alone or in combination, can also be utilized in methods of contraception and the 25 treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syncrome, carcinomas and adenocarcimomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the inventioninclude stimulation of food intake. When used in contraception the progesterone receptor agonists of the 30 durrent invention are preferably used in combination or sequentially with an 20 estrogen agonist (e.g. ethinyl estradiao). The preferred dose of the progesterone receptor agonist is 0.01 mg and 500 mg per day. This invention also includes pharmaceutical compositions comprising one or more compounds described herein, preferably in combination with one 5 or more pharmaceutically acceptable carriers or excipients. When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers, or excipients, for example, solvents, diluents and the like and may be administered orally in such forms as tablets, caplules, dispersible powders, granules, or suspensions containing, for 10 example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugan, and elixirs containing, for example, from 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectale solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations 15 may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the 20 severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in dibided doses two to four times a day, or in a sustained release from. For most large mammals, the total daily dosage is from about 1 25 to 100 mg, preferably from about 2 to 80 mg Dosage froms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic respose. For example, several divided doses may be administered daily or the dose may 30 be proportionally reduced as indicated by the exigencies of the therapeutic situation. 21 These active compounds may be administered orally as well as by intervenous, imtramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic 5 surfactants and edible oils such as corn, peanut and sesame oil, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for 10 example, vitamin E, ascorbic acid, BHT and BHA. The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hardfilled or liquid-filled capsules. Oral administration of the compounds is preferred. 15 These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxylpropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures 20 thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions of dispersions. In all cases, the form 25 must be sterile and must be fluid to the extent that easy syring ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and 30 liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil. 22 The following non-limiting examples illustrate preparation and use of the compounds of the invention. Example 1 5 A. 2-Amino-5-bromo-1-ethoxvcarbonvlmethyl-pyridinium; bromide Br Br- NH 2 OEt 0 2-Amino-5-bromopyridine (10.88 g, 62.9 mmol) was dissolved in acetone (65 mL). To this solution was added ethyl bromoacetate (7.7 mL, 69.2 mmol). The solution was heated to reflux overnight under nitrogen. The 10 reaction mixture was cooled and an off-white solid was filtered off. The solid was washed with acetone and dried to provide title compound as an off-white solid (13.74 g, 64%). 'H NMR (DMSO-d) 8 8.91 (s, 2H), 8.42 (d, J= 2.2 Hz, 1 H), 8.09 (dd, J= 2.2 and 9.5 Hz, 1H), 7.10 (d, J= 9.5 Hz, 1H), 5.11 (s, 2H), 4.21 (q, J= 7.1 and 14.2, 2H), 1.26 (t, J= 7.1, 3H); MS (m/e): 259 (MH*). 15 B. 6-Bromo-imidazo[l,2-alpyridin-2-one Br ~' N 20 To a solution of 2-Amino-5-bromo-1 -ethoxycarbonylmethyl-pyridinium; bromide (2.86 g, 8.4 mmol) in methanol (30 mL) was added sodium methoxide (25 wt %, 2.5 mL, 10.1 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was diluted with 25 water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan solid. The crude material was purified by column chromatography 23 eluting with 3, 5, and 10% methanol/dichloromethane. The product was obtained as a brown solid (56 mg, 3%). 'H NMR (CDCI 3 ) 5 7.85 (s, 1 H), 7.67 (dd, J= 1.6, 9.5 Hz, 1H), 7.07 (d, J = 9.5 Hz, 1H), 4.52 (s, 2H); MS (m/e): 215 (MH*); HRMS: calc'd MH* for C 7

H

5 BrN 2 O 212.9672; found 212.9664. 5 C1. 6-Bromo-3,3-dimethyl-imidazo[1,2-alpyridin-2-one Br 10 A solution of 2-Amino-5-bromo-1 -ethoxycarbonylmethyl-pyridinium; bromide (6.11 g, 17.97 mmol) in 100 mL of ethanol was prepared followed by sodium ethoxide (21 wt %, 20.5 mL, 54.9 mmol). After one hour, iodomethane was added (2.3 mL, 37.7 mmol) and the reaction was stirred at room 15 temperature overnight. The solvent was evaporated and the residue was taken up in dichloromethane. The mixture was filtered and the filtrate was purified by column chromatography eluting with 5% methanol/dichloromethane. The product was obtained as a tan solid (1.07 g, 25%). 'H NMR (CDCl 3 ) 8 7.73 (s, 1H), 7.67 (dd, J= 1.8 and 9.4 Hz, 1H), 7.13 (d, J= 9.4 Hz, 1H), 1.59 (s, 6H); 20 MS (m/e): 241 (MH*). C2. 6-Bromo-3,3-spiroicyclopentanel-imidazol,2-alpyridin-2-one Br O 25 6-Bromo-imidazo[1,2-alpyridin-2-one (0.211 g 1 mmol), NaOMe (25 % in MeOH, 0.26 g, 1.2 mmole), was stirred in MeOH (5.0 mL). 1,4-Diiodobutane (0.310 g, 1.0 mmol) was added slowly. This was stirred at ambient 24 temperature for 16 hours. . The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan solid. The crude material was purified by column chromatography eluting 5 with 5% methanol/dichloromethane. The product was obtained as a white solid (20 mg, 20%). Several runs with different scale was carried out and the best yield is 50%. 'H NMR (CDCl 3 ) 6 7.68 (s, 1H), 7.62 (d, 1H, J = 12 Hz), 7.04 (d, 1 H, J = 12 Hz), 2.52 - 1.83 (m, 8H); MS (m/e): 267(MH*). 10 C3. 6-Bromo-3.3-spiro[cyclohexanel-imidazo[1.2-alpyridin-2-one Br N A solution of 2-Amino-5-bromo-1-ethoxycarbonylmethyl-pyridinium; bromide (4.66 g, 13.70 mmol) in 80 mL of ethanol was prepared followed by 15 sodium ethoxide (21 wt %, 15.4 mL, 41.11 mmol). After one hour, 1, 5 diiodopentane was added (2.2 mL, 15.07 mmol) and the reaction allowed to proceed overnight. . The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan 20 solid. The crude material was purified by column chromatography eluting with 5% methanol/dichloromethane. The product was obtained as an orange solid (1.15 g, 30%). 'H NMR (CDCI 3 ) 8 7.73 (d, J= 1.8 Hz, 1H), 7.63 (dd, J= 2.2 and 9.4 Hz, 1 H), 7.07 (d, J = 9.0 Hz, 1 H), 2.35-2.24 (m, 2H), 2.01-1.96 (m, 2H), 1.88-1.81 (m, 1 H), 1.75-1.64 (m, 4H), 1.46-1.37 (s, 1 H); MS (m/e): 282(MH*). 25 Example 2 6-(3-Chloro-phenvl)-3,3-dimethyl-imidazol,2-alpyridin-2-one 25 C1 N To a round-bottom flask was added 6-bromo-3,3-dimethyl-imidazo[1,2 a]pyridin-2-one (60 mg, 0.25 mmol), 3-chlorophenylboronic acid (39 mg, 0.25 mmol), potassium carbonate (69 mg, 0.25 mmol), Pd(PPh 3

)

4 (29 mg, 0.025 mmol), dioxane (5 mL) and water (1 mL). The mixture was heated at reflux until the starting material was consumed monitored by HPLC-MS. The solution was cooled and water was added. The reaction mixture was extracted twice with ethyl acetate and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to provide the desired product as an off white solid (43 mg, 63%). 'H NMR (CDC3l) S 7.84 (dd, J = 1.8 and 9.1 Hz, 1 H), 7.74 (s, 1H), 7.46-7.27 (m, 5H), 1.64 (s, 6H); MS (m/e): 273 (MH*); HRMS: calc'd MH* for C 1 5

H

13

CIN

2 0 273.0794; found 273.0800. Example 3 6-(3-chloro-phenyl)-3,3-spirorcyclohexanel-imidazo[1,2-alpyridin-2 one CI 0 N The title compound was prepared in 71% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohepane-imidazo[1,2-a]pyridin-2-one and the corresponding boronic 5 acid. 1 H NMR (CDCi 3 ) 6 7.81 (dd, J== 2.1 and 9.2 Hz, 1 H), 7.76 (d, J = 1.4, 1 H), 7.45-7.33 (m, 3H), 7.25-7.23 (m, 2H), 2.40-2.30 (m, 2H), 2.05-2.00 (m, 26 2H), 1.91-1.86 (m, 1H), 1.78-1.71 (m, 4H), 1.49-1.42 (m, 1H); MS (m/e): 313 (MH*). Example 4 5 3-(3,3-Dimethyl-2-oxo-2,3-dihvdro-imidazof1 ,2-alpyrildin-6-vl) benzonlitrille (JNJ-27385696) CN 0 N The title product was prepared in 12% yield as a yellow solid according 0 to the procedure described in Example 2 using 3-cyanophenylboronic acid as starting material. 'H NMR (CDCl 3 ) 8 7.82 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.76 7.69 (m, 4H), 7.61 (m, 1H), 7.31 (d, J= 9.3 Hz, 1H), 1.65 (s, 6H); MS (m/e): 264( MH*); HRMS: calc'd MH* for C, 6 H1 3

N

3 0 264.1137; found 264.1130. 5 Example 5 6-Chloro-3.3-dimethyl-imidazor.2-alpyridin-2-one Cl The title compound was prepared in 44% yield according to the procedure described in Example 1-C1, starting from 5-ch loro-pyridin-2-ylamine. 20 1 H NMR (CDCl 3 ) 6 7.62 (d, J= 2.2 Hz, 1H), 7.57 (dd, J= 2.3 and 9.5 Hz, 1H), 7.16 (d, J= 9.5 Hz, 1H), 1.59 (s, 6H); MS (m/e): 197 (MI*). Example 6 6-Chloro-spirorcvclohexanel-Imidazor1,2-alpyridin-2-one C1 N 7N 27 The title compound was prepared in 14% yield according to the procedure described in Example 1-C3, starting from 5-chloro-pyridin-2-ylamine. 'H NMR (CDC1 3 ) 6 7.63 (t, J = 1.8 and 0.4 Hz, 1 H), 7.53 (dd, J = 2.3 and 9.4 Hz, 1H), 7.11 (dd, J= 0.4, 9.4 Hz, 1H), 2.36-2.25 (m, 2H), 2.00-1.96 (m, 2H), 1.88-1.81 (m, 1 H), 1.75-1.63 (m, 4H), 1 .46-1.36 (m, 1 H); MS (m/e): 237 (MH*). Example 7 6-(3,5-Difluoro-phenvl)-3,3-d i methyl-imidazof1.2-alpyridin-2-one (JNJ-27446913) F F N O 'N The title product was prepared in 73% yield as a yellow solid according to the procedure described in Example 2 using 3,5-difluorophenylboronic acid as starting material. 1H NMR (CDC1 3 ) S 7.81 (dd, J= 2.1 and 9.2 Hz, 1H), 7.77 (d, J= 1.4 Hz, 1 H), 7.29 (d, J = 0.6 Hz, 1 H), 7.02-6.98 (m, 2H), 6.90-6.84 (m, 1 H), 1.64 (s, 6H); MS (m/e): 275( MH*); HRMS: calc'd MH* for C 15

H

12

FN

2 0 275.0996; found 275.1009. Example 8 3,3-Dimethyl-6-(3-nitro-phenvl)-imidazofl,2-alpyridin-2-one

(JNJ

27504646)

NO

2 N The title product was prepared i n 37% yield as a yellow solid according to the procedure described in Example 2, using 3-nitrophenylboronic acid as 28 starting material. 'H NMR (400 MHz, CDCl 3 ) 8 8.35 (t, J= 2.0 Hz, 1H), 8.30 8.27 (m, 1H), 7.89 (dd, J= 2.1 and 9.2 Hz, 1H), 7.83-7.80 (m, 2H), 7.70 (t, J= 8.0 Hz, 1 H), 7.33 (d, J = 9.3 Hz, 1 H), 1.66 (s, 6H); MS (m/e): 284 (MH*); HRMS calc'd MH* for C1 5 H1 3

N

3 0 3 284.1035; found 284.1028. Example 9 3,3-Dimethyl-6-(3-trifluoromethyl-phenyl)-imidazorl.2-alpyridin-2 one (JNJ-27512277)

CF

3 N D The title product was prepared in 73% yield as an off-white solid according to the procedure described in Example 2, using 3 trifluoromethylphenylboronic acid as starting material. 'H NMR (CDC13) 8 7.86 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.76 (s, J = 1.5 Hz, 1 H), 7.70-7.61 (m, 4H), 7.30 5 (d, J = 9.2, 1 H), 1.65 (s, 6H); MS (m/e): 307 (MH*); HRMS: calc'd MH* for CI1H1aF 3

N

2 0 307.1058; found 307.1052. Example 10 6-(2.4-Difluoro-phenyl)-3,3-dimethyl-imidazo[1,2-alpyridin-2-one 20 (JNJ-27518738) F F The title product was prepared in 65% yield as a white solid according to the procedure described in Example 2 using 2, 4-di-fluorophenylboronic acid as starting material. 'H NMR (CDC13) 5 7.78-7.74 (m, 2H), 7.37 (m, 1H), 7.28-7.26 25 (m, 1 H), 7.05-6.95 (m, 2H), 1.62 (s, 6H); MS (m/e): 275 (MH*); HRMS: calc'd MH* for C1 5

H

12

FN

2 0 275.0996; found 275.1008. 29 Example 11 6-(3,5-Bis-trifluoromethyl-phenyl)-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one (27518803)

CF

3

F

3 C N O0 The title compound was prepared in 75% yield according to the procedure described in Example 2, starting from 3, 5-di-trifluoromethylphenyl boronic acid. IH NMR (CDC13) 6 7.93-7.91 (m, 3H), 7.88-7.86 (m, 2H), 7.33 (dd, J= 1.8 and 8.4 Hz, 1H), 1.67 (s, 6H); MS (m/e): 375 (MH*). Example 12 6-(3-Methoxy-phenvi)-3,3-dimethyl-imidazo[l,2-alpyridin-2-one OMe & 5: N O 'N The title compound was prepared in 54% yield according to the procedure described in Example 2, starting from 6-bromo-3,3-dimethyl imidazo[1,2-a]pyridin-2-one and 3-methoxyphenyl boronic acid. 'H NMR (CDC13) 6 7.86 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.73 (d, J = 1.5 Hz, 1 H), 7.43-7.39 (m, 1 H), 7.28-7.25 (m, 1 H), 7.05 (m, 1 H), 6.97-6.94 (m, 2H), 3.88 (s, 3H), 1.63 (s, 6H); MS (m/e): 269 (MH*). 0 Example 13 6-(3-Fluoro-phenyl)-3,3-dimethl-imidazo[l,2-alpyridin-2-one 30 F NY0 N The title compound was prepared in 72% yield according to the procedure described in Example 2, starting from 6-bromo-3,3-dimethyl imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1 H NMR 5 (CDCl 3 ) 6 7.84 (dd, J= 2,1 and 9.2 Hz, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.49-7.43 (m, 1H), 7.29-7.24 (m, 2H), 7.19-7.10 (m, 2H), 1.64 (m, 6H); MS (m/e): 257 (MH*). Example 14 0 6-(2-Chloro-phenvl)-3,3-dimethyl-imldazo1 ,2-alpyridin-2-one CI N~§ The title compound was prepared in 46% yield according to the procedure described in Example 2, starting from 6-bromo-3,3-dimethyl imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 'H NMR 5 (CDCl 3 ) 6 7.77-7.73 (m, 2H), 7.55-7.51 (m, 1 H), 7.40-7.32 (m, 3H), 7.28-7.23 (m, 1 H), 1.62 (s, 6H); MS (m/e): 273 (MH*). Example 15 6-(3-Fluro-phenvl)-3,3-spirofcvclohexanel-imidazo[l,2-alpyridin-2 20 one F N The title compound was prepared in 39% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 31 spiro[cyclohexane)-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 'H NMR (CDCl 3 ) 6 7.81 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.77 (d, J = 1.4, 1H), 7.50-7.40 (m, 1H), 7.25-7.23 (m, 2H), 7.18-7.10 (m, 2H), 2.40-2.30 (m, 2H), 2.05-2.00 (m, 2H), 1.91-1.81 (m, 1H), 1.77-1.71 (m, 4H), 1.50-1.38 (m, 5 1 H); MS (m/e): 297 (MH). Example 16 6-(3-Methoxy-phenyl)-3,3-spiro[cyclohexanel-imidazofl,2-alpyridin 2-one OMe NN 100 10 N The title compound was prepared in 67% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohexane]-imidazo[1,2-a)pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDC 3 ) 6 7.83 (dd, J= 2.1 and 9.2 Hz, 1H), 7.77 (d, J= 1.4 Hz, 15 1H), 7.40-7.38 (m, 1H), 7.24-7.22 (m, 1H), 7.04-7.02 (m, 1H), 6.97-6.95 (m, 2H), 3.88 (s, 3H), 2.40-2.30 (m, 2H), 2.05-2.00 (m, 2H), 1,92-1.80 (s, 1 H), 1.77-1.68 (m, 4H), 1.50-1.38 (m, 1 H); MS (m/e): 309 (MH*). Example 17 20 6-(3,5-BIs-trifluoromethvl -phenyl)-3,3-spiro[cyclohexanel Imidazof1,2-alpvridin-2-one

CF

3 F3CrN O N The title compound was prepared in 35% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 25 spiro[cyclohexane-imidazo[1,2-a~pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDCl 3 ) 6 7.93-7.79 (m, 5H), 7.30-7.28 (m, 1H), 2.40-2.36 (m, 32 2H), 2.06-2.01 (m, 2H), 1.92-1.88 (m, 1H), 1.82-1.72 (m, 4H), 1.50-1.38 (m, 1H); MS (m/e): 415 (MH*). Example 18 6-(3-nitro-phenyl)-3,3-spiro[cyclohexanel-imidazor1.2-alpyri ciin-2 one

NO

2 N The title compound was prepared in 8% yield according to the procedure described in Example 2, starting from 6-bromo-3,3- spiro[cyclohexane] imidazo[1,2-a)pyridin-2-one and the corresponding boronic acid. 'H NWIV R (CDC 3 ) 6 8.34 (t, J= 1.9 Hz, 1H), 8.29-8.26 (m, 1H), 7.88-7.79 (m, 3H), 7.69 (t, J= 7.9, 1 H), 7.31-7.26 (m, 1 H), 2.45-2.30 (m, 2H), 2.10-2.00 (m, 2H), 1.93-1.83 (m, 1 H), 1.81-1.70 (m, 4H), 1.50-1.40 (m, 1H); MS (m/e): 324 (MH*). 5 Example 19 6-(3-trifluoromethvl -phenvi)-3,3-spiro[cyclohexanel-imidazol.2 alpyridin-2-one

CF

3 N O N 20 The title compound was prepared in 65% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDCl 3 ) 6 7.84 (dd, J = 2.2 and 9.2 Hz, 1 H), 7.78 (d, J = 1.4 Hz, 1H), 7.69-7.62 (m, 4H), 7.28-7.25 (m, 1H), 2.39-2.32 (m, 2H), 2.05-2.00 (m, 25 2H), 1.91-1.86 (m, 1 H), 1.80-1.71 (m, 4H), 1.47-1.43 (m, 1 H); MS (m/e): 347 (MH*). 33 Example 20 6-(3-cvano-phenyl)-3,3-spiro[cyclohexanel-imidazo[1,2-alpyridin-2 one 5 CN N The title compound was prepared in 47% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic 10 acid. 'H NMR (CDCI 3 ) 6 7.82-7.79 (m, 2H), 7.77-7.70 (m, 3H), 7.28-7.26 (m, 1H), 7.28-7.26 (m, 1H), 2.38-2.30 (m, 2H), 2.05-2.01 (m, 2H), 1.91-1.87 (m, 1 H), 1.80-1.71 (m, 4H), 1.49-1.43 (m, 1 H); MS (m/e): 304 (MH*). Example 21 15 6-(3, 5-Difluoro-phenvl)-3,3-spirorcvclohexanel-imidazor1,2 alpyridin-2-one F N The title compound was prepared in 36% yield according to the 20 procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 'H NMR (CDC1 3 ) 6 7.78-7.75 (m, 2H), 7.23 (s, 1H), 7.00-6.97 (m, 2H), 6.90-6.84 (m, 1 H), 2.40-2.23 (m, 2H), 2.05-1.95 (m, 2H), 1.91-1.81 (m, 1 H), 1.77-1.65 (m, 4H), 1.50-1.37 (m, 1H); MS (m/e): 315 (MH*). 25 Example 22 34 6-(3, 5-Dichlaro-phenyi)-3,3-spiroicyclohexanel-imidazo[l2 alpyridin-2-one C1 CI N N The title compound was prepared in 48% yield according to the 5 procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohexanel-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDCI 3 ) 6 7.79-7.76 (m, 1H), 7.69-7.64 (m, 1H), 7.58-7.53 (m, 1H), 7.49-7.45 (m, 1H), 7.31-7.23 (m, 2H), 2.38-2.30 (m, 2H), 2.04-2.00 (m, 2H), 1.90-1.85 (m, 1H), 1.79-1.65 (m, 4H), 1.50-1.38 (m, 1H); MS (mle): 347 10 (MH*). Example 23 642, 4-Difluoro-phenyl)-3,3-spiro[cyclohexanel-imidazol,2 alpyridin-2-one 15 F F NNN N The title compound was prepared in 48% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic 20 acid. 'H NMR (CDC1 3 ) 6 7.81 (s, 1H), 7.75-7.72 (m, 1H), 7.40-7.33 (m, 1H), 7.25-7.22 (m, 1 H), 7.08-6.95 (m, 2H), 2.37-2.28 (m, 2H), 2.05-2.02 (m, 2H), 1.87-1.84 (m, 1H), 1.75-1.71 (m, 4H), 1.45-1.39 (m, 1H); MS (m/e): 315 (MH*). 25 35 Example 24 6-(3-chloro-phenvi)-3.3-spiro[rentanel-imidazol .2-alpyridin-2-one CI NN N 5 The title compound was prepared in 60% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDCI 3 ) 6 7.80 (dd, J= 2.1 and 9.2 Hz, 1H), 7.73 (d, J= 1.6 Hz, 1 H), 7.45-7.39 (m, 3H), 7.34-7.31 (m, 1 H), 7.25-7.23 (m, 1 H), 2.53-2.48 (m, 10 2H), 2.20-2.16 (m, 2H), 2.05-1.94 (m, 4H); MS (m/e): 299 (MH*). Example 25 6-(3-cyano-phenv)-3,3-spirofpentanel-imidazo[1,2-alpyridin-2-one 15 CN N The title compound was prepared in 31% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic 20 acid. 'H NMR (CDCI 3 ) 6 7.80 (dd, J= 2.2 and 9.2 Hz, 1 H), 7.75-7.68 (m, 4H), 7.62 (t, J= 7.7 Hz, 1H), 7.28 (s, 1H), 2.55-2.48 (m, 2H), 2.22-2.18 (m, 2H), 2.06-1.95 (m, 4H); MS (m/e): 290 (MH). 25 Example 26 6-(3-Fluoro-phenvI)-3,3-spiroipentanel-imidazor1,2-alpyridin-2-one 36 F brN N The title compound was prepared in 58% yield according to the procedure described in Example 2, starting from 6-b romo-3,3 spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 'H NMR (CDCIs) 6 7.81 (dd, J= 2.0 and 9.1 Hz, 1H), 7.74 (d, J= 1.8 Hz, 1H), 7.49-7.43 (m, 1H), 7.27-7.22 (m, 2H), 7.17-7.10 (m, 2H), 2.54-2.48 (m, 2H), 2.21-2.14 (m, 2H), 2.08-1.94 (m, 4H); MS (m/e): 283 (MH*). Example 27 6-(3-nitro-phenvl)-3,3-spiro[pentanel-imiciazo[1,2-alpyridin-2-one

NO

2 N 5 The title compound was prepared in 48% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1H NMR (CDCl 3 ) 6 8.33 (t, J = 2.0 Hz, 1 H), 8.29-8.27 (m, 1 H), 7.87 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.83-7.68 (m, 2H), 7.70 (t, J= 8.0 Hz, 1 H), 7.30 (d, J= 20 9.2 Hz, 1H), 2.54-2.49 (m, 2H), 2.22-2.18 (m, 2H), 2.07-1.97 (m, 4H); MS (m/e): 310 (MH*). Example 28 6-(3, 4-Dichloro-phenvl)-3,3-spirorpentanel-imidazorl,2-alpyridin-2 25 .one 37 CI C1 N The title compound was prepared in 58% yield according to the procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclopenane]-imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDC1 3 ) 6 7.77 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.72 (m, 1 H), 7.57 7.53 (m, 2H), 7.30-7.23 (m, 2H), 2.53-2.47 (m, 2H), 2.21-2.14 (m, 2H), 2.08 1.94 (m, 4H); MS (m/e): 331 (MH~). Example 29 6-(3,5-Bis-trifiluoromethyl-phenvl)-3,3-spiro[pentanel-imidazor1,2 alpyridin-2-one

CF

3 -N The title compound was prepared in 80% yield according to the 3 procedure described in Example 2, starting from 6-bromo-3,3 spiro[cyclopenane]-imidazo(1,2-a]pyridin-2-one and the corresponding boronic acid. 1H NMR (CDCl 3 ) 6 7.93 (s, 1 H), 7.88 (s, 2H), 7.84-7.79 (m, 2H), 7.30 7.28 (m, 1H), 2.54-2.48 (m, 2H), 2.23-2.16 (m, 2H), 2.09-1.97 (m, 4H); MS (m/e): 401 (MH*). !O Example 30 6-(3-Chloro-4-f luoro-phenvi)-3,3-spirorpentanel-imidazo[l,2 alpyridin-2-one 25 38 CI F N O N The title compound was prepared in 44% yield according to the procedure described in Example 2, starting from 6-bromo-3,3- spiro[cyclopenane] imidazo[1,2-a]pyridin-2-one and the corresponding boronic acid. 1 H NMR (CDCI 3 ) 5 6 7.76 (dd, J = 2.1 and 9.2 Hz, 1 H), 7.70 (d, J = 1.4 Hz, 1 H), 7.49 (dd, J = 2.3 and 6.7 Hz, 1H), 7.34-7.22 (m, 3H), 2.53-2.47 (m, 2H), 2.22-2.12 (m, 2H), 2.07-1.94 (m, 4H); MS (m/e): 317 (MH*). Example 31 A. 5-(3-Fluoro-phenvi)-1,3-dihydro-pyrroloF2,3-blpvridin-2-one F l o NN N N H The title compound was prepared in 32% yield according to the procedure described in Example 2, starting from 5-bromo-1,3-dihydro 5 pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedure described in W02003082868, Page33) and 3-fluoro-phenyl boronic acid. 1 H NMR is the same as the one reported in W02003082868, page 34. B. 5-(3-Fluoro-phenvl)-3,3-dimethyl-1,3-dlhydro-pyrrolo[2,3 20 blpyridin-2-one F N0 N N H 39 A solution of 5-(3-Fluoro-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (91 mg, 0.40 mmol) in THF (8 mL) was cooled to between -10 and -30 'C under argon. To this solution was added n-butyllithium (0.34 mL, 0.84 mmol) followed by N,N,N',N'-tetramethylenediamine (0.13 mL, 0.84 mmol). The solution was stirred at -10 QC for 0.5 hours. lodomethane was added (0.05 mL, 0.84 mmol) and the solution was allowed to warm to room temperature overnight. . The reaction mixture was diluted with water and then extracted three times with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, evaporated to yield a tan solid. The ) crude material was purified by column chromatography eluting with 40% ethyl acetate/hexanes. The product was obtained as off-white solid (23 mg, 22%). H NMR (CDCl 3 ) 6 8.74 (s, 1H), 8.36 (d, J= 1.9 Hz, 1H), 7.62 (d, J= 2.0 Hz, 1H), 7.46-7.41 (m, 1H), 7.33 (d, J= 7.8 Hz, 1H), 7.24-7.23 (m, 1H), 7.11-7.06 (m, 1H), 1.48 (s, 6H); MS (m/e): 257 (MH*). Example 32 5-(3-Fluoro-phenvl)-3,3-spiro[cyclohxanel-1,3-dihvdro-pyrrolof2,3 blpyridln-2-one F 0 N N 20 H The title compound was prepared in 24% yield according to the procedure described in Example 30B, starting from 5-(3-Fluoro-phenyl)-1,3-dihydro pyrrolo[2,3-b]pyridin-2-one and 1,5-diiodopentane. 'H NMR (CDCls) 6 9.40 (s, 1 H), 8.37 (s, 1 H), 7.87 (d, J= 1.9 Hz, 1 H), 7.47-7.38 (m, 1 H), 7.33 (d, J = 7.8 Hz, 25 1H), 7.24-7.23 (m, 1H), 7.11-7.06 (m, 1H), 1.99-1.67 (m, 1OH); MS (m/e): 297 (MH*). 40 Example 33 In Vitro Test T47D human breast cancer cells are grown in RPMI medium without phenol red (Invitrogen) containing 10% (v/v) heat-inactivated fetal bovine serum (FBS; Hyclone), 1% (v/v) penicillin-streptomycin (Invitrogen), 1% (w/v) glutamine (Invitrogen), and 10 mg/mL insulin (Sigma). Incubation conditions are 37 OC in a humidified 5% (v/v) carbon dioxide environment. For assay, the cells are plated in 96-well tissue culture plates at 10,000 cells per well in assay medium [RPM[ medium without phenol red (Invitrogen) containing 5% (v/v) ) charcoal-treated FBS (Hyclone) and 1 % (v/v) penicillin-streptomycin (Invitrogen)]. Two days later, the medium is decanted and the compounds are added in a final concentration of 0.1% (v/v) dimethyl sulfoxide in fresh assay medium. Twenty-four hours later, an alkaline phosphatase assay is performed using a SEAP kit (BD Biosciences Clontech, Palo Alto, CA). Briefly, the 5 medium is decanted and the cells are fixed for 30 minutes at room temperature with 5% (v/v) formalin (Sigma). The cells are washed once with room temperature Hank's buffered saline solution (Invitrogen). Equal volumes (0.05 mL) of 1X Dilution Buffer, Assay Buffer and 1:20 substrate/enhancer mixture are added. After 1-hour incubation at room temperature in the dark, the lysate 3 is transferred to a white 96-well plate (Dynex) and luminescence is read using a LuminoSkan Ascent (Thermo Electron, Woburn, MA). Table 3 R1 R3R20 R3 N 0 2 25 Ex.# R1, R2 R4 % inh. 1-C3 Spirocyclohexane Br 3 Spirocyclohexyl 3-Cl-phenyl 104% 41 1-Cl Dimethyl Br 53% 2 Dimethyl 3-CI-phenyl 15% 4 Dimethyl 3-CN-phenyl 190/ 5 Dimethyl Cl 31% 6 Spirocyclohexyl Cl 42% 7 Dimethyl 3,5-di-F-phenyl 400/ 8 Dimethyl 3-N0 2 -phenyl 33% 9 Dimethyl 3-CF 3 -phenyl 17% 10 Dimethyl 2,4-di-F-phenyl 29% 11 Dimethyl 3,5-di-CF 3 -phenyl 19% 12 Dimethyl 3-MeO-phenyi 3.1% 13 Dimethyl 3-F-phenyl 14% 14 Dimethyl 2-CI-phenyl 0% 1-C2 spirocyclopentane Br 35% 15 spirocyclohexane 3-F-phenyl 0% 16 spirocyclohexane 3-MeO-phenyl 01% 17 spirocyclohexane 3,5-di-CF 3 -phenyl 04% 18 spirocyclohexane 3-N0 2 -phenyl 98% 19 spirocyclohexane 3-CF 3 -phenyl 97% 20 spirocyclohexane 3-CN-phenyl 96% 21 spirocyclohexane 3,5-di-F-phenyl 99% 22 spirocyclohexane 3,4-di-CI-phenyl 88% 23 spirocyclohexane 2,4-di-F-pheny 96% 24 spirocyclopentane 3-Cl-phenyl 1% 25 spirocyclopentane 3-CN-phenyl 2% 26 spirocyclopentane 3-F-phenyl 2% 27 spirocyclopentane 3-NO 2 -phenyl 86% *28 spirocyclopentane 3, 4-di-Cl-phenyl 22% 29 spirocyclopentane 3,5-di-CF 3 -phenyl 25% 30 spirocyclopentane 3-CI-4-F-phenyl 21% *: % activation: 93.82% @ 3000 nM, EC50 = 1950 nM. 42 Table 4 R1 R3 R 20 N N (II) H Ex.# R 1 , R 2

R

3 % inh. ICrO (nM) 31 Spirocydo 3-F-phenyl 92% @ 10 uM 4484 hexane 95% @ 3uM 32 Dimethyl 3-F-phenyl 58% @ 10 uM 7027 58% @ 3 uM Example 34 While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the ) following claims and their equivalents. 43

Claims (9)

1. The present invention provides novel pyridine imidazoles and aza-indole derivatives of the formula: R3 2 R 3 2 'N N (I) R4 wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl and heteroaryl-alkyl; wherein the cycloalkyl, aralkyl or heteroaryl-alkyl group is optionally substituted Vwith one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, S(alkyl), S0 2 (alkyl), NO 2 , CN, CO 2 H, -ORc, -S02-NR'RE, -NRDRE, NRD-SO 2 R F, -(alkyl)0-4-C(O)NR"R E, (alkyI)0-4-NR -_C(O)-RF, -(alkyl)lo-4-(Q)o-1-(alkyl)0-4 NRDRE; wherein Rc is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), S0 2 (alkyl), NO 2 , CN, CO 2 H, RC, -S0 2 -NRD R E, NR R E, NR D-SO 2 -R F, -(alkyl)o.4-C(O)-NRDRE, -(alkyl)o

4-NR'-C(O)-RF, -(alkyl)0-4-(0)0-1-(alkyl)0)-4-NR'RE, 5 wherein 0 is selected from the group consisting of 0, S, NH, N(alkyl) and -CH=CH-; wherein RD and RE are each independently selected from the group consisting of hydrogen and alkyl; alternatively RD and RE are taken together 44 with the nitrogen atom to which they are bound to form a 4 to 8 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; wherein RF is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, ) heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 5 R 3 is selected from the group consisting of halogen, CF 3 , hydroxy, Rc, nitro, cyano, SO 2 (alkyl), -C(O)RG, -C(O)ORG, -OC(O)RG, -OC(O)ORG, OC(O)N(RG) 2 , -N(RG)C(O)RG, -OSi(RG) 3 -OR", -SO 2 N(RG) 2 , -O-(alkyl) 1 . 4 C(O)RG, -(alkyl)1.4C(O)ORG, aryl and heteroaryl, wherein aryl or heteroaryl is optionally substituted with one or more substituents independently selected 3 from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, - OC(O) alkyl or -C(O)O-alkyl; wherein each RG is independently selected from hydrogen, alkyl, aryl, aralkyl; wherein the alkyl, aryl or aralkyl group is optionally substituted with one ?5 or more substituents independently selected from alkyl, halogenated alkyl, alkoxy, halogen, hydroxy, nitro, cyano, - OC(0)-alkyl or -C(O)O-alkyl; alternatively two RG groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted with one or more substituents 30 independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 45 R 4 is selected from the group consisting of hydrogen, acetyl, S0 2 (alkyl), alkyl, cycloalkyl, aralkyl or heteroaryl-alkyl; wherein the cycloalkyl, aralkyl or heteroaryl-alkyl group is optionally substituted with one or more substituents 5 independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), S0 2 (alkyl), NO 2 , CN, CO 2 H, -ORc, -SO 2 -NRDRE, -NR RE, NRDS02-RF (alkyl)0..4-C(0)NR DR E, (alkYl)0-4-NR D-C(0)-R F, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDR E, wherein Rc is selected from the group consisting of alkyl, cycloalkyl, 10 cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, -SH, -S(alkyl), S0 2 (alkyl), NO 2 , CN, 15 C0 2 H, RC, -SO 2 -NRDRE, NRDRE, NRD-SO 2 -RF, -(alkyl)0. 4 -C(O)-NRDRE, -(alkyl)o 4-NRD-C(O)-RF, -(aikyl)0-4-(Q)o-1-(alkyi)0.4-NR RE wherein Q is selected from the group consisting of 0, S, NH, N(alkyl) and -CH=CH-; 20 wherein RD and RE are each independently selected from the group consisting of hydrogen and alkyl; alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 4 to 8 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl; wherein 25 the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; wherein RF is selected from the group consisting of hydrogen, alkyl, 30 cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, 46 heteroaryl, heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 5 or a pharmaceutically acceptable salt thereof. 2. The compound of Claim 1 wherein R 1 and R 2 are methy. 3. The compound of claim 1 wherein R 1 and R 2 are connected by 0 -(CH 2 ) 4 - to form a 5-membered spiro ring. 4. The compound of claim 1 wherein R 1 and R 2 are connected by (CH 2 ) 5 - to form a 6-membered spiro ring. 5 5. The compound of Claim 1 wherein R 3 is halogen, CN, CF 3 , NO 2 or S0 2 (alkyl).

6. The compound of Claim 1 wherein R 3 is aryl or heteroaryl, wherein said aryl or heteroaryl are mono-, di-, or tri-substituted by halogen, NO 2 , CF 3 .0 or CN, O(alkyl).

7. The compound of Claim 1 wherein R 4 is hydrogen, lower alkyl, aralkyl, heteroarylalkyl or acetyl. 25 8. The compound of Claim 1 selected from the group consisting of: 6-(3-nitro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2-one, 6-(3-trifluoromethyl -phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2 a]pyridin-2-one, 30 6-(3-cyano-phenyl)-3,3-spiro[cyclohexane]-imidazoll,2-a]pyridin-2-one, 47 6-(3, 5-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2 one, 6-(3, 5-Dichloro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2 one, 5 6-(2, 4-Difluoro-phenyl)-3,3-spiro[cyclohexane]-imidazo[1,2-a]pyridin-2 one, 5-(3-Fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one; and 5-(3-Fluoro-phenyl)-3,3-spiro[cyclohxane]-1,3-dihydro-pyrrolo[2,3 0 b]pyridin-2-one.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1. 15 10. A method of treating a disorder mediated by an eprogesteron receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Claim 1.

11. The method of Claim10, wherein the disorder mediated by an M progesterone receptor is selected from the group consisting of related to the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minication of side effects of cyclid menstrual bleeding. 25

12. The method of Claim 10, wherein the disorder mediated by a progesterone receptor is selected from the group consisting of contraception.

13. A method of treating a disorder mediated by a progesterone 30 receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of Claim 9. 48

14. A method of contraception comprising co-therapy with a therapeutically effective amount of a compound of claim 1 and estrogen or an estrogen agonist. 5 49