Title of Invention: Gonadotropin-releasing hormone receptor antagonists and methods relating thereto Abstract: GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates, and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof. Detailed Description: Part general_description_paragraphs: Part BACKGROUND: 1. Technical Field This invention relates generally to gonadotropin-releasing hormone (GnRH) receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof. 2. Description of the Related Art Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) that plays an important role in human reproduction. GnRH is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is responsible for the regulation of gonadal steroid production in both males and females, while FSH regulates spermatogenesis in males and follicular development in females. Due to its biological importance, synthetic antagonists and agonists to GnRH have been the focus of considerable attention, particularly in the context of prostate cancer, breast cancer, endometriosis, uterine leiomyoma (fibroids), ovarian cancer, prostatic hyperplasia, assisted reproductive therapy, and precocious puberty (The Lancet 358:1793-1803, 2001; Mol. Cell. Endo. 166:9-14, 2000). For example, peptidic GnRH agonists, such as leuprorelin (pGIu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt), have been used to treat such conditions. Such agonists appear to function by binding to the GnRH receptor in the pituitary gonadotropins, thereby inducing the synthesis and release of gonadotropins. Chronic administration of GnRH agonists depletes gonadotropins and subsequently down-regulates the receptor, resulting in suppression of steroidal hormones after some period of time (e.g., on the order of 2-3 weeks following initiation of chronic administration). In contrast, GnRH antagonists are believed to suppress gonadotropins from the onset, and thus have received the most attention over the past two decades. To date, some of the primary obstacles to the clinical use of such antagonists have been their relatively low bioavailability and adverse side effects caused by histamine release. However, several peptidic antagonists with low histamine release properties have been reported, although they still must be delivered via sustained delivery routes (such as subcutaneous injection or intranasal spray) due to limited bioavailability. In view of the limitations associated with peptidic GnRH antagonists, a number of nonpeptidic compounds have been proposed. Recently published PCT applications which disclose compounds and their use as GnRH antagonists include WO 00/69859, WO 01/29044, WO 01/55119, WO 03/013528, WO 03/011870, WO 03/011841, WO 03/011839, WO 03/011293, WO 05/007164, WO 05/007165 and WO 05/007633. While significant strides have been made in this field, there remains a need in the art for effective small molecule GnRH receptor antagonists. There is also a need for pharmaceutical compositions containing such GnRH receptor antagonists, as well as methods relating to the use thereof to treat, for example, sex-hormone related conditions. The present invention fulfills these needs, and provides other related advantages. Part BRIEF SUMMARY: In brief, this invention is generally directed to gonadotropin-releasing hormone (GnRH) receptor antagonists, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. More specifically, the GnRH receptor antagonists of this invention are compounds having the following general structure (I): including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined below. The GnRH receptor antagonists of this invention may have utility over a wide range of therapeutic applications, and may be used to treat a variety of sex-hormone related conditions in both men and women, as well as a mammal in general (also referred to herein as a “subject”). For example, such therapeutic applications include endometriosis, uterine fibroids, polycystic ovarian disease, dysmenorrhea, dyspareunia, menorrhagia, nonmenstrual pelvic pain, pelvic tenderness, induration, general disorders of the menstrual cycle, premature ovarian failure due to chemotherapy or early menopause, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, adenomyosis, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, lower urinary tract symptoms (LUTS), contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization). The compounds of this invention may also be useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis. The compounds also may be useful in combination with androgens, estrogens, progesterones, antiestrogens, antiprogestogens, angiotensin-converting enzyme inhibitors, angiotensin II-receptor antagonists, renin inhibitors, bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, aromatase inhibitors, analgesics such as non-steroidal anti-inflamatory drugs (NSAIDS), other COX inhibitors, and anti-NGF agents. The methods of this invention include administering an effective amount of a GnRH receptor antagonist, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in still a further embodiment, pharmaceutical compositions are disclosed containing one or more GnRH receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent. These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety. Part DETAILED DESCRIPTION: As mentioned above, the present invention is directed generally to compounds useful as gonadotropin-releasing hormone (GnRH) receptor antagonists. The compounds of this invention have the following structure (I): and stereoisomers, esters, solvates, and pharmaceutically acceptable salts thereof, wherein: A is pyridyl, phenyl, quinolinyl, naphthyridinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl are substituted with 0-5 R4; R1a is H, halogen, C1-4alkyl, C1-4alkoxy or trifluoromethyl; R1b and R1c are the same or different and are independently H, halogen, hydroxy, haloC1-4alkyl, —C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, or —S(O)m—C1-6alkyl-(R5)p; R1d is F, Cl, methyl, CF3 or cyano; R2 is C1-4alkyl-(R5)p; R2a is phenyl substituted with 0-4 R3, heteroaryl substituted with 0-4 R3, C1-6alkyl substituted with 0-4 R3, aryl-C1-4alkyl substituted with 0-4 R3, or heteroaryl-C1-4alkyl substituted with 0-4 R3; or R2 and R2a taken together with the nitrogen to which they are attached form a heterocycle which is substituted with 0-4 R3; R3 at each occurrence is independently halogen, cyano, halo-C1-4alkyl, R5, —C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, —S(O)m—C1-6alkyl-(R5)p, —O—C1-6alkyl-NR7—C1-6alkyl-(R5)p, heterocycle-(R5)p; R4 at each occurrence is independently halogen, C1-6alkyl, haloC1-4alkyl, C1-6alkoxy, hydroxy, cyano, thioC1-6alkyl, —C(O)NR7R8 or 5 member heteroaryl; R5 at each occurrence is independently H, hydroxy, —OC(O)—C1-6alkyl, —OC(O)O—C1-6alkyl, —OC(O)—C1-6alkyl-NR7R8, —COOR6, —C(O)NR7R8, —NR7C(O)NR7R8, —S(O)2NR9R9, —S(O)m—C1-4alkyl, —NR7R8, C1-6alkoxy, —O-heterocycle, or heterocycle wherein said heterocycle and said —O-heterocycle are substituted with 0-4 groups selected from halogen, C1-6alkyl, C1-4haloalkyl, hydroxy, oxo, thio, —NH2, —S(O)2C1-4alkyl and —COOH; R6 at each occurrence is independently H, C1-4alkyl, C1-4alkyl-O—C(O)—C1-6alkyl, or C1-4alkyl-O—C(O)—O—C1-6alkyl; R7 at each occurrence is independently H, C1-4alkyl, hydroxy, or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C1-6alkyl, hydroxy, keto, —NH2 and —COOH; R8 at each occurrence is independently H, C1-4alkyl, haloC1-4alkyl, —C(O)—C1-4alkyl, —C(O)-haloC1-4alkyl, —C(O)NR7C1-4alkyl, —S(O)m-haloC1-4alkyl or —S(O)m—C1-4alkyl; R9 at each occurrence is independently H, C1-4alkyl, or —C(O)C1-4alkyl; m is 0-2; and p at each occurrence is independently 1-3. As used herein, the above terms have the following meaning: “Alkyl” means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms. The term “C1-4alkyl” has the same meaning as alkyl but contains from 1 to 4 carbon atoms while the term “C1-6alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH2-cyclopropyl, —CH2-cyclobutyl, —CH2-cyclopentyl, —CH2-cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls, also referred to as “homocyclic rings,” and include di- and poly-homocyclic rings such as decalin and adamantyl. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like. “Aryl” means an aromatic carbocyclic moiety such as phenyl or naphthyl. “Arylalkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as —CH2pyridinyl, —CH2pyrimidinyl, and the like. “Heteroaryl” means an aromatic heterocycle ring of 5- to 10-members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. “Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as —CH2pyridinyl, —CH2pyrimidinyl, and the like. “Heterocycle” (also referred to herein as a “heterocycle ring”) means a 5- to 7-membered monocyclic, or 7- to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperizinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. “Haloalkyl” means an alkyl group having at least one hydrogen atom replaced with a halogen, such as trifluoromethyl and the like. “Halogen” means fluoro, chloro, bromo or iodo, typically fluoro or chloro. “Hydroxy” means —OH. “Oxo” means an oxygen double bonded to a carbon (means C═O). “Thio” means a sulfur double bonded to a carbon (means C═S). “Alkoxy” means an alkyl moiety attached through an oxygen bridge (i.e., —O-alkyl) and includes groups such as methoxy and ethoxy. “Alkylthio” means an alkyl moiety attached through a sulfur bridge (i.e., —S-alkyl) and includes groups such as methylthio and ethylthio. In an embodiment, compounds of the present invention have the following structure: or a stereoisomer, ester, solvate or pharmaceutically acceptable salt thereof, wherein: A is pyridyl, phenyl, quinolinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl are substituted with 0-4 R4; R1a is H, halogen, C1-4alkyl, C1-4alkoxy or trifluoromethyl; R1b and R1c are the same or different and are independently H, halogen, hydroxy, haloC1-4alkyl, —C1-6alkyl-(R5)p, —C1-6O—C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, or —S(O)m—C1-6alkyl-(R5)p; R1d is Cl, methyl, CF3 or cyano; R2 is C1-4alkyl-(R5)p; R2a is phenyl substituted with 0-4 R3; or R2 and R2a taken together with the nitrogen to which they are attached form a heterocycle which is substituted with 0-4 R3; R3 at each occurrence is independently halogen, haloalkyl, hydroxy, —C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, —S(O)m—C1-6alkyl-(R5)p, —CO2R6, —C(O)NR7R8; R4 at each occurrence is independently halogen, alkyl, haloalkyl, alkoxy, hydroxy, cyano, thioalkyl, —C(O)NR7R8 or 5 member heteroaryl; R5 at each occurrence is independently H, hydroxy, —OC(O)—C1-6alkyl, —OC(O)O—C1-6alkyl, —OC(O)—C1-6alkyl-NR7R5, —C(O)OR6, —C(O)NR7R8, —S(O)2NR9R9, —S(O)mC1-6alkyl, —NR7R8, C1-6alkoxy, or a heterocycle selected from the group consisting of R6 at each occurrence is independently H, C1-4alkyl, C1-4alkyl-O—C(O)—C1-6alkyl, or C1-4alkyl-O—C(O)—O—C1-6alkyl; R7 is H, C1-4alkyl or hydroxy; R8 is H, C1-4alkyl, —C(O)—C1-4alkyl, —C(O)NR7—C1-4alkyl, or —S(O)m—C1-4alkyl; R9 at each occurrence is independently H, C1-4alkyl, or —(O)C1-4alkyl; m is 0-2; and p at each occurrence is independently 1-3. In embodiments of the present invention, A of structure (I) may be 2-pyridyl substituted with an R4 group as shown in structure (II) and 3-pyridyl substituted in the 4 and 6 positions with R4 as shown in structure (III). In an embodiment, R2 of structure (I) is methyl and R2a is phenyl substituted with one R3 group as shown in structure (IV). In other embodiments, R2 and R2a of structure (I) taken together with the nitrogen to which they are attached cyclize to form a heterocycle ring where the heterocycle ring is 1,2,3,4-tetrahydro-quinolin-1-yl (here shown as substituted with two R3 groups at the 4 position) as shown in structure (V) and 1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-on-5-yl (here shown as substituted with a R3 group) as shown in structure (VI). In other embodiments, R2 and R2a of structure (I) taken together with the nitrogen to which they are attached cyclize to form a heterocycle ring where the heterocycle ring is 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl (here shown as substituted with two R3 groups at the 4 position and another R3 elsewhere) as shown in structure (VII) and the same ring instead substituted with 3 R3 groups, 2 of which are at the 5 position as shown in structure (VIII). In an embodiment, A of structure (I) is quinolin-2-yl substituted with cyano at the 3 position and with 2 R4 substituents as shown in structure (IX). Structure (X) shows an embodiment of structure (I) where A is a pyrimidin-2-one with 2 R4 substitutions. Structure (XI) shows an embodiment of structure (I) where R2a is phenyl substituted with two R3 groups, wherein one of the R3 groups is —O—C1-6alkyl-R5, where R5 is COOR6 and R6 is hydrogen. In other embodiments of structure (I), R1b is —O—C1-6alkyl-R5, where R5 is H, OH, and COOH as shown in structures (XII), (XIII), and (XIV), respectively. In an embodiment of structure I, R1d is a chloro group as illustrated in structure (XV). In another embodiment of structure (I), R1a and R1c can be hydrogen, while R1d is chloro group and R1b is —O—C1-6alkyl-R5 as shown in structure (XVI). In other embodiments, A of structure (I) is 2-trifluoromethyl-isonicotinonitrile as shown in structure (XVII). In a further embodiment of structure (XVII), R1d may be a chloro group as illustrated in Structure (XVIII). In an embodiment, R1b of structure (XVIII) is —O—C1-6alkyl-R5, specifically alkyl is one carbon and R5 is H giving a methoxy as shown in structure (XIX). In an embodiment of structure (I), A is 2-cyano-4-trifluoromethyl-phenyl group as shown in Structure (XX). In another embodiment, R2 and R2a of structure (I) taken together with the nitrogen to which they are attached cyclize to form a heterocycle ring where the heterocycle ring is 1,2,3,4-tetrahydro-[1,8]naphthyridin1-yl substituted with 2 R3 groups as shown in structure (XXI) and 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl substituted with an -alkyl-R5 group as shown in structure (XXII). In an embodiment of structure (I), R2a is a benzyl group and R2 is a methyl group. In an embodiment of structure (I), R2a is a substituted benzyl group where the benzyl group is substituted with 1-3 R3 and R2 is a methyl group. In an embodiment of structure (I), R1b is O—C1-6alkyl(R5)p group, where alkyl is —CH2CH2—, R5 is CO2H and p is 1. In an embodiment of structure (I), R1b is O—C1-6alkyl(R5)p group, where alkyl is —CH2CH2CH2—, R5 is CO2H and p is 1. In an embodiment of structure (I), R1b is O—C1-6alkyl(R5)p group, where alkyl is —CH2CH2CH2—, R5 is CO2H and p is 1. In an embodiment of structure (I), R1b is O—C1-6alkyl(R5)p group, where alkyl is —CH2CH2CH2—, R5 is tetrazole group and p is 1. In an embodiment, A of structure (I) is 2-pyridyl substituted with 0-4 R4. In an embodiment, A of structure (I) is 2-pyridyl substituted with 2 R4 groups at the 3 and 5 position. In an embodiment, A of structure (I) is 3-pyridyl substituted with 0-4 R4. In an embodiment, A of structure (I) is 3-pyridyl substituted with 2 R4 groups at the 4 and 6 position. In a further embodiment, A of structure (I) is 4-cyano-6-trifluoromethylpyridin-3-yl. In an embodiment, A of structure (I) is 3-cyano-5-fluoro-quinoline-2-yl. In an embodiment, A of structure (I) is 3-cyano-5-trifluoromethyl-quinoline-2-yl. In an embodiment, A of structure (I) is 3-cyano-[1,5]naphthyridin-2-yl. In an embodiment, A of structure (I) is phenyl substituted with 0-4 R4. In an embodiment, R4 is selected from halogen, haloalkyl, alkyl and cyano. In an embodiment, A is substituted with 2 R4 groups wherein each R4 is independently selected from halogen cyano and trifluoromethyl. R1a and R1c, in an embodiment, are both H. In an embodiment, R1d is Cl, F, CF3 or methyl. In an embodiment, R1d is Cl. In an embodiment, R1b is H, hydroxy, —C1-6alkyl-(R5)p, or —O—C1-6alkyl-(R5)p. In an embodiment, R1b is H, hydroxy, or —O—C1-6alkyl-(R5)p where R5 at each occurrence is H. In an embodiment, R1b is —O—C1-6alkyl-(R5)p. In an embodiment, R1b is —O—C1-6alkyl-(R5)p where —C1-6alkyl- is —C2-4alkyl-. In an embodiment, R1b is —O—C1-6alkyl-(R5)p where —C1-6alkyl- is —CH2CH2CH2—. In an embodiment, R1b is —O—C1-6alkyl-(R5)p where R5 is hydroxy or COOH. In an embodiment, R1b is —O—C1-6alkyl-(R5)p where R5 is H and p is 1. In an embodiment, R2 is —C1-6alkyl-(R5)p where R5 at each occurrence is H. In an embodiment, R2a is phenyl substituted with 0-4 R3 or heteroaryl substituted with 0-4 R3. In an embodiment, R2a is phenyl substituted with 0-4 R3 where R3 is selected from halogen, cyano, halo-C1-4alkyl, R5, —C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, —S(O)m—C1-6alkyl-(R5)p, —O—C1-6alkyl-NR7—C1-6alkyl-(R5)p, heterocycle-(R5)p. In an embodiment, R2a is a heteroaryl substituted with 0-4 R3, where R3 is selected from halogen, cyano, halo-C1-4alkyl, R5, —C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, —S(O)m—C1-6alkyl-(R5)p, —O—C1-6alkyl-NR7—C1-6alkyl-(R5)p, heterocycle-(R5)p. In an embodiment, R2a is pyridyl substituted with 0-4 R3 where R3 is selected from halogen, cyano, halo-C1-4alkyl, R5, —C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, —S(O)m—C1-6alkyl-(R5)p, —O—C1-6alkyl-NR7—C1-6alkyl-(R5)p, heterocycle-(R5)p. In an embodiment, R2 and R2a taken together with the nitrogen to which they are attached form a heterocycle which is substituted with 0-4 R3. In an embodiment, R3 is halogen, cyano, halo-C1-4alkyl, —O—C1-6alkyl-(R5)p, or heterocycle-(R5)p. In an embodiment, R3 is halogen, cyano, —O—C1-4alkyl-(R5)p, or heterocycle-(R5)p. In an embodiment, R3, at one occurrence, is —O—C1-6alkyl-(R5)p, where R5 is H, hydroxy, —COOH or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C1-4alkyl, C1-4haloalkyl, hydroxy, oxo, thio, —NH2, —S(O)2C1-4alkyl and —COOH. In an embodiment, R3, at one occurrence, is —O—C1-6alkyl-(R5)p, where R5 is OH or —COOH. In an embodiment, R3, at one occurrence is —O—C1-6alkyl-(R5)p where —C1-6alkyl- is —C2-3alkyl-. In an embodiment, R3, at one occurrence is —O—C1-6alkyl-(R5)p where —C1-6alkyl- is —CH2CH2—. In an embodiment, one of R1b and R3 is —O—C1-6alkyl-(R5)p, where R5 is OH, —COOR6 or heterocycle wherein said heterocycle is substituted with 0-4 groups selected from halogen, C1-4alkyl, C1-4haloalkyl, hydroxy, oxo, thio, —NH2, —S(O)2C1-4alkyl and —COOH. In an embodiment, one of R1b and R3 is —O—C1-6alkyl-(R5)p, where R5 is OH or —COOH. In an embodiment, R1b is —O—C1-6alkyl-(R5)p, where R5 is OH or —COOH; and R2a is phenyl substituted with 1-4 R3, where R3 is selected from halogen, cyano, CF3, methoxy, methyl, or CO2R6. In an embodiment, R1b is hydrogen and R2a is phenyl substituted with 1-2 R3, where one R3 is selected from O—C1-6alkyl-(R5)p and another R3 is selected from hydrogen, halogen, cyano, CF3, methoxy, or methyl. In an embodiment, R1b is —O—CH3 and R2a is phenyl substituted with 1-2 R3, where one R3 is selected from O—C1-6alkyl-(R5)p and another R3 is selected from hydrogen, halogen, cyano, CF3, methoxy, or methyl. In an embodiment, R5 is heterocycle and may be: Representative compounds of the present invention include: 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(5,5-difluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid; 3-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(5,5-difluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-propionic acid; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(5,5-difluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-difluoro-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid; 3-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-difluoro-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-propionic acid; [5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-difluoro-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-acetic acid; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3-dihydro-benzo[1,4]thiazine-4-sulfonyl)-phenoxy]-butyric acid; 3-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3-dihydro-benzo[1,4]thiazine-4-sulfonyl)-phenoxy]-propionic acid; [5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3-dihydro-benzo[1,4]thiazine-4-sulfonyl)-phenoxy]-acetic acid; 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butyl)-phenyl]-2-trifluoromethyl-isonicotinonitrile; 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(3-hydroxy-propyl)-phenyl]-2-trifluoromethyl-isonicotinonitrile; 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(2-hydroxy-ethyl)phenyl]-2-trifluoromethyl-isonicotinonitrile; 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butyl)-phenyl]-pyridine-2,4-dicarbonitrile; 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(3-hydroxy-propyl)-phenyl]-pyridine-2,4-dicarbonitrile; 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(2-hydroxy-ethyl)-phenyl]-pyridine-2,4-dicarbonitrile; 4-[5-Chloro-4-(4,6-dicyano-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(5-fluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-fluoro-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid; 4-[5-Chloro-2-(2,3-dihydro-benzo[1,4]thiazine-4-sulfonyl)-4-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric acid; 4-[5-Chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric acid; 4-[5-Chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-4-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric acid; 3-{1-[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzenesulfonyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-9-yloxy}-propionic acid; 3-{1-[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzenesulfonyl]-1,2,3,4-tetrahydro-quinolin-8-yloxy}-propionic acid; 3-{1-[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzenesulfonyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yloxy}-propionic acid; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid ethyl ester; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid 1-isopropoxycarbonyloxy-ethyl ester; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid 1-cyclohexyloxycarbonyloxy-ethyl ester; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid 2,2-dimethyl-propionyloxymethyl ester; 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-methoxy-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid; 3-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-methoxy-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenyl]-propionic acid; 4-[5-Chloro-4-(4,6-dicyano-pyridin-3-yl)-2-(4-methoxy-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid; 4-[5-Chloro-4-(4-ethynyl-6-trifluoromethyl-pyridin-3-yl)-2-(4-methoxy-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid; and 4-[5-Chloro-2-(4-methoxy-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-prop-1-ynyl-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric acid. The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. In general, the compounds of structure (I) above may be made by the following reaction schemes, wherein all substituents are as defined above unless indicated otherwise. 4-Chloro-3-nitrobenzenesulfonyl chloride (I) is coupled with an aniline of formula (II) to form the sulfonamide (III), which is further reduced to aniline (IV). The aniline (IV) is then converted to the bromide (V). Generally the bromide is reacted with bis(pinacolato)diboron to form the boronic ester (VI) or a boronic acid. The boron species (VI or boronic acid) is coupled with a suitable aryl or heteroaryl halide to yield structure (VII). Alternatively, bromide (V) is directly coupled with a suitable aryl or heteroaryl boronic acid to yield (VII). Typically the heteroaryl group exemplified is a substituted pyridine or quinoline. 1-Bromo-2-chloro-4-fluoro-benzene (VIII) is chlorosulfonylated to the benzenesulfonyl chloride (IX) which is further coupled with amines of general formula (II) to provide the fluorosulfonamides (X). Treatment (X) with sodium methoxide affords the aryl ether (XI). Demethylation with boron tribromide or HBr gives the phenol (XII). The phenol is further alkylated with a suitable alkyl halide to yield the aryl ether (XIII). Generation of the intermediate (XIV) is accomplished by the boronic ester formation through a palladium (0) catalyzed reaction. Subsequent Suzuki coupling with a suitable aryl or heteroaryl halide provides compound (XV). If applicable, the protecting group on R5 can be removed after Suzuki coupling reaction. Phenol (XII) may first be converted to the boron ester (XVI) through a palladium (0) catalyzed reaction. Subsequent Suzuki coupling with a suitable aryl or heteroaryl halide affords biaryl alcohol (XVII). This intermediate is further alkylated with a suitable alkyl halide to provide compounds of general formula (XV). If applicable, the protecting group on R5 can be removed after Suzuki coupling reaction. For compounds containing fluorine in the central ring, bromide (X) is independently converted to its corresponding boron ester (XVIII). Suzuki reaction with a suitable aryl or heteroaryl halide affords fluoro-substituted sulfonamides (XIX) Compounds of general formula (XX) may be modified to the carboxylic acid (XXI) by deprotection under suitable acidic or basic conditions. Alternatively the alcohol (XXII) may be oxidized using, for example, a ruthenium catalyst to give the corresponding acid (XXI). When desirable the acid (XXI) may in turn be converted to a suitable ester of formula (XX) through coupling with a suitable alcohol. Compounds of general formula (XXII) may also be prepared starting with a displacement reaction of (X) with an alkane diol under basic conditions to give (XXIII). (XXIII) in turn is converted via a palladium (0) catalyzed reaction to provide the boron ester (XXIV) which under Suzuki conditions with a suitable aryl or heteroaryl halide yields (XXII). Intermediate aniline (IV) is converted to the urea (XXV) through a condensation with urea at elevated temperature. Further condensation with a suitable di-ketone (XXVI) yields the pyrimidinone (XXVII). Substituted aniline (IV) may be directly condensed with a suitable β-keto ester (XXVIII) to yield intermediate (XXVIX). Further reaction with acetic anhydride facilitates a ring closure reaction that generates the pyrimidinone (XXX). Boronic acid (XXXI) is subjected to Suzuki conditions to yield product (XXXII) which is chlorosulfonylated to the benzenesulfonyl chloride (XXXIII). Further coupling of XXXIII with amines of general formula (II) to provide the sulfonamides (XXXV). Compound X is treated with malonate and followed by decarboxylation in DMSO at elevated temperature to produce compound XXXVI. A boronic ester formation as described in several previous schemes and followed by Suzuki coupling and acidic ester hydrolysis yield compound XXXVII. The compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids which form non-toxic salts. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term “pharmaceutically acceptable salt” of structure (I) is intended to encompass any and all acceptable salt forms. In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or acid groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or acid groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (—COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. The compounds of the present invention may exist in a continum of solid states ranging from fully amorphous to fully crystalline. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. The term solvate is used herein to describe a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules. Such solvates are similarly included within the scope of this invention. The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of structure (I) where on or more atoms are replaced by atoms having the same atomic number but a different atomic mass. Examples include 2H and 3H for hydrogen, 11C, 13C and 14C for carbon, 36Cl for chlorine, 18F for fluorine, 123I and 125I for iodine, 13N and 15N for nitrogen, and 35S for sulfur. Compounds of the present invention include compounds of structure (I) as defined, including all polymorphs, prodrugs, isomers (including optical, geometric and tautomeric), salts, solvates and isotopes thereof. The effectiveness of a compound as a GnRH receptor antagonist may be determined by various assay techniques. Assay techniques well known in the field include the use of cultured pituitary cells for measuring GnRH activity (Vale et al., Endocrinology 91:562-572, 1972) and the measurement of radioligand binding to rat pituitary membranes (Perrin et al., Mol. Pharmacol. 23:44-51, 1983) or to membranes from cells expressing cloned receptors as described below. Other assay techniques include (but are not limited to) measurement of the effects of GnRH receptor antagonists on the inhibition of GnRH-stimulated calcium flux, modulation of phosphoinositol hydrolysis, activation of ERK1/2, mast cell histamine release, and the circulating concentrations of gonadotropins in the castrate animal. Descriptions of these techniques, the synthesis of radiolabeled ligand, the employment of radiolabeled ligand in radioimmunoassay, and the measurement of the effectiveness of a compound as a GnRH receptor antagonist follow. Cloning and Expression of GnRH Receptors cDNA's of human, rhesus macaque, rabbit, dog and rat GnRH receptors are cloned into pcDNA3.1 (+) (Invitrogen). Full length sequences of all receptors are confirmed by DNA sequencing. HEK 293, CHO, COS-7, or rat basophilic leukemia (RBL) cells are stably transfected with human, rat, or macaque GnRH receptors and high expressing single cell clones (Bmax≧0.4 pMol/mg membrane protein) are isolated and maintained in Dulbecco's Modified Eagles Medium (DMEM) with following supplements: 10 mM HEPES; 2 mM L-glutamine; 1 mM Sodium Pyruvate; 50 U/mL penicillin, 50 μg/mL streptomycin; 10% Heat-inactivated Fetal Bovine Serum and 200 μg/mL Geneticin (G-418-Sulfate). Non-essential amino acids (0.1 mM) (Irvine Scientific; Santa Ana, Calif.) are included in the RBL cell media. In general, initial peptide radioligand binding assays are carried out using membranes from stably transfected RBL cells. RBL stable clones are found to more consistently express high levels of GnRH receptor and are therefore used for subsequent binding studies as well as Ca++ flux and inositol phosphate accumulation assays. Transiently transfected COS-7 cells are used for preparation of membranes containing GnRH receptors from multiple species (as well as those of mutant receptors for other studies) because of the convenience for rapidly analyzing multiple receptors. Stably transfected CHO cells are used for ERK1/2 stimulation assays because of superior signal/noise characteristics in this assay. Membrane Preparation HEK293 cells stably transfected with the human GnRH receptor are grown for two days after achieving confluence then are harvested by striking tissue culture flasks against a firm surface. Cells are collected by centrifugation at 1000 g for 5 minutes. Cell pellets are resuspended in 5% sucrose and homogenized using a polytron homogenizer for two 15 second homogenization steps. Cell homogenates are then centrifuged for 5 minutes at 3000 g to remove nuclei and the supernatant subsequently centrifuged for 30 minutes at 44,000 g to collect the membrane fraction. The membrane pellet is resuspended in GnRH binding buffer (10 mM HEPES, pH 7.5, 150 mM NaCl and 0.1% BSA) and aliquots immediately snap-frozen in liquid nitrogen and stored at −80° C. Protein content of the membrane suspension is determined using the Bio-Rad protein assay kit (Bio-Rad). RBL cells stably transfected with the human GnRH receptor are grown to 80% confluency prior to harvesting. The cells are incubated at 37° C. for 10 min in 0.5 mM EDTA/PBS (Ca++, Mg++ free), and are dislodged from the plate by gentle rapping of the flasks. Cells are collected and pelleted by centrifugation at 1000 g for 5 minutes. Cell pellets are resuspended in buffer (DPBS supplemented with 10 mM MgCl2, 2 mM EGTA, pH=7.4), and cell lysis is performed using a pressure cell and applying N2 at a pressure of 900 psi for 30 min at 4° C. Unbroken cells and larger debris were removed by centrifugation at 1200 g for 10 min at 4° C. The cell membrane supernatant is then centrifuged at 45,000 g and the resulting membrane pellet is resuspended in assay buffer and homogenized on ice using a tissue homogenizer. Protein concentrations are determined using the Coomassie Plus Protein Reagent kit. Membranes are aliquoted and stored at −80° C. until ready for use. COS-7 cells transiently transfected with GnRH receptors from different species (human, macaque, dog, rabbit, rat) or mutant GnRH receptors are prepared by bulk electroporation. COS-7 cells are obtained from American Type Cell Culture (Manassas, Va.) and are maintained in Dulbeccos's modified Eagle's medium (DMEM) (MediaTech Inc., Herndon, Va.) containing 10% fetal bovine serum, 10 mM HEPES, 2 mM L-glutamine, 1 mM sodium pyruvate, 50 U/mL penicillin, 50 μg/mL streptomycin. COS-7 cells are seeded in 500 cm2 tissue culture plates and grown to confluency prior to cell transfection. 5×107 cells are transfected with 50 μg of the appropriate GnRH receptor DNA construct by electroporation in a BTX ElectroCell Manipulator ECM 600 (Fisher Scientific, Pittsburgh, Pa.) using the following settings: 1000 μF capacitance, 48Ω resistance, and 300 V/cm charging voltage. Transfected cells are cultured for 36-48 h prior to membrane preparation. Transiently transfected COS-7 cells are harvested, washed, and resuspended in membrane buffer (20 mM HEPES pH 7.2, 6 mM MgCl2, 1 mM EDTA). Cells are centrifuged and the cell pellets are resuspended in a small volume of membrane buffer. Cells are lysed by release of pressure following incubation at 900 psi for 30 minutes at 4° C. in a nitrogen chamber. The homogenate is centrifuged at 1000 g for 10 minutes at 4° C. to remove nuclei and cellular debris. Membranes are collected from the supernatant by centrifugation at 44,000 g for 45 minutes at 4° C. Membranes are resuspended in membrane buffer at a concentration of 1 mg/mL, quick-frozen in liquid nitrogen, and stored at −80° C. until used. Radioligand Binding Assays Radioligand binding displacement assays using the peptide radioligands are performed in buffer containing 10 mM HEPES, 150 mM NaCl and 0.1% BSA, pH=7.5. Radioligand binding assays employing the use of [3H]-1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (here the 3-methoxy group is tritiated) are run in buffer containing 50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 0.01% saponin and 0.5 mM EDTA, pH=7.5. Radioligand displacement assays are performed by incubating radioligand ([125I-Tyr5, DLeu6, NMeLeu7, Pro9-NEt]GnRH (0.1 nM), [His5, 125I-DTyr6]GnRH (0.2 nM) (31) or [3H]-1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (1 nM)), unlabeled competitors at concentrations ranging from 0.3 μM to 10 μM, and membranes for 2 snguyen@example.net. 10 to 20 μg protein/well is used from membrane preparations for human, monkey and rabbit GnRH receptor. 5 μg/well and 60 μg/well of membranes are used for rat and dog GnRH receptors, respectively. Binding assays are performed in either Millipore 96-well GF/C filtration plates (for ([125I-Tyr5, DLeu6, NMeLeu7, Pro9-NEt]GnRH assays), or in 96 well low binding plates, which are subsequently filtered onto GF/C Unifilters. Filters are pretreated with 0.5% PEI for 30 min prior to use. Reactions are terminated by rapid vacuum filtration, and the filters are washed twice with 250 μL ice cold PBS pH=7.4 (0.01% Tween-20 is included in wash media for [His5, 125I-DTyr6]GnRH and [3H]-1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil radioligands). The filters are dried, and the Millipore filters are monitored for radioactivity using a Cobra II gamma counter (Perkin Elmer Life Sciences). For assays filtered onto the GF/C Unifilter plates, 50 μL scintillation fluid is added to each filter, and radioactivity is monitored using a TopCount NXT. For iodinated radioligands, total radioligand is monitored on a gamma counter, and for the tritiated radioligand, total radioligand is monitored using a Perkin Elmer 1600TR liquid scintillation counter. Total radioligand bound does not exceed 10% of the total radioligand added, a level of depletion which does not appreciably affect the measurement of Ki. Nonspecific binding does not exceed 2% of the total radioligand added in any of the displacement assays. Inhibition of radioligand binding is fit to one-site and two-site competition binding equations and the best fit determined using an F-test. For all displacement binding experiments a single site binding model fit best (p<0.05). The Ki values are calculated from the IC50 values using the method of Cheng and Prusoff (Biochem. Pharmacol. 22:3099, 1973) and may be converted to a pKi value (negative log of the Ki value). K i = IC 50 1 + L / K D where L=radioligand and KD=affinity of radioligand for receptor. GnRH receptor antagonists of this invention have a Ki of 10 μM or less. In other embodiments of this invention, the GnRH receptor antagonists have a Ki of less than 1 μM, and in many instances have a Ki of less than 0.1 μM (i.e., 100 nM). Compounds of the present invention as shown in Examples 3 to 19 below (not including chemical intermediates) which were tested in one or more of the peptide competitive human receptor binding assays shown have Ki values of 1 μM or less. Additionally, the following compounds of the present invention as shown in Examples 3 to 19 below (not including chemical intermediates) which were tested in one or more of the peptide competitive human receptor binding assays shown have Ki values of 100 nM or less, while the underlined compounds have Ki values of 10 nM or less: 4-1, 4-2, 4-3, 4-4, 4-5, 4-8, 4-9, 4-10, 4-11, 4-13, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-23, 4-24, 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 6-1, 6-4, 6-5, 7-1, 7-2, 7-3, 7-4, 7-5, 8-2, 8-3, 9-1, 9-2, 10-1, 10-2, 11-1, 11-2, 11-3, 12-1, 12-2, 12-3, 13-1, 13-4, 15-1, 15-2, 15-3, 15-5, 15-6, 15-7, 15-8, 15-9, 15-10, 15-11, 15-12, 15-14, 15-15, 15-16, 15-17, 15-18, 15-19, 15-20, 15-21, 15-22, 15-23, 15-26, 15-28, 15-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-38, 15-39, 15-43, 15-44, 16-1, 17-1, 18-1, 18-2, 18-3, and 19-1. Wheat-germ agglutinin (WGA)-coupled polystyrene (PS) imaging beads (Amersham Biosciences, Piscataway, N.J.) are used in our scintillation proximity assay, permitting whole-plate light imaging with a CCD imaging system, as used by Viewlux (PerkinElmer Life Sciences, Boston, Mass.). Integrity of the receptor and radiolabel is monitored by saturation analysis measured at each time point to ensure a consistent Kd. Generally, the GnRH SPA assay produced reliable binding data up to 16 h of incubation. The optimal membrane/SPA bead ratio is determined for each membrane preparation and is typically 40 μg membrane/0.5 mg bead per well. Typically, the instrument is set to measure luminescence for 300 sec using a 613-nm filter to capture the red-shifted emission of the imaging beads and programmed to record at 60-min intervals for 11 h. Reactions typically consist of 50 μL unlabeled compound various concentrations; 50 μL radiolabeled [125I]-His5, D-Tyr6 GnRH ligand (˜300 μM, 2200 Ci/mmol; PerkinElmer Life Sciences); and 100 μL membrane/SPA bead added sequentially in assay buffer (10 mM HEPES, 150 mM NaCl, 0.1% bovine serum albumin [BSA; Fraction V], pH 7.5) to low binding 96-well plates (Corning, Palo Alto, Calif.). Cell membrane fractions were prepared as previously described and resuspended in assay buffer. SPA beads and membrane (rat basophilic leukemia [RBL] cells stably expressing human GnRH-R) are pre-incubated for 2 h prior to compound and radiolabel addition. The complete reaction is briefly shaken and allowed to settle at room temperature in the Viewlux instrument. The amount of bound radioligand is determined at the indicated time intervals. A single-site binding model is applied for all displacement binding experiments, as determined by a partial F test (p>0.05). Dose-response curves for both time points of all compounds tested are normalized to zero and 100% specific binding, and Ki values are calculated using the Cheng-Prusoff equation with a sigmoidal dose-response fit using Prism 4.0 software (GraphPad Software, San Diego, Calif.) using Kd values of 0.2 nM for [125I]-His5, D-Tyr6 GnRH, as determined from saturation binding experiments. Hill slopes for all curves routinely range from −0.8 to −1.1. Radioligand association experiments to estimate the affinity of compounds of the present invention may be initiated by the addition of cell membranes to wells containing an appropriate amount of a radiolabeled tracer, in the absence and presence of a range of concentrations of compound (Sullivan et al., Biochemical Pharmacology, 72, 2006, 838-849). All buffers are pre-heated to 37° C. prior to initiation of experiment, and assay plates are maintained at this temperature throughout the experiment. The assay mixture (total volume of 200 μL) is incubated at 37° C. for 1 min to 3 hr (15 time points), and the assay is terminated by rapid vacuum filtration through a cell harvester (UniFilter-96 Filtermate; Packard, PerkinElmer Life Sciences) onto Unifilter GF/B filter plate pretreated with 0.5% polyethylenimine in distilled water for 30 min. After filtration, membranes are washed two times with 400 μL wash buffer (Dulbecco's Phosphate-Buffered Saline, 0.01% Tween-20, pH 7.5). Filter plates are dried, 50 μL scintillation fluid is added (Microscint 20; PerkinElmer Life Sciences), and the plate is monitored for radioactivity using a TopCount NXT at 30% efficiency (PerkinElmer Life Sciences). The total amount of radioligand added to the assay is measured using a 1600TR liquid scintillation counter (PerkinElmer Life Sciences) at 47% efficiency. Analyses are performed using Prism 4.1 Software (GraphPad Software, San Diego, Calif.). Ca++ Flux Measurement To determine the inhibition of GnRH-stimulated calcium flux in cells expressing the human GnRH receptor, a 96-well plate is seeded with RBL cells stably transfected with the human GnRH receptor at a density of 50,000 cells/well and allowed to attach overnight. Cells were loaded for 1 hour at 37° C. in the following medium: DMEM with 20 mM HEPES, 10% FBS, 2 μM Fluo-4, 0.02% pluronic acid and 2.5 mM probenecid. Cells are washed 4 times with wash buffer (Hanks balanced salt, 20 mM HEPES, 2.5 mM probenecid) after loading, leaving 150 μL in the well after the last wash. GnRH is diluted in 0.1% BSA containing FLIPR buffer (Hanks balanced salt, 20 mM HEPES) to a concentration of 20 nM and dispensed into a low protein binding 96-well plate. Various concentrations of antagonists are prepared in 0.1% BSA/FLIPR buffer in a third 96-well plate. Cell, agonist, and antagonist containing plates are loaded into a fluorometric imaging plate reader (FLIPR) (Molecular Devices, FLIPR384 system, Sunnyvale, Calif.) for liquid handling and fluorescence measurements according to manufacturer's instructions. The instrument is programmed such that antagonist (50 μL at varying concentrations) is added to cell plates and preincubated for 1 minute prior to addition of agonist (50 μL, or 4 nM final concentration of GnRH). Measurement of [3H]IP Production The procedure is modified from published protocols (Zhou et al., J Biol Chem 270:18853-7). Briefly, RBL cells stably transfected with human GnRH receptors are seeded in 24 well plates at a density of 200,000 cell/well for 24 hrs. Cells are washed once with inositol-free medium containing 10% dialyzed FBS and then labeled with 1 μCi/mL of [myo-3H]inositol. After 20-24 hrs, cells are washed with buffer (140 mM NaCl, 4 mM KCl, 20 mM Hepes, 8.3 mM glucose, 1 mM MgCl2, 1 mM CaCl2 and 0.1% BSA) and treated with native GnRH peptide in the same buffer with or without various concentrations of antagonist and 10 mM LiCl for 1 hour at 37° C. Cells are extracted with 10 mM formic acid at 4° C. for 30 min and loaded to the Dowex AG1-X8 column, washed and eluted with 1M ammonium formate and 0.1M formic acid. The eluate is counted in a scintillation counter. Data from PI hydrolysis assay are plotted using non-linear least square regression by Prism program (GraphPad Software, San Diego, Calif.), from which dose ratio is also calculated. The Schild linear plot is generated from the dose-ratios obtained in four independent experiments by linear regression, the X-intercept is used to determine the affinity of the antagonist. Activation of ERK1/2 CHO cells stably expressing GnRH receptor are serum-starved for 1 hour, incubated for 5 min with various doses of antagonist, and stimulated with 1 nM GnRH for 5 min at 37° C. Cells are washed once with PBS and harvested directly into 2×SDS sample buffer. Cell extracts are sonicated, heated at 55° C. for 5 min, and subjected to SDS-PAGE. Resolved proteins are transferred onto nitrocellulose membranes. The activated phosphorylated form of ERK1/2 is detected using an anti-phosphoMAPK p42/44 antibody (Cell Signaling Technology, Danvers, Mass.) diluted at 1:3000 in 1% nonfat dried milk in TBST (20 mM Tris-HCl, pH 7.4, 137 mM NaCl, 0.1% Tween20). Total ERK1/2 is detected with the anti-ERK2 antibody (K23, Santa Cruz Biotechnology, Santa Cruz, Calif.). Chemiluminescent detection is performed with SuperSignal West Pico reagent (Pierce, Rockford, Ill.) and quantified on the VersaDoc3000 (Bio-Rad) imaging system. Dose-response data are plotted and analyzed with GraphPad Prism software. Histamine Release Rat peritoneal mast cells are obtained in accordance with the current NIH guidelines for the humane and ethical use of laboratory animals and animal welfare, and under an IACUC approved protocol. This method has been previously described for the evaluation of mast cell histamine release by peptide GnRH antagonists (Sundaram et al., Agents Actions 25:307-13). Briefly, six male Sprague Dawley rats 240-300 g are sacrificed by CO2 asphyxiation and 40 mL of cold PIPES buffer (25 mM PIPES, 110 mM NaCl, 5 mM KCl, 1 mg/mL glucose, 1 mg/mL BSA and 20 U/mL heparin, pH7.4) is injected into the peritoneal cavity and the abdomen massaged gently. Peritoneal wash is recovered and stored on ice. Cells from the peritoneal wash are washed 3 times with 5 mL PIPES buffer, pooled and purified on a Percoll gradient (Wells and Mann, Biochem Pharmacol 32:837-42). For stimulation assays, approximately 2×105 cells in 300 μL PIPES buffer are placed into a 1.5 mL eppendorf tube and test compound (100 μL) is added to the cell suspension. The tubes are incubated at 37° C. for 15 min and the reaction is stopped with 600 μl of ice-cold PIPES buffer. After centrifugation at 4° C., the histamine level in the supernatant is determined by histamine EIA kit from SPI-BIO (Cayman Chemical, Ann Arbor, Mich.) following manufacturer's instructions. 50 μM cetrorelix may be used as a positive control. LH Suppression in Castrate Macaques This study in macaques is conducted in accordance with the current NIH guidelines for the humane and ethical use of laboratory animals and animal welfare, and under an IACUC approved protocol. A complete orchiectomy (both testes) is performed approximately 4 weeks prior to the first dose on male cynomolgus monkeys approximately 3.7 to 6.5 years of age (3.7 to 4.8 kg). Sexual maturity is verified by testicular volume and testosterone levels prior to surgery. Blood samples are collected weekly during the 4-week post-surgery recovery period for measurement of testosterone, FSH and LH to verify the rise in gonadotropins. Antagonist is administered to the stomach by nasogastric gavage or by i.v. infusion (over ˜15 minutes). Blood samples are collected prior to and after each dose for analysis of serum LH and plasma antagonist concentrations. For the intravenous infusion dose, samples are snguyen@example.net, 0.33, 0.5, 1, 1.5, 4, 8, and 24 hrs after the initiation of the infusion. Samples are snguyen@example.net, 0.5, 1, 1.5, 2, 4, 8, and 24 hrs postdose for the oral doses. Bioactive LH concentrations in serum samples are measured at the Oregon Regional Primate Center (Beaverton, Oreg.) or the Yerkes Primate Research Center at Emory University using a previously reported mouse Leydig cell bioassay, which detects as little as 3 ng LH/mL using cynomolgus LH RP-1 as the reference preparation (Ellenwood and Resko, Endocrinology 107:902-7). As mentioned above, the GnRH receptor antagonists of this invention may have utility over a wide range of therapeutic applications, and may be used to treat a variety of sex-hormone related conditions in both men and women, as well as mammals in general. For example, such applications include endometriosis, uterine fibroids, polycystic ovarian disease, dysmenorrhea, dyspareunia, menorrhagia, nonmenstrual pelvic pain, pelvic tenderness, induration, general disorders of the menstrual cycle, premature ovarian failure due to chemotherapy or early menopause, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, adenomyosis sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, lower urinary tract symptoms (LUTS), contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization). The compounds of this invention may also be useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis. In addition, the compounds may be useful in combination with androgens, estrogens, progesterones, antiestrogens, antiprogestogens, angiotensin-converting enzyme inhibitors, angiotensin II-receptor antagonists, renin inhibitors, bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, aromatase inhibitors, analgesics such as non-steroidal anti-inflamatory drugs (NSAIDS), other COX inhibitors, and anti-NGF agents. In another embodiment of the invention, pharmaceutical compositions containing one or more GnRH receptor antagonists are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a GnRH receptor antagonist of the present invention and a pharmaceutically acceptable carrier and/or diluent. The GnRH receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably with acceptable toxicity to the patient. Appropriate concentrations and dosages can be readily determined by one skilled in the art. Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a GnRH receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the GnRH receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990. In another embodiment, the present invention provides a method for treating sex-hormone related conditions as discussed above. Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, “treat” includes prophylactic administration. Such methods include systemic administration of a GnRH receptor
{'bibliographic_information': "{'country': 'US', 'doc-number': '12594815', 'kind': 'B2', 'date': '20080404', 'extension': '253', 'invention_title': 'Gonadotropin-releasing hormone receptor antagonists and methods relating thereto'}", 'source_file': './grant/2012/ipg120911.xml', 'source_data': 'USPTO-Grant'}