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COMPOSITIONS AND METHODS FOR THE TREATMENT OF ESTROGEN-DEPENDENT DISORDERS

20220305017 · 2022-09-29

    Inventors

    Cpc classification

    International classification

    Abstract

    The present disclosure provides compositions and methods for treating estrogen-dependent disorders, such as disorders of the female reproductive system, including uterine fibroids and endometriosis, among others. Compounds described herein that may be used to treat such indications include gonadotropin-releasing hormone (GnRH) antagonists. Suitable GnRH antagonists useful in conjunction with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid and the choline salt thereof, among others. Using the compositions and methods described herein, GnRH antagonists may be periodically administered to a patient, such as one or more times per day, week, or month. Advantageously, using the dosing schedules of the present disclosure, the periodic administration the GnRH antagonist may be temporarily halted, allowing a patient to recover any lost bone mineral density, without an accompanying return in the patient's symptoms.

    Claims

    1. A method of treating an estrogen-dependent disease in a human patient in need thereof, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a gonadotropin-releasing hormone (GnRH) antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    2. The method of claim 1, wherein the estrogen-dependent disease is uterine fibroids.

    3. A method of reducing the volume of menstrual blood loss in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    4. A method of inducing amenorrhea in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    5. A method of reducing the volume of one or more uterine fibroids in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    6. A method of preserving or increasing hemoglobin in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    7. The method of claim 1, wherein the estrogen-dependent disease is endometriosis.

    8. A method of reducing the volume of one or more endometriosis nodes in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    9. A method of reducing pelvic pain in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    10. A method of reducing dysmenorrhea in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    11. A method of reducing dyspareunia in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    12. A method of reducing dyschezia in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    13. A method of reducing uterine bleeding in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    14. A method of inducing amenorrhea in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    15. The method of claim 1, wherein the estrogen-dependent disease is adenomyosis.

    16. A method of reducing uterine volume in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    17. A method of reducing the thickness of the anterior and/or posterior region of the uterine myometrium in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    18. A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    19. A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    20. A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    21. A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    22. A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    23. A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    24. A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    25. The method of claim 1, wherein the estrogen-dependent disease is rectovaginal endometriosis.

    26. A method of reducing the volume of one or more rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    27. A method of reducing the volume of one or more type III rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    28. A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    29. A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    30. A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    31. A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    32. A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    33. A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the second treatment period commences at least one week after the end of the first treatment period, and wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    34. The method of any one of claims 1-33, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    35. The method of any one of claims 1-34, wherein the GnRH antagonist that is periodically administered to the patient during the first treatment period is not a compound represented by formula (I), and the GnRH antagonist that is periodically administered to the patient during the second treatment period is a compound represented by formula (I) ##STR00609## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

    36. A method of treating an estrogen-dependent disease in a human patient in need thereof, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    37. The method of claim 36, wherein the estrogen-dependent disease is uterine fibroids.

    38. A method of reducing the volume of menstrual blood loss in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    39. A method of inducing amenorrhea in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    40. A method of reducing the volume of one or more uterine fibroids in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    41. A method of preserving or increasing hemoglobin in a human patient diagnosed as having uterine fibroids, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    42. The method of claim 36, wherein the estrogen-dependent disease is endometriosis.

    43. A method of reducing the volume of one or more endometriosis nodes in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    44. A method of reducing pelvic pain in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    45. A method of reducing dysmenorrhea in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    46. A method of reducing dyspareunia in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    47. A method of reducing dyschezia in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    48. A method of reducing uterine bleeding in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    49. A method of inducing amenorrhea in a human patient diagnosed as having endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    50. The method of claim 36, wherein the estrogen-dependent disease is adenomyosis.

    51. A method of reducing uterine volume in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    52. A method of reducing the thickness of the anterior and/or posterior region of the uterine myometrium in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    53. A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    54. A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    55. A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    56. A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    57. A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    58. A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    59. A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    60. The method of claim 36, wherein the estrogen-dependent disease is rectovaginal endometriosis.

    61. A method of reducing the volume of one or more rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    62. A method of reducing the volume of one or more type III rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    63. A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    64. A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    65. A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    66. A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    67. A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    68. A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising: a) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a first treatment period, b) monitoring the patient's bone mineral density at the end of the first treatment period, and, if the patient is determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, c) periodically administering to the patient a therapeutically effective amount of a GnRH antagonist during a second treatment period, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    69. The method of any one of claims 36-68, wherein the second treatment period commences at least one week after the end of the first treatment period.

    70. The method of claim 69, wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    71. The method of any one of claims 36-70, wherein the GnRH antagonist that is periodically administered to the patient during the first treatment period is not a compound represented by formula (I), and the GnRH antagonist that is periodically administered to the patient during the second treatment period is a compound represented by formula (I) ##STR00610## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

    72. A method of treating an estrogen-dependent disease in a human patient in need thereof, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00611## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    73. The method of claim 72, wherein the estrogen-dependent disease is uterine fibroids.

    74. A method of reducing the volume of menstrual blood loss in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00612## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or WV and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    75. A method of inducing amenorrhea in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00613## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    76. A method of reducing the volume of one or more uterine fibroids in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00614## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and WV are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    77. A method of preserving or increasing hemoglobin in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00615## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    78. The method of claim 72, wherein the estrogen-dependent disease is endometriosis.

    79. A method of reducing the volume of one or more endometriosis nodes in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00616## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    80. A method of reducing pelvic pain in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00617## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    81. A method of reducing dysmenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00618## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    82. A method of reducing dyspareunia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00619## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    83. A method of reducing dyschezia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00620## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    84. A method of reducing uterine bleeding in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00621## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    85. A method of inducing amenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00622## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    86. The method of claim 72, wherein the estrogen-dependent disease is adenomyosis.

    87. A method of reducing uterine volume in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00623## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    88. A method of reducing the thickness of the anterior and/or posterior region of the uterine myometrium in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00624## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    89. A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00625## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    90. A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00626## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    91. A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00627## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    92. A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00628## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    93. A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00629## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    94. A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00630## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    95. A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00631## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    96. The method of claim 72, wherein the estrogen-dependent disease is rectovaginal endometriosis.

    97. A method of reducing the volume of one or more rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00632## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    98. A method of reducing the volume of one or more type III rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00633## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    99. A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00634## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    100. A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00635## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    101. A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00636## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    102. A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00637## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    103. A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00638## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    104. A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient, during a second treatment period, a therapeutically effective amount of a GnRH antagonist represented by formula (I) ##STR00639## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof, wherein the patient has previously been administered, during a first treatment period, a GnRH antagonist that is not a compound represented by formula (I).

    105. The method of any one of claims 72-104, wherein the GnRH antagonist that is not a compound represented by formula (I) has been periodically administered to the patient during the first treatment period.

    106. The method of any one of claims 72-105, wherein the patient has been determined to exhibit a reduced bone mineral density at the end of the first treatment period relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period.

    107. The method of any one of claims 72-106, wherein the second treatment period commences at least one week after the end of the first treatment period.

    108. The method of claim 107, wherein the patient is not administered a GnRH antagonist during the time elapsed between the end of the first treatment period and commencement of the second treatment period.

    109. The method of any one of claims 72-108, wherein the amount of the GnRH antagonist that is periodically administered to the patient during the second treatment period is less than the amount of the GnRH antagonist that is periodically administered to the patient during the first treatment period.

    110. The method of any one of claims 1-34 and 36-70, wherein the GnRH antagonist administered during the first treatment period is a compound represented by formula (I) ##STR00640## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

    111. The method of claim 110, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00641##

    112. The method of claim 110 or 111, wherein m is 1.

    113. The method of claim 112, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00642##

    114. The method of any one of claims 110-113, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.

    115. The method of claim 114, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

    116. The method of any one of claims 110-115, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

    117. The method of claim 116, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00643##

    118. The method of any one of claims 110-117, wherein n is 2.

    119. The method of claim 118, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00644##

    120. The method of any one of claims 110-119, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.

    121. The method of claim 120, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

    122. The method of any one of claims 110-121, wherein U is a single bond.

    123. The method of any one of claims 110-122, wherein X is a group represented by —O-L-Y.

    124. The method of any one of claims 110-123, wherein L is a methylene group.

    125. The method of any one of claims 110-124, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00645## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.

    126. The method of claim 125, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00646##

    127. The method of claim 110, wherein the compound is represented by formula (Ia) ##STR00647## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.

    128. The method of claim 127, wherein the compound is represented by formula (Ib) ##STR00648##

    129. The method of claim 128, wherein the compound is represented by formula (Ic) ##STR00649## or a pharmaceutically acceptable salt thereof.

    130. The method of claim any one of claims 110-129, wherein the compound is represented by formula (VI) ##STR00650## or a pharmaceutically acceptable salt thereof.

    131. The method of claim 130, wherein the compound is the choline salt of the compound represented by formula (VI).

    132. The method of claim 131, wherein the compound is in a crystalline state.

    133. The method of claim 132, wherein the compound exhibits characteristic X-ray powder diffraction (XRPD) peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ.

    134. The method of claim 132 or 133, wherein the compound exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm.

    135. The method of any one of claims 132-134, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.

    136. The method of any one of claims 110-135, wherein the compound is orally administered to the patient during the first treatment period.

    137. The method of any one of claims 110-136, wherein the compound is administered to the patient one or more times per day, week, or month during the first treatment period.

    138. The method of claim 137, wherein the compound is administered to the patient one or more times daily during the first treatment period.

    139. The method of claim 138, wherein the compound is administered to the patient once daily during the first treatment period.

    140. The method of any one of claims 137-139, wherein the compound is administered to the patient in an amount of from about 25 mg per day to about 400 mg per day during the first treatment period.

    141. The method of claim 140, wherein the compound is administered to the patient in an amount of from about 35 mg to about 65 mg per day during the first treatment period.

    142. The method of claim 141, wherein the compound is administered to the patient in an amount of about 50 mg per day during the first treatment period.

    143. The method of claim 140, wherein the compound is administered to the patient in an amount of from about 60 mg per day to about 90 mg per day during the first treatment period.

    144. The method of claim 143, wherein the compound is administered to the patient in an amount of about 75 mg per day during the first treatment period.

    145. The method of claim 140, wherein the compound is administered to the patient in an amount of from about 85 mg to about 115 mg per day during the first treatment period.

    146. The method of claim 145, wherein the compound is administered to the patient in an amount of about 100 mg per day during the first treatment period.

    147. The method of claim 140, wherein the compound is administered to the patient in an amount of from about 185 mg to about 215 mg per day during the first treatment period.

    148. The method of claim 147, wherein the compound is administered to the patient in an amount of about 200 mg per day during the first treatment period.

    149. The method of any one of claims 1-109, wherein the GnRH antagonist administered during the first treatment period is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.

    150. The method of claim 149, wherein the GnRH antagonist administered during the first treatment period is elagolix.

    151. The method of claim 150, wherein the GnRH antagonist is orally administered to the patient during the first treatment period.

    152. The method of claim 150 or 151, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month during the first treatment period.

    153. The method of claim 152, wherein the GnRH antagonist is administered to the patient one or more times daily during the first treatment period.

    154. The method of claim 153, wherein the GnRH antagonist is administered to the patient once daily during the first treatment period.

    155. The method of any one of claims 150-154, wherein the GnRH antagonist is administered to the patient in an amount of from about 100 mg to about 600 mg per day during the first treatment period.

    156. The method of claim 155, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day during the first treatment period.

    157. The method of claim 155, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day during the first treatment period.

    158. The method of claim 155, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day during the first treatment period, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 200 mg per dose during the first treatment period.

    159. The method of claim 155, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day during the first treatment period, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 300 mg per dose during the first treatment period.

    160. The method of claim 149, wherein the GnRH antagonist administered during the first treatment period is relugolix.

    161. The method of claim 160, wherein the GnRH antagonist is orally administered to the patient during the first treatment period.

    162. The method of claim 160 or 161, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month during the first treatment period.

    163. The method of claim 162, wherein the GnRH antagonist is administered to the patient one or more times daily during the first treatment period.

    164. The method of claim 163, wherein the GnRH antagonist is administered to the patient once daily during the first treatment period.

    165. The method of any one of claims 160-164, wherein the GnRH antagonist is administered to the patient in an amount of from about 10 mg to about 60 mg per day during the first treatment period.

    166. The method of claim 165, wherein the GnRH antagonist is administered to the patient in an amount of from about 20 mg to about 50 mg per day during the first treatment period.

    167. The method of claim 166, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day during the first treatment period.

    168. The method of any one of claims 1-34, 36-70, and 110-167, wherein the GnRH antagonist administered during the second treatment period is a compound represented by formula (I) ##STR00651## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W and v are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

    169. The method of claim 168, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00652##

    170. The method of claim 168 or 169, wherein m is 1.

    171. The method of claim 170, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00653##

    172. The method of any one of claims 168-171, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.

    173. The method of claim 172, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

    174. The method of any one of claims 168-173, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

    175. The method of claim 174, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00654##

    176. The method of any one of claims 168-175, wherein n is 2.

    177. The method of claim 176, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00655##

    178. The method of any one of claims 168-177, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.

    179. The method of claim 178, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

    180. The method of any one of claims 168-179, wherein U is a single bond.

    181. The method of any one of claims 168-180, wherein X is a group represented by —O-L-Y.

    182. The method of any one of claims 168-181, wherein L is a methylene group.

    183. The method of any one of claims 168-182, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00656## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.

    184. The method of claim 183, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00657##

    185. The method of claim 168, wherein the compound is represented by formula (Ia) ##STR00658## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.

    186. The method of claim 185, wherein the compound is represented by formula (Ib) ##STR00659##

    187. The method of claim 186, wherein the compound is represented by formula (Ic) ##STR00660## or a pharmaceutically acceptable salt thereof.

    188. The method of claim any one of claims 168-187, wherein the compound is represented by formula (VI) ##STR00661## or a pharmaceutically acceptable salt thereof.

    189. The method of claim 188, wherein the compound is the choline salt of the compound represented by formula (VI).

    190. The method of claim 189, wherein the compound is in a crystalline state.

    191. The method of claim 190, wherein the compound exhibits characteristic X-ray powder diffraction (XRPD) peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ.

    192. The method of claim 190 or 191, wherein the compound exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm.

    193. The method of any one of claims 190-192, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.

    194. The method of any one of claims 168-193, wherein the compound is orally administered to the patient during the second treatment period.

    195. The method of any one of claims 168-194, wherein the compound is administered to the patient one or more times per day, week, or month during the second treatment period.

    196. The method of claim 195, wherein the compound is administered to the patient one or more times daily during the second treatment period.

    197. The method of claim 196, wherein the compound is administered to the patient once daily during the second treatment period.

    198. The method of any one of claims 195-197, wherein the compound is administered to the patient in an amount of from about 25 mg per day to about 400 mg per day during the second treatment period.

    199. The method of claim 198, wherein the compound is administered to the patient in an amount of from about 35 mg to about 65 mg per day during the second treatment period.

    200. The method of claim 199, wherein the compound is administered to the patient in an amount of about 50 mg per day during the second treatment period.

    201. The method of claim 198, wherein the compound is administered to the patient in an amount of from about 60 mg per day to about 90 mg per day during the second treatment period.

    202. The method of claim 201, wherein the compound is administered to the patient in an amount of about 75 mg per day during the second treatment period.

    203. The method of claim 198, wherein the compound is administered to the patient in an amount of from about 85 mg to about 115 mg per day during the second treatment period.

    204. The method of claim 203, wherein the compound is administered to the patient in an amount of about 100 mg per day during the second treatment period.

    205. The method of claim 198, wherein the compound is administered to the patient in an amount of from about 185 mg to about 215 mg per day during the second treatment period.

    206. The method of claim 205, wherein the compound is administered to the patient in an amount of about 200 mg per day during the second treatment period.

    207. The method of any one of claims 1-34, 36-70, and 110-167, wherein the GnRH antagonist administered during the second treatment period is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.

    208. The method of claim 207, wherein the GnRH antagonist administered during the second treatment period is elagolix.

    209. The method of claim 208, wherein the GnRH antagonist is orally administered to the patient during the second treatment period.

    210. The method of claim 208 or 209, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month during the second treatment period.

    211. The method of claim 210, wherein the GnRH antagonist is administered to the patient one or more times daily during the second treatment period.

    212. The method of claim 211, wherein the GnRH antagonist is administered to the patient once daily during the second treatment period.

    213. The method of any one of claims 208-212, wherein the GnRH antagonist is administered to the patient in an amount of from about 100 mg to about 600 mg per day during the second treatment period.

    214. The method of claim 213, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day during the second treatment period.

    215. The method of claim 213, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day during the second treatment period.

    216. The method of claim 213, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day during the second treatment period, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 200 mg per dose during the second treatment period.

    217. The method of claim 213, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day during the second treatment period, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 300 mg per dose during the second treatment period.

    218. The method of claim 207, wherein the GnRH antagonist administered during the second treatment period is relugolix.

    219. The method of claim 218, wherein the GnRH antagonist is orally administered to the patient during the second treatment period.

    220. The method of claim 218 or 219, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month during the second treatment period.

    221. The method of claim 220, wherein the GnRH antagonist is administered to the patient one or more times daily during the second treatment period.

    222. The method of claim 221, wherein the GnRH antagonist is administered to the patient once daily during the second treatment period.

    223. The method of any one of claims 218-222, wherein the GnRH antagonist is administered to the patient in an amount of from about 10 mg to about 60 mg per day during the second treatment period.

    224. The method of claim 223, wherein the GnRH antagonist is administered to the patient in an amount of from about 20 mg to about 50 mg per day during the second treatment period.

    225. The method of claim 224, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day during the second treatment period.

    226. The method of any one of claims 1-225, wherein the first treatment period has a duration of at least four weeks.

    227. The method of claim 226, wherein the first treatment period has a duration of at least eight weeks.

    228. The method of claim 227, wherein the first treatment period has a duration of at least 10 weeks.

    229. The method of claim 228, wherein the first treatment period has a duration of at least 12 weeks.

    230. The method of claim 229, wherein the first treatment period has a duration of at least 24 weeks.

    231. The method of any one of claims 1-225, wherein the first treatment period has a duration of from about four weeks to about 12 months.

    232. The method of claim 231, wherein the first treatment period has a duration of from about four weeks to about 44 weeks.

    233. The method of claim 232, wherein the first treatment period has a duration of from about four weeks to about 40 weeks.

    234. The method of claim 233, wherein the first treatment period has a duration of from about four weeks to about 36 weeks.

    235. The method of claim 234, wherein the first treatment period has a duration of from about four weeks to about 24 weeks.

    236. The method of claim 235, wherein the first treatment period has a duration of from about five weeks to about 20 weeks.

    237. The method of claim 236, wherein the first treatment period has a duration of from about six weeks to about 18 weeks.

    238. The method of claim 237, wherein the first treatment period has a duration of from about eight weeks to about 16 weeks.

    239. The method of claim 238, wherein the first treatment period has a duration of from about 10 weeks to about 14 weeks.

    240. The method of claim 239, wherein the first treatment period has a duration of about 12 weeks.

    241. The method of claim 231, wherein the first treatment period has a duration of from about 14 weeks to about 40 weeks.

    242. The method of claim 241, wherein the first treatment period has a duration of from about 16 weeks to about 32 weeks.

    243. The method of claim 242, wherein the first treatment period has a duration of from about 18 weeks to about 30 weeks.

    244. The method of claim 243, wherein the first treatment period has a duration of from about 20 weeks to about 28 weeks.

    245. The method of claim 244, wherein the first treatment period has a duration of from about 22 weeks to about 26 weeks.

    246. The method of claim 245, wherein the first treatment period has a duration of about 24 weeks.

    247. The method of any one of claims 1-246, wherein the second treatment period has a duration of at least four weeks.

    248. The method of claim 247, wherein the second treatment period has a duration of at least eight weeks.

    249. The method of claim 248, wherein the second treatment period has a duration of at least 10 weeks.

    250. The method of claim 249, wherein the second treatment period has a duration of at least 12 weeks.

    251. The method of claim 250, wherein the second treatment period has a duration of at least 24 weeks.

    252. The method of any one of claims 1-246, wherein the second treatment period has a duration of from about four weeks to about 12 months.

    253. The method of claim 252, wherein the second treatment period has a duration of from about four weeks to about 44 weeks.

    254. The method of claim 253, wherein the second treatment period has a duration of from about four weeks to about 40 weeks.

    255. The method of claim 254, wherein the second treatment period has a duration of from about four weeks to about 36 weeks.

    256. The method of claim 255, wherein the second treatment period has a duration of from about four weeks to about 24 weeks.

    257. The method of claim 256, wherein the second treatment period has a duration of from about five weeks to about 20 weeks.

    258. The method of claim 257, wherein the second treatment period has a duration of from about six weeks to about 18 weeks.

    259. The method of claim 258, wherein the second treatment period has a duration of from about eight weeks to about 16 weeks.

    260. The method of claim 259, wherein the second treatment period has a duration of from about 10 weeks to about 14 weeks.

    261. The method of claim 260, wherein the second treatment period has a duration of about 12 weeks.

    262. The method of claim 252, wherein the second treatment period has a duration of from about 14 weeks to about 40 weeks.

    263. The method of claim 262, wherein the second treatment period has a duration of from about 16 weeks to about 32 weeks.

    264. The method of claim 263, wherein the second treatment period has a duration of from about 18 weeks to about 30 weeks.

    265. The method of claim 264, wherein the second treatment period has a duration of from about 20 weeks to about 28 weeks.

    266. The method of claim 265, wherein the second treatment period has a duration of from about 22 weeks to about 26 weeks.

    267. The method of claim 266, wherein the second treatment period has a duration of about 24 weeks.

    268. The method of any one of claims 1-267, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is at least about two weeks.

    269. The method of claim 268, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is at least about four weeks.

    270. The method of claim 269, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is at least about eight weeks.

    271. The method of claim 270, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is at least about 12 weeks.

    272. The method of claim 271, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is at least about 24 weeks.

    273. The method of any one of claims 1-267, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about one week to about 48 weeks.

    274. The method of claim 273, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about one week to about 12 weeks.

    275. The method of claim 274, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about one week to about six weeks.

    276. The method of claim 275, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about two weeks to about four weeks.

    277. The method of claim 273, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is about two weeks, about three weeks, about four weeks, about five weeks, or about six weeks.

    278. The method of claim 273, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about one month to about eight months.

    279. The method of claim 278, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about one month to about six months.

    280. The method of claim 279, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is from about one month to about four months.

    281. The method of claim 273, wherein the time elapsed between the end of the first treatment period and commencement of the second treatment period is about one month, about two months, about three months, or about four months.

    282. The method of any one of claims 1-281, wherein add-back therapy is periodically administered to the patient during the first treatment period.

    283. The method of any one of claims 1-282, wherein add-back therapy is periodically administered to the patient during the second treatment period.

    284. The method of claim 282 or 283, wherein the add-back therapy is administered to the patient one or more times daily during the first and/or second treatment period.

    285. The method of claim 284, wherein the add-back therapy is administered to the patient once daily, concurrently with the GnRH antagonist, during the first and/or second treatment period.

    286. The method of claim 284, wherein the add-back therapy is administered to the patient once daily, prior to administration of the GnRH antagonist, during the first and/or second treatment period.

    287. The method of claim 284, wherein the add-back therapy is administered to the patient once daily, following administration of the GnRH antagonist, during the first and/or second treatment period.

    288. The method of claim 287, wherein the add-back therapy is administered to the patient in the form of a pharmaceutical composition comprising the GnRH antagonist.

    289. The method of any one of claims 282-288, wherein the add-back therapy comprises an estrogen.

    290. The method of claim 289, wherein the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens.

    291. The method of claim 290, wherein the estrogen is β17-estradiol.

    292. The method of claim 291, wherein the β17-estradiol is administered to the patient in an amount of about 1.0 mg/day during the first and/or second treatment period.

    293. The method of claim 291, wherein the β17-estradiol is administered to the patient in an amount of about 0.5 mg/day during the first and/or second treatment period.

    294. The method of claim 290, wherein the estrogen is ethinyl estradiol.

    295. The method of claim 294, wherein the ethinyl estradiol is administered to the patient in an amount of about 5.0 μg/day during the first and/or second treatment period.

    296. The method of claim 294, wherein the ethinyl estradiol is administered to the patient in an amount of about 2.5 μg/day during the first and/or second treatment period.

    297. The method of claim 290, wherein the estrogen is a conjugated estrogen.

    298. The method of claim 297, wherein the conjugated estrogen is administered to the patient in an amount of about 0.625 mg/day during the first and/or second treatment period.

    299. The method of claim 297, wherein the conjugated estrogen is administered to the patient in an amount of about 0.45 mg/day during the first and/or second treatment period.

    300. The method of claim 297, wherein the conjugated estrogen is administered to the patient in an amount of about 0.3 mg/day during the first and/or second treatment period.

    301. The method of any one of claims 282-300, wherein the add-back therapy comprises a progestin.

    302. The method of claim 301, wherein the progestin is selected from the group consisting of norethindrone or an ester thereof, progesterone, norgestimate, medroxyprogesterone, and drospirenone.

    303. The method of claim 302, wherein the progestin is norethindrone or norethindrone acetate.

    304. The method of claim 303, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 1.0 mg/day during the first and/or second treatment period.

    305. The method of claim 303, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.5 mg/day during the first and/or second treatment period.

    306. The method of claim 303, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.1 mg/day during the first and/or second treatment period.

    307. The method of claim 302, wherein the progestin is progesterone.

    308. The method of claim 307, wherein the progesterone is administered to the patient in an amount of about 200 mg/day during the first and/or second treatment period.

    309. The method of claim 307, wherein the progesterone is administered to the patient in an amount of about 100 mg/day during the first and/or second treatment period.

    310. The method of claim 302, wherein the progestin is norgestimate.

    311. The method of claim 310, wherein the norgestimate is administered to the patient in an amount of about 0.09 mg/day during the first and/or second treatment period.

    312. The method of claim 302, wherein the progestin is medroxyprogesterone.

    313. The method of claim 312, wherein the medroxyprogesterone is administered to the patient in an amount of about 5 mg/day during the first and/or second treatment period.

    314. The method of claim 312, wherein the medroxyprogesterone is administered to the patient in an amount of about 2.5 mg/day during the first and/or second treatment period.

    315. The method of claim 312, wherein the medroxyprogesterone is administered to the patient in an amount of about 1.5 mg/day during the first and/or second treatment period.

    316. The method of claim 302, wherein the progestin is drospirenone.

    317. The method of claim 316, wherein the drospirenone is administered to the patient in an amount of about 0.5 mg/day during the first and/or second treatment period.

    318. The method of claim 316, wherein the drospirenone is administered to the patient in an amount of about 0.25 mg/day during the first and/or second treatment period.

    319. The method of any one of claims 282-318, wherein the add-back therapy comprises about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.

    320. The method of any one of claims 282-318, wherein the add-back therapy comprises about 0.5 mg of β17-estradiol and about 0.1 mg of norethindrone acetate.

    321. The method of any one of claims 1-320, wherein the patient is a pre-menopausal female of from about 18 to about 48 years of age.

    322. The method of any one of claims 1-321, wherein the patient has been determined to exhibit a serum concentration of follicle-stimulating hormone (FSH) of about 20 IU/L or less prior to commencement of the first and/or second treatment period.

    323. The method of any one of claims 1-322, wherein the patient has been determined to exhibit a rectal (type II) and/or vaginal (type III) endometriosis node of at least 2 cm prior to commencement of the first and/or second treatment period.

    324. The method of claim 323, wherein the length of the type II and/or type III endometriosis node is assessed by way of magnetic resonance imaging (MRI).

    325. The method of any one of claims 1-324, wherein the patient has been determined to exhibit a junctional-zone width of about 12 mm or more prior to commencement of the first and/or second treatment period.

    326. The method of claim 325, wherein the junctional-zone width is assessed by way of MRI.

    327. The method of any one of claims 1-326, wherein the patient exhibits a reduction in serum concentration of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and/or β17-estradiol (E2) following administration of the GnRH antagonist to the patient.

    328. The method of claim 327, wherein the patient exhibits the reduction in serum concentration of LH, FSH, and/or E2 within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    329. The method of any one of claims 1, 2, 4-12, 14-22, 24-31, 33-37, 39-47, 49-57, 59-66, 68-73, 75-83, 85-93, 95-102, and 104-328, wherein the patient exhibits a reduction in uterine bleeding following administration of the GnRH antagonist to the patient.

    330. The method of any one of claims 3, 13, 23, 32, 38, 48, 58, 67, 74, 84, 94, 103, and 329, wherein the patient exhibits the reduction in uterine bleeding within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    331. The method of any one of claims 3, 13, 23, 32, 38, 48, 58, 67, 74, 84, 94, 103, 329, and 330, wherein the reduction in uterine bleeding is assessed by way of an alkaline hematin method.

    332. The method of any one of claims 1-3, 5-13, 15-23, 25-32, 34-38, 40-48, 50-58, 60-67, 69-74, 76-84, 86-94, 96-103, and 105-331, wherein the patient exhibits amenorrhea following administration of the GnRH antagonist to the patient.

    333. The method of any one of claims 4, 14, 24, 33, 39, 49, 59, 68, 75, 85, 95, 104, and 332, wherein the patient exhibits the amenorrhea within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the amenorrhea within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    334. The method of any one of claims 1-25, 27-60, 62-96, and 98-333, wherein the patient exhibits a reduction in the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient.

    335. The method of any one of claims 26, 61, 97, and 334, wherein the patient exhibits the reduction in volume of the one or more rectovaginal endometriosis nodes within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    336. The method of any one of claims 26, 61, 97, 334, and 335, wherein the reduction in volume of the one or more rectovaginal endometriosis nodes is assessed by way of MRI or TVUS.

    337. The method of any one of claims 1-336, wherein the patient exhibits a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient.

    338. The method of claim 337, wherein the patient exhibits the reduction in bowel involvement of the one or more type III endometriosis nodes within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    339. The method of any one of claims 1-8, 10-17, 19-27, 29-43, 45-52, 54-62, 64-79, 81-88, 90-98, and 100-338, wherein the patient exhibits a reduction in pelvic pain following administration of the GnRH antagonist to the patient.

    340. The method of any one of claims 9, 18, 28, 44, 53, 63, 80, 89, 99, and 339, wherein the patient exhibits the reduction in pelvic pain within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    341. The method of any one of claims 9, 18, 28, 44, 53, 63, 80, 89, 99, 339, and 340, wherein the reduction in pelvic pain is assessed by way of a modified Biberoglu & Behrman (mB&B) score, Numerical Rating Scale (NRS) score, or Verbal Rating Scale (VRS) score.

    342. The method of any one of claims 1-9, 11-18, 20-28, 30-44, 46-53, 55-63, 65-80, 82-89, 91-99, and 101-340, wherein the patient exhibits a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient.

    343. The method of any one of claims 10, 19, 29, 45, 54, 64, 81, 90, 100, and 342, wherein the patient exhibits the reduction in dysmenorrhea within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    344. The method of any one of claims 10, 19, 29, 45, 54, 64, 81, 90, 100, 342, and 343, wherein the reduction in dysmenorrhea is assessed by way of an mB&B score, NRS score, or VRS score.

    345. The method of any one of claims 1-10, 12-19, 21-29, 31-45, 47-54, 56-64, 66-81, 83-90, 92-100, and 102-344, wherein the patient exhibits a reduction in dyspareunia following administration of the GnRH antagonist to the patient.

    346. The method of any one of claims 11, 20, 30, 46, 55, 65, 82, 91, 101, and 345, wherein the patient exhibits the reduction in dyspareunia within from about one day to about 36 weeks commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    347. The method of any one of claims 11, 20, 30, 46, 55, 65, 82, 91, 101, 345, and 346, wherein the reduction in dyspareunia is assessed by way of an mB&B score, NRS score, or VRS score.

    348. The method of any one of claims 1-11, 13-20, 22-30, 32-46, 48-55, 57-65, 67-82, 84-91, 93-101, and 103-347, wherein the patient exhibits a reduction in dyschezia following administration of the GnRH antagonist to the patient.

    349. The method of any one of claims 12, 21, 31, 47, 56, 66, 83, 92, 102, and 348, wherein the patient exhibits the reduction in dyschezia within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    350. The method of any one of claims 12, 21, 31, 47, 56, 66, 83, 92, 102, 348, and 349, wherein the reduction in dyschezia is assessed by way of an mB&B score, NRS score, or VRS score.

    351. The method of any one of claims 1-15, 17-50, 52-86, and 88-349, wherein the patient exhibits a reduction in uterine volume following administration of the GnRH antagonist to the patient.

    352. The method of any one of claims 16, 51, 87, and 351, wherein the patient exhibits the reduction in uterine volume within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    353. The method of any one of claims 16, 51, 87, 351, and 352, wherein the reduction in uterine volume is assessed byway of MRI or transvaginal ultrasound (TVUS).

    354. The method of any one of claims 1-16, 18-51, 53-87, and 89-353, wherein the patient exhibits a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient.

    355. The method of any one of claims 17, 52, 88, and 354, wherein the patient exhibits the reduction in thickness of the anterior and/or posterior region of the uterine myometrium within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    356. The method of any one of claims 1-21, 23-56, 58-92, and 94-355, wherein the patient exhibits a reduction in uterine tenderness following administration of the GnRH antagonist to the patient.

    357. The method of any one of claims 22, 57, 93, and 356, wherein the patient exhibits the reduction in uterine tenderness within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    358. The method of any one of claims 1-357, wherein the patient exhibits a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient.

    359. The method of claim 358, wherein the patient exhibits the reduction in the diameter of the junctional zone of adenomyosis within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    360. The method of any one of claims 1-359, wherein the patient exhibits an improvement in Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient.

    361. The method of claim 360, wherein the patient exhibits the improvement in the EHP-30 score within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the improvement within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    362. The method of any one of claims 1-361, wherein the patient exhibits a positive Patient Global Impression of Change (PGIC) score core following administration of the GnRH antagonist to the patient.

    363. The method of claim 362, wherein the patient exhibits the positive PGIC score within from about one day to about 36 weeks of commencement of the second treatment period, optionally wherein the patient exhibits the positive PGIC score within from about 12 weeks to about 24 weeks of commencement of the second treatment period.

    364. The method of any one of claims 1-363, wherein the patient does not exhibit a reduction in bone mineral density (BMD) of greater than 5% at the end of the second treatment period relative to a measurement of the patient's bone mineral density obtained prior to, or during, the first treatment period.

    365. The method of claim 364, wherein the patient does not exhibit a reduction in BMD of greater than 3% at the end of the second treatment period relative to a measurement of the patient's bone mineral density obtained prior to, or during, the first treatment period.

    366. The method of claim 365, wherein the patient does not exhibit a reduction in BMD of greater than 2% at the end of the second treatment period relative to a measurement of the patient's bone mineral density obtained prior to, or during, the first treatment period.

    367. The method of claim 366, wherein the patient does not exhibit a reduction in BMD of greater than 1% at the end of the second treatment period relative to a measurement of the patient's bone mineral density obtained prior to, or during, the first treatment period.

    368. The method of any one of claims 364-367, wherein the BMD is assessed by dual energy X-ray absorptiometry.

    369. The method of claim 368, wherein the BMD is assessed in the spine or femur of the patient.

    370. The method of any one of claims 364-367, wherein the BMD is assessed by comparing the concentration of bone specific alkaline phosphatase (BAP) in a sample isolated from the patient following the administration to the concentration of BAP in a sample isolated from the patient prior to the administration.

    371. The method of any one of claims 364-367, wherein the BMD is assessed by comparing the concentration of deoxypyridinoline (DPD) in a sample isolated from the patient following the administration to the concentration of DPD in a sample isolated from the patient prior to the administration.

    372. The method of any one of claims 364-367, wherein the BMD is assessed by comparing the concentration of type I collagen C-terminal telopeptide (CTX) in a sample isolated from the patient following the administration to the concentration of CTX in a sample isolated from the patient prior to the administration.

    373. The method of any one of claims 364-367, wherein the BMD is assessed by comparing the concentration of procollagen 1 N-terminal peptide (P1NP) in a sample isolated from the patient following the administration to the concentration of P1NP in a sample isolated from the patient prior to the administration.

    374. A kit comprising a GnRH antagonist and a package insert instructing a user of the kit to administer the GnRH antagonist to a human patient in accordance with the method of any one of claims 1-373.

    375. The kit of claim 374, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00662## wherein ring A is a thiophene ring; each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; ring B is an aryl group or a monocyclic heteroaryl group; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; U is a single bond; X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group; Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; and Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof.

    376. The kit of claim 375, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00663##

    377. The kit of claim 375 or 376, wherein m is 1.

    378. The kit of claim 377, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00664##

    379. The kit of any one of claims 375-378, wherein each R.sup.A is independently a halogen atom, an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.

    380. The kit of claim 379, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

    381. The kit of any one of claims 375-380, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

    382. The kit of claim 381, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00665##

    383. The kit of any one of claims 375-382, wherein n is 2.

    384. The kit of claim 383, wherein ring B is represented by a formula selected from the group consisting of: ##STR00666##

    385. The kit of any one of claims 375-384, wherein each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group.

    386. The kit of claim 385, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

    387. The kit of any one of claims 375-386, wherein U is a single bond.

    388. The kit of any one of claims 375-387, wherein X is a group represented by —O-L-Y.

    389. The kit of any one of claims 375-388, wherein L is a methylene group.

    390. The kit of any one of claims 375-389, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00667## wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3.

    391. The kit of claim 390, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00668##

    392. The kit of claim 375, wherein the compound is represented by formula (Ia) ##STR00669## wherein each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; m is an integer from 0 to 3; each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group; n is an integer from 0 to 2; q is an integer from 0 to 3; each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and p is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.

    393. The kit of claim 392, wherein the compound is represented by formula (Ib) ##STR00670##

    394. The kit of claim 393, wherein the compound is represented by formula (Ic) ##STR00671## or a pharmaceutically acceptable salt thereof.

    395. The kit of any one of claims 375-394, wherein the compound is represented by formula (VI) ##STR00672## or a pharmaceutically acceptable salt thereof.

    396. The kit of claim 395, wherein the compound is the choline salt of the compound represented by formula (VI).

    397. The kit of claim 374, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.

    Description

    BRIEF DESCRIPTION OF THE FIGURES

    [0642] FIG. 1 is a graph showing the median serum concentration of β17-estradiol (E2) in a series of female human patients suffering from endometriosis that were treated with varying amounts of a GnRH antagonist represented by formula (VI). As described in Example 1, below, patients were administered the indicated amount of the GnRH antagonist once daily over the course of 24 weeks. After 24 weeks, treatment with the GnRH antagonist was discontinued. Values along the x-axis denote the time at which the patients' E2 level was assessed relative to the onset of GnRH antagonist administration. Values along the y-axis represent the concentration of E2 in a serum sample obtained from the patient, in pg/ml. Patients were treated with the GnRH antagonist represented by formula (VI) in an amount of 50 mg/day, 75 mg/day, 100 mg/day, or 200 mg/day. Patients initially treated with placebo (plc) were administered the GnRH antagonist in an amount of 100 mg/day after 12 weeks. Also, after 12 weeks, patients that were initially administered 75 mg/day were provided a higher (100 mg/day) or lower (50 mg/day) dosage of the GnRH antagonist based on the patients' E2 levels at the 12-week point. The E2 levels for this group of patients is represented by “75 mg (TD).” Patients that were administered 75 mg through the end of the treatment period are represented by “75 mg (FD).”

    [0643] FIG. 2 a graph showing the dyspareunia score in a series of female human patients suffering from endometriosis that were treated with varying amounts of a GnRH antagonist represented by formula (VI). As described in Example 1, below, patients were administered the indicated amount of the GnRH antagonist once daily over the course of 24 weeks. After 24 weeks, treatment with the GnRH antagonist was discontinued. Values along the x-axis denote the time at which patients' dyspareunia score was assessed using the Verbal Rating Score (VRS). Values along the y-axis represent the average change in the patients' VRS score relative to a baseline measurement of the patients' VRS score obtained prior to the onset of GnRH antagonist treatment (CFB). Patients were treated with the GnRH antagonist represented by formula (VI) in an amount of 50 mg/day, 75 mg/day, 100 mg/day, or 200 mg/day. Patients initially treated with placebo (plc) were administered the GnRH antagonist in an amount of 100 mg/day after 12 weeks. Also, after 12 weeks, patients that were initially administered 75 mg/day were provided a higher (100 mg/day) or lower (50 mg/day) dosage of the GnRH antagonist based on the patients' E2 levels at the 12-week point. The E2 levels for this group of patients is represented by “75 mg (TD).” Patients that were administered 75 mg through the end of the treatment period are represented by “75 mg (FD).”

    [0644] FIG. 3 a graph showing the dyschezia score in a series of female human patients suffering from endometriosis that were treated with varying amounts of a GnRH antagonist represented by formula (VI). As described in Example 1, below, patients were administered the indicated amount of the GnRH antagonist once daily over the course of 24 weeks. After 24 weeks, treatment with the GnRH antagonist was discontinued. Values along the x-axis denote the time at which patients' dyschezia score was assessed using the Numerical Rating Score (NRS). Values along the y-axis represent the average change in the patients' NRS score relative to a baseline measurement of the patients' NRS score obtained prior to the onset of GnRH antagonist treatment (CFB). Patients were treated with the GnRH antagonist represented by formula (VI) in an amount of 50 mg/day, 75 mg/day, 100 mg/day, or 200 mg/day. Patients initially treated with placebo (plc) were administered the GnRH antagonist in an amount of 100 mg/day after 12 weeks. Also, after 12 weeks, patients that were initially administered 75 mg/day were provided a higher (100 mg/day) or lower (50 mg/day) dosage of the GnRH antagonist based on the patients' E2 levels at the 12-week point. The E2 levels for this group of patients is represented by “75 mg (TD).” Patients that were administered 75 mg through the end of the treatment period are represented by “75 mg (FD).”

    [0645] FIGS. 4A-4D are magnetic resonance imaging (MRI) results showing the uterine adenomyotic condition of a patient prior to, and during the course of her treatment with, a GnRH antagonist represented by formula (VI). As described in Example 3, below, a cohort of n=6 female human patients suffering from uterine adenomyosis was treated with a GnRH antagonist represented by formula (VI). One of these patients in particular was extensively monitored prior to commencement of GnRH antagonist therapy as part of a longitudinal case study. Before undergoing treatment with the GnRH antagonist represented by formula (VI), this patient was first administered a selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA), in an effort to treat the adenomyosis. After failing to respond to treatment with UPA, the patient was re-evaluated and administered compound (VI). FIGS. 4A-4D are MRI scans of this patient's uterus throughout the duration of this longitudinal case study. FIG. 4A is an MRI scan showing the condition of the patient's uterus prior to the commencement of treatment with UPA. FIG. 4A shows an enlarged uterus with diffuse and disseminated adenomyosis. FIG. 4B is an MRI scan obtained after the conclusion of 3 months of treatment with UPA, which was administered in an amount of 5 mg/day. FIG. 4B shows a worsened disease state, as evidenced by numerous spots typical of adenomyosis. FIG. 4B also shows an asymmetric, heterogeneous myometrium with multiple myometrial cysts, which is evidence of dilated islets of ectopic endometrium. FIG. 4C is an MRI scan obtained over one year after treatment with UPA discontinued. FIG. 4C shows a very large uterus, with clear indications typical of severe, full-thickness adenomyosis. FIG. 4D is an MRI scan obtained from the patient after 12 weeks of treatment with the GnRH antagonist represented by formula (VI), which was administered in a once-daily dose of 200 mg/day. As FIG. 4D shows, after 12 weeks of this treatment modality, the patient exhibited a significant reduction in uterine size and adenomyotic lesions.

    [0646] FIG. 5 is a graph showing the effect of compound (VI) on menstrual bleeding patterns in uterine fibroids patients treated with compound (VI) for 24 weeks in accordance with the procedure described in Example 4, below. Values along the y axis represent the proportion of patients exhibiting menstrual blood loss of less than ≤80 mL, as assessed by way of the alkaline hematin method, and a 50% reduction in menstrual blood loss relative to baseline. Error bars represent 95% confidence intervals.

    [0647] FIG. 6 is a graph showing the effect of compound (VI) on menstrual bleeding patterns in uterine fibroids patients treated with compound (VI) for 52 weeks in accordance with the procedure described in Example 4, below. Values along the y axis represent the proportion of patients exhibiting menstrual blood loss of less than ≤80 mL, as assessed by way of the alkaline hematin method, and a 50% reduction in menstrual blood loss relative to baseline. Error bars represent 95% confidence intervals.

    [0648] FIGS. 7A and 7B are graphs showing the effect of compound (VI) on menstrual bleeding patterns in uterine fibroids patients treated with compound (VI) for 52 weeks in accordance with the procedure described in Example 4, below. Particularly, FIGS. 7A and 7B show the effect of compound (VI) on menstrual blood loss as assessed at various timepoints during the PRIMROSE 1 and PRIMROSE 2 trials described in Example 4, below. Values along the y axis represent the average change from baseline (CFB) in menstrual blood loss. Error bars represent 95% confidence intervals.

    [0649] FIGS. 8A and 8B are graphs showing the effect of compound (VI) on pain levels in uterine fibroids patients treated with compound (VI) for 24 weeks in accordance with the procedure described in Example 4, below. Particularly, FIGS. 8A and 8B show the effect of compound (VI) on pain as assessed at various timepoints during the PRIMROSE 1 and PRIMROSE 2 trials by way of a Verbal Rating Score (VRS). Values along the y axis represent the average change from baseline (CFB) in pain score (FIG. 8A) and the proportion of patients with a score of 1 or less after 24 weeks of treatment (FIG. 8B).

    [0650] FIG. 9 is a graph showing the effect of compound (VI) on bone mineral density levels in uterine fibroids patients treated with compound (VI) for 24 weeks and 52 weeks in accordance with the procedure described in Example 4, below. Bone mineral density was assessed in the lumbar spine. Values along the y axis represent the average change from baseline (CFB) in bone mineral density throughout the PRIMROSE 1 and PRIMROSE 2 studies, descried in Example 4.

    DETAILED DESCRIPTION

    [0651] The compositions and methods of the present disclosure can be used to treat a variety of estrogen-dependent disorders, including uterine fibroids and endometriosis, among others. For example, using the compositions and methods described herein, a patient, such as a female human patient, may be administered a gonadotropin-releasing hormone (GnRH) antagonist in order to not only treat the cause of the estrogen-dependent pathology, but also to alleviate one or more symptoms associated these conditions. Exemplary disease that are induced by elevated estrogen production, and that can be treated using the compositions and methods described herein, include, without limitation, uterine fibroids, endometriosis (e.g., rectovaginal endometriosis), and adenomyosis, among others.

    [0652] GnRH antagonists that may be used for the treatment of an estrogen-dependent disorder as described herein include optionally substituted thieno[3,4d]pyrimidine derivatives, such as 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or the choline salt thereof. Other GnRH antagonists useful in conjunction with the compositions and methods of the disclosure include optionally substituted 3-aminoalkyl pyrimidine-2,4(1H,3H)-dione derivatives, such as sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, also referred to as elagolix, or the carboxylic acid conjugate thereof. In some embodiments, the GnRH antagonist is an optionally substituted thieno[2,3d]pyrimidine derivative, such as N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, also referred to as relugolix, or a pharmaceutically acceptable salt thereof. In some embodiments, the GnRH antagonist is an optionally substituted propane-1,3-dione derivative, such as (2R)—N-{5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorobenzene-1-sulfonyl}-2-hydroxypropanimidamide, also referred to as opigolix or ASP-1707. Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include SK12670 and BAY-784, as well as derivatives and variants thereof, among others.

    [0653] Estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis), and adenomyosis, among others described herein, may be effectuated by circulating concentrations of β17-estradiol (E2) in excess of about 60 pg/ml. Using the compositions and methods described herein, a GnRH antagonist may be administered to the patient so as to suppress E2 production to healthy levels, such as a concentration of from about 10 pg/ml to about 60 pg/ml, in order to correct the underlying physiological cause of the disease and ameliorate one or more symptoms associated therewith. However, excessive depletion of endogenous E2 (for example, to levels of less than about 10 pg/ml) may lead to undesirable side effects, such as a reduction in bone mineral density.

    [0654] The present disclosure is based, in part, on the surprising observation that administration of a GnRH antagonist, such as an optionally substituted thieno[3,4d]pyrimidine derivative (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or the choline salt thereof), effectuates a sustained reduction in estrogen-dependent disease symptomology, even after administration of the GnRH antagonist is halted. This enables administration of the GnRH antagonist to be temporarily paused so as to allow a patient's serum E2 concentration to be replenished, for example, in the event of a reduction in bone mineral density, while maintaining an alleviating effect on estrogen-dependent disease symptoms. In some embodiments, once the patient's bone mineral density has increased, administration of the GnRH antagonist is re-initiated.

    [0655] In some embodiments, in addition (or as an alternative) to temporarily pausing GnRH antagonist treatment, a patient suffering from an estrogen-dependent disease may be administered a reduced dosage of a GnRH antagonist if a reduction in bone mineral density occurs. The disclosure also provides dosing regimens in which a patient is administered a GnRH antagonist that is not an optionally substituted thieno[3,4d]pyrimidine derivative (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or the choline salt thereof) and is subsequently treated with such a compound, in view, for example, of such compound's beneficial ability to sustain a reduction in disease symptoms even after its administration has been discontinued.

    [0656] The sections that follow provide a detailed description of GnRH antagonists and other agents that may be used in conjunction with the compositions and methods of the disclosure, as well as a description of various estrogen-dependent diseases that may be treated using these therapeutics.

    GnRH Antagonists

    Thieno[3,4d]pyrimidines

    [0657] GnRH antagonists for use with the compositions and methods described herein include thieno[3,4d]pyrimidine derivatives and variants, such as those described in U.S. Pat. No. 9,040,693, the disclosure of which is incorporated herein by reference in its entirety. Exemplary GnRH antagonists include those represented by formula (I)

    ##STR00067##

    [0658] wherein ring A is a thiophene ring;

    [0659] each R.sup.A is independently a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted sulfonyl group, an optionally substituted sulfinyl group, a tetrazolyl group, OW.sup.1, SW.sup.1, COW.sup.1, COOW.sup.1, NHCOW.sup.1, NHCONW.sup.2W.sup.3, NW.sup.2W.sup.3, CONW.sup.2W.sup.3, or SO.sub.2NW.sup.2W.sup.3, wherein W.sup.1 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;

    [0660] m is an integer from 0 to 3;

    [0661] ring B is an aryl group or a monocyclic heteroaryl group;

    [0662] each R.sup.B is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW.sup.4, COW.sup.4, COOW.sup.4, or CONW.sup.5W.sup.6, wherein W.sup.4 to W.sup.6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.5 and W.sup.6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;

    [0663] n is an integer from 0 to 2;

    [0664] U is a single bond;

    [0665] X is a group represented by —S-L-Y, —O-L-Y, —CO-L-Y, or —SO.sub.2-L-Y, wherein L is an optionally substituted lower alkylene group;

    [0666] Y is a group represented by Z or —NW.sup.7W.sup.8, wherein W.sup.7 and W.sup.8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W.sup.7 and W.sup.8 are not simultaneously hydrogen atoms, or W.sup.7 and W.sup.8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;

    [0667] Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group, or an optionally fused and optionally substituted heteroaryl group;

    [0668] or a pharmaceutically acceptable salt thereof.

    [0669] In some embodiments, the ring A is a thiophene ring represented by formula (IIa)

    ##STR00068##

    [0670] In some embodiments, m is 1 or 2. In some embodiments, m is 1. For instance, the ring A may be an optionally substituted thiophene ring represented by formula (IIb)

    ##STR00069##

    [0671] Each R.sup.A may independently be, for example, a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), an optionally substituted lower alkyl group, COOW.sup.1, or CONW.sup.2W.sup.3, wherein W.sup.2 to W.sup.3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W.sup.2 and W.sup.3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group. In some embodiments, each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

    [0672] In some embodiments, ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring. For instance, ring B may be represented by a formula selected from the group consisting of:

    ##STR00070##

    [0673] In some embodiments, n is 1 or 2. For instance, in some embodiments, n is 1. Ring B may be, for example, represented by a formula selected from the group consisting of:

    ##STR00071##

    [0674] In some embodiments, each R.sup.B is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.4, wherein each W.sup.4 is independently a hydrogen atom or an optionally substituted lower alkyl group. For instance, each R.sup.B may be independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

    [0675] In some embodiments, U is a single bond. X may be, for example, a group represented by —O-L-Y. L may be, for example, a methylene group. In some embodiments, Y is an optionally substituted benzene ring represented by formula (V)

    ##STR00072##

    [0676] wherein each R.sup.C is independently a halogen atom, an optionally substituted lower alkyl group, or OW.sup.9, wherein each W.sup.9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and

    [0677] p is an integer from 0 to 3.

    [0678] In some embodiments, Y is a substituted benzene ring represented by formula (Va)

    ##STR00073##

    [0679] For example, GnRH antagonists that may be used for the treatment of the endometrial growth disorders described herein include those thieno[3,4d]pyrimidine compounds described in Table 1, below. The synthesis and characterization of these compounds is reported, for instance, in U.S. Pat. No. 9,040,693, incorporated herein by reference.

    TABLE-US-00001 TABLE 1 Exemplary Thieno[3,4d]pyrimidine GnRH Antagonists Useful for the Treatment of Estrogen-Dependent Diseases No. Compound Reported .sup.1H NMR spectral properties  1 [00074]embedded image (CDCl.sub.3) 1.6-1.75 (2H, m), 2.45-2.6 (2H, m), 3.7-3.85 (2H, m), 3.94 (3H, s), 6.82 (1H, s), 7.0-7.15 (2H, m), 7.15-7.25 (1H, m), 7.49 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.6 (1H, d, J = 2.0 Hz), 7.7-7.8 (1H, m), 9.47 (1H, s)  2 [00075]embedded image (CDCl.sub.3) 1.6-1.75 (2H, m), 2.4-2.6 (2H, m), 3.7-3.8 (1H, m), 3.8-3.9 (1H, m), 6.82 (1H, d, J = 5.2 Hz), 7.0-7.15 (2H, m), 7.15-7.25 (1H, m), 7.46 (1H, dd, J = 8.3 Hz, 2.1 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.65 (1H, d, J = 2.1 Hz), 7.7-7.8 (2H, m), 9.65 (1H, s)  3 [00076]embedded image (CDCl.sub.3) 1.6-1.75 (2H, m), 2.4-2.6 (2H, m), 3.7-3.9 (2H, m), 6.89 (1H, d, J = 5.8 Hz), 7.0- 7.15 (2H, m), 7.15-7.25 (1H, m), 7.32 (1H, d, J = 5.8 Hz), 7.46 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.64 (1H, d, J = 2.1 Hz), 7.75- 7.8 (1H, m), 9.54 (1H, brs)  4 [00077]embedded image (CDCl.sub.3) 1.6-1.8 (2H, m), 2.4-2.6 (2H, m), 3.65-3.8 (4H, m), 3.8-3.9 (1H, m), 7.0-7.15 (2H, m), 7.15-7.25 (1H, m), 7.49 (1H, dd, J = 8.4 Hz, 1.9 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.59 (1H, d, J = 1.9 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.91 (1H, s)  5 [00078]embedded image (CDCl.sub.3) 1.95-2.05 (2H, m), 2.75-2.85 (2H, m), 3.3-3.35 (2H, m), 4.48 (2H, s), 6.5 (1H, d, J = 8.4 Hz), 6.55-6.65 (1H, m), 6.81 (1H, d, J = 5.6 Hz), 6.9-7.0 (2H m), 7.2-7.35 (3H, m), 7.51 (1H, d, J = 8.4 Hz), 9.94 (1H, brs)  6 [00079]embedded image (CDCl.sub.3) 1.38 (3H, t, J = 7.1 Hz), 1.6- 1.75 (2H, m), 2.4-2.6 (2H, m), 3.7-3.85 (2H, m), 4.41 (2H, q, J = 7.1 Hz), 6.82 (1H, s), 7.0-7.15 (2H, m), 7.15-7.25 (1H, m), 7.47 (1H, dd, J = 8.5 Hz, 2.2 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.6 (1H, d, J = 2.2 Hz), 7.7-7.8 (1H, m), 9.11 (1H, s)  7 [00080]embedded image (CDCl.sub.3) 1.2-1.35 (2H, m), 1.75-1.9 (2H, m), 2.4-2.55 (2H, m), 3.2-4.3 (2H, br), 6.87 (1H, d, J = 5.3 Hz), 7.1-7.2 (3H, m), 7.25-7.35 (2H, m), 7.63 (1H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.5 Hz, 1.9 Hz), 7.78 (1H, d, J = 1.9 Hz), 9.5-10.2 (1H, br)  8 [00081]embedded image (CDCl.sub.3) 3.2 (3H, s), 6.87 (1H, d, J = 5.4 Hz), 7.1-7.15 (2H, m), 7.2-7.35 (4H, m), 7.54 (1H, dd, J = 8.4 Hz, 2.0 Hz), 7.6 (1H, d, J = 2.0 Hz), 7.64 (1H, d, J = 8.4 Hz), 9.5-11.0 (1H, br)  9 [00082]embedded image (CDCl.sub.3) 0.9-1.8 (10H, m), 2.77 (3H, s), 3.7-3.8 (1H, m), 6.87 (1H, d, J = 5.7 Hz), 7.3 (1H, d, J = 5.7 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.8-7.9 (2H, m), 9.5-10.5 (1H, br)  10 [00083]embedded image (DMSO-d.sub.6) 3.26 (3H, s), 7.19 (1H, d, J = 5.7 Hz), 7.22 (1H, d, J = 5.7 Hz), 7.25- 7.3 (1H, m), 7.45-7.55 (1H, m), 7.62 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.8-7.9 (2H, m), 8.04 (1H, d, J = 2.1 Hz), 8.3-8.4 (1H, m), 12.54 (1H, s)  11 [00084]embedded image (DMSO-d.sub.6) 3.16 (3H, s), 7.05 (1H, d, J = 7.8 Hz), 7.15-7.45 (4H, m), 7.5-7.6 (1H, m), 7.75-8.1 (3H, m), 12.55 (1H, s)  12 [00085]embedded image (DMSO-d.sub.6) 0.8-0.9 (6H, m), 1.75-1.95 (1H, m), 2.6-2.8 (5H, m), 7.15-7.25 (2H, m), 7.8- 7.95 (2H, m), 8.0-8.1 (1H, m), 12.53 (1H, s)  13 [00086]embedded image (DMSO-d.sub.6) 1.6-1.75 (2H, m), 2.4-2.55 (2H, m), 3.7-3.85 (2H, m), 6.95 (1H, d, J = 3.1 Hz), 7.05-7.25 (3H, m), 7.52 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.56 (1H, d, J = 8.1 Hz), 7.78 (1H, d, J = 8.5 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.52 (1H, d, J = 3.1 Hz), 11.53 (1H, s)  14 [00087]embedded image (CDCl.sub.3) 1.75-1.9 (2H, m), 2.55-2.7 (2H, m), 3.75-3.95 (2H, m), 6.9 (1H, d, J = 5.5 Hz), 7.05-7.25 (4H, m), 7.29 (1H, d, J = 5.5 Hz), 7.74 (1H, d, J = 8.2 Hz), 10.17 (1H, s)  15 [00088]embedded image (DMSO-d.sub.6) 1.6-1.7 (2H, m), 2.4-2.5 (2H, m), 3.7-3.8 (2H, m), 7.05-7.1 (2H, m), 7.1-7.25 (3H, m), 7.45-7.65 (4H, m), 7.74 (1H, d, J = 1.0 Hz), 12.37 (1H, s)  16 [00089]embedded image (DMSO-d.sub.6) 3.18 (3H, s), 7.0-7.1 (1H, m), 7.15- 7.25 (3H, m), 7.35-7.4 (2H, m), 7.6 (1H, dd, J = 8.5 Hz, 2.3 Hz), 7.87 (1H, d, J = 8.5 Hz), 7.96 (1H, d, J = 2.3 Hz), 12.54 (1H, s)  17 [00090]embedded image (DMSO-d.sub.6) 2.26 (3H, s), 3.15 (3H, s), 6.8-6.95 (2H, m), 7.05-7.25 (4H, m), 7.6 (1H, dd, J = 8.4 Hz, 2.3 Hz), 7.8-7.9 (2H, m), 12.54 (1H, s)  18 [00091]embedded image (DMSO-d.sub.6) 5.1 (2H, s), 7.14 (1H, dd, J = 9.0 Hz, 2.9 Hz), 7.18 (1H, d, J = 5.6 Hz), 7.22 (1H, d, J = 5.6 Hz), 7.25 (1H, d, J = 2.9 Hz), 7.3-7.5 (5H, m), 7.53 (1H, d, J = 9.0 Hz), 12.48 (1H, s)  19 [00092]embedded image (DMSO-d.sub.6) 1.85-2.0 (2H, m), 2.7-2.8 (2H, m), 3.3-3.4 (2H, m), 3.81 (3H, s), 4.5 (2H, s), 6.4-6.5 (2H, m), 6.85-6.95 (2H, m), 7.2 (1H, s), 7.31 (1H, dd, J = 8.2 Hz, 2.1 Hz), 7.4 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J = 8.2 Hz), 11.61 (1H, s)  20 [00093]embedded image (DMSO-d.sub.6) 7.05-7.3 (7H, m), 7.75-7.9 (2H, m), 7.95-8.05 (1H, m), 10.48 (1H, s), 12.56 (1H, s)  21 [00094]embedded image (DMSO-d.sub.6) 7.0-7.3 (7H, m), 7.55-7.7 (2H, m), 7.75-7.85 (2H, m), 10.4 (1H, s), 12.4 (1H, s)  22 [00095]embedded image (DMSO-d.sub.6) 1.6-1.7 (2H, m), 2.4-2.55 (2H, m), 3.7-3.8 (2H, m), 7.05-7.25 (3H, m), 7.39 (1H, s), 7.55 (1H, d, J = 8.2 Hz), 7.6 (1H, dd, J = 8.5 Hz, 2.4 Hz), 7.83 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J = 2.4 Hz), 12.03 (1H, s), 14.23 (1H, s)  23 [00096]embedded image (DMSO-d.sub.6) 5.11 (2H, s), 7.19 (1H, dd, J = 9.0 Hz, 2.9 Hz), 7.3-7.45 (5H, m), 7.45-7.5 (2H, m), 7.57 (1H, d, J = 9.0 Hz), 12.04 (1H, s), 14.45 (1H, brs)  24 [00097]embedded image (DMSO-d.sub.6) 1.85-2.0 (2H, m), 2.7-2.8 (2H, m), 3.3-3.4 (2H, m), 4.52 (2H, s), 6.44 (1H, d, J = 8.2 Hz), 6.45-6.5 (1H, m), 6.85-6.95 (2H, m), 7.36 (1H, d, J = 8.2 Hz), 7.38 (1H, s), 7.48 (1H, d, J = 2.1 Hz), 7.61 (1H, d, J = 8.2 Hz), 12.0 (1H, s), 14.45 (1H, brs)  25 [00098]embedded image (DMSO-d.sub.6) 2.33 (3H, s), 5.09 (2H, s), 7.15-7.3 (4H, m), 7.35 (1H, d, J = 2.7 Hz), 7.41 (1H, s), 7.43 (1H, d, J = 7.7 Hz), 7.58 (1H, d, J = 9.0 Hz), 12.04 (1H, s), 14.44 (1H, s)  26 [00099]embedded image (DMSO-d.sub.6) 2.32 (3H, s), 5.07 (2H, s), 7.1-7.35 (6H, m), 7.41 (1H, s), 7.57 (1H, d, J = 8.7 Hz), 12.04 (1H, s), 14.45 (1H, brs)  27 [00100]embedded image (DMSO-d.sub.6) 5.24 (2H, s), 7.2 (1H, dd, J = 8.8 Hz, 3.0 Hz), 7.35 (1H, d, J = 3.0 Hz), 7.41 (1H, s), 7.59 (1H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz), 12.04 (1H, s), 14.43 (1H, s)  28 [00101]embedded image (DMSO-d.sub.6) 1.5-1.6 (3H, m), 5.45-5.55 (1H, m), 7.0-7.1 (1H, m), 7.23 (1H, dd, J = 6.1 Hz, 2.9 Hz), 7.25-7.5 (7H, m), 11.95-12.1 (1H, m), 14.42 (1H, s)  29 [00102]embedded image (DMSO-d.sub.6) 2.85-3.0 (4H, m), 7.15-7.35 (8H, m), 7.38 (1H, s), 7.41 (1H, t, J = 7.7 Hz), 11.92 (1H, s), 14.94 (1H, brs)  30 [00103]embedded image (DMSO-d.sub.6) 1.6-1.7 (2H, m), 2.4-2.55 (2H, m), 3.7-3.85 (2H, m), 7.0-7.2 (3H, m), 7.24 (1H, s), 7.56 (1H, d, J = 8.3 Hz), 7.59 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.81 (1H, d, J = 8.5 Hz), 8.05-8.15 (2H, m), 9.55 (1H, s), 11.81 (1H, s)  31 [00104]embedded image (CDCl.sub.3) 1.65-1.75 (2H, m), 2.4-2.6 (2H, m), 2.99 (3H, d, J = 4.7 Hz), 3.7-3.9 (2H, m), 6.91 (1H, s), 6.95-7.15 (2H, m), 7.15-7.25 (1H, m), 7.5-7.65 (3H, m), 7.7-7.8 (1H, m), 8.91 (1H, s), 10.05- 10.15 (1H, m)  32 [00105]embedded image (CDCl.sub.3) 1.55 (6H, s), 1.6-1.75 (2H, m), 2.4-2.55 (2H, m), 3.7-3.9 (2H, m), 6.04 (1H, s), 6.49 (1H, s), 7.0-7.15 (2H, m), 7.15-7.25 (2H, m), 7.5-7.55 (1H, m), 7.55-7.6 (2H, m), 7.76 (1H, d, J = 8.3 Hz), 8.41 (1H, s)  33 [00106]embedded image (DMSO-d.sub.6) 1.6-1.75 (2H, m), 2.45-2.55 (2H, m), 3.7-3.85 (2H, m), 4.95-5.05 (2H, m), 5.99 (1H, t, J = 5.5 Hz), 6.73 (1H, s), 7.05-7.15 (2H, m), 7.15-7.25 (1H, m), 7.5-7.6 (2H, m), 7.78 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 2.3 Hz), 11.41 (1H, s)  34 [00107]embedded image (DMSO-d.sub.6) 1.6-1.75 (2H, m), 2.45-2.55 (2H, m), 3.7-3.8 (2H, m), 7.05-7.15 (2H, m), 7.15-7.25 (1H, m), 7.5-7.6 (3H, m), 7.82 (1H, d, J = 8.5 Hz), 8.09 (1H, d, J = 2.1 Hz), 10.5-10.55 (1H,m), 11.88 (1H, s)  35 [00108]embedded image (DMSO-d.sub.6) 1.64 (3H, d, J = 6.5 Hz), 3.8- 3.9 (6H, m), 5.79 (1H, q, J = 6.5 Hz), 6.7-6.8 (1H, m), 6.85-6.95 (2H, m), 6.95- 7.05 (1H, m), 7.15-7.25 (2H, m), 7.25- 7.35 (1H, m), 11.63 (1H, s)  36 [00109]embedded image (DMSO-d.sub.6) 3.83 (3H, s), 3.85 (3H, s), 4.99 (2H, s), 6.85-7.0 (2H, m), 7.1-7.2 (2H, m), 7.21 (1H, s), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 11.68 (1H, s)  37 [00110]embedded image (DMSO-d.sub.6) 3.75 (3H, s), 3.85 (3H, s), 4.99 (2H, s), 6.85-7.0 (2H, m), 7.1-7.2 (2H, m), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 7.65 (1H, s), 12.64 (1H, s)  38 [00111]embedded image (DMSO-d.sub.6) 1.54 (3H, d, J = 6.3 Hz), 3.8- 3.85 (3H, m), 5.46 (1H, q, J = 6.3 Hz), 6.9-7.0 (1H, m), 7.05-7.1 (1H, m), 7.15- 7.45 (7H, m), 11.63 (1H, s)  39 [00112]embedded image (DMSO-d.sub.6) 1.7 (3H, d, J = 6.8 Hz), 3.8- 3.85 (3H, m), 5.7-5.8 (1H, m), 6.9-7.0 (1H, m), 7.05-7.15 (3H, m), 7.15-7.3 (2H, m), 7.35-7.5 (1H, m), 11.63 (1H, s)  40 [00113]embedded image (DMSO-d.sub.6) 1.71 (3H, d, J = 6.6 Hz), 3.82 (3H, s), 5.95-6.05 (1H, m), 6.8-6.9 (1H, m), 7.0-7.05 (1H, m), 7.15-7.3 (2H, m), 7.3-7.4 (1H, m), 7.45-7.5 (2H, m), 11.63 (1H, s)  41 [00114]embedded image (DMSO-d.sub.6) 1.58 (3H, d, J = 6.3 Hz), 3.8- 3.85 (3H, m), 5.66 (1H, q, J = 6.3 Hz), 6.9-7.0 (1H, m), 7.05-7.15 (1H, m), 7.15-7.3 (4H, m), 7.3-7.4 (1H, m), 7.45- 7.55 (1H, m), 11.63 (1H, s)  42 [00115]embedded image (DMSO-d.sub.6) 1.69 (3H, d, J = 6.4 Hz), 3.7- 3.75 (3H, m), 5.7-5.8 (1H, m), 6.9-7.0 (1H, m), 7.05-7.15 (3H, m), 7.2-7.3 (1H, m), 7.35-7.5 (1H, m), 7.6-7.65 (1H, m), 12.59 (1H, s)  43 [00116]embedded image (DMSO-d.sub.6) 1.71 (3H, d, J = 6.6 Hz), 3.74 (3H, s), 5.95-6.05 (1H, m), 6.8-6.9 (1H, m), 6.95-7.05 (1H, m), 7.2-7.3 (1H, m), 7.3-7.4 (1H, m), 7.4-7.5 (2H, m), 7.6-7.65 (1H, m), 12.59 (1H, s)  44 [00117]embedded image (DMSO-d.sub.6) 1.64 (3H, d, J = 6.7 Hz), 3.7- 3.8 (3H, m), 3.8-3.9 (3H, m), 5.75-5.85 (1H, m), 6.7-6.8 (1H, m), 6.85-6.95 (2H, m), 6.95-7.05 (1H, m), 7.15-7.25 (1H, m), 7.25-7.35 (1H, m), 7.63 (1H, s), 12.58 (1H, s)  45 [00118]embedded image (DMSO-d.sub.6) 1.51 (3H, d, J = 6.3 Hz), 3.8- 3.9 (6H, m), 5.6-5.7 (1H, m), 6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.0-7.1 (2H, m), 7.15-7.3 (3H, m), 7.3-7.4 (1H, m), 11.6 (1H, s)  46 [00119]embedded image (DMSO-d.sub.6) 1.57 (3H, d, J = 6.3 Hz), 3.8- 3.85 3H, m), 5.6-5.7 (1H, m), 6.8-6.9 (1H, m), 7.05-7.1 (1H, m), 7.15-7.3 (2H, m), 7.3-7.4 m), 7.45-7.5 (1H, m), 7.5-7.6 (1H, m), 11.61 (1H, s)  47 [00120]embedded image (DMSO-d.sub.6) 1.54 (3H, d, J = 6.2 Hz), 3.75-3.85 (3H, m), 5.45-5.55 (1H, m), 6.95-7.05 (1H, m), 7.05-7.15 (1H, m), 7.15-7.25 (2H, m), 7.3-7.45 (3H, m), 7.49 (1H, s), 11.61 (1H, s)  48 [00121]embedded image (DMSO-d.sub.6) 1.65 (3H, d, J = 6.5 Hz), 3.8- 3.9 3H, m), 5.75-5.85 (1H, m), 6.7-6.8 (1H, m), 6.85-7.0 (2H, m), 7.05-7.1 (1H, m), 7.2-7.35 (2H, m), 7.37 (1H, d, J = 3.6 Hz), 12.01 (1H, s), 14.43 (1H, s)  49 [00122]embedded image (DMSO-d.sub.6) 3.85 (3H, s), 5.0 (2H, s), 6.88 (1H, t, J = 8.7 Hz), 6.95 (1H, d, J = 8.7 Hz), 7.15-7.25 (2H, m), 7.3-7.5 (3H, m), 12.06 (1H, s), 14.43 (1H, s)  50 [00123]embedded image (DMSO-d.sub.6) 3.85 (3H, s), 5.0 (2H, s), 6.88 (1H, t, J = 8.6 Hz), 6.95 (1H, d, J = 8.6 Hz), 7.1-7.2 (1H, m), 7.2-7.25 (1H, m), 7.3-7.4 (1H, m), 7.4-7.5 (1H, m), 7.94 (1H, s), 13.04 (1H, s), 13.93 (1H, s)  51 [00124]embedded image (DMSO-d.sub.6) 1.5-1.6 (3H, m), 5.4-5.5 (1H, m), 6.95-7.05 (1H, m), 7.1-7.2 (1H, m), 7.2-7.4 (5H, m), 7.4-7.45 (2H, m), 11.95-12.05 (1H, m), 14.42 (1H, s)  52 [00125]embedded image (DMSO-d.sub.6) 1.7 (3H, d, J = 6.6 Hz), 5.76 (1H, q, J = 6.6 Hz), 7.0-7.2 (4H, m), 7.25-7.35 (1H, m), 7.35-7.5 (2H, m), 11.95-12.05 (1H, m), 14.42 (1H, s)  53 [00126]embedded image (DMSO-d.sub.6) 1.65-1.75 (3H, m), 6.03 (1H, q, J = 6.6 Hz), 6.85-6.95 (1H, m), 7.05- 7.15 (1H, m), 7.25-7.4 (3H, m), 7.4-7.5 (2H, m), 11.95-12.05 (1H, m), 14.4 (1H, s)  54 [00127]embedded image (DMSO-d.sub.6) 1.55-1.65 (3H, m), 5.65 (1H, q, J = 6.5 Hz), 7.0-7.05 (1H, m), 7.15- 7.25 (3H, m), 7.25-7.4 (3H, m), 7.45- 7.55 (1H, m), 11.95- 12.05 (1H, m), 14.42 (1H, s)  55 [00128]embedded image (DMSO-d.sub.6) 1.65-1.75 (3H, m), 5.7-5.8 (1H, m), 6.95-7.2 (4H, m), 72-7.5 (2H, m), 7.93 (1H, d, J = 7.2 Hz), 12.98 (1H, s), 13.85-14.0 (1H, m)  56 [00129]embedded image (DMSO-d.sub.6) 1.72 (3H, d, J = 6.6 Hz), 6.0- 6.1 (1H, m), 6.85-6.95 (1H, m), 7.05-7.1 (1H, m), 7.25-7.4 (2H, m), 7.45-7.5 (2H, m), 7.92 (1H, d, J = 11.1 Hz), 12.98 (1H, brs), 13.85-14.0 (1H, m)  57 [00130]embedded image (DMSO-d.sub.6) 1.65 (3H, d, J = 6.6 Hz), 3.8- 3.9 (3H, m), 5.79 (1H, q, J = 6.6 Hz), 6.7-6.8 (1H, m), 6.85-6.95 (2H, m), 7.0- 7.1 (1H, m), 7.2-7.35 (2H, m), 7.85-8.0 (1H, m), 12.98 (1H, brs), 13.85-14.05 (1H, m)  58 [00131]embedded image (DMSO-d.sub.6) 1.52 (3H, d, J = 6.3 Hz), 3.8- 3.9 (3H, m), 5.64 (1H, q, J = 6.3 Hz), 6.85-7.0 (2H, m), 7.0-7.15 (2H, m), 7.2- 7.4 (4H, m), 11.95-12.0 (1H, m), 14.41 (1H, s)  59 [00132]embedded image (DMSO-d.sub.6) 1.45-1.65 (3H, m), 5.55-5.8 (1H, m), 6.8-7.7 (8H, m), 11.98 (1H, s), 14.39 (1H, s)  60 [00133]embedded image (DMSO-d.sub.6) 1.45-1.65 (3H, m), 5.4-5.6 (1H, m), 6.95-7.6 (8H, m), 11.99 (1H, s), 14.39 (1H, s)  61 [00134]embedded image (DMSO-d.sub.6) 1.56 (3H, s), 1.57 (3H, s), 3.82 (3H, s), 7.15-7.45 (8H, m), 7.8-7.9 (1H, m), 11.68 (1H, s)  62 [00135]embedded image (DMSO-d.sub.6) 1.5-1.6 (6H, m), 3.34 (3H, s), 3.82 (3H, s), 6.84 (1H, d, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.1-7.3 (3H, m), 7.3-7.4 (1H, m), 7.5-7.6 (1H, m), 7.8-7.9 (1H, m), 11.63 (1H, s)  63 [00136]embedded image (DMSO-d.sub.6) 1.59 (3H, s), 1.6 (3H, s), 3.82 (3H, s), 7.05-7.15 (1H, m), 7.19 (1H, s), 7.2-7.4 (3H, m), 7.4-7.5 (1H, m), 7.65-7.75 (1H, m), 7.9-8.0 (1H, m), 11.7 (1H, s)  64 [00137]embedded image (DMSO-d.sub.6) 1.57 (3H, s), 1.58 (3H, s), 3.82 (3H, s), 7.06 (1H, d, J = 8.4 Hz), 7.1-7.25 (3H, m), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.8-7.9 (1H, m), 11.68 (1H, s)  65 [00138]embedded image (DMSO-d.sub.6) 1.54 (6H, s), 3.31 (3H, s), 3.82 (3H, s), 6.8-6.9 (1H, m), 7.0-7.1 (1H, m), 7.15-7.25 (2H, m), 7.3-7.45 (2H, m), 7.8-7.9 (1H, m), 11.63 (1H, s)  66 [00139]embedded image (DMSO-d.sub.6) 1.55-1.6 (6H, m), 7.25-7.45 (8H, m), 7.9-8.0 (1H, m), 12.0 (1H, s), 14.29 (1H, s)  67 [00140]embedded image (DMSO-d.sub.6) 1.55 (3H, s), 1.56 (3H, s), 3.33 (3H, s), 6.84 (1H, d, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.15-7.3 (2H, m), 7.37 (1H, s), 7.4-7.5 (1H, m), 7.5-7.55 (1H, m), 7.9-7.95 (1H, m), 11.99 (1H, s), 14.35 (1H, s)  68 [00141]embedded image (DMSO-d.sub.6) 1.59 (3H, s), 1.62 (3H, s), 7.0-7.1 (1H, m), 7.25-7.4 (4H, m), 7.5- 7.6 (1H, m), 7.65-7.75 (1H, m), 7.95- 8.05 (1H, m), 12.01 (1H, s), 14.29 (1H, s)  69 [00142]embedded image (DMSO-d.sub.6) 1.58 (3H, s), 1.59 (3H, s), 7.0-7.25 (3H, m), 7.3-7.45 (3H, m), 7.45-7.55 (1H, m), 7.9-7.95 (1H, m), 12.02 (1H, s), 14.29 (1H, s)  70 [00143]embedded image (DMSO-d.sub.6) 1.54 (3H, s), 1.56 (3H, s), 3.31 (3H, s), 6.8-6.9 (1H, m), 7.0-7.1 (1H, m), 7.26 (1H, t, J = 9.2 Mz), 7.3-7.4 (2H, m), 7.5-7.6 (1H, m), 7.85-7.95 (1H, m), 11.99 (1H, s), 14.36 (1H, s)  71 [00144]embedded image (DMSO-d.sub.6) 1.55-1.6 (3H, m), 3.82 (3H, s), 4.6-4.7 (1H, m), 7.1-7.2 (2H, m), 7.2- 7.45 (8H, m), 11.49 (1H, s)  72 [00145]embedded image (DMSO-d.sub.6) 1.36 (3H, d, J = 7.2 Hz), 3.82 (3H, s), 4.05-4.15 (1H, m), 7.15- 7.65 (10H, m), 11.54 (1H, s)  73 [00146]embedded image (DMSO-d.sub.6) 1.56 (3H, d, J = 7.1 Hz), 3.83 (3H, s), 4.71 (1H, q, J = 7.1 Hz), 7.18 (1H, s), 7.2-7.35 (5H, m), 7.6-7.7 (3H, m), 7.75-7.8 (1H, m), 11.56 (1H, s)  74 [00147]embedded image (DMSO-d.sub.6) 3.82 (3H, s), 4.44 (2H, s), 7.1-7.25 (2H, m), 7.3-7.4 (1H, m), 7.4- 7.45 (3H, m), 7.45-7.55 (2H, m), 11.5 (1H, s)  75 [00148]embedded image (DMSO-d.sub.6) 1.64 (6H, s), 3.82 (3H, s), 7.05-7.25 (4H, m), 7.25-7.4 (4H, m), 7.4-7.5 (2H, m), 11.45 (1H, s)  76 [00149]embedded image (DMSO-d.sub.6) 1.57 (3H, d, J = 6.9 Hz), 3.74 (3H, s), 4.66 (1H, q, J = 6.9 Hz), 7.1-7.15 (1H, m), 7.2-7.45 (8H, m), 7.59 (1H, s), 12.44 (1H, s)  77 [00150]embedded image (DMSO-d.sub.6) 1.56 (3H, d, J = 6.8 Hz), 3.76 (3H, s), 4.65-4.75 (1H, m), 7.2-7.35 (5H, m), 7.6-7.75 (4H, m), 7.78 (1H, s), 12.52 (1H, s)  78 [00151]embedded image (DMSO-d.sub.6) 3.74 (3H, s), 4.44 (2H, s), 7.15-7.25 (1H, m), 7.3-7.55 (6H, m), 7.59 (1H, s), 12.45 (1H, s)  79 [00152]embedded image (DMSO-d.sub.6) 1.58 (3H, d, J = 6.9 Hz), 4.65 (1H, q, J = 6.9 Hz), 7.2-7.5 (10H, m), 11.93 (1H, s), 14.87 (1H, s)  80 [00153]embedded image (DMSO-d.sub.6) 1.39 (3H, d, J = 7.3 Hz), 4.05-4.15 (1H, m), 7.2-7.8 (10H, m), 11.95 (1H, s), 14.8 (1H, s)  81 [00154]embedded image (DMSO-d.sub.6) 1.59 (3H, d, J = 7.7 Hz), 4.72 (1H, q, J = 7.7 Hz), 7.2-7.35 (5H, m), 7.39 (1H, s), 7.65-7.9 (4H, m), 11.96 (1H, s), 14.73 (1H, s)  82 [00155]embedded image (DMSO-d.sub.6) 4.44 (2H, s), 7.25-7.45 (3H, m), 7.45-7.55 (5H, m), 11.93 (1H, s), 14.87 (1H, s)  83 [00156]embedded image (DMSO-d.sub.6) 4.94 (2H, s), 7.35-7.55 (4H, m), 7.75-7.85 (3H, m), 7.95-8.0 (1H, m), 11.96 (1H, s), 14.75 (1H, s)  84 [00157]embedded image (DMSO-d.sub.6) 1.65 (6H, s), 7.1-7.5 (10H, m), 11.88 (1H, s), 14.84 (1H, s)  85 [00158]embedded image (DMSO-d.sub.6) 1.58 (3H, d, J = 7.0 Hz), 4.66 (1H, q, J = 7.0 Hz), 7.15-7.45 (9H, m), 8.0 (1H, s), 12.94 (1H, s), 14.43 (1H, s)  86 [00159]embedded image (DMSO-d.sub.6) 1.58 (3H, d, J = 7.0 Hz), 4.72 (1H, q, J = 7.0 Hz), 7.2-7.35 (5H, m), 7.65-7.8 (3H, m), 7.84 (1H, s), 7.98 (1H, s), 12.96 (1H, s), 14.26 (1H, s)  87 [00160]embedded image (DMSO-d.sub.6) 4.45 (2H, s), 7.25-7.3 (1H, m), 7.3-7.4 (1H, m), 7.45-7.55 (5H, m), 8.0 (1H, s), 12.94 (1H, s), 14.42 (1H, s)  88 [00161]embedded image (DMSO-d.sub.6) 4.94 (2H, s), 7.35-7.45 (1H, m), 7.45-7.55 (2H, m), 7.7-7.85 (3H, m), 7.95-8.0 (2H, m), 12.96 (1H, s), 14.3 (1H, s)  89 [00162]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 3.83 (3H, s), 7.15-7.25 (5H, m), 7.25-7.35 (2H, m), 7.44 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 1.9 Hz), 11.63 (1H, s)  90 [00163]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 3.83 (3H, s), 7.15-7.35 (8H, m), 7.53 (1H, dd, J = 7.3 Hz, 1.9 Hz), 11.63 (1H, s)  91 [00164]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 3.82 (3H, s), 7.1-7.4 10H, m), 11.46 (1H, s)  92 [00165]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 3.74 (3H, s), 7.1-7.4 (9H, m), 7.58 (1H, s), 12.42 (1H, s)  93 [00166]embedded image (DMSO-d.sub.6) 3.38 (3H, s), 7.15-7.4 (8H, m), 7.5-7.6 (1H, m), 11.96 (1H, s), 14.34 (1H, s)  94 [00167]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 7.15-7.4 (7H, m), 7.44 (1H, d, J = 8.7 Hz), 7.72 (1H, s)  95 [00168]embedded image (DMSO-d.sub.6) 3.38 (3H, s), 7.15-7.25 (3H, m), 7.25-7.35 (3H, m), 7.38 (1H, s), 7.5 (1H, d, J = 7.5 Hz), 7.58 (1H, d, J = 1.9 Hz), 11.98 (1H, s), 14.33 (1H, s)  96 [00169]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 7.15-7.4 (10H, m), 11.89 (1H, s), 14.81 (1H, s)  97 [00170]embedded image (DMSO-d.sub.6) 3.37 (3H, s), 7.15-7.4 (9H, m), 7.99 (1H, s), 12.9 (1H, s), 14.37 (1H, s)  98 [00171]embedded image (DMSO-d.sub.6) 3.75-3.85 (3H, m), 6.3-6.4 (1H, m), 7.05-7.15 (1H, m), 7.2 (1H, s), 7.32 (1H, dd, J = 7.6 Hz, 2.9 Hz), 7.45- 7.55 (4H, m), 7.55-7.65 (2H, m), 11.66 (1H, s)  99 [00172]embedded image (DMSO-d.sub.6) 3.75-3.95 (6H, m), 6.2-6.35 (1H, m), 6.9-7.0 (1H, m), 7.0-7.1 (1H, m), 7.17 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.31 (1H, dd, J = 6.4 Hz, 3.0 Hz), 7.4-7.55 (3H, m), 11.64 (1H, s) 100 [00173]embedded image (DMSO-d.sub.6) 3.7-3.75 (3H, m), 3.85-3.95 (3H, m), 6.2-6.35 (1H, m), 6.9-7.0 (1H, m), 7.04 (1H, t, J = 7.6 Hz), 7.15-7.2 (1H, m), 7.25-7.35 (1H, m), 7.4-7.55 (3H, m), 7.64 (1H, s), 12.6 (1H, s) 101 [00174]embedded image (DMSO-d.sub.6) 6.3-6.4 (1H, m), 7.1-7.2 (1H, m), 7.35-7.4 (2H, m), 7.45-7.55 (3H, m), 7.55-7.65 (3H, m), 11.95-12.1 (1H, m), 14.32 (1H, s) 102 [00175]embedded image (DMSO-d.sub.6) 3.85-3.95 (3H, m), 6.25-6.35 (1H, m), 6.95-7.1 (2H, m), 7.15-7.2 (1H, m), 7.35-7.5 (4H, m), 7.56 (1H, d, J = 8.9 Hz), 12.0-12.1 (1H, m), 14.34 (1H, s) 103 [00176]embedded image (DMSO-d.sub.6) 3.85-3.95 (3H, m), 6.25-6.35 (1H, m), 6.95-7.1 (2H, m), 7.15-7.2 (1H, m), 7.3-7.4 (1H, m), 7.4-7.5 (2H, m), 7.55 (1H, d, J = 9.0 Hz), 7.92 (1H, d, J = 4.5 Hz), 13.0 (1H, brs), 13.8-13.95 (1H, m) 104 [00177]embedded image (CDCl3) 3.89 (3H, s), 6.84 (1H, d, J = 5.8 Hz), 7.05-7.1 (1H, m), 7.28 (1H, d, J = 5.8 Hz), 7.45-7.55 (1H, m), 7.59 (1H, d, J = 8.5 Hz), 7.65-7.75 (1H, m), 7.8- 7.85 (1H, m), 7.85-8.0 (2H, m), 10.06 (1H, s), 10.75 (1H, s) 105 [00178]embedded image (CDCl3) 1.6-1.75 (2H, m), 2.45-2.55 (2H, m), 3.45-3.6 (1H, m), 3.7-3.85 (2H, m), 6.45 (1H, d, J = 0.5 Hz), 7.01 (1H, d, J = 7.0 Hz), 7.05-7.25 (2H, m), 7.5-7.6 (3H, m), 7.76 (1H, d, J = 7.7 Hz), 10.68 (1H, s) 106 [00179]embedded image (DMSO-d6) 3.74 (3H, s), 3.83 (3H, s), 4.15-4.2 (2H, m), 6.75-6.85 (1H, m), 7.21 (1H, s), 7.25-7.4 (2H, m), 7.4-7.5 (1H, m), 7.5-7.55 (1H, m), 11.65 (1H, s) 107 [00180]embedded image (DMSO-d6) 3.77 (3H, s), 3.83 (3H, s), 4.15 (2H, s), 6.75-6.9 (2H, m), 7.15-7.55 (5H, m), 11.65 (1H, s) 108 [00181]embedded image (CDCl3) 3.16 (3H, s), 6.88 (1H, d, J = 5.8 Hz), 7.0-7.1 (2H, m), 7.25-7.35 (3H, m), 7.5-7.6 (2H, m), 7.6-7.7 (1H, m), 9.5-11.0 (1H, br) 109 [00182]embedded image (DMSO-d6) 7.1-7.25 (3H, m), 7.44 (1H, d, J = 8.5 Hz), 7.5-7.6 (1H, m), 7.87 (1H, d, J = 8.5 Hz), 7.9-8.0 (2H, m), 8.18 (1H, d, J = 2.2 Hz), 11.0-12.0 (1H, br), 12.52 (1H, s) 110 [00183]embedded image (CDCl3) 3.22 (3H, s), 7.05-7.15 (3H, m), 7.25-7.35 (3H, m), 7.45-7.55 (1H, m), 7.71 (1H, s), 9.22 (1H, s), 14.14 (1H, s) 111 [00184]embedded image (CDCl3) 1.11 (3H, t, J = 7.1 Hz), 3.5-3.6 (1H, m), 3.65-3.8 (1H, m), 7.05-7.1 (2H, m), 7.13 (1H, s), 7.25-7.35 (3H, m), 7.55 (1H, d, J = 2.2 Hz), 7.7 (1H, d, J = 8.4 Hz), 7.77 (1H, dd, J = 8.4 Hz, 2.2 Hz), 9.22 (1H, s), 14.17 (1H, s) 112 [00185]embedded image (CDCl3) 3.33 (3H, s), 7.1 (1H, s), 7.15- 7.2 (1H, m), 7.57 (1H, d, J = 8.2 Hz), 7.6-7.75 (4H, m), 8.3-8.4 (1H, m), 9.05 (1H, s), 14.09 (1H, s) 113 [00186]embedded image (DMSO-d6) 1.6-1.75 (2H, m), 2.45-2.55 (2H, m), 3.7-3.85 (2H, m), 6.9-7.0 (1H, m), 7.05-7.25 (3H, m), 7.5-7.6 (2H, m), 7.78 (1H, d, J = 8.5 Hz), 8.0-8.05 (1H, m), 8.5-8.55 (1H, m), 11.52 (1H, s) 114 [00187]embedded image (DMSO-d6) 3.17 (3H, s), 7.05-7.15 (2H, m), 7.25-7.4 (3H, m), 7.63 (1H, dd, J = 8.6 Hz, 2.2 Hz), 7.85-7.95 (3H, m), 12.5- 13.5 (1H, br), 13.79 (1H, s) 115 [00188]embedded image (DMSO-d6) 3.26 (3H, s), 7.25-7.3 (1H, m), 7.45-7.55 (1H, m), 7.65-7.75 (1H, m), 7.8-7.95 (3H, m), 8.05-8.1 (1H, m), 8.3-8.4 (1H, m) 116 [00189]embedded image (CDCl3) 3.17 (3H, s), 6.9-7.0 (1H, m), 7.13 (1H, s), 7.29 (1H, d, J = 2.5 Hz), 7.39 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 1.2 Hz), 7.7-7.8 (2H, m), 9.12 (1H, s), 14.05 (1H, s) 117 [00190]embedded image (CDCl3) 3.25 (3H, s), 6.75-6.9 (2H, m), 7.13 (1H, s), 7.2-7.3 (1H, m), 7.63 (1H, d, J = 2.1 Hz), 7.75 (1H, d, J = 8.6 Hz), 7.8-7.85 (1H, m), 9.03 (1H, s), 14.11 (1H, s) 118 [00191]embedded image (CDCl3) 3.22 (3H, s), 7.08 (1H, s), 7.15- 7.25 (2H, m), 7.38 (1H, d, J = 1.7 Hz), 7.7-7.8 (2H, m), 8.55-8.65 (2H, m) 119 [00192]embedded image (DMSO-d6) 3.23 (3H, s), 3.8 (3H, s), 6.9-6.95 (1H, m), 7.35-7.55 (3H, m), 7.7-7.85 (2H, m), 7.9-8.0 (2H, m), 12.03 (1H, s), 14.29 (1H, s) 120 [00193]embedded image (DMSO-d6) 3.12 (3H, s), 3.73 (3H, s), 6.85-6.9 (2H, m), 6.95-7.0 (2H, m), 7.39 (1H, s), 7.68 (1H, dd, J = 8.4 Hz, 2.3 Hz), 7.85-7.95 (2H, m), 12.03 (1H, s), 14.3 (1H, s) 121 [00194]embedded image (DMSO-d6) 3.51 (3H, s), 6.85-6.95 (2H, m), 7.15-7.25 (2H, m), 7.38 (1H, s), 7.7- 7.8 (1H, m), 7.85-7.95 (1H, m), 7.95-8.0 (1H, m), 9.74 (1H, s), 12.02 (1H, s), 13.5-15.0 (1H, br) 122 [00195]embedded image (DMSO-d6) 3.67 (3H, s), 6.6-6.75 (3H, m), 7.1-7.2 (1H, m), 7.38 (1H, s), 7.84 (1H, dd, J = 8.5 Hz, 2.2 Hz), 7.89 (1H, d, J = 8.5 Hz), 8.13 (1H, d, J = 2.2 Hz), 10.49 (1H, s), 12.04 (1H, s), 14.22 (1H, s) 123 [00196]embedded image (DMSO-d6) 3.69 (3H, s), 6.83 (2H, d, J = 8.9 Hz), 6.99 (2H, d, J = 8.9 Hz), 7.38 (1H, s), 7.75 (1H, dd, J = 8.5 Hz, 2.0 Hz), 7.88 (1H, d, J = 8.5 Hz), 7.99 (1H, d, J = 2.0 Hz), 10.08 (1H, s), 12.03 (1H, s), 14.24 (1H, s) 124 [00197]embedded image (DMSO-d6) 3.17 (3H, s), 3.47 (3H, s), 6.9-7.0 (2H, m), 7.15-7.2 (1H, m), 7.25- 7.35 (1H, m), 7.39 (1H, s), 7.71 (1H, dd, J = 8.6 Hz, 2.2 Hz), 7.9 (1H, d, J = 8.6 Hz), 8.02 (1H, d, J = 2.2 Hz), 12.02 (1H, s), 14.31 (1H, s) 125 [00198]embedded image (DMSO-d6) 3.18 (3H, s), 3.69 (3H, s), 6.55-6.7 (2H, m), 6.8-6.9 (1H, m), 7.2- 7.3 (1H, m), 7.35-7.4 (1H, m), 7.6-7.7 (1H, m), 7.85-8.05 (2H, m), 12.04 (1H, s), 14.26 (1H, s) 126 [00199]embedded image (DMSO-d6) 3.18 (3H, s), 7.1-7.35 (3H, m), 7.35-7.45 (2H, m), 7.81 (1H, d, J = 2.3 Hz), 7.95 (1H, d, J = 8.5 Hz), 8.03 (1H, d, J = 2.3 Hz), 12.03 (1H, s), 14.29 (1H, s) 127 [00200]embedded image (DMSO-d6) 3.19 (3H, s), 6.95-7.05 (2H, m), 7.1-7.2 (1H, m), 7.35-7.45 (2H, m), 7.7-7.75 (1H, m), 7.9-8.0 (2H, m), 12.04 (1H, s), 14.27 (1H, s) 128 [00201]embedded image (DMSO-d6) 3.15 (3H, s), 7.05-7.25 (4H, m), 7.38 (1H, s), 7.69 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.9 (1H. d, J = 2.5 Hz), 7.93 (1H, d, J = 8.5 Hz), 12.05 (1H, s), 14.29 (1H, s) 129 [00202]embedded image (DMSO-d6) 3.15 (3H, s), 7.1-7.15 (2H, m), 7.35-7.45 (3H, m), 7.7 (1H, dd, J = 8.6 Hz, 2.1 Hz), 7.9-7.95 (2H, m), 12.05 (1H, s), 14.28 (1H, s) 130 [00203]embedded image (DMSO-d6) 3.19 (3H, s), 7.05-7.1 (1H, m), 7.2-7.25 (1H, m), 7.35-7.45 (3H, m), 7.72 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.9- 8.0 (2H, m), 12.06 (1H, s), 14.3 (1H, s) 131 [00204]embedded image (DMSO-d6) 3.16 (3H, s), 7.0-7.1 (1H, m), 7.25-7.45 (3H, m), 7.55-7.6 (1H, m), 7.85-7.9 (1H, m), 7.97 (1H, d, J = 8.5 Hz), 8.1 (1H, s), 12.06 (1H, s), 14.31 (1H, s) 132 [00205]embedded image (DMSO-d6) 3.13 (3H, s), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.45-7.55 (2H, m), 7.86 (1H, dd, J = 8.5 Hz, 2.4 Hz), 7.98 (1H, d, J = 8.5 Hz), 8.02 (1H, d, J = 2.4 Hz), 12.03 (1H, s), 14.3 (1H, s) 133 [00206]embedded image (DMSO-d6) 3.17 (3H, s), 7.2-7.3 (2H, m), 7.3-7.4 (3H, m), 7.71 (1H, dd, J = 8.5 Hz, 2.1 Hz), 7.9 (1H, d, J = 2.1 Hz), 7.93 (1H, d, J = 8.5 Hz), 12.0 (1H, s), 14.25 (1H, s) 134 [00207]embedded image (DMSO-d6) 3.15 (3H, s), 7.06 (1H, d, J = 8.5 Hz), 7.35-7.45 (2H, m), 7.76 (1H, d, J = 2.4 Hz), 7.85-7.9 (1H, m), 7.97 (1H, d, J = 8.54 Hz), 8.07 (1H, d, J = 2.2 Hz), 12.03 (1H, s), 14.27 (1H, s) 135 [00208]embedded image (DMSO-d6) 3.16 (3H, s), 7.05-7.1 (2H, m), 7.25-7.4 (4H, m), 7.55-7.65 (1H, m), 7.7-7.8 (3H, m), 11.95 (1H, s), 14.77 (1H, s) 136 [00209]embedded image (DMSO-d6) 3.16 (3H, s), 7.05-7.1 (2H, m), 7.25-7.4 (3H, m), 7.55-7.65 (1H, m), 7.7-7.8 (3H, m), 7.98 (1H, s), 12.95 (1H, s), 14.31 (1H, s) 137 [00210]embedded image (DMSO-d6) 3.16 (3H, s), 3.47 (3H, s), 6.85-7.0 (2H, m), 7.1-7.2 (1H, m), 7.25- 7.35 (1H, m), 7.69 (1H, dd, J = 8.4 Hz, 2.1 Hz), 7.85-7.95 (2H, m), 7.99 (1H, d, J = 2.1 Hz), 12.5-13.5 (1H, br), 13.83 (1H, brs) 138 [00211]embedded image (DMSO-d6) 3.17 (3H, s), 7.1-7.25 (2H, m), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.65-7.75 (1H, m), 7.8-7.9 (1H, m), 8.02 (1H, dd, J = 6.6 Hz, 2.3 Hz), 12.03 (1H, s), 14.31 (1H, s) 139 [00212]embedded image (DMSO-d6) 3.16 (3H, s), 3.47 (3H, s), 6.9-7.0 (2H, m), 7.19 (1H, dd, J = 8.0 Hz, 1.5 Hz), 7.3-7.35 (1H, m), 7.37 (1H, s), 7.6-7.7 (1H, m), 7.7-7.8 (1H, m), 8.0 (1H, dd, J = 6.6 Hz, 2.5 Hz), 12.02 (1H, s), 14.32 (1H, s) 140 [00213]embedded image (DMSO-d6) 1.6-1.7 (2H, m), 2.45-2.55 (5H, m), 3.7-3.8 (2H, m), 7.05-7.25 (3H, m), 7.56 (1H, d, J = 8.5 Hz), 7.6-7.65 (1H, m), 7.84 (1H, d, J = 8.5 Hz), 8.1 (1H, d, J = 2.4 Hz), 11.94 (1H, s), 14.22 (1H, s) 141 [00214]embedded image (CD3OD) 3.36 (3H, s), 3.54 (3H, s), 4.01 (3H, s), 6.85-6.95 (2H, m), 7.15- 7.35 (4H, m), 7.69 (1H, d, J = 8.4 Hz) 142 [00215]embedded image (DMSO-d6) 3.3 (3H, s), 3.87 (3H, s), 7.15-7.4 (6H, m), 7.42 (1H, d, J = 11.7 Hz), 7.92 (1H, d, J = 8.3 Hz), 11.95 (1H, s), 14.39 (1H, s) 143 [00216]embedded image (DMSO-d6) 3.17 (3H, s), 7.05-7.15 (2H, m), 7.25-7.4 (4H, m), 7.6-7.75 (2H, m), 7.9-8.0 (1H, m), 12.02 (1H, s), 14.29 (1H, s) 144 [00217]embedded image (DMSO-d6) 4.42 (2H, s), 7.2-7.45 (6H, m), 7.86 (1H, d, J = 8.5 Hz), 8.2 (1H, dd, J = 8.5 Hz, 2.2 Hz), 8.29 (1H, d, J = 2.2 Hz), 12.06 (1H, brs), 14.32 (1H, brs) 145 [00218]embedded image (DMSO-d6) 1.4-1.5 (3H, m), 4.9-5.0 (1H, m), 7.15-7.45 (6H, m), 7.7-7.8 (1H, m), 8.1-8.15 (1H, m), 8.2-8.3 (1H, m), 12.0-12.1 (1H, m), 14.2-14.35 (1H, m) 146 [00219]embedded image (DMSO-d6) 1.57 (6H, s), 7.25-7.45 (7H, m), 7.5-7.6 (1H, m), 7.9-8.0 (1H, m), 11.9-12.1 (1H, br), 14.2-14.4 (1H, br) 147 [00220]embedded image (DMSO-d6) 1.55 (3H, s), 1.57 (3H, s), 3.33 (3H, s), 6.8-6.85 (1H, m), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.3-7.5 (3H, m), 7.5-7.55 (1H, m), 7.94 (1H, d, J = 2.4 Hz), 12.0 (1H, s), 14.37 (1H, brs) 148 [00221]embedded image (DMSO-d6) 1.6 (3H, s), 1.62 (3H, s), 7.0-7.15 (1H, m), 7.25-7.4 (3H, m), 7.47 (1H, dd, J = 8.7 Hz, 2.0 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.65-7.75 (1H, m), 8.01 (1H, d, J = 2.0 Hz), 12.03 (1H, s), 14.3 (1H, brs) 149 [00222]embedded image (DMSO-d6) 4.42 (2H, s), 7.2-7.35 (5H, m), 7.86 (1H, d, J = 8.5 Hz), 7.94 (1H, s), 8.15-8.3 (2H, m), 13.84 (1H, s) 150 [00223]embedded image (DMSO-d6) 1.55 (6H, s), 7.25-7.55 (8H, m), 7.6-7.65 (1H, m), 11.99 (1H, s), 14.46 (1H, brs) 151 [00224]embedded image (DMSO-d6) 1.49 (3H, s), 1.5 (3H, s), 3.66 (3H, s), 6.55-6.65 (1H, m), 6.75- 6.85 (1H, m), 6.95-7.05 (1H, m), 7.25- 7.5 (4H, m), 7.5-7.6 (1H, m), 11.99 (1H, s), 14.5 (1H, s) 152 [00225]embedded image (DMSO-d6) 1.536 (3H, s), 1.543 (3H, s), 3.61 (3H, s), 6.75-6.85 (2H, m), 7.3-7.4 (3H, m), 7.45-7.6 (2H, m), 11.98 (1H, s), 14.5 (1H, s) 153 [00226]embedded image (DMSO-d6) 1.49 (3H, s), 1.5 (3H, s), 3.66 (3H, s), 6.55-6.65 (1H, m), 6.75- 6.85 (1H, m), 6.95-7.05 (1H, m), 7.25- 7.55 (4H, m), 7.94 (1H, s), 12.8-13.1 (1H, br), 14.01 (1H, s) 154 [00227]embedded image (DMSO-d6) 5.15 (2H, s), 6.9-7.1 (3H, m), 7.25-7.35 (2H, m), 7.4 (1H, s), 7.55- 7.65 (1H, m), 7.65-7.75 (2H, m), 12.05 (1H, s), 14.42 (1H, s) 155 [00228]embedded image (DMSO-d6) 2.85-2.95 (4H, m), 7.1-7.6 (9H, m), 12.04 (1H, s), 14.46 (1H, s) 156 [00229]embedded image (DMSO-d6) 2.8-3.0 (4H, m), 7.15-7.45 (9H, m), 12.03 (1H, s), 14.46 (1H, brs) 157 [00230]embedded image (DMSO-d6) 2.8-2.9 (4H, m), 3.79 (3H, s), 6.8-6.9 (1H, m), 6.9-7.0 (1H, m), 7.1-7.25 (2H, m), 7.25-7.45 (4H, m), 12.02 (1H, s), 14.48 (1H, brs) 158 [00231]embedded image (DMSO-d6) 2.85-3.0 (4H, m), 7.05-7.2 (2H. m), 7.2-7.45 (6H, m), 12.03 (1H, s). 14.46 (1H, brs) 159 [00232]embedded image (DMSO-d6) 2.8-2.95 (4H, m), 3.72 (3H, s), 6.7-6.85 (3H, m), 7.15-7.25 (1H, m), 7.25-7.45 (4H, m), 11.95-12.1 (1H, br), 14.35-14.55 (1H, br) 160 [00233]embedded image (DMSO-d6) 2.75-2.95 (4H, m), 3.71 (3H, s), 6.8-6.9 (2H, m), 7.1-7.2 (2H, m), 7.25-7.45 (4H, m), 12.01 (1H, brs), 14.4- 14.55 (1H, br) 161 [00234]embedded image (DMSO-d6) 2.85-3.0 (4H, m), 6.95-7.05 (1H, m), 7.05-7.15 (2H, m), 7.25-7.45 (5H, m), 12.03 (1H, brs), 14.3-14.6 (1H, br) 162 [00235]embedded image (DMSO-d6) 2.8-2.95 (4H, m), 7.05-7.15 (2H, m), 7.2-7.45 (6H, m), 12.03 (1H, brs), 14.3-14.6 (1H, br) 163 [00236]embedded image (DMSO-d6) 2.28 (3H, s), 2.8-2.9 (4H, m), 7.05-7.25 (4H, m), 7.25-7.5 (4H, m), 12.04 (1H, brs), 14.47 (1H, brs) 164 [00237]embedded image (DMSO-d6) 2.27 (3H, s), 2.8-2.95 (4H, m), 6.95-7.1 (3H, m), 7.1-7.2 (1H, m), 7.25-7.45 (4H, m), 12.03 (1H, brs), 14.47 (1H, brs) 165 [00238]embedded image (DMSO-d6) 2.25 (3H, s), 2.8-2.95 (4H, m), 7.05-7.15 (4H, m), 7.25-7.45 (4H, m), 12.03 (1H, brs), 14.35-14.6 (1H, br) 166 [00239]embedded image (DMSO-d6) 1.23 (3H, s), 1.25 (3H, s), 2.85 (2H, s), 3.67 (3H, s), 6.7-6.8 (2H, m), 6.85- 6.95 (1H, m), 7.1-7.2 (1H, m), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.5-7.6 (1H, m), 12.0 (1H, s), 14.55 (1H, s) 167 [00240]embedded image (DMSO-d6) 2.65-2.75 (2H, m), 2.8-2.9 (2H, m), 3.75 (6H, s), 6.55-6.7 (2H, m), 7.1-7.2 (1H, m), 7.25-7.45 (4H, m), 12.0 (1H, s), 14.48 (1H, brs) 168 [00241]embedded image (DMSO-d6) 2.8-2.95 (4H, m), 3.77 (3H, s), 6.9-7.1 (3H, m), 7.25-7.45 (4H, m), 12.01 (1H, s), 14.46 (1H, brs) 169 [00242]embedded image (DMSO-d6) 2.85-2.95 (4H, m), 3.75 (3H, s), 6.9-7.05 (1H, m), 7.05-7.2 (1H, m), 7.3-7.45 (4H, m), 12.01 (1H, s), 14.45 (1H, brs) 170 [00243]embedded image (DMSO-d6) 2.75-2.85 (2H, m), 2.85- 2.95 (2H, m), 3.77 (3H, s), 6.75-6.85 (1H, m), 7.15-7.35 (4H, m), 7.37 (1H, s), 11.99 (1H, s), 14.46 (1H, brs) 171 [00244]embedded image (DMSO-d6) 2.75-2.9 (4H, m), 3.86 (3H, s), 7.08 (1H, d, J = 12.2 Hz), 7.15-7.35 (6H, m), 7.38 (1H, s), 11.97 (1H, s), 14.55 (1H, brs) 172 [00245]embedded image (DMSO-d6) 4.28 (2H, s), 7.2-7.35 (3H, m), 7.35-7.5 (4H, m), 7.58 (1H, d, J = 8.5 Hz), 7.66 (1H, d, J = 2.2 Hz), 12.06 (1H, s), 14.41 (1H, s) 173 [00246]embedded image (DMSO-d6) 4.29 (2H, s), 7.2-7.45 (6H, m), 7.57 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 2.3 Hz), 7.94 (1H, s), 13.03 (1H, s), 13.94 (1H, s) 174 [00247]embedded image (DMSO-d6) 1.69 (6H, s), 7.0-7.2 (4H, m), 7.25-7.4 (5H, m), 11.89 (1H, s), 14.86 (1H, s) 175 [00248]embedded image (DMSO-d6) 4.24 (2H, s), 7.2-7.5 (8H, m), 7.62 (1H, dd, J = 6.7 Hz, 2.2 Hz), 12.05 (1H, s), 14.41 (1H, s) 176 [00249]embedded image (DMSO-d6) 1.65 (6H, s), 7.0-7.1 (1H, m), 7.1-7.45 (8H, m), 11.88 (1H, s), 14.83 (1H, s) 177 [00250]embedded image (DMSO-d6) 2.8-2.9 (2H, m), 3.15-3.25 (2H, m), 7.15-7.55 (8H, m), 7.58 (1H, dd, J = 6.8 Hz, 2.3 Hz) 178 [00251]embedded image (DMSO-d6) 4.21 (2H, s), 7.0-7.15 (2H, m), 7.3-7.45 (3H, m), 7.5-7.65 (2H, m), 12.0 (1H, s), 14.37 (1H, s) 179 [00252]embedded image (DMSO-d6) 3.76 (3H, s), 4.15 (2H, s), 6.75-6.9 (2H, m), 7.25-7.35 (2H, m), 7.35-7.45 (1H, m), 7.45-7.6 (2H, m) 180 [00253]embedded image (DMSO-d6) 4.27 (2H, s), 7.15-7.5 (10H, m), 11.93 (1H, s), 14.88 (1H, s) 181 [00254]embedded image (DMSO-d6) 1.65-1.7 (6H, m), 3.86 (3H, s) 6.75-6.85 (1H, m), 7.0-7.15 (3H, m), 7.2-7.3 (2H, m), 7.37 (1H, s), 7.42 (1H, dd, J = 6.9 Hz, 2.2 Hz), 11.98 (1H, s), 14.38 (1H, s) 182 [00255]embedded image (DMSO-d6) 3.79 (3H, s), 4.16 (2H, s), 6.8-6.9 (1H, m), 6.95-7.05 (1H, m), 7.2- 7.3 (2H, m), 7.3-7.5 (3H, m), 7.59 (1H, dd, J = 7.0 hz, 2.2 Hz), 12.02 (1H, s), 14.39 (1H, s) 183 [00256]embedded image (DMSO-d6) 1.69 (6H, s), 7.0-7.35 (6H, m), 7.37 (1H, s), 7.46 (1H, dd, J = 6.7 Hz, 2.2 Hz), 11.98 (1H, s), 14.37 (1H, brs) 184 [00257]embedded image (DMSO-d6) 4.24 (2H, s), 7.05-7.25 (2H, m), 7.25-7.45 (4H, m), 7.45-7.55 (1H, m), 7.63 (1H, dd, J = 6.8 Hz, 2.5 Hz), 12.03 (1H, s), 14.38 (1H, s) 185 [00258]embedded image (DMSO-d6) 4.25 (2H, s), 7.0-7.1 (1H, m), 7.15-7.2 (2H, m), 7.25-7.5 (4H, m), 7.62 (1H, dd, J = 6.7 Hz, 2.3 Hz), 12.03 (1H, s), 14.37 (1H, s) 186 [00259]embedded image (DMSO-d6) 4.4 (2H, s), 7.3-7.6 (6H, m), 7.65-7.75 (1H, m), 12.01 (1H, s), 14.37 (1H, s) 187 [00260]embedded image (DMSO-d6) 1.75-1.8 (6H, m), 7.05-7.15 (1H, m), 7.15-7.3 (4H, m), 7.37 (1H, s), 7.4-7.5 (2H, m), 11.97 (1H, s), 14.37 (1H, s) 188 [00261]embedded image (DMSO-d6) 1.65 (6H, s), 7.15-7.25 (1H, m), 7.25-7.45 (6H, m), 7.5-7.6 (1H, m), 12.0 (1H, s), 14.38 (1H, s) 189 [00262]embedded image (DMSO-d6) 1.64 (6H, s), 7.15-7.35 (5H, m), 7.37 (1H, s), 7.4-7.45 (2H, m), 7.52 (1H, dd, J = 7.3 Hz, 2.3 Hz), 11.99 (1H, s), 14.37 (1H, brs) 190 [00263]embedded image (DMSO-d6) 1.75-1.85 (6H, m), 3.77 (3H, s), 6.6-6.7 (1H, m), 6.85 (1H, d, J = 8.1 Hz), 7.05-7.15 (1H, m), 7.2-7.35 (2H, m), 7.37 (1H, s), 7.4-7.45 (1H, m), 11.97 (1H, s), 14.4 (1H, brs) 191 [00264]embedded image (DMSO-d6) 1.65-1.7 (6H, m), 3.85 (3H, s), 6.75-6.8 (1H, m), 7.0-7.1 (2H, m), 7.1-7.2 (1H, m), 7.25-7.35 (1H, m), 7.37 (1H, s), 7.4 (1H, dd, J = 7.3 Hz, 2.2 hz), 11.98 (1H, s), 14.39 (1H, brs) 192 [00265]embedded image (DMSO-d6) 1.81 (6H, s), 6.9-7.05 (2H, m), 7.1-7.2 (1H, m), 7.25-7.4 (3H, m), 7.45-7.5 (1H, m), 11.97 (1H, s), 14.38 (1H, brs) 193 [00266]embedded image (DMSO-d6) 1.8-1.85 (6H, m), 3.76 (3H, s), 6.75-6.85 (1H, m), 7.15-7.45 (5H, m), 11.98 (1H, s), 14.38 (1H, brs) 194 [00267]embedded image (DMSO-d6) 4.29 (2H, s), 7.2-7.35 (2H, m), 7.35-7.55 (5H, m), 7.6-7.7 (1H, m), 12.02 (1H, s), 14.38 (1H, brs) 195 [00268]embedded image (DMSO-d6) 4.24 (2H, s), 7.25-7.5 (7H, m), 7.6-7.65 (1H, m), 12.03 (1H, s), 14.38 (1H, brs) 196 [00269]embedded image (DMSO-d6) 3.73 (3H, s), 4.16 (2H, s), 6.75-6.85 (1H, m), 7.1-7.6 (5H, m) 197 [00270]embedded image (DMSO-d6) 3.77 (3H, s), 4.15 (2H, s), 6.95-7.15 (3H, m), 7.35-7.5 (3H, m), 7.6-7.65 (1H, m), 12.06 (1H, s), 14.41 (1H, s) 198 [00271]embedded image (DMSO-d6) 1.6-1.7 (6H, m), 7.0-7.1 (1H, m), 7.15-7.25 (3H, m), 7.3-7.4 (3H, m), 7.5-7.55 (1H, m), 12.01 (1H, s), 14.4 (1H, s) 199 [00272]embedded image (DMSO-d6) 1.66 (3H, s), 1.67 (3H, s), 3.86 (3H, s), 7.0 (1H, d, J = 2.5 Hz), 7.06 (1H, d, J = 8.8 Hz), 7.1-7.2 (1H, m), 7.25-7.35 (2H, m), 7.38 (1H, s), 7.4-7.5 (1H, m), 12.01 (1H, s), 14.41 (1H, brs) 200 [00273]embedded image (DMSO-d6) 1.75-1.9 (1H, m), 2.15-2.3 (1H, m), 2.4-2.65 (4H, m), 7.0-7.2 (4H, m), 7.2-7.35 (3H, m), 7.37 (1H, s), 7.45- 7.5 (1H, m), 11.98 (1H, s), 14.41 (1H, brs) 201 [00274]embedded image (DMSO-d6) 2.05-2.25 (4H, m), 3.5-3.65 (2H, m), 3.85-3.95 (2H, m). 6.85-6.95 (1H, m), 7.15-7.4 (8H, m), 11.98 (1H, s), 14.38 (1H, brs) 202 [00275]embedded image (DMSO-d6) 1.73 (6H, s), 7.3-7.4 (7H, m), 7.5-7.6 (1H, m), 7.95 (1H, dd, J = 6.7 Hz, 2.2 Hz), 12.01 (1H, s), 14.25 (1H, s) 203 [00276]embedded image (DMSO-d6) 1.7 (6H, s), 6.89 (1H, s), 7.2-7.4 (6H, m), 7.5-7.7 (3H, m) 204 [00277]embedded image (DMSO-d6) 4.77 (2H, s), 7.15-7.25 (2H, m), 7.25-7.35 (3H, m), 7.39 (1H, s), 7.87 (1H, dd, J = 8.6 Hz, 2.2 Hz), 7.95 (1H, d, J = 8.6 Hz), 8.09 (1H, d, J = 2.2 Hz), 12.08 (1H, s), 14.26 (1H, s) 205 [00278]embedded image (DMSO-d6) 4.77 (2H, s), 7.15-7.25 (2H, m), 7.25-7.35 (3H, m), 7.8-8.0 (3H, m), 8.08 (1H, d, J = 2.3 Hz), 13.78 (1H, s) 206 [00279]embedded image (DMSO-d6) 4.76 (2H, s), 7.05-7.15 (2H, m), 7.36 (1H, s), 7.4-7.55 (1H, m), 7.7- 7.8 (1H, m), 7.95-8.1 (2H, m), 12.02 (1H, s), 14.26 (1H, s) 207 [00280]embedded image (DMSO-d6) 1.89 (6H, s), 7.0-7.1 (2H, m), 7.36 (1H, s), 7.4-7.5 (1H, m), 7.6-7.7 (2H, m), 8.0-8.1 (1H, m), 12.0 (1H, s), 14.28 (1H, s) 208 [00281]embedded image (DMSO-d6) 4.72 (2H, s), 7.15-7.25 (2H, m), 7.25-7.35 (3H, m), 7.39 (1H, s), 7.7- 7.95 (4H, m), 11.97 (1H, s), 14.72 (1H, s) 209 [00282]embedded image (DMSO-d6) 1.86 (6H, s), 3.35 (3H, s), 6.83 (1H, d, J = 8.6 Hz), 6.9-7.0 (1H, m), 7.25-7.35 (2H, m), 7.37 (1H, s), 7.4-7.45 (1H, m), 7.5-7.6 (1H, m), 7.85-7.95 (1H, m), 12.0 (1H, s), 14.29 (1H, s) 210 [00283]embedded image (DMSO-d6) 3.46 (3H, s), 4.63 (2H, s), 6.85-6.95 (2H, m), 7.2-7.35 (2H, m), 7.37 (1H, s), 7.6-7.75 (2H, m), 7.9-8.0 (1H, m), 12.02 (1H, s), 14.26 (1H, s) 211 [00284]embedded image (DMSO-d6) 1.81 (6H, s), 7.05-7.2 (2H, m), 7.3-7.45 (3H, m), 7.5-7.65 (2H, m), 7.98 (1H, dd, J = 6.7 Hz, 2.3 Hz), 12.01 (1H, s), 14.27 (1H, s) 212 [00285]embedded image (DMSO-d6) 4.81 (2H, s), 6.95-7.05 (2H, m), 7.1-7.2 (1H, m), 7.3-7.4 (2H, m), 7.7-7.75 (1H, m), 7.9-8.0 (1H, m), 8.04 (1H, dd, J = 6.8 Hz, 2.6 Hz), 12.05 (1H, s), 14.24 (1H, s) 213 [00286]embedded image (DMSO-d6) 4.7-4.8 (2H, m), 7.1-7.3 (3H, m), 7.35-7.45 (2H, m), 7.65-7.75 (1H, m), 7.9-8.0 (1H, m), 8.05 (1H, dd, J = 6.8 Hz, 2.5 Hz), 12.03 (1H, s), 14.25 (1H, s) 214 [00287]embedded image (DMSO-d6) 1.75-1.85 (6H, m), 7.05-7.2 (2H, m), 7.3-7.5 (4H, m), 7.6-7.8 (3H, m), 11.91 (1H, s), 14.72 (1H, s) 215 [00288]embedded image (DMSO-d6) 4.74 (2H, s), 7.15-7.2 (2H, m), 7.25-7.35 (3H, m), 7.37 (1H, s), 7.65-7.75 (1H, m), 7.85-7.95 (1H, m), 8.07 (1H, dd, J = 6.6 Hz, 2.5 Hz), 12.04 (1H, s), 14.24 (1H, s) 216 [00289]embedded image (DMSO-d6) 1.72 (6H, s), 7.1-7.25 (3H, m), 7.3-7.45 (3H, m), 7.6-7.7 (1H, m), 7.7-7.8 (2H, m), 11.92 (1H, s), 14.7 (1H, s) 217 [00290]embedded image (DMSO-d6) 2.85-2.95 (2H, m), 3.65- 3.75 (2H, m), 7.15-7.3 (5H, m), 7.37 (1H, s), 7.7-7.8 (1H, m), 8.1-8.15 (1H, m), 8.27 (1H, dd, J = 6.6 Hz, 2.6 Hz), 12.05 (1H, s), 14.23 (1H, brs) 218 [00291]embedded image (DMSO-d6) 3.47 (3H, s), 4.62 (2H, s), 6.75 (1H, d, J = 8.4 Hz), 6.8-6.9 (1H, m), 7.3-7.4 (2H, m), 7.65-7.75 (1H, m), 7.8- 7.9 (1H, m), 7.95-8.05 (1H, m), 12.0 (1H, s), 14.27 (1H, brs) 219 [00292]embedded image (DMSO-d6) 3.45 (3H, s), 4.68 (2H, s), 6.7-6.75 (1H, m), 7.35-7.45 (2H, m), 7.65-7.75 (1H, m), 7.85-8.0 (2H, m), 12.01 (1H, s), 14.25 (1H, brs) 220 [00293]embedded image (DMSO-d6) 1.9-2.0 (6H, m), 3.38 (3H, s), 6.65-6.8 (2H, m), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 7.55-7.6 (1H, m), 7.95- 8.0 (1H, m), 12.0 (1H, s), 14.28 (1H, brs) 221 [00294]embedded image (DMSO-d6) 1.85 (6H, s), 3.34 (3H, s), 6.84 (1H, dd, J = 9.1 Hz, 5.2 Hz), 7.1- 7.25 (2H, m), 7.37 (1H, s), 7.4-7.45 (1H, m), 7.55-7.65 (1H, m), 7.9-8.0 (1H, m), 12.0 (1H, s), 14.29 (1H, brs) 222 [00295]embedded image (DMSO-d6) 1.9-2.0 (6H, m), 3.36 (3H, s), 6.65-6.7 (1H, m), 7.35-7.45 (2H, m), 7.5-7.65 (2H, m), 7.95-8.0 (1H, m), 12.0 (1H, s), 14.28 (1H, brs) 223 [00296]embedded image (DMSO-d6) 4.85 (2H, s), 7.3-7.45 (5H, m), 7.65-7.75 (1H, m), 7.8-7.9 (1H, m), 8.05-8.1 (1H, m), 12.03 (1H, s), 14.25 (1H, brs) 224 [00297]embedded image (DMSO-d6) 4.81 (2H, s), 7.05-7.15 (1H, m), 7.25-7.45 (4H, m), 7.7-7.8 (1H, m), 7.9-8.0 (1H, m), 8.05-8.1 (1H, m), 12.05 (1H, s), 14.24 (1H, brs) 225 [00298]embedded image (DMSO-d6) 1.95 (6H, s), 7.25-7.45 (5H, m), 7.5-7.65 (2H, m), 8.03 (1H, dd, J = 6.8 Hz, 2.4 Hz), 12.0 (1H, s), 14.28 (1H, s) 226 [00299]embedded image (DMSO-d6) 1.72 (6H, s), 7.3-7.5 (6H, m), 7.55-7.65 (1H, m), 8.01 (1H, dd, J = 6.7 Hz, 2.3 Hz), 12.02 (1H, s), 14.25 (1H, s) 227 [00300]embedded image (DMSO-d6) 4.96 (2H, s), 7.35-7.45 (2H, m), 7.45-7.55 (2H, m), 7.65-7.75 (1H, m), 7.85-7.95 (1H, m), 8.15-8.2 (1H, m), 12.05 (1H, s), 14.28 (1H, s) 228 [00301]embedded image (DMSO-d6) 3.43 (3H, s), 4.6-4.7 (2H, m), 6.85-6.9 (1H, m), 7.1-7.2 (2H, m), 7.37 (1H, s), 7.65-7.7 (1H, m), 7.75-7.85 (1H, m), 7.9-8.0 (1H, m), 12.04 (1H, s), 14.29 (1H, s) 229 [00302]embedded image (DMSO-d6) 1.72 (3H, s), 1.73 (3H, s), 7.15-7.25 (3H, m), 7.35-7.45 (2H, m), 7.45-7.55 (1H, m), 7.6 (1H, t, J = 9.1 Hz), 7.9-8.0 (1H, m), 12.04 (1H, s), 14.28 (1H, brs) 230 [00303]embedded image (DMSO-d6) 1.86 (6H, s), 6.87 (1H, d, J = 8.8 Hz), 7.35-7.45 (4H, m), 7.55-7.65 (1H, m), 7.95-8.0 (1H, m), 12.03 (1H, s), 14.3 (1H, brs) 231 [00304]embedded image (DMSO-d6) 1.8-1.95 (1H, m), 2.0-2.15 (1H, m), 2.55-2.7 (2H, m), 3.0-3.15 (2H, m), 6.95-7.05 (2H, m), 7.2-7.35 (4H, m), 7.37 (1H, s), 7.45-7.55 (1H, m), 7.9- 8.0 (1H, m), 12.0 (1H, s), 14.28 (1H, brs) 232 [00305]embedded image (DMSO-d6) 2.2-2.35 (2H, m), 3.05-3.2 (2H, m), 3.8-3.9 (2H, m), 7.2-7.4 (7H, m), 7.45-7.55 (1H, m), 7.8-7.9 (1H, m), 12.02 (1H. s), 14.25 (1H, brs) 233 [00306]embedded image (DMSO-d6) 3.75-3.85 (6H, m), 4.96 (2H, s), 6.85-6.95 (1H, m), 7.13 (1H, d, J = 11.3 Hz), 7.26 (1H, d, J = 7.2 Hz), 7.39 (1H, s), 7.4-7.55 (1H, m), 12.0 (1H, s), 14.53 (1H, s) 234 [00307]embedded image (DMSO-d6) 1.7-2.1 (4H, m), 2.65-2.9 (2H, m), 5.45-5.5 (1H, m), 7.1-7.45 (7H, m), 7.57 (1H, d, J = 9.0 Hz), 12.0-12.1 (1H, m), 14.45 (1H, s) 235 [00308]embedded image (DMSO-d6) 5.14 (2H, s), 7.15-7.5 (6H, m), 7.55-7.65 (2H, m), 12.05 (1H, s), 14.43 (1H, s) 236 [00309]embedded image (DMSO-d6) 5.14 (2H, s), 7.15-7.25 (2H, m), 7.25-7.5 (5H, m), 7.58 (1H, d, J = 9.1 Hz), 12.05 (1H, s), 14.43 (1H, s) 237 [00310]embedded image (DMSO-d6) 5.09 (2H, s), 7.15-7.3 (3H, m), 7.32 (1H, d, J = 2.9 Hz), 7.41 (1H, s), 7.5-7.6 (3H, m), 12.04 (1H, s), 14.44 (1H, s) 238 [00311]embedded image (DMSO-d6) 5.13 (2H, s), 7.19 (1H, dd, J = 9.0 Hz, 3.0 Hz), 7.3-7.5 (5H, m), 7.5- 7.6 (2H, m), 12.05 (1H, s), 14.44 (1H, s) 239 [00312]embedded image (DMSO-d6) 3.76 (3H, s), 5.08 (2H, s), 6.85-6.95 (1H, m), 7.0-7.05 (2H, m), 7.18 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.25- 7.35 (2H, m), 7.41 (1H, s), 7.57 (1H, d, J = 9.1 Hz), 12.04 (1H, s), 14.44 (1H, s) 240 [00313]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 5.45-5.55 (1H, m), 7.0-7.1 (1H, m), 7.23 (1H, dd, J = 6.1 Hz, 2.9 Hz), 7.25-7.5 (7H, m), 11.95-12.1 (1H, m), 14.42 (1H, s) 241 [00314]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 5.45-5.55 (1H, m), 7.0-7.1 (1H, m), 7.23 (1H, dd, J = 6.1 Hz, 2.9 Hz), 7.25-7.5 (7H, m), 11.95-12.1 (1H, m), 14.42 (1H, s) 242 [00315]embedded image (DMSO-d6) 3.82 (3H, s), 5.04 (2H, s), 6.95-7.0 (1H, m), 7.06 (1H, d, J = 7.9 Hz), 7.17 (1H, dd, J = 9.1 Hz, 2.9 Hz), 7.3-7.45 (4H, m), 7.56 (1H, d, J = 9.1 Hz), 12.04 (1H, s), 14.46 (1H, s) 243 [00316]embedded image (DMSO-d6) 3.76 (3H, s), 5.02 (2H, s), 6.9-7.0 (2H, m), 7.15-7.2 (1H, m), 7.3 (1H, d, J = 3.3 Hz), 7.35-7.45 (3H, m), 7.56 (1H, d, J = 9.0 Hz), 12.04 (1H, s), 14.46 (1H, s) 244 [00317]embedded image (DMSO-d6) 5.18 (2H, s), 7.02 (1H, s), 7.16 (1H, dd, J = 9.0 Hz, 2.7 Hz), 7.25- 7.4 (2H, m), 7.5-7.6 (2H, m), 7.8-7.9 (1H, m), 8.58 (1H, d, J = 4.5 Hz), 11.0- 12.5 (1H, br) 245 [00318]embedded image (DMSO-d6) 5.11 (2H, s), 7.15-7.2 (1H, m), 7.32 (1H, d, J = 2.9 Hz), 7.41 (1H, s), 7.45-7.55 (4H, m), 7.57 (1H, d, J = 8.6 Hz), 12.06 (1H, s), 14.43 (1H, s) 246 [00319]embedded image (DMSO-d6) 5.16 (2H, s), 7.1-7.25 (2H, m), 7.31 (1H, d, J = 2.9 Hz), 7.4-7.5 (1H, m), 7.56 (1H, d, J = 9.0 Hz), 7.85-7.95 (1H, m), 8.5-8.6 (1H, m), 8.69 (1H, s), 11.0-13.0 (1H, br) 247 [00320]embedded image (DMSO-d6) 2.1-2.25 (2H, m), 4.1-4.2 (1H, m), 4.25-4.35 (1H, m), 5.45-5.55 (1H, m), 6.8-6.95 (2H, m), 7.2-7.35 (3H, m), 7.35-7.45 (2H, m), 7.59 (1H, d, J = 8.7 Hz), 12.0-12.05 (1H, m), 14.42 (1H, s) 248 [00321]embedded image (DMSO-d6) 5.2 (2H, s), 7.1-7.2 (2H, m), 7.3 (1H, d, J = 2.9 Hz), 7.4-7.5 (2H, m), 7.56 (1H, d, J = 8.8 Hz), 8.55-8.65 (2H, m), 11.0-13.0 (1H, br) 249 [00322]embedded image (DMSO-d6) 1.6 (3H, d, J = 6.3 Hz), 5.65-5.75 (1H, m), 7.0-7.1 (1H, m), 7.15-7.3 (3H, m), 7.3-7.45 (2H, m), 7.45-7.55 (2H, m), 11.95-12.1 (1H, m) 14.42 (1H, s) 250 [00323]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 5.5-5.6 (1H, m), 7.0-7.15 (2H, m), 7.2-7.3 (3H, m), 7.35-7.55 (3H, m), 11.95-12.0 (1H, m), 14.41 (1H, s) 251 [00324]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 5.45-5.6 (1H, m), 7.0-7.1 (1H, m), 7.15-7.25 (3H, m), 7.4 (1H, d, J = 4.1 Hz), 7.45-7.55 (3H, m), 11.95-12.05 (1H, m), 14.42 (1H, s) 252 [00325]embedded image (DMSO-d6) 1.35-1.5 (1H, m), 1.65-2.05 (5H, m), 2.8-3.0 (2H, m), 5.45-5.6 (1H, m), 7.05-7.2 (4H, m), 7.25-7.35 (2H, m), 7.39 (1H, d, J = 3.8 Hz), 7.52 (1H, d, J = 8.8 Hz), 12.02 (1H, s), 14.43 (1H, s) 253 [00326]embedded image (DMSO-d6) 1.73 (3H, d, J = 6.6 Hz), 6.07 (1H, q, J = 6.6 Hz), 6.89 (1H, dd, J = 9.0 Hz, 3.0 Hz), 7.15-7.2 (1H, m), 7.3-7.4 (2H, m), 7.45-7.55 (3H, m), 12.0 (1H, s), 14.4 (1H, s) 254 [00327]embedded image (DMSO-d6) 1.53 (3H, d, J = 6.2 Hz), 5.68 (1H, q, J = 6.2 Hz), 6.85-7.0 (2H, m), 7.05 (1H, d, J = 8.4 Hz), 7.2 (1H, t, J = 3.2 Hz), 7.25-7.4 (3H, m), 7.47 (1H, d, J = 9.3 Hz), 12.01 (1H, S), 14.45 (1H, s) 255 [00328]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 3.7-3.75 (3H, m), 5.4-5.5 (1H, m), 6.8-6.9 (1H, m), 6.95-7.1 (3H, m), 7.2-7.3 (2H, m), 7.4 (1H, d, J = 3.4 Hz), 7.47 (1H, dd, J = 9.0 Hz, 1.6 Hz), 11.95-12.05 (1H, m), 14.43 (1H, s) 256 [00329]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 3.73 (3H, s), 5.4-5.5 (1H, m), 6.85-6.95 (2H, m), 7.0-7.05 (1H, m), 7.15-7.25 (1H, m), 7.3-7.5 (4H, m), 11.95-12.05 (1H, m), 14.44 (1H, s) 257 [00330]embedded image (DMSO-d6) 0.93 (3H, t, J = 7.5 Hz), 1.9- 2.05 (1H, m), 2.1-2.25 (1H, m), 5.55 (1H, t, J = 7.3 Hz), 6.95-7.25 (4H, m), 7.35-7.5 (2H, m), 7.52 (1H, d, J = 8.7 Hz), 11.95-12.05 (1H, m), 14.4 (1H, s) 258 [00331]embedded image (DMSO-d6) 0.93 (3H, t, J = 7.4 Hz), 1.9- 2.05 (1H, m), 2.1-2.25 (1H, m), 5.5-5.6 (1H, m), 6.95-7.25 (4H, m), 7.35-7.5 (1H, m), 7.52 (1H, d, J = 9.2 Hz), 7.95 (1H, d, J = 6.7 Hz), 12.99 (1H, s), 13.8- 14.0 (1H, m) 259 [00332]embedded image (DMSO-d6) 1.55-1.65 (3H, m), 5.65-5.8 (1H, m), 6.9-7.0 (1H, m), 7.2-7.3 (1H, m), 7.35-7.45 (1H, m), 7.45-7.6 (2H, m), 7.7-7.85 (3H, m), 12.03 (1H, s), 14.41 (1H, s) 260 [00333]embedded image (DMSO-d6) 1.55-1.65 (3H, m), 5.6-5.7 (1H, m), 7.05-7.15 (1H, m), 7.25-7.3 (1H, m), 7.4 (1H, d, J = 5.6 Hz), 7.45- 7.55 (1H, m), 7.55-7.85 (4H, m), 11.95- 12.1 (1H, m), 14.4 (1H, s) 261 [00334]embedded image (DMSO-d6) 1.55-1.65 (3H, m), 5.6-5.7 (1H, m), 7.0-7.1 (1H. m), 7.25(1H, dd, J = 6.6 Hz, 3.0 Hz), 7.4 (1H, d, J = 5.3 Hz), 7.45-7.55 (1H, m), 7.6-7.7 (2H, m), 7.7-7.8 (2H, m), 11.95-12.1 (1H, m), 14.4 (1H, s) 262 [00335]embedded image (DMSO-d6) 5.13 (2H, s), 7.15-7.3 (3H, m), 7.34 (1H, d, J = 2.9 Hz), 7.4 (1H, s), 7.5-7.65 (2H, m), 12.03 (1H, s), 14.4 (1H, s) 263 [00336]embedded image (DMSO-d6) 5.24 (2H, s), 7.2-7.65 (7H, m), 12.02 (1H, s), 14.39 (1H, s) 264 [00337]embedded image (DMSO-d6) 5.12 (2H, s), 7.15-7.25 (3H, m), 7.32 (1H, d, J = 3.1 Hz), 7.5-7.65 (2H, m), 7.94 (1H, s), 12.8-13.2 (1H, br), 13.93 (1H, s) 265 [00338]embedded image (DMSO-d6) 1.59 (3H, d, J = 6.3 Hz), 5.71 (1H, q, J = 6.3 Hz), 6.85-6.95 (1H, m), 7.2-7.25 (1H, m), 7.3-7.45 (3H, m), 7.45-7.55 (3H, m), 11.95-12.05 (1H, m), 14.39 (1H, s) 266 [00339]embedded image (DMSO-d6) 1.56 (3H, d, J = 6.2 Hz), 5.45-5.6 (1H, m), 7.0-7.1 (1H, m), 7.2- 7.55 (7H, m), 11.95-12.05 (1H, m), 14.39 (1H, s) 267 [00340]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 5.45-5.6 (1H, m), 7.0-7.05 (1H, m), 7.22 (1H, dd, J = 8.9 Hz, 3.0 Hz), 7.35-7.5 (6H, m), 11.9-12.05 (1H, m), 14.39 (1H, s) 268 [00341]embedded image (DMSO-d6) 1.9-2.15 (4H, m), 3.75-3.85 (1H, m), 4.1-4.25 (1H, m), 5.45-5.55 (1H, m), 6.95-7.45 (7H, m), 7.53 (1H, d, J = 8.9 Hz), 11.95-12.05 (1H, m), 14.42 (1H, s) 269 [00342]embedded image (DMSO-d6) 0.91 (3H, t, J = 7.5 Hz), 1.75-2.0 (2H, m), 5.2-5.3 (1H, m), 6.95- 7.05 (1H, m), 7.15-7.5 (8H, m), 11.95- 12.05 (1H, m), 14.39 (1H, s) 270 [00343]embedded image (DMSO-d6) 1.71 (3H, d, J = 6.5 Hz), 5.81 (1H, q, J = 6.5 Hz), 7.0-7.15 (3H, m), 7.2-7.25 (1H, m), 7.35-7.5 (2H, m), 7.53 (1H, d, J = 9.2 Hz), 11.95-12.05 (1H, m), 14.41 (1H, s) 271 [00344]embedded image (DMSO-d6) 1.65-1.75 (6H, m), 6.64 (1H, dd, J = 8.7 Hz, 2.8 Hz), 7.07 (1H, d, J = 2.8 Hz), 7.25-7.5 (7H, m), 11.97 (1H, s), 14.42 (1H, s) 272 [00345]embedded image (DMSO-d6) 0.82 (3H, d, J = 6.4 Hz), 0.95-1.05 (3H, m), 2.05-2.15 (1H, m), 5.0-5.1 (1H, m), 6.95-7.05 (1H, m), 7.15-7.5 (8H, m), 11.95-12.05 (1H, m), 14.4 (1H, s) 273 [00346]embedded image (DMSO-d6) 0.91 (3H, t, J = 7.4 Hz), 1.25-1.5 (2H, m), 1.7-1.8 (1H, m), 1.85- 2.0 (1H, m), 5.3-5.35 (1H, m), 6.95-7.05 (1H, m), 7.15-7.5 (8H, m), 11.95-12.05 (1H, m), 14.41 (1H, brs) 274 [00347]embedded image (DMSO-d6) 0.91 (3H, t, J = 7.4 Hz), 1.75-2.0 (2H, m), 5.25-5.35 (1H, m), 7.0-7.1 (1H, m), 7.2-7.25 (1H, m), 7.3- 7.55 (6H, m), 11.95-12.05 (1H, m), 14.4 (1H, s) 275 [00348]embedded image (DMSO-d6) 0.85 (3H, t, J = 7.1 Hz), 1.2- 1.45 (4H, m), 1.7-1.85 (1H, m), 1.9-2.0 (1H, m), 5.25-5.35 (1H, m), 6.95-7.05 (1H, m), 7.15-7.5 (8H, m), 11.95-12.05 (1H, m), 14.41 (1H, s) 276 [00349]embedded image (DMSO-d6) 3.05 (2H, t, J = 7.0 Hz), 4.19 (2H, t, J = 7.0 Hz), 7.05-7.15 (1H, m), 7.2-7.35 (6H, m), 7.4 (1H, s), 7.54 (1H, d, J = 9.2 Hz), 12.03 (1H, s), 14.45 (1H, s) 277 [00350]embedded image (DMSO-d6) 3.09 (2H, t, J = 6.8 Hz), 4.19 (2H, t, J = 6.8 Hz), 7.05-7.35 (5H, m), 7.35-7.45 (2H, m), 7.54 (1H, d, J = 8.9 Hz), 12.03 (1H, s), 14.45 (1H, s) 278 [00351]embedded image (DMSO-d6) 1.22 (3H, d, J = 6.0 Hz), 2.8-2.9 (1H, m), 2.95-3.05 (1H, m), 4.6- 4.75 (1H, m), 7.09 (1H, dd, J = 9.0 Hz, 3.0 Hz), 7.15-7.35 (6H, m), 7.35-7.45 (1H, m), 7.52 (1H, d, J = 9.2 Hz), 12.02 (1H, s), 14.46 (1H, s) 279 [00352]embedded image (DMSO-d6) 0.93 (3H, t, J = 7.5 Hz), 1.8- 2.05 (2H, m), 5.47 (1H, t, J = 6.1 Hz), 6.95-7.05 (1H, m), 7.15-7.25 (3H, m), 7.3-7.55 (4H, m), 11.95-12.05 (1H, m), 14.35-14.45 (1H, m) 280 [00353]embedded image (DMSO-d6) 1.32 (3H, d, J = 6.9 Hz), 3.15-3.3 (1H, m), 4.0-4.15 (2H, m), 7.09 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.15-7.45 (7H, m), 7.52 (1H, d, J = 8.9 Hz), 12.02 (1H, s), 14.45 (1H, s) 281 [00354]embedded image (DMSO-d6) 0.93 (3H, t, J = 7.5 Hz), 1.8- 2.05 (2H, m), 5.48 (1H, t, J = 6.5 Hz), 6.95-7.05 (1H, m), 7.15-7.25 (3H, m), 7.3-7.4 (1H, m), 7.4-7.55 (2H, m), 7.94 (1H, d, J = 3.4 Hz), 12.98 (1H, s), 13.93 (1H, s) 282 [00355]embedded image (DMSO-d6) 1.32 (3H, d, J = 6.9 Hz), 3.15-3.3 (1H, m), 4.0-4.15 (2H, m), 7.05-7.1 (1H, m), 7.15-7.4 (6H, m), 7.52 (1H, d, J = 9.0 Hz), 7.95 (1H, s), 13.0 (1H, s), 13.98 (1H, s) 283 [00356]embedded image (DMSO-d6) 5.15 (2H, s), 7.15-7.3 (4H, m), 7.35 (1H, d, J = 2.8 Hz), 7.46 (1H, s), 7.59 (1H, d, J = 8.8 Hz), 12.19 (1H, s) 284 [00357]embedded image (DMSO-d6) 5.14 (2H, s), 7.2-7.5 (6H, m), 7.6 (1H, d, J = 8.7 Hz), 12.11 (1H, s), 14.44 (1H, s) 285 [00358]embedded image (DMSO-d6) 1.4 (6H, s), 4.01 (2H, s), 7.05-7.15 (1H, m), 7.15-7.25 (2H, m), 7.3-7.35 (2H, m), 7.39 (1H, s), 7.4-7.5 (2H, m), 7.52 (1H, d, J = 9.2 Hz), 12.0 (1H, s), 14.44 (1H, s) 286 [00359]embedded image (DMSO-d6) 1.52 (3H, d, J = 6.3 Hz), 3.67 (3H, s), 3.75-3.85 (3H, m), 5.65 (1H, q, J = 6.3 Hz), 6.8-7.0 (4H, m), 7.15-7.25 (1H, m), 7.39 (1H, d, J = 1.9 Hz), 7.48 (1H, d, J = 8.9 Hz), 11.99 (1H, s), 14.42 (1H, s) 287 [00360]embedded image (DMSO-d6) 1.55 (3H, d, J = 6.3 Hz), 3.31 (3H, s), 3.7-3.75 (3H, m), 5.35-5.45 (1H, m), 6.35-6.45 (1H, m), 6.5-6.6 (2H, m), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.39 (1H, d, J = 2.0 Hz), 7.45-7.5 (1H, m), 11.95-12.05 (1H, m), 14.41 (1H, s) 288 [00361]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 3.81 (3H, s), 5.4-5.5 (1H, m), 7.0-7.3 (5H, m), 7.4 (1H, d, J = 3.9 Hz), 7.48 (1H, dd, J = 8.9 Hz, 1.6 Hz), 11.95-12.05 (1H, m), 14.41 (1H, s) 289 [00362]embedded image (DMSO-d6) 1.58 (3H, d, J = 6.4 Hz), 3.75 (3H, s), 5.55-5.7 (1H, m), 6.75-6.9 (2H, m), 6.95-7.05 (1H, m), 7.15-7.55 (4H, m), 11.95-12.05 (1H, m), 14.42 (1H, s) 290 [00363]embedded image (DMSO-d6) 1.75 (6H, s), 6.78 (1H, dd, J = 9.0 Hz, 3.0 Hz), 7.0-7.55 (7H, m), 11.91 (1H, brs), 14.0-14.8 (1H, br) 291 [00364]embedded image (DMSO-d6) 0.8 (3H, t, J = 7.3 Hz), 1.65- 1.7 (3H, m), 1.85-2.05 (2H, m), 6.55- 6.65 (1H, m), 7.08 (1H, dd, J = 6.6 Hz, 3.0 Hz), 7.25-7.45 (7H, m), 11.97 (1H, s), 14.43 (1H, s) 292 [00365]embedded image (DMSO-d6) 1.83 (6H, s), 6.69 (1H, dd, J = 9.1 Hz, 3.1 Hz), 7.06 (1H, d, J = 3.1 Hz), 7.3-7.5 (5H, m), 7.61 (1H, dd, J = 7.7 Hz, 1.8 Hz), 11.96 (1H, s), 14.42 (1H, s) 293 [00366]embedded image (DMSO-d6) 5.15 (2H, s), 7.15-7.75 (7H, m), 12.03 (1H, s), 14.41 (1H, s) 294 [00367]embedded image (DMSO-d6) 5.14 (2H, s), 7.23 (1H, dd, J = 8.8 Hz, 3.2 Hz), 7.3-7.45 (3H, m), 7.45-7.55 (1H, m), 7.59 (1H, d, J = 9.1 Hz), 7.65-7.7 (1H, m), 12.03 (1H, s), 14.41 (1H, s) 295 [00368]embedded image (DMSO-d6) 1.56 (3H, d, J = 6.3 Hz), 5.45-5.55 (1H, m), 6.85-6.9 (1H, m), 6.95-7.05 (2H, m), 7.25-7.45 (7H, m), 11.9 (1H, s) 296 [00369]embedded image (DMSO-d6) 1.56 (3H, d, J = 6.4 Hz), 5.5 (1H, q, J = 6.4 Hz), 6.85-6.9 (1H, m), 6.9-7.05 (2H, m), 7.25-7.4 (4H, m), 7.4- 7.45 (2H, m), 7.99 (1H, s), 12.86 (1H, s), 14.43 (1H, s) 297 [00370]embedded image (DMSO-d6) 1.52 (3H, d, J = 6.0 Hz), 3.84 (3H, s), 5.6-5.7 (1H, m), 6.85-7.55 (7H, m), 11.99 (1H, s), 14.42 (1H, s) 298 [00371]embedded image (DMSO-d6) 1.52 (3H, d, J = 6.4 Hz), 3.85-3.9 (3H, m), 5.6-5.7 (1H, m), 6.75- 6.8 (1H, m), 6.85-7.0 (2H, m), 7.15-7.25 (1H, m), 7.3-7.45 (2H, m), 7.48 (1H, d, J = 9.2 Hz), 12.0 (1H, s), 14.44 (1H, s) 299 [00372]embedded image (DMSO-d6) 1.3-1.4 (3H, m), 1.54 (3H, d, J = 6.3 Hz), 4.05-4.2 (2H, m), 5.65-5.75 (1H, m), 6.85-7.0 (2H, m), 7.0-7.05 (1H, m), 7.15-7.35 (3H, m), 7.39 (1H, d, J = 4.2 Hz), 7.48 (1H, d, J = 9.1 Hz), 11.95- 12.05 (1H, m), 14.42 (1H, s) 300 [00373]embedded image (DMSO-d6) 1.66 (3H, d, J = 6.6 Hz), 3.85-3.9 (3H, m), 5.8-5.9 (1H, m), 6.75- 6.85 (1H, m), 6.85-7.0 (2H, m), 7.17 (1H, d, J = 2.6 Hz), 7.25-7.4 (2H, m), 7.48 (1H, d, J = 8.6 Hz), 12.0 (1H, s), 14.42 (1H, s) 301 [00374]embedded image (DMSO-d6) 1.5-1.6 (3H, m), 1.95 (3H, s), 5.4-5.5 (1H, m), 6.85-6.95 (1H, m), 6.98 (1H, dd, J = 5.8 Hz, 2.6 Hz), 7.15- 7.45 (7H, m), 11.85-11.95 (1H, m), 14.76 (1H, s) 302 [00375]embedded image (DMSO-d6) 1.56 (3H, d, J = 6.3 Hz), 5.52 (1H, q, J = 6.3 Hz), 7.03 (1H, dd, J = 9.0 Hz, 3.0 Hz), 7.15-7.5 (7H, m), 7.9-8.0 (1H, m), 12.99 (1H, brs), 13.95 (1H, s) 303 [00376]embedded image (DMSO-d6) 3.85 (3H, s), 5.03 (2H, s), 6.85-7.0 (2H, m), 7.21 (1H, dd, J = 8.9 Hz, 3.1 Hz), 7.32 (1H, d, J = 3.1 Hz), 7.4-7.5 (2H, m), 7.58 (1H, d, J = 8.9 Hz), 12.06 (1H, s), 14.43 (1H, s) 304 [00377]embedded image (DMSO-d6) 1.73 (3H, d, J = 6.7 Hz), 6.0-6.1 (1H, m), 6.8-6.85 (1H, m), 6.9- 7.0 (2H, m), 7.3-7.4 (3H, m), 7.45-7.5 (2H, m), 11.89 (1H, s), 14.86 (1H, s) 305 [00378]embedded image (DMSO-d6) 1.73 (3H, d, J = 6.7 Hz), 6.05 (1H, q, J = 6.7 Hz), 6.8-7.0 (3H, m), 7.3-7.4 (2H, m), 7.45-7.5 (2H, m), 7.99 (1H, s), 12.92 (1H, s), 14.43 (1H, s) 306 [00379]embedded image (DMSO-d6) 1.56 (3H, d, J = 5.7 Hz), 5.45-5.55 (1H, m), 7.0-7.5 (8H, m), 11.95-12.05 (1H, m), 14.4 (1H, brs) 307 [00380]embedded image (DMSO-d6) 1.52 (3H, d, J = 6.2 Hz), 3.84 (3H, s), 5.55-5.65 (1H, m), 6.9-7.0 (1H, m), 7.0-7.15 (4H, m), 7.2-7.3 (1H, m), 7.35-7.4 (1H, m), 11.98 (1H, s), 14.4 (1H, s) 308 [00381]embedded image (DMSO-d6) 5.2-5.35 (2H, m), 7.25 (1H, dd, J = 9.1 Hz, 3.0 Hz), 7.38 (1H, d, J = 3.0 Hz), 7.41 (1H, s), 7.55-7.65 (2H, m), 7.75-7.8 (2H, m), 7.94 (1H, d, J = 7.7 Hz), 12.05 (1H, s), 14.43 (1H, s) 309 [00382]embedded image (DMSO-d6) 3.26 (3H, s), 3.6-3.7 (2H, m), 4.1-4.2 (2H, m), 5.07 (2H, s), 6.95- 7.0 (1H, m), 7.07 (1H, d, J = 8.0 Hz), 7.15-7.2 (1H, m), 7.3-7.4 (2H, m), 7.4- 7.45 (2H, m), 7.55 (1H, d, J = 9.3 Hz), 12.04 (1H, s), 14.46 (1H, s) 310 [00383]embedded image (DMSO-d6) 3.83 (3H, s), 5.0-5.1 (2H, m), 6.9-6.95 (1H, m), 7.15-7.25 (2H, m), 7.3-7.4 (2H, m), 7.45-7.55 (1H, m), 12.02 (1H, s), 14.4 (1H, s) 311 [00384]embedded image (DMSO-d6) 1.66 (3H, d, J = 6.5 Hz), 3.8-3.9 (3H, m), 5.75-5.85 (1H, m), 6.8- 7.0 (2H, m), 7.05-7.15 (1H, m), 7.2-7.4 (3H, m), 11.95-12.05 (1H, m), 14.39 (1H, s) 312 [00385]embedded image (DMSO-d6) 2.48 (3H, s), 5.09 (2H, s), 7.15-7.25 (2H, m), 7.34 (1H, d, J = 2.9 Hz), 7.35-7.45 (3H, m), 7.49 (1H, d, J = 7.2 Hz), 7.58 (1H, d, J = 9.0 Hz), 12.04 (1H, s), 14.45 (1H, s) 313 [00386]embedded image (DMSO-d6) 5.1 (2H, s), 6.95-7.0 (1H, m), 7.05-7.15 (2H, m), 7.3-7.5 (7H, m), 11.88 (1H, s), 14.89 (1H, s) 314 [00387]embedded image (DMSO-d6) 5.14 (2H, s), 7.2-7.3 (3H, m), 7.35-7.45 (2H, m), 7.55-7.65 (1H, m), 12.02 (1H, s), 14.38 (1H, s) 315 [00388]embedded image (DMSO-d6) 5.08 (2H, s), 7.15-7.25 (1H, m), 7.25-7.3 (1H, m), 7.35-7.4 (2H, m), 7.55-7.7 (1H, m), 7.7-7.8 (1H, m), 12.0 (1H, s), 14.4 (1H, s) 316 [00389]embedded image (DMSO-d6) 5.2 (2H, s), 7.2-7.3 (2H, m), 7.35-7.45 (2H, m), 7.95-8.05 (1H, m), 12.02 (1H, s), 14.38 (1H, s) 317 [00390]embedded image (DMSO-d6) 3.82 (3H, s), 5.02 (2H, s), 6.95-7.0 (1H, m), 7.06 (1H, d, J = 8.2 Hz), 7.1-7.2 (1H, m), 7.24 (1H, dd, J = 6.0 Hz, 3.2 Hz), 7.3-7.45 (4H, m), 12.01 (1H, s), 14.44 (1H, s) 318 [00391]embedded image (DMSO-d6) 1.31 (3H, t, J = 6.9 Hz), 4.09 (2H, q, J = 6.9 Hz), 5.03 (2H, s), 6.9-7.0 (1H, m), 7.04 (1H, d, J = 8.2 Hz), 7.1-7.2 (1H, m), 7.2-7.25 (1H, m), 7.3- 7.45 (4H, m), 12.01 (1H, s), 14.43 (1H, s) 319 [00392]embedded image (DMSO-d6) 5.08 (2H, s), 7.05-7.5 (7H, m), 7.55-7.65 (1H, m), 12.01 (1H, s), 14.42 (1H, s) 320 [00393]embedded image (DMSO-d6) 2.34 (6H, s), 5.03 (2H, s), 7.0-7.45 (7H, m), 12.0 (1H, s), 14.4 (1H, s) 321 [00394]embedded image (DMSO-d6) 5.17 (2H, s), 7.2-7.3 (2H, m), 7.35-7.45 (2H, m), 7.74 (1H, d, J = 8.2 Hz), 7.9-8.0 (1H, m), 12.02 (1H, s), 14.38 (1H, s) 322 [00395]embedded image (DMSO-d6) 2.2-2.3 (3H, m), 5.05-5.15 (2H, m), 7.2-7.3 (2H, m), 7.32 (1H, d, J = 8.6 Hz), 7.35-7.45 (3H, m), 12.02 (1H, s), 14.39 (1H, s) 323 [00396]embedded image (DMSO-d6) 3.85-3.95 (3H, m), 5.07 (2H, s), 7.1-7.4 (7H, m), 12.01 (1H, s), 14.42 (1H, s) 324 [00397]embedded image (DMSO-d6) 5.18 (2H, s), 7.15-7.25 (1H, m), 7.25-7.35 (1H, m), 7.35-7.5 (3H, m), 7.55-7.7 (2H, m), 12.01 (1H, s), 14.41 (1H, s) 325 [00398]embedded image (DMSO-d6) 3.81 (3H, s), 5.02 (2H, s), 7.0-7.1 (1H, m), 7.1-7.2 (2H, m), 7.2- 7.4 (4H, m), 12.01 (1H, s), 14.42 (1H, s) 326 [00399]embedded image (DMSO-d6) 3.75 (3H, s), 5.08 (2H, s), 6.9-7.0 (1H, m), 7.1-7.25 (3H, m), 7.27 (1H, dd, J = 6.1 Hz, 3.2 Hz), 7.3-7.4 (2H, m), 12.02 (1H, s), 14.41 (1H, s) 327 [00400]embedded image (DMSO-d6) 5.14 (2H, s), 7.15-7.35 (3H, m), 7.35-7.45 (2H, m), 7.7-7.8 (1H, m), 12.02 (1H, s), 14.39 (1H, s) 328 [00401]embedded image (DMSO-d6) 3.83 (3H, s), 5.01 (2H, s), 7.09 (1H, d, J = 8.8 Hz), 7.15-7.2 (1H, m), 7.25-7.35 (1H, m), 7.3-7.45 (3H, m), 7.48 (1H, d, J = 2.6 Hz), 12.02 (1H, s), 14.43 (1H, s) 329 [00402]embedded image (DMSO-d6) 5.12 (2H, s), 7.15-7.25 (1H, m), 7.27 (1H, dd, J = 6.0 Hz, 3.2 Hz), 7.3-7.4 (2H, m), 7.4-7.5 (2H, m), 7.5-7.6 (1H, m), 7.7 (1H, dd, J = 7.4 Hz, 1.6 Hz), 12.01 (1H, s), 14.41 (1H, s) 330 [00403]embedded image (DMSO-d6) 3.85 (3H, s), 5.1 (2H, s), 7.2-7.35 (2H, m), 7.35-7.45 (3H, m), 7.63 (1H, d, J = 8.7 Hz), 12.01 (1H, s), 14.38 (1H, s) 331 [00404]embedded image (DMSO-d6) 5.21 (2H, s), 7.2-7.35 (2H, m), 7.35-7.45 (2H, m), 7.53 (1H, t, J = 9.2 Hz), 7.8-7.9 (1H, m), 8.02 (1H, d, J = 6.1 Hz), 12.02 (1H, s), 14.4 (1H, s) 332 [00405]embedded image (DMSO-d6) 5.21 (2H, s), 7.15-7.25 (1H, m), 7.3 (1H, dd, J = 5.8 Hz, 3.0 Hz), 7.35-7.5 (3H, m), 7.65-7.75 (1H, m), 7.89 (1H, dd, J = 8.7 Hz, 5.4 Hz), 12.01 (1H, s), 14.4 (1H, s) 333 [00406]embedded image (DMSO-d6) 2.24 (3H, s), 5.08 (2H, s), 7.05-7.15 (1H, m), 7.15-7.3 (2H, m), 7.35-7.45 (3H, m), 12.02 (1H, s), 14.4 (1H, s) 334 [00407]embedded image (DMSO-d6) 2.13 (3H, s), 3.82 (3H, s), 5.0 (2H, s), 6.85-6.95 (1H, m), 7.25 (1H, d, J = 10.0 Hz), 7.32 (1H, d, J = 6.4 Hz), 7.39 (1H, s), 7.4-7.55 (1H, m), 12.01 (1H, s), 14.47 (1H, s) 335 [00408]embedded image (DMSO-d6) 2.12 (3H, s), 3.84 (3H, s), 4.96 (2H, s), 6.8-7.0 (2H, m), 7.24 (1H, d, J = 10.2 Hz), 7.32 (1H, d, J = 6.3 Hz), 7.35-7.5 (2H, m), 12.04 (1H, s), 14.48 (1H, s) 336 [00409]embedded image (DMSO-d6) 2.36 (3H, s), 5.1-5.15 (2H, m), 7.2-7.3 (3H, m), 7.35-7.45 (2H, m), 7.5 (1H, dd, J = 8.7 Hz, 6.2 Hz), 12.03 (1H, s), 14.4 (1H, s) 337 [00410]embedded image (DMSO-d6) 3.86 (3H, s), 5.04 (2H, s), 7.0 (1H, d, J = 9.3 Hz), 7.15-7.25 (2H, m), 7.3-7.4 (2H, m), 7.55-7.65 (1H, m), 12.03 (1H, s), 14.41 (1H, s) 338 [00411]embedded image (DMSO-d6) 2.3 (3H, s), 5.06 (2H, s), 7.1-7.45 (7H, m), 12.03 (1H, s), 14.43 (1H, s) 339 [00412]embedded image (DMSO-d6) 3.88 (3H, s), 5.13 (2H, s), 7.15-7.25 (3H, m), 7.27 (1H, dd, J = 6.0 Hz, 3.2 Hz), 7.3-7.4 (3H, m), 12.02 (1H, s), 14.42 (1H, s) 340 [00413]embedded image (DMSO-d6) 3.85 (3H, s), 5.11 (2H, s), 7.05-7.3 (5H, m), 7.3-7.4 (2H, m), 12.02 (1H, s), 14.42 (1H, s) 341 [00414]embedded image (DMSO-d6) 1.1 (3H, t, J = 7.5 Hz), 2.45- 2.6 (2H, m), 3.82 (3H, s), 5.0 (2H, s), 6.9-6.95 (1H, m), 7.23 (1H, d, J = 10.3 Hz), 7.34 (1H, d, J = 6.3 Hz), 7.39 (1H, s), 7.4-7.55 (1H, m), 12.03 (1H, s), 14.47 (1H, s) 342 [00415]embedded image (DMSO-d6) 3.84 (3H, s), 5.1 (2H, s), 7.13 (1H, dd, J = 9.2 Hz, 4.0 Hz), 7.15- 7.3 (2H, m), 7.3-7.4 (2H, m), 7.45-7.55 (1H, m), 12.03 (1H, s) 343 [00416]embedded image (DMSO-d6) 1.73 (3H, d, J = 6.7 Hz), 2.5-2.55 (3H, m), 6.07 (1H, q, J = 6.7 Hz), 6.85-6.95 (1H, m), 7.15-7.2 (1H, m), 7.3-7.4 (1H, m), 7.45-7.55 (3H, m), 11.89 (1H, s), 14.37 (1H, s) 344 [00417]embedded image (DMSO-d6) 3.86 (3H, s), 5.12 (2H, s), 7.1-7.3 (3H, m), 7.3-7.4 (2H, m), 7.69 (1H, d, J = 8.7 Hz), 12.03 (1H, s), 14.41 (1H, s) 345 [00418]embedded image (DMSO-d6) 2.15-2.2 (3H, m), 3.81 (3H, s), 5.0 (2H, s), 6.84 (1H, d, J = 8.5 Hz), 7.15-7.25 (2H, m), 7.25-7.4 (3H, m), 12.03 (1H, s), 14.42 (1H, s) 346 [00419]embedded image (DMSO-d6) 5.08 (2H, s), 7.1-7.5 (9H, m), 12.01 (1H, s), 14.42 (1H, s) 347 [00420]embedded image (DMSO-d6) 1.1 (3H, t, J = 7.5 Hz), 2.45- 2.55 (2H, m), 3.84 (3H, s), 4.97 (2H, s), 6.85-7.0 (2H, m), 7.22 (1H, d, J = 10.2 Hz), 7.33 (1H, d, J = 6.4 Hz), 7.35-7.5 (2H, m), 12.02 (1H, s), 14.47 (1H, brs) 348 [00421]embedded image (DMSO-d6) 5.11 (2H, s), 7.1-7.3 (2H, m), 7.3-7.45 (2H, m), 7.5-7.65 (3H, m), 12.0 (1H, brs), 14.41 (1H, brs) 349 [00422]embedded image (DMSO-d6) 2.33 (3H, s), 3.78 (3H, s), 5.04 (2H, s), 6.8-6.95 (2H, m), 7.1-7.3 (3H, m), 7.3-7.4 (2H, m), 12.01 (1H, s), 14.42 (1H, brs) 350 [00423]embedded image (DMSO-d6) 1.19 (3H, t, J = 7.5 Hz), 2.68 (2H, q, J = 7.5 Hz), 5.07 (2H, s), 7.15-7.4 (7H, m), 7.4-7.5 (1H, m), 12.0 (1H, brs), 14.3-14.55 (1H, br) 351 [00424]embedded image (DMSO-d6) 3.84 (3H, s), 5.09 (2H, s), 7.2-7.25 (1H, m), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.58 (1H, d, J = 2.7 Hz), 7.68 (1H, d, J = 2.7 Hz), 12.01 (1H, brs), 14.41 (1H, brs) 352 [00425]embedded image (DMSO-d6) 5.25 (2H, s), 7.2-7.35 (2H, m), 7.35-7.45 (2H, m), 7.95-8.05 (1H, m), 8.1-8.2 (1H, m), 12.01 (1H, brs), 14.4 (1H, brs) 353 [00426]embedded image (DMSO-d6) 1.19 (3H, t, J = 7.6 Hz), 2.62 (2H, q, J = 7.6 Hz), 5.05 (2H, s), 7.1-7.4 (8H, m), 12.01 (1H, brs), 14.43 (1H, brs) 354 [00427]embedded image (DMSO-d6) 3.3 (3H, s), 4.53 (2H, s), 5.13 (2H, s), 7.1-7.3 (2H, m), 7.3-7.45 (5H, m), 7.45-7.55 (1H, m), 12.01 (1H, brs), 14.42 (1H, brs) 355 [00428]embedded image (DMSO-d6) 3.29 (3H, s), 4.43 (2H, s), 5.09 (2H, s), 7.1-7.2 (1H, m), 7.2-7.45 (7H, m), 12.01 (1H, brs), 14.42 (1H, brs) 356 [00429]embedded image (DMSO-d6) 5.19 (2H, s), 7.15-7.25 (1H, m), 7.25-7.3 (1H, m), 7.35-7.45 (2H, m), 7.92 (1H, t, J = 8.0 Hz), 8.21 (2H, d, J = 28.0 Hz), 12.01 (1H, s), 14.38 (1H, brs) 357 [00430]embedded image (DMSO-d6) 2.25 (3H, s), 2.44 (3H, s), 3.7 (3H, s), 5.02 (2H, s), 7.1-7.25 (3H, m), 7.25-7.3 (1H, m), 7.3-7.4 (2H, m), 12.01 (1H, brs), 14.3-14.55 (1H, br) 358 [00431]embedded image (DMSO-d6) 3.85 (3H, s), 5.09 (2H, s), 7.05-7.35 (4H, m), 7.35-7.45 (2H, m), 12.02 (1H, brs), 14.39 (1H, brs) 359 [00432]embedded image (DMSO-d6) 3.89 (3H, s), 5.07 (2H, s), 7.15-7.3 (2H, m), 7.3-7.5 (4H, m), 7.6- 7.7 (1H. m), 12.01 (1H, s), 14.4 (1H, brs) 360 [00433]embedded image (DMSO-d6) 5.18 (2H, s), 7.2-7.45 (5H, m), 7.5-7.65 (1H, m), 12.02 (1H, s), 14.4 (1H, brs) 361 [00434]embedded image (DMSO-d6) 5.14 (2H, s), 7.15-7.3 (2H, m), 7.3-7.45 (2H, m), 7.6-7.8 (3H, m), 12.02 (1H, s), 14.39 (1H, s) 362 [00435]embedded image (DMSO-d6) 3.82 (3H, s), 5.1 (2H, s), 7.15-7.45 (5H, m), 7.45-7.55 (1H, m), 12.01 (1H, s), 14.4 (1H, s) 363 [00436]embedded image (DMSO-d6) 2.27 (3H, s), 3.71 (3H, s), 5.05 (2H, s), 7.05-7.25 (3H, m), 7.25-7.3 (1H, m), 7.3-7.4 (2H, m), 12.02 (1H, s), 14.42 (1H, brs) 364 [00437]embedded image (DMSO-d6) 3.76 (3H, s), 3.85 (3H, s), 5.03 (2H, s), 7.05-7.3 (4H, m), 7.3-7.4 (2H, m), 12.02 (1H, brs), 14.42 (1H, brs) 365 [00438]embedded image (DMSO-d6) 3.8-3.9 (3H, m), 5.08 (2H, s), 7.15-7.25 (2H, m), 7.25-7.45 (4H, m), 12.02 (1H, brs), 14.41 (1H, brs) 366 [00439]embedded image (DMSO-d6) 3.79 (3H, s), 3.83 (3H, s), 4.92 (2H, s), 6.8-7.0 (2H, m), 7.11 (1H, d, J = 11.2 Hz), 7.27 (1H, d, J = 27.6 Hz), 7.38 (1H, s), 7.4-7.5 (1H, m), 11.99 (1H, brs), 14.55 (1H, brs) 367 [00440]embedded image (DMSO-d6) 3.23 (3H, s), 3.55-3.65 (2H, m), 4.1-4.2 (2H, m), 5.09 (2H, s), 6.9-7.0 (1H, m), 7.15-7.3 (2H, m), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 12.03 (1H, brs), 14.42 (1H, brs) 368 [00441]embedded image (DMSO-d6) 1.02 (3H, t, J = 6.9 Hz), 3.43 (2H, q, J = 6.9 Hz), 3.6-3.7 (2H, m), 4.1-4.2 (2H, m), 5.08 (2H, s), 6.9-7.0 (1H, m), 7.15- 7.25 (2H, m), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 12.02 (1H, s), 14.42 (1H, brs) 369 [00442]embedded image (DMSO-d6) 3.71 (3H, s), 3.77 (3H, s), 4.99 (2H, s), 6.85-6.95 (1H, m), 6.95- 7.05 (2H, m), 7.1-7.2 (1H, m), 7.2-7.3 (1H, m), 7.3-7.4 (2H, m), 12.01 (1H, s), 14.44 (1H, brs) 370 [00443]embedded image (DMSO-d6) 2.25 (3H, s), 3.78 (3H, s), 4.98 (2H, s), 6.94 (1H, d, J = 7.9 Hz), 7.1-7.2 (2H, m), 7.2-7.3 (2H, m), 7.3-7.4 (2H, m), 12.01 (1H, brs), 14.45 (1H, brs) 371 [00444]embedded image (DMSO-d6) 1.85-1.95 (2H, m), 3.16 (3H, s), 3.39 (2H, t, J = 6.2 Hz), 4.08 (2H, t, J = 6.2 Hz), 5.06 (2H, s), 6.85-6.95 (1H, m), 7.15-7.3 (2H, m), 7.3-7.5 (3H, m), 12.03 (1H, s), 14.42 (1H, brs) 372 [00445]embedded image (DMSO-d6) 3.78 (3H, s), 3.85 (3H, s), 4.94 (2H, s), 7.0-7.1 (1H, m), 7.1-7.2 (2H, m), 7.2-7.35 (2H, m), 7.36 (1H, s), 11.96 (1H, brs), 14.56 (1H, brs) 373 [00446]embedded image (DMSO-d6) 1.36 (3H, t, J = 6.9 Hz), 3.78 (3H, s), 4.13 (2H, q, J = 6.9 Hz), 4.96 (2H, s), 7.0-7.1 (1H, m), 7.1-7.2 (2H, m), 7.2-7.35 (2H, m), 7.37 (1H, s) 11.97 (1H, brs), 14.56 (1H, brs) 374 [00447]embedded image (DMSO-d6) 1.3 (3H, t, J = 7.0 Hz), 3.82 (3H, s), 4.08 (2H, q, J = 27.0 Hz), 4.94 (2H, s), 6.8-7.0 (2H, m), 7.1 (1H, d, J = 11.6 Hz), 7.26 (1H, d, J = 7.6 Hz), 7.35- 7.5 (2H, m), 11.99 (1H, s), 14.55 (1H, brs) 375 [00448]embedded image (DMSO-d6) 1.31 (3H, t, J = 7.0 Hz), 3.79 (3H, s), 4.09 (2H, q, J = 7.0 Hz), 4.95-5.05 (2H, m), 6.85-6.95 (1H, m), 7.12 (1H, d, J = 11.7 Hz), 7.23 (1H, d, J = 7.3 Hz), 7.38 (1H, s), 7.4-7.5 (1H, m), 11.99 (1H, s), 14.54 (1H, brs) 376 [00449]embedded image (DMSO-d6) 3.83 (3H, s), 5.18 (2H, s), 6.9-7.0 (1H, m), 7.38 (1H, s), 7.45-7.6 (1H, m), 7.7-7.85 (1H, m), 8.0-8.1 (1H, m), 12.08 (1H, s), 14.16 (1H, brs) 377 [00450]embedded image (DMSO-d6) 3.81 (3H, s), 5.07 (2H, s), 6.9-6.95 (1H, m), 7.39 (1H, s), 7.45- 7.55 (1H, m), 7.55-7.65 (2H, m), 12.06 (1H, s), 14.37 (1H, brs) 378 [00451]embedded image (DMSO-d6) 3.82 (3H, s), 5.08 (2H, s), 6.9-7.0 (1H, m), 7.39 (1H, s), 7.45-7.6 (1H, m), 7.61 (1H, d, J = 6.7 Hz), 7.73 (1H, d J = 9.1 Hz), 12.07 (1H, s), 14.33 (1H, brs) 379 [00452]embedded image (DMSO-d6) 3.82 (3H, s), 5.07 (2H, s), 6.9-7.0 (1H, m), 7.39 (1H, s), 7.45-7.55 (1H, m), 7.58 (1H, d, J = 6.5 Hz), 7.84 (1H, d, J = 8.8 Hz), 12.07 (1H, s), 14.33 (1H, s) 380 [00453]embedded image (DMSO-d6) 3.81 (3H, s), 5.0 (2H, s), 7.1-7.25 (3H, m), 7.29 (1H, d, J = 7.4 Hz), 7.39 (1H, s), 7.45-7.6 (1H, m), 12.01 (1H, s), 14.54 (1H, s) 381 [00454]embedded image (DMSO-d6) 3.82 (3H, s), 5.13 (2H, s), 7.15 (1H, d, J = 11.4 Hz), 7.33 (1H, d, J = 7.3 Hz), 7.39 (1H, s), 7.45-7.6 (3H, m), 12.01 (1H, s), 14.54 (1H, s) 382 [00455]embedded image (DMSO-d6) 5.12 (2H, s), 7.15-7.25 (2H, m), 7.39 (1H, s), 7.5-7.7 (3H, m), 12.06 (1H, s), 14.36 (1H, brs) 383 [00456]embedded image (DMSO-d6) 5.24 (2H, s), 7.39 (1H, s), 7.45-7.55 (1H, m), 7.55-7.75 (4H, m), 12.06 (1H, s), 14.36 (1H, brs) 384 [00457]embedded image (DMSO-d6) 3.78 (3H, s), 3.81 (3H, s), 4.96 (2H, s), 6.85-7.0 (2H, m), 7.07 (1H, d, J = 8.4 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.37 (1H, s), 7.4-7.55 (1H, m), 11.87 (1H, s), 14.97 (1H, s) 385 [00458]embedded image (DMSO-d6) 3.2 (3H, s), 3.5-3.6 (2H, m), 3.81 (3H, s), 4.05-4.15 (2H, m), 5.01 (2H, s); 6.85-6.95 (1H, m), 7.13 (1H, d, J = 11.2 Hz), 7.23 (1H, d, J = 7.0 Hz), 7.39 (1H, s), 7.4-7.5 (1H, m), 11.99 (1H, s) 14.52 (1H, s) 386 [00459]embedded image (DMSO-d6) 1.0 (3H, t, J = 7.0 Hz), 3.4 (2H, q, J = 7.0 Hz), 3.55-3.65 (2H, m), 3.81 (3H, s), 4.05-4.15 (2H, m), 5.0 (2H, s), 6.85-6.95 (1H, m), 7.13 (1H, d, J = 11.4 Hz), 7.23 (1H, d, J = 7.7 Hz), 7.38 (1H, s), 7.4-7.5 (1H, m), 11.99 (1H, s), 14.53 (1H, brs) 387 [00460]embedded image (DMSO-d6) 3.19 (3H, s), 3.5-3.65 (2H, m), 4.05-4.2 (2H, m), 5.13 (2H, s), 6.9- 7.0 (1H, m), 7.38 (1H, s), 7.4-7.65 (3H, m), 12.03 (1H, s), 14.34 (1H, brs) 388 [00461]embedded image (DMSO-d6) 0.99 (3H, t, J = 7.0 Hz), 3.4 (2H, q, J = 7.0 Hz), 3.55-3.7 (2H, m), 4.05-4.2 (2H, m), 5.11 (2H, s), 6.9-7.0 (1H, m), 7.38 (1H, s), 7.4-7.65 (3H, m), 12.03 (1H, s), 14.35 (1H, brs) 389 [00462]embedded image (DMSO-d6) 1.75-1.9 (1H, m), 1.9-2.05 (1H, m), 2.5-2.7 (4H, m), 6.55-6.6 (1H, m), 6.9- 6.95 (1H, m), 7.1-7.2 (1H, m), 7.25-7.45 (4H, m), 7.45-7.55 (2H, m), 11.96 (1H, s), 14.41 (1H, s) 390 [00463]embedded image (DMSO-d6) 3.82 (3H, s), 5.08 (2H, s), 6.9-7.0 (1H, m), 7.0-7.1 (1H, m), 7.3- 7.4 (2H, m), 7.4-7.55 (2H, m), 11.91 (1H, brs), 14.82 (1 H, brs) 391 [00464]embedded image (DMSO-d6) 1.8-1.95 (1H, m), 2.25-2.4 (1H, m), 2.6-2.8 (4H, m), 3.6 (3H, s), 6.65-6.75 (1H, m), 7.05-7.15 (1H, m), 7.25-7.35 (2H, m), 7.35-7.5 (1H, m), 11.7-12.2 (1H, br), 14.1-14.8 (1H, br) 392 [00465]embedded image (DMSO-d6) 3.78 (3H, s), 3.81 (3H, s), 4.9-5.1 (4H, m), 5.95 (1H, t, J = 5.6 Hz), 6.71 (1H, s), 6.85-6.95 (1H, m), 7.05 (1H, d, J = 11.2 Hz), 7.17 (1H, d, J = 7.4 Hz), 7.4-7.55 (1H, m), 11.32 (1H, s) 393 [00466]embedded image (DMSO-d6) 3.8 (3H, s), 3.81 (3H, s), 4.95 (2H, s), 6.85-6.95 (1H, m), 7.1 (1H, d, J = 11.5 Hz), 7.2-7.3 (2H, m), 7.4- 7.55 (1H, m), 8.05-8.15 (1H, m), 9.65- 9.75 (1H, m), 11.77 (1H, s) 394 [00467]embedded image (DMSO-d6) 1.58 (3H, d, J = 6.4 Hz), 5.65-5.75 (1H, m), 6.85-6.9 (1H, m), 7.2-7.25 (2H, m), 7.3-7.45 (2H, m), 7.45-7.55 (3H, m), 8.05-8.15 (1H, m), 9.6-9.7 (1H, m), 11.7-11.8 (1H, m) 395 [00468]embedded image (DMSO-d6) 5.16 (2H, s), 7.19 (1H, dd, J = 8.9 Hz, 3.2 Hz), 7.24 (1H, s), 7.35- 7.45 (3H, m), 7.5-7.7 (3H, m), 8.11 (1H, d, J = 2.1 Hz), 9.65-9.7 (1H, m), 11.8 (1H, s) 396 [00469]embedded image (DMSO-d6) 3.6-3.75 (2H, m), 4.04 (2H, t, J = 4.9 Hz), 4.8-4.95 (1H, m), 5.13 (2H, s), 6.9-6.95 (1H, m), 7.15-7.3 (2H, m), 7.3-7.4 (2H, m), 7.4-7.5 (1H, m), 12.01 (1H, s), 14.4 (1H, brs) 397 [00470]embedded image (DMSO-d6) 1.75-1.9 (2H, m), 3.45-3.55 (2H, m), 4.1 (2H, t, J = 6.2 Hz), 4.9-5.0 (1H, m), 5.06 (2H, s), 6.85-6.95 (1H, m), 7.15-7.25 (2H, m), 7.3-7.4 (2H, m), 7.4- 7.5 (1H, m), 12.02 (1H, s), 14.4 (1H, brs) 398 [00471]embedded image (DMSO-d6) 3.55-3.65 (1H, m), 3.7-3.8 (1H, m), 5.15-5.25 (1H, m), 5.25-5.35 (1H, m), 7.0-7.05 (1H, m), 7.2-7.5 (8H, m), 11.95-12.05 (1H, m), 14.42 (1H, s) 399 [00472]embedded image (DMSO-d6) 4.61 (2H, s), 5.16 (2H, s), 5.21 (1H, brs), 7.15-7.5 (7H, m), 7.57 (1H, d, J = 8.6 Hz), 12.0 (1H, s) 400 [00473]embedded image (DMSO-d6) 4.51 (2H, d, J = 5.2 Hz), 5.1 (2H, s), 5.22 (1H, t, J = 5.2 Hz), 7.15-7.2 (1H, m), 7.25-7.45 (6H, m), 7.57 (1H, d, J = 8.6 Hz), 12.03 (1H, s), 14.44 (1H, s) 401 [00474]embedded image (DMSO-d6) 4.61 (2H, s), 5.15 (2H, s), 7.15-7.5 (6H, m), 7.57 (1H, d, J = 9.2 Hz), 7.95 (1H, s), 13.95 (1H, s) 402 [00475]embedded image (DMSO-d6) 3.55-3.65 (1H, m), 3.7-3.8 (1H, m), 5.0-5.4 (2H, m), 7.0-7.1 (1H, m), 7.15-7.5 (7H, m), 7.95 (1H, d, J = 5.9 Hz), 12.98 (1H, brs), 13.95 (1H, s) 403 [00476]embedded image (DMSO-d6) 1.55 (3H, d, J = 6.3 Hz), 3.6-3.8 (2H, m), 3.95-4.15 (2H, m), 4.85-4.95 (1H, m), 5.75-5.9 (1H, m), 6.9-7.05 (3H, m), 7.15-7.5 (5H, m), 11.95-12.05 (1H, m), 14.43 (1H, s) 404 [00477]embedded image (DMSO-d6) 1.55 (3H, d, J = 6.3 Hz), 3.6-3.8 (2H, m), 3.95-4.15 (2H, m), 4.8- 5.0 (1H, br), 5.75-5.85 (1H, m), 6.9-7.05 (3H, m), 7.15-7.35 (3H, m), 7.43 (1H, d, J = 8.9 Hz), 7.9-8.0 (1H, m), 12.8-13.2 (1H, br), 13.99 (1H, s) 405 [00478]embedded image (DMSO-d6) 1.57 (3H, d, J = 6.2 Hz), 4.55-4.65 (1H, m), 4.65-4.75 (1H, m), 5.3-5.35 (1H, m), 5.7-5.8 (1H, m), 6.95- 7.05 (1H, m), 7.2-7.5 (7H, m), 11.95- 12.05 (1H, m), 14.42 (1H, s) 406 [00479]embedded image (DMSO-d6) 3.65-3.75 (2H, m), 4.0-4.1 (2H, m), 4.87 (1H, brs), 5.12 (2H, s), 6.95-7.0 (1H, m), 7.05 (1H, d, J = 8.1 Hz), 7.19 (1H, dd, J = 9.0 Hz, 3.0 Hz), 7.25-7.45 (4H, m), 7.56 (1H, d, J = 9.0 Hz), 12.04 (1H, s), 14.46 (1H, s) 407 [00480]embedded image (DMSO-d6) 1.54 (3H, d, J = 6.3 Hz), 1.85-1.95 (2H, m), 3.55-3.65 (2H, m), 4.05-4.2 (2H, m), 4.54 (1H, brs), 5.65- 5.75 (1H, m), 6.85-7.0 (2H, m), 7.0-7.1 (1H, m), 7.15-7.2 (1H, m), 7.2-7.35 (2H, m), 7.4 (1H, d, J = 4.6 Hz), 7.47 (1H, d, J = 9.0 Hz), 11.95-12.05 (1H, m), 14.42 (1H, s) 408 [00481]embedded image (DMSO-d6) 1.66 (3H, d, J = 6.4 Hz), 1.85-1.95 (2H, m), 3.5-3.6 (2H, m), 4.05-4.2 (2H, m), 5.75-5.85 (1H, m), 6.7-7.1 (4H, m), 7.2-7.4 (3H, 7), 11.95- 12.05 (1H, m), 14.35-14.45 (1H, m) 409 [00482]embedded image (DMSO-d6) 1.66 (3H, d, J = 6.6 Hz), 3.55-3.8 (2H, m), 3.85-4.0 (1H, m), 4.05-4.2 (1H, m), 4.9-5.05 (1H, m), 5.9- 6.0 (1H, m), 6.7-6.9 (2H, m), 7.0-7.4 (5H, m), 11.95-12.05 (1H, m), 14.44 (1H, s) 410 [00483]embedded image (DMSO-d6) 1.66 (3H, d, J = 6.4 Hz), 1.8-1.95 (2H, m), 3.5-3.6 (2H, m), 4.0- 4.2 (2H, m), 5.8 (1H, q, J = 6.4 Hz), 6.7- 6.8 (1H, m), 6.8-7.0 (2H, m), 7.0-7.05 (1H, m), 7.2-7.35 (2H, m), 7.9-7.95 (1H, m), 13.93 (1H, s) 411 [00484]embedded image (DMSO-d6) 1.85-2.0 (1H, m), 2.2-2.35 (1H, m), 2.65-2.85 (4H, m), 6.75-6.85 (1H, m), 7.0-7.1 (3H, m), 7.24 (1H, t, J = 9.3 Hz), 7.3-7.45 (2H, m), 11.97 (1H, brs), 13.5-15.0 (1H, br) 412 [00485]embedded image (DMSO-d6) 1.820 (3H, s), 1.823 (3H, s), 6.75-6.8 (1H, m), 6.95-7.1 (3H, m), 7.15-7.25 (1H, m), 7.3-7.45 (2H, m), 11.96 (1H, brs), 14.43 (1H, brs) 413 [00486]embedded image (DMSO-d6) 3.79 (3H, s), 5.05-5.2 (2H, m), 6.8-6.8 (1H, m), 7.05-7.2 (1H, m), 7.37 (1H, s), 7.5-7.6 (1H, m), 7.65-7.75 (1H, m), 12.02 (1H, s), 14.35 (1H, s) 414 [00487]embedded image (DMSO-d6) 3.79 (3H, s), 3.85 (3H, s), 5.0-5.1 (2H, m), 6.8-6.9 (1H, m), 7.05- 7.2 (2H, m), 7.38 (1H, s), 7.51 (1H, d, J = 8.5 Hz), 11.98 (1H, s), 14.54 (1H, brs) 415 [00488]embedded image (DMSO-d6) 3.27 (3H, s), 3.6-3.7 (2H, m), 4.1-4.2 (2H, m), 5.13 (2H, s), 6.85- 6.95 (1H, m), 7.05-7.2 (1H, m), 7.39 (1H, s), 7.4-7.5 (1H, m), 7.6-7.7 (2H, m), 12.05 (1H, s), 14.42 (1H, s) 416 [00489]embedded image (DMSO-d6) 1.05 (3H, t, J = 7.1 Hz), 3.46 (2H, q, J = 7.1 Hz), 3.65-3.75 (2H, m), 4.1-4.2 (2H, m), 5.14 (2H, s), 6.85- 6.95 (1H, m), 7.05-7.2 (1H, m), 7.38 (1H, s), 7.4-7.5 (1H, m), 7.55-7.7 (2H, m), 12.05 (1H, s), 14.41 (1H, s) 417 [00490]embedded image (DMSO-d6) 1.27 (3H, t, J = 7.1 Hz), 3.68 (2H, t, J = 4.8 Hz), 4.05 (2H, t, J = 4.8 Hz), 4.3 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 6.85-6.95 (1H, m), 7.1-7.25 (3H, m), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 11.63 (1H, s) 418 [00491]embedded image (DMSO-d6) 1.13 (3H, t, J = 7.0 Hz), 1.27 (3H, t, J = 7.1 Hz), 4.03 (2H, q, J = 7.0 Hz), 4.25-4.35 (4H, m), 4.35-4.45 (2H, m), 5.07 (2H, s), 6.9-7.0 (1H, m), 7.1-7.2 (3H, m), 7.25-7.35 (1H, m), 7.4- 7.55 (1H, m), 11.63 (1H, s) 419 [00492]embedded image (DMSO-d6) 1.04 (9H, s), 1.27 (3H, t, J = 7.1 Hz), 4.2-4.35 (6H, m), 5.05 (2H, s), 6.9-7.05 (1H, m), 7.05-7.2 (3H, m), 7.25-7.35 (1H, m), 7.4-7.55 (1H, m), 11.63 (1H, s) 420 [00493]embedded image (DMSO-d6) 2.7-2.75 (3H, m), 3.71 (3H, s), 4.1-4.25 (2H, m), 6.95-7.15 (4H, m), 7.38 (1H, s), 7.41 (1H, d, J = 8.6 Hz), 11.95 (1H, s), 14.57 (1H, brs) 421 [00494]embedded image (DMSO-d6) 2.73 (3H, s), 3.74 (3H, s), 4.15-4.25 (2H, m), 7.08 (1H, d, J = 12.4 Hz), 7.15-7.2 (1H, m), 7.36 (1H, s), 7.4- 7.45 (2H, m), 7.56 (1H, d, J = 8.7 Hz), 11.96 (1H, brs), 14.61 (1H, brs) 422 [00495]embedded image (DMSO-d6) 2.68 (3H, s), 3.81 (3H, s), 4.15 (2H, s), 6.7-6.85 (2H, m), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.45-7.55 (2H, m), 11.98 (1H, s), 14.45 (1H, s) 423 [00496]embedded image (DMSO-d6) 2.75 (3H, s), 4.22 (2H, s), 6.95-7.15 (3H, m), 7.35-7.45 (2H, m), 7.45-7.5 (2H, m), 12.02 (1H, s) 424 [00497]embedded image (DMSO-d6) 2.72 (3H, s), 4.3 (2H, s), 7.15-7.25 (1H, m), 7.35-7.5 (4H, m), 7.55-7.65 (2H, m), 12.03 (1H, s) 425 [00498]embedded image (DMSO-d6) 2.7-2.75 (3H, m), 3.23 (3H, s), 3.6-3.7 (2H, m), 4.05-4.1 (2H, m), 4.22 (2H, s), 6.7-6.8 (1H, m), 7.0-7.1 (1H, m), 7.3-7.4 (2H, m), 7.45-7.55 (2H, m), 12.03 (1H, s), 14.46 (1H, brs) 426 [00499]embedded image (DMSO-d6) 2.7-2.75 (3H, m), 3.79 (3H, s), 4.2 (2H, s), 6.7-6.8 (1H, m), 7.0-7.15 (1H, m), 7.3-7.4 (2H, m), 7.45-7.55 (2H, m), 12.02 (1H, s), 14.47 (1H, brs) 427 [00500]embedded image (DMSO-d6) 3.7-3.8 (2H, m), 4.04 (2H, t, J = 4.6 Hz), 4.85-4.95 (1H, m), 5.17 (2H, s), 6.85-6.95 (1H, m), 7.05-7.15 (1H, m), 7.39 (1H, s), 7.4-7.5 (1H, m), 7.6-7.7 (2H, m), 12.05 (1H, s), 14.44 (1H, s) 428 [00501]embedded image (DMSO-d6) 2.7-2.75 (3H, m), 3.7-3.8 (6H, m), 4.1-4.2 (2H, m), 6.7-6.75 (1H, m), 6.95-7.1 (2H, m), 7.37 (1H, s), 7.41 (1H, d, J = 8.8 Hz), 11.95 (1H, s), 14.57 (1H, s)

    [0680] For example, the GnRH antagonist may be 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid, or a pharmaceutically acceptable salt thereof. The salt may be, for instance, the choline salt thereof, represented by formula (VIa), below.

    ##STR00502##

    [0681] Compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof (compound (VIa)), can be synthesized, for example, using the methodology described in WO 2014/042176, the disclosure of which is incorporated herein by reference in its entirety. An exemplary synthetic scheme that may be used for the preparation of compound (VI) and the choline salt thereof is shown in Scheme 1, below.

    ##STR00503##

    [0682] wherein R.sub.1 and R.sub.2 are each independently C.sub.1-6 alkoxy groups; LG is a nucleofugal leaving group, such as chlorine or bromine, among others; R.sub.3 represents an optional substituent, such as halogen, acyl group, C.sub.1-6 alkyl group, or a nitro substituent; DMAP denotes N-dimethylaminopyridine; and TEA denotes trimethylamine.

    [0683] Crystalline compound (VIa) has been characterized spectroscopically, for instance, in U.S. Pat. No. 9,169,266, the disclosure of which is incorporated herein by reference in its entirety. The foregoing crystalline form has been shown to exhibit characteristic X-ray powder diffraction peaks at about 7.1° 2θ, about 11.5° 2θ, about 19.4° 2θ, about 21.5° 2θ, about 22.0° 2θ, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ. Additionally, this crystalline form exhibits .sup.13C solid-state nuclear magnetic resonance (NMR) peaks centered at about 55.5 ppm, about 57.1 ppm, about 58.7 ppm, about 69.8 ppm, about 98.1 ppm, about 110.3 ppm, about 111.6 ppm, about 113.7 ppm, about 118.0 ppm, about 145.3 ppm, about 149.8 ppm, and about 155.8 ppm. This crystalline form further exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.

    [0684] Compound (VI), as well as pharmaceutically acceptable salts thereof, such as the choline salt thereof, exhibit a high affinity for human GnRH receptor (27.4 nM). Using the compositions and methods described herein, a patient that is presenting with or has been diagnosed as having an estrogen-dependent disease (e.g., uterine fibroids, endometriosis, such as rectovaginal endometriosis, and/or adenomyosis, among others described herein) may be administered a compound of formula (VI), or a pharmaceutically acceptable salt thereof, such as the choline salt thereof, to treat the disease or ameliorate one or more symptoms of the disease. Exemplary doses of compound (VI) and pharmaceutically acceptable salts thereof, such as the choline salt thereof, include doses of from 25 mg to 500 mg daily, such as doses of 100 mg per day and 200 mg per day. Additional dosing information is provided below.

    3-Aminoalkyl pyrimidine-2,4(1H,3H)-diones

    [0685] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted 3-aminoalkyl pyrimidine-2,4(1H,3H)-dione derivatives, such as compounds represented by formula (VII)

    ##STR00504##

    [0686] wherein R.sub.1a, R.sub.1b and R.sub.1c are the same or different and are each independently hydrogen, halogen, C.sub.1-4alkyl, hydroxy or alkoxy, or R.sub.1a and R.sub.1b taken together form —OCH.sub.2O— or —OCH.sub.2CH.sub.2—;

    [0687] R.sub.2a and R.sub.2b are the same or different and are each independently hydrogen, halogen, trifluoromethyl, cyano or —SO.sub.2CH.sub.3;

    [0688] R.sub.3 is hydrogen or methyl;

    [0689] R.sub.4 is phenyl or C.sub.3-7alkyl;

    [0690] R.sub.5 is hydrogen or C.sub.1-4alkyl;

    [0691] R.sub.6 is —COOH or an acid isostere; and

    [0692] X is C.sub.1-6alkanediyl optionally substituted with from 1 to 3 C.sub.1-6alkyl groups;

    [0693] or a pharmaceutically acceptable salt thereof.

    [0694] For example, the GnRH antagonist may be the conjugate acid of elagolix, which is represented by formula (VIII),

    ##STR00505##

    [0695] or a pharmaceutically acceptable salt thereof. In some embodiments, the GnRH antagonist is the sodium salt of the compound represented by formula (VIII), which is represented by formula (IX), below.

    ##STR00506##

    Compound (IX), also referred to as sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, is known as elagolix. Other GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 7,056,927, the contents of which are incorporated herein by reference. Exemplary GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the present disclosure include the compounds set forth in Table 2, below.

    TABLE-US-00002 TABLE 2 Exemplary 3-Aminoalkyl pyrimidine-2,4(1H,3H)-dione GnRH Antagonists Useful for the Treatment of Estrogen-Dependent Diseases No. Compound Reported spectral properties 1 [00507]embedded image HPLC MS (Cl) m/z 632.2 (MH+), tR = 26.45 2 [00508]embedded image MS (Cl) m/z 618.2 (MH+) tR = 1.005 3 [00509]embedded image HPLC-MS (Cl) m/z 656.2 (MH+), tR = 2.128 min 4 [00510]embedded image MS (Cl) m/z 588.3 (MH+) 5 [00511]embedded image HPLC-MS (Cl) m/z 604.1, 606.1 (MH+), tR = 2.511 6 [00512]embedded image HPLC-MS (Cl) m/z 604.1, 606.1 (MH+), tR = 26.98 7 [00513]embedded image HPLC-MS (Cl) m/z 634.2, 636.2 (MH+), tR = 24.925 8 [00514]embedded image MS (Cl) m/z 614.1, 616.1 (MH+), tR = 6.550 min 9 [00515]embedded image HPLC-MS (Cl) m/z 592.3 (MH+), tR = 2.150 10 [00516]embedded image HPLC-MS (Cl) m/z = 556.2 (M + H+), tR = 2.354 11 [00517]embedded image

    Thieno[2,3d]pyrimidines

    [0696] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted thieno[2,3d]pyrimidine derivatives, such as compounds represented by formula (X)

    ##STR00518##

    [0697] wherein R.sup.a is a hydrogen atom, an optionally substituted aryl group (such as an aryl group that may have 1 to 5 substituents selected from halogen, nitro, cyano, amino, a carboxyl group that may be esterified or amidated, an alkylenedioxy, alkyl, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl), an optionally substituted cycloalkyl group, or an optionally substituted heterocyclic group;

    [0698] R.sup.b is an optionally substituted nitrogen-containing heterocyclic group;

    [0699] R.sup.c is an optionally substituted amino group;

    [0700] R.sup.d is an optionally substituted aryl group;

    [0701] p is an integer from 0 to 3; and

    [0702] q is an integer from 0 to 3;

    [0703] or a pharmaceutically acceptable salt thereof.

    [0704] In some embodiments, the GnRH antagonist is a thieno[2,3d]pyrimidine compound represented by formula (XI)

    ##STR00519##

    [0705] wherein R.sup.1 is C.sub.1-4alkyl;

    [0706] R.sup.2 is (1) a C.sub.1-6alkyl which may have a substituent selected from the group consisting of (1) a hydroxy group, (2′) a C.sub.1-4alkoxy, (3′) a C.sub.1-4alkoxy-carbonyl, (4′) a di-C.sub.1-4alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C.sub.1-4alkyl-carbonyl and (7) a halogen, (2) a C.sub.3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C.sub.1-4alkyl-carbonylamino, (3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) a halogen, (2′) a hydroxy group, (3′) a C.sub.1-4alkyl and (4′) a C.sub.1-4alkoxy, (4) a phenyl which may have a substituent selected from the group consisting of (1) a halogen, (2′) a C.sub.1-4alkoxy-C.sub.1-4alkyl, (3′) a mono-C.sub.1-4alkyl-carbamoyl-C.sub.1-4alkyl, (4′) a C.sub.1-4alkoxy and (5′) a mono-C.sub.1-4alkylcarbamoyl-C.sub.1-4alkoxy, or (5) a C.sub.1-4alkoxy;

    [0707] R.sup.3 is C.sub.1-4alkyl;

    [0708] R.sup.4 is (1) hydrogen, (2) C.sub.1-4alkoxy, (3) C.sub.6-10aryl, (4) N—C.sub.1-4alkyl-N—C.sub.1-4alkylsulfonylamino, (5) hydroxyl, or (6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C.sub.1-4alkyl, (3′) a hydroxy-C.sub.1-4alkyl, (4′) a C.sub.1-4alkoxy-carbonyl, (5′) a mono-C.sub.1-4alkyl-carbamoyl and (6′) a C.sub.1-4alkylsulfonyl; and n is an integer from 1 to 4;

    [0709] optionally provided that when R.sup.2 is a phenyl which may have a substituent, R.sup.4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) hydroxy-C.sub.1-4alkyl, (3) C.sub.1-4alkoxy-carbonyl, (4) mono-C.sub.1-4alkyl-carbamoyl and (5) C.sub.1-4alkylsulfonyl;

    [0710] or a pharmaceutically acceptable salt thereof. For example, the GnRH antagonist may be a compound represented by formula (XII), below.

    ##STR00520##

    Compound (XII), also referred to as N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, is known as relugolix. Other GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 7,300,935, the contents of which are incorporated herein by reference. Exemplary GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the present disclosure include the compounds set forth in Table 3, below.

    TABLE-US-00003 TABLE 3 Exemplary Thieno[2,3d]pyrimidine GnRH Antagonists Useful for the Treatment of Estrogen- Dependent Diseases No. Compound Reported spectral properties 1 [00521]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.89 (2H, s), 5.34 (2H, brs), 6.91 (2H, t, J = 8.0 Hz), 7.1- 7.45 (9H, m), 7.56 (2H, d, J = 8.8 Hz), 7.65 (1H, s), 7.75 (2H, d, J = 8.8 Hz), 7.91 (1H, dt, J = 2.0, 7.7 Hz), 8.7-8.75 (1H, m). 2 [00522]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.11 (3H, s), 2.45-2.6 (2H, m), 2.70 (3H, s), 2.75 (3H, s), 3.1-3.25 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2- 7.6 (7H, m), 7.65 (1H, s), 7.85- 7.95 (1H, m), 8.65-8.75 (1H, m). 3 [00523]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.7-1.85 (2H, m), 2.17 (3H, s), 2.15-2.3 (2H, m), 2.5-2.6 (2H, m), 3.15 (2H, t, J = 7.0 Hz), 3.2-3.4 (2H, m), 3.76 (2H, s), 3.83 (3H, s), 5.36 (2H, brs), 6.93 (2H, t, J = 8.4 Hz), 7.16 (1H, s), 7.2- 7.7 (8H, m), 7.85-7.95 (1H, m), 8.65-8.75 (1H, m). 4 [00524]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.10 (3H, s), 3.70 (2H, s), 3.82 (3H, s), 3.96 (3H, s), 5.34 (2H, brs), 6.85-7.7 (14H, m), 7.85-7.95 (1H, m), 8.4-8.5 (1H, m), 8.65- 8.75 (1H, m). 5 [00525]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.04 (3H, s), 2.5-2.65 (1H, m), 3.58 (2H, s), 3.83 (3H, s), 3.91 (2H, s), 3.9-4.0 (2H, m), 4.37 (2H, t, J = 5.0 Hz), 5.34 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.4 (7H, m), 7.54 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.6- 7.7 (1H, m). 6 [00526]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.04 (3H, s), 3.51 (2H, s), 3.82 (3H, s), 3.86 (2H, s), 4.57 (2H, t, J = 6.2 Hz), 4.81 (2H, t, J = 6.2 Hz), 5.28 (2H, s), 6.91 (2H, t, J = 8.4 (2H, s), 7.53 (2H, d, J = 8.6 Hz), 7.62 (1H, s), 7.70 (2H, t, J = 8.6 Hz), 7.75 (1H, s). 7 [00527]embedded image 2-yl Form (1) .sup.1H-NMR (CDCl.sub.3) δ: 2.02 (3H, s), 3.51 (2H, s), 3.83 (5H, s), 4.6-4.7 (2H, m), 5.0-5.1 (2H, m), 5.28 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, s), 7.2- 7.75 (11H, m), 8.38 (1H, s). [00528]embedded image 1-yl Form (2) .sup.1H-NMR (CDCl.sub.3) δ: 2.01 (3H, s), 3.51 (2H, s), 3.83 (3H, s), 3.8-4.0 (2H, m), 4.6-4.7 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.65-6.75 (1H, m), 6.85-7.0 (2H, m), 7.1-7.7 (11H, m), 8.68 (1H, s). 8 [00529]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.11 (3H, s), 2.65 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.46 (2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.9-4.0 (2H, m), 4.35 (2H, t, J = 5.2 Hz), 5.34 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.14 (1H, s), 7.2-7.35 (1H, m), 7.5-7.65 (5H, m). 9 [00530]embedded image 2-yl Form (1) .sup.1H-NMR (CDCl.sub.3) δ: 2.10 (3H, brs), 2.55-2.65 (2H, m), 3.31 (3H, s), 3.4-3.5 (2H, m), 3.76 (2H, s), 3.82 (3H, s), 4.62 (2H, t, J = 5.8 Hz), 5.02 (2H, t, J = 5.8 Hz), 5.27 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.25- 7.4 (1H, m), 7.5-7.65 (5H, m), 8.43 (1H, s). [00531]embedded image 1-yl Form (2) .sup.1H-NMR (CDCl.sub.3) δ: 2.07 (3H, s), 2.55-2.65 (2H, m), 3.30 (3H, s), 3.4-3.5 (2H, m), 3.74 (2H, s), 3.82 (3H, s), 4.55-4.65 (2H, m), 4.8-4.9 (2H, m), 5.30 (2H, s), 6.93 (2H, t, J = 7.8 Hz), 7.10 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m), 8.69 (1H, s). 10 [00532]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.11 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.31 (3H, s), 3.44 (2H, t, J = 5.8 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.55 (2H, t, J = 5.6 Hz), 4.79 (2H, t, J = 5.6 Hz), 5.27 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.10 (1H, s), 7.2-7.4 (2H, m), 7.51 (2H, s), 7.45-7.65 (4H, m). 11 [00533]embedded image 2-yl Form (1) .sup.1H-NMR (CDCl.sub.3) δ: 2.23 (3H, s), 3.00 (2H, t, J = 6.3 Hz), 3.78 (2H, s), 3.82 (3H, s), 4.45 (2H, t, J = 6.3 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.11 (1H, s), 7.2-7.6 (12H, m). [00534]embedded image 1-yl Form (2) .sup.1H-NMR (CDCl.sub.3) δ: 2.14 (3H, s), 2.82 (2H, t, J = 6.0 Hz), 3.80 (2H, s), 3.82 (3H, s), 4.39 (2H, t, J = 6.0 Hz), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.63 (1H, s). 12 [00535]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.20 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 6.95-7.1 (2H, m), 7.14 (1H, s), 7.2-7.55 (11H, m), 7.60 (1H, s), 8.43 (1H, d, J = 4.0 Hz). 13 [00536]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.18 (3H, s), 2.68 (4H, s), 3.83 (5H, s), 5.37 (2H, s), 6.85-7.0 (5H, m), 7.16 (1H, s), 7.2-7.65 (10H, m), 8.35-8.4 (2H, m). 14 [00537]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.15 (1H, s), 7.2-7.35 (4H, m), 7.4-7.65 (9H, m), 8.4-8.5 (1H, m). 15 [00538]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.10 (3H, s), 3.71 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 5.35 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.0-7.7 (14H, m), 8.4-8.5 (1H, m). 16 [00539]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.19 (3H, s), 2.85 (4H, s), 3.82 (5H, s), 5.36 (2H, s), 6.9-7.55 (13H, m), 7.60 (1H, s), 8.4-8.45 (1H, m). 17 [00540]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.21 (3H, s), 2.8-2.9 (4H, m), 3.82 (5H, s), 5.34 (2H, brs), 6.85-7.75 (13H, m), 7.60 (1H, s), 7.85- 7.95 (1H, m), 8.4-8.5 (1H, m), 8.65-8.75 (1H, m). 18 [00541]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.04 (3H, s), 3.58 (2H, s), 3.83 (3H, s), 3.92 (2H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.05-7.7 (14H, m), 8.35-8.45 (2H, m). 19 [00542]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 4.05-4.1 (1H, m), 4.65-4.75 (2H, m), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 6.9- 7.05 (1H, m), 7.1-7.2 (2H, m), 7.2-7.7 (12H, m). 20 [00543]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.09 (3H, s), 3.76 (2H, s), 3.83 (3H, s), 3.93 (3H, s), 3.99 (2H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.26 (1H, s), 7.2-7.6 (11H, m), 7.64 (1H, s), 8.05-8.15 (1H, m), 9.0-9.05 (1H, s). 21 [00544]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.21 (3H, s), 3.00 (3H, d, J = 4.6 Hz), 3.74 (2H, s), 3.84 (3H, s), 3.92 (2H, s), 5.36 (2H, s), 6.5-6.65 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.15-7.6 (12H, m), 7.71 (1H, s), 7.9-8.0 (1H, m), 8.80-8.85 (1H, m). 22 [00545]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.40 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.79 (2H, s), 3.83 (3H, s), 4.01 (2H, s), 4.43 (2H, q, J = 7.2 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.15 (1H, s), 7.2-7.7 (13H, m), 7.88 (1H, d, J = 7.4 Hz). 23 [00546]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.95 (3H, d, J = 5.2 Hz), 3.74 (2H, s), 3.84 (3H, s), 3.99 (2H, s), 5.36 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.15-7.7 (13H, m), 7.9-8.1 (3H, m). 24 [00547]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.17 (3H, s), 2.6-2.8 (2H, m), 3.80 (2H, s), 3.83 (3H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.78 (1H, s), 6.85-7.0 (3H, m), 7.2-7.6 (12H, m), 7.71 (1H, s). 25 [00548]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.9-2.1 (2H, m), 2.16 (3H, s), 2.6-2.8 (4H, m), 3.78 (2H, s), 3.83 (2H, s), 3.9-4.0 (2H, m), 5.38 (2H, s), 6.70 (1H, s), 6.80 (1H, s), 6.94 (2H, t, J = 8.0 Hz), 7.2- 7.6 (11H, m), 7.73 (1H, s). 26 [00549]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.09 (3H, s), 2.93 (3H, d, J = 4.8 Hz), 3.72 (2H, s), 3.83 (3H, s), 3.97 (2H, s), 4.55 (2H, s), 5.35 (2H, s), 6.55-6.65 (1H, m), 6.92 (2H, t, J = 8.0 Hz), 7.0-7.65 (14H, m), 8.44 (1H, d, J = 6.0 Hz). 27 [00550]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.10 (3H, t, J = 7.2 Hz), 2.10 (3H, s), 3.2- 3.4 (2H, m), 3.64 (2H, s), 3.72 (2H, s), 3.83 (3H, s), 3.98 (2H, s), 5.36 (2H, s), 5.45-5.55 (1H, m), 6.93 (2H, t, J = 8.0 Hz), 7.0- 7.1 (1H, m), 7.16 (1H, s), 7.25- 7.7 (12H, m), 8.44 (1H, d, J = 4.0 Hz). 28 [00551]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.10 (3H, s), 2.65-2.8 (2H, m), 3.68 (3H, s), 3.72 (2H, s), 3.83 (3H, s), 3.98 (2H, s), 4.3-4.5 (2H, m), 5.31 (2H, s), 6.91 (2H, t, J = 7.6 Hz), 7.0-7.4 (5H, m), 7.45-7.65 (5H, m), 8.4-8.5 (1H, m). 29 [00552]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.09 (3H, s), 2.75 (3H, d, J = 7.8 Hz), 2.94 (3H, s), 3.02 (3H, s), 3.73 (2H, s), 3.83 (3H, s), 4.07 (2H, s), 4.40 (2H, t, J = 7.8 Hz), 5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.35 (5H, m), 7.5-7.65 (5H, m), 8.45 (1H, d, J = 4.0 Hz). 30 [00553]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.4-1.8 (4H, m), 2.0-2.1 (2H, m), 2.12 (3H, s), 2.55-2,75 (2H, m), 3.73 (2H, s), 3.7-3.8 (1H, m), 3.82 (3H, s), 3.98 (2H, s), 4.9- 5.1 (1H, brm), 5.29 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.4 (7H, m), 7.45-7.65 (5H, m), 8.45 (1H, d, J = 4.8 Hz). 31 [00554]embedded image 2-yl Form (1) .sup.1H-NMR (CDCl.sub.3) δ: 2.25 (3H, s), 3.04 (2H, t, J = 6.2 Hz), 3.78 (2H, s), 3.83 (3H, s), 4.66 (2H, t, J = 6.2 Hz), 5.38 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.16 (1H, s), 7.2-7.6 (10H, m), 7.64 (1H, s), 8.30 (1H, s). [00555]embedded image 1-yl Form (2) .sup.1H-NMR (CDCl.sub.3) δ: 2.02 (3H, s), 2.7-2.8 (2H, m), 3.78 (2H, s), 3.83 (3H, s), 4.4-4.5 (2H, m), 5.38 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 7.17 (1H, s), 7.25- 7.65 (10H, m), 7.66 (1H, s). 32 [00556]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.22 (3H, s), 3.3-3.5 (1H, br), 3.78 (2H, s), 3.83 (3H, s), 3.9-4.05 (2H, m), 3.99 (2H, s), 4.35-4.4 (2H, m), 5.27 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 6.9-7.1 (1H, m), 7.15 (1H, s), 7.2-7.65 (8H, m), 8.35-8.4 (1H, m). 33 [00557]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.5-1.7 (2H, m), 1.8-2.0 (2H, m), 2.05 (3H, s), 2.25-2.45 (4H, m), 3.15 (2H, t, J = 7.8 Hz), 3.23 (2H, t, J = 7.2 Hz), 3.76 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.15 (1H, s), 7.2-7.6 (10H, m), 7.67 (1H, s). 34 [00558]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.7-1.85 (2H, m), 2.14 (3H, s), 2.21 (2H, t, J = 8.1 Hz), 2.54 (2H, t, J = 6.2 Hz), 3.19 (2H, t, J = 7.0 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77 (2H, s), 3.83 (3H, s), 5.38 (2H, s), 6.93 (2H, t, J = 8.1 Hz), 7.18 (1H, s), 7.25-7.7 (11H, m). 35 [00559]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.7-1.9 (2H, m), 2.15 (3H, s), 2.15-2.3 (2H, m), 2.52 (2H, t, J = 6.2 Hz), 3.20 (2H, t, J = 6.8 Hz), 3.29 (2H, t, J = 6.2 Hz), 3.77 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.35 (6H, m), 7.5-7.65 (4H, m), 7.64 (1H, s). 36 [00560]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.55 (2H, t, J = 6.4 Hz), 2.70 (3H, s), 2.71 (3H, s), 3.15 (2H, t, J = 6.4 Hz), 3.81 (2H, s), 3.83 (3H, s), 5.37 (2H, s), 6.93 (2H, t, J = 8.2 Hz), 7.1-7.7 (11H, m). 37 [00561]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7- 3.9 (3H, m), 3.83 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.7 (11H, m). 38 [00562]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.7-1.85 (4H, m), 2.09 (3H, s), 2.25- 2.35 (1H, m), 2.55-2.65 (1H, m), 2.71 (3H, s), 3.15-3.3 (2H, m), 3.65-3.7 (2H, m), 3.74 (1H, d, J = 12.0 Hz), 3.83 (3H, s), 3.87 (1H, d, J = 12.0 Hz), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 6.85-6.95 (1H, m), 7.1-7.35 (5H, m), 7.49 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.62 (1H, s). 39 [00563]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.7-1.85 (4H, m), 2.08 (3H, s), 2.2-2.4 (1H, m), 2.5-2.65 (1H, m), 2.72 (3H, s), 3.15-3.3 (2H, m), 3.7- 3.9 (3H, m), 3.83 (3H, s), 5.37 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.7 (11H, m). 40 [00564]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.15 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 (3H, s), 3.81 (2H, brs), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.24-7.40 (4H, m), 7.53 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.65 (1H, s), 7.88 (1H, dt, J = 1.5 Hz, 7.8 Hz), 8.67-8.69 (1H, m). 41 [00565]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.13 (3H, t, J = 6.9 Hz), 2.15 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.39 (2H, q, J = 6.9 Hz), 3.44 (2H, t, J = 6.2 Hz), 3.80 (2H, brs), 3.81 (3H, s), 5.34 (2H, brs), 6.91 (2H, t, J = 8.1 Hz), 7.19 (1H, s), 7.27- 7.32 (1H, m), 7.35-7.41 (2H, m), 7.53 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.64 (2H, d, J = 8.4 Hz), 7.88 (1H, dt, J = 1.2 Hz, 7.5 Hz), 8.68 (1H, dt, J = 0.9 Hz, 4.8 Hz). 42 [00566]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.80 (2H, brs), 3.82 (3H, s), 5.33 (2H, brs), 6.92 (2H, t, J = 8.3 Hz), 7.19 (1H, s), 7.28- 7.38 (2H, m), 7.52-7.63 (6H, m), 8.51 (1H, d, J = 3.0 Hz). 43 [00567]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.78 (2H, brs), 3.80 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.1 Hz), 7.27 (1H, d, J = 8.4 Hz), 7.27-7.33 (1H, m), 7.37 (1H, s), 7.98 (1H, dd, J = 2.7 Hz, 8.4 Hz), 8.72 (1H, d, J = 2.7 Hz). 44 [00568]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.14 (3H, s), 2.39 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.77 (2H, brs), 3.80 (3H, s), 5.26 (1H, brs), 5.38 (1H, brs), 6.91 (2H, t, J = 8.3 Hz), 7.23-7.34 (2H, m), 7.42 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.62 (2H, d, J = 8.7 Hz), 7.66 (1H, s), 7.66-7.69 (1H, m), 8.48 (1H, d, J = 2.4 Hz). 45 [00569]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.15 (3H, s), 2.60 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.66-3.94 (2H, m), 3.81 (3H, s), 5.15 (1H, d, J = 15.3 Hz), 5.48 (1H, d, J = 15.3 Hz), 6.91 (2H, t, J = 8.1 Hz), 7.16 (1H d, J = 7.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 7.25 (1H, s), 7.26-7.35 (1H, m), 7.53 (2H, d, J = 8.7 Hz), 7.63 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.64 (2H, d, J = 8.7 Hz), 7.76 (1H, t, J = 7.8 Hz). 46 [00570]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.51 (3H, s), 2.62 (2H, t, J = 5.9 Hz), 3.26 (3H, s), 3.40 (2H, t, J = 5.9 Hz), 3.77 (1H, d, J = 12.3 Hz), 3.77 (3H, s), 3.79 (3H, s), 3.86 (1H, d, J = 12.3 Hz), 5.24 (1H, d, J = 15.6 Hz), 5.40 (1H, d, J = 15.6 Hz), 6.90 (2H, t, J = 8.1 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.23-7.34 (1H, m), 7.27 (1H, d, J = 8.4 Hz), 7.51 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.65 (1H, s), 7.69 (1H, s). 47 [00571]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.11 (3H, s), 2.48 (3H, s), 2.51-2.59 (2H, m), 3.20 (3H, s), 3.30-3.46 (4H, m), 3.60 (1H, d, J = 12.3 Hz), 3.79 (3H, s), 4.05 (1H, d, J = 12.3 Hz), 5.21 (1H, d, J = 15.6 Hz), 5.31 (1H, d, J = 15.6 Hz), 6.88 (2H, t, J = 8.1 Hz), 7.07 (1H, d, J = 8.1 Hz), 7.21-7.31 (2H, m), 7.43-7.51 (4H, m), 7.69 (1H, s). 48 [00572]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.20 (3H, s), 2.63 (2H, t, J = 6.2 Hz), 3.28 (3H, s), 3.41 (2H, t, J = 6.2 Hz), 3.78 (1H, d, J = 12.3 Hz), 3.82 (3H, s), 3.84 (3H, s), 3.88 (1H, d, J = 12.3 Hz), 5.35 (2H, s), 6.92 (2H, t, J = 8.1 Hz), 7.17 (1H, s), 7.23-7.39 (3H, m), 7.54 (2H, d, J = 8.8 Hz), 7.57 (1H, s), 7.69 (2H, d, J = 8.8 Hz), 8.23-8.27 (1H, m). 49 [00573]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.60 (6H, s), 1.79 (1H, s), 2.14 (3H, s), 2.63 (2H, t, J = 5.9 Hz), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.82 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20-7.34 (4H, m), 7.53 (2H, d, J = 8.7 Hz), 7.60-7.63 (5H, m). 50 [00574]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.62 (6H, s), 1.77 (1H, s), 2.05 (3H, s), 3.56 (2H, s), 3.82 (3H, s), 3.90 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.1 Hz), 7.14-7.38 (9H, m), 7.55 (2H, d, J = 9.0 Hz), 7.62 (1H, s), 7.64 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.4 Hz). 51 [00575]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.55 (6H, s), 2.15 (3H, s), 2.64 (2H, t, J = 5.9 Hz), 3.11 (3H, s), 3.27 (3H, s), 3.41 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.83 (2H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.16 (1H, s), 7.24-7.36 (4H, m), 7.51-7.63 (6H, m). 52 [00576]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.15 (3H, s), 2.61 (2H, dt, J = 1.8 Hz, 6.90 Hz), 3.27 (3H, s), 3.40 (2H, dt, J = 1.8 Hz, 6.0 Hz), 3.53 (3H, s), 3.75 (1H, d, J = 12.3 Hz), 3.80 (3H, s), 3.81 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 15.9 Hz), 5.57 (1H, d, J = 15.9 Hz), 6.91 (2H, t, J = 8.1 Hz), 6.99 (1H, d, J = 1.5 Hz), 7.14 (1H, d, J = 1.5 Hz), 7.28 (1H, s), 7.25-7.34 (1H, m), 7.53 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.70 (1H, s). 53 [00577]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 0.98 (6H, d, J = 6.3 Hz), 1.52-1.58 (2H, m), 1.64-1.71 (1H, m), 2.14 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.85 (2H, s), 4.04-4.09 (2H, m), 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.17 (1H, s), 7.24-7.35 (1H, m), 7.51 (2H, d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (1H, s). 54 [00578]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.14 (3H, s), 2.65 (2H, t, J = 5.9 Hz), 3.30 (3H, s), 3.36 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.66 (2H, t, J = 5.9 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.30 (2H, t, J = 5.9 Hz), 5.33 (2H, s), 6.90 (2H, t, J = 8.3 Hz), 7.15 (1H, s), 7.24-7.34 (1H, m), 7.51 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz), 7.60 (1H, m). 55 [00579]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.15 (3H, t, J = 6.9 Hz), 2.14 (3H, s), 2.66 (2H, t, J = 6.0 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 6.0 Hz), 3.54 (2H, q, J = 6.9 Hz), 3.69 (2H, t, J = 6.0 Hz), 3.81 (3H, s), 3.84 (2H, s), 4.29 (2H, t, J = 6.0 Hz), 5.32 (2H, s), 6.89 (2H, t, J = 8.1 Hz), 7.17 (1H, s), 7.23-7.34 (1H, m), 7.52 (2H, d, J = 8.7 Hz), 7.57 (2H, d, J = 8.7 Hz), 7.60 (1H, m). 56 [00580]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.52 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.46 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.31 (2H, s), 5.34 (1H, m), 6.90 (2H, t, J = 8.1 Hz), 7.16 (1H, s), 7.24- 7.35 (1H, m), 7.52 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.60 (1H, m). 57 [00581]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.62 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 5.7 Hz), 3.74 (2H, brs), 3.82 (3H, s), 4.18 (3H, s), 5.32 (2H, brs), 6.92 (2H, t, J = 8.3 Hz), 7.12 (1H, d, J = 9.3 Hz), 7.24 (1H, s), 7.29-7.35 (1H, m), 7.41 (2H, d, J = 9.3 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.66 (1H, s). 58 [00582]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.12 (3H, s), 2.61 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.39 (2H, t, J = 5.7 Hz), 3.78 (2H, brs), 3.82 (3H, s), 5.34 (2H, brs), 6.93 (2H, t, J = 8.1 Hz), 7.26 (1H, s), 7.29- 7.37 (1H, m), 7.53-7.61 (5H, m), 7.67 (1H, s), 7.69 (1H, dd, J = 4.8 Hz, 8.4 Hz), 9.28 (1H, dd, J = 1.8 Hz, 4.8 Hz). 59 [00583]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.14 (3H, s), 2.68 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.47 (2H, t, J = 6.0 Hz), 3.82 (3H, s), 3.83 (2H, s), 4.06 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.3 Hz), 7.20 (1H, s), 7.29-7.35 (1H, m), 7.55 (4H, s), 7.63 (1H, s). 60 [00584]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.66 (2H, t, J = 5.9 Hz), 3.31 (3H, s), 3.45 (3H, s), 3.48 (2H, t, J = 5.9 Hz), 3.82 (3H, s), 3.84 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.3 Hz), 7.17 (1H, s), 7.25-7.35 (1H, m), 7.55 (4H, s), 7.62 (1H, s). 61 [00585]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.27 (3H, d, J = 5.6 Hz), 2.12 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 2.9-3.05 (1H, m), 3.30 (3H, s), 3.45 (2H, d, J = 5.8 Hz), 3.82 (5H, s), 4.05- 4.25 (1H, m), 4.18 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.2-7.4 (1H, m), 7.5-7.6 (3H, m), 7.63 (1H, s). 62 [00586]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.27 (3H, s), 2.55-2.65 (2H, m), 3.29 (3H, s), 3.4-3.5 (2H, m), 3.82 (5H, s), 4.88 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.2-7.35 (1H, m), 7.5-7.65 (4H, m). 63 [00587]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.30 (9H, s), 2.12 (3H, s), 2.62 (2H, t, J = 5.8 Hz), 3.29 (3H, s), 3.44 (2H, d, J = 5.8 Hz), 3.80 (2H, s), 3.82 (3H, s), 5.04 (2H, s), 5.33 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.3 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s). 64 [00588]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.12 (3H, s), 2.65 (2H, t, J = 6.0 Hz), 3.31 (3H, s), 3.45 (2H, d, J = 6.0 Hz), 3.82 (5H, s), 4.75-4.85 (2H, m), 5.36 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2- 7.35 (1H, m), 7.55-7.6 (4H, m), 7.62 (1H, s). 65 [00589]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.04 (9H, s), 2.12 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 2.96 (1H, d, J = 6.0 Hz), 3.31 (3H, s), 3.46 (2H, d, J = 6.0 Hz), 3.5-3.6 (1H, m), 3.82 (3H, s), 3.75-3.9 (2H, m), 4.05-4.2 (1H, m), 4.3-4.45 (1H, m), 5.25-5.45 (2H, m), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.35 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s). 66 [00590]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.28 (6H, s), 2.3 (3H, s), 2.64 (2H, t, J = 5.8 Hz), 3.30 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.82 (5H, s), 3.99 (1H, s), 4.25 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s). 67 [00591]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 0.96 (6H, s), 2.13 (3H, s), 2.64 (2H, t, J = 6.2 Hz), 3.13 (2H, s), 3.30 (3H, s), 3.45 (2H, t, J = 6.2 Hz), 3.82 (5H, s), 3.95-4.15 (2H, brm), 5.1-5.5 (2H, br), 6.91 (2H, t, J = 8.2 Hz), 7.14 (1H, s), 7.2-7.4 (1H, m), 7.5-7.6 (4H, m), 7.61 (1H, s). 68 [00592]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 0.46 (2H, t, J = 5.4 Hz), 0.85 (2H, t, J = 5.4 Hz), 2.11 (3H, s), 2.64 (2H, t, J = 6.0 Hz), 3.25 (2H, s), 3.31 (3H, s), 3.46 (2H, t, J = 6.0 Hz), 3.82 (5H, s), 3.95-4.15 (1H, br), 4.14 (2H, s), 5.37 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.54 (4H, s), 7.61 (1H, s). 69 [00593]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.35-1.65 (3H, m), 1.65-1.8 (2H, m), 2.07 (3H, s), 2.5-2.8 (2H, m), 3.58 (2H, s), 3.7-3.9 (1H, m), 3.82 (3H, s), 3.91 (2H, s), 4.9-5.1 (1H, m), 5.29 (2H, s), 6.90 (2H, t, J = 7.8 Hz), 7.13 (1H, s), 7.15-7.35 (6H, m), 7.53 (2H, d, J = 8.6 Hz), 7.61 (1H, s), 7.66 (2H, d, J = 8.6 Hz). 70 [00594]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.2-1.6 (3H, m), 1.6-1.8 (2H, m), 2.0- 2.1 (2H, m), 2.14 (3H, s), 2.5- 2.75 (4H, m), 3.31 (3H, s), 3.45 (2H, t, J = 5.8 Hz), 3.65- 3.85 (3H, m), 3.82 (3H, s), 4.9- 5.05 (1H, br), 5.30 (2H, s), 6.90 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.25-7.4 (1H, m), 7.5- 7.6 (4H, m), 7.60 (1H, s). 71 [00595]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.61 (2H, t, J = 5.8 Hz), 2.79 (3H, s), 3.26 (3H, s), 3.41 (2H, t, J = 5.8 Hz), 3.75-3.85 (2H, m), 3.82 (3H, s), 5.25-5.45 (2H, brm), 6.92 (2H, t, J = 8.2 Hz), 7.18 (1H, s), 7.2-7.7 (8H, m). 72 [00596]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.30 (3H, d, J = 6.0 Hz), 2.06 (3H, s), 2.90 (1H, d, J = 5.2 Hz), 3.57 (2H, s), 3.82 (3H, s), 3.91 (2H, s), 4.1- 4.25 (1H, m), 4.20 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.0 Hz), 7.16 (1H, s), 7.2-7.4 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.8 Hz). 73 [00597]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.29 (6H, s), 2.06 (3H, s), 3.56 (2H, s), 3.83 (3H, s), 3.91 (2H, s), 3.96 (1H, s), 4.28 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.13 (1H, s), 7.2-7.35 (6H, m), 7.54 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.67 (2H, d, J = 8.8 Hz). 74 [00598]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.28 (3H, d, J = 5.8 Hz), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.0-3.1 (1H, m), 3.82 (5H, s), 4.1-4.2 (1H, m), 4.17 (2H, s), 5.34 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 6.95- 7.1 (2H, m), 7.14 (1H, s), 7.2- 7.4 (1H, m), 7.4-7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J = 5.0 Hz). 75 [00599]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.26 (6H, s), 2.21 (3H, s), 2.75-2.95 (4H, m), 3.82 (5H, s), 3.99 (1H, s), 4.24 (2H, s), 5.36 (2H, s), 6.91 (2H, t, J = 8.2 Hz), 7.0-7.1 (2H, m), 7.13 (1H s), 7.2-7.35 (1H m), 7.45-7.55 (5H, m), 7.59 (1H, s), 8.43 (1H, d, J = 4.0 Hz). 76 [00600]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (3H, s), 2.62 (2H, t, J = 6.0 Hz), 3.26 (3H, s), 3.41 (2H, t, J = 6.0 Hz), 3.79 (2H, s), 3.83 (1H, s), 5.36 (2H, s), 6.94 (2H, t, J = 8.0 Hz), 7.12 (1H, s), 7.2-7.4 (1H, m), 7.5-7.65 (5H, m), 8.65-8.7 (3H, m). 77 [00601]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.06 (3H, s), 3.55 (2H, s), 3.83 (3H, s), 3.87 (2H, s), 4.19 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.1-7.45 (9H, m), 7.55 (2H, d, J = 8.4 Hz), 7.63 (1H, s), 7.72 (2H, d, J = 8.4 Hz). 78 [00602]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.20 (3H, s), 2.7-2.9 (4H, m), 3.78 (2H, s), 3.82 (3H, s), 4.19 (3H, s), 5.34 (2H, s), 6.85-7.2 (5H, m), 7.25-7.45 (2H, m), 7.45-7.7 (7H, m), 8.42 (1H, d, J = 4.0 Hz). 79 [00603]embedded image .sup.1H NMR (CDCl.sub.3) δ 2.20 (3H, s), 2.86 (4H, m), 3.82-3.84 (8H, m), 5.36 (2H, s), 6.92 (2H, d, J = 8.3 Hz), 7.00-7.06 (4H, m), 7.14-7.33 (4H, in), 7.46-7.51 (5H, m), 7.61 (1H, s), 8.42 (1H, d, J = 5.7 Hz). 80 [00604]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.12 (3H, s), 2.63 (2H, t, J = 5.8 Hz), 3.28 (3H, s), 3.43 (2H, t, J = 5.8 Hz), 3.79 (2H, s), 3.83 (3H, s), 5.35 (2H, s), 6.94 (2H, t, J = 8.2 Hz), 7.0-7.1 (1H, m), 7.2-7.4 (3H, m), 7.5-7.65 (4H, m), 7.63 (1H, s), 10.5-10.6 (1H, brs). 81 [00605]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.98 (3H, s), 2.45-2.5 (2H, m), 2.9-3.2 (1H, m), 3.5-3.55 (2H, m), 3.65-3.85 (2H, brm), 3.82 (3H, s), 4.18 (3H, s), 5.34 (2H, s), 6.93 (2H, t, J = 8.0 Hz), 7.11 (1H, d, J = 9.0 Hz), 7.18 (1H, s), 7.25-7.35 (1H, m), 7.35-7.45 (3H, m), 7.57 (2H, d, J = 8.7 Hz), 7.66 (1H, s). 82 [00606]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 1.99 (3H, s), 2.45-2.55 (2H, m), 3.5-3.6 (2H, m), 3.79 (2H, s), 3.82 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 6.92 (2H, t, J = 8.0 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.1-7.3 (4H, m), 7.39 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.64 (1H, s). 83 [00607]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s). 84 [00608]embedded image .sup.1H-NMR (CDCl.sub.3) δ: 2.13 (6H, s), 3.68 (2H, s), 3.83 (3H, s), 3.96 (3H, s), 5.36 (2H, s), 6.8- 7.0 (3H, m), 7.13 (1H, s), 7.2- 7.4 (1H, m), 7.45-7.65 (6H, m), 8.10 (1H, d, J = 2.6 Hz).

    Propane-1,3-diones

    [0711] Additional GnRH antagonists that may be used in conjunction with the compositions and methods described herein include optionally substituted propane-1,3-dione derivatives, such as (2R)—N-{5-[3-(2,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-2-fluorobenzene-1-sulfonyl}-2-hydroxypropanimidamide, also referred to as opigolix or ASP-1707. Other GnRH antagonists of this chemical class that may be used for the treatment of estrogen-dependent diseases in accordance with the compositions and methods of the disclosure include compounds described in U.S. Pat. No. 6,960,591, the contents of which are incorporated herein by reference.

    Add-Back Therapy

    [0712] Among the potential side-effects of GnRH antagonist therapy is a reduction in bone mineral density due to excessive depletion of estrogen (Newhall-Perry et al., American Journal of Obstetrics and Gynecology 173:824-829 (1995)). To combat this potential side effect, a patient undergoing GnRH antagonist therapy using the compositions and methods described herein can be administered add-back therapy. Add-back therapy may contain an estrogen (such as β17-estradiol, ethinyl estradiol, or a conjugated estrogen, such as a conjugated equine estrogen) optionally in combination with a progestin (such as norethindrone or an ester thereof, e.g., norethindrone acetate, or another agent such as progesterone, norgestimate, medroxyprogesterone, or drospirenone).

    [0713] Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 μg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Circulating estrogens modulate the pituitary secretion of the gonadotropins, LH and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

    [0714] Progestin compounds, such as norethindrone and esters thereof (e.g., norethindrone acetate), as well as progesterone, norgestimate, medroxyprogesterone, and drospirenone, enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone. Progestins may be included in combination with estrogen in add-back therapy. For instance, according to the methods described herein, one can administer estrogen (e.g., E2) in conjunction with a progestin (e.g., norethindrone or an ester thereof, such as norethindrone acetate) to a patient undergoing GnRH antagonist therapy as to counteract the hypoestrogenemia that may be induced by the antagonist. In this way, add-back therapy can be used to mitigate or prevent potentially deleterious side effects, such as a reduction in bone mineral density.

    [0715] Add-back therapy may be formulated for oral administration. For instance, add-back therapy administered in conjunction with the compositions and methods described herein may be formulated as a tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. In some embodiments, the add-back therapy includes both an estrogen, such as β17-estradiol, and a progestin, such as norethindrone or norethindrone acetate. The estrogen and progestin may be administered separately or admixed in a single composition, such as a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension. For example, add-back therapy may feature a co-formulation containing estrogen (e.g., in the form of E2) and an additional agent such as a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate). In some embodiments, add-back therapy is administered to a patient in the form of a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension that contains both estrogen (e.g., in the form of E2) and a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate). In some embodiments, add-back therapy is administered as a fixed dose combination containing a GnRH antagonist, estrogen, and one or more additional agents, such as a progestin, in a single pharmaceutical composition. For instance, add-back therapy may be administered as a fixed dose combination of a GnRH antagonist, estrogen (e.g., in the form of E2) and a progestin (e.g., norethindrone or a compound that is metabolized in vivo to produce norethindrone, such as an ester of norethindrone that is de-esterified in vivo to produce norethindrone, for instance, norethindrone acetate) in the form of a single pharmaceutical composition, such as a single tablet, capsule, gel cap, powder, liquid solution, or liquid suspension.

    Methods of Treating Estrogen-Dependent Diseases

    [0716] Using the compositions and methods described herein, a patient having an estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis), and/or adenomyosis, among others, may be administered a GnRH antagonist as described herein. Additional examples of estrogen-dependent diseases that may be treated using the compositions and methods of the disclosure include, without limitation, benign prostatic hypertrophy, precocious puberty, premenstrual syndrome, polycystic ovary syndrome, hirsutism, short stature, a sleep disorder, acne, baldness, and irritable bowel syndrome.

    [0717] A variety of methods known in the art and described herein can be used to determine whether a patient is responding favorably to GnRH antagonist treatment. For instance, beneficial clinical results in response to GnRH antagonist therapy include, without limitation, alleviation of symptoms of the endometrial growth disorder. Indications of successful treatment of a uterine fibroids patient include, for example, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in uterine blood loss following administration of the GnRH antagonist to the patient, (iii) elimination of heavy menstrual bleeding following administration of the GnRH antagonist to the patient, and (iv) induction of amenorrhea in the patient following administration of the GnRH antagonist to the patient.

    [0718] Similarly, clinical indicators of successful treatment of an endometriosis patient (e.g., a rectovaginal endometriosis patient) that is administered a GnRH antagonist include, without limitation, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in the volume of one or more endometriosis nodes (e.g., rectovaginal endometriosis nodes) following administration of the GnRH antagonist to the patient, (iii) a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (ix) achievement of amenorrhea following administration of the GnRH antagonist to the patient; and (x) an improvement in the patient's overall well-being as determined by an improvement in the patient's Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.

    [0719] Exemplary indicia of successful treatment of an adenomyosis patient that is administered a gonadotropin-releasing hormone (GnRH) antagonist include, without limitation, (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in uterine volume following administration of the GnRH antagonist to the patient, (iii) a reduction in the thickness of the anterior and/or posterior region of the uterine myometrium following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine tenderness following administration of the GnRH antagonist to the patient; (ix) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (x) achievement of amenorrhea following administration of the GnRH antagonist to the patient; (xi) a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient; and (xii) an improvement in the patient's overall well-being as determined by an improvement in the patient's EHP-30 score following administration of the GnRH antagonist to the patient and/or by way of a positive PGIC score following administration of the GnRH antagonist to the patient.

    Modified Biberoglu and Behrman Symptom Severity Scale

    [0720] Exemplary methods for assessing a patient's response to GnRH antagonist therapy for the treatment of estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein, include administration of a modified Biberoglu and Behrman questionnaire, as described herein. An exemplary mB&B questionnaire for use in conjunction with the compositions and methods described herein is shown in Table 4, below.

    Endometriosis Health Profile Questionnaire

    [0721] Additional methods for assessing patient respond to GnRH antagonist therapy for the treatment of estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein, include analyzing the patient's score on an Endometriosis Health Profile questionnaire. An exemplary Endometriosis Health Profile questionnaire for use in conjunction with the compositions and methods described herein is the EHP-30 questionnaire shown in Table 5, below.

    Patient Global Impression of Change Score

    [0722] Additional methods for assessing patient response to GnRH antagonist therapy for the treatment of an estrogen-dependent disease described herein, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis, and/or adenomyosis, among others) include analyzing the patient's score on a Patient Global Impression of Change (PGIC) scale. An exemplary PGIC questionnaire for use in conjunction with the compositions and methods described herein is shown in Table 6, below.

    Quantitation of Uterine Blood Loss by the Alkaline Hematin Method

    [0723] Techniques for quantifying uterine blood loss are known in the art and include, for instance, the alkaline hematin method, as described, for instance, in Hallberg et al., Scand. J. Clin. Lab. Invest. 16:244-248 (1964), the disclosure of which is incorporated herein by reference as it pertains to techniques for assessing the volume of blood lost by a patient. In the alkaline hematin approach, uterine blood soaked into, for example, a sanitary napkin, vaginal tampon, or cotton pad, is reconstituted in a basic aqueous solution, such as a solution of 5% (w/v) sodium hydroxide. This incubation enables (i) extraction of the iron-containing porphyrin of hemoglobin and (ii) oxidation of the ferrous ion to a hydroxy-coordinated ferric ion in each chelate, thus forming hematin. Hematin is a detectable chromophore, absorbing light at between 550 and 546 nm. By comparing the concentration of hematin obtained from incubation of a soaked menstrual blood sample with aqueous sodium hydroxide to the concentration of hematin obtained from incubation of a sample of venous blood with aqueous sodium hydroxide, one can stoichiometrically determine the volume of menstrual blood lost by a patient, such as a patient having an estrogen-dependent disease. Improvements to the original alkaline hematin method are known in the art and are described, for example, in Newton et al., Contraception 16:269-282 (1977), and in van Eijkeren et al., Eur. J. Obstet. Gynecol. Reprod. Biol. 22:345-351 (1986), the disclosures of each of which are incorporated herein by reference as they pertain to methods of determining the volume of blood lost by a patient.

    Routes of Administration and Dosing of GnRH Antagonists

    [0724] The GnRH antagonists described herein may be administered to a patient in need thereof (e.g., a patient suffering from an estrogen-dependent disease, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein) by a variety of routes of administration. For instance, the GnRH antagonists described herein may be formulated for oral administration, among other routes. Exemplary non-oral routes of administration of the GnRH antagonists described herein include, without limitation, intravenous administration, parenteral administration, subcutaneous administration, intramuscular administration, and intradermal administration, among others.

    [0725] In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(VIa), above, and is administered to the patient in an amount of from about 25 mg to about 500 mg per dose, and may be administered in one or more doses per day, for example, in accordance with a dosing schedule described above. For instance, the GnRH antagonist may a compound of any one of formulas (I)-(VIa), above, and may be administered to the patient in an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose, and may be administered in one or more doses per day (e.g., in a single daily dose). In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(VIa), above, and is administered to the patient once daily in an amount of from 100 mg to 300 mg, per dose, such as from 105 mg to 295 mg, 110 mg to 290 mg, 115 mg to 285 mg, 120 mg to 280 mg, 125 mg to 275 mg, 130 mg to 270 mg, 135 mg to 265 mg, 140 mg to 260 mg, 145 mg to 255 mg, 150 mg to 250 mg, 155 mg to 245 mg, 160 mg to 240 mg, 165 mg to 235 mg, 170 mg to 230 mg, 175 mg to 225 mg, 180 mg to 220 mg, 185 mg to 215 mg, 190 mg to 210 mg, or 195 mg to 205 mg, per dose. In some embodiments, the GnRH antagonist is a compound of any one of formulas (I)-(VIa), above, and is administered to the patient once daily in an amount of about 50 mg, 75 mg, 100 mg, or 200 mg per dose.

    [0726] The GnRH antagonists described herein may be administered to a patient a plurality of times over the course of a treatment period. For instance, the GnRH antagonists described herein may be administered to a patient periodically over a treatment period of at least two weeks (e.g., a treatment period of from about two weeks to about six months, about three weeks to about five months, about four weeks to about four months, or about one month to about three months). The GnRH antagonist may be administered to the patient, for example, over a treatment period of from about four weeks to about six months (e.g., from about 28 days to about 180 days, about 30 days to about 175 days, about 35 days to about 170 days, about 40 days to about 165 days, about 45 days to about 160 days, about 50 days to about 155 days, about 55 days to about 150 days, about 60 days to about 145 days, about 65 days to about 140 days, about 70 days to about 135 days, about 75 days, to about 130 days, about 80 days to about 125 days, about 85 days, to about 120 days, or about 90 days to about 115 days). In some embodiments, the GnRH antagonist is periodically administered to the patient over the course of from about eight weeks to about sixteen weeks (e.g., from about 60 days to about 110 days, about 65 days to about 105 days, about 70 days to about 100 days, about 75 days to about 95 days, or about 80 days, to about 90 days). In some embodiments, the GnRH antagonist is periodically administered to the patient over a treatment period of about 12 weeks. In some embodiments, the GnRH antagonist is periodically administered to the patient over a treatment period of about 24 weeks.

    [0727] Additional dosing schedules for the treatment of estrogen-dependent diseases, such as uterine fibroids, endometriosis (e.g., rectovaginal endometriosis) and/or adenomyosis, among others described herein, using other GnRH antagonists disclosed herein are described in detail above.

    Pharmaceutical Compositions

    [0728] GnRH antagonists suitable for use with the compositions and methods described herein can be formulated into a pharmaceutical composition for administration to a patient, such as a female human patient, in a biologically compatible form suitable for administration in vivo. A pharmaceutical composition containing a GnRH antagonist, such as a compound described herein (e.g., 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid or a pharmaceutically acceptable salt thereof, such as the choline salt thereof), may additionally contain a suitable diluent, carrier, or excipient. GnRH antagonists can be administered to a patient, for example, orally or by intravenous injection. Under ordinary conditions of storage and use, a pharmaceutical composition may contain a preservative, e.g., to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22.sup.nd ed.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33).

    [0729] Pharmaceutical compositions may include sterile aqueous solutions, dispersions, or powders, e.g., for the extemporaneous preparation of sterile solutions or dispersions. In all cases the form may be sterilized using techniques known in the art and may be fluidized to the extent that may be easily administered to a patient in need of treatment.

    [0730] A pharmaceutical composition may be administered to a patient, e.g., a human patient, alone or in combination with one or more pharmaceutically acceptable carriers, e.g., as described herein, the proportion of which may be determined by the solubility and/or chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

    Compound for Use

    [0731] In another aspect, the disclosure provides a GnRH antagonist (e.g., a GnRH antagonist described herein) for use in any of the methods described herein. For example, the disclosure features a GnRH antagonist, such as a GnRH antagonist described herein, for use in a method of treating an estrogen-dependent disease, such as uterine fibroids, endometriosis, adenomyosis, or rectovaginal endometriosis. The method may feature, for example, any one or more of the method steps recited herein.

    Medicament

    [0732] In another aspect, the disclosure provides a GnRH antagonist (e.g., a GnRH antagonist described herein) for use in the manufacture of a medicament for performing any of the methods described herein. For example, the disclosure features a GnRH antagonist, such as a GnRH antagonist described herein, for use in the manufacture of a medicament for use in a method of treating an estrogen-dependent disease, such as uterine fibroids, endometriosis, adenomyosis, or rectovaginal endometriosis.

    [0733] The method may feature, for example, any one or more of the method steps recited herein.

    EXAMPLES

    [0734] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regards as their invention.

    Example 1. Administration of a GnRH Antagonist Effectuates a Sustained Alleviation of Estrogen-Dependent Disease Symptoms Even after Treatment is Halted

    Methods

    [0735] This example describes the results of a Phase 2b human clinical trial undertaken to evaluate the efficacy of a GnRH antagonist represented by formula (VI) in a series of patients suffering from an estrogen-dependent disease. In this trial, a series of human female patients diagnosed as having endometriosis were administered the choline salt of 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid periodically over the course of a 24-week treatment period. After 24 weeks of treatment, various patients entered a 24-week post-treatment follow-up period during which the patients were monitored for serum β17-estradiol (E2) concentration, severity of disease symptoms, and bone mineral density.

    Results

    [0736] A series of n=328 human female patients having clinically-diagnosed endometriosis were randomly assigned to treatment arms in which patients were to be administered placebo or the GnRH antagonist in a once-daily amount of 50 mg/day, 100 mg/day, 75 mg/day, or 200 mg/day. Patients initially treated with placebo (plc) were administered the GnRH antagonist in an amount of 100 mg/day after 12 weeks. Also, after 12 weeks, patients that were initially administered 75 mg/day were provided a higher (100 mg/day) or lower (50 mg/day) dosage of the GnRH antagonist based on the patients' E2 levels at the 12-week point. The E2 levels for this group of patients is represented by “75 mg (TD)” in FIGS. 1-3. Patients that were administered 75 mg through the end of the treatment period are represented by “75 mg (FD)” in FIGS. 1-3.

    [0737] After 24 weeks of continuous, once-daily treatment, administration of the GnRH antagonist ceased. A set of n=65 patients entered the 24-week post-treatment follow-up study. Following the 24-week treatment period, these patients were periodically monitored. The median E2 levels of patients that were administered the GnRH antagonist during the original 24-week treatment period and that subsequently entered the 24-week post-treatment follow-up study are shown in FIG. 1. FIGS. 2 and 3 show the mean change in dyspareunia and dyschezia scores for such patients over the 24-week treatment period and a 12-week portion of the post-treatment follow-up period. As shown in FIGS. 2 and 3, despite cessation of GnRH antagonist administration, patients continued to exhibit a sustained reduction in dyspareunia, as assessed using the Verbal Rating Score (VRS), as well as a sustained reduction in dyschezia, as assessed using the Numerical Rating Score (NRS).

    [0738] In addition to demonstrating a continuous reduction in dyspareunia and dyschezia, patients that entered the 24-week post-treatment follow-up period exhibited a reduction in overall pelvic pain, as shown in Table 7, below. This table depicts the proportion of patients that exhibited an overall pelvic pain score reduction of greater than 30% from baseline using a VRS scale at 12 weeks following the cessation of GnRH antagonist treatment.

    TABLE-US-00004 TABLE 7 Overall Pelvic Pain Responder Rates (Defined has patients exhibiting an overall pelvic pain VRS score reduction of > 30% from baseline VRS score) Overall Pelvic Pain Responder Rate (%) Dose (Once-daily) 75 mg 200 mg After 24 weeks of GnRH 70.8 77.3 antagonist treatment (n = 48) (n = 44) After 12 weeks following 87.5 70.0 cessation of GnRH antagonist (n = 7)  (n = 10) treatment

    [0739] Surprisingly, in addition to exhibiting a sustained reduction in disease symptomology, patients that were monitored during the post-treatment follow-up period exhibited an increase in bone mineral density. Table 8, below, depicts the mean change in bone mineral density from a baseline, pre-treatment measurement following completion of the 24-week treatment period and at 12 weeks following the cessation of the GnRH antagonist. All bone mineral density measurements shown below were obtained by assessing bone mineral density at each patient's spine.

    TABLE-US-00005 TABLE 8 Bone mineral density following 24-week treatment period and 12 weeks after cessation of treatment Bone Mineral Density (Mean % change from baseline) Dose (Once-daily) 75 mg 200 mg After 24 weeks of GnRH −0.798% −2.602% antagonist treatment After 12 weeks following +0.313% +1.135% cessation of GnRH antagonist treatment
    As shown in Table 8, patients that exhibited a reduction in bone mineral density during the 24-week treatment period effectively recovered bone mineral density upon cessation of GnRH antagonist treatment.

    Conclusions

    [0740] Taken together, the results of these experiments demonstrate that patients administered a GnRH antagonist represented by formula (VI) over the course of a treatment period exhibit a sustained alleviation in symptoms of an estrogen-dependent disease, even after administration of the GnRH antagonist is halted. Additionally, patients that exhibited a reduction in bone mineral density during treatment with the GnRH antagonist demonstrated a recovery in bone mineral density once the treatment was discontinued. Surprisingly, this recovery in bone mineral density occurred without the detriment of a return in disease symptoms.

    Example 2. Use of a GnRH Antagonist for the Treatment of a Patient Having Uterine Fibroids or Endometriosis

    [0741] Using the compositions and methods described herein, a patient may be administered a GnRH antagonist so as to treat, and/or ameliorate the symptoms of, uterine fibroids or endometriosis, among other estrogen-dependent diseases. The GnRH antagonist (e.g., a compound of formula (I), above, such as compound (VI) or the choline salt thereof) may be administered to the patient in an amount sufficient to reduce the serum concentration of LH, FSH, and/or E2 in circulation. The GnRH antagonist may be administered, for example, in an amount of from about 25 mg to about 500 mg per dose. Exemplary doses of the GnRH antagonist include, without limitation, an amount of from 25 mg to 500 mg, 30 mg to 495 mg, 35 mg to 490 mg, 40 mg to 485 mg, 45 mg to 480 mg, 50 mg to 475 mg, 55 mg to 470 mg, 60 mg to 465 mg, 65 mg to 460 mg, 70 mg to 455 mg, 75 mg to 450 mg, 80 mg to 445 mg, 85 mg to 440 mg, 90 mg to 435 mg, 95 mg to 430 mg, 100 mg to 425 mg, 105 mg to 420 mg, 110 mg to 415 mg, 115 mg to 410 mg, 120 mg to 405 mg, 125 mg to 400 mg, 130 mg to 395 mg, 135 mg to 390 mg, 140 mg to 385 mg, 145 mg to 380 mg, or 150 mg to 375 mg, per dose. For example, when the GnRH antagonist is compound (VI) or the choline salt thereof, the compound may be administered at a dose of 200 mg.

    [0742] The GnRH antagonist may be administered to the patient periodically over a first treatment period of, for example, two or more weeks (e.g., a first treatment period of 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer). The GnRH antagonist may be provided to the patient in combination with add-back therapy. The patient may then be monitored for bone mineral density loss, for example, using dual energy X-ray absorptiometry. If the patient is determined to exhibit a reduction in bone mineral density relative to a measurement of the patient's bone mineral density obtained during, or prior to commencement of, the first treatment period, administration of the GnRH antagonist may be temporarily halted. After a time, such as once the patient has demonstrated an increase in bone mineral density, administration of the GnRH antagonist may commence again.

    [0743] To determine the responsiveness of the patient to the GnRH antagonist, a physician may monitor the time required for the patient to achieve a reduction in uterine blood loss in the case of a patient having uterine fibroids. For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in menstrual blood loss to less than 80 ml per menstrual cycle, such that the patient no longer exhibits heavy menstrual blood loss, the volume of one or more rectovaginal endometriosis nodes following administration of the GnRH antagonist to the patient, and/or (ii) an improvement in the patient's overall well-being as determined by an improvement in the patient's Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.

    [0744] In the case of a patient having endometriosis, the physician may monitor the patient to assess whether the patient exhibits a reduction in pain, such as overall pelvic pain, dysmenorrhea, dyspareunia, or dyschezia. For example, the physician may observe one or more of the following responses of the patient as an indicator of successful treatment: (i) a reduction in serum concentration of FSH, LH, and/or E2 following administration of the GnRH antagonist to the patient, (ii) a reduction in the volume of one or more endometriosis nodes (e.g., rectovaginal endometriosis nodes) following administration of the GnRH antagonist to the patient, (iii) a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient, (iv) a reduction in pelvic pain following administration of the GnRH antagonist to the patient; (v) a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient; (vi) a reduction in dyspareunia following administration of the GnRH antagonist to the patient; (vii) a reduction in dyschezia following administration of the GnRH antagonist to the patient; (viii) a reduction in uterine bleeding following administration of the GnRH antagonist to the patient; (ix) achievement of amenorrhea following administration of the GnRH antagonist to the patient; and/or (x) an improvement in the patient's overall well-being as determined by an improvement in the patient's Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient and/or by way of a positive Patient Global Impression of Change (PGIC) score following administration of the GnRH antagonist to the patient.

    Example 3. Use of a GnRH Antagonist for the Treatment of a Patient Having Adenomyosis

    [0745] This examples describes the results of a human clinical trial conducted to evaluate the ability of a GnRH antagonist, 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid (represented by formula (VI)), or a pharmaceutically acceptable salt thereof, to treat adenomyosis, an estrogen-dependent disease, in human patients diagnosed as having this condition.

    [0746] One aim of this study was to investigate the ability of the GnRH antagonist to maintain its therapeutic effects despite being administered to patients in a progressively lower dosage throughout the trial. To this end, the patients treated in this study was first administered the GnRH antagonist of formula (VI) in an amount of 200 mg/day during an initial 12-week period. The GnRH antagonist was then administered to the patients in a reduced amount of 100 mg/day during a subsequent 12-week period. The patients' responsiveness to the GnRH antagonist was monitored throughout the study.

    [0747] In addition to assessing the effectiveness of the GnRH antagonist when administered at lower doses, another aim of this study was to evaluate the ability of the GnRH antagonist to sustain its therapeutic effects even after treatment was ceased altogether. Accordingly, after being periodically administered the GnRH antagonist of formula (VI) over the course of 24 weeks, first in an amount of 200 mg/day and then in an amount of 100 mg/day, treatment with the GnRH antagonist was halted entirely. The patients were then monitored during a post-treatment follow-up period to analyze the extent to which the therapeutic effects of the compound were sustained.

    [0748] To test the effects of compound (VI), a total of n=6 human female patients diagnosed as having adenomyosis were administered compound (VI) in accordance with the dosing schedule described above. One of these patients in particular was closely monitored beginning well before her treatment with compound (VI) was initiated. The specific results of this patient's therapy are described in the section entitled “Single-Patient Longitudinal Case Study,” below. The cumulative set of results for all 6 patients is reported in the section entitled “Multi-Patient Analysis,” below.

    Introduction

    [0749] Adenomyosis is a commonly encountered estrogen-dependent disease characterized by the presence of endometrial glands and stroma in the myometrium having a depth of greater than 2.5 mm. The endometrial glands and stroma are surrounded by hyperplastic and hypertrophic smooth muscle. Affecting 19.5% of women of reproductive age, uterine adenomyosis is responsible for heavy menstrual bleeding, infertility, and pelvic pain. The symptomology adenomyosis may overlap with that of other estrogen-dependent diseases, including endometriosis and uterine fibroids. Despite its prevalence and severity of symptoms, there has been a paucity of treatment options available for treating the underlying pathology of this disease.

    Single-Patient Longitudinal Case Study

    [0750] Methods

    [0751] As part of the clinical trial, a case study was conducted in which a single, female patient of reproductive age having clinically diagnosed adenomyosis was monitored during the course of treatment with compound (VI). The patient, born in 1981, was nulliparous. Two years before the study began, the patient presented with heavy menstrual bleeding, pelvic pain, and dysmenorrhea. On clinical examination, her uterine volume was equivalent to 12 weeks of gestation and magnetic resonance imaging (MRI) revealed an enlarged uterus with diffuse and disseminated adenomyosis (FIG. 4A). Her gynecologist prescribed ulipristal acetate (UPA), a selective progesterone receptor modulator (SPRM), to be administered in an amount of 5 mg/day over the course of a treatment period lasting three months.

    [0752] As is described in further detail below, treatment with UPA was largely unsuccessful. After being administered UPA in an amount of 5 mg/day for three months, treatment with UPA was discontinued.

    [0753] The patient was then recommended for treatment with the GnRH antagonist represented by formula (VI) herein. Accordingly, the patient was orally administered compound (VI) in an amount of 200 mg/day for three months. Following this initial three-month period, the patient was orally administered compound (VI) in a reduced amount of 100 mg/day for a subsequent three-period. During both treatment periods, compound (VI) was administered to the patient in the form of a choline salt.

    [0754] Results

    [0755] During the course of the patient's treatment with UPA in an amount of 5 mg/day for three months, the patient's symptoms of pelvic pain and dysmenorrhea worsened. Moreover, the patient experienced breakthrough bleeding and spotting. At the end of the UPA course, MRI examination revealed that the patient exhibited a significantly increased quantity of adenomyotic lesions. Moreover, the lesions were substantially aggravated relative to the state of the lesions prior to treatment with UPA (FIG. 4B). Particularly, the results of the patient's MRI obtained following UPA treatment showed numerous spots typical of adenomyosis in the myometrium. The MRI also revealed an extension of the lesions, featuring enlarged, asymmetric, heterogeneous myometrial tissue with multiple myometrial cysts. The presence of this cystic tissue is indicated of dilated islets of ectopic endometrium (see, e.g., Bazot et al., Fertil Steril. 109:389-397 (2018)). In sum, the patient's MRI results clearly revealed a worsened state of the myometrium after UPA treatment, reflecting the exacerbation of symptoms. Accordingly, after the patient's three-month UPA treatment period, treatment with UPA was discontinued.

    [0756] The patient subsequently sought another form of treatment for her pelvic pain, heavy bleeding, and infertility. On clinical examination, the patient's uterus was enlarged, now showing the equivalence of 14-15 weeks of gestation. Treatment with a GnRH agonist was proposed, but the patient rejected this form of therapy because of the mode of administration and the risk of symptom aggravation due to the likelihood of a transient increase in GnRH activity at the beginning of the treatment period. One year later, the patient again sought treatment for her still-worsening adenomyosis condition. At this point, upon clinical examination, the patient's uterus had a volume equivalent to 16-17 weeks of gestation.

    [0757] The patient was recommended for once-daily treatment with the GnRH antagonist of formula (VI). Accordingly, the patient was administered the GnRH antagonist of formula (VI) in an amount of 200 mg/day during a first treatment period, which lasted three months. At the conclusion of the first treatment period, the patient began a second treatment period in which she was administered compound (VI) in a reduced amount of 100 mg/day for three months. During both treatment periods, compound (VI) was administered to the patient in the form of a choline salt.

    [0758] At baseline, prior to treatment with compound (VI), the patient's hemoglobin (Hb) level was 10 g/dL. This level of Hb was indicative of moderate anemia. Additionally, at baseline, the patient exhibited an estrogen (E2) level of 45 pg/mL. The patient's concentration of E2 rapidly decreased to less than 20 pg/mL after four weeks of treatment with the GnRH antagonist of formula (VI). The results of the patient's MRI at baseline (FIG. 4C) revealed a very large uterus, with multiple images typical of severe full-thickness adenomyosis. The patient's baseline uterine volume was estimated to be approximately 875 cm.sup.3. The patient's baseline quality of life was profoundly affected by her adenomyosis, according to the Endometriosis Health Profile (EHP)-30 questionnaire. Specifically, the patient exhibit a pain score of 97.8 and an emotional well-being score of 58.3. The patient's scores on each of the three remaining scales (control and powerlessness, social support, and self-image) were 100.

    [0759] During the initial 12-week period in which compound (VI) was administered once-daily in an amount of 200 mg, the patient remained in amenorrhea and, at week 12, noted a significant improvement in symptoms. Particularly, the patient's 5-scaled EHP-30 score at the conclusion of the first 12-week period was 0, and her Hb level was 12.2 g/dL. The results of the patient's MRI after the conclusion of the first 12 weeks of treatment with compound (VI) showed a reduction in uterine volume had to 290 cm.sup.3. Additionally, the patient's adenomyotic lesions had significantly regressed (FIG. 4D). Clinical evaluation revealed that the patient's uterus now had a volume equivalent to 10 weeks of gestation. Both the clinical evaluation and the MRI illustrated the highly significant response to compound (VI) administered in an amount of 200 mg/day.

    [0760] Following the initial 12-week period of treatment with compound (VI), the patient was administered compound (VI) at a reduced amount of 100 mg/day for the next 12 weeks (weeks 13-24). During this subsequent treatment period, the patient's E2 levels were 38 pg/ml, 26 pg/ml, and 52 pg/mL at weeks 16, 20, and 24, respectively. After the conclusion of 24 weeks of treatment with compound (VI), the patient was still in amenorrhea and had an Hb level of 13.6 g/dL. She reported continued alleviation of symptoms even after treatment ceased. Moreover, she reported a high quality of life, scoring 4.2 on the EHP-30 scale for emotional well-being and scoring 0 on all of the remaining EHP-30 scales. The patient's endometrial thickness, which was evaluated by vaginal ultrasound, was 3 mm, and her uterine volume was 440 cm.sup.3, as assessed by MRI. After treatment with the GnRH antagonist of formula (VI) ceased, the patient's adenomyotic lesions remained significantly smaller compared to the MRI done at baseline.

    [0761] With regard to the patient's bone mineral density (BMD), at baseline, her femoral neck T-score and Z-score were +1.6 and +0.3, respectively, and her baseline lumbar spine T-score and Z-score were +0.7 and −0.5, respectively. These values were found to be unchanged at week 24. All BMD values were measured using Dual Energy X-ray Absorptiometry (DEXA).

    [0762] As for side effects, the patient experienced a few instances of hot flushes and vaginal dryness during the first treatment period in which she was administered compound (VI) in an amount of 200 mg/day. These side effects disappeared upon reducing the amount of compound (VI) administered to the patient to 100 mg/day.

    [0763] Taken together, these findings demonstrate that a partial suppression of E2 can be achieved using reduced dosages of compound (VI), and that this therapeutic effect can be maintained even after treatment ceases. This partial suppression of E2 simultaneously resolves adenomyotic lesions in the endometrium while avoiding potentially harmful side effects associated with excessive E2 depletion.

    Multi-Patient Analysis

    [0764] Methods

    [0765] As was the case for the patient described in the “Single-Patient Longitudinal Case Study,” above, all n=6 patients in the clinical trial were diagnosed as having adenomyosis. All were orally administered compound (VI) in an amount of 200 mg/day for three months. Following this initial three-month period, all patients were orally administered compound (VI) in a reduced amount of 100 mg/day for a subsequent three-period. During both treatment periods, compound (VI) was administered to the patient in the form of a choline salt.

    [0766] Results

    [0767] At baseline, all n=6 patients presented with pelvic pain, severe dysmenorrhea, heavy menstrual bleeding, and anemia. MRI analysis at baseline revealed, for all patients, an enlarged uterus with severe adenomyosis, characterized by heterogenous myometrial tissue with multiple myometrial cysts. The patients exhibited a mean uterine volume of 320 cm.sup.3 and a range of from 83 cm.sup.3 to 875 cm.sup.3. The uterine volumes of the n=6 patients observed at various timepoints throughout the study are summarized in Table 9, below.

    TABLE-US-00006 TABLE 9 Uterine volumes of n = 6 adenomyosis patients treated with compound (VI) Baseline Uterine Week 12 Uterine Week 24 Uterine Patient Volume Volume Volume 1 875 cm.sup.3 290 cm.sup.3 440 cm.sup.3 2 198 cm.sup.3  84 cm.sup.3  75 cm.sup.3 3 228 cm.sup.3 138 cm.sup.3 266 cm.sup.3 4 354 cm.sup.3  81 cm.sup.3 NR 5 183 cm.sup.3  70 cm.sup.3 NR 6  83 cm.sup.3  70 cm.sup.3 NR *NR: Not reported

    [0768] After 12 weeks of treatment, MRI analysis showed significant reduction in uterine volume to a mean of 122 cm.sup.3 and a range of 70 cm.sup.3 to 290 cm.sup.3. Significant regression of adenomyotic lesions was also observed for all patients. After 12 weeks, the patients exhibited sustained amenorrhea, substantially reduced pelvic pain, and anemia was resolved for all patients. In all cases, serum E2 decreased rapidly to less than 20 pg/ml.

    [0769] During the subsequent 12 weeks (weeks 13-24), patients remained in amenorrhea and reported continued alleviation of symptoms. Serum E2 values were between 25 pg/ml and 55 pg/ml.

    [0770] After 24 weeks, all patients' adenomyotic lesions remained smaller than those observed at baseline by MRI analysis. Each patient's BMD, as assessed by DEXA, showed either minimal change or no change from baseline. Side effects of hot flushes and vaginal dryness observed during the 200 mg/day treatment period resolved following the reduction to the 100 mg/day regime.

    [0771] The results of all n=6 patients reinforce the findings of the single-patient longitudinal case study and demonstrate that the GnRH antagonist of formula (VI) maintains its therapeutic effect on patients suffering from an estrogen-dependent disease even when administered at reduced dosages and even after treatment has ceased.

    Discussion

    [0772] The results of this study demonstrate the effectiveness of the GnRH antagonist of formula (VI) for treating the pathology that underlies adenomyosis, an estrogen-dependent disorder. Particularly, the results show that compound (VI) sustains its therapeutic effect when administered at reduced dosages and even after treatment is halted.

    [0773] Additionally, the results of the single-patient longitudinal case study show the ability of GnRH antagonists, such as the compound of formula (VI), to effectively treat adenomyosis in patients who previously failed to respond to treatment with SPRMs, such as UPA. As the results of this study demonstrate, GnRH antagonists, such as the compound of formula (VI), are efficacious in patients suffering from uterine adenomyosis and whose adenomyotic condition was exacerbated by SPRM treatment.

    [0774] In sum, the results of treatment of all n=6 patients with compound (VI), including the specific results of the singe patient for whom a longitudinal study was conducted, demonstrate that GnRH antagonists, such as compound (VI), can be used to effectively treat the etiology that gives rise to estrogen-dependent diseases and alleviate associated symptoms. Importantly, GnRH antagonists, such as compound (VI), can maintain their therapeutic effect despite reductions in dosage and after treatment has ceased, providing patients with the flexibility to down-titrate doses and/or pause their therapy as needed without experiencing a setback in estrogen-dependent disease progression.

    Example 4. The GnRH Antagonist Represented by Formula (VI) Effectuates a Sustained Reduction in Uterine Fibroids Symptomology and can Safely be Administered to Patients Over Extended Treatment Periods

    Objective

    [0775] Uterine fibroids is a common estrogen-dependent disease characterized by the growth of benign tumors of the muscular tissue of the uterus. Uterine fibroids affect women of childbearing age and can vary in size from undetectable to a large bulky mass. The symptoms of uterine fibroids are wide-ranging and include heavy menstrual bleeding, anemia, pelvic pressure and bloating, urinary frequency, and pain that can be extremely debilitating with a significant impact on quality of life. These symptoms can also have an impact on mental health, creating the additional burden of anxiety and distress. The purpose of the experiments described in this example was to evaluate the safety and efficacy of the GnRH antagonist represented by formula (VI), herein, in patients suffering from uterine fibroids.

    Methods

    [0776] This example describes the results of two Phase 3, double-blind, randomized, placebo-controlled, multicenter, human clinical trials undertaken to evaluate the efficacy of the GnRH antagonist represented by formula (VI) in a series of patients suffering from uterine fibroids. In these trials, referred to herein as “PRIMROSE 1” and “PRIMROSE 2,” human female patients diagnosed as having uterine fibroids were periodically administered compound (VI), 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylic acid, in the form of a choline salt over the course of a 12-month treatment period. Patients were administered compound (VI) once daily in an amount of either 100 mg or 200 mg. Patients receiving compound (VI) in a daily amount of 200 mg also received once daily hormonal add-back therapy (ABT), which consisted of 1 0.0 mg of β17-estradiol (E2) per day and 0.5 mg of norethindrone acetate (NETA) per day. Patients participating in the PRIMROSE 1 and PRIMROSE 2 studies did not receive Vitamin D or calcium supplementation at any point during the treatment period.

    [0777] The PRIMROSE 1 study, conducted in the United States, enrolled 526 women. The PRIMROSE 2 study, conducted in the United States and Europe, enrolled 535 women. Baseline characteristics of randomized and treated patients are shown in Table 10, below.

    TABLE-US-00007 TABLE 10 Demographics and baseline characteristics PRIMROSE 1 PRIMROSE 2 200 mg + 200 mg + Placebo 100 mg ABT Placebo 100 mg ABT n = 103 n = 94 n = 102 n = 102 n = 97 n = 98 Age (years): 42.0 (5.7) 41.3 (5.9) 41.8 (5.9) 42.9 (5.3) 43.4 (5.4) 43.1 (4.8) mean (SD) White/ 33/63/4 95/5/0 Black/ Other (%) BMI (kg/m.sup.2): 32.2 (6.8) 33.3 (7.4) 33.0 (7.3) 26.8 (5.4) 27.4 (5.7) 26.8 (5.5) mean (SD) Weight (kg): 87.4 (18.9) 90.4 (22.4) 88.6 (20.2) 74.4 (16.0) 75.2 (15.6) 72.7 (15.2) mean (SD) Hb < 10 26 (25.2) 31 (33.0) 31 (30.4) 14 (13.7) 21 (21.6) 24 (24.5) g/dL: n (%) Hb < 12 76 (73.8) 68 (72.3) 72 (70.6) 51 (50.0) 61 (62.9) 56 (57.1) g/dL: n (%)* MBL** (mL) 195 (110) 197 (110) 195 (117) 218 (128) 247 (162) 213 (143) mean (SD) *Patients were characterized as anemic if they exhibited a hemoglobin (Hb) value of less than 12.0 g/dL **Menstrual blood loss (MBL) was characterized as “heavy” if total blood lost per menstrual cycle exceeded 80 mL, as assessed by way of the alkaline hematin method, described herein.

    Dosing Regimens

    [0778] Patients were randomized to one of several cohorts: (i) placebo, (ii) 100 mg/day of compound (VI), or (iii) 200 mg/day of compound (VI). Patients receiving 200 mg/day of compound (VI) also received once-daily ABT containing 1.0 mg E2 and 0.5 mg NETA.

    Endpoints

    [0779] Patients were assessed for uterine fibroid symptomology at baseline, after 24 weeks of treatment, and again after 52 weeks of treatment. Particularly, to monitor the efficacy of compound (VI), patients were evaluated to determine the extent to which they exhibited a reduction in menstrual blood loss relative to their menstrual blood loss patterns at baseline. Patients were also assessed in order to determine the number of days of uterine bleeding during their last 28-day interval prior to week 24 of treatment with placebo or compound (VI).

    [0780] Apart from analyzing the ability of compound (VI) to engender a reduction in uterine blood loss, patients were also assessed to determine the proportion of subjects that exhibited sustained amenorrhea after 24 weeks of treatment with compound (VI). Patients that exhibited anemia at baseline were evaluated to determine whether they exhibited an improvement in their condition, particularly by assessing whether they exhibited an increase in hemoglobin level during the studies. Pelvic pain is yet another symptom of uterine fibroids; accordingly, patients were also assessed to determine the extent to which they exhibited a reduction in pain during the studies. Pain levels were measured using a Verbal Rating Score (VRS), as described herein. Patients were also assessed to determine the proportion that reported an improvement in quality of life using the Uterine Fibroids Symptoms and Health-Related Quality of Life questionnaire.

    [0781] To evaluate the safety of compound (VI), patients' bone mineral density levels were measured at baseline and at various timepoints during the studies.

    Results

    [0782] Patients treated with compound (VI), either in an amount of 100 mg/day without ABT or in an amount of 200 mg/day with once-daily ABT, exhibited a sustained reduction in menstrual blood loss and pain symptoms throughout the duration of the PRIMROSE 1 and PRIMROSE 2 studies. Specifically, in the PRIMROSE 1 study, after 24 weeks of treatment, patients receiving compound (VI) experienced a clinically and statistically significant reduction in menstrual bleeding, defined as ≤80 mL of menstrual blood loss and a ≥50% reduction in menstrual blood loss from baseline. Among women receiving 200 mg of compound (VI) per day in combination with ABT, 75.5% (p<0.001) achieved a reduction in menstrual blood loss to a level of ≤80 mL and a ≥50% reduction in menstrual blood loss from baseline. Among patients receiving 100 mg of compound (VI) without ABT, 56.4% (p=0.003) achieved a reduction in menstrual blood loss to a level of ≤80 mL and a ≥50% reduction in menstrual blood loss from baseline. In contrast, among patients receiving placebo, 35% exhibited a reduction in menstrual blood loss to a level of ≤80 mL and a ≥50% reduction in menstrual blood loss from baseline.

    [0783] Importantly, the therapeutic effects of compound (VI) were sustained for up to 52 weeks, as demonstrated by the data obtained from the PRIMROSE 2 study. In the PRIMROSE2 trial, among patients being administered 200 mg of compound (VI) per day in combination with ABT for 52 weeks, 91.6% achieved a reduction in menstrual blood loss to a level of ≤80 mL and a ≥50% reduction in menstrual blood loss from baseline. Similarly, among patients receiving 100 mg of compound (VI) without ABT for 52 weeks, 53.2% achieved a reduction in menstrual blood loss to a level of 80 mL and a 50% reduction in menstrual blood loss from baseline. Both of these values mirror the response rates observed after 24 weeks of treatment in the PRIMROSE 2 study. These results are shown graphically in FIGS. 5-8.

    [0784] Not only was compound (VI) capable of attenuating uterine blood loss, reducing pain, and improving patients' quality of life, the data from the PRIMROSE 1 and PRIMROSE 2 studies demonstrate that compound (VI) does not induce a substantial decrease in bone mineral density. This is shown, for example, in FIG. 9, which depicts the lumbar spine bone mineral density of patients treated with compound (VI) after 24 weeks and 52 weeks of once-daily treatment with compound (VI).

    [0785] The efficacy of compound (VI) in the PRIMROSE 1 and PRIMROSE 2 studies is summarized in Table 11, below.

    TABLE-US-00008 TABLE 11 Efficacy of compound (VI) in reducing uterine fibroids symptomology and improving quality of life in PRIMROSE 1 and PRIMROSE 2 studies 200 mg/day of compound (VI) + once-daily ABT 100 mg/day of (1.0 mg E2 + 0.5 compound (VI) mg NETA) PRIMROSE PRIMROSE PRIMROSE PRIMROSE Endpoint 1 2 1 2 Reduction in p = 0.002 p < 0.001 p < 0.001 p < 0.001 menstrual p = 0.001 p < 0.001 p < 0.001 p < 0.001 blood loss • Time to reduced menstrual blood loss (≤80 mL and ≥ 50% reduction from baseline) up to Week 24 • Number of days of uterine bleeding for the last 28-day interval prior to Week 24 Amenorrhea p = 0.009 p < 0.001 p < 0.001 p < 0.001 • Percentage at p = 0.007 p < 0.001 p < 0.001 p < 0.001 Week 24 • Time to amenorrhea up to Week 24 Improvement in p = 0.019 p = 0.002 p < 0.001 p < 0.001 anemia Hemoglobin level at week 24 in anemic subjects.sup.+ Reduction p < 0.001 p = 0.002 p < 0.001 p < 0.001 in pain Change from baseline pain score at week 24 Reduction in p = 0.149 p = 0.055 p = 0.671 p = 0.008 volume p = 0.014 p = 0.003 p = 0.223 p < 0.001 • Fibroid volume change from baseline at Week 24 • Uterine volume change from baseline at Week 24 Improvement in p = 0.002 p = 0.004 p < 0.001 p < 0.001 quality of life Change from baseline in quality of life (QoL) symptom severity score (LS mean) .sup.+Defined as subjects with Hb < 12 g/dL at baseline

    CONCLUSION

    [0786] As the results of the PRIMROSE 1 and PRIMROSE 2 studies show, compound (VI) can safely be administered to patients over the course of extended treatment periods, such as those having a duration of one year or longer, so as to reduce estrogen-dependent disease symptomology and treat the underlying etiology of the disease. The therapeutic effects of compound (VI) that are observed after initial treatment periods (e.g., of 24 weeks) are observed over extended periods of time (e.g., for 52 weeks or longer). Advantageously, compound (VI) achieves these desirable treatment outcomes without inducing a substantial reduction in bone mineral density.

    OTHER EMBODIMENTS

    [0787] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

    [0788] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

    [0789] Other embodiments are within the claims.