GNRH ANTAGONISTS FOR THE TREATMENT OF ESTROGEN-DEPENDENT DISORDERS

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, over the course of an extended treatment period, such as a treatment period having a duration of multiple years. Advantageously, using the compositions and methods of the present disclosure, the GnRH antagonist may be administered to a patient over a lengthy treatment period without inducing adverse side effects, such as a loss in bone mineral density, which is otherwise known to be a risk associated with GnRH antagonism.

Claims

1. A method of treating an estrogen-dependent disease in a human patient in need thereof, the method comprising periodically administering to the patient a therapeutically effective amount of a gonadotropin-releasing hormone (GnRH) antagonist over the course of a treatment period having a duration of at least 52 weeks.

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 periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

4. A method of inducing amenorrhea in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

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 periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

6. A method of preserving or increasing hemoglobin in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

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 periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

9. A method of reducing pelvic pain in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

10. A method of reducing dysmenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

11. A method of reducing dyspareunia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

12. A method of reducing dyschezia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

13. A method of reducing uterine bleeding in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

14. A method of inducing amenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

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 periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

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 periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

18. A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

19. A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

20. A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

21. A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

22. A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

23. A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

24. A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

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 periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

27. A method of reducing the volume of one or more type Ill rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

28. A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

29. A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

30. A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

31. A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

32. A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

33. A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient a therapeutically effective amount of a GnRH antagonist over the course of a treatment period having a duration of at least 52 weeks.

34. The method of any one of claims 1-33, wherein the GnRH antagonist is a compound represented by formula (I) ##STR00607## 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.

35. The method of claim 34, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00608##

36. The method of claim 34 or 35, wherein m is 1.

37. The method of claim 36, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00609##

38. The method of any one of claims 34-37, 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.

39. The method of claim 38, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

40. The method of any one of claims 34-39, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

41. The method of claim 40, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00610##

42. The method of any one of claims 34-41, wherein n is 2.

43. The method of claim 42, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00611##

44. The method of any one of claims 34-43, 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.

45. The method of claim 44, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

46. The method of any one of claims 34-45, wherein U is a single bond.

47. The method of any one of claims 34-46, wherein X is a group represented by —O-L-Y.

48. The method of any one of claims 34-47, wherein L is a methylene group.

49. The method of any one of claims 34-48, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00612## 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.

50. The method of claim 49, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00613##

51. The method of claim 34, wherein the compound is represented by formula (Ia) ##STR00614## 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.

52. The method of claim 35, wherein the compound is represented by formula (Ib) ##STR00615##

53. The method of claim 36, wherein the compound is represented by formula (Ic) ##STR00616## or a pharmaceutically acceptable salt thereof.

54. The method of claim any one of claims 34-53, wherein the compound is represented by formula (VI) ##STR00617## or a pharmaceutically acceptable salt thereof.

55. The method of claim 54, wherein the compound is the choline salt of the compound represented by formula (VI).

56. The method of claim 55, wherein the compound is in a crystalline state.

57. The method of claim 56, 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.

58. The method of claim 56 or 57, 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.

59. The method of any one of claims 56-58, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.

60. The method of any one of claims 34-59, wherein the compound is orally administered to the patient.

61. The method of any one of claims 34-60, wherein the compound is administered to the patient one or more times per day, week, or month during the treatment period.

62. The method of claim 61, wherein the compound is administered to the patient one or more times daily during the treatment period.

63. The method of claim 62, wherein the compound is administered to the patient once daily during the treatment period.

64. The method of any one of claims 61-63, 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 treatment period.

65. The method of claim 64, wherein the compound is administered to the patient in an amount of from about 35 mg to about 65 mg per day during the treatment period.

66. The method of claim 65, wherein the compound is administered to the patient in an amount of about 50 mg per day during the treatment period.

67. The method of claim 64, 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 treatment period.

68. The method of claim 67, wherein the compound is administered to the patient in an amount of about 75 mg per day during the treatment period.

69. The method of claim 64, wherein the compound is administered to the patient in an amount of from about 85 mg to about 115 mg per day during the treatment period.

70. The method of claim 69, wherein the compound is administered to the patient in an amount of about 100 mg per day during the treatment period.

71. The method of claim 64, wherein the compound is administered to the patient in an amount of from about 185 mg to about 215 mg per day during the treatment period.

72. The method of claim 71, wherein the compound is administered to the patient in an amount of about 200 mg per day during the treatment period.

73. The method of any one of claims 1-33, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.

74. The method of claim 73, wherein the GnRH antagonist is elagolix.

75. The method of claim 74, wherein the GnRH antagonist is orally administered to the patient.

76. The method of claim 74 or 75, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month during the treatment period.

77. The method of claim 76, wherein the GnRH antagonist is administered to the patient one or more times daily during the treatment period.

78. The method of claim 77, wherein the GnRH antagonist is administered to the patient once daily during the treatment period.

79. The method of any one of claims 74-78, 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 treatment period.

80. The method of claim 79, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day during the treatment period.

81. The method of claim 79, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day during the treatment period.

82. The method of claim 79, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day during the treatment period, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 200 mg per dose during the treatment period.

83. The method of claim 79, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day during the treatment period, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 300 mg per dose during the treatment period.

84. The method of claim 73, wherein the GnRH antagonist is relugolix.

85. The method of claim 84, wherein the GnRH antagonist is orally administered to the patient.

86. The method of claim 84 or 85, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month during the treatment period.

87. The method of claim 86, wherein the GnRH antagonist is administered to the patient one or more times daily during the treatment period.

88. The method of claim 87, wherein the GnRH antagonist is administered to the patient once daily during the treatment period.

89. The method of any one of claims 84-88, 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 treatment period.

90. The method of claim 89, 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 treatment period.

91. The method of claim 90, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day during the treatment period.

92. The method of any one of claims 1-91, wherein the treatment period has a duration of at least 13 months.

93. The method of claim 92, wherein the treatment period has a duration of at least 14 months.

94. The method of claim 93, wherein the treatment period has a duration of at least 15 months.

95. The method of claim 94, wherein the treatment period has a duration of at least 16 months.

96. The method of claim 95, wherein the treatment period has a duration of at least 17 months.

97. The method of claim 96, wherein the treatment period has a duration of at least 18 months.

98. The method of claim 97, wherein the treatment period has a duration of at least 19 months.

99. The method of claim 98, wherein the treatment period has a duration of at least 20 months.

100. The method of claim 99, wherein the treatment period has a duration of at least 21 months.

101. The method of claim 100, wherein the treatment period has a duration of at least 22 months.

102. The method of claim 101, wherein the treatment period has a duration of at least 23 months.

103. The method of claim 102, wherein the treatment period has a duration of at least 24 months.

104. The method of any one of claims 1-91, wherein the treatment period has a duration of from about 12 months to about 60 months.

105. The method of claim 104, wherein the treatment period has a duration of from about 12 months to about 48 months.

106. The method of claim 105, wherein the treatment period has a duration of from about 12 months to about 36 months.

107. The method of claim 106, wherein the treatment period has a duration of from about 12 months to about 24 months.

108. The method of any one of claims 1-91, wherein the treatment period has a duration of about 12 months.

109. The method of any one of claims 1-91, wherein the treatment period has a duration of about 18 months.

110. The method of any one of claims 1-91, wherein the treatment period has a duration of about 24 months.

111. The method of any one of claims 1-91, wherein the treatment period has a duration of about 30 months.

112. The method of any one of claims 1-91, wherein the treatment period has a duration of about 36 months.

113. The method of any one of claims 1-91, wherein the treatment period has a duration of about 42 months.

114. The method of any one of claims 1-91, wherein the treatment period has a duration of about 48 months.

115. The method of any one of claims 1-91, wherein the treatment period has a duration of about 54 months.

116. The method of any one of claims 1-91, wherein the treatment period has a duration of about 60 months.

117. The method of any one of claims 1-116, wherein add-back therapy is periodically administered to the patient during the treatment period.

118. The method of claim 117, wherein the add-back therapy is administered to the patient one or more times daily during the treatment period.

119. The method of claim 118, wherein the add-back therapy is administered to the patient once daily, concurrently with the GnRH antagonist, during the treatment period.

120. The method of claim 118, wherein the add-back therapy is administered to the patient once daily, prior to administration of the GnRH antagonist, during the treatment period.

121. The method of claim 118, wherein the add-back therapy is administered to the patient once daily, following administration of the GnRH antagonist, during the treatment period.

122. The method of claim 121, wherein the add-back therapy is administered to the patient in the form of a pharmaceutical composition comprising the GnRH antagonist.

123. The method of any one of claims 117-122, wherein the add-back therapy comprises an estrogen.

124. The method of claim 123, wherein the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens.

125. The method of claim 124, wherein the estrogen is β17-estradiol.

126. The method of claim 125, wherein the β17-estradiol is administered to the patient in an amount of about 1.0 mg/day during the treatment period.

127. The method of claim 125, wherein the β17-estradiol is administered to the patient in an amount of about 0.5 mg/day during the treatment period.

128. The method of claim 124, wherein the estrogen is ethinyl estradiol.

129. The method of claim 128, wherein the ethinyl estradiol is administered to the patient in an amount of about 5.0 μg/day during the treatment period.

130. The method of claim 128, wherein the ethinyl estradiol is administered to the patient in an amount of about 2.5 μg/day during the treatment period.

131. The method of claim 124, wherein the estrogen is a conjugated estrogen.

132. The method of claim 131, wherein the conjugated estrogen is administered to the patient in an amount of about 0.625 mg/day during the treatment period.

133. The method of claim 131, wherein the conjugated estrogen is administered to the patient in an amount of about 0.45 mg/day during the treatment period.

134. The method of claim 131, wherein the conjugated estrogen is administered to the patient in an amount of about 0.3 mg/day during the treatment period.

135. The method of any one of claims 117-134, wherein the add-back therapy comprises a progestin.

136. The method of claim 135, wherein the progestin is selected from the group consisting of norethindrone or an ester thereof, progesterone, norgestimate, medroxyprogesterone, and drospirenone.

137. The method of claim 136, wherein the progestin is norethindrone or norethindrone acetate.

138. The method of claim 137, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 1.0 mg/day during the treatment period.

139. The method of claim 137, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.5 mg/day during the treatment period.

140. The method of claim 137, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.1 mg/day during the treatment period.

141. The method of claim 136, wherein the progestin is progesterone.

142. The method of claim 141, wherein the progesterone is administered to the patient in an amount of about 200 mg/day during the treatment period.

143. The method of claim 141, wherein the progesterone is administered to the patient in an amount of about 100 mg/day during the treatment period.

144. The method of claim 136, wherein the progestin is norgestimate.

145. The method of claim 144, wherein the norgestimate is administered to the patient in an amount of about 0.09 mg/day during the treatment period.

146. The method of claim 136, wherein the progestin is medroxyprogesterone.

147. The method of claim 146, wherein the medroxyprogesterone is administered to the patient in an amount of about 5 mg/day during the treatment period.

148. The method of claim 146, wherein the medroxyprogesterone is administered to the patient in an amount of about 2.5 mg/day during the treatment period.

149. The method of claim 146, wherein the medroxyprogesterone is administered to the patient in an amount of about 1.5 mg/day during the treatment period.

150. The method of claim 136, wherein the progestin is drospirenone.

151. The method of claim 150, wherein the drospirenone is administered to the patient in an amount of about 0.5 mg/day during the treatment period.

152. The method of claim 150, wherein the drospirenone is administered to the patient in an amount of about 0.25 mg/day during the treatment period.

153. The method of any one of claims 117-152, wherein the add-back therapy comprises about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.

154. The method of any one of claims 117-152, wherein the add-back therapy comprises about 0.5 mg of β17-estradiol and about 0.1 mg of norethindrone acetate.

155. The method of any one of claims 1-154, wherein the patient is a pre-menopausal female of from about 18 to about 48 years of age.

156. The method of any one of claims 1-155, 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 administration of the GnRH antagonist to the patient.

157. The method of any one of claims 1-156, wherein the patient has been determined to exhibit a rectal (type II) and/or vaginal (type Ill) endometriosis node of at least 2 cm prior to administration of the GnRH antagonist to the patient.

158. The method of claim 157, wherein the length of the type II and/or type Ill endometriosis node is assessed by way of magnetic resonance imaging (MRI).

159. The method of any one of claims 1-158, wherein the patient has been determined to exhibit a junctional-zone width of about 12 mm or more prior to administration of the GnRH antagonist to the patient.

160. The method of claim 159, wherein the junctional-zone width is assessed by way of MRI.

161. The method of any one of claims 1-160, 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.

162. The method of claim 161, 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 the onset of administration of the GnRH antagonist to the patient.

163. The method of any one of claims 1, 2, 5-12, 15-22, 25-31, and 34-162, wherein the patient exhibits a reduction in uterine bleeding following administration of the GnRH antagonist to the patient.

164. The method of any one of claims and 3, 13, 23, 32, and 163, wherein the patient exhibits the reduction in uterine bleeding within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

165. The method of any one of claims 3, 13, 23, 32, 163, and 164, wherein the reduction in uterine bleeding is assessed by way of an alkaline hematin method.

166. The method of any one of claims 1-3, 5-13, 15-23, 25-32, and 34-165, wherein the patient exhibits amenorrhea following administration of the GnRH antagonist to the patient.

167. The method of any one of claims 4, 14, 24, 33, and 166, wherein the patient exhibits the amenorrhea within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

168. The method of any one of claims 1-7, 9-25, and 28-167, 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.

169. The method of any one of claims 8, 26, 27, and 168, 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 the onset of administration of the GnRH antagonist to the patient.

170. The method of any one of claims 8, 26, 27, 168, and 169, wherein the reduction in volume of the one or more rectovaginal endometriosis nodes is assessed by way of MRI or TVUS.

171. The method of any one of claims 1-170, wherein the patient exhibits a reduction in bowel involvement of one or more type Ill endometriosis nodes following administration of the GnRH antagonist to the patient.

172. The method of claim 171, wherein the patient exhibits the reduction in bowel involvement of the one or more type Ill endometriosis nodes within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

173. The method of any one of claims 1-8, 10-17, 19-27, and 29-172, wherein the patient exhibits a reduction in pelvic pain following administration of the GnRH antagonist to the patient.

174. The method of any one of claims 9, 18, 28, and 173, wherein the patient exhibits the reduction in pelvic pain within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

175. The method of any one of claims 9, 18, 28, 173, and 174, 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.

176. The method of any one of claims 1-9, 11-18, 20-28, and 39-175, wherein the patient exhibits a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient.

177. The method of any one of claims 10, 19, 29, and 176, wherein the patient exhibits the reduction in dysmenorrhea within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

178. The method of any one of claims 10, 19, 29, 176, and 177, wherein the reduction in dysmenorrhea is assessed by way of an mB&B score, NRS score, or VRS score.

179. The method of any one of claims 1-10, 12-19, 21-29, and 31-178, wherein the patient exhibits a reduction in dyspareunia following administration of the GnRH antagonist to the patient.

180. The method of any one of claims 11, 20, 30, and 179, wherein the patient exhibits the reduction in dyspareunia within from about one day to about 36 weeks commencement of the onset of administration of the GnRH antagonist to the patient.

181. The method of any one of claims 11, 20, 30, 179, and 180, wherein the reduction in dyspareunia is assessed by way of an mB&B score, NRS score, or VRS score.

182. The method of any one of claims 1-11, 13-20, 22-30, and 32-181, wherein the patient exhibits a reduction in dyschezia following administration of the GnRH antagonist to the patient.

183. The method of any one of claims 12, 21, 31, and 182, wherein the patient exhibits the reduction in dyschezia within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

184. The method of any one of claims 12, 21, 31, 182, and 183, wherein the reduction in dyschezia is assessed by way of an mB&B score, NRS score, or VRS score.

185. The method of any one of claims 1-15 and 17-184, wherein the patient exhibits a reduction in uterine volume following administration of the GnRH antagonist to the patient.

186. The method of any one of claims 16 and 185, wherein the patient exhibits the reduction in uterine volume within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

187. The method of any one of claims 16, 185, and 186, wherein the reduction in uterine volume is assessed by way of MRI or transvaginal ultrasound (TVUS).

188. The method of any one of claims 1-16 and 18-187, 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.

189. The method of any one of claims 17 and 188, 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 the onset of administration of the GnRH antagonist to the patient.

190. The method of any one of claims 1-21 and 23-189, wherein the patient exhibits a reduction in uterine tenderness following administration of the GnRH antagonist to the patient.

191. The method of any one of claims 22 and 190, wherein the patient exhibits the reduction in uterine tenderness within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

192. The method of any one of claims 1-191, wherein the patient exhibits a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient.

193. The method of claim 192, 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 the onset of administration of the GnRH antagonist to the patient.

194. The method of any one of claims 1-193, wherein the patient exhibits an improvement in Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient.

195. The method of claim 194, wherein the patient exhibits the improvement in the EHP-30 score within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

196. The method of any one of claims 1-195, wherein the patient exhibits a positive Patient Global Impression of Change (PGIC) score core following administration of the GnRH antagonist to the patient.

197. The method of claim 196, wherein the patient exhibits the positive PGIC score within from about one day to about 36 weeks of the onset of administration of the GnRH antagonist to the patient.

198. The method of any one of claims 1-197, the method further comprising monitoring the patient's bone mineral density (BMD) at the end of the treatment period.

199. The method of claim 198, the method further comprising determining that the patient does not exhibit a reduction in BMD of greater than 5% at the end of the treatment period relative to a measurement of the patient's BMD obtained prior to, or during, the treatment period.

200. The method of any one of claims 1-199, wherein the patient does not exhibit a reduction in BMD of greater than 5% at the end of the treatment period relative to a measurement of the patient's BMD obtained prior to, or during, the treatment period.

201. The method of claim 200, wherein the patient does not exhibit a reduction in BMD of greater than 4% at the end of the treatment period relative to a measurement of the patient's BMD obtained prior to, or during, the treatment period.

202. The method of claim 201, wherein the patient does not exhibit a reduction in BMD of greater than 3% at the end of the treatment period relative to a measurement of the patient's BMD obtained prior to, or during, the treatment period.

203. The method of claim 202, wherein the patient does not exhibit a reduction in BMD of greater than 2% at the end of the treatment period relative to a measurement of the patient's BMD obtained prior to, or during, the treatment period.

204. The method of claim 203, wherein the patient does not exhibit a reduction in BMD of greater than 1% at the end of the treatment period relative to a measurement of the patient's BMD obtained prior to, or during, the treatment period.

205. The method of any one of claims 198-204, wherein the BMD is assessed by dual energy X-ray absorptiometry.

206. The method of claim 205, wherein the BMD is assessed in the spine or femur of the patient.

207. The method of any one of claims 198-204, 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 of the GnRH antagonist to the concentration of BAP in a sample isolated from the patient prior to the administration of the GnRH antagonist.

208. The method of any one of claims 198-204, wherein the BMD is assessed by comparing the concentration of deoxypyridinoline (DPD) in a sample isolated from the patient following the administration of the GnRH antagonist to the concentration of DPD in a sample isolated from the patient prior to the administration of the GnRH antagonist.

209. The method of any one of claims 198-204, 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 of the GnRH antagonist to the concentration of CTX in a sample isolated from the patient prior to the administration of the GnRH antagonist.

210. The method of any one of claims 198-204, 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 of the GnRH antagonist to the concentration of P1NP in a sample isolated from the patient prior to the administration of the GnRH antagonist.

211. The method of any one of claims 1-210, wherein the patient does not exhibit an increase in total cholesterol level of greater than 10% after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period relative to a measurement of the patient's total cholesterol level obtained prior to the treatment period.

212. The method of any one of claims 1-211, wherein the patient does not exhibit an increase in low-density lipoprotein-cholesterol level of greater than 10% after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period relative to a measurement of the patient's low-density lipoprotein-cholesterol level obtained prior to the treatment period.

213. The method of any one of claims 1-212, wherein the patient does not exhibit an increase in their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol of greater than 10% after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period relative to a measurement of the patient's ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol obtained prior to the treatment period.

214. The method of any one of claims 1-213, wherein the patient does not exhibit an increase in low-density lipoprotein-cholesterol level to a level greater than 160 mg/dl after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period.

215. The method of any one of claims 1-214, wherein the patient does not exhibit an increase in low-density lipoprotein-cholesterol level from a level less than 160 mg/dl (e.g., from a level less than 130 mg/dl) to a level greater than 190 mg/dl after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period.

216. The method of any one of claims 1-215, wherein the patient does not exhibit an increase in serum triglyceride level of greater than 30% after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period relative to a measurement of the patient's serum triglyceride level obtained prior to the treatment period.

217. The method of any one of claims 1-216, wherein the patient does not exhibit an increase in serum triglyceride level to a level greater than 200 mg/dl after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period.

218. The method of any one of claims 1-217, wherein the patient does not exhibit an increase in serum triglyceride level from a level less than 300 mg/dl to a level greater than 500 mg/dl after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period.

219. The method of any one of claims 1-218, the method comprising: a) monitoring the patient's total cholesterol level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in total cholesterol level of greater than 10% relative to a measurement of the patient's total cholesterol level obtained prior to the treatment period; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

220. The method of any one of claims 1-219, the method comprising: a) monitoring the patient's low-density lipoprotein-cholesterol level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level of greater than 10% relative to a measurement of the patient's low-density lipoprotein-cholesterol level obtained prior to the treatment period; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

221. The method of any one of claims 1-220, the method comprising: a) monitoring the patient's ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol of greater than 10% relative to a measurement of the patient's ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol obtained prior to the treatment period; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

222. The method of any one of claims 1-221, the method comprising: a) monitoring the patient's low-density lipoprotein-cholesterol level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level to a level greater than 160 mg/dl; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

223. The method of any one of claims 1-222, the method comprising: a) monitoring the patient's low-density lipoprotein-cholesterol level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level from a level less than 160 mg/dl (e.g., from a level less than 130 mg/dl) to a level greater than 190 mg/dl; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

224. The method of any one of claims 1-223, the method comprising: a) monitoring the patient's serum triglyceride level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in serum triglyceride level of greater than 30% relative to a measurement of the patient's serum triglyceride level obtained prior to the treatment period; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

225. The method of any one of claims 1-224, the method comprising: a) monitoring the patient's serum triglyceride level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in serum triglyceride level to a level greater than 200 mg/dl; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

226. The method of any one of claims 1-224, the method comprising: a) monitoring the patient's serum triglyceride level after from about 6 weeks to about 52 weeks of being administered the GnRH antagonist during the treatment period; b) determining that the patient does not exhibit an increase in serum triglyceride level from a level less than 300 mg/dl to a level greater than 500 mg/dl; and c) continuing to administer the GnRH antagonist to the patient for the remainder of the treatment period.

227. 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 1-226.

228. The kit of claim 227, wherein the GnRH antagonist is a compound 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.

229. The kit of claim 228, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00619##

230. The kit of claim 228 or 229, wherein m is 1.

231. The kit of claim 230, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00620##

232. The kit of any one of claims 228-231, 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.

233. The kit of claim 232, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

234. The kit of any one of claims 228-233, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

235. The kit of claim 234, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00621##

236. The kit of any one of claims 228-235, wherein n is 2.

237. The kit of claim 236, wherein ring B is represented by a formula selected from the group consisting of: ##STR00622##

238. The kit of any one of claims 228-237, 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.

239. The kit of claim 238, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

240. The kit of any one of claims 228-239, wherein U is a single bond.

241. The kit of any one of claims 228-240, wherein X is a group represented by —O-L-Y.

242. The kit of any one of claims 228-241, wherein L is a methylene group.

243. The kit of any one of claims 228-242, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00623## 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.

244. The kit of claim 243, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00624##

245. The kit of claim 228, wherein the compound is represented by formula (Ia) ##STR00625## 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.

246. The kit of claim 245, wherein the compound is represented by formula (Ib) ##STR00626##

247. The kit of claim 246, wherein the compound is represented by formula (Ic) ##STR00627## or a pharmaceutically acceptable salt thereof.

248. The kit of any one of claims 228-247, wherein the compound is represented by formula (VI) ##STR00628## or a pharmaceutically acceptable salt thereof.

249. The kit of claim 248, wherein the compound is the choline salt of the compound represented by formula (VI).

250. The kit of claim 227, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.

251. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit a significant increase in total cholesterol level relative to a measurement of the patient's total cholesterol level obtained prior to the treatment period, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

252. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit a significant increase in low-density lipoprotein-cholesterol level relative to a measurement of the patient's low-density lipoprotein-cholesterol level obtained prior to the treatment period, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

253. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit a significant increase in their ratio of ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol relative to a measurement of the patient's ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol obtained prior to the treatment period, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

254. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level to a level greater than 160 mg/dl, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

255. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level from a level less than 160 mg/dl (e.g., from a level less than 130 mg/dl) to a level greater than 190 mg/dl, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

256. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit an increase in serum triglyceride level of greater than 30% relative to a measurement of the patient's serum triglyceride level obtained prior to the treatment period, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

257. A method of treating an estrogen-dependent disease or alleviating one or more symptoms of 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 treatment period, b) determining that the patient does not exhibit an increase in serum triglyceride level to a level greater than 200 mg/dl, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

258. 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 treatment period, b) determining that the patient does not exhibit an increase in serum triglyceride level from a level less than 300 mg/dl to a level greater than 500 mg/dl, optionally wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period, and c) continuing to periodically administer the GnRH antagonist to the patient for the remainder of the treatment period.

259. The method of any one of claims 251-258, wherein the estrogen-dependent disease is uterine fibroids, endometriosis, adenomyosis, or rectovaginal endometriosis.

260. The method of any one of claims 251-259, wherein the GnRH antagonist is a compound 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.5, 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.

261. The method of claim 260, wherein the ring A is a thiophene ring represented by formula (IIa) ##STR00630##

262. The method of claim 260 or 261, wherein m is 1.

263. The method of claim 262, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb) ##STR00631##

264. The method of any one of claims 260-263, 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.

265. The method of claim 264, wherein each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

266. The method of any one of claims 260-265, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

267. The method of claim 266, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00632##

268. The method of any one of claims 260-267, wherein n is 2.

269. The method of claim 268, wherein the ring B is represented by a formula selected from the group consisting of: ##STR00633##

270. The method of any one of claims 260-269, 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.

271. The method of claim 270, wherein each R.sup.B is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

272. The method of any one of claims 260-271, wherein U is a single bond.

273. The method of any one of claims 260-272, wherein X is a group represented by —O-L-Y.

274. The method of any one of claims 260-273, wherein L is a methylene group.

275. The method of any one of claims 260-274, wherein Y is an optionally substituted benzene ring represented by formula (V) ##STR00634## 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.

276. The method of claim 275, wherein Y is a substituted benzene ring represented by formula (Va) ##STR00635##

277. The method of claim 260, wherein the compound is represented by formula (Ia) ##STR00636## 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.

278. The method of claim 277, wherein the compound is represented by formula (Ib) ##STR00637##

279. The method of claim 278, wherein the compound is represented by formula (Ic) ##STR00638## or a pharmaceutically acceptable salt thereof.

280. The method of claim any one of claims 260-279, wherein the compound is represented by formula (VI) ##STR00639## or a pharmaceutically acceptable salt thereof.

281. The method of claim 280, wherein the compound is the choline salt of the compound represented by formula (VI).

282. The method of claim 281, wherein the compound is in a crystalline state.

283. The method of claim 282, 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° 20, about 22.6° 2θ, about 23.5° 2θ, and about 26.2° 2θ.

284. The method of claim 282 or 283, 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.

285. The method of any one of claims 282-284, wherein the compound exhibits .sup.19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.

286. The method of any one of claims 260-285, wherein the compound is orally administered to the patient.

287. The method of any one of claims 260-286, wherein the compound is administered to the patient one or more times per day, week, or month during the treatment period.

288. The method of claim 287, wherein the compound is administered to the patient one or more times daily during the treatment period.

289. The method of claim 288, wherein the compound is administered to the patient once daily during the treatment period.

290. The method of any one of claims 287-289, 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 treatment period.

291. The method of claim 290, wherein the compound is administered to the patient in an amount of from about 35 mg to about 65 mg per day during the treatment period.

292. The method of claim 291, wherein the compound is administered to the patient in an amount of about 50 mg per day during the treatment period.

293. The method of claim 290, 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 treatment period.

294. The method of claim 293, wherein the compound is administered to the patient in an amount of about 75 mg per day during the treatment period.

295. The method of claim 290, wherein the compound is administered to the patient in an amount of from about 85 mg to about 115 mg per day during the treatment period.

296. The method of claim 295, wherein the compound is administered to the patient in an amount of about 100 mg per day during the treatment period.

297. The method of claim 290, wherein the compound is administered to the patient in an amount of from about 185 mg to about 215 mg per day during the treatment period.

298. The method of claim 297, wherein the compound is administered to the patient in an amount of about 200 mg per day during the treatment period.

299. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 52 weeks after the onset of the treatment period.

300. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 48 weeks after the onset of the treatment period.

301. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 44 weeks after the onset of the treatment period.

302. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 42 weeks after the onset of the treatment period.

303. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 38 weeks after the onset of the treatment period.

304. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 36 weeks after the onset of the treatment period.

305. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 32 weeks after the onset of the treatment period.

306. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 28 weeks after the onset of the treatment period.

307. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 24 weeks after the onset of the treatment period.

308. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 18 weeks after the onset of the treatment period.

309. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 16 weeks after the onset of the treatment period.

310. The method of any one of claims 251-298, wherein the determining occurs from about 6 weeks to about 12 weeks after the onset of the treatment period.

311. The method of any one of claims 251-298, wherein the determining occurs from about 12 weeks to about 36 weeks after the onset of the treatment period.

312. The method of any one of claims 251-298, wherein the determining occurs from about 16 weeks to about 32 weeks after the onset of the treatment period.

313. The method of any one of claims 251-298, wherein the determining occurs from about 20 weeks to about 28 weeks after the onset of the treatment period.

314. The method of any one of claims 251-298, wherein the determining occurs from about 21 weeks to about 27 weeks after the onset of the treatment period.

315. The method of any one of claims 251-298, wherein the determining occurs from about 22 weeks to about 26 weeks after the onset of the treatment period.

316. The method of any one of claims 251-298, wherein the determining occurs from about 23 weeks to about 25 weeks after the onset of the treatment period.

317. The method of any one of claims 251-298, wherein the determining occurs about 6 weeks after the onset of the treatment period.

318. The method of any one of claims 251-298, wherein the determining occurs about 8 weeks after the onset of the treatment period.

319. The method of any one of claims 251-298, wherein the determining occurs about 10 weeks after the onset of the treatment period.

320. The method of any one of claims 251-298, wherein the determining occurs about 12 weeks after the onset of the treatment period.

321. The method of any one of claims 251-298, wherein the determining occurs about 14 weeks after the onset of the treatment period.

322. The method of any one of claims 251-298, wherein the determining occurs about 16 weeks after the onset of the treatment period.

323. The method of any one of claims 251-298, wherein the determining occurs about 18 weeks after the onset of the treatment period.

324. The method of any one of claims 251-298, wherein the determining occurs about 20 weeks after the onset of the treatment period.

325. The method of any one of claims 251-298, wherein the determining occurs about 22 weeks after the onset of the treatment period.

326. The method of any one of claims 251-298, wherein the determining occurs about 24 weeks after the onset of the treatment period.

327. The method of any one of claims 251-298, wherein the determining occurs about 26 weeks after the onset of the treatment period.

328. The method of any one of claims 251-298, wherein the determining occurs about 28 weeks after the onset of the treatment period.

329. The method of any one of claims 251-298, wherein the determining occurs about 30 weeks after the onset of the treatment period.

330. The method of any one of claims 251-298, wherein the determining occurs about 32 weeks after the onset of the treatment period.

331. The method of any one of claims 251-298, wherein the determining occurs about 34 weeks after the onset of the treatment period.

332. The method of any one of claims 251-298, wherein the determining occurs about 36 weeks after the onset of the treatment period.

333. The method of any one of claims 251-298, wherein the determining occurs about 38 weeks after the onset of the treatment period.

334. The method of any one of claims 251-298, wherein the determining occurs about 40 weeks after the onset of the treatment period.

335. The method of any one of claims 251-298, wherein the determining occurs about 42 weeks after the onset of the treatment period.

336. The method of any one of claims 251-298, wherein the determining occurs about 44 weeks after the onset of the treatment period.

337. The method of any one of claims 251-298, wherein the determining occurs about 46 weeks after the onset of the treatment period.

338. The method of any one of claims 251-298, wherein the determining occurs about 48 weeks after the onset of the treatment period.

339. The method of any one of claims 251-298, wherein the determining occurs about 50 weeks after the onset of the treatment period.

340. The method of any one of claims 251-298, wherein the determining occurs about 52 weeks after the onset of the treatment period.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0752] FIG. 1 is a graph showing the effects of extended administration 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, on endometriosis-associated pain in human female human patients, as described in Example 1, below. Values shown represent the mean±95% confidence interval for pain scores from baseline through 52 weeks of continuous, once-daily treatment.

[0753] FIG. 2 is a graph showing the effects of extended administration 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, on bone mineral density (BMD) in human female human patients, as described in Example 1, below. Values represent the percent change in BMD as assessed in the lumbar spine.

[0754] FIGS. 3A and 3B are graphs showing the effects of extended administration 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, on quality of life in human female human patients, as described in Example 1, below. FIG. 3A shows the effects of GnRH antagonist treatment on quality of life after 12 weeks of continuous treatment, and FIG. 3B shows the effects of GnRH antagonist treatment on quality of life after 52 weeks of continuous treatment. Quality of life was assessed at both timepoints using the Endometriosis Health Profile-30 questionnaire.

[0755] FIG. 4 is a graph showing the response rate among endometriosis patients treated with 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 accordance with the protocol described in Example 1, below. “Responders” were considered to be those patients that exhibited at least a 30% reduction in overall pelvic pain relative to baseline.

[0756] FIG. 5 is a graph showing the improvement in quality of life achieved among endometriosis patients treated with 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 accordance with the protocol described in Example 1, below. Quality of life is measured in FIG. 5 using the Patient Global Impression of Change (PGIC) survey. Proportions of patients reporting “much” or “very much” improvement are shown along the y axis.

[0757] FIG. 6 is a graph showing the effects of continuous administration 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 on overall pelvic pain among endometriosis patients treated in accordance with the protocol described in Example 1, below.

[0758] FIG. 7 is a graph showing the effects of continuous administration 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 on dysmenorrhea among endometriosis patients treated in accordance with the protocol described in Example 1, below.

[0759] FIG. 8 is a graph showing the effects of continuous administration 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 on non-menstrual pelvic pain among endometriosis patients treated in accordance with the protocol described in Example 1, below.

[0760] FIG. 9 is a graph showing the effects of continuous administration 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 on dyspareunia among endometriosis patients treated in accordance with the protocol described in Example 1, below.

[0761] FIG. 10 is a graph showing the effects of continuous administration 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 on dyschezia among endometriosis patients treated in accordance with the protocol described in Example 1, below.

[0762] FIG. 11 is a graph showing the effects of continuous administration 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 on difficulty in doing daily activities among endometriosis patients treated in accordance with the protocol described in Example 1, below.

[0763] FIG. 12 is a graph showing the effects of continuous administration 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 on total cholesterol levels among endometriosis patients treated in accordance with the protocol described in Example 1, below. Values along the y axis represent the mean (±95% confidence interval) serum lipid level at each indicated timepoint.

[0764] FIG. 13 is a graph showing the effects of continuous administration 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 on serum triglyceride levels among endometriosis patients treated in accordance with the protocol described in Example 1, below. Values along the y axis represent the mean (±95% confidence interval) serum lipid level at each indicated timepoint.

[0765] FIG. 14 is a graph showing the effects of continuous administration 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 on high-density lipoprotein-cholesterol levels among endometriosis patients treated in accordance with the protocol described in Example 1, below. Values along the y axis represent the mean (±95% confidence interval) serum lipid level at each indicated timepoint.

[0766] FIG. 15 is a graph showing the effects of continuous administration 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 on low-density lipoprotein-cholesterol levels among endometriosis patients treated in accordance with the protocol described in Example 1, below. Values along the y axis represent the mean (±95% confidence interval) serum lipid level at each indicated timepoint.

[0767] FIG. 16 is a graph showing the effects of continuous administration 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 on the ratio of low-density lipoprotein-cholesterol level to high-density lipoprotein-cholesterol level among endometriosis patients treated in accordance with the protocol described in Example 1, below. Values along the y axis represent the mean (±95% confidence interval) lipid ratio at each indicated timepoint.

[0768] FIG. 17 is a graph showing the effects of continuous administration 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 on serum estradiol level among endometriosis patients treated in accordance with the protocol described in Example 1, below. Values along the y axis represent the mean (±95% confidence interval) lipid ratio at each indicated timepoint. FAS denotes the “full analysis set” of patients, which are those that were randomized and treated with the GnRH antagonist for the initial 24 weeks of the study described in Example 1. TEAS denotes the “treatment extension analysis set” of patients, which are those that completed 52 weeks of continuous treatment with the GnRH antagonist.

[0769] FIG. 18 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 3, 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.

[0770] FIG. 19 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 3, 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.

[0771] FIGS. 20A and 20B 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 3, below. Particularly, FIGS. 20A and 20B 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 3, below. Values along the y axis represent the average change from baseline (CFB) in menstrual blood loss. Error bars represent 95% confidence intervals.

[0772] FIGS. 21A and 21B 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 3, below. Particularly, FIGS. 21A and 21B 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. 21A) and the proportion of patients with a score of 1 or less after 24 weeks of treatment (FIG. 21B).

[0773] FIG. 22 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 3, 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 3.

DETAILED DESCRIPTION

[0774] 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.

[0775] 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 SKI2670 and BAY-784, as well as derivatives and variants thereof, among others.

[0776] 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 μg/ml. Using the compositions and methods described herein, a GnRH antagonist may be administered to the patient so as to suppress E2 production 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 μg/ml) may lead to undesirable side effects, such as a reduction in bone mineral density or an elevation in serum cholesterol concentration.

[0777] 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), can be periodically administered to a patient (e.g., a human patient suffering from an estrogen-dependent disease) over extended period of time, such as over the course of a treatment period lasting multiple years. Unexpectedly, administration of the GnRH antagonist over such lengthy treatment periods effectuates a sustained reduction in estrogen-dependent disease symptomology without inducing side effects that are associated with estrogen depletion, such as loss of bone mineral density or increases in serum cholesterol.

[0778] 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

[0779] 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)

##STR00065##

[0780] wherein ring A is a thiophene ring;

[0781] 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;

[0782] m is an integer from 0 to 3;

[0783] ring B is an aryl group or a monocyclic heteroaryl group;

[0784] 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;

[0785] n is an integer from 0 to 2;

[0786] U is a single bond;

[0787] 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;

[0788] 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;

[0789] 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;

[0790] or a pharmaceutically acceptable salt thereof.

[0791] In some embodiments, the ring A is a thiophene ring represented by formula (IIa)

##STR00066##

[0792] 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)

##STR00067##

[0793] 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.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. In some embodiments, each R.sup.A is COOH or pharmaceutically acceptable salt thereof.

[0794] 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:

##STR00068##

[0795] 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:

##STR00069##

[0796] 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.

[0797] 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)

##STR00070##

[0798] 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

[0799] p is an integer from 0 to 3.

[0800] In some embodiments, Y is a substituted benzene ring represented by formula (Va)

##STR00071##

[0801] 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 [00072] (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 [00073] (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 [00074] (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 [00075] (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 [00076] (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), 6.55-6.56 (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 [00077] (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 [00078] (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 [00079] (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 [00080] (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 [00081] (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 [00082] (DMSO-d.sub.6) 3.16 (3H, s), 7.05 (1H, d, J = 7.8 Hz), 7.15-7.45 (4H, m), 7.5-7.8 (1H, m), 7.75-7.81 (3H, m), 12.55 (1H, s) 12 [00083] (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 [00084] (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 [00085] (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 [00086] (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 [00087] (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 [00088] (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 [00089] (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 [00090] (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 [00091] (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 [00092] (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 [00093] (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 [00094] (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 [00095] (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 [00096] (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 [00097] (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 [00098] (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 [00099] (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 [00100] (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 [00101] (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, 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 [00102] (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 [00103] (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 [00104] (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 [00105] (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 [00106] (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 [00107] (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 [00108] (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), 12.63 (1H, s) 38 [00109] (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), 7.05-7.11 (1H, m), 7.15- 7.45 (7H, m), 11.63 (1H, s) 39 [00110] (DMSO-d.sub.6) 1.7 (3H, d, J = 6.6 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 [00111] (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 [00112] (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 [00113] (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 [00114] (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 [00115] (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 [00116] (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 [00117] (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 [00118] (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 [00119] (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 [00120] (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 [00121] (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 [00122] (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 [00123] (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 [00124] (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 [00125] (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 [00126] (DMSO-d.sub.6) 1.65-1.75 (3H, m), 5.7-5.8 (1H, m), 6.95-7.42 (4H, m), 7.2-7.5 (2H, m), 7.93 (1H, d, J = 7.2 Hz), 12.98 (1H, s), 13.85-14.0 (1H, m) 56 [00127] (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 [00128] (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 [00129] (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 [00130] (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 [00131] (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 [00132] (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 [00133] (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 [00134] (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 [00135] (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 [00136] (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 [00137] (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 [00138] (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 [00139] (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 [00140] (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 [00141] (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 [00142] (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 [00143] (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 [00144] (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 [00145] (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 [00146] (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 [00147] (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 [00148] (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 [00149] (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 [00150] (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 [00151] (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 [00152] (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 [00153] (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 [00154] (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 [00155] (DMSO-d.sub.6) 1.65 (6H, s), 7.1-7.5 (10H, m), 11.88 (1H, s), 14.84 (1H, s) 85 [00156] (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 [00157] (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 [00158] (DMSO-d.sub.6) 4.45 (2H, s), 7.25-7.3 (1H, m), 7.3-7.4 (1H, m), 7.4-7.55 (5H, m), 8.0 (1H, s), 12.94 (1H, s), 14.42 (1H, s) 88 [00159] (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 [00160] (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 [00161] (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 [00162] (DMSO-d.sub.6) 3.37 (3H, s), 3.82 (3H, s), 7.1-7.4 10H, m), 11.46 (1H, s) 92 [00163] (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 [00164] (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 [00165] (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 [00166] (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 [00167] (DMSO-d.sub.6) 3.37 (3H, s), 7.15-7.4 (10H, m), 11.89 (1H, s), 14.81 (1H, s) 97 [00168] (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 [00169] (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 [00170] (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 [00171] (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 [00172] (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 [00173] (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 [00174] (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 [00175] (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 [00176] (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 [00177] (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 [00178] (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 [00179] (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 [00180] (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 [00181] (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 [00182] (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 [00183] (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 [00184] (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 [00185] (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 [00186] (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 [00187] (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 [00188] (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 [00189] (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 [00190] (DMSO-d6) 3.32 (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 [00191] (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 [00192] (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 [00193] (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 [00194] (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 [00195] (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 [00196] (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 [00197] (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), 14.92 (1H, s) 127 [00198] (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 [00199] (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 [00200] (DMSO-d6) 3.15 (3H, s), 7.1-7.5 (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 [00201] (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 [00202] (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 [00203] (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 [00204] (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 [00205] (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 [00206] (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 [00207] (DMSO-d6) 3.16 (3H, 2), 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 [00208] (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 [00209] (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 [00210] (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 [00211] (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 [00212] (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 [00213] (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 [00214] (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 [00215] (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 [00216] (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 [00217] (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 [00218] (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 [00219] (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 [00220] (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 [00221] (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 [00222] (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 [00223] (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 [00224] (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 [00225] (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 [00226] (DMSO-d6) 2.85-2.95 (4H, m), 7.1-7.6 (9H, m), 12.04 (1H, s), 14.46 (1H, s) 156 [00227] (DMSO-d6) 2.8-3.0 (4H, m), 7.15-7.45 (9H, m), 12.03 (1H, s), 14.46 (1H, brs) 157 [00228] (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 [00229] (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 [00230] (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 [00231] (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 [00232] (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 [00233] (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 [00234] (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 [00235] (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 [00236] (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 [00237] (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 [00238] (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 [00239] (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 [00240] (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 [00241] (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 [00242] (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 [00243] (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 [00244] (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 [00245] (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 [00246] (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 [00247] (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 [00248] (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 [00249] (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 [00250] (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 [00251] (DMSO-d6) 4.27 (2H, s), 7.15-7.5 (10H, m), 11.93 (1H, s), 14.88 (1H, s) 181 [00252] (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 [00253] (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 [00254] (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 [00255] (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 [00256] (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 [00257] (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 [00258] (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 [00259] (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 [00260] (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 [00261] (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 [00262] (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 [00263] (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 [00264] (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 [00265] (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 [00266] (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 [00267] (DMSO-d6) 3.73 (3H, s), 4.16 (2H, s), 6.75-6.85 (1H, m), 7.1-7.6 (5H, m) 197 [00268] (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 [00269] (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 [00270] (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 [00271] (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 [00272] (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 [00273] (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 [00274] (DMSO-d6) 1.7 (6H, s), 6.89 (1H, s), 7.2-7.4 (6H, m), 7.5-7.7 (3H, m) 204 [00275] (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 [00276] (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 [00277] (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 [00278] (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), 8.0-8.01 (1H, m), 12.0 (1H, s), 14.28 (1H, s) 208 [00279] (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 [00280] (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), 7.85-7.96 (1H, m), 12.0 (1H, s), 14.29 (1H, s) 210 [00281] (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 [00282] (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 [00283] (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 [00284] (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 [00285] (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 [00286] (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, 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(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 [00328] (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 [00329] (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 [00330] (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 [00331] (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 [00332] (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 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7.2-7.3 (1H, m), 7.35-7.4 (1H, m), 11.98 (1H, s), 14.4 (1H, s) 308 [00379] (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 [00380] (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 [00381] (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 [00382] (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 [00383] (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 [00384] (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 [00385] (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 [00386] (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 [00387] (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 [00388] (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 [00389] (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 [00390] (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 [00391] (DMSO-d6) 2.34 (6H, s), 6.03 (2H, s), 7.0-7.45 (7H, m), 12.0 (1H, s), 14.4 (1H, s) 321 [00392] (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 [00393] (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 [00394] (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 [00395] (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 [00396] (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 [00397] (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 [00398] (DMSO-d6) 5.14 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(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 [00431] (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 [00432] (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 [00433] (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 [00434] (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 [00435] (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 [00436] (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 [00437] (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 [00438] (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 [00439] (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 [00440] (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 [00441] (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 [00442] (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 [00443] (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 [00444] (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 [00445] (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 [00446] (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), 14.55 (1H, brs) 376 [00447] (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 [00448] (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 [00449] (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 [00450] (DMSO-d6) 3.82 (3H, s), 5.07 (2H, s), 6.9-7.0 (1H, m), 7.39 (1H, m), 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 [00451] (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 [00452] (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 [00453] (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 [00454] (DMSO-d6) 5.24 (2H, s), 7.39 (1H, s), 7.45-7.55 (1H, m), 7.55-7.45 (4H, m), 12.06 (1H, s), 14.36 (1H, brs) 384 [00455] (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 [00456] (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 [00457] (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 [00458] (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 [00459] (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 [00460] (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 [00461] (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 [00462] (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 [00463] (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 [00464] (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 [00465] (DMSO-d6) 1.58 (3H, d, J = 6.4 Hz), 5.65-5.75 (1H, m), 6.86-6.9 (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 [00466] (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 [00467] (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 [00468] (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 [00469] (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 [00470] (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 [00471] (DMSO-d6) 4.51 (2H, 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 [00472] (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 [00473] (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 [00474] (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 [00475] (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 [00476] (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 [00477] (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 [00478] (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 [00479] (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 [00480] (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 [00481] (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 [00482] (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 [00483] (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 [00484] (DMSO-d6) 3.79 (3H, s), 5.05-5.2 (2H, m), 6.8-6.9 (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 [00485] (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 [00486] (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 [00487] (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 [00488] (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 [00489] (DMSO-d6) 1.13 (3H, t, J = 7.1 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 [00490] (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 [00491] (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 [00492] (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 [00493] (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 [00494] (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 [00495] (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 [00496] (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 [00497] (DMSO-d6) 2.7-2.75 (3H, m), 3.79 (3H, s), 4.2 (2H, s), 6.7-6.8 (1H, m), 7.0-7.5 (1H, m), 7.3-7.4 (2H, m), 7.45-7.55 (2H, m), 12.02 (1H, s), 14.47 (1H, brs) 427 [00498] (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 [00499] (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)

[0802] 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.

##STR00500##

[0803] 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.

##STR00501##

[0804] 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.

[0805] 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.

[0806] 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

[0807] 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)

##STR00502##

[0808] 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—;

[0809] 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;

[0810] R.sub.3 is hydrogen or methyl;

[0811] R.sub.4 is phenyl or C.sub.3-7alkyl;

[0812] R.sub.5 is hydrogen or C.sub.1-4alkyl;

[0813] R.sub.6 is —COOH or an acid isostere; and

[0814] X is C.sub.1-6alkanediyl optionally substituted with from 1 to 3 C.sub.1-6alkyl groups;

[0815] or a pharmaceutically acceptable salt thereof.

[0816] For example, the GnRH antagonist may be the conjugate acid of elagolix, which is represented by formula (VIII),

##STR00503##

[0817] 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.

##STR00504##

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 [00505] HPLC-MS (Cl) m/z 632.2 (MH+), tR = 26.45 2 [00506] MS (Cl) m/z 618.2 (MH+) tR = 1.005 3 [00507] HPLC-MS (Cl) m/z 656.2 (MH+), tR = 2.128 min 4 [00508] MS (Cl) m/z 588.3 (MH+) 5 [00509] HPLC-MS (Cl) m/z 604.1, 606.1 (MH+), tR = 2.511 6 [00510] HPLC-MS (Cl) m/z 604.1, 606.1 (MH+), tR = 26.98 7 [00511] HPLC-MS (Cl) m/z 634.2, 636.2 (MH+), tR-24.925 8 [00512] MS (Cl) m/z 614.1, 616.1 (MH+), tR = 6.550 min 9 [00513] HPLC-MS (Cl) m/z 592.3 (MH+), tR = 2.150 10 [00514] HPLC-MS (Cl) m/z = 556.2 (M + H+), tR = 2.354 11 [00515]

Thieno[2,3d]pyrimidines

[0818] 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)

##STR00516##

[0819] 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;

[0820] R.sup.b is an optionally substituted nitrogen-containing heterocyclic group;

[0821] R.sup.c is an optionally substituted amino group;

[0822] R.sup.d is an optionally substituted aryl group;

[0823] p is an integer from 0 to 3; and

[0824] q is an integer from 0 to 3;

[0825] or a pharmaceutically acceptable salt thereof.

[0826] In some embodiments, the GnRH antagonist is a thieno[2,3d]pyrimidine compound represented by formula (XI)

##STR00517##

[0827] wherein R.sup.1 is C.sub.1-4alkyl;

[0828] 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;

[0829] R.sup.3 is C.sub.1-4alkyl;

[0830] 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

[0831] n is an integer from 1 to 4;

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;

[0832] or a pharmaceutically acceptable salt thereof. For example, the GnRH antagonist may be a compound represented by formula (XII), below.

##STR00518##

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 [00519] .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 [00520] .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 [00521] .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 [00522] .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 [00523] .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 (1 H, m). 6 [00524] .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 Hz), 7.15-7.35 (6H, m), 7.46 (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 [00525] 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). [00526] 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 [00527] .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 [00528] 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). [00529] 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 [00530] .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 [00531] 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). [00532] 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 [00533] .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 [00534] .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 [00535] .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 [00536] .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 [00537] .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 [00538] .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 [00539] .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 [00540] .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 [00541] .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 [00542] .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 [00543] .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 [00544] .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 [00545] .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 [00546] .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 [00547] .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 [00548] .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 [00549] .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 [00550] .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 [00551] .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 [00552] 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). [00553] 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 [00554] .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 [00555] .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 [00556] .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 [00557] .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 [00558] .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 [00559] .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 [00560] .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 [00561] .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 [00562] .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 [00563] .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 (1 H, 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 [00564] .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 [00565] .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), 7.54 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.64 (1H, s), 7.98 (1H, dd, J = 2.7 Hz, 8.4 Hz), 8.72 (1H, d, J = 2.7 Hz). 44 [00566] .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 [00567] .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 [00568] .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 [00569] .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 [00570] .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 [00571] .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 [00572] .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 [00573] .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 [00574] .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 [00575] .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 [00576] .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 [00577] .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 [00578] .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 [00579] .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 [00580] .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 [00581] .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 [00582] .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 [00583] .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 [00584] .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 [00585] .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 [00586] .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 [00587] .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 [00588] .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 [00589] .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 [00590] .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 [00591] .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 J = 8.6 Hz), 7.61 (1H, s), 7.66 (2H, d, J = 8.6 Hz). 70 [00592] .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 [00593] .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 [00594] .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 [00595] .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 [00596] .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 (1 H, 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 [00597] .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 [00598] .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 [00599] .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 [00600] .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 [00601] .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, m), 7.46-7.51 (5H, m), 7.61 (1H, s), 8.42 (1H, d, J = 5.7 Hz). 80 [00602] .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 [00603] .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 [00604] .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 [00605] .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 [00606] .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

[0833] 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

[0834] 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).

[0835] 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.

[0836] 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.

[0837] 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.

[0838] Despite the utility of add-back therapy, periodic administration of an estrogen and/or progestin can be associated with adverse side effects (see, for example, Activella® Physician Insert, Novo Nordisk Inc. (Princeton, N.J.), December 2006, the disclosure of which is incorporated herein by reference in its entirety. The present disclosure is based, in part, on the surprising and advantageous discovery that add-back therapy can be safely administered to patients, such as patients suffering from an estrogen-dependent disease described herein, over the course of extended treatment periods when administered in combination with a GnRH antagonist (particularly a thieno[3,4d]pyrimidine compound, 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 a pharmaceutically acceptable salt thereof).

Effects of GnRH Antagonist Therapy on Serum Lipids

[0839] The present disclosure is based, at least in part, on the discovery that GnRH antagonists, particularly thieno[3,4d]pyrimidine compounds, 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 a pharmaceutically acceptable salt thereof (e.g., the choline salt thereof) can be administered to a patient having an estrogen-dependent disease over extended periods of time without inducing a significant increase in serum lipid levels. The compositions and methods of the disclosure thus provide the benefit of being able to alleviate the symptoms and the underlying pathology of an estrogen-dependent disease without causing an elevation in total cholesterol and low-density lipoprotein-cholesterol.

[0840] In addition, the compositions and methods of the disclosure can also be used to monitor a patient's concentration one or more endogenous serum lipids over the course of a treatment period during which the patient is periodically administered a GnRH antagonist. For example, in some embodiments of the disclosure, a method is provided in which a patient is periodically treated with a GnRH antagonist over the course of a treatment period (e.g., a treatment period having a duration of at least 1 year) so as to treat, or alleviate the symptoms of, an estrogen-dependent disease, such as endometriosis, uterine fibroids, adenomyosis, or rectovaginal endometriosis. In some embodiments, the method includes monitoring the patient's level of total cholesterol during the treatment period. The method may further include determining that the patient does not exhibit an increase (e.g., a significant increase) in total cholesterol relative to a measurement of the patient's total cholesterol obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period). For example, the method may include monitoring the patient's level of total cholesterol after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in total cholesterol (e.g., of greater than 20% (e.g., determining that the patient does not exhibit an increase in total cholesterol of greater than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%)) relative to a measurement of the patient's total cholesterol obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0841] In some embodiments, the method includes monitoring the patient's low-density lipoprotein-cholesterol level during the treatment period. The method may further include determining that the patient does not exhibit an increase (e.g., a significant increase) in low-density lipoprotein-cholesterol relative to a measurement of the patient's low-density lipoprotein-cholesterol level obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period). For example, the method may include monitoring the patient's low-density lipoprotein-cholesterol level after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level (e.g., of greater than 40% (e.g., determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level of greater than 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%)) relative to a measurement of the patient's low-density lipoprotein-cholesterol level obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0842] In some embodiments, the method includes monitoring the patient's low-density lipoprotein-cholesterol level after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level to a level greater than 160 mg/dl (e.g., determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level to a level greater than 160 mg/dl, 159 mg/dl, 158 mg/dl, 157 mg/dl, 156 mg/dl, 155 mg/dl, 154 mg/dl, 153 mg/dl, 152 mg/dl, 151 mg/dl, 150 mg/dl, 149 mg/dl, 148 mg/dl, 147 mg/dl, 146 mg/dl, 145 mg/dl, 144 mg/dl, 143 mg/dl, 142 mg/dl, 141 mg/dl, 140 mg/dl, 139 mg/dl, 138 mg/dl, 137 mg/dl, 136 mg/dl, 135 mg/dl, 134 mg/dl, 133 mg/dl, 132 mg/dl, 131 mg/dl, or 130 mg/dl), and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0843] In some embodiments, the method includes monitoring the patient's low-density lipoprotein-cholesterol level after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in low-density lipoprotein-cholesterol level from a level less than 160 mg/dl (e.g., from a level less than 160 mg/dl, 159 mg/dl, 158 mg/dl, 157 mg/dl, 156 mg/dl, 155 mg/dl, 154 mg/dl, 153 mg/dl, 152 mg/dl, 151 mg/dl, 150 mg/dl, 149 mg/dl, 148 mg/dl, 147 mg/dl, 146 mg/dl, 145 mg/dl, 144 mg/dl, 143 mg/dl, 142 mg/dl, 141 mg/dl, 140 mg/dl, 139 mg/dl, 138 mg/dl, 137 mg/dl, 136 mg/dl, 135 mg/dl, 134 mg/dl, 133 mg/dl, 132 mg/dl, 131 mg/dl, or 130 mg/dl) to a level greater than 190 mg/dl, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0844] In some embodiments, the method includes monitoring the patient's ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol during the treatment period. The method may further include determining that the patient does not exhibit an increase (e.g., a significant increase) in their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol relative to a measurement of their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period). In some embodiments, the method includes monitoring the patient's ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol (e.g., of greater than 40% (e.g., determining that the patient does not exhibit an increase in their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol of greater than 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%)) relative to a measurement of their ratio of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0845] In some embodiments, the method includes monitoring the patient's serum triglyceride level during the treatment period. The method may further include determining that the patient does not exhibit an increase (e.g., a significant increase) in serum triglyceride level relative to a measurement of the patient's triglyceride level obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period). In some embodiments, the method includes monitoring the patient's serum triglyceride level after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in serum triglyceride level (e.g., of greater than 50% (e.g., determining that the patient does not exhibit an increase in serum triglyceride level of greater than 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%)) relative to a measurement of the patient's triglyceride level obtained prior to the treatment period, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0846] In some embodiments, the method includes monitoring the patient's serum triglyceride level during the treatment period, determining that the patient does not exhibit an increase in serum triglyceride level to a level greater than 200 mg/dl, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period). In some embodiments, the method includes monitoring the patient's serum triglyceride level after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in serum triglyceride level to a level greater than 200 mg/dl, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0847] In some embodiments, the method includes monitoring the patient's serum triglyceride level during the treatment period, determining that the patient does not exhibit an increase in serum triglyceride level from a level less than 300 mg/dl to a level greater than 500 mg/dl, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period). In some embodiments, the method includes monitoring the patient's serum triglyceride level after from about 6 weeks to about 52 weeks (e.g., after about 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks) of treatment with the GnRH antagonist, determining that the patient does not exhibit an increase in serum triglyceride level from a level less than 300 mg/dl to a level greater than 500 mg/dl, and continuing to administer (e.g., periodically) the GnRH antagonist to the patient during the treatment period (e.g., for the remainder of the treatment period).

[0848] Assays that can be used to assess the level of total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and/or triglycerides in a patient (e.g., in a sample, such as a blood serum sample, obtained from the patient are described, for example, in U.S. Pat. Nos. 9,051,599; 5,814,472; and 5,215,886, the disclosures of each of which are incorporated herein by reference as they pertain to compositions and methods for lipid detection.

Methods of Treating Estrogen-Dependent Diseases

[0849] 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.

[0850] 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.

[0851] 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.

[0852] 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

[0853] 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

[0854] 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

[0855] 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

[0856] 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

[0857] 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.

[0858] 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.

[0859] The GnRH antagonists described herein may be administered to a patient a plurality of times over the course of a treatment period, such as a treatment period of at least 52 weeks, as described herein.

Pharmaceutical Compositions

[0860] 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).

[0861] 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.

[0862] 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

[0863] 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

[0864] 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. The method may feature, for example, any one or more of the method steps recited herein.

EXAMPLES

[0865] 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. GnRH Antagonist Therapy Alleviates Estrogen-Dependent Disease Symptoms without Inducing Significant Bone Mineral Density Loss, Even when Administered Over an Extended Treatment Period

Objective

[0866] Endometriosis, an estrogen-dependent gynecological condition defined as the presence of endometrial-like tissue outside the uterus, is one of the most common gynecological diseases, affecting about 1 in 10 women during their reproductive years. A chronic, inflammatory reaction, induced by the ectopic endometrial cells, results in a variety of pain symptoms including dysmenorrhea (DYS), non-menstrual pelvic pain (NMPP), overall pelvic pain (OPP), dyspareunia, and dyschezia. Complete suppression of estrogen (E2) can reduce estrogen-associated pain (EAP), but may also result in substantial bone mineral density (BMD) loss. The purpose of the experiments described in this example was to evaluate the effects of prolonged GnRH antagonist treatment on patients suffering from an estrogen-dependent disease, such as endometriosis.

Methods

[0867] This example describes the results of a Phase 2b, double-blind, randomized, placebo-controlled, multicenter, 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 52-week treatment period. After 52 weeks of treatment, the patients were monitored for severity of disease symptoms and bone mineral density.

[0868] Participants were women aged 18 to 45 years with surgically confirmed endometriosis and moderate to severe EAP. Women with a history of osteoporosis or other metabolic bone disease were excluded. Certain subjects completing an initial 24-week treatment period were invited to continue in a treatment extension phase, resulting in a total of up to 52 weeks of treatment. Subjects that completed 52 weeks of treatment constituted the treatment extension analysis set (TEAS) of patients.

[0869] Patients were randomized to either (i) 50 mg/day, 75, mg/day, 100 mg/day, or 200 mg/day 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, administered as a choline salt, or (ii) matching placebo. Patients assigned to the placebo cohort were switched to 100 mg/day 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 at week 12.

[0870] Patients that received 75 mg/day of compound (VI) were divided into two groups: those that received a fixed dose (FD) of compound (VI) at 75 mg/day throughout the 52-week treatment period, and those that received a titrated dose (TD) of 75 mg/day of compound (VI) for the first 12 weeks of the treatment period, followed by a daily dose of either 50 mg, 75 mg, or 100 mg of the compound depending on each patient's serum E2 concentration after 4 weeks or 8 weeks of treatment. Dosages from week 12 onward for patients in the 75 mg/day TD cohort were determined according to the following schedule:

TABLE-US-00004 TABLE 7 Dosing schedule for patients in the 75 mg/day TD cohort Mean Serum E2 Initial Daily Concentration New Daily Dosage of Dosage of at Week 4 or 8 of the Compound (VI) from Compound (VI) Treatment Period Week 12 Onward 75 mg/day   <20 pg/ml 50 mg/day 75 mg/day 20-50 pg/ml 75 mg/day 75 mg/day   >50 pg/ml 100 mg/day 

[0871] Patients that were treated with 200 mg/day of the compound at the 24-week timepoint in the treatment period were switched to 100 mg/day for the final 24 weeks of the study.

[0872] EAP was assessed using questionnaires in a daily electronic diary. Mean 28-day scores for pelvic pain were calculated at each month up to 12 months and compared to baseline. Efficacy was assessed as the proportion of patients who had at least 30% reduction in OPP at 12 weeks. DYS, NMPP, dyspareunia, and dyschezia were also assessed.

[0873] Quality of life endpoints included a measurement of each patient's difficulty of doing daily activities, Patient Global Impression of Change (PGIC), and Endometriosis Health Profile-30 (EHP-30) score.

[0874] Another goal of this study was to monitor changes in patients' levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and serum triglycerides, as well as patients' ratios of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol (LDL-C/HDL-C) throughout the duration of the treatment period. Accordingly, patients were evaluated for changes in the foregoing serum lipids at various timepoints throughout the course of the study. Patients were not required to be fasted for serum lipid analysis except at baseline.

[0875] Patients were not required to take calcium or vitamin D supplements. Patients were allowed to use analgesics for treatment of pelvic pain.

[0876] BMD of the femoral neck, total hip and lumbar spine was assessed by DXA at baseline and after 12 and 24 weeks of treatment. Reading of DXA scans and monitoring of scan quality, including cross-calibration between sites, was centralized.

Results

[0877] A series of n=327 human female patients having clinically-diagnosed endometriosis were randomly assigned to, and treated in, cohorts in which patients were administered placebo or the GnRH antagonist in a once-daily amount of 50 mg/day, 100 mg/day, 75 mg/day (FD or TD), or 200 mg/day. Of these, 253 subjects (77.1%) completed the initial 24-week treatment, of which 176 subjects participated in the treatment extension phase, resulting in a total of 52 weeks of continuous treatment. 108 subjects (60.0%) completed the full treatment period of 52 weeks.

[0878] Baseline characteristics of randomized and treated subjects are shown in Table 8, below.

TABLE-US-00005 TABLE 8 Demographics and baseline characteristics Placebo 50 mg 75 mg FD 75 mg TD 100 mg 200 mg (N = 53) (N = 49) (N = 56) (N = 58) (N = 51) (N = 56) Median age-   32 (22-45)  31 (22-43)  33 (18-45) 31.5 (21-45)   33 (22-44)    31 (19-45) years (range) Mean BMI- 27 (7.6)  26 (7.7)  26 (6.0)  27 (7.2)  26 (6.0)  25 (5.5) kg/m.sup.2 (SD) Race: % White, 92.5, 7.5 95.9, 4.1 91.1, 10.7 86.2, 13.8 94.1, 7.8 94.6, 7.1 % Black Mean OPP score 1.8 (0.46) 1.7 (0.49) 1.7 (0.47) 1.7 (0.49) 1.8 (0.46) 1.7 (0.51) (0-3 VRS) (SD) Mean DYS score 2.1 (0.44) 2.1 (0.39) 2.1 (0.43) 2.1 (0.45) 2.1 (0.40) 2.1 (0.42) (0-3 VRS) (SD) Mean NMPP 1.7 (0.50) 1.5 (0.56) 1.6 (0.53) 1.5 (0.56) 1.7 (0.50) 1.6 (0.58) score (0-3 VRS) (SD) Mean 1.7 (0.80) 1.4 (0.82) 1.7 (0.86) 1.7 (0.89) 1.6 (0.84) dyspareunia score (0-3 VRS) (SD) Mean dyschezia 5.9 (2.40) 4.6 (2.84) 5.8 (2.51) 5.9 (2.65) 5.4 (2.56) score (0-10 NRS) (SD) Mean HDL-C 59 (15)  67 (19)  67 (19)  66 (15)  64 (15)  65 (15)  level (mg/dl) (SD) Mean LDL-C 109 (31)   103 (24)   107 (30)   106 (29)   104 (25)   102 (22)   level (mg/dl) (SD) Mean 105 (64)   101 (97)   96 (47)  105 (67)   107 (72)   96 (60)  triglyceride level (mg/dl) (SD) Ratio of mean 2.0 (0.82) 1.7 (0.68) 1.8 (0.74) 1.7 (0.76) 1.7 (0.59) 1.6 (0.51) LDL-C level to mean HDL-C level

[0879] Therapeutic Effects of GnRH Antagonist Treatment

[0880] After 52 weeks of continuous, once-daily treatment, administration of the GnRH antagonist ceased. Patients treated with 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 exhibited a sustained reductions in overall pelvic pain, dysmenorrhea, non-menstrual pelvic pain, dyspareunia, and dyschezia, as well as improvements in quality of life. For example, GnRH antagonist-treated patients exhibited an overall reduction in overall pelvic pain, as shown in Table 9, below, for patients treated with 75 mg/day or 200 mg/day of the GnRH antagonist. 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 following the cessation of GnRH antagonist treatment.

TABLE-US-00006 TABLE 9 Overall Pelvic Pain Responder Rates (Defined as 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 52 weeks of GnRH 69.2% 82.4% antagonist treatment

[0881] In addition to exhibiting a sustained reduction in disease symptomology, patients that were treated with the GnRH antagonist over the full 52-week treatment period did not exhibit a significant decrease in bone mineral density. Table 10, below, depicts the mean change in bone mineral density from a baseline, pre-treatment measurement following completion of the 52-week treatment period for patients treated with 75 mg/day or 200 mg/day 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-00007 TABLE 10 Bone mineral density following 52-week treatment period Bone Mineral Density (Mean % change from baseline) Dose (Once-daily) 75 mg 200 mg After 52 weeks of GnRH −1.139% −2.188% antagonist treatment

[0882] Table 11, below, and FIGS. 3-11 and 17 provide a summary of the effects of 52 weeks of continuous treatment with 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 on patients from all treatment groups. As shown in Table 11, after 12 weeks of treatment, patients exhibited a substantial reduction in symptomology, including OPP, DYS, and NMPP, particularly for doses of 75 mg/day and above compared to placebo. These effects were generally maintained or increased at the 24-weeks and 52-weeks timepoints. Patients in the 200 mg/day treatment group exhibited particularly strong improvements in dyspareunia and dyschezia scores at the 12-week timepoint, which were maintained or increased at 24 and 52 weeks.

[0883] Mean OPP 4-week scores from baseline to week 52 are shown in FIG. 1. As this figure shows, pain scores generally decreased over time, with the highest decreases in the 200 mg/day group and the lowest in placebo. Decreases in pain scores continued after week 12, and were relatively stable after week 24.

[0884] Mean BMD losses, as assessed in the lumbar spine, for each treatment group after 24 weeks and 52 weeks of continuous GnRH antagonist treatment are reported in FIG. 2. As shown in the figure, after 23 weeks of treatment, BMD losses were generally less than 1% at doses of 50 mg/day, 75 mg/day, and 100 mg/day, and were 2.6% for the 200 mg/day treatment group, within the safe limit of 5%. A similar pattern was observed after 52 weeks of continuous treatment. BMD changes in the femur and hip were similar to those observed in the lumbar spine, but were generally smaller.

TABLE-US-00008 TABLE 11 Pain assessments after 12 weeks (12 w), 24 weeks (24 w), and 52 weeks (52 w) of continuous GnRH antagonist treatment Placebo.sup.‡ 50 mg 75 mg 100 mg 200.sup.†/100 mg N 12 w 53 49 56   51   56   24 w 40 48   39   44   52 w 30 36   22   30   % 12 w 34.5 49.4  61.5*  56.4*  56.3* responders 24 w 52.5 70.8 66.7 77.3 OPP 52 w 66.7 69.2 53.8 82.4 % 12 w 28.5 43.3  68.2*  68.6*  78.9* responders 24 w 47.5 58.3 82.1 84.1 DYS 52 w 50 69.2 69.2 64.7 % 12 w 37.1 46.2  58.5*  61.5* 47.7 responders 24 w 50 72.9 64.1 72.7 NMPP 52 w 66.7 69.2 53.8 76.5 Dyspareunia 12 w −0.4 (0.9) −0.6 (0.7) −0.7 (0.8) −0.7 (0.9)  −0.8 (1.1)* Mean (SD) 24 w −0.7 (0.8) −0.7 (0.8) −0.6 (0.8) −1.0 (1.0) Change 52 w −0.5 (1.1) −0.9 (0.8) −0.7 (1.1) −0.9 (0.9) from baseline (CFB) Dyschezia 12 w −0.7 (1.7) −1.4 (1.7)  −2.1 (2.5)*  −2.0 (1.8)*  −1.7 (2.3)* Mean (SD) 24 w −1.5 (2.1) −2.2 (2.5) −2.0 (2.3) −2.5 (2.6) CFB 52 w −2.3 (1.8) −2.1 (2.9) −2.9 (3.1) −2.6 (2.7) .sup.‡PBO only to 12 w; .sup.†Subjects randomized to 200 mg received 100 mg from 24 to 52 w; *p < 0.05 compared to PBO.

[0885] As shown in Tables 9-11, patients that were treated with the GnRH antagonist over the year-long treatment period exhibited a reduction in overall pelvic pain symptoms without incurring a significant loss of bone mineral density, as average bone mineral density losses were less than 5%.

[0886] Serum Lipid Levels

[0887] Patients treated with the GnRH antagonist exhibited minor percentage increases in LDL-C level, HDL-C level, LDL-C/HDL-C ratio, and serum triglyceride levels, which did not increase further after 24 weeks and 52 weeks of continuous treatment. Except for LDL-C/HDL-C ratio, the largest increases were observed in the 200 mg/day cohort. In this group, after 24 weeks of treatment, patients, on average, exhibited approximately an 8% increase in HDL-C level, a 10% increase in LDL-C level, and a 24% increase in serum triglyceride level relative to baseline. After 52 weeks of treatment, patients exhibited, on average, approximately a 4% increase in HDL-C level, a 10% increase in LDL-C level, and a 32% increase in serum triglyceride level relative to baseline.

[0888] Notably, a fasting state was not required for blood sampling except at screening. This may have impacted the triglyceride results, as shown by a 20% increase in the placebo group at Week 12.

[0889] In all treatment groups, the percentage of women with LDL-C levels exceeding 160 mg/dL or serum triglyceride levels exceeding 200 mg/dL was less than 10% at most time points.

[0890] There were no shifts in LDL-C levels from ≤130 mg/dL at baseline to 190 mg/dL at week 24 or 52. A shift in LDL-C level from ≤160 mg/dL at baseline to 190 mg/dL was reported for one subject in the 100 mg/day cohort at week 24, and for one subject in the placebo/100 mg cohort at week 52. One subject in the 75 mg TD cohort exhibited a shift in serum triglyceride level from ≤300 mg/dL at baseline to >500 mg/dL at Week 24. There were no such increases in serum triglyceride level observed at week 52.

[0891] The overall effects of GnRH antagonist treatment on patients' serum lipid levels over the course of this study are summarized in Table 12, below, and in FIGS. 12-16.

TABLE-US-00009 TABLE 12 Effects of GnRH antagonist treatment on serum lipid levels Placebo 50 mg 75 mg FD 75 mg TD 100 mg 200 mg Cohort Cohort Cohort Cohort Cohort Cohort Patients with LDL-C level > 160 mg/dl-N (%) Baseline 3 (5.5) 0 (0)   2 (3.4) 4 (7.1) 2 (3.8) 0 (0)   Week 24 4 (7.3) 1 (2.0) 2 (3.4) 4 (7.1) 3 (5.8) 1 (1.8) Patients showing an increase in LDL-C level from ≤ 130-160 mg/dl to ≥ 190 mg/dl-N (%) Week 24 0 (0)   0 (0)   0 (0)   0 (0)   1 (1.9) 0 (0)   Patients with serum triglyceride level > 200 mg/dl-N (%) Baseline 4 (7.3) 2 (4.1) 2 (3.4)  6 (10.7) 5 (9.6) 4 (7.0) Week 24 4 (7.3)  5 (10.2) 2 (3.4) 4 (7.1) 5 (9.6) 3 (5.3) Patients showing an increase in serum triglyceride level from < 300 mg/dl to > 500 mg/dl-N (%) Week 24 0 (0)   0 (0)   0 (0)   1 (1.8) 0 (0)   0 (0)   TEAS N = 29 N = 30 N = 36 N = 29 N = 22 N = 30 Patients with LDL-C level > 160 mg/dl-N (%) Week 52  5 (17.2) 1 (3.3)  4 (11.1) 2 (6.9) 0 (0)   0 (0)   Patients showing an increase in LDL-C level from < 160 mg/dl to > 190 mg/dl-N (%) Week 52 1 (3.4) 0 (0)   0 (0)   0 (0)   0 (0)   0 (0)   Patients with serum triglyceride level > 200 mg/dl-N (%) Week 52  6 (20.7)  3 (10.0) 1 (2.8) 1 (3.4) 2 (9.1) 1 (3.3) Patients showing an increase in serum triglyceride level from < 300 mg/dl to > 500 mg/dl-N (%) Week 52 0 (0)   0 (0)   0 (0)   0 (0)   0 (0)   0 (0)  

CONCLUSIONS

[0892] Taken together, the results of these experiments demonstrate that patients administered a GnRH antagonist represented by formula (VI) over the course of an extended, year-long treatment period exhibit a sustained alleviation in symptoms of an estrogen-dependent disease. Patients that were administered the compound at a dose of from 75 mg/day to 200 mg/day exhibited particularly substantial reductions in overall pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and non-menstrual pelvic pain.

[0893] Patients that underwent 52 weeks of treatment with compound (VI) generally exhibited a reduction in endometriosis-associated pain after 24 weeks of treatment, and the reduction was maintained with continued treatment through the conclusion of the one-year treatment period. Likewise, quality of life measurements, as assessed by way of patients' PGIC scores, difficulty in performing daily activities, and EHP-30 scores showed maintained improvements after 52 weeks of treatment.

[0894] Advantageously, the patients treated with the GnRH antagonist over the lengthy treatment period did not exhibit a significant reduction in bone mineral density, as average bone mineral density losses at the end of the 52-week treatment period remained well within the safe limit of 5%.

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

[0895] 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.

[0896] The GnRH antagonist may be administered to the patient periodically over a treatment period of, for example, 52 or more weeks (e.g., a treatment period lasting 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 95 weeks, 96 weeks, 97 weeks, 98 weeks, 99 weeks, 100 weeks, 101 weeks, 102 weeks, 103 weeks, 104 weeks, 105 weeks, 106 weeks, 107 weeks, 108 weeks, 109 weeks, 110 weeks, 111 weeks, 112 weeks, 113 weeks, 114 weeks, 115 weeks, 116 weeks, 117 weeks, 118 weeks, 119 weeks, 120 weeks, 121 weeks, 122 weeks, 123 weeks, 124 weeks, 125 weeks, 126 weeks, 127 weeks, 128 weeks, 129 weeks, 130 weeks, 131 weeks, 132 weeks, 133 weeks, 134 weeks, 135 weeks, 136 weeks, 137 weeks, 138 weeks, 139 weeks, 140 weeks, 141 weeks, 142 weeks, 143 weeks, 144 weeks, 145 weeks, 146 weeks, 147 weeks, 148 weeks, 149 weeks, 150 weeks, or more). 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. The physician may then determine that the patient does not exhibit a substantial reduction in bone mineral density. For example, the physician may determine that, at the conclusion of the treatment period, the patient exhibits a loss of bone mineral density of no greater than 5% (e.g., a reduction in bone mineral density of from 0.1% to 5%, such as a loss of bone mineral density of 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5%).

[0897] 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.

[0898] 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. 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

[0899] 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

[0900] 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 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.

[0901] 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 13, below.

TABLE-US-00010 TABLE 13 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/Black/ 33/63/4 95/5/0 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

[0902] 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

[0903] 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).

[0904] 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.

[0905] To evaluate the safety of compound (VI), patients' bone mineral density levels were measured at baseline and at various timepoints during the studies.

Results

[0906] 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 580 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.

[0907] 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. 18-21.

[0908] 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. 22, 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).

[0909] The efficacy of compound (VI) in the PRIMROSE 1 and PRIMROSE 2 studies is summarized in Table 14, below.

TABLE-US-00011 TABLE 14 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) Endpoint PRIM- PRIM- PRIM- PRIM- ROSE 1 ROSE 2 ROSE 1 ROSE 2 Reduction in p = 0.002 p < 0.001 p < 0.001 p < 0.001 menstrual blood p = 0.001 p < 0.001 p < 0.001 p < 0.001 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 in pain p < 0.001 p = 0.002 p < 0.001 p < 0.001 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

[0910] 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

[0911] 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.

[0912] 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.

[0913] Other embodiments are within the claims.