# US 2023/0067378 A1 · Compositions and methods for the treatment of estrogen-dependent disorders

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- Number: US 2023/0067378 A1
- Document ID: US20230067378A1
- Status: Published application
- Kind: A1
- Application number: 17/291,192
- Filed: 2019-11-06
- Published: 2023-03-02
- Earliest claimed: 2018-11-07
- Assignees: ObsEva S.A.
- Applicants: ObsEva S.A.
- Inventors: Jean-Pierre GOTTELAND; Ernest LOUMAYE; Oliver POHL
- Web page: https://patentgrep.com/patent/US20230067378A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K 31/567: substituted in position 17 alpha, e.g. mestranol, norethandrolone
- A61K 31/57: substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K 31/585: containing lactone rings, e.g. oxandrolone, bufalin
- A61P 5/24: of the sex hormones
- A61P 5/30: Oestrogens
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/12: for climacteric disorders
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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, in combination with periodic add-back therapy, thereby preventing bone mineral density loss that may otherwise accompany estrogen depletion effectuated by GnRH antagonist activity. Advantageously, using the dosing schedules of the present disclosure, the periodic administration the GnRH antagonist and add-back therapy may commence together, such as on the same day.

## Claims

### Claim 1

A method of treating an estrogen-dependent disease in a human patient in need thereof, the method comprising periodically administering to the patient therapeutically effective amounts of a gonadotropin-releasing hormone (GnRH) antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 2 (depends on 1)

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

### Claim 3

A method of reducing the volume of menstrual blood loss a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 4

A method of inducing amenorrhea in a human patient diagnosed as having uterine fibroids, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 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 therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 6 (depends on 1)

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

### Claim 7

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 therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 8

A method of reducing pelvic pain in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 9

A method of reducing dysmenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 10

A method of reducing dyspareunia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 11

A method of reducing dyschezia in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 12

A method of reducing uterine bleeding in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 13

A method of inducing amenorrhea in a human patient diagnosed as having endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 14 (depends on 1)

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

### Claim 15

A method of reducing uterine volume in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 16

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 therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 17

A method of reducing pelvic pain in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 18

A method of reducing dysmenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 19

A method of reducing dyspareunia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 20

A method of reducing dyschezia in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 21

A method of reducing uterine tenderness in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 22

A method of reducing uterine bleeding in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 23

A method of inducing amenorrhea in a human patient diagnosed as having adenomyosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 24 (depends on 1)

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

### Claim 25

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 therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 26

A method of reducing the volume of one or more type III rectovaginal endometriosis nodes in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 27

A method of reducing pelvic pain in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 28

A method of reducing dysmenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 29

A method of reducing dyspareunia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 30

A method of reducing dyschezia in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 31

A method of reducing uterine bleeding in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 32

A method of inducing amenorrhea in a human patient diagnosed as having rectovaginal endometriosis, the method comprising periodically administering to the patient therapeutically effective amounts of a GnRH antagonist and add-back therapy, wherein administration of the GnRH antagonist and administration of the add-back therapy begin on the same day.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The method of any one of claims 1-32, wherein the GnRH antagonist is a compound represented by formula (I)
wherein ring A is a thiophene ring;
each RA 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, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, wherein W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 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 RB is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW4, COW4, COOW4, or CONW5W6, wherein W4 to W6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W5 and W6 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 —SO2-L-Y, wherein L is an optionally substituted lower alkylene group;
Y is a group represented by Z or —NW7W8, wherein W7 and W8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W7 and W8 are not simultaneously hydrogen atoms, or W7 and W8 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.

### Claim 34 (depends on 33)

The method of claim 33, wherein the ring A is a thiophene ring represented by formula (IIa)

### Claim 35 (depends on 33, 34)

The method of claim 33 or 34, wherein m is 1.

### Claim 36 (depends on 35)

The method of claim 35, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb)

### Claim 37 (depends on 33, 34, 35, 36)

The method of any one of claims 33-36, wherein each RA is independently a halogen atom, an optionally substituted lower alkyl group, COOW1, or CONW2W3, wherein W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.

### Claim 38 (depends on 37)

The method of claim 37, wherein each RA is COOH or pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 33, 34, 35, 36, 37, 38)

The method of any one of claims 33-38, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

### Claim 40 (depends on 39)

The method of claim 39, wherein the ring B is represented by a formula selected from the group consisting of:

### Claim 41 (depends on 33, 34, 35, 36, 37, 38, 39, 40)

The method of any one of claims 33-40, wherein n is 2.

### Claim 42 (depends on 41)

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

### Claim 43 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The method of any one of claims 33-42, wherein each RB is independently a halogen atom, an optionally substituted lower alkyl group, or OW4, wherein each W4 is independently a hydrogen atom or an optionally substituted lower alkyl group.

### Claim 44 (depends on 43)

The method of claim 43, wherein each RB is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

### Claim 45 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The method of any one of claims 33-44, wherein U is a single bond.

### Claim 46 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

The method of any one of claims 33-45, wherein X is a group represented by —O-L-Y.

### Claim 47 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46)

The method of any one of claims 33-46, wherein L is a methylene group.

### Claim 48 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The method of any one of claims 33-47, wherein Y is an optionally substituted benzene ring represented by formula (V)
wherein each RC is independently a halogen atom, an optionally substituted lower alkyl group, or OW9, wherein each W9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and
p is an integer from 0 to 3.

### Claim 49 (depends on 48)

The method of claim 48, wherein Y is a substituted benzene ring represented by formula (Va)

### Claim 50 (depends on 33)

The method of claim 33, wherein the compound is represented by formula (Ia)
wherein each RA 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, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, wherein W3 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 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 RB is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW4, COW4, COOW4, or CONW5W6, wherein W4 to W6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W5 and W6 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 RC is independently a halogen atom, an optionally substituted lower alkyl group, or OW9, wherein each W9 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.

### Claim 51 (depends on 50)

The method of claim 50, wherein the compound is represented by formula (Ib)

### Claim 52 (depends on 51)

The method of claim 51, wherein the compound is represented by formula (Ic)
or a pharmaceutically acceptable salt thereof.

### Claim 53 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52)

The method of claim any one of claims 33-52, wherein the compound is represented by formula (VI)
or a pharmaceutically acceptable salt thereof.

### Claim 54 (depends on 53)

The method of claim 53, wherein the compound is administered to the patient in the form of the choline salt of (VI), choline 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4d]pyrimidine-5-carboxylate.

### Claim 55 (depends on 54)

The method of claim 54, wherein the compound is in a crystalline state.

### Claim 56 (depends on 55)

The method of claim 55, 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 26.2θ.

### Claim 57 (depends on 55, 56)

The method of claim 55 or 56, wherein the compound exhibits 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.

### Claim 58 (depends on 55, 56, 57)

The method of any one of claims 55-57, wherein the compound exhibits 19F solid-state NMR peaks centered at about −151.8 ppm, −145.2 ppm, and −131.6 ppm.

### Claim 59 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The method of any one of claims 33-58, wherein the compound is orally administered to the patient.

### Claim 60 (depends on 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59)

The method of any one of claims 33-59, wherein the compound is administered to the patient one or more times per day, week, or month.

### Claim 61 (depends on 60)

The method of claim 60, wherein the compound is administered to the patient one or more times daily.

### Claim 62 (depends on 61)

The method of claim 61, wherein the compound is administered to the patient once daily.

### Claim 63 (depends on 60, 61, 62)

The method of any one of claims 60-62, wherein the compound is administered to the patient in an amount of from about 25 mg per day to about 400 mg per day.

### Claim 64 (depends on 63)

The method of claim 63, wherein the compound is administered to the patient in an amount of from about 35 mg to about 65 mg per day.

### Claim 65 (depends on 64)

The method of claim 64, wherein the compound is administered to the patient in an amount of about 50 mg per day.

### Claim 66 (depends on 63)

The method of claim 63, wherein the compound is administered to the patient in an amount of from about 60 mg per day to about 90 mg per day.

### Claim 67 (depends on 66)

The method of claim 66, wherein the compound is administered to the patient in an amount of about 75 mg per day.

### Claim 68 (depends on 63)

The method of claim 63, wherein the compound is administered to the patient in an amount of from about 85 mg to about 115 mg per day.

### Claim 69 (depends on 68)

The method of claim 68, wherein the compound is administered to the patient in an amount of about 100 mg per day.

### Claim 70 (depends on 63)

The method of claim 63, wherein the compound is administered to the patient in an amount of from about 185 mg to about 215 mg per day.

### Claim 71 (depends on 70)

The method of claim 70, wherein the compound is administered to the patient in an amount of about 200 mg per day.

### Claim 72 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71)

The method of any one of claims 60-71, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least four weeks.

### Claim 73 (depends on 72)

The method of claim 72, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least eight weeks.

### Claim 74 (depends on 73)

The method of claim 73, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least 10 weeks.

### Claim 75 (depends on 74)

The method of claim 74, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least 12 weeks.

### Claim 76 (depends on 75)

The method of claim 75, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least 24 weeks.

### Claim 77 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71)

The method of any one of claims 60-71, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about four weeks to about 48 months.

### Claim 78 (depends on 77)

The method of claim 77, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about five weeks to about 36 months.

### Claim 79 (depends on 78)

The method of claim 78, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about six weeks to about 24 months.

### Claim 80 (depends on 79)

The method of claim 79, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about seven weeks to about 12 months.

### Claim 81 (depends on 80)

The method of claim 80, wherein the compound and add-back therapy are administered to the patient over a treatment period of from about eight weeks to about six months.

### Claim 82 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71)

The method of any one of claims 60-71, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about four weeks to about 12 months.

### Claim 83 (depends on 82)

The method of claim 82, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about five weeks to about 24 weeks.

### Claim 84 (depends on 83)

The method of claim 83, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about six weeks to about 18 wees.

### Claim 85 (depends on 84)

The method of claim 84, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about seven weeks to about 14 weeks.

### Claim 86 (depends on 85)

The method of claim 85, wherein the compound and add-back therapy are administered to the patient over a treatment period of at least from about eight weeks to about 12 weeks.

### Claim 87 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The method of any one of claims 1-32, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.

### Claim 88 (depends on 87)

The method of claim 87, wherein the GnRH antagonist is elagolix.

### Claim 89 (depends on 88)

The method of claim 88, wherein the GnRH antagonist is orally administered to the patient.

### Claim 90 (depends on 88, 89)

The method of claim 88 or 89, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.

### Claim 91 (depends on 90)

The method of claim 90, wherein the GnRH antagonist is administered to the patient one or more times daily.

### Claim 92 (depends on 91)

The method of claim 91, wherein the GnRH antagonist is administered to the patient once daily.

### Claim 93 (depends on 88, 89, 90, 91, 92)

The method of any one of claims 88-92, wherein the GnRH antagonist is administered to the patient in an amount of from about 100 mg to about 600 mg per day.

### Claim 94 (depends on 93)

The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 150 mg per day.

### Claim 95 (depends on 93)

The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 300 mg per day.

### Claim 96 (depends on 93)

The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 400 mg per day, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 200 mg per dose.

### Claim 97 (depends on 93)

The method of claim 93, wherein the GnRH antagonist is administered to the patient in an amount of about 600 mg per day, optionally wherein the GnRH antagonist is administered to the patient in two daily doses of 300 mg per dose.

### Claim 98 (depends on 87)

The method of claim 87, wherein the GnRH antagonist is relugolix.

### Claim 99 (depends on 98)

The method of claim 98, wherein the GnRH antagonist is orally administered to the patient.

### Claim 100 (depends on 98, 99)

The method of claim 98 or 99, wherein the GnRH antagonist is administered to the patient one or more times per day, week, or month.

### Claim 101 (depends on 100)

The method of claim 100, wherein the GnRH antagonist is administered to the patient one or more times daily.

### Claim 102 (depends on 101)

The method of claim 101, wherein the GnRH antagonist is administered to the patient once daily.

### Claim 103 (depends on 98, 99, 100, 101, 102)

The method of any one of claims 98-102, wherein the GnRH antagonist is administered to the patient in an amount of from about 10 mg to about 60 mg per day.

### Claim 104 (depends on 103)

The method of claim 103, wherein the GnRH antagonist is administered to the patient in an amount of from about 20 mg to about 50 mg per day.

### Claim 105 (depends on 104)

The method of claim 104, wherein the GnRH antagonist is administered to the patient in an amount of about 40 mg per day.

### Claim 106 (depends on 1, 105)

The method of any one of claims 1-105, wherein the add-back therapy is administered to the patient one or more times daily.

### Claim 107 (depends on 106)

The method of claim 106, wherein the add-back therapy is administered to the patient once daily, concurrently with the GnRH antagonist.

### Claim 108 (depends on 106)

The method of claim 106, wherein the add-back therapy is administered to the patient once daily, prior to administration of the GnRH antagonist.

### Claim 109 (depends on 106)

The method of claim 106, wherein the add-back therapy is administered to the patient once daily, following administration of the GnRH antagonist.

### Claim 110 (depends on 107)

The method of claim 107, wherein the add-back therapy is administered to the patient in the form of a pharmaceutical composition comprising the GnRH antagonist.

### Claim 111 (depends on 1, 110)

The method of any one of claims 1-110, wherein the add-back therapy comprises an estrogen.

### Claim 112 (depends on 111)

The method of claim 111, wherein the estrogen is selected from the group consisting of β17-estradiol, ethinyl estradiol, and conjugated estrogens.

### Claim 113 (depends on 112)

The method of claim 112, wherein the estrogen is β17-estradiol.

### Claim 114 (depends on 113)

The method of claim 113, wherein the β17-estradiol is administered to the patient in an amount of about 1.0 mg/day.

### Claim 115 (depends on 113)

The method of claim 113, wherein the β17-estradiol is administered to the patient in an amount of about 0.5 mg/day.

### Claim 116 (depends on 112)

The method of claim 112, wherein the estrogen is ethinyl estradiol.

### Claim 117 (depends on 116)

The method of claim 116, wherein the ethinyl estradiol is administered to the patient in an amount of about 5.0 μg/day.

### Claim 118 (depends on 116)

The method of claim 116, wherein the ethinyl estradiol is administered to the patient in an amount of about 2.5 μg/day.

### Claim 119 (depends on 112)

The method of claim 112, wherein the estrogen is a conjugated estrogen.

### Claim 120 (depends on 119)

The method of claim 119, wherein the conjugated estrogen is administered to the patient in an amount of about 0.625 mg/day.

### Claim 121 (depends on 119)

The method of claim 119, wherein the conjugated estrogen is administered to the patient in an amount of about 0.45 mg/day.

### Claim 122 (depends on 119)

The method of claim 119, wherein the conjugated estrogen is administered to the patient in an amount of about 0.3 mg/day

### Claim 123 (depends on 1, 122)

The method of any one of claims 1-122, wherein the add-back therapy comprises a progestin.

### Claim 124 (depends on 123)

The method of claim 123, wherein the progestin is selected from the group consisting of norethindrone or an ester thereof, progesterone, norgestimate, medroxyprogesterone, and drospirenone.

### Claim 125 (depends on 124)

The method of claim 124, wherein the progestin is norethindrone or norethindrone acetate.

### Claim 126 (depends on 125)

The method of claim 125, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 1.0 mg/day.

### Claim 127 (depends on 125)

The method of claim 125, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.5 mg/day.

### Claim 128 (depends on 125)

The method of claim 125, wherein the norethindrone or norethindrone acetate is administered to the patient in an amount of about 0.1 mg/day.

### Claim 129 (depends on 124)

The method of claim 124, wherein the progestin is progesterone.

### Claim 130 (depends on 129)

The method of claim 129, wherein the progesterone is administered to the patient in an amount of about 200 mg/day.

### Claim 131 (depends on 129)

The method of claim 129, wherein the progesterone is administered to the patient in an amount of about 100 mg/day.

### Claim 132 (depends on 124)

The method of claim 124, wherein the progestin is norgestimate.

### Claim 133 (depends on 132)

The method of claim 132, wherein the norgestimate is administered to the patient in an amount of about 0.09 mg/day.

### Claim 134 (depends on 124)

The method of claim 124, wherein the progestin is medroxyprogesterone.

### Claim 135 (depends on 134)

The method of claim 134, wherein the medroxyprogesterone is administered to the patient in an amount of about 5 mg/day.

### Claim 136 (depends on 134)

The method of claim 134, wherein the medroxyprogesterone is administered to the patient in an amount of about 2.5 mg/day.

### Claim 137 (depends on 134)

The method of claim 134, wherein the medroxyprogesterone is administered to the patient in an amount of about 1.5 mg/day.

### Claim 138 (depends on 124)

The method of claim 124, wherein the progestin is drospirenone.

### Claim 139 (depends on 138)

The method of claim 138, wherein the drospirenone is administered to the patient in an amount of about 0.5 mg/day.

### Claim 140 (depends on 138)

The method of claim 138, wherein the drospirenone is administered to the patient in an amount of about 0.25 mg/day.

### Claim 141 (depends on 1, 140)

The method of any one of claims 1-140, wherein the add-back therapy comprises about 1.0 mg of β17-estradiol and about 0.5 mg of norethindrone acetate.

### Claim 142 (depends on 1, 140)

The method of any one of claims 1-140, wherein the add-back therapy comprises about 0.5 mg of β17-estradiol and about 0.1 mg of norethindrone acetate.

### Claim 143 (depends on 1, 142)

The method of any one of claims 1-142, wherein the patient is a pre-menopausal female of from about 18 to about 48 years of age.

### Claim 144 (depends on 1, 143)

The method of any one of claims 1-143, wherein the patient exhibits 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.

### Claim 145 (depends on 1, 144)

The method of any one of claims 1-144, wherein the patient exhibits a rectal (type II) and/or vaginal (type III) endometriosis node of at least 2 cm prior to administration of the GnRH antagonist to the patient.

### Claim 146 (depends on 145)

The method of claim 145, wherein the length of the type II and/or type III endometriosis node is assessed by way of magnetic resonance imaging (MRI).

### Claim 147 (depends on 1, 146)

The method of any one of claims 1-146, wherein the patient exhibits a junctional-zone width of about 12 mm or more prior to administration of the GnRH antagonist to the patient.

### Claim 148 (depends on 147)

The method of claim 147, wherein the junctional-zone width is assessed by way of MRI.

### Claim 149 (depends on 1, 148)

The method of any one of claims 1-148, 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.

### Claim 150 (depends on 149)

The method of claim 149, 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 first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 151 (depends on 1, 2, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28, 29, 30)

The method of any one of claims 1, 2, 5-11, 14-21, 24-30, and 33-150, wherein the patient exhibits a reduction in uterine bleeding following administration of the GnRH antagonist to the patient.

### Claim 152 (depends on 151)

The method of claim 151, wherein the patient exhibits the reduction in uterine bleeding within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 153 (depends on 3, 4, 12, 13, 22, 23, 31, 32, 151)

The method of any one of claims 3, 4, 12, 13, 22, 23, 31, 32, 151, and 152, wherein the reduction in uterine bleeding is assessed by way of an alkaline hematin method.

### Claim 154 (depends on 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31)

The method of any one of claims 1-3, 5-12, 14-22, 24-31, and 33-153, wherein the patient exhibits amenorrhea following administration of the GnRH antagonist to the patient.

### Claim 155 (depends on 154)

The method of claim 154, wherein the patient exhibits the amenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the amenorrhea within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 156 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 155)

The method of any one of claims 1-24 and 27-155, wherein the patient exhibits a reduction in the volume of one or more rectovaginal endometiosis nodes following administration of the GnRH antagonist to the patient.

### Claim 157 (depends on 156)

The method of claim 156, 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 first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 158 (depends on 26, 156)

The method of any one of claims 26, 156, and 157, wherein the reduction in volume of the one or more rectovaginal endometriosis nodes is assessed by way of MRI or TVUS.

### Claim 159 (depends on 1, 158)

The method of any one of claims 1-158, wherein the patient exhibits a reduction in bowel involvement of one or more type III endometriosis nodes following administration of the GnRH antagonist to the patient.

### Claim 160 (depends on 159)

The method of claim 159, wherein the patient exhibits the reduction in bowel involvement of the one or more type III endometriosis nodes within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 161 (depends on 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The method of any one of claims 1-7, 9-16, 18-26, and 28-160, wherein the patient exhibits a reduction in pelvic pain following administration of the GnRH antagonist to the patient.

### Claim 162 (depends on 161)

The method of claim 161, wherein the patient exhibits the reduction in pelvic pain within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 163 (depends on 8, 17, 27, 161)

The method of any one of claims 8, 17, 27, 161, and 162, 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.

### Claim 164 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27)

The method of any one of claims 1-8, 10-17, 19-27, and 29-163, wherein the patient exhibits a reduction in dysmenorrhea following administration of the GnRH antagonist to the patient.

### Claim 165 (depends on 164)

The method of claim 164, wherein the patient exhibits the reduction in dysmenorrhea within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 166 (depends on 9, 18, 28, 164)

The method of any one of claims 9, 18, 28, 164, and 165, wherein the reduction in dysmenorrhea is assessed by way of an mB&B score, NRS score, or VRS score.

### Claim 167 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1-9, 11-18, 20-28, and 30-166, wherein the patient exhibits a reduction in dyspareunia following administration of the GnRH antagonist to the patient.

### Claim 168 (depends on 167)

The method of claim 167, wherein the patient exhibits the reduction in dyspareunia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 169 (depends on 10, 19, 29, 167)

The method of any one of claims 10, 19, 29, 167, and 168, wherein the reduction in dyspareunia is assessed by way of an mB&B score, NRS score, or VRS score.

### Claim 170 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The method of any one of claims 1-10, 12-19, 21-29, and 31-169, wherein the patient exhibits a reduction in dyschezia following administration of the GnRH antagonist to the patient.

### Claim 171 (depends on 170)

The method of claim 170, wherein the patient exhibits the reduction in dyschezia within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 172 (depends on 11, 20, 30, 170)

The method of any one of claims 11, 20, 30, 170, and 171, wherein the reduction in dyschezia is assessed by way of an mB&B score, NRS score, or VRS score.

### Claim 173 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 172)

The method of any one of claims 1-14 and 16-172, wherein the patient exhibits a reduction in uterine volume following administration of the GnRH antagonist to the patient.

### Claim 174 (depends on 173)

The method of claim 173, wherein the patient exhibits the reduction in uterine volume within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 175 (depends on 15, 173)

The method of any one of claims 15, 173, and 174, wherein the reduction in uterine volume is assessed by way of MRI or transvaginal ultrasound (TVUS).

### Claim 176 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 175)

The method of any one of claims 1-15 and 17-175, 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.

### Claim 177 (depends on 176)

The method of claim 176, 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 first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 178 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 177)

The method of any one of claims 1-20 and 22-177, wherein the patient exhibits a reduction in uterine tenderness following administration of the GnRH antagonist to the patient.

### Claim 179 (depends on 178)

The method of claim 178, wherein the patient exhibits the reduction in uterine tenderness within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 180 (depends on 1, 179)

The method of any one of claims 1-179, wherein the patient exhibits a reduction in the diameter of a junctional zone of adenomyosis following administration of the GnRH antagonist to the patient.

### Claim 181 (depends on 180)

The method of claim 180, 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 first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the reduction within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 182 (depends on 1, 181)

The method of anyone of claims 1-181, wherein the patient exhibits an improvement in Endometriosis Health Profile questionnaire (EHP-30) score following administration of the GnRH antagonist to the patient.

### Claim 183 (depends on 182)

The method of claim 182, wherein the patient exhibits the improvement in the EHP-30 score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the improvement within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 184 (depends on 1, 183)

The method of any one of claims 1-183, wherein the patient exhibits a positive Patient Global Impression of Change (PGIC) score core following administration of the GnRH antagonist to the patient.

### Claim 185 (depends on 184)

The method of claim 184, wherein the patient exhibits the positive PGIC score within from about one day to about 36 weeks of the first administration of the GnRH antagonist to the patient, optionally wherein the patient exhibits the positive PGIC score within from about 12 weeks to about 24 weeks of the first administration of the GnRH antagonist to the patient.

### Claim 186 (depends on 1, 185)

The method of any one of claims 1-185, wherein the patient does not exhibit a reduction in bone mineral density (BMD) of greater than 5% following administration of the GnRH antagonist to the patient.

### Claim 187 (depends on 186)

The method of claim 186, wherein the patient does not exhibit a reduction in BMD of greater than 3% following administration of the GnRH antagonist to the patient.

### Claim 188 (depends on 187)

The method of claim 187, wherein the patient does not exhibit a reduction in BMD of greater than 2% following administration of the GnRH antagonist to the patient.

### Claim 189 (depends on 188)

The method of claim 188, wherein the patient does not exhibit a reduction in BMD of greater than 1% following administration of the GnRH antagonist to the patient.

### Claim 190 (depends on 186, 187, 188, 189)

The method of any one of claims 186-189, wherein the BMD is assessed by dual energy X-ray absorptiometry.

### Claim 191 (depends on 190)

The method of claim 190, wherein the BMD is assessed in the spine or femur of the patient.

### Claim 192 (depends on 186, 187, 188, 189)

The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of bone specific alkaline phosphatase (BAP) in a sample isolated from the patient following the administration to the concentration of BAP in a sample isolated from the patient prior to the administration.

### Claim 193 (depends on 186, 187, 188, 189)

The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of deoxypyridinoline (DPD) in a sample isolated from the patient following the administration to the concentration of DPD in a sample isolated from the patient prior to the administration.

### Claim 194 (depends on 186, 187, 188, 189)

The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of type I collagen C-terminal telopeptide (CTX) in a sample isolated from the patient following the administration to the concentration of CTX in a sample isolated from the patient prior to the administration.

### Claim 195 (depends on 186, 187, 188, 189)

The method of any one of claims 186-189, wherein the BMD is assessed by comparing the concentration of procollagen 1 N-terminal peptide (P1NP) in a sample isolated from the patient following the administration to the concentration of P1NP in a sample isolated from the patient prior to the administration.

### Claim 196 (depends on 1, 195)

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 1-195.

### Claim 197 (depends on 196)

The kit of claim 196, wherein the GnRH antagonist is a compound represented by formula (I)
wherein ring A is a thiophene ring;
each RA 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, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, wherein W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 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 RB is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW4, COW4, COOW4, or CONW5W6, wherein W4 to W6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W5 and Wa 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 —SO2-L-Y, wherein L is an optionally substituted lower alkylene group;
Y is a group represented by Z or —NW7W8, wherein W7 and W8 independently are a hydrogen atom, an optionally substituted lower alkyl group, or Z with the proviso that W7 and W8 are not simultaneously hydrogen atoms, or W7 and W8 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.

### Claim 198 (depends on 197)

The kit of claim 197, wherein the ring A is a thiophene ring represented by formula (IIa)

### Claim 199 (depends on 197, 198)

The kit of claim 197 or 198, wherein m is 1.

### Claim 200 (depends on 199)

The kit of claim 199, wherein the ring A is an optionally substituted thiophene ring represented by formula (IIb)

### Claim 201 (depends on 197, 198, 199, 200)

The kit of any one of claims 197-200, wherein each RA is independently a halogen atom, an optionally substituted lower alkyl group, COOW1, or CONW2W3, wherein W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group.

### Claim 202 (depends on 201)

The kit of claim 201, wherein each RA is COOH or pharmaceutically acceptable salt thereof.

### Claim 203 (depends on 197, 198, 199, 200, 201, 202)

The kit of any one of claims 197-202, wherein the ring B is an optionally substituted benzene ring, pyridine ring, or thiophene ring.

### Claim 204 (depends on 203)

The kit of claim 203, wherein the ring B is represented by a formula selected from the group consisting of:

### Claim 205 (depends on 197, 198, 199, 200, 201, 202, 203, 204)

The kit of any one of claims 197-204, wherein n is 2.

### Claim 206 (depends on 205)

The kit of claim 205, wherein ring B is represented by a formula selected from the group consisting of:

### Claim 207 (depends on 197, 198, 199, 200, 201, 202, 203, 204, 205, 206)

The kit of any one of claims 197-206, wherein each RB is independently a halogen atom, an optionally substituted lower alkyl group, or OW4, wherein each W4 is independently a hydrogen atom or an optionally substituted lower alkyl group.

### Claim 208 (depends on 207)

The kit of claim 207, wherein each RB is independently a fluorine atom, chlorine atom, bromine atom, methyl group, or methoxy group.

### Claim 209 (depends on 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208)

The kit of any one of claims 197-208, wherein U is a single bond.

### Claim 210 (depends on 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209)

The kit of any one of claims 197-209, wherein X is a group represented by —O-L-Y.

### Claim 211 (depends on 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210)

The kit of any one of claims 197-210, wherein L is a methylene group.

### Claim 212 (depends on 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211)

The kit of any one of claims 197-211, wherein Y is an optionally substituted benzene ring represented by formula (V)
wherein each RC is independently a halogen atom, an optionally substituted lower alkyl group, or OW9, wherein each W9 is independently a hydrogen atom or an optionally substituted lower alkyl group; and
p is an integer from 0 to 3.

### Claim 213 (depends on 212)

The kit of claim 212, wherein Y is a substituted benzene ring represented by formula (Va)

### Claim 214 (depends on 196)

The kit of claim 196, wherein the compound is represented by formula (Ia)
wherein each RA 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, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3, or SO2NW2W3, wherein W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 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 RB is independently a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW4, COW4, COOW4, or CONW5W6, wherein W4 to W6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W5 and W6 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 RC is independently a halogen atom, an optionally substituted lower alkyl group, or OW9, wherein each W9 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.

### Claim 215 (depends on 214)

The kit of claim 214, wherein the compound is represented by formula (Ib)

### Claim 216 (depends on 215)

The kit of claim 215, wherein the compound is represented by formula (Ic)
or a pharmaceutically acceptable salt thereof.

### Claim 217 (depends on 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216)

The kit of any one of claims 197-216, wherein the compound is represented by formula (VI)
or a pharmaceutically acceptable salt thereof.

### Claim 218 (depends on 217)

The kit of claim 217, wherein the compound is the choline salt of the compound represented by formula (VI).

### Claim 219 (depends on 196)

The kit of claim 196, wherein the GnRH antagonist is elagolix, relugolix, opigolix (ASP1707), BAY-784, or SK-2706.