Tetrahydrocarbazole derivatives as ligands of G-protein coupled receptors

1. A method of treating a condition in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of at least one tetrahydrocarbazole to the subject to treat the condition,

wherein the condition is a benign tumor disease, a malignant tumor disease, male fertility control, controlled ovarian stimulation in in vitro fertilization (COS/ART), prostate cancer, breast cancer, endometrial cancer, ovarian cancer, benign prostate hyperplasia (BPH), endometriosis, uterine fibroids, uterine myomas, endometrium hyperplasia, pubertas praecox, polycystic ovary syndrome, or a hormone-dependent tumor disease,

wherein the at least one tetrahydrocarbozole is selected from the group consisting of:

Compound 31 (S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-1-[5-(3-ethyl-ureido)-[1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide;

Compound 36 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(morpholin-4-ylmethyl)-carbamoyl]-butyl}amide

Compound 51 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(2-diethylamino-ethylcarbamoyl)-2-methyl-butyl]-amide;

Compound 52 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl}-amide;

Compound 54 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl-ethylthiocarbamoyl)-butyl]-amide;

Compound 60 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyridin-4-ylmethyl)-thiocarbamoyl]-butyl}-amide;

Compound 69 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy-phenylcarbamoyl)-2-methyl-butyl]-amide;

Compound 71 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(2-hydroxy-4-methoxy-phenylcarbamoyl)-2-methyl-butyl]-amide;

Compound 73 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-cyclohexylcarbamoyl)-2-methyl-butyl]-amide;

Compound 74 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(3-imidazol-1-yl-propylthiocarbamoyl)-2-methyl-butyl]-amide;

Compound 114 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(4-[1,2,4]triazol-1-yl-butylthiocarbamoyl)-butyl]-amide;

Compound 118 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-thiocarbamoyl]-butyl}-amide;

Compound 137 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(quinolin-6-ylcarbamoyl)-butyl]-amide;

Compound 144 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(N′-phenyl-hydrazinocarbonyl)-butyl]-amide;

Compound 164

Compound 167

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid {(S)-1-[(3-

ethyl-ureido)-methyl]-2-methyl-butyl}-amide;

Compound 173

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid {(S)-1-[(3-

ethyl-thioureido)-methyl]-2-methyl-butyl}-amide;

Compound 178

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(2-tert-

butyl-2H-tetrazol-5-ylcarbamoyl)-2-methyl-butyl]-amide;

Compound 183

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid (S)-2-methyl-

1-[(pyrimidin-5-ylmethyl)-carbamoyl]-butyl}-amide;

Compound 188

1-tert-butyl-4-(3-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro-

phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-

trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-

carbonyl)-amino]-3-methyl-pentanoylamino}-propyl)-4H-

tetrazol-1-ium; Trifluoro-acetate;

Compound 190

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-

methyl-1-(3-pyridin-4-ylmethyl-ureidomethyl)-butyl]-amide;

Compound 205

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-

methyl-1-(3-pyridin-4-ylmethyl-thioureidomethyl)-butyl]-amide;

Compound 219

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-

methyl-1-(morpholin-4-ylcarbamoyl)-butyl]-amide;

Compound 230

(R)-3-[(S)-3-Methyl-2-(2-pyridin-3-yl-acetylamino)-

pentanoylamino]-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-

methyl-1-thiocarbamoyl-butyl)-amide;

Compound 236

(R)-3-[(S)-3-Methyl-2-(2-pyridin-4-yl-acetylamino)-

pentanoylamino]-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-

methyl-1-thiocarbamoyl-butyl)-amide;

Compound 239

(R)-3-{(S)-2-[3-(4-Methoxy-benzyl)-ureido]-3-methyl-

pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-

methyl-1-thiocarbamoyl-butyl)-amide;

Compound 242

(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-

methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(N′-

benzoyl-hydrazinocarbonyl)-2-methyl-butyl]-amide;

Compound 244

(R)-3-{(S)-2-[3-(2-Fluoro-benzyl)-ureido]-3-methyl-

pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-

methyl-1-(N′-phenyl-hydrazinocarbonyl)-butyl]-amide;

Compound 249

(R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-

3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid [(1S,2S)-

2-methyl-1-(4-phenyl-thiazol-2-yl)-butyl]-amide;

Compound 250

(R)-3-{(2S, 3S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-

pentanoylamino}-8-trifluoromethyl-2,3,4,9-

tetrahydro-1H-carbazole-3-carboxylic acid {(1S,2S)-1-

[4-(4-methoxy-phenyl)-thiazol-2-yl]-2-methyl-butyl}-amide;

Compound 251

2-{(1R,2S)-1-[((R)-3-{(2S,3S)-2-[2-(2-Fluoro-

phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-

trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-

carbonyl)-amino]-2-methyl-butyl}-thiazole-4-carboxylic acid ethyl ester;

Compound 256

2-{(1S,2S)-1-[((R)-3-{(2S,3S)-2-[2-(2-Fluoro-

phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-

trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-

carbonyl)-amino]-2-methyl-butyl}-thiazole-4-carboxylic acid; and

Compound 258

2-{(1S,2S)-1-[((R)-3-{(2S,3S)-2-[3-(2-Fluoro-

benzyl)-ureido]-3-methyl-pentanoylamino}-8-

trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-

carbonyl)-amino]-2-methyl-butyl}-thiazole-4-carboxylic acid ethyl ester.

2. The method of claim 1 , wherein the at least one compound is

Compound 52 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl)-amide.

3. The method of claim 1 , where the at least one compound is administered in a unit dose of from 0.001 mg to 100 mg per kg of body weight of the subject.

4. The method of claim 1 , where the at least one compound is administered in a unit dose of from 0.001 mg to 100 mg per kg of body weight of the subject.

5. The method of claim 2 , wherein the condition is a benign tumor disease.

6. The method of claim 2 , wherein the condition is a malignant tumor disease.

7. The method of claim 2 , wherein the condition is male fertility control.

8. The method of claim 2 , wherein the condition is controlled ovarian stimulation in in vitro fertilization (COS/ART).

9. The method of claim 2 , wherein the condition is prostate cancer.

10. The method of claim 2 , wherein the condition is breast cancer.

11. The method of claim 2 , wherein the condition is endometrial cancer.

12. The method of claim 2 , wherein the condition is ovarian cancer.

13. The method of claim 2 , wherein the condition is benign prostate hyperplasia (BPH).

14. The method of claim 2 , wherein the condition is endometriosis.

15. The method of claim 2 , wherein the condition is uterine fibroids.

16. The method of claim 2 , wherein the condition is uterine myomas.

17. The method of claim 2 , wherein the condition is endometrium hyperplasia.

18. The method of claim 2 , wherein the condition is pubertas praecox.

19. The method of claim 2 , wherein the condition is polycystic ovary syndrome.

20. The method of claim 2 , wherein the condition is a hormone-dependent tumor disease.