Tetrahydrocarbazole derivatives as ligands of G-protein coupled receptors

1. A tetrahydrocarbazole compound 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;

Comp- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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;

Com- pound 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-carboxlic acid; and

Com- pound 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 tetrahydrocarbazole compound of claim 1 , which 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. A composition comprising at least one compound of claim 1 and at least one pharceutically acceptable carrier, auxiliary, a diluent, or a combination thereof.

4. The composition of claim 3 , 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

5. The composition of claim 3 , where the at least one compound is present in a unit dose of from 0.001 mg to 100 mg per kg of body weight of a patient.

6. The composition of claim 4 , where the at least one compound is present in a unit dose of from 0.001 mg to 100 mg per kg of body weight of a patient.

7. The composition of claim 3 , where the composition further comprises at least one additional pharmacologically active substance.

8. The composition of claim 4 , where the composition further comprises at least one additional pharmacologically active substance.

9. The composition of claim 7 , where the at least one additional pharmacologically active substance is selected from the group consisting of: androgen, estrogen, progestin, progestagen, selective estrogen receptor modulator (SERM), selective androgen receptor modulator (SARM), receptor-type tyrosine kinase inhibitor, 5alpha reductase inhibitor, 5alpha-reductase 1 inhibitor, 5alpha-reductase 2 inhibitor, alpha-receptor inhibitor (alpha blockers), alpha1-adrenergic receptor antagonist, aromatase inhibitor, lyase inhibitor, GnRH/LHRH receptor agonist, GnRH/LHRH receptor antagonist, NK 1 receptor antagonist, NK 2 receptor antagonist, NK 1 receptor agonist, and NK 2 receptor agonist.

10. The composition of claim 8 , where the at least one additional pharmacologically active substance is selected from the group consisting of: androgen, estrogen, progestin, progestagen, selective estrogen receptor modulator (SERM), selective androgen receptor modulator (SARM), receptor-type tyrosine kinase inhibitor, 5alpha-reductase inhibitor, 5alpha-reductase 1 inhibitor, 5alpha-reductase 2 inhibitor, alpha-receptor inhibitor (alpha blockers), alpha1-adrenergic receptor antagonist, aromatase inhibitor, lyase inhibitor, GnRH/LHRH receptor agonist, GnRH/LHRH receptor antagonist, NK 1 receptor antagonist, NK 2 receptor antagonist, NK 1 receptor agonist, and NK 2 receptor agonist.

11. The composition of claim 7 , where the at least one additional pharmacologically active substance is selected from the group consisting of: testosterone, oestradiol, oestriol, oestrone, progesterone, raloxifene, arzoxifene, lasofoxifene, ospemifene, TSE-424, HMR-3339, SERM-3339, SPC-8490, HM-101, bazedoxifene (WAY 140424), flutamide, casodex, nilutamide, tamoxifen, fulvestrant, finasteride, dutasteride, izonsteride, epristeride, tamsulosin, prazosin, terazosin, doxazosin, silodosin, alfuzosin, anastrozole, letrozole, finrozole, exemestane, gefitinib, imatinib, semaxanib, SU-6668, SU-101, CI-1033, E-6006, R-116301, aprepitant, GW-2016, ZD-4794, BL-1832, BL-1833, GW-597599, GW-679769, KRP-103, TKA-457, L-758298, L-760735, L-759274, NIP-530, CJ-17493, R-1124, ezlopitant, CP-122721, PD-154075, CP-96345, R-673, SSR 240600, MK-0869, SR 140333, CP-99,994, NKP-608, TAK-637, MEN-11467, GR 73632, phenoxybenzamine, sildenafil, bicalutamide, cyproterone acetate, ketoconazole, aminoglutethimide, and danazol.

12. The composition of claim 8 , where the at least one additional pharmacologically active substance is selected from the group consisting of: testosterone, oestradiol, oestriol, oestrone, progesterone, raloxifene, arzoxifene, lasofoxifene, ospemifene, TSE-424, HMR-3339, SERM-3339, SPC-8490, HM-101, bazedoxifene (WAY 140424), flutamide, casodex, nilutamide, tamoxifen, fulvestrant, finasteride, dutasteride, izonsteride, epristeride, tamsulosin, prazosin, terazosin, doxazosin, silodosin, alfuzosin, anastrozole, letrozole, finrozole, exemestane, gefitinib, imatinib, semaxanib, SU-6668, SU-101, CI-1033, E-6006, R-116301, aprepitant, GW-2016, ZD-4794, BL-1832, BL-1833, GW-597599, GW-679769, KRP-103, TKA-457, L-758298, L-760735, L-759274, NIP-530, CJ-17493, R-1124, ezlopitant, CP-122721, PD-154075, CP-96345, R-673, SSR 240600, MK-0869, SR 140333, CP-99,994, NKP-608, TAK-637, MEN-11467, GR 73632, phenoxybenzamine, sildenafil, bicalutamide, cyproterone acetate, ketoconazole, aminoglutethimide, and danazol.

13. A kit comprising a pharmacologically active amount of at least one tetrahydrocarbazole compound of claim 1 and at least one of a reagent and a buffer.

14. The kit of claim 13 , wherein the at least one tetrahydrocarbazole 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