Substituted-indole-compounds as estrogen receptor down-regulators

1. A compound represented by formula (I), a pharmaceutically acceptable salt or a hydrate thereof,

wherein,

R 1 is selected from

X is selected from single bond, O and S;

Y and Z are CH;

ring A is selected from 5-10 membered aryl and 5-10 membered heteroaryl;

R 2 is selected from H, halogen, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R 3 is selected from H, halogen, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R 6 is selected from the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(═O)NH 2 , or the group consisting of C 1-8 alkyl, C 1-8 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and C 3-6 cycloalkyl-C 1-3 alkyl-, each of which is optionally substituted with 1, 2, or 3 R′;

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1, 2, 3 and 4;

P is selected from 0, 1, 2 and 3;

or, when m is 2, R 3 and R 3 are connected together to form a 5-6 membered ring;

R′ is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 and N(CH 3 ) 2 ;

“hetero” represents a heteroatom or a heteroatom group, which is selected from the group consisting of —C(═O)N(R)—, —N(R)—, —S(═O) 2 N(R)—, —S(═O) N(R)—, —O—, —S—, ═O, ═S, —O—N═, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O) 2 — and —N(R)C(═O)N(R)—;

in any of the above cases, the number of the heteroatom or the heteroatom group is independently selected from 1, 2 and 3.

2. A compound represented by formula (I), a pharmaceutically acceptable salt or a hydrate thereof,

wherein,

R 1 is selected from

Y and Z are CH;

ring A is selected from 5-10 membered aryl and 5-10 membered heteroaryl;

R 2 is selected from H, halogen, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R 3 is selected from H, halogen, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R 4 and R 5 are each independently selected from H, halogen, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R 6 is selected from the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 R;

R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(═O)NH 2 , or the group consisting of C 1-8 alkyl, C 1-8 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and C 3-6 cycloalkyl-C 1-3 alkyl-, each of which is optionally substituted with 1, 2, or 3 R′;

n is selected from 0, 1, 2, 3 and 4;

m is selected from 0, 1, 2, 3 and 4;

or, when m is 2, R 3 and R 3 are connected together to form a 5-6 membered ring;

R′ is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 and N(CH 3 ) 2 ;

“hetero” represents a heteroatom or a heteroatom group, which is selected from the group consisting of —C(═O)N(R)—, —N(R)—, —S(═O) 2 N(R)—, —S(═O)N(R)—, —O—, —S—, ═O, ═S, —O—N═, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O) 2 — and —N(R)C(═O)N(R)—;

in any of the above cases, the number of the heteroatom or the heteroatom group is independently selected from 1, 2 and 3.

3. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 2 , wherein, R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, or the group consisting of C 1-5 alkyl, C 1-5 heteroalkyl, C 3-6 cycloalkyl-C 1-3 alkyl-, each of which is optionally substituted with 1, 2, or 3 R′.

4. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 3 , wherein, R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(═O)NH 2 , or the group consisting of CH 3 , CH 3 CH 2 , S(═O)CH 3 ,

each of which is optionally substituted with 1, 2, or 3 R′.

5. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 4 , wherein, R is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(═O)NH 2 , CH 3 , CH 2 Cl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CH 2 OH, Et, S(═O)CH 3 ,

6. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 1 , wherein, R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, or the group consisting of C 1-5 alkyl, C 1-5 heteroalkyl and C 3-6 cycloalkyl-C 1-3 alkyl-, each of which is optionally substituted with 1, 2, or 3 R′.

7. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 6 , wherein, R is selected from H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(═O)NH 2 , or the group consisting of CH 3 , CH 3 CH 2 , S(═O)CH 3 ,

each of which is optionally substituted with 1, 2, or 3 R′.

8. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 7 , wherein, R is selected from the group consisting of H, F, Cl, Br, I, OH, CN, NH 2 , COOH, C(═O)NH 2 , CH 3 , CH 2 Cl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CH 2 OH, Et, S(═O)CH 3 ,

9. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 1 , wherein, the structural unit

is selected from

10. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 9 , wherein, the structural unit

is selected from

11. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 10 , wherein, the structural unit

is selected from the group consisting of

12. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 1 , wherein, R 2 is selected from H, F, Cl, Br, I, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, NH(C 1-4 alkyl), N,N-di(C 1-3 alkyl)amino and C 3-6 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R, and/or,

R 3 is selected from H, F, Cl, Br, I, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, NH(C 1-4 alkyl), N,N-di(C 1-3 alkyl)amino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 R, and/or,

R 4 and R 5 are each independently selected from H, F, Cl, Br, I, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, NH(C 1-4 alkyl), N,N-di(C 1-3 alkyl)amino and C 3-6 cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R, and/or, ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl and isoquinolinyl, and/or, R 6 is selected from

13. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 12 , wherein, R 3 is selected from H, F, Cl, Br, I, CN, NO 2 , OH, COOH, NH 2 , or the group consisting of CH 3 , CH 3 CH 2 , CH 3 O, CH 3 CH 2 O and

each of which is optionally substituted with 1, 2, or 3 R.

14. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 13 , wherein, R 3 is selected from the group consisting of H, F, Cl, CN, CH 3 , CF 3 and

15. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 12 , wherein, R 4 and R 5 are each independently selected from the group consisting of H, F, Cl, Br, CN and CH 3 .

16. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 12 , wherein, the structural unit

is selected from the group consisting of

17. The compound, the pharmaceutically acceptable salt the hydrate thereof as defined in claim 16 , wherein, the structural unit

is selected from the group consisting of

18. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 2 , wherein, the structural unit

is selected from

19. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 18 , wherein, the structural unit

is selected from

20. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 1 , wherein, the compound is selected from the group consisting of

wherein, R 2 , R 3 , R 4 and R 5 are defined as claim 1 .

21. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 2 , wherein, the compound is selected from

wherein, R 3 , R 5 and R are defined as in claim 2 .

22. The compound, pharmaceutically acceptable salt or hydrate thereof as defined in claim 1 , wherein, the compound is selected from the group consisting of

23. A pharmaceutical composition comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 1 and a pharmaceutically acceptable carrier.

24. A method for treating a disorder associated with estrogen receptor in a subject in need thereof, comprising: administrating an effective amount of the compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 1 , wherein, the disorder associated with estrogen receptor is estrogen receptor-positive breast cancer.

25. The compound, the pharmaceutically acceptable salt or the hydrate thereof as defined in claim 2 , wherein, the compound is selected from the group consisting of