Novel Substituted N-(3-Fluoropropyl)-Pyrrolidine Compounds, Processes for their Preparation and Therapeutic Uses Thereof

Abstract

The present invention relates to novel substituted N-(3-fluoropropyl)-pyrrolidine compounds of formula (I-A):

##STR00001##

wherein R1 and R2 represent independently a hydrogen atom or a deuterium atom; A represents an oxygen or nitrogen atom; and SERM-F represents a selective estrogen receptor modulator fragment comprising an aryl or heteroaryl group linked to the adjacent “A” group.

The invention also relates to the preparation and to the therapeutic uses of the compounds of formula (I-A) as inhibitors and degraders of estrogen receptors.

Claims

1. A compound of the formula (I-A): ##STR00516## wherein: R1 and R2 represent independently a hydrogen atom or a deuterium atom; A represents an oxygen or nitrogen atom; and SERM-F represents a selective estrogen receptor modulator fragment comprising an aryl or heteroaryl group linked to the adjacent “A” group; or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I-A) according to claim 1, with the proviso that the compounds of formula (I-B) below are excluded: ##STR00517## wherein, in formula (I-B): R1 and R2 represent independently a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group, a —OH group or a —OPO(OH).sub.2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a —OH group; wherein: at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a —COOH group, a —OH group or a —OPO(OH).sub.2 group, then R5 represents a hydrogen atom; when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms; R6 is selected from: a phenyl group or a heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, said phenyl and heteroaryl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more (such as 1, 2 or 3) fluorine atoms; a halogen atom; a —OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more (such as 1, 2 or 3) fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C.sub.1-C.sub.6)-alkyl groups substituted with two or more (such as 2 or 3) fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group are unsubstituted or substituted with two or more (such as 2 or 3) fluorine atoms; a silane group substituted with 3 (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (such as 1 or 2) (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (such as 1 or 2) (C.sub.1-C.sub.6)-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulphur; or a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur and being unsubstituted or substituted with an oxo group; and a cycloalkyl group or a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulphur, said cycloalkyl or heterocycloalkyl groups being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from: a fluorine atom; a —OH group; a (C.sub.1-C.sub.6)-alkyl group; a —COOR7 group wherein R7 is a (C.sub.1-C.sub.6)-alkyl group; or an oxo group; or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I-A) according to claim 1, wherein SERM-F is selected from the following structures (aI), (bII), (cIII) and (dIV), provided that when A represents a nitrogen atom then SERM-F represents the structure (aI): ##STR00518## wherein: B, D, E and G represent independently ═CH— or nitrogen atoms; n is an integer selected from 0 and 1; X represents —CH.sub.2—, —O—, —S—, —SO— or —SO.sub.2—; when n=1 and X=CH.sub.2, then at least one of A, B, D, E or G is a nitrogen atom; R3 represents a hydrogen atom or an —OH, —COOH or —OPO(OH).sub.2 group; R4 represents a hydrogen, fluorine or chlorine atom or a methyl group; R5 represents a hydrogen, fluorine or chlorine atom, or a methyl or —OH group; wherein R3 and R5 do not simultaneously represent —OH groups or hydrogen atoms; R6 is selected from: a phenyl group, which is unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms or —OH groups; a halogen atom; an —OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms, (C.sub.1-C.sub.6)-alkoxy or heterocycloalkyl groups; a cyano group; a sulphur group substituted with 5 fluorine atoms or with a (C.sub.1-C.sub.6)-alkyl group substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with three (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkoxy groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur; a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; a —SO.sub.2NH.sub.2 group; a —COOH group; a —O-cycloalkyl group; a —O-heterocycloalkyl group; and a —OCD.sub.3 group; a heteroaryl group comprising 3 to 9 carbon atoms and comprising between 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, said heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; an —OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or with a (C.sub.1-C.sub.6)-alkyl group substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group wherein said (C.sub.1-C.sub.6)-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with three (C.sub.1-C.sub.6)-alkyl groups; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl or (C.sub.1-C.sub.6)-alkoxy groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur; a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; a —COO—(C.sub.1-C.sub.6)-alkyl group; and an oxo group; a cycloalkyl group comprising 4 to 9 carbon atoms, which is saturated or partially saturated, and which is unsubstituted or substituted with 1 to 4 substituents independently selected from: a fluorine atom; an —OH group; a (C.sub.1-C.sub.6)-alkyl group; a —COOR7 group wherein R7 is a (C.sub.1-C.sub.6)-alkyl group; and an oxo group; and a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur, said heterocycloalkyl group being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from: a fluorine atom; an —OH group; a (C.sub.1-C.sub.6)-alkyl group; a —COOR7 group wherein R7 is a (C.sub.1-C.sub.6)-alkyl group; and an oxo group; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein the compound is a compound of formula (I), wherein R1, R2, R3, R4, R5, R6, A, B, D, E, G, X and n are as defined in claim 3: ##STR00519## or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, characterized in that R6 is selected from: a phenyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from: a (C.sub.1-C.sub.6)-alkyl group unsubstituted or substituted with one or more fluorine atoms or —OH groups; a halogen atom; an —OH group; a (C.sub.1-C.sub.6)-alkoxy group unsubstituted or substituted with one or more fluorine atoms, (C.sub.1-C.sub.6)-alkoxy or heterocycloalkyl groups; a sulphur group substituted with a (C.sub.1-C.sub.6)-alkyl group substituted with two or more fluorine atoms; a sulfonyl-(C.sub.1-C.sub.6)-alkyl group; an amine group unsubstituted or substituted with one or more (C.sub.1-C.sub.6)-alkyl groups; an amide group substituted with an (C.sub.1-C.sub.6)-alkoxy group; a —SO.sub.2NH.sub.2 group; a —COOH group; a —O-cycloalkyl group; a —O-heterocycloalkyl group; and a —OCD.sub.3 group; a heteroaryl group selected from an indole, pyridinyl, benzofuran, isoxazole, quinolyl and thiazolyl group, said heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C.sub.1-C.sub.6)-alkyl group; a halogen atom; an —OH group; a (C.sub.1-C.sub.6)-alkoxy group; an amine group; an amide group substituted with a (C.sub.1-C.sub.6)-alkoxy group; and a heterocycloalkyl group selected from an indolinyl, dihydroazaindolinyl, dihydrobenzodioxinyl, benzodioxolyl, 2,3-dihydrobenzofuranyl, dihydrobenzoxazinyl and 5,6-dihydro-2H-pyranyl group, said heterocycloalkyl group being unsubstituted or substituted with 1 to 4 substituents independently selected from: a fluorine atom; a (C.sub.1-C.sub.6)-alkyl group; a —COOR7 group wherein R7 is a (C.sub.1-C.sub.6)-alkyl group; and an oxo group; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 3, wherein the compound is a compound of formula (I-2), wherein X, n, R1, R2, R3, R4, R5, R6, B, D, E and G are as defined in claim 3: ##STR00520## or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 3, wherein the compound is a compound of formula (I-3), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00521## or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 3, wherein the compound is a compound of formula (I-4), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00522## or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 3, wherein the compound is a compound of formula (I-5), wherein E, D, R1, R2, R3, R4, R5 and R6 are as defined in claim 3 and wherein one or two of E and D represent nitrogen atoms: ##STR00523## or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 3, wherein the compound is a compound of formula (I-6), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00524## or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 3, wherein the compound is a compound of formula (I-7), wherein n, R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00525## or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 3, wherein the compound is a compound of formula (I-8), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00526## or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 3, wherein the compound is a compound of formula (I-9), wherein D, R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00527## or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 3, wherein the compound is a compound of formula (I-10), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00528## or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 3, characterized in that they respond to wherein the compound is a compound of formula (I-11), wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00529## or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 3, wherein the compound is a compound of formula (I-12), wherein B, D, E, G, R1, R2, R3, R4, R5 and R6 are as defined in claim 3: ##STR00530## or a pharmaceutically acceptable salt thereof.

17. (canceled)

18. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

19. A method for inhibiting and/or degrading estrogen receptors, comprising administering to a person a compound according to claim 1.

20. A method of treating a disease or disorder, comprising administering to a patient in need thereof a compound according to claim 1 wherein the disease or disorder is chosen from ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy and inflammation.

21. The method according to claim 20, wherein the disease or disorder is an estrogen receptor dependent cancer.

22. The method according to claim 20, wherein the disease or disorder is breast, ovarian, endometrial, prostate, uterine, cervical or lung cancer, or a metastasis thereof.

23. The method according to claim 20, a wherein the cancer is resistant to anti-hormonal treatment.

Description

EXAMPLES

Example 1. 8-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-7-(3-fluoro-4-pyridyl)-5,6-dihydronaphthalen-2-ol

[0918] ##STR00478##

[0919] Method A:

[0920] To a solution of 7-bromo-8-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-5,6-dihydronaphthalen-2-ol (Intermediate Ig1, 150 mg, 336.06 μmol) in dioxane (1.6 ml), was added 3-fluoropyridin-4-yl boronic acid (52.09 mg, 369.66 μmol), Cs.sub.2CO.sub.3 (0.8 ml of a 1.5 N aqueous solution, 1.20 mmol), and Pd(dppf)Cl.sub.2 (12.94 mg, 16.80 μmol). The reaction mixture was heated at 70° C. for 2 hours. Water was added, and the reaction mixture was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of diisopropyl ether and MeOH (95/5 and 90/10; V:V) to give 56 mg (36%) of 8-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-7-(3-fluoro-4-pyridyl)-5,6-dihydronaphthalen-2-ol.

Example 16. 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol

[0921] ##STR00479##

[0922] To a solution of 3-bromo-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol (Intermediate Ig7, 80 mg, 0.17 mmol), in dioxane (2.6 ml) and water (0.7 ml), was added 2-fluoro-4-methylphenyl boronic acid (30 mg, 0.19 mmol), Cs.sub.2CO.sub.3 (118 mg, 0.36 mmol), and Pd(dppf)Cl.sub.2 (8 mg, 0.01 mmol). The reaction mixture was microwaved at 90° C. for 30 minutes. After cooling, the reaction mixture was concentrated under reduced pressure. The residue obtained was partitioned between water and DCM. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 05%; v/v) to give 20 mg (23%) of 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol as a beige solid.

Example 25. 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromene-7-carboxylic Acid

Step 1. [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl] trifluoromethanesulfonate

[0923] ##STR00480##

[0924] To a solution of 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol (Example 16, 426 mg, 863.03 μmol) in DCM (15 ml), was added pyridine (139.60 μl, 1.73 mmol) and trifluoromethanesulfonic anhydride (302.49 μl, 1.73 mmol). The reaction mixture was stirred at room temperature for 1 hour, and poured onto ice. The aqueous phase was extracted with DCM, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 132 mg (70%) of [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl] trifluoromethanesulfonate. LC/MS (m/z, MH.sup.+): 626

Step 2. 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromene-7-carboxylic Acid

[0925] ##STR00481##

[0926] To a solution of [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl]trifluoromethanesulfonate (277 mg, 442.73 μmol) in water (1.3 ml) was added pyridine (144 μL, 1.77 mmol), 1,1′-bis(diphenylphosphino)ferrocene (25.30 mg, 44.27 μmol), Pd(OAc).sub.2 (9.94 mg, 44.27 μmol), and molybdenum hexacarbonyl (58.50 mg, 221.36 μmol). The reaction mixture was microwaved at 150° C. for 20 minutes, and poured into water. The aqueous phase was extracted with EtOAc and the organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (0 to 20%; V/V) to give 65 mg (28.1%) of 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromene-7-carboxylic acid.

Example 29. 3-(2,2-dimethylindolin-5-yl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol

Step 1. 1-[5-[4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-7-hydroxy-2H-thiochromen-3-yl]-2,2-dimethyl-indolin-1-yl]ethanone

[0927] ##STR00482##

[0928] To a solution of 3-bromo-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol (Intermediate Ig7, 160 mg, 344.54 μmol) in a mixture of dioxane and water (8 ml; 80/20; V/V), was added 1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone (130.32 mg, 413.44 μmol), Pd(dppf)Cl.sub.2 (16.88 mg, 20.67 μmol), and Cs.sub.2CO.sub.3 (235.98 mg, 723.53 μmol). The reaction mixture was heated at reflux for 30 minutes, and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 140 mg 70.9%) of 1-[5-[4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-7-hydroxy-2H-thiochromen-3-yl]-2,2-dimethyl-indolin-1-yl]ethanone. LC/MS (m/z, MH.sup.+): 573

Step 2. 3-(2,2-dimethylindolin-5-yl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol

[0929] ##STR00483##

[0930] To a solution of 1-[5-[4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-7-hydroxy-2H-thiochromen-3-yl]-2,2-dimethyl-indolin-1-yl]ethanone (121 mg, 211.27 μmol) in dioxane (2.5 ml), was added hydrochloric acid (2N, 1.24 ml). The reaction mixture was microwaved at 120° C. for 1 hour and poured onto a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with EtOAc and the gathered organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 60 mg (53.5%) of 3-(2,2-dimethylindolin-5-yl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol.

Example 48. [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl] dihydrogen phosphate

Step 1. diethyl [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl]phosphate

[0931] ##STR00484##

[0932] To a solution of 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol (Example 16, 160 mg, 0.32 mmol), in tetrachloromethane (8 ml), was added diisopropylethylamine (0.21 ml, 1.04 mmol), and diethyl chlorophosphate (0.11 ml, 0.81 mmol). The reaction mixture was heated at 105° C. for 2 hours, and concentrated under reduced pressure. The residue was purified by strong cation exchange (SCX) column to give 160 mg (88%) of diethyl [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl]phosphate.

[0933] LC/MS (m/z, MH.sup.+): 629

Step 2 [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl] dihydrogen phosphate

[0934] ##STR00485##

[0935] To a solution of diethyl [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl] phosphate (80 mg, 0.13 mmol), in acetonitrile (3 ml), was added iodotrimethylsilane (0.09 ml, 0.64 mmol). The reaction mixture was stirred at 60° C. for 1.5 hours, and concentrated under reduced pressure. The residue was purified by strong cation exchange (SCX) column and reverse phase column chromatography, eluting with a gradient of acetonitrile in water (20% to 80%; v/v) to give 37 mg (51%) of [3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-yl] dihydrogen phosphate.

Example 57. 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-2H-thiochromen-7-ol

[0936] ##STR00486##

[0937] To a solution of 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol (Example 16, 50 mg, 101.29 μmol) in MeOH (4 ml) was added a solution of potassium peroxymonosulfate (OXONE®, 124.55 mg, 202.59 μmol) in water (1 ml) at 0° C. (ice bath). The reaction mixture was stirred for 30 minutes, and a solution of saturated sodium thiosulphate was added (5 ml) followed by a saturated solution of sodium bicarbonate until pH 7-8. The aqeuous phase was extracted with DCM and the gathered organic extracts, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (97/3; V/V) to give 35 mg (67.8%) of 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-2H-thiochromen-7-ol as a racemate.

Example 70. 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-2H-thiochromen-7-ol

[0938] ##STR00487##

[0939] 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-2H-thiochromen-7-ol (Example 57, 210 mg, 412.08 μmol) was separated by chiral HPLC on Chiralpak IC 20 μm column, eluting with a mixture of heptane, ethanol and triethylamine (70/30/0.1; V/V) to give 82.9 mg (39.5%) of diastereomer 1.

Example 71. 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-2H-thiochromen-7-ol

[0940] ##STR00488##

[0941] 3-(2-fluoro-4-methyl-phenyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-2H-thiochromen-7-ol (Example 57, 210 mg, 412.08 μmol) was separated by chiral HPLC on Chiralpak IC 20 μm column, eluting with a mixture of heptane, ethanol and triethylamine (70/30/0.1; V/V) to give 80.4 mg (38.3%) of diastereomer 2.

Example 72. 3-(6-amino-2-fluoro-3-pyridyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol

[0942] ##STR00489##

[0943] To a solution of tert-butyl N-[6-fluoro-5-[4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-7-hydroxy-2H-thiochromen-3-yl]-2-pyridyl]carbamate (Example 65, 94 mg, 157.80 μmol) in THF (5 ml) was added Hydrochloric acid (1.5 ml, 4M in dioxane, 40 eq.). The reaction mixture was heated at 50° C. for 16 hours, and poured into a saturated sodium bicarbonate solution. The aqueous phase was extracted with EtOAc and the gathered organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc to give 53 mg (67.8%) of 3-(6-amino-2-fluoro-3-pyridyl)-4-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2H-thiochromen-7-ol.

Example 84. 7-(2-chloro-4-fluoro-phenyl)-8-[4-[[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]amino]phenyl]-5,6-dihydronaphthalen-2-ol

[0944] ##STR00490##

[0945] To a solution of 7-(2-chloro-4-fluoro-phenyl)-8-[4-[[(3S)-pyrrolidin-3-yl]amino]phenyl]-5,6-dihydronaphthalen-2-ol (Intermediate 112, 78.6 mg, 180.72 μmol) in N,N-dimethylformamide (3.5 ml) was added potassium carbonate (18.73 mg, 135.54 μmol), and 1-fluoro-3-iodopropane (20.44 μl, 189.75 μmol). The reaction mixture was heated at 70° C. for 1 hour, and 30 ml of water was added. The aqueous phase was extracted with EtOAc, and the gathered organic extracts, were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (97/3; V/V) to give 41.5 mg (46%) of 7-(2-chloro-4-fluoro-phenyl)-8-[4-[[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]amino]phenyl]-5,6-dihydronaphthalen-2-ol.

Example 116. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-indolin-6-yl-2,3-dihydro-1-benzoxepin-8-ol

[0946] ##STR00491##

[0947] Method B:

[0948] To a solution of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-(1H-indol-6-yl)-2,3-dihydro-1-benzoxepin-8-ol (Example 103, 60 mg, 120.34 μmol) in acetic acid (6 ml), was added sodium cyanoborohydride (22.29 mg, 336.95 μmol). The reaction mixture was stirred at room temperature for 24 hours, and 20 ml of an aqueous sodium bicarbonate solution was added to reach pH 7. The aqueous phase was extracted with DCM, and the gathered organic phases dried over an hydrophobic column, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of MeOH in DCM (0 to 10%; V/V) to give 36 mg (59.8%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-indolin-6-yl-2,3-dihydro-1-benzoxepin-8-ol.

Example 166. 4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol

[0949] ##STR00492##

[0950] To a solution of 4-bromo-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol (Intermediate Ig20, 600 mg, 1.25 mmol), in dioxane (16 ml) and water (4 ml), was added 2,4-dichlorophenyl boronic acid (260 mg, 1.34 mmol), Cs.sub.2CO.sub.3 (859 mg, 2.63 mmol), and Pd(dppf)Cl.sub.2 (61 mg, 0.75 mmol). The reaction mixture was heated at 120° C. for 1 hour, and concentrated under reduced pressure. The residue was partitioned between water and DCM, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 05%; v/v) to give a solid which was further purified on strong cation exchange (SCX) column to give 409 mg (60%) of 4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol.

Example 198. 4-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol

Step 1. 1-[5-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8-hydroxy-2,3-dihydro-1-benzothiepin-4-yl]-2,2-dimethyl-indolin-1-yl]ethanone

[0951] ##STR00493##

[0952] To a solution of 4-bromo-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol (Intermediate Ig20, 160 mg, 334.44 μmol) in a mixture of dioxane and water (8 ml; 80/20; V/V), was added 1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone (126.50 mg, 401.32 μmol), Pd(dppf)Cl.sub.2 (16.39 mg, 20.07 μmol), and Cs.sub.2CO.sub.3 (229.06 mg, 702.32 μmol). The reaction mixture was heated at reflux for 1 hour, and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 112 mg (62.2%) of 1-[5-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8-hydroxy-2,3-dihydro-1-benzothiepin-4-yl]-2,2-dimethyl-indolin-1-yl]ethanone. LC/MS (m/z, MH.sup.+): 587

Step 2. 4-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol

[0953] ##STR00494##

[0954] To a solution of 1-[5-[5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8-hydroxy-2,3-dihydro-1-benzothiepin-4-yl]-2,2-dimethyl-indolin-1-yl]ethanone (100 mg, 170.43 μmol) in dioxane (2.5 ml), was added hydrochloric acid (2N, 1 ml). The reaction mixture was microwaved at 120° C. for 1 hour and poured onto a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with EtOAc and the gathered organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 81 mg (87.3%) of 4-(2,2-dimethylindolin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol.

Example 203. 4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic Acid

Step 1. [4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate

[0955] ##STR00495##

[0956] To a solution of 4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol (Example 166, 100 mg, 183.65 μmol) in DCM (5 ml), was added pyridine (23.21 μl, 275.48 μmol) and trifluoromethanesulfonic anhydride (62.42 μl, 367.30 μmol). The reaction mixture was stirred at room temperature for 1 hour, and poured onto ice. The aqueous phase was extracted with DCM, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 100 mg (80.5%) of [4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate. LC/MS (m/z, MH.sup.+): 676

Step 2. 4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic Acid

[0957] ##STR00496##

[0958] A mixture of [4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate (100 mg, 0.15 mmol), pyridine (0.12 ml, 1.48 mmol), water (0.5 ml), 1,1′-bis(diphenylphosphino)ferrocene (8 mg, 0.015 mmol), palladium acetate (3 mg, 0.015 mmol) and molybdenum hexacarbonyl (19 mg, 0.074 mmol) was microwaved at 150° C. for 20 minutes. The reaction mixture was partitioned between DCM (25 ml) and water (25 ml) and the phases were separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (0 to 10%, V/V) to give 7 mg (8%) of 4-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic acid.

Example 210. 4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic Acid

Step 1. [4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate

[0959] ##STR00497##

[0960] To a solution of 4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol (Example 164, 50 mg, 295.49 μmol) in DCM (7 ml), was added pyridine (37.34 μl, 443.23 μmol) and trifluoromethanesulfonic anhydride (100.43 μl, 590.98 μmol). The reaction mixture was stirred at room temperature for 1 hour, and poured onto ice. The aqueous phase was extracted with DCM, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 128 mg (67.7%) of [4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl]trifluoromethanesulfonate. LC/MS (m/z, MH.sup.+): 639

Step 2. 4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic Acid

[0961] ##STR00498##

[0962] A mixture of [4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate (127 mg, 198.53 μmol), pyridine (161.38 μl, 1.99 mmol), water (0.5 ml), 1,1′-bis(diphenylphosphino)ferrocene (11.35 mg, 19.85 μmol)), palladium acetate (4.46 mg, 19.85 μmol) and molybdenum hexacarbonyl (26.23 mg, 99.27 μmol) was microwaved at 150° C. for 20 minutes. The reaction mixture was partitioned between DCM (25 ml) and water (25 ml) was the phases were separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with with a gradient of MeOH in DCM (0 to 10%; V/V) to give 41 mg (38.6%) of 4-(2-fluoro-4-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic acid.

Example 211. 4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic Acid

Step 1. [4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate

[0963] ##STR00499##

[0964] To a solution of 4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-ol (Example 162, 150 mg, 286.21 μmol) in DCM (7 ml), was added pyridine (36.17 μl, 429.32 μmol) and trifluoromethanesulfonic anhydride (97.28 μl, 572.42 μmol). The reaction mixture was stirred at room temperature for 1 hour, and poured onto ice. The aqueous phase was extracted with DCM, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (2 to 5%; V/V) to give 180 mg (95.8) of [4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl]trifluoromethanesulfonate. LC/MS (m/z, MH.sup.+): 657

Step 2. 4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic Acid

[0965] ##STR00500##

[0966] A mixture of [4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepin-8-yl] trifluoromethanesulfonate (180 mg, 274.33 μmol), pyridine (222.99 μl, 2.74 mmol), water (0.5 ml), 1,1′-bis(diphenylphosphino)ferrocene (15.68 mg, 27.43 μmol), palladium acetate (6.16 mg, 27.43 μmol) and molybdenum hexacarbonyl (36.25 mg, 137.16 μmol) was microwaved at 150° C. for 20 minutes. The reaction mixture was partitioned between DCM (25 ml) and water (25 ml), and the phases were separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with with a gradient of MeOH in DCM (0 to 10%; V/V) to give 60 mg (39.6%) of 4-(4-chloro-3-methyl-phenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic acid.

Example 225. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol

[0967] ##STR00501##

[0968] To a solution of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1-benzothiepin-8-ol (Example 214, 450 mg, 804.12 μmol) in MeOH (40 ml) was added dropwise a solution of potassium peroxymonosulfate (OXONE®, 988.69 mg, 1.61 mmol) in water (10 ml) at 0° C. (ice bath). The reaction mixture was stirred for 20 minutes, and a saturated solution of sodium thiosulfate (50 ml) was added, followed by a saturated aqueous solution of sodium bicarbonate until pH 7-8. The aqueous phase was extracted with DCM and the gathered organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in dichlorormethane (3 to 5%; V/V) to give 235 mg (50.8%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol as a racemate.

Example 226. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol

[0969] ##STR00502##

[0970] 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol (Example 225, 210 mg, 363.95 μmol) was separated by chiral HPLC on Chiralpak AD 20 μm column, eluting with a mixture of heptane, ethanol and triethylamine (75/25/0.1; V/V) to give 101.9 mg (48%) of diastereomer 1. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol.

Example 227. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol

[0971] ##STR00503##

[0972] 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol (Example 225, 210 mg, 363.95 μmol) was separated by chiral HPLC on Chiralpak AD 20 μm column, eluting with a mixture of heptane, ethanol and triethylamine (75/25/0.1; V/V) to give 98.8 mg (47%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-1-oxo-4-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-benzothiepin-8-ol, diastereomer 2.

Example 228. 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-(3-hydroxyphenyl)-1,1-dioxo-2,3-dihydro-benzothiepin-8-ol

[0973] ##STR00504##

[0974] Method C:

[0975] To a solution of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-(3-hydroxyphenyl)-2,3-dihydro-1-benzothiepin-8-ol (Example 158, 59 mg, 120.01 μmol) in MeOH (2 ml), was added potassium peroxymonosulfate (OXONE®, 221.34 mg, 360.04 μmol) in solution in water (2 ml). The reaction mixture was stirred at room temperature for 3 hours, and 10 ml of a saturated thiosulfate solution was added, followed by a saturated sodium bicarbonate aqueous solution until pH 7-8 is reached. The aqueous phase was extracted with DCM, and the organic phase was dried over hydrophobic column, and evaporated under reduced pressure The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (from 0 to 10% V/V) to give 55 mg (87.5%) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-4-(3-hydroxyphenyl)-1,1-dioxo-2,3-dihydro-benzothiepin-8-ol.

Example 242. 6-(2,2-dimethylindolin-5-yl)-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

Step 1. 1-[5-[5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-2,2-dimethyl-indolin-1-yl]ethanone

[0976] ##STR00505##

[0977] To a solution of 6-bromo-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol (Intermediate It2, 80 mg, 173.40 μmol) in a mixture of dioxane and water (8 ml; 80/20; V/V), was added 1-(2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)ethanone (130.32 mg, 413.44 μmol), Pd(dppf)Cl.sub.2 (16.88 mg, 20.67 μmol), and Cs.sub.2CO.sub.3 (235.98 mg, 723.53 μmol). The reaction mixture was heated at 60° C. for 1 hour, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of MeOH and di-isopropyl ether (10/90; V/V) to give 81 mg (82%) of 1-[5-[5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-2,2-dimethyl-indolin-1-yl]ethanone. LC/MS (m/z, MH.sup.+): 570

Step 2. 6-(2,2-dimethylindolin-5-yl)-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

[0978] ##STR00506##

[0979] To a solution of 1-[5-[5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-2-hydroxy-8,9-dihydro-7H-benzo[7]annulen-6-yl]-2,2-dimethyl-indolin-1-yl]ethanone (80 mg, 140.42 μmol) in dioxane (2 ml), was added hydrochloric acid (2N, 0.8 ml). The reaction mixture was microwaved at 120° C. for 1 hour and poured onto a saturated aqueous solution of sodium bicarbonate. The aqueous phase was extracted with EtOAc and the gathered organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure The residue was purified by flash chromatography eluting with a mixture of MeOH and di-isopropyl ether (10/90; V/V) to give 42 mg (56.7%) of 6-(2,2-dimethylindolin-5-yl)-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 243. 6-(4-chloro-3-fluoro-phenyl)-5-[5-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxypyrazin-2-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

[0980] ##STR00507##

[0981] To a solution of 6-(4-chloro-3-fluoro-phenyl)-5-[5-[(3S)-pyrrolidin-3-yl]oxypyrazin-2-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol (Intermediate Iac2, 696 mg, 1.54 mmol) n N,N-dimethylformamide (20 ml) was added potassium carbonate (212.85 mg, 11.54 mmol), and 1-fluoro-3-iodopropane (182.48 μl, 1.69 mmol). The reaction mixture was heated at 70° C. for 1 hour, and poured into water. The aqueous phase was extracted with EtOAc, and the gathered organic extracts, were dried over magnesium sulfate, filtered, and concentrated under reduced pressure The residue was purified by flash chromatography eluting with a gradient of heptane and EtOAc (50/50 to 0/100; V/V) to give 482 mg (61.1%) of 6-(4-chloro-3-fluoro-phenyl)-5-[5-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxypyrazin-2-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 247. 6-(2,4-dichlorophenyl)-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid

[0982] ##STR00508##

[0983] To a solution of methyl 6-(2,4-dichlorophenyl)-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate(Intermediate (I)8, 80 mg, 140.48 μmol) in MeOH (5 ml) was added a solution of NaOH 5M (280.95 μl, 1.40 mmol) and the reaction mixture was heated to 60° C. for 1 hour and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous hydrochloric acid (5 M) added to pH 7. The slurry was extracted with DCM, dried over hydrophobic column and concentrated under reduced pressure. The residue was purified by column chromatography eluting first with a with a gradient of MeOH in DCM (0 to 15%; V/V) then a mixture of DCM/ammoniac 7N in MeOH (2/1; V/V), to give 56 mg (72%) of (S)-8-(2,4-dichlorophenyl)-9-(6-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a white powder.

Example 248. 6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[6-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid

Step 1. methyl 6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate

[0984] ##STR00509##

[0985] To a solution of methyl 6-bromo-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate (Intermediate Iag1, 100 mg, 198.65 μmol), in dioxane and water (3 ml; 80/20; V/V) was added 2-(4-difluoromethoxy-3-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (57.22 mg, 198.65 μmol), Cs.sub.2CO.sub.3 (136.06 mg, 417.16 μmol), and Pd(dppf)Cl.sub.2 (9.73 mg, 11.92 μmol). The reaction mixture was microwaved at 90° C. for 30 minutes, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 85 mg (73.2%) of methyl 6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate. LC/MS (m/z, MH.sup.+): 585

Step 2. 6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic Acid

[0986] ##STR00510##

[0987] To a solution of methyl 6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate (90 mg, 153.95 μmol) in MeOH (5 ml), was added sodium hydroxide (307.90 μl, 1.54 mmol). The reaction mixture was stirred at 60° C. for 1 hour, and water and hydrochloric acid (5M) were added until pH 7. The aqueous phase was extracted with DCM and the gathered organic extracts, dried over hydrophobic column and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (0 to 40%; V/V) to give 66 mg (75.1%) of 6-[4-(difluoromethoxy)-3-fluoro-phenyl]-5-[6-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-3-pyridyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

Example 254. 6-(4-chloro-3-fluoro-phenyl)-5-[5-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxypyrimidin-2-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol

[0988] ##STR00511##

[0989] To a solution of 6-(4-chloro-3-fluoro-phenyl)-5-[5-[(3S)-pyrrolidin-3-yl]oxypyrimidin-2-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol(Intermediate Iac4, 248 mg, 548.77 μmol) in N,N-dimethylformamide (5 ml) was added potassium carbonate (75.84 mg, 548.77 μmol), and 1-fluoro-3-iodopropane (65.02 μl, 603.65 μmol). The reaction mixture was heated at 70° C. for 3 hour, and poured over water. The aqueous phase was extracted with EtOAc, and the gathered organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (50 to 100%; V/V) to give 125 mg (44.5%) of 6-(4-chloro-3-fluoro-phenyl)-5-[5-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxypyrimidin-2-yl]-8,9-dihydro-7H-benzo[7]annulen-2-ol.

Example 255. 5-[(E)-2-(2-chloro-4-fluoro-phenyl)-1-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]but-1-enyl]-1H-indazole

[0990] ##STR00512##

[0991] The mixture of isomers 5-[(1E)-2-(2-chloro-4-fluorophenyl)-1-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)but-1-en-1-yl]-1H-indazole and 5-[(1Z)-1-(2-chloro-5-fluorophenyl)-2-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)but-1-en-1-yl]-1H-indazole (Intermediates III and III′, 523 mg, 0.1 mmol) was separated by chiral chromatography (column Chiralcel OD 10 μm, Dimension 250×30 mm, mobile phase: CO.sub.2 65% [MeOH 0.1% TEA] 35% to give 195 mg (37%) of 5-[(1E)-2-(2-chloro-4-fluorophenyl)-1-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)but-1-en-1-yl]-1H-indazole.

Example 256. 1-[2,6-difluoro-4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole

[0992] ##STR00513##

[0993] The mixture of trans isomers 1-[2,6-difluoro-4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (Intermediate IId, 130 mg, 0.25 mmol) was separated by chiral chromatography (column Chiralpak AD-H 5 μm, Dimension 3×25 cm, mobile phase: heptane 75% EtOH 25% TEA 0.1%) to give the first trans isomer 1 levogyre: 50.7 mg (39%). [α].sub.D.sup.20=−38.8+/−2.9, c=0.0958 in DMSO at 589 nm.

Example 257. 1-[2,6-difluoro-4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole

[0994] ##STR00514##

[0995] The mixture of trans isomers 1-[2,6-difluoro-4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (Intermediate IId, 130 mg, 0.25 mmol) were separated by chiral chromatography (column Chiralpak AD-H 5 μm, Dimension 3×25 cm, mobile phase: heptane 75% EtOH 25% TEA 0.1%) to give the second trans isomer 2 dextrogyre: 50.6 mg (39%). [α].sub.D.sup.20=+39.2+/−2.7, c=0.056 in DMSO at 589 nm.

Example 258. 2-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-3-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol

[0996] ##STR00515##

[0997] The mixture of isomers 2-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-3-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol (Intermediate IVk, 52 mg, 0.108 mmol) were separated by chiral chromatography (column Chiralpak AD 10 μm, Dimension 250×30 mm, mobile phase: heptane/ethanol/triethylamine 70/30/0.1) to give the stereomer 1: 13.5 mg (26%).

[0998] The compounds according to the invention were subjected to pharmacological tests for determining their antagonist, antiproliferative and degradation effects on estrogen receptors.

[0999] Test A: Biochemical Antagonist Activity on Wild Type (WT) and Mutants Estrogen Receptors

[1000] Test A involves measuring the in vitro antagonist activity of the compounds of the invention on estrogen receptors.

[1001] The measurements of the antagonist activities were made using an estrogen receptor coactivator assay as described hereunder.

[1002] Antagonistic potency of compounds was evaluated using LanthaScreen® TR-FRET ERα Coactivator Assay (ThermoFisher) with modifications. It is a competition assay, where binding of a test compound to a complex comprised of (i) His6-ERα298-554 protein representing ERα ligand-binding domain, (ii) Tb-labeled His6 antibody, (iii) a fluorescein-labeled PGC1a coactivator peptide (EAEEPSLLKKLLLAPANTQ), and (iv) estradiol, results in a decrease of the TR-FRET signal due to dissociation of the coactivator peptide. His6-ERα298-554 proteins were expressed as WT or D538G or Y537S mutants in E. coli and purified by affinity chromatography. The assay works in a homogeneous mix-and-read format. In a typical experiment, a 4 μL mixture of 0.5 nM His6-ERα298-554, 0.5 nM Tb-labeled His6 antibody, 250 nM PGC1a peptide, and 3 nM estradiol (or 10 nM estradiol) in 100 mM potassium phosphate, pH 7.4, 0.01% Tween-20, 0.02% NaN.sub.3, 5 mM DTT, was added to 40 nL test compound in DMSO and incubated overnight at room temperature. The TR-FRET 520:495 nm emission ratio was calculated and used to determine the IC50 value from a dose response curve fit to the 4-parameter logistic equation.

[1003] The antagonist activity with respect to estrogen receptors in this test is given by the concentration which inhibits 50% of the estrogen receptor activity (or IC50) in nM.

[1004] The Table 2 below indicates the biochemical results of antagonist activity on WT and mutants estrogen receptors for the compounds according to the invention, and demonstrates that the compounds tested have an antagonist activity regarding estrogen receptors. In table 2, the FIGURES indicated have been obtained using the above protocol with 3 nM estradiol, unless they are noted with an asterisk (*), which indicates a protocol using 10 nM estradiol.

TABLE-US-00002 TABLE 2 Antagonism Antagonism Antagonism WT D538G Y537S Examples IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) 1 460  N/A N/A 2 11    60.0   37.0 3 1511   N/A N/A 4 284  N/A N/A 5 28   209.0 72 6 2 13  8 7 1474*  >4000*  >4000*  8 1391*  >4000*  >4000*  9 2288*  >4000*  >4000*  10 1273*  >4000*  >4000*  11 >4000*   >4000*  >4000*  12 585  >4000*  >4000*  13 151*  2010*  1561*  14 225*  3310*  2303*  15 9 161  83 16 4 16  6 17 7 39 14 18 9 39 15 19 7 23 11 20 15  46 21 21 9 47 19 22 6 27  9 23 50* 803* 678* 24  5*  80*  44* 25 1420*  >4000*  >4000*  26 3 67 39 27  2*  38*  21* 28  4*  68*  41* 29 14* 240* 130* 30 34  694  415  31 5 101  59 32 19* 314* 168* 33 66* 1691*  596* 34  4*  83*  46* 35 16* 421* 220* 36 11* 257* 154* 37 41  745  475  38 604*  >4000*  3708* 39  9* 221* 127* 40 44* 901* 605* 41 27* 740* 407* 42 674*  >4000*  >4000*  43 96* 1135*  673* 44 172*  2926*  1818*  45  1*  34*  14* 46  5* 101*  59* 47 388*  >4000*  3051*  48 >4000*   >4000*  >4000*  49 37* 888* 472* 50 72* 1553*  1172*  51 350*  >4000*  3598*  52 351*  >4000*  2914*  53  2*  36*  25* 54 246*  3032*  2641*  55 48* 971* 444* 56 37* 721* 358* 57 1071*  >4000*  >4000*  58 27* 590* 295* 59 879*  >4000*  >4000*  60  9* 215* 103* 61 37* 686* 437* 62 27* 523* 271* 63 318*  >4000*  2450* 64 24* 492* 204* 65 1223*  >4000*  >4000*  66 59  1801  362  67 120*  1812*  1275*  68 104*  1835*  1151*  69 1568*  >4000*  >4000*  70 1658*  >4000*  >4000*  71 2744*  >4000*  >4000*  72 11* 202* 108* 73 1107*  >4000*  >4000*  74 322*  >4000*  2385* 75 2486*  >4000*  >4000*  76  4* 100*  61* 77 16* 323* 197* 78  1*  29*  15* 79    0.5*  6*  5* 80 12* 283* 154* 81 520*  >4000*  >4000*  82 297*  >4000*  2293*  83 81  1324  1162  84 30  1746  958  85  1*  21*  15* 86  0.5*  7*  5* 87 23* 568* 294* 88 12* 293* 159* 89 27* 726* 423* 90 12* 293* 165* 91 2 10  6 92 7 59 22 93 8 59 26 94 2 10  6 95 6 43 20 96 7 47 19 97 50  358  18 98 14  106  40 99 5 36 25 100 7 54 25 101 6 50 25 102 12  106  51 103 38  252  101  104 12  54 23 105 5 38 23 106 5 31 16 107 19  79 55 108 30  221  129  109 29  215  150  110 5 39 26 111 91  822  407  112 91  838  543  113 6 32 19 114 29  178  104  115 88  322  200  116 31  120  86 117 32  309  214  118 152  442  237  119 2 10  6 120 2  7  4 121 2 27 13 122 3 41 24 123 156  2287  1428  124 22  849  1243  125 190  1342  945  126 5 94 55 127 3 49 24 128 96  1212  933  129 502  >4000   2676  130 70  1193  777  131 19  340  276  132 28  473  334  133 4 64 39 134 19  328  225  135 21  591  352  136 4 59 44 137 250  1712  1218  138 18  360  253  139 68  1170  819  140 36  644  542  141 23  1504  1124  142 41  1820  1154  143 464  4000  4000  144 528  4000  4000  145 256  4000  3274  146 51* 1171*  845* 147 390*  >4000*  3814*  148 >4000*   >4000*  >4000*  149 23* 303* 289* 150 31* 489* 425* 151  6*  88*  68* 152  9* 154* 107* 153  6* 117*  86* 154  5*  77*  51* 155 21* 365* 228* 156 19* 409* 254* 157  2*  56*  36* 158 1  4  3 159 3 17 10 160 3 13  8 161 6 31 22 162 4 24 19 163 5 24 19 164 3 13  9 165 3 11  8 166 6 34 25 167 5 26 16 168 3 14  9 169 2  5  3 170 18  129  82 171 24  140  87 172 6 24 18 173 21  145  87 174 53  422  222  175 20  116  65 176 6 28 20 177 4 41 29 178 2 10  7 179 12  114  80 180 7 36 16 181 25  135  54 182 21  110  45 183 7 122  70 184 1  6  4 185   2.9 104  65 186  1*  21*  16* 187   1.5 43 22 188   8.2 266  157  189  2*  31*  19* 190 39* 638* 425* 191 3 51 32 192  9* 205* 109* 193  1*  25*  20* 194 10* 206* 141* 195 14* 335* 170* 196  3*  63*  36* 197  1*  20*  13* 198 1  8  6 199 21* 456* 316* 200  3*  51*  33* 201  1*  21*  15* 202  1*  15*  11* 203 65* 1446*  803* 204 24*  24*  15* 205  1*  16*  11* 206   0.7*  13*  9* 207  2*  9*  6* 208   0.6*  7*  5* 209  2*  35*  20* 210 103*  2224*  1334*  211 39* 964* 475* 212 34* 800* 412* 213  4*  96*  55* 214 38* 539* 457* 215  8* 190*  86* 216 33* 662* 543* 217  4*  61*  39* 218  1*  25*  22* 219 12* 233* 149* 220  8* 164*  84* 221 11* 265* 133* 222 18* 371* 238* 223  2*  42*  24* 224 71* 1478*  1029*  225 750*  >4000*  >4000*  226 >4000*   >4000*  >4000*  227 392*  3333*  3499*  228 6 73 38 229 12  85 34 230 14  99 41 231 38  240  141  232 16  99 78 233 20  128  70 234 9 59 33 235 13  100  83 236 8 54 29 237   0.6*  7*  5* 238  3*  59*  33* 239 13*  13*  9* 240  6*  6*  4* 241  1*  27*  16* 242  1*  9*  7* 243 12* 386* 179* 244  3*  67*  34* 245   0.4  4  3 246  2*  42*  26* 247  5* 136*  72* 248 141*  3443*  1917*  249  1*  24*  14* 250  7* 113*  70* 251  4* 104*  57* 252   0.7*  8*  9* 253  7* 155*  95* 254 2848*  >4000*  >4000*  255 15* 190* 140* 256  6* 120* 101* 257 3310*  >4000*  >4000*  258 203*  >4000*  2423*  N/A: not available

[1005] Test B: Cell Proliferation/Viability Assay on MCF7 (Breast Tumor Cells) WT and Mutants Cell Lines

[1006] Test B involves measuring the in vitro proliferation activity of the compounds of the invention by analyzing the viability of the tumor cells.

[1007] The measurements of the viability were made using a breast cancer cell viability assay as described hereunder.

[1008] MCF7 cells expressing (and dependent) on mutants estrogen receptor Tyr 537 Ser or Asp 538 Gly were generated by transfection of MCF7 parental cells (ATCC) with expression vectors coding for different mutants of estrogen receptor Tyr 537 Ser or Asp 538 Gly. The cells were first selected by antibiotic (related to vector expression) and then selected for their growth dependence on estrogen receptor based on their ability to grow in vitro in absence of estradiol (parental cell line die in absence of estradiol).

[1009] MCF7 cells (ATCC) or MCF7 cells expressing (and dependent) on mutants estrogen receptor Tyr 537 Ser or Asp 538 Gly were seeded in 384 wells microplate at concentration of >999 cells/30 μL per well in red phenol free MEM medium containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound were added to the cells in 20 μL at final concentrations ranging from 3-0.000001 μM. After 7 days of compound exposure, 50 μL of CellTiter-Glo (promega) was added to the cells and relative luminescence arbitrary units (RLUs) were determined in luminescence plate reader (Envision device). CellTiter-Glo was added to 50 μL medium without cells to determine the background signal.

[1010] The percent of viability of each sample was determined as follows: (RLU sample−RLU background/RLU untreated−RLU background)*100=% viability.

[1011] The viability activity with respect to estrogen receptors in this test is given by the concentration which inhibits 50% of the viability activity (or IC50) in nM.

[1012] The Table 3 below indicates the cell proliferation/viability assay results on MCF7 (breast tumor cells) WT and mutants cell lines, for some of the compounds according to the invention, and demonstrates that the compounds tested have a significant antiproliferative activity regarding estrogen receptors.

TABLE-US-00003 TABLE 3 proliferation proliferation proliferation MCF7 MCF7 MCF7 (WT) Y537S D538G Examples IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) 1 N/A N/A N/A 2 N/A N/A N/A 3 N/A N/A N/A 4 N/A N/A N/A 5 N/A N/A N/A 6 N/A N/A N/A 7 13   >999   18   8 >999    >999   >999    9 44   >999   47   10 85   >999   29   11 44   >999   162    12 1   9 5   13 0.4 8 3   14 0.5 6 1   15 0.2 30  25   16 0.9 10  2   17 0.4 3 1   18 0.5 7 1   19 N/A N/A N/A 20 N/A N/A N/A 21 N/A N/A N/A 22 N/A N/A N/A 23 7   >999   14   24 0.3 6 0.9 25 16   160  31   26 0.9 10  2   27 0.4 6 2   28 0.7 11  2   29 0.4 6 0.9 30 1   16  2   31 0.4 6 1   32 0.4 6 1   33 4   22  2   34 0.5 4 0.5 35 0.2 2 0.3 36 0.5 3 0.5 37 0.6 4 0.6 38 12.00 >999   16   39 0.4 2 0.5 40 1   20  2   41 0.9 4 1   42 46   809  31   43 0.4 11  1   44 >999    >999   >999    45 0.1 2 0.6 46 0.1 2 0.5 47 17   103  38   48 1   17  6   49 0.3 3 0.9 50 0.6 7 2   51 91   230  148    52 2   41  3   53 0.2 5 0.2 54 3   21  3   55 0.7 5 0.3 56 0.6 14  0.7 57 33   >999   >999    58 2   5 0.8 59 27   >999   >999    60 0.5 3 0.4 61 2   17  0.6 62 0.4 6 0.2 63 5   >999   5   64 1   5 0.7 65 21   572  21   66 2   8 2   67 12   86  16   68 14   125  7   69 0.2   0.8 0.2 70 64   478  97   71 12   414  88   72 2   1 0.5 73 95   377  119    74 12   173  16   75 63   >999   74   76 0.6 6 1   77 2   29  5   78 0.3 4 0.9 79 0.3   0.8 5   80 0.3 3 0.4 81 18   17  3.5 82 15   18  1   83 2   18  13   84 0.4 6 2   85 0.4 7 0.7 86 0.2 1 0.2 87 0.2 3 1   88 0.3 3 0.6 89 0.4 5 1   90 0.3 4 0.5 91 N/A N/A N/A 92 N/A N/A N/A 93 N/A N/A N/A 94 N/A N/A N/A 95 N/A N/A N/A 96 2   16  5   97 N/A N/A N/A 98 0.5 5 2   99 N/A N/A N/A 100 N/A N/A N/A 101 N/A N/A N/A 102 0.5 5 0.8 103 0.3 4 1   104 N/A N/A N/A 105 0.5 11  2   106 0.7 12  3   107 19   147  33   108 N/A N/A N/A 109 N/A N/A N/A 110 1   45  6   111 N/A N/A N/A 112 N/A N/A N/A 113 5   31  14   114 N/A N/A N/A 115 N/A N/A N/A 116 6   150  17   117 N/A N/A N/A 118 N/A N/A N/A 119 0.6 5 0.5 120 1   10  2   121 0.3 3 1   122 N/A N/A N/A 123 N/A N/A N/A 124 8   165  33   125 N/A N/A N/A 126 N/A N/A N/A 127 N/A N/A N/A 128 N/A N/A N/A 129 245    >999   456    130 N/A N/A N/A 131 N/A N/A N/A 132 N/A N/A N/A 133 N/A N/A N/A 134 N/A N/A N/A 135 N/A N/A N/A 136 N/A N/A N/A 137 N/A N/A N/A 138 2   51  7   139 N/A N/A N/A 140 N/A N/A N/A 141 1   22  4   142 8   154  34   143 24   357  63   144 38   653  64   145 9   124  17   146 6   69  12   147 52   >999   90   148 222    >999   314    149 0.5 12  2   150 0.4 14  2   151 0.3 7 1   152 0.5 4 3   153 0.3 3 0.7 154 0.2 4 0.6 155 0.4 6 1   156 0.6 14  2   157 0.2 4 0.6 158 N/A N/A N/A 159 N/A N/A N/A 160 N/A N/A N/A 161 N/A N/A N/A 162 0.4 5 1   163 N/A N/A N/A 164 0.6 5 0.6 165 N/A N/A N/A 166 0.2 8 1   167 N/A N/A N/A 168 N/A N/A N/A 169 N/A N/A N/A 170 N/A N/A N/A 171 N/A N/A N/A 172 0.2 12  2   173 N/A N/A N/A 174 N/A N/A N/A 175 N/A N/A N/A 176 3   48  9   177 N/A N/A N/A 178 0.5 16  2   179 N/A N/A N/A 180 N/A N/A N/A 181 N/A N/A N/A 182 N/A N/A N/A 183 1   73  5   184 0.3 4 0.7 185 0.4 6 1   186 0.3 5 0.4 187 0.2 4 0.7 188 0.2 4 2   189 0.2 4 1   190 0.2 6 0.8 191 0.3 3 0.4 192 0.3 5 0.9 193 0.3 5 0.5 194 0.2 3 0.4 195 0.3 3 0.7 196 0.4 6 1   197 0.3 5 0.6 198 0.4 6 1   199 0.2 4 0.2 200 0.7 12  2   201 0.2 8 1   202 0.4 6 1   203 0.8 13  1   204 0.4 5 0.8 205 0.2 3 0.2 206 0.3 4 0.7 207 0.1 2 0.3 208 0.2 4 0.7 209 0.3 4 0.7 210 0.8 15  1   211 0.4 10  0.6 212 0.4 3 0.5 213 0.3 2 0.2 214 0.4 6 0.7 215 0.1 3 0.2 216 0.6 13  1   217 0.1 5 0.6 218 0.1 1 0.1 219 0.1 2 0.4 220 0.4 5 0.5 221 0.5 8 0.6 222 4   1 0.4 223 1     0.1 0.2 224 3   83  8   225 18   249  36   226 87   >999   288    227 6   134  9   228 N/A N/A N/A 229 N/A N/A N/A 230 N/A N/A N/A 231 N/A N/A N/A 232 N/A N/A N/A 233 N/A N/A N/A 234 N/A N/A N/A 235 N/A N/A N/A 236 N/A N/A N/A 237 0.3 5 0.7 238 0.3 3 0.5 239 0.3 3 1   240 0.3 3 0.5 241 0.1 2 0.2 242 0.7 11  2   243 0.2 3 0.5 244 0.9 6 2   245 0.3 3 0.1 246 0.4 7 0.4 247 0.2 6 0.4 248 0.7 15  1   249 0.3 4 0.6 250 0.3 4 0.3 251 0.4 5 0.5 252 0.6 9 0.4 253 0.1 2 0.1 254 16   129  17   255 0.1 6 0.9 256 0.1 2 0.7 257 18   272  85   258 6   17  1   N/A: not available

[1013] Test C: Estrogen Receptor Degradation Activity

[1014] Test C involves measuring the in vitro degradation activity of the compounds of the invention.

[1015] The measurements of the degradation activities were made using a breast cancer cell ERα in cell western assay as described hereunder.

[1016] MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at concentration of >9990 cells/30 μL per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound were added to the cells in 2.5 μL at final concentrations ranging from 3-0.000018 μM or 0.1 μM for fulvestrant (using as positive control). At 4 hours post compounds addition the cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 μL anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted at 1:>999 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37° C. for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:>999) and Syto-64 a DNA dye (2 μM final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech). Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ERα and DNA respectively.

[1017] The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC50) in nM.

[1018] The % of ERα levels decrease were determined as follows: % inhibition=100*(1−(sample−fulvestrant: DMS−fulvestrant)).

[1019] The Table 4 below indicates the estrogen receptor degradation activity results for some of the compounds according to the invention, and demonstrates that compounds tested have a significant degradation activity on estrogen receptors, namely more than 70%, and more than 80% for most of the tested compounds.

TABLE-US-00004 TABLE 4 Degradation % Degradation Examples IC.sub.50 (nM) at 3 μM 1 34 84 2 0.3 84 3 85 80 4 12 87 5 0.5 81 6 0.2 84 7 22 82 8 25 84 9 28 79 10 15 78 11 49 80 12 5 89 13 2 87 14 3 89 15 0.3 89 16 1 90 17 2 87 18 0.6 90 19 3 78 20 3 86 21 3 92 22 1 95 23 0.3 93 24 0.2 91 25 19 93 26 0.8 90 27 0.6 94 28 0.3 80 29 0.2 92 30 1 91 31 0.7 86 32 0.8 87 33 1 84 34 0.4 85 35 1 89 36 0.2 83 37 3 83 38 12 86 39 0.7 86 40 0.2 81 41 1 85 42 11 89 43 0.8 97 44 8 89 45 0.2 87 46 0.2 83 47 1 84 48 0.8 89 49 0.2 89 50 0.2 84 51 12 85 52 1 84 53 0.2 84 54 1 74 55 0.2 88 56 0.2 86 57 3 89 58 0.2 78 59 0.9 81 60 0.2 73 61 0.2 82 62 0.2 80 63 0.3 86 64 0.2 81 65 38 71 66 0.2 84 67 1 90 68 0.6 87 69 0.2 81 70 25 73 71 11 75 72 0.2 91 73 6 86 74 4 83 75 27 92 76 0.6 88 77 1 91 78 0.2 88 79 0.2 89 80 0.2 89 81 7 77 82 7 86 83 2 75 84 2 78 85 1 86 86 0.5 95 87 0.4 83 88 0.2 88 89 1 91 90 0.4 91 91 0.4 91 92 0.5 96 93 0.4 87 94 0.2 87 95 0.2 93 96 0.6 91 97 0.2 94 98 0.5 93 99 0.7 89 100 0.2 88 101 0.6 92 102 2 87 103 3 89 104 0.2 88 105 0.2 91 106 0.5 90 107 2 82 108 3 86 109 1 90 110 0.2 87 111 6 86 112 4 87 113 0.7 80 114 5 71 115 6 77 116 2 88 117 3 92 118 126 74 119 1 91 120 0.7 91 121 0.2 90 122 0.3 91 123 15 81 124 5 76 125 4 84 126 0.3 91 127 0.8 90 128 14 72 129 44 75 130 18 73 131 3 83 132 2 88 133 2 83 134 3 85 135 3 87 136 1 79 137 5 75 138 0.5 89 139 9 73 140 3 85 141 2 87 142 2 83 143 14 74 144 18 75 145 0.5 82 146 2 86 147 49 77 148 448 77 149 0.9 91 150 4 82 151 0.4 90 152 0.2 92 153 0.2 91 154 0.2 92 155 0.2 81 156 0.4 85 157 0.2 90 158 0.2 88 159 0.5 89 160 0.2 75 161 0.7 93 162 0.8 90 163 0.6 94 164 0.5 91 165 0.2 90 166 2 90 167 0.5 87 168 0.7 86 169 0.2 85 170 1 81 171 0.2 85 172 0.4 87 173 4 82 174 4 81 175 0.3 83 176 0.2 85 177 0.2 75 178 0.4 87 179 4 80 180 3 80 181 3 83 182 5 79 183 1 83 184 0.7 87 185 0.7 84 186 0.6 85 187 0.5 92 188 0.8 90 189 0.3 88 190 0.5 91 191 0.2 95 192 0.4 91 193 0.2 91 194 0.2 89 195 0.4 97 196 0.3 93 197 0.2 88 198 0.2 87 199 0.4 94 200 0.5 91 201 0.8 85 202 0.5 89 203 0.6 93 204 0.6 88 205 0.4 84 206 0.4 85 207 0.5 85 208 0.4 86 209 0.4 92 210 2 89 211 0.3 93 212 2 90 213 0.9 86 214 1 82 215 0.2 93 216 0.2 88 217 0.2 87 218 0.2 78 219 0.2 90 220 0.2 89 221 0.2 84 222 1 80 223 0.2 85 224 3 85 225 6 82 226 103 93 227 4 90 228 0.2 87 229 0.2 89 230 0.8 93 231 2 96 232 0.2 95 233 0.2 94 234 0.2 90 235 0.9 95 236 0.3 91 237 0.2 92 238 0.5 87 239 0.6 87 240 0.3 89 241 0.2 85 242 0.8 83 243 0.3 91 244 0.4 92 245 0.5 87 246 0.5 82 247 0.2 93 248 0.7 95 249 0.3 87 250 0.5 87 251 0.5 89 252 0.2 86 253 0.2 85 254 10 84 255 0.6 92 256 0.2 91 257 37 87 258 5 77

[1020] It is therefore apparent that the compounds of the invention have degradation activities for estrogen receptors, and that most of them have as well antagonist and/or antiproliferative activity. The compounds according to the invention can therefore be used for preparing medicaments, especially medicaments which are antagonists and degraders of estrogen receptors.

[1021] Accordingly, in another of its aspects, the invention provides medicaments which comprise a compound of the formula (I-A), (I) or (I′) or a pharmaceutically acceptable salt thereof.

[1022] The invention also relates to the compounds of formula (I-A), (I) or (I′) defined above, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors.

[1023] The invention also relates to the compounds of formula (I-A), (I) or (I′) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[1024] In particular, the invention relates to the compounds of formula (I-A), (I) or (I′) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[1025] In an embodiment, the cancer is a hormone dependent cancer.

[1026] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.

[1027] In another embodiment, the cancer is a cancer with wild type estrogen receptors.

[1028] In another embodiment, the cancer is a cancer with deregulated function of estrogen receptors related to, but not limited to, at least one epigenetic and genetic alteration of estrogen receptors such us mutation, amplification, splice variant.

[1029] In another embodiment, the cancer is a cancer with mutated estrogen receptors.

[1030] In another embodiment, the mutations of estrogen receptors can include, but not limited to, new or known mutations such us Leu536Arg, Tyr537Ser, Tyr537Asn, Asp538Gly.

[1031] In another embodiment, the cancer is an estrogen-sensitive cancer.

[1032] In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical or lung cancer, or a metastasis thereof.

[1033] In another embodiment, the metastasis is a cerebral metastasis.

[1034] In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERα positive breast cancer).

[1035] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[1036] In a further embodiment, the anti-hormonal treatment is as single agent or in combination with other agents such as CDK4/6 or PI3K inhibitors.

[1037] In a further embodiment, the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a non-steroidal aromatase inhibitor.

[1038] The present invention, according to another of its aspects, also relates to a method of treating the pathological conditions indicated above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I-A), (I) or (I′) defined above, or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.

[1039] The present invention also relates to the use of a compound of the formula (I-A), (I) or (I′) defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for treating any of the pathological conditions indicated above, more particularly for treating cancer.

[1040] According to another of its aspects, the present invention relates to pharmaceutical compositions comprising as active principle a compound of the formula (I-A), (I) or (I′) defined above, or a pharmaceutically acceptable salt thereof. These pharmaceutical compositions comprise an effective dose of at least one compound compound of the formula (I-A), (I) or (I′), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[1041] The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[1042] In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active principle of formula (I-A), (I) or (I′) above, or its pharmaceutically acceptable salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.

[1043] The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants. For topical application it is possible to use the compounds according to the invention in creams, gels, ointments or lotions.

[1044] As an example, a unit administration form of a compound according to the invention in tablet form may comprise the following components:

TABLE-US-00005 Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

[1045] There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.