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1. WO2019200217 - COMPOUNDS AND METHODS FOR SELECTIVE PROTEOLYSIS OF GLUCOCORTICOID RECEPTORS

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

What is claimed is:

1. A compound of structural Formula I


or a salt thereof, wherein:

E is an E3 ligase ligand;

L is chosen from *-(CH2)nCH2N(R7)CO(CH2)pCH2-**, *-CO(CH2)nCH2-**, *-CO(CH2)qO(CH2CH2O)nCH2(CH2)p-**, *-(CH2)nCH2-* * *_ (CH2)qO(CH2CH2O)nCH2(CH2)p-**,


* represents the point of attachment to E;

** represents the point of attachment to X;

X is chosen from O, NR10, S, SO, and SO2;

R1 and R2 are independently chosen from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenyl, alkynyl, halo, alkylamino, dialkylamino, cyano, and hydroxy;

R3 and R4 are independently chosen from H, alkyl, alkoxy, alkenyl, alkylnyl, and hydroxyl, or

R3 and R4, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl ring, either of which is optionally substituted with 1, 2, or 3 R11 groups;

R5 and R6 are independently chosen from H, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, CONR12R13, SO2NR12R13, SOR14, SO2R14, halo, hydroxy, and cyano, or

R5 and R6, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl ring, either of which is optionally substituted with 1, 2, or 3 R15 groups;

R7 is chosen from H, alkyl, cycloalkyl, (cycloalkyl)alkyl, (CH2)tCOOH, alkylcarbonyl, and -CO(CH2)tCOOH;

R8 and R9 are independently chosen from H, alkyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, -(CH2)tCOOH, - CO(CH2)tCOOH, -COO(CH2)tCOOH, and -(CH2)tSO2OH.

R10 is chosen from H, alkyl, alkoxyalkyl, cycloalkyl, and heterocycloalkyl; each R11 is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy;

each R12 and R13 is independently chosen from H, alkyl, cycloalkyl, and heterocycloalkyl;

each R14 is independently chosen from alkyl, cycloalkyl, and heterocycloalkyl; each R15 is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy;

n and p are independently chosen from 0-11, inclusive;

q is chosen from 0-11, inclusive;

r and s are independently chosen from 1-4, inclusive; and

t is chosen from 1-8, inclusive.

2. The compound as recited in claim 1 wherein:

E is chosen from
3. The compound as recited in claim 2, wherein:

R3 and R4 are independently chosen from H, alkyl, alkoxy, alkenyl, alkynyl, and hydroxyl, or

R3 and R4, together with the atom to which they are attached, form a cycloalkyl ring which is optionally substituted with 1, 2, or 3 R11 groups, or

R3 and R4, together with the atom to which they are attached, form a heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 R11 groups, and which contains 1 or 2 groups selected from -O-, -NH-, -S-, -SO-, and -SO2-.

4. The compound as recited in claim 3, wherein

at least one of R3 and R4 is chosen from alkenyl and alkynyl.

5. The compound as recited in claim 4, wherein

R1 and R2 are independently chosen from H, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, halo, alkylamino, dialkylamino, cyano, and hydroxy.

6 The compound as recited in claim 5, wherein X is NR10.

7. The compound as recited in claim 6, wherein R10 is chosen from H and alkyl.

8 The compound as recited in claim 7, wherein R7 is chosen from H, alkyl, and cycloalkyl.

9. The compound as recited in claim 1, having structural Formula (II)


or a salt thereof, wherein:

E is an E3 ligase ligand;

L is chosen from *-(CH2)nCH2N(R7)CO(CH2)pCH2-**, *-CO(CH2)nCH2-**,

CO(CH2)qO(CH2CH2O)nCH2(CH2)p-* * , *-(CH2)nCH2-**, *

(CH2)qO(CH2CH2O)nCH2(CH2)p-**,

* represents the point of attachment to E;

** represents the point of attachment to X;

X is chosen from O, NR10, S, SO, and SO2;

R1 and R2 are independently chosen from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenyl, alkynyl, halo, alkylamino, dialkylamino, cyano, and hydroxy;

R5 and R6 are independently chosen from H, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, CONR12R13, SO2NR12R13, SOR14, SO2R14, halo, hydroxy, and cyano, or

R5 and R6, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl ring, either of which is optionally substituted with 1, 2, or 3 R15 groups;

R7 is chosen from H, alkyl, cycloalkyl, (cycloalkyl)alkyl, (CH2)tCOOH, alkylcarbonyl, and -CO(CH2)tCOOH;

R8 and R9 are independently chosen from H, alkyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, -(CH2)tCOOH, - CO(CH2)tCOOH, -COO(CH2)tCOOH, and -(CH2)tSO2OH.

R10 is chosen from H, alkyl, alkoxyalkyl, cycloalkyl, and heterocycloalkyl;

each R11 is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy;

each R12 and R13 is independently chosen from H, alkyl, cycloalkyl, and heterocycloalkyl;

each R14 is independently chosen from alkyl, cycloalkyl, and heterocycloalkyl; each R15 is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy;

n and p are independently chosen from 0-11, inclusive;

q is chosen from 0-11, inclusive;

r and s are independently chosen from 1-4, inclusive; and

t is chosen from 1-8, inclusive.

10. A compound chosen from

or a salt thereof.


11. A compound as recited in any one of claims 1-10 for use as a medicament.

12. A compound as recited in any one of claims 1-10 for use in the treatment of cancer.

13. A compound as recited in any one of claims 1-10 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of the glucocorticoid receptor

14. A pharmaceutical composition comprising a compound as recited in any one of claims 1- 10 together with a pharmaceutically acceptable carrier.

15. A method of inhibition of the glucocorticoid receptor comprising contacting the glucocorticoid receptor with a compound as recited in any one of claims 1-10.

16. A method of degradation of the glucocorticoid receptor comprising contacting the glucocorticoid receptor with a compound as recited in any one of claims 1-10.

17. The method of degradation as recited in claim 16, wherein said degradation is selective for the glucocorticoid receptor as compared to other nuclear receptors.

18. The method of degradation as recited in claim 16, wherein said degradation does not decrease at elevated levels of said compound.

19. A method of treatment of a glucocorticoid receptor-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in any one of claims 1-10 to a patient in need thereof.

20. The method as recited in claim 19 wherein said disease is cancer.

21. The method as recited in claim 20, wherein said cancer is characterized by high expression of the glucocorticoid receptor.

22. The method as recited in claim 21, wherein said cancer is chosen from prostate cancer, breast cancer, ovarian cancer, and endometrial cancer.

23. The method as recited in claim 22, wherein said cancer is prostate cancer.

24. The method as recited in claim 23, wherein said prostate cancer is castration resistant prostate cancer.

25. The method as recited in claim 22, wherein said cancer is breast cancer.

26. The method as recited in claim 25, wherein said breast cancer is triple negative breast cancer.

27. The method as recited in claim 22, wherein said cancer is ovarian cancer.

28. The method as recited in claim 22, wherein said cancer is endometrial cancer.

29. The method as recited in claim 19, wherein said disease is an inflammatory disease.

30. The method as recited in claim 29, wherein said inflammatory disease is chosen from inflammatory bowel disease, systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, cirrhosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis, plaque psoriasis, and psoriatic arthritis.

31. The method as recited in claim 19, wherein said disease is a topical disease.

32. The method as recited in claim 31, wherein said topical disease is chosen from inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous

pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitis, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma and ocular diseases.

33. A method of treatment of cancer comprising the administration of:

a. a therapeutically effective amount of a compound as recited in any one of claims 1-10; and

b. another therapeutic agent.

34. The method as recited in claim 33 wherein said other agent is chosen from Abiraterone Acetate, Apalutamide, Bicalutamide, Cabazitaxel, Casodex (Bicalutamide), Degarelix, Docetaxel, Enzalutamide, Erleada (Apalutamide), Flutamide, Goserelin Acetate, Jevtana (Cabazitaxel), Leuprolide Acetate, Lupron (Leuprolide Acetate), Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped (Leuprolide Acetate), Mitoxantrone Hydrochloride, Nilandron (Nilutamide), Nilutamide, Provenge (Sipuleucel-T), Radium 223 Dichloride, Sipuleucel-T, Taxotere (Docetaxel), Viadur (Leuprolide Acetate), Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamide), Zoladex (Goserelin Acetate), and Zytiga (Abiraterone Acetate).

35. A method for treating cancer with a reduced incidence of one or more side effects in a patient comprising the administration of a therapeutically effective amount of a compound as recited in any one of claims 1-10 to a patient, wherein the effect is chosen from weight loss, loss of appetite, anemia, bone pain, neurologic defects from spinal cord compression, lower extremity pain, and lower extremity edema.

36. The method as recited in any of claims 19-35 wherein the therapeutically effective amount of the compound is not limited by competition of the ligand for ternary complex formation.