2-[1-PHENYL-5-HYDROXY-4a-SUBSTITUTED-HEXAHYDROCYCLOPENTA[F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS

1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:

wherein

“ ” is an optional double bond;

X is —CH═ or —N═;

R 1 is selected from the group consisting of:

(1) phenyl, and

(2) HET;

wherein each of items (1) and (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(c) —C(O)—R a ,

(d) —C(O)—OR a ,

(e) —C(O)NR a R b ,

(f) C 1 -6alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NR a R b ,

(g) C 3-6 cycloalkyl,

(h) —SO 2 R a , and

(i) nitrile;

R 2 is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl, and

(3) hydroxy;

R 3 is selected from the group consisting of:

(1) ethyl,

(2) —CH 2 CF 3 , and

(3) cyclopropyl;

each of R 4 and R 5 is independently selected from the group consisting of:

(1) hydrogen, and

(2) halogen; and

each of R a and R b is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, C 3-6 cycloalkyl, and —C(O)NH 2 , and

(3) C 3-6 cycloalkyl, optionally substituted with one to three groups selected from halogen, C 1-6 alkyl, and C 1-6 alkoxy; and

HET is selected from the group consisting of: pyridazinyl, pyridyl, pyrimidyl, furanyl, thiazolyl, and oxazolyl.

2 . The compound of claim 1 , wherein

R 1 is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

wherein each of items (1) to (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(c) —C(O)—R a ,

(d) —C(O)—OR a ,

(e) —C(O)NR a R b ,

(f) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NR a R b ,

(g) C 3-6 cycloalkyl,

(h) —SO 2 R a , and

(i) nitrile.

3 . The compound of claim 1 , wherein

X is —CH—; and

R 1 is pyridyl, wherein the pyridyl is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b)—OR a ,

(c)—C(O)—OR a ,

(d) —C(O)—OR a ,

(e) —C(O)NR a R b ,

(f) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NR a R b ,

(g) C 3-6 cycloalkyl,

(h) —SO 2 R a , and

(i) nitrile.

4 . The compound of claim 1 , wherein

X is —N═; and

R 1 is selected from the group consisting of

(1) phenyl, and

(2) pyridyl;

wherein each of items (1) to (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(c) —C(O)—R a ,

(d) —C(O)—OR a ,

(e) —C(O)NR a R b ,

(f) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NR a R b ,

(g) C 3-6 cycloalkyl,

(h) —SO 2 R a , and

(i) nitrile.

5 . The compound of claim 1 , wherein

R 2 is hydrogen or hydroxy.

6 . The compound of claim 1 , wherein

R 3 is selected from the group consisting of:

(1) ethyl, and

(2) cyclopropyl.

7 . The compound of claim 1 , wherein

each of R 4 and R 5 is independently selected from the group consisting of:

(1) hydrogen,

(2) chloro,

(3) fluoro, and

(4) bromo.

8 . The compound of claim 1 , wherein

each of R a and R b is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, cyclopropyl, and —C(O)NH 2 , and

(3) cyclopropyl, optionally substituted with one to three groups selected from halogen, methyl, ethyl, propyl, methoxy, and ethoxy.

9 . The compound of claim 1 of Formula Ia:

wherein

R 1 is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

wherein each of items (1) and (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(e) —C(O)—R a ,

(d) —C(O)—OR a ,

(f) —C(O)NR a R b ,

(f) C 1-6 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NR a R b ,

(g) C 3-6 cycloalkyl,

(h) —SO 2 R a , and

(i) nitrile;

R 2 is hydrogen or hydroxy;

R 3 is selected from the group consisting of:

(1) ethyl, and

(2) cyclopropyl;

each of R 4 and R 5 is independently selected from the group consisting of:

(1) hydrogen, and

(2) halogen; and

each of R a and R b is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, cyclopropyl, and —C(O)NH 2 , and

(3) cyclopropyl, optionally substituted with one to three groups selected from halogen, methyl, ethyl, propyl, methoxy, and ethoxy.

10 . The compound of claim 9 , wherein

R 1 is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

wherein each of items (1) and (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(c)—C(O)—R a ,

(d) —C(O)—OR a ,

(e) —C(O)NH 2 ,

(f) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NH 2 ,

(g) cyclopropyl,

(h) —SO 2 R a , and

(i) nitrile; and

R a is selected from the group consisting of:

(1) hydrogen,

(2) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, cyclopropyl, and —C(O)NH 2 , and

(3) cyclopropyl, optionally substituted with one to three groups selected from methyl, ethyl, propyl, and methoxy.

11 . The compound of claim 9 , wherein

R 4 is hydrogen or fluoro, and

R 5 is hydrogen or fluoro.

12 . The compound of claim 1 of Formula Ib:

wherein

R 1 is selected from the group consisting of

(1) phenyl, and

(2) pyridyl;

wherein each of items (1) and (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(c)—C(O)—R a ,

(d) —C(O)—OR a ,

(e) —C(O)NR a R b ,

(f) C 1-6 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NR a R b ,

(g) C 3-6 cycloalkyl,

(h) —SO 2 R a , and

(i) nitrile;

R 2 is hydrogen or hydroxy;

R 3 is selected from the group consisting of:

(1) ethyl, and

(2) cyclopropyl; and

each of R a and R b is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, cyclopropyl, and —C(O)NH 2 , and

(3) cyclopropyl, optionally substituted with one to three groups selected from halogen, methyl, ethyl, propyl, methoxy, and ethoxy.

13 . The compound of claim 12 , wherein

R 1 is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

wherein each of items (1) and (2) is optionally substituted with one to three groups independently selected from:

(a) halogen,

(b) —OR a ,

(c) —C(O)—R a ,

(d) —C(O)—OR a ,

(e) —C(O)NH 2 ,

(f) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, and —C(O)NH 2 ,

(g) cyclopropyl,

(h) —SO 2 R a , and

(i) nitrile; and

R a is selected from the group consisting of:

(1) hydrogen,

(2) C 1-4 alkyl, optionally substituted with one to three groups selected from halogen, hydroxy, cyclopropyl, and —C(O)NH 2 , and

(3) cyclopropyl, optionally substituted with one to three groups selected from methyl, ethyl, propyl, and methoxy.

14 . The compound of claim 1 , selected from the group consisting of:

Compound Structure

15 . A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

16 . A method for treating a glucocorticoid receptor mediated disease or condition in a mammalian patient in need of such treatment comprising administering to the patient a compound of claim 1 in an amount that is effective for treating the glucocorticoid receptor mediated disease or condition.

17 . The method of claim 16 wherein the glucocorticoid receptor mediated disease or condition is selected from the group consisting of: tissue rejection, leukemias, lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, obesity, metabolic syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis, 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, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma, Human Immunodeficiency Virus (HIV), cell apoptosis, cancer, Kaposi's sarcoma, retinitis pigmentosa, cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, sleep disorders, and anxiety.

18 . A method of selectively modulating the activation, repression, agonism or antagonism effect of the glucocorticoid receptor in a mammal comprising administering to the mammal a compound of claim 1 in an amount that is effective to modulate the glucocorticoid receptor.

19 . Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a glucocorticoid receptor mediated disease or condition in a mammalian patient in need of such treatment.