Title of Invention

FLUORINATED 4-AZASTEROID DERIVATIVES AS ANDROGEN RECEPTOR MODULATORS

Abstract Compounds of structural formula I are modulators of the androgen receptor (AR) in a tiSS:l.' selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the Iztcrus of a female patient. These compounds are therefore useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by and, rlgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone recor'5tructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postml:nopausal symptoms in women, atherosclerosis, hypercholesterolemia, h'!perlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, cancer cachexia, muscular dJ~;!rophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.
Full Text This invention rclates to tiorinalcd 4-a7asteroid derivaiives as androgen receptor modulators
FIELD OF THE INVENTION
The present invention relates to fluorinated 4-azasteroid derivatives, their synthesis, and there use as androgen receptor modulators. More particularly, the compounds of the present invention are tissue-selective androgen receptor modulators and arc thereby useful Tor the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, such as osteoporosis, periodontal disease, bone fracture, frailty, and sarcopenia.
BACKGROUND OF THE INVF.NI ION
The androgen receptor (AR) belongs to the superfamily of steroid/thyroid hormone nuclear receptors, whose other members include the estrogen receptor (F^R), the progj:terone receptor (PR), the glucocorticoid receptor (GR), and the mineralocorticoid receptor (MR). The AR is expressed in numerous tissues of the body and is the receptor thioiigh which the physiological as well as the pathophysiological cflecls of cndogcnc-us androgen ligands, such as testosterone (T) and dihydrotestosterone (FMT), are expressed. Structurally, the AR is composed of three main functional domaiiis: the ligand binding domain (LBD). the DNA-binding domain, and amino-terminal . A compound that binds to the AR and mimics the effects ofan endogenous AR ligand is referred to as an AR agonist, whereas a compound thai inhibits the effects ofan endogenous AR ligand is termed an AR antagonist.
Androgci; ligand binding to (he AR affords a ligand/receptor complex, which, subsequent to translocation inside the nucleus of the cell, binds to specific regulatory DNA .sequences (referred to as androgen response elements or AREs) within the promoter or enhancer regions of the target gene or genes present in the cell"s nucleus. Other proteins termed cofaclors are next recruited which bind to the amino-terminal domain or .he LBD of the receptor leading to gene transcription and subsequent translation tc produce the protein(s) encoded by that gene or genes.
Androj.-""n therapy has been used in the clinic to treat a variety of male disorders, such as reproductive disorders and primary or secondary male hypogonadism. Moreover, a number of natural or synthetic AR agonists have been clinically investigated for the treatment of musculoskeletal disorders, such as bone

disease, hematopoietic disorders, neuromuscular disease, rheumatological disease, wasting disease, and for hormone replacement therapy (HRT), such as female androgen deficiency. In addition, AR antagonists, such as flutamide and bicalutamide, have been used to treat prostate CHiicer. It would therefore be useful to have available compounds that can activate (""agoii/e") the function of the AR in a tissue-selective manner which would afford the desired beneficial osteo- and myoanabotic effects of androgens but without the negative androgenic properties, such as virilization and induction of an atherogenic lipid profile which can lead to cardiovascular disease.
fhe role of androgens in bone formation has been documented. For csample. anabolic sVcoids, such as nandrolone decanoate or sVanozolol, have been shown to increase borie mass in postmenopausal women. The beneficial effects of androgens on bone in postmenopausal osteoporosis were documented in recent studies using combined testosterone and estrogen administration [Hofbauer, et al., "Androgen cITcclson bone metabolism: recent progress and controversies." Eur. J. Endocrinol. 140: 271-286 (1999)1- Coml^infid treatment significantly increased the rate and extent ofthc ri.se in bone mineral de.isily (BMD) in the lumbar and hip regions, relative to treatment with estrogen alone. Additionally, estrogen - progestin combinations that incorporated an androgenic progestin (such as norcthindrone), rather than medroxyprogesterone acetate, yielded greater improvements in hip BMD. These results have recently been confirmed in a larger 2-ycar, double-blind comparison study in which oral conjugated estrogen (Crii) and methyl testosterone combinations were demonstrated to be effective in promoting accrual c" bone mass in the spine and hip, while conjugated estrogen therapy alone prevented bone loss ["A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women: Effects on bone mineral density, symptojiis and lipid profiles," J. Reprod. Med.. 44: 1012-1020 (1999)j. Despite the beneficial effects of androgens in postmenopausal women, the use of androgens has been limited because of the undesirable virilizing and metabolic action of androgens. The diua from Watts and colleagues demonstrate that hot flushes decrease in women treated with CEE and melhyltestosterone; however, 30% of these women sufTcrcd from significant increases in acne and facial hair, a complication of all current androgen phanr.^icotherapies | Watts, et al., "Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles ia surgical menopause." Obstet. Gynecol.. 85: 529-537 (1995)]. Moreover, the addition of melhyltestosterone to CEE markedly decreased HDL levels,

as seen in other studies. Therefore, non-tissue selective AR agonists may increase the risk of cardiovascular Jisease. Thus, the virilizing potential and negative effects on lipid profile of current androgen therapies provide a strong rationale for developing tissue-selective androgen receptor agonists for bone. Reference is made to J. A. Kanis, "Other agents for generalized osteoporosis," in Osteoporosis. Blackwell Science, Ch. 8, pp 196-227 (1994) for -i discussion of non-selective anabolic steroids in the treatment of osteoporosis.
It is alsu well established that androgens play an important role in bone metabolism in men, which parallels the role of estrogens in women [Anderson, et al., ""Androgen supplementntion in eugonadal men with osteoporosis - effects of six months of treatment on bone mineral density and cardiovascular risk factors," Bone. 18: 171-177 (1996)|. F.ven in eugonadal men with established osteoporosis, the therapeutic response to testosterone treatment provided additional evidence that androgens exert impoi am osteoanabolie effects. Mean lumbar BMD increased from 0.799 giTi/cm2 to 0.839 g/cm2, in 5 to 6 months in response to 250 mg of testosterone ester administered intramuscularly every fortnight. A common scenario for androgen deficiency occurs in men with stage D prostate cancer (metastatic) who undergo androgen deprivation therapy (ADT). Endocrine orchiectomy is achieved by long acting GnRH agonists, while androgen receptor blockade is implemented with flutamidc, nilutamidc, bicalutamide, or RU 58841 (AR antagonists). In response to hormonal deprivation, these men suffered from hot flushes, significant bone loss, weakness, and fatigue. In a recent pilot study of men with stage D prostate cancer, osteopenia (50% vs. 38%) and osteoporosis (38% vs. 25%) were more common in men who had undergone A DT for greater than one year than the patients who did not undergo ADT [Wei, ct al.. "Androgen deprivation therapy for prostate cancer results in significant loss of bor.i density," Urology. 54: 607-611 (1999)]. Lumbar spine BMD was significantly lower =n men who had undergone ADT. Thus, in addition to the use of tissue selective AR agonists for osteoporosis, tissue selective AR antagonists in the prostate that lack antagonistic action in bone and muscle may be useful agents for the treatment of prostate cancer, either alone or as an adjunct to traditional ADT such as with a GnRH agonist/antagonist [See also A. Stoch, et al., J. Clin. Endocrin. Metab.. 86: 2787-2791 (2001)] Tissue-selective AR antagonists may also have utility in the treatment of polycysiic ovarian syndrome in postmenopausal women [see C.A. liagleson, et al.. ""Polycystic ovarian syndrome: evidence that flutamide restores

sensitivity of the gon^jdolropin-releasing hormone pulse generator to inhibition by estradiol and progesterone," J. Clin. Bndocrinol. Metab.. 85: 4047-4052 (2000) and E. Diamanti-Kandarakis. "I"hc Effect of a Pure Antiandrogen Receptor Blocker, Flulamidc. on the Lipid Profile in the Polycystic Ovary Syndrome," Int. J. Endocrinol. Mel_a_k, 83: 2699-2705 , i998).
There is a need for more effective agents to treat osteopeaia and osteoporosis in both rrien and women. Osteoporosis is characterized by bone loss, resulting from an imbalance between bone resorption (destruction) and bone formation, which starts in the fourth decade and continues throughout life at the rate of about 1-4% per year lEasteit, " Treatment of postmenopausal osteoporosis," New Engl. J. Med., 338: 736 (I998)|. In tiv; United States, there are currently about 20 million people with detectable fractures of J.K vertebrae due to osteoporosis. In addition, there arc about 250,000 hip fractures per year due to osteoporosis, associated with a l2%-20% mortality rate within the first two years, while 30% of patients require nursing home care after the fracture and many never become fully ambulatory again. In postmenopausal women, estrogen deficiency leads to increased bone resorption resulting in bone loss n the vertebrae of around 5% per year, immediately following menopause. Thus, first line treatment/prevention of this condition is inhibition of bone resorption by bisphosphonates, estrogens, selective estrogen receptor modulators (SERMs), and calcitonin. However, inhibitors of bone resorption are not sufficient to restore bone mass for n^i"-icnts who have already lost a significant amount of bone. The increase in spinal liMD attained by bisphosphonate treatment can reach 11% after 7 years of treatment wit: alendronate. In addition, as the rate of bone turnover differs from site to site, highf "n the trabecular bone of the vertebrae than in the cortex of the long bones, the bone resorption inhibitors are less effective in increasing hip BMD and preventing hip fracture. Therefore, osteoanabolic agents, which increase cortical bone formation and bone mass of long bones by stimulating periosteal bone formation, would address an unmet need in the treatment of osteoporosis especially for patients with high risk of hip fractures. The osteoanabolic agents also complement the bone resorption inhibitors th:."t target the trabecular envelope, leading to a biomechanically favorable bone structure (Schmidt, et al., "Anabolic steroid: Steroid effects on bone in women," In; J. P. Bilezikian, el al., Ed., Principles of Bone Biology- San Diego: Academic Press, 1996). Tissue-selective AR agonists with diminished deleterious effects on ihe cardiovascular system and limited virilizing potential may be useful as a

monotherapy for the prevention and/or treatment of female osteoporosis. In addition, a compound with ostcoai.abolic properties in bone and muscle but with reduced activity in the prostate and s".-: accessory tissues may be useful for the prevention and/or treatment of male osle Selective androgen receptor modulators may also be useful to treat certain hematopoietic disorders. It is known that androgens stimulate renal hypertrophy and erythropoietin (HfCJ) production. Prior to the introduction of recombinant human tPO, androgens were employed to treat anemia caused by chronic renal failure. In addition, androgens at pharmacological doses were found to increase serum EPO levels in anemic patients with non-severe aplastic anemia and myelodysplastic syndromes but not in non-anemic pa"."fnls. Treatment modalities for anemia will require selective action such as may be provided by selective androgen receptor modulators.
I-urthermore, selective androgen receptor modulators may also have clinical value as an adjunct to the treatment of obesity. This approach to lowering body fat is supported by ;*iiblished observations that androgen administration reduced subcutaneous and visceral abdominal fat in obese men [J.C. Lovejoy. et al., "Oral anabolic steroid treatment, but not parenteral androgen treatment, decreases abdominal fat in obese, older men," Int. J. Obesity. 19: 614-624 (1995)]. Therefore, SARMs devoid of androgenic .;rfects on prostate may be beneficial in the treatmem of obese men. In a separate st"idy, androgen administration resulted in loss of subcutaneous abdominal fat in obcpc postmenopausal women [ J.C. Lovejoy, et al., "Exogenous Androgens Influence Body Composition and Regional Body Fat Distribution in Obese Postmenopausal Womf;n - A Clinical Research Center Study," J. Clin. Endocrinol. Metab.. 81: 21^8-2203 (19%)]. In the latter study, nandrolone decanoate, a weak androgen and anabolv agent, was found to increase lean body mass and resting metabolic rate in obese postmenopausal women consuming a weight-reducing diet.
Non-ste.oidal compounds having androgen receptor modulating properties were disclosed in U.S. Patent Nos. 5,688,808; 5,696,130; 6,017,924; 6.093.821; WO 01/1613") (published 8 March 2001); and WO 01/16108 (published 8 March 2001), all assigned to Ligand Pharmaceuticals, and in WO 01/27086, assigned to Kaken Pharm. Co. Ar^ditional background for the rationale behind the development of Selective Androgen Receptor Modulators is found in L. Zhi and E. Martinborough in Ann. Rep. Med. Chcm. 36: 169-180 (2001). Non-steroidal SARMs were disclosed in J.P. Udwards. "New Nonsteroidal Androgen Receptor Modulators Based on 4-

(Trinuoromethyl}-2(l I !i-Pyrrolidino[3.2-g]quinolinone,"" Bioorg, Med. Chem. Lett.. 8: 745-750 (1998) and in L. Zhi et al., "Switching Androgen Receptor Antagonists to Agonists by Modifying C-ring Substituents on Piperidino[3,4-g]quinolinone." Bioorg. Med. .Chem^etl.. 9: 1009-1012 (1999).
There exists a need in the clinical art for more effective agents that can elicit the positive responses of androgen replacement therapy but without the undesired side effects of non-liss"."e selective agonists of the AR. What is needed are compounds that can produce the same positive responses as androgen replacement therapy but without the undesired side effects. Also needed are androgenic compounds that exert selective effects on different tissues of the body. In this invention, we have identified compounds that function cis selective androgen receptor modulators (SARMs) using a series of m vilro cell-a-ssays that profile ligand mediated activation of AR, such as (i) N-C interaction, (ii) transcriptional repression, and (iii) transcriptional activation. SARM compounds in ilils invention, identified with the methods listed above, exhibit tissue selective AR agonism in vivo, i.e. agonism in bone (stimulation of bone formation in a rodent model of osteoporosis) and antagonism in prostate (minimal elTects on prostate growih in castrated rodents and antagonism of prostate growth induced by AR agonists,.
The compounds of the present invention identified as SARMs are useful to treat diseases or conui".ions caused by androgen deficiency which can be ameliorated by androgen administration. Such compounds are ideal for the treatment of osteoporosis in women and men as a monotherapy or in combination with inhibitors of bone resorption, such at> bisphosphonates, estrogens, SERMs, cathepsin K inhibitors, av33 integrin receptor antagonists, calcitonin, and proton pump inhibitors. They can also be used with agents that stimulate bone formation, such as parathyroid hormone or analogs thereof. The SARM compounds of the present invention may also be employed for treatment of prostate disease, such as prostate cancer and benign prostatic hyperplasia (til"H). Moreover, compounds of this invention exhibit minimal effects on skin (acne and facial nair growth) and may be useful for treatment of hirsutism. Additionally, compounJs of this invention can stimulate muscle growth and may be useful for treatment "•■i sarcopcnia and frailty. They can be employed to reduce subcutaneous and visceral abdominal fat in the treatment of obesity. Moreover, compounds of this invention can exhibit androgen agonism in the central nervous system and may be useful to treat vasomotor symptoms (hot flush) and to increase

energy and libido, particularly in postmenopausal women. The compounds of the present invention may be used in the treatment of prostate cancer, either aione or as an adjunct to traditional GnRfl agonist/antagonist therapy, for their ability to restore bone, or as a replacement for antiandrogen therapy because of their ability to antagonize androgen in the prostaic and minimiz-c bone depletion in the skeletal system. Further, the compounds of [he present invention may be used for their abihiy to restore bone in the treatment of pancrealic cancer as an adjunct to treatment with antiandrogen, or as monolhcrapy for their antiandrogenic properties, offering the advantage over traditional anliandrogens of being bone-sparing. Additionally, compounds of this invention can increase the number of blood ccUs, such as red blood cell.s and platelets, and may be useful for the treaimciii of hematopoietic disorders, such as aplastic anemia. Finally, compounds of this invention have minimal effects on lipid metabolism. Thus, considering their tissue selective androgen receptor agonism listed above, the compounds of this invention are ideal for hormone replacement therapy in hypogonadtc (androgen deficient) men.
It is therefore an object of the present invention to provide fluorinated 4-azasteroid derivatives v hich are useful as selective androgen receptor modulators.
It is another object of the present invention to provide pharmaceutical compositions comprising the fluorinated 4-azasteroid derivatives of the present invention in association with a pharmaceuUcally acceptable carrier.
It is anotiicr object of the present invention to provide pharmaceutical compositions comprisirjg the fiuorinated 4-azasteroid derivatives for use as selective androgen receptor mod"iiators.
It is anullicr object of the present invention to provide methods for the treatment of diseases or conditions caused by androgen deficiency which can be ameliorated by androgen administration.
It is anodicr object of the present invention to provide methods for the treatment of diseases or conditions caused by androgen deficiency which can be ameliorated by androgen administration in combination with other agents.
It is another object of the present invention to provide fluorinated 4-azasteroid derivatives and their pharmaceutical compositions for use as a medicament for the treatment of diseases or conditions caused by androgen deficiency which can be ameliorated by androgen administration.

It is arT^thcr object of the present invention to provide Huorinated 4-a/asteroid derivatives nnd tlieir piiarmaceutical compositions for the manufacture of a medicament for the ireainjent of diseases or conditions caused by androgen deficiency which can be ameliorated by androgen administration.
These and other objects will become readily apparent from the detailed description which rollows,

n is 0. 1 or 2;
a-b represents CI--CII. CHI-"CIb, or CF;CH2;
Rl is hydrogen. hydro.;ymethyl, or Ci-3 alkyl, wherein alkyl is unsubstituted or
substituted with one lo seven fluorine atoms;
R2 is hydrogen or C|,4 alkyl;
R^ is selected from CI-4 alkyl,
{Cll2)n-cyclohcicroal!s,yI. and (CH2)n"3ryl, wherein ury! is selected from phenyl,
(2) naphthyl.
(3) ben/imida/olyl,
(4) benzofuranyl,

(5) ben/oihiophcnyl,
(6) bcnzo.\a/olyl,
(7) bcnzothia/olyl,

(8) bcn/odihydrofuran>l,
(9) 1,3-benzodioxolyl,
(10) 2,3-dihydro-1,4-kT/"odioxinyl.
(ll)indo!yl.
(12)quinolyl.
(13) isoquinolyl,
(14) furanyl, (I5)thienyl,

(16) imidazolyl.
(17) oxazolyl, (18)thia/olyl.

(19) isoxa/olyl.
(20) isolhiazolyl,
(21) pyra/.olyl,
(22) pyrrolyl. (23)pyridyl,

(24) pyrimidyl,
(25) pyrazinyl.
(26) thiadiazolyl. (27)oxadiazolyl. (28) triazolyl.

(29) lctrr,zolyl. and
(30) inc" ■nyl;
wherein the alkyl gronp or the cycloheteroalkyl group is unsubstituted or substituted with one to three subs"•iiicnts independently selected from halogen, hydroxy, and C|-4 alkoxy; the aryl group as defined in items (I) to (30) is unsubstituted or substituted with one to three groups Independently selected from halogen, phenyl, Cj.g alkyl, C}-8 cycloalkyi, C3.8 cycioheteroaikyl, phenyl-Cj-g alkyl, amino-Co-6 alkyl, C]-6 alkylamino-Cfl-g alkvl. (C|.6 alkyl)2amino-C0-6 alky"> phenyl-Co-6 at(;y(amino-Co-6 alkyl. (phenyl-Co-6 aiky!)2amino-Co-6 alkyl, C|-6 alkyUhio, phenyl-Co-6 alkylthio, Ci-6 alkylsulfinyl, phcnyl-Co-6 alkylsulfinyl, Ci-6 alkylsulfonyl, phenyl-Co.6 aikylsulfonyl,

C|-6 alkoxy-Co-6 alkyl, phcnyl-Co-6 alkoxy-Co-6 alkyl, hydroxycarbonyl-Co-6 alkyl, Ci-6 alkoxycarbonyl-Co-6 alkyl. phenyl-Co-6 alkoxycarbonyl-Co-6 a"^y"" hydroxycarbonyl-C|.6 i^"kyloxy, hydroxy-Co.6 alkyl, cyano, nitro, perfluoro-C1.4 alkyl, pernuoro-C|-4 alkoxy, 0x0, C|.6 alkylcarbonyloxy, phenyl-Co-6 alkylcarbonyloxy, C|.6 alkylcarbonylamino, phenyl-Co-6 alkyIcarbonylamino, C|-6 alkylsulfonylamino. rl,cnyl-Co-6 alkylsulfonylamino, C].6 alkoxycarbonylamino, phenyl-Co-6 alkoxycarbonylamino. Ci-6 alkylaminocarbonylamino, phenyl-Co-6 a(kyiaminocarbony(an:""o. (C]-6 a(kyi)2 aminocarbonyiamino, (phenyi-Co-6 alkyl)2 aminocarbonylamino. (Ci-g alkyl)2 aminocarbonyloxy, and (phenyl-Co-6 alkyl)2 aminocarbonyloxy; anu wherein any methylene (CH2) carbon atom in {CH2)n is imsubslitutcd or substituted with one to two groups independently selected from halogen, hydroxy, and C]..4 alkyl; or two substituents when on the same methylene (CI )2) group arc taken "ugether with the carbon atom to which they are attached to form a cyclopropyl group;
or R2 and R3 together form a 5- or 6-membered saturated ring fused with a 5- or 6-mcmbered aromatic ring system having 0, 1, or 2 heteroatoms selected from N, O, and S.
These compounds are effective as androgen receptor agonists and are particularly effective ?s selective androgen receptor agonists (SARMs). They arc therefore useful for the >rcatmcnt of conditions caused by androgen deficiency or which can be ameliorated by androgen administration.
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutical ly acceptable carrier.
The present invention also relates to methods for the treatment of conditions caused by -mdrogen deficiency or which can be ameliorated by androgen administration in a manunal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for the trealmeni of osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone dan^agc following bone reconstructive surgery, sarcopertia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, [iy|/crlipidemia. obesity, aplastic anemia and other hematopoietic

disorders, arthritic conditions, such as for example, inflammatory arthrilis and joint repair. !llV-wasting. p"""^slate cancer, cancer cachexia, muscular dystrophies, premature ovarian failure, and autoimmune disease by administering the compounds and pharmaceutical compcsitions of the present invention, alone or in combination with a therapeutically effective amount of another agent known to be useful to treat these cofidilions.

n isO. 1 or 2;
a-b represents CF=CH, CIIFCH2, or Cl-jClh:
RI is hydrogen, hydroxymethyl, or C|-3 aikyl, wherein alkyl is unsubstituted or
substituted with one to seven fluorine atoms;
R2 is hydrogen
R3 is selected from
C|-4 alkyl.
(C[l2)n-cyclohcteroalky|. and
phenyl,
(2) naphihyl.
(3) bcnzimidazolyl,
(4) ben/ofuranyl.
(5) bcn/othiophcnyl.

(6) benzoxazolyl,
(7) bcnzothia/.olyl.
{8} benzodihydroCurany;.
(9) 1,3-ben/odioxolyl
(10) 2,3-dihydro-1,4-bp.rzodioxinyl.
(IDindolyl,
(12) quinolyl,
(13) isoquinolyl.
(14) furanyl. (15)thit;nyl, (16) imidazotyl. (17)oxazolyl. (!8)thia/olyl,

(19) isoxazolyl.
(20) isothiazolyl. (2 I) pyrazolyi. (22) pyrrolyl, (23)pyridyl,

(24) pyrimidyl.
(25) pyrazinyt. (26)lhiadiazolyl. (27) oxadiazolyl, (28)triazolyl, (29) telrazolyl, i30) ifidanyl; and
(3 I) a/abenzimidazoly!
wherein the alkyl group or the cycloheteroalkyi group is unsubsiituted or substituted with one to three subsMuents independently selected from halogen, hydroxy, and C1.4 alkoxy; the aryl group as defined in items (1) to (30) is unsubstituted or substituted with one to three groups i"xlependently selected from halogen, phenyl, Ci,g alkyl, C3.8 cycloalkyi, C3-8 cycloheleroalkyi. phenyl-Ci-6 alkyl, amino-Co-6 alkyl, Ci-6 alky!am(no-C()-6 alk;". (C\.^ alkyl)2ainino-Cfl-6 alkyl, phenyl-Co-6 alkylamino-Co-6 alkyl. (phcnyl-C{)-6 ar^yl)2amino-Co.6 alkyl, C]-6 alkyllhio, phenyl-Co-6 alkylthio,

Ci-6 alkylsulFmyl. !:iicnyl-Co-6 alkylsulfinyl, Ci-6 alkylsulfonyl, phenyl-Co-6
aJkylsullbny],
C|.6 alkoxy-Co-6 alkyl. phenyl-Co-6 alkoxy-Co-6 a"kyl, hydroxycarbonyl-Co-6 alky"-
CI -6 alkoxycarbony]-Co-6 alkyl, phenyl-CO-6 alkoxycarbonyl-Co-6 alkyl,
hydroxycarbonyl-Ci-C alkyloxy, hydrDxy-Co-6 alkyl, cyano, nitro, perfluoro-
Ci-4 alkyl. pernuorr.-Ci-4 alkoxy, oxo, C|.6 alkylcarbonyloxy, phenyl-Co-6
alkylcarbonyloxy. C].,, alkylcarbonylamino. phenyl-Co-6 alkylcarbonylamino, C|.6
alkyfsiilfonylamino. i:::cny}-Co.6 alkylsulfonyl amino, C|.6 alkoxycarbonylamino,
phenyl-Co-6 alkoxycarDonylamino, C | -6 alkylaminocarbonylamino, phenyl-Co-6
alkylaminocarbonylamino. (Ci-6 alkyl)2 aminocarbonylamino. (phcnyl-Co-6 alkyl)2
aminocarbonylamino, (C1.5 alky()2 aminocarbonyloxy, and (phenyl-Co.6 alkyl)2
aminocarbonyloxy; arL.l wherein any methylene (CH2) carbon atom in (CH2)n is
unsubslituted or subsiiiutcd with one to two groups independently selected from
halogen, hydroxy, and C1.4 alkyl; or two substituents when on the same methylene
(CI 12) group arc taken together wilh the carbon atom to which they are attached to form
a cyclopropyl group;
or R2 and R^ together form a 5- or 6-membered saturated ring fused with a 5- or 6-
membcred aromatic rin-r system having 0, 1, or 2 heteroatoms selected from N, O, and
S.
In one embodiment of the compounds of the present invention. R" is hydrogen or
methyl. In a class of this embodiment, Rl is methyl.
In a sci-ond embodiment of the compounds of the present invention, a-b represents Ct"-Cl I.
In a thi.-.l embodiment of the compounds of the present invention, a-b represents CllFCI-b.
In a fouriii embodiment of the compounds of the present invention, R2 is hydrogen and R3 is (CH2)ti-aryl. In a class of this embodiment, n is 0 or 1.
In a fifth embodiment of the compounds of the present invention, R1 is methyl, a-b represents wF=CH, R2 is hydrogen, and R3 is (CH2)n-aryl- In a class of this embodiment, n is 0 or- I.

In a sixth embodiment of the compounds of the present invention, R" is methyl, a-b represents Ci!l-"CH2. R2 is hydrogen, and R3 is (CI-l2)n-aO"l- "" ^ class of this embodiment, n is 0 ^r I.
In anot"i-r embodiment, Rl is chosen from hydrogen and methyl, a-b is chosen from CJII-"Cn2, "i^ is hydrogen, and R^ is (CH2)n-cycloheteroatkyl. In a class of this embodiment. R" is methyl, and a-b represents CF=CH,
In yet another embodiment of the invention, R^ is chosen from: (CU2)n-cyc[ohctcroaIkyl, L".nd (CH2)n-a""yI, wherein aryl is selected from
(1) phenyl,
(2) naphlhyl,
(3) bcn/imidazolyl.
(4) bcnzofuranyl,
(5) bcnzothiophenyl.
(6) bcn^oxazolyl.
(7) benzothiazolyl.
(8) bcnzodihydrofuran-1,
(9) 1.3-benzodioxolyl.
(10) 2.3-dihydro-1.4-benzodioxiny[,
(ll)indolyl.
(12)quino[yl.
(13) isoquinolyi.
(14) furany}. (I5)thienyl, (16) imidazolyl. (17)o\a/olyl. (I 8) thia/olyl,

(19) isoxa/olyl.
(20) isothiazolyl.
(21) pyra/olyl.
(22) pyrrolyl.
(23) pyridyl.
(24) pyrimidyl. (25)pyray.inyl.

(25) thiadia/olyl
(26) oxadiazolyl,
(27) triazolyl,
(28) tctra/oJy).
(29) indanyl; ; and
(3 I) azabenzimidazolyl
wherein the cyclohctcioalkyl group is unsubslituted or substituted with one to three subsljlucnts indGpcndcnlh" seiecled from halogen, hydroxy, and C|-4 alkoxy; the aryl group as defined in iter/is (I) to (30) is unsubstituted or substituted with one to three groups independently selected from halogen, phenyl, C|-8 alkyl, C3.8 cycloalkyl, C3,8 cyclohclcroalkyi, pbc-jl-C"i-^ alkyl, amifio-Co.6 alkyl, Ci-6 alkylamino-Co-6 ^^^yl (Ci-6 alkyl)2amino-Cr, 6 alkyl, phenyl-Co-6 alkylamino-Co-6 alkyl, (phenyl-Co-6 alkyl)2amino-Co-6 al";l. C|-6 alkylthio. phenyl-Co-6 alkylthio, Ci.6 alkylsulfinyl, phenyl-Co-^j alkylsulfi,._i 1. Ci-6 alkylsulfonyl, phenyl-CQ.^ alkylsiilfonyl, C|.6 alkoxy-CO-6 a"kyi. phenyl-Co-6 alkoxy-CO-6 a"kyl, hydroxycarbonyl-Co-6 alkyl. C]-6 alkoxycarbonyl-Co-6 alkyl, phenyl-Co-6 alkoxycarbonyl-Co-6 alkyl, hydroxycarbonyl-C | -6 aik^"loxy, hydro,\y-Co-6 alkyl, cyano. nitro, pcrfluoro-C]_4 alkyl, pcrnuor>-Ci.4 alkoxy, 0x0, Ci.6 alkylcarbonyloxy, phenyI-Co-6 alkylcarbonyloxy. C|. Illustrall.c but nonlimiting examples of compounds of the present invention that are uselni as androgen receptor modulators are the following:

N-{2,2,2-lrinLiorocthyl,i-2-nuoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-[7p-
carboxamide; N-(2-nuorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carhoxam"ide;
N-(3-nuorophenylmcthyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-l7p-
carboxainide;
N-{2-trinijoromelhylphL"nyl)-2-fluoro-4-mclhyl-3-oxo-4-aza-5a-androsl-l-en-17p-
carboxamidc;
N-(2-chloroplicnyl)-2-fluoro-4-melhyl-3-oxo-4-aza-5a-androst-l-en-17P-carboxamide;
N-(4-mclhoxyphcnyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androsl-l-en-17p-
carboxamidc:
N-(3-mclhoxyphcnyl)-"-rluoro-4-meihyl-3-oxo-4-aza-5a-androst-l-en-l7p-
carboxamide;
N-(2-mcthylphenyl)-2-("(uuro-4-methyl-3-oxo-4-aza-5a-androst-I-en-I7p-carboxatnide;
N-(3-methylphcnyl}-2-fluoro-4-melhyl-3-oxo-4-aza-5a-androst-1 -en-17p-carboxamide;
N-(2-nuorophenyl)-2-nuoro-4-mcthyl-3-oxo-4-aza-5a-androst-l-en-l73-carboxamidc
N-(3-fluorophenyl)-2-tluoiO-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamide
N-(4-fluorophcnyl)-2-fiuoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-l73-carboxamide
N-f4-ch(oro-2-nuoroph;ny()-2-nuoro-4-methy(-3-oxo-4-aza-5a-androst-[-en-l7p-
carboxamide;
N-(2,4-difluorophenyl)-2-nuoro-4-methyl-3-oxo-4-aza-5a-androsI-]-cn-17p-
carboxamide;
N-(a-mcthylphcnylincthyl) 2-nuoro-4-melhyl-3-oxo-4-aza-5a-androsl-1 -en-17p-
carboxamidc;
N-(phenyl)-2-fluoro-4-iiicthyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamide;
N-{4-chloro-2-lrinuoroiiic:hylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17P-carboxamidc:
N-(5-meihylpyridin-2-yl)-2-fluoro-4-niethyl-3-oxo-4-aza-5a-androst-l-en-l7P-
carboxamide;
N-(thiophen-2-ylmelhyi>2-nuoro-4-niethyl-3-oxo-4-aza-5a-androst-l-en-i7P"
carboxamide;
N-({h(ophen-3-ylmcthy;; 2-fluoro-4-methyl-3-oxo-4-aza-5a-atidros(-l-en-l7P-
carboxamidc:

N-{tctrahydrofuran-2(R)-ylmcthyl)-2-nuoro-4-methyI-3-oxo-4-a/-a-5a-androsl-[-en-
!7p-carboxamide;
N-(3//-imidazo[4,5-i|ii>ridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-
1 -en-) 7p-carboxamidc;
N-{2-tluorophcnylmcthyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-
carboxamidc:
N-{2-lrifluoromclhylphcn> lniethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17(5-
carboxamide;
N-(3-me(hDxyphcnyl)-2::-1tJoro-4-(ne[hyl-3-oxo-4-aza-5a-addrostafi-l7p-carboxamide;
N-(4-methoxyphenyl)-2a-(luoro-4-melhyl-3-oxo-4-aza-5a-androstan-17p-carboxamide;
N-{2-lrinuoromelhylphcnyl)-2a-fluoro-4-melhyl-3-oxo-4-aza-5a-androstan-17p-
carboxamide;
N-{2-chlorophenyl)-2a-fluoro-4-melhyl-3-oxo-4-aza-5a-androstan-17p-carboxamtde;
N-(2-nuorophcny(rm:t."-.;,"I)-2a-fiuoro-4-methy(-3-oxo-4-aza-5a-androstan-l7p-
carboxamidc;
N-(ben/iiTiida/ol-2-ylmpt|iyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-l7p-
carboxamide;
N-(l-methylben/.imida/cl-2-ylmethyl)-2a-tluoro-4-melhy!-3-oxo-4-aza-5a-androstan-
(7p-carboxamide;
N-(thia/,ol-2-ylmcthyl) ".!a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-
carboxamidc;
N-(fijran-2-y)melhyl)-2a-j]iJoro-4-j7ictby)-3-oxo-4-aza-5a-androstan-}7p-carboxamide;
and
N-(thiophen-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-
carhoxamide;
pharmaceutically acccr-table salts and enantiomers thereof.
In yet tnothcr embodiment of the invention, the compounds of ihc present invention are chosen from:
N-{2-nuorophcnylmcthyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-1 -en-17p-carboxamide;
N-(3-nuorophenylmcthyi(-2-f]uoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-l7p-carboxamide;
N-(5-chlorobenzimida. ■ )l-2-y!methyl)-2-fluoro-4-methy[-3-oxo-4-aza-5a-androst-1 -en-17|l-carboxamidc:

N-{2-lrifluororrn;lhylphcnylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carboxamide:
N-(benzimidazDl-2-ylmeiliyl)-2-nuoro-4-mcthy]-3-oxo-4-aza-5a-androst-!-en-17p-
carboxamide;
N-(l-mcthylben/.imide,.ol-2-ylnicthyl)-2-fluoro-4-melhyl-3-oxo-4-aza-5a-androst-l-en-
]7f4-carboxamide;
N-(I-tnethyl-5-tnn[ioromeihylbefi>"imidazol-2-ylmcthyl}-2-fluoro-4-methyl-3-oxo-4-
aza-5a-androst-l-cn-l7p-carboxamide;
N-(5-chloroben/imida7oi-2-ylmethyl}-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carboxaniide;
N-(5-methoxybenzimi(iazol-2-ylmethy!)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-
en-1 yp-carboxamidc;
N-(bcnzlhiazol-2-ylmcttiyl)-2-fluoro-4-inethy]-3-oxo-4-aza-5a-androst-l-en-l7p-
carboxamidc;
N-(2,3-diliydro-l.4-berizodioxin-2-ylmcthyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androsl-l-en-np-carbo^amide;
N-{Ihiazol-2-yImcthyl_i-2-lluoro-4-melhyl-3-oxo-4-aza-5a-androst-l-en-l7P-
carboxajTiide;
N-(4-mclhylthiazol-2-yimcthyl)-2-fluoro-4-methy]-3-oxo-4-aza-5a-androst-i-en-l7p-
carboxamidc;
N-(thia/o!-4-ylmcthyl)-2!1uoro-4-melhyi-3-oxo-4-aza-5a-androst-l-cn-l7p-
carboxamide;
N-( I -meIhylimidazo(-2 ■yimethyl)-2-f[uoro-4-methyi-3-oxo-4-aza-5a-androst-1 -en-17p-
carboxamide;
N-(tctrahydro-2//-pyraii-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5ii-androst-l-
en- ] 7|3-carboxamidc;
N-(lctrahydro-2//-pyran-2(R)-ylmcthyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-
cn-17p-carboxamidc;
NI-(2,3-dihydro-l.4-bciv_cdioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-l-cn-17p-carbo-,r>mide;
N-(2.3-dihydro-l,4-bciiiudioxin-2(S)-y[methyI)-2-fluoro-4-methyI-3-oxo-4-aza-5ct-
androst-1 -en-17p-carboxamide;
N-(lctrahydrofuran-2(:5) ylmethyl)-2-fluoro-4-methyl-3-oxo-4-a/a-5a-androst-1 -en-
I 7p-carboxa(nJdc;

N-(5-methoxybcnzimT,:. "i(.2-ylmethyl)-2-fIuoro-4-methyl-3-oxo-4-aza-5a-androst-l-cn-l 7fi-carboxamide:
N-(bcny.thiazol-2-ylmethyn-2-nuoro-4-methyl-3-oxo-4-aza-5a-androsl-l-en-17P-carboxamide;
N-(tctrahydro-2//-pyrar.-2(S)-ylmcthyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androsM-c(i-17p-carboxainidc;
N-(tetrahydro-2//-pyr£."-?(R)-ylmelhyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-cn-17p-carboxamide:
N-(2.3-dihydro-l.4-bcn/odioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-1 -en-17P"Carbi"^^midc;
N-(2.3-dihydro-1,4-bcp"odioxiJ)-2(S)-y)methy))-2-fluoro-4-metbyl-3-oxo-4-aza-5a-androst-1-en-17|i-carb.... ■.^mide;
N-(iclrahydrorijran-2{Si ylinethy[)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-cn-l7p-carboxamidc:
N-{ictrahydroruran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-l7j5-carbQxaniidc:
N-(3//-iiTiidazo|4.5-/)|p,vridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-I -en- i 7(i-carboxamidc;
N-(2-nuorophcnylniclh- !)-2cI-fluo^o-4-meIhyl-3-oxo-4-aza-5a-and^ostan-17{i-carboxamide;
N-(thiazo!-2-y!iTicthyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17P-carboxamide;
N-(ruran-2-ylmelbyl)-2".-lltioro-4-JTie£hyl-3-oxo-4-aza-5a-andros(an-17p-carboxa(nidc: and
N-(thiophen-2-ylmethy"V2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-carboxamide; pharmaceutically acceptable salts and enantiomers thereof.
In yet another variant, !he compounds of the present invention arc chosen from:
N-{tetrahydro-2//-pyrs.i-2(S)-yImethyI)-2-nuoro-4-niethyl-3-oxo-4-aza-5a-androst-l-cn-17p-carboxamidc;
N-(telrahydro-2/7-pyra""-2(R)-ylmelhyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-andrQst-l-cn-17p-carboxamidc;

N-(2.3-dihydro-1.4-bcn/odioxin-2(R)-y!mcthyl)-2-nuoro-4-methy[-3-oxo-4-aza-5a-
androsl-l-en-l7[l-carb.ixamidc;
N-{2.3-dihydro-1.4-bcn-.odioxin-2(S)-ylmcthyl)-2-fluoro-4-methy!-3-oxo-4-aza-5a-
androsl-)-en-I7P-carb..":3n)ide;
N-(tetrahydrorLiran-2(SVyimethyl)-2-fluoro-4-melhyl-3-oxo-4-aza-5a-androst-l-en-
!7p-carboxamidc;
N-(lctrahydroruran-2(R)-ylniethyl)-2-nuoro-4-melhyl-3-oxo-4-aza-5a-androst-l-cn-
!7p-carboxamide;
N-(3//"imidazo{4,5-b]pyndm~2-yliricthyl)-2-fluQro-4-methy}-3-o\o-4-aza-5a-ari 1 -en-17P-carboxamidf-:
pharmaccutically accentf>ble salts and enanliomers thereof.
In one c"-"ihodiment of the invention, the compounds are chosen from: N-(2-tluorophcnylniethyl)-2-nuoro-4-mcthyl-3-oxo-4-aza-5a-androst-l-en-l7p-carboxainrde;
N-(3-nuorophcnyhTicth",!)-2-tluoro-4-methyl-3-oxo-4-a2a-5a-androst-l-en-17P-carboxamide;
N-(5-chlorobcnzimida7ol-2-ylmethyl)-2-nuoro-4-methyl-3-oxo-4-aza-5a-androst-l-cn-l7p-carboxamidc:
N-{5-mcthoxybcnzimidazo(-2-yimelhyI}-2-nuoro-4-niethyl-3-oxo-4-aza-5a-androsl-[-en-17p-carboxamidc;
N-{benzthiazol-2-ylmel"iyl)-2-nuoro-4-mcthyl-3-oxo-4-aza-5a-androst-l-en-l7p-carboxamide;
N-(2-nuorophenylmethyr)-2a-fliioro-4-mcthyl-3-oxo-4-a2a-5a-androstan-17p-carboxamide;
N-{lhiazol-2-ylmelhyl)-2u-f!uoro-4-methyl-3-oxo-4-aza-5a-androstan-]7P-carboxamide;
"N-{f"uran-2-y]mcthyi}-2ff-i]uQro-4-mcthyl-3-oxO"4-a7-a-5a-androstan-)7^-carbQxamidc; and
N-(thiophen-2-ylmelhyi)-2a-fluoro-4-niethy[-3-oxo-4-aza-5a-androstan-17P-carboxainide; pharmaceutically acceptable salts and enantiomers thereof.
7he con-pounds of the present invetttion can have asymmelric centers, chiral axes, and chiral planes (as described in: \r..L. Eliel and S.H. Wilen, Slereochem-

islry of Carbon Compounds. John Wiley & Sons, New York, 1994, pages f 119-1190), and occur as raccmali.-;, racemic mixtures, and as individual diaslereomers. with all possible isomers and rr^ytures thereof, including optical isomers, being included in Ihc present invention. In arldition. the compounds disclosed herein can exist as tautomers and both tautomeric forms are intended to be encompassed by Ihe scope of the invention, even though only one tautomeric structure is depicted. For example, any claim to compound A below is understood to include tautomeric structure B. and vice versa, as well as mixtures thereof. Here, X represents the remainder of the fluorinatcd 4-azastcro(d derivativt.. of (he present invention.

The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, I-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term "CQ alkyf (as in "Co-8 alkylaryl") shall refer to the abscr?c of an alkyl group,
I"he icrm "alkenyl" shall mean slraighl or branched cham alkenes of two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range.
The term "alkylidene" shall mean a straight or branched chain alkylidene group oTone to ten lotpl carbon atoms, or any number within this range_
The term "cycloalkyi" shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopcntyl, cyclohcxyl. (.ycloheptyl, or cyclooctyl).

"Ihc tciii "cycloheteroalkyl," as used herein, shall mean a 3- to 8-mcinbered fully saluraiLd helerocycJic ring containing one or two heteroaloms chosen from N, O. or S. H\ainpics of cycloheteroalkyl groups include, but are not limited to. pipcridinyl, pyrrolidinyl, azetidinyl, morpholinyl, oxacyclopentane, oxacyclohexane, and piperayjnyl. In o.-.e embodiment of the present invention, cycloheteroalkyl is selected from piperidmyl, pyrrolidinyl, oxacyclopentane, oxacyclohexane, and morpholinyl.
The tern": "alkoxy." as used herein, refers to straight or branched chain alkoxidcs of the number of carbon atoms specified (e.g., C1.5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
The term "aryl." as used herein, refers to a monocyclic or bicyclic system comprising at least one aromatic ring, wherein the monocylie or bicyclic system contains 0. I, 2, 3, or 4 hcteroatoms chosen from N, O. or S, and wherein the monocylie or bicylic system is cither unsubstituted or substituted with one or more groups independently sclecleci from halogen, phenyl, Cj.g alkyl, C3.8 cycloalkyl, C3-8
cycloheteroalkyl, phcnyl-C|.6 alkyl, amino-Co-6 alkyl, C].6 alkylamino-Co.6 alkyl,
(C|-6 alkyl)2amino-C0-(,alkyl, phenyl-Co-6 alkylamino-C0-6alkj"l. (phenyl-Co-6
alkyl)2amino-Co-6 a\k\"\. Ci-6 alkylthio, phenyl-Co-6 alkylthio, C\.(, alkylsulfmyl,
phenyl-Co-6 alkylsuin::yl. Ci-6 alkylsulfonyl, phenyl-Co-6 alkylsulfonyl, Ci-6 alkoxy-
Co-6alkyl. phenyJ-Co-o aIkoxy-Co-6 alkyl, hydroxycarbonyl-Co-6 a"kyl, Ci.6
alkoxycarbonyl-Co-6 alkyl, phenyl-Co-6 alkoxycarbonyl-Co-6alkyl, hydroxycarbonyl
C|-6 alkyloxy, hydro>y-Co-6 alkyl, cyano, nitro, perfluoroCi-4 alkyl, perfluoroC].4
alkoxy. 0x0, C | .5 alkylcarbonyloxy, phenyl-Co-6 alkylcarbonylcxy, C1.(,
alkylcarbonylamino, phenyl-CQ.^ alkylcarbonylamino, Ci-6 alkylsulfonylamino.
phcnyl-Co.6 alkylsi^irnnylamino, Ci-6 alkoxycarbonylamino. phenyl-Co-6
alkoxycarbonylamino, C|.6 alkylaminocarbonylamino, phenyl-Cfl-fi
alkylaminocarbonylamino. {Cj-g a"kyl)2 aminocarbonylamino, (phenyl-Co-6 alkyi)2 aminocarbonylamino, (C|.6 alkyl)2 aminocarbonyloxy, and (phenyl-Co-6 alkyl)2 aminocarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-. or tri-substituted with one to three of the above-named substituents; more preferably, the aryl group is unsubstituted. mono- or di-substituted with one 10 two of the above-named substituents.

Whenever the term "alkyl" or "aryl" or either of their prefix roots appears in a name oi ^ substituent (e.g., ary! CO-8 alkyO^ "* shall be interpreted as including those limitati.-"ns given above for "alkyl" and "aryl," Designated numbers of carbon atoms (e.g., Co~o) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl muic"y or to the alkyl portion of a larger substituent in which alkyl appears as its prefix rotn.
The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above ^ind include an aryl portion where aryl is as defined above. [:xamples of arylalk:,! include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phcnyieihyl, phenylpropyl, fluorophenylethyl, chlorophenylcthyl, thicnylmethyl, thienylc!:!} I, and thienylpropyl. Examples of alkylaryl include, but arc not limited lo, toluene, ethylbenzenc, propyl benzene, melhylpyridine, ethylpyridinc. propylpyridine and butylpyridine.
The lerin "halogen" shall include iodine, bromine, chlorine, and fluorine.
The terr" "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom, "fhc lj];n "oxo" means "=0". The term ""carbonyl" means""C^O.""
The ten"! "substituted" shall be deemed to include multiple degrees of substitution by a named iubstitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant "liat the (two or more) substituents can be the same or different.
When any variable (e.g., R2, R3, etc.) occurs more than one time in any substituent or in fornuiln I, its definition in each occurrence is independent of its definition at every oiiic: occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Under standard nomenclature used throughout this disclosure, the terminal portion of the s"esignated side chain is described first, followed by the adjacent functionality toward trx point of attachment. For example, a C1.5 alkylcarbonylamino C; -6 alkyl substituent ^-j, (equivalent to


In choosing compounds oftfie present invention, one of ordinary skil! in the art will recognize that the various subslituents, i.e. R", R^, R3, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity.
Compounds of the present invention have been found to be tissue-selective modulators of liic androgen receptor (SARMs). In one aspect, compounds of the present invention in^y be useful to activate the function of the androgen receptor in a mammal, and in parixular to activate the function of the androgen receptor in bone and/or muscle tissue and block or inhibit ("antagonize") the function of the androgen receptor in the prostate ol a male individual or in the uterus of a female individual. The activation of the AR in bone can be assayed through stimulation of bone formation in a rodent model of osleopo.osis. and the antagonism of the AR in the prostate can be assayed through observation of minimal effects on prostate growth in castrated rodents and antagonism of p:ostate growth induced by AR agonists, as detailed in the I"Aamples,
A further aspect of the present invention is concerned with compounds of slruclural formula 1 that block the function of the androgen receptor in the prostate of a male individual or in ihe uterus of a female individual induced by AR agonists, but not in hair-growing skin or vocal cords, and activate the function of the androgen receptor in bone and/or muscle tissue, but not in organs which control blood lipid levels (e.g. liver).
I"he compounds of the present invention may be used to treat conditions which are caused by androgen deficiency or which can be ameliorated by androgen replacement, including, fiui not limited to osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, (j:;riodontal disease, bone fracture, bone damage following bone reconstructive surgCi", sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal synipioms in women, atherosclerosis, hypercholesterolemia, hyperlipidcmia, obesity, aplastic anemia and other hematopoietic disorders, arthritic condilions, such as for example, innammatory arthritis and joint repair, HlV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, premature ovarian failure, and autoimmune disease, £!">ne or in combination with other active agents. Treatment is effected by adminislia.ion of a therapeutically effective amount of a compound of structural formula I t.,- a mammal in need of such treatment. In addition, these compounds arc usefu, LLS ingredients in pharmaceutical compositions alone or in combination with other active agents.

In one embodiment, ihe compounds of the present invention may be used lo treat condition--, in a male individual which are caused by androgen deficiency or which can be ameliorated by androgen replacement, including, but not limited to, osteoporosis, osleopcji;a, glucocorticoid-induced osteoporosis, periodontal disease, lilV-wasting. prostate cancer, cancer cachexia, obesity, aplastic and other anemias, and muscular dystrophics, alone or in combination with other active agents. Treatment is effected by administration of a therapeutically effective amount of a compound of structural formula 1 to .">. male individual in need of such treatment.
"Arthritic condition" or "arthritic conditions" refers to a disease wherein inflammatory lesions H"C confined to the joints or any infiammatory conditions of the joints, most notably osteoarthritis and rheumatoid arthritis (Academic Press Dictionary of Science Tcchnolopy; Academic Press; 1st edition, January 15, 1992). fhc compounds of Formula 1 are also useful, alone or in combination, to treat or prevent arthritic conditions, such as Behcet"s disease; bursitis and tendinitis; CPPD deposition disease; carpal tunnel syndrome; Ehlers-Danlos syndrome; fibromyalgia; gout; infectious arthritis; intLmmatory bowel disease; juvenile arthritis; lupus erythematosus; lyme disease; marfan syndrome; myositis; osteoarthritis; osteogenesis imperfecta; osteonecrosis; polyarteritis; polymyalgia rheumatica; psoriatic arthritis; Raynaud"s phenomenon; reflex sympathetic dystrophy syndrome; Reiter"s syndrome; rheumatoid arthritis; scleroderma; and Sjogren"s syndrome. An embodiment of the invention encompasses the treatment or prevention of an arthrtic condition which comprises adminisiering a !bcrap-:ulica)ly efteclive amount of a Compound of Formula I.. A subcmbodiment is th^. treatment or prevention of osteoarthritis which comprises adminisiering a therapeinically effective amount of a Compound of Formula I. See: Cutolo M. Seriolo B. Villaggio B, Pizzorni C, Craviotto C, SuUi A. Ann. N.Y. Acad. Sci.2Q02 Jun;%6:131-42; Cutolo.M. Rheum Pis Clin North Am 2QQ0Nov;26(4>:S81-95: Bijhma JW, Van den Brink HR. Am J Reprod Immunol 1992 Oct-Dec;2S(3-4):231-4: Jansson I., llolmdahl R.; Arthritis Rheum 2001 Sep;44(9):2168-75; and Purdic DW, Br Med biiH 2000;56(3):809-23. Also, see Merck Manual, I7th edition, pp. 449-451.
When used in combination to treat arthritic conditions, the Compounds of l-"ormula I can be used with any of the drugs diclosed herein as useful for combination therapy, or can be used with drugs known to treat or prevent arrthritic conditions, such as corticosteroids, cytoxic drugs (or other disease modifying or

remission inducing d"ugs). gold treatment, methotrexate. NSAIDs, and COX-2 inhibitors.
In another embodiment, the compounds of the present Invention may be used to treat conditions in a female individual which are caused by androgen deficiency or which can be ameliorated by androgen replacement, including, but not limited to. osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, postmenopausal symptoms, periodontal disease, HIV-wasting, cancer cachexia, obesity, aplastic and other anemias, musci.inr dystrophies, premature ovarian failure, and autoimmune disease, alone or in comoination with other active agents. Treatment is effected by administration of a therapeutically effective amount of a compound of structural formula i to a female individual in need of such treatment.
The compounds of structural formula I may also be employed as adjuncts to traditional pndrogen depletion therapy in the treatment of prostate cancer to restore bone, minimize: hone loss, and maintain or increase bone mineral density. In this manner, they may be employed together with traditional androgen deprivation therapy, including GnRH agonists/antagonists, such as those disclosed in P. Limonta, ct al., "LIIRH analogues as anticancer agents: phuitary and extrapituitary shes of action." lixp. Opin. Invest. Drugs. 10: 709-720 (2001); H.J. Strieker, ""Luteinizing hormone-releasing hormone ant^"-onists," Urology, 58 (Suppl. 2A): 24-27 (2001); R.P. Millar, et al., "Progress towa; is the development of non-peptide orally-active GnRll antagonists." British Medical Bulletin. 56: 761-772 (2000); and A.V. Schally et al., "Rational use of agonists and antagonists of LH-RH in the treatment of hormone-sensitive neoplasms and gynecologic conditions," Advanced Drug Delivery Reviews. 28: 157-169 (1997). It is also possible that the compounds of structural formula I may be used in combination with antiandrogens, such as flutamide, 2-hydroxyflutamide (the active metabolite of liutamide), nilutamide, and bicalutamide (Casodex™) in the treatment of prostate caii^cr.
Further, tiie compounds of the present invention may also be employed in the treatment of pancreatic cancer, either for their androgen antagonist properties or as an adjunct to an ami androgen, such as flutamide, 2-hydroxynutamide (the active metabolite of flutamide,, nilutamide, and bicalutamide (Casodex^").
Compounds of structural formula 1 have minimal negative effects on lipid metabolism, fji^rcfore, considering Iheir tissue selective androgen agonistic properties, the compounds of this invention have advantages over existing approaches

for hormone rcplaci.r.ii-nl therapy in hypogonadic (androgen deficient) male individuals.
Additionally, compounds of the present invention can increase the number of blood cell^, such as red blood cells and platelets, and can be used for treatment of hcmatopoi-^lic disorders, such as aplastic anemia.
Rcpres It is g"jTicrally preferable to administer compounds of the present invention in their cnantiomerically pure form. Racemic mixtures can be separated into their individual enanti^^mers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chrom aography or crystallization, and fractional crystallization of diaslcrcomeric sails.
As usee! herein, a compound of the present invention which functions as an "agonist" of the androgen receptor can bind to the androgen receptor and initiate a physiological or a pharmacological response characteristic of that receptor. The term "tissue-selective androgen receptor modulator" refers to an androgen receptor ligand thai mimics the actior of a natural ligand in some tissues but not in others. A "partial agonist" is an agonist "hich is unable to induce maximal activation of the receptor population, regardless i.>rthe amount of compound applied. A "full agonist" induces full activation of the androgen receptor population at a given concentration. A compound of the preseni invention which functions as an "antagonist" of the androgen receptor can bind to the androgen receptor and block or inhibit the androgen-associated responses normally inciijced by a natural androgen receptor ligand.

The te"-Li "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inn.ganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manptinous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived frr,.-, pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted ",nines, cyclic amines, and basic ion exchange resin.s, such as argininc, betaine, caffeine, choline, N.N"-dibenzylethylencdiamine, diethylaminc, 2-diclhylaminocthanol. ""-dimethylaminoethanol, ethanolamine, ethylenediamine, N-eihyl-morpholine, N-cthylpiperidine, glucamine, glucosamine, histidine, hydrabaminc, isopropylamine, lysine, methylglucamine, morpholine. piperazine, piperidinc. polyaminc resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylaminc. trometliamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, campfiorsulfonic, citric, clhanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic. lactic, male"c. malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, tmluoroacetic acid, and the like. Particularly preferred are citric, fumaric, hydrobromic. hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
The ler-n "therapeutically effective amount" means the amount the compound of structural formula i that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other ,.linician.
The lenr; "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which result*;, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[iy "ph;;rmaceutically acceptable" it is meant that the carrier, diluent or excipienl must be compatible with the other ingredients of the formulation and not be deleterious to the recipient thereof
The terms "administration of a compound" and "administering a compound" should be unucrstood to mean providing a compound of the invention or a prodrug of a compouml of the invention to the individual in need of treatment.
By the \ --rm "modulating a function mediated by the androgen receptor in a tissue selective manner" is meant modulating a function mediated by the androgen receptor selectively (or discriminateiy) in anabolic (bone and/or muscular) tissue (bone and muscular) in the absence of such modulation at androgenic (reproductive) tissue, such as the prostate, tesiis, seminal vesicles, ovary, uterus, and other sex accessory tissues. In one embodniicnt the function of the androgen receptor in anabolic tissue is activated whereas the tinction of the androgen receptor in androgenic tissue is blocked or suppressed.
The administration of a compound of structural formula [ in order to practice the present methods of therapy is carried out by administering an effective amount of the compound .T structural formula I to the patient in need of such treatment or prophylaxis, "fhc need for a prophylactic administration according to the methods of the present invention i-: uclermined via the use of well-known risk factors. The effective amount of an individuiii compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of aan.i""stration. other drugs and treatments which the patient may concomitantly require, and other factors in the physician"s judgment.
Generai"y. the daily dosage of a compound of structural formula I may be varied over a wide .aige from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 200 mg/day. For oral administration, the composilions arc preferably provided in the form of tablets containing 0.01 to JOOOmg, particularly 0.01. 0,0j, 0.1. 0.5. 1,0, 2.5, 3.0. 5.0, 6.0, 10.0, 15.0. 25.0, 50.0, 75, 100. 125, 150. 175. 180. 2:"), 225. and 500 milligrams of the active ingredient for the symptomatic adjustmtr.. of the dosage to the mammal to be treated.
The do:;-: may be administered in a single daily dose or the total daily dosage may be admir.ij"xrcd in divided doses of two, three or four times daily, l-urthcrmore, based on the properties of the individual compound selected for

administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the (ess frequent administra"ion.
When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, ^r through an intravenous solution, the dosage administration will, of course, be cont;; Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutical ly acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutical ly acceptable carrier. An illustration of the invi.ntion is a process for making a pharmaceutical composition comprising combining iiny of the compounds described above and a pharmaceutically acceptable carrier.
Formulations of the tissue-selective androgen receptor modulator employed in the present method for medical use comprise a compound of structural formula I together wiin an acceptable carrier thereof and optionally other iherapeutically active :;:grcdrcnts. The carrier must be pharmaceutically acceptable in the sense of being co.,:patibie with the other ingredients of the formulation and noi being deleterious to the recipient subject of the formulation.
The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of structural formula 1 together with a pharmaceutically acccptaoie carrier thereof
The formulations include those suitable for oral, rectal, intravaginal, topical or parcntcra" (incJuding subcutaneous, inlramuscular and intravenous administration). Preferred formulations are those suitable for oral administration.
The formulations may be presented in a unit dosage form and may be prepared by any ofthc methods known in the art of pharmacy. All methods include the step of bringing the active compound in association with a carrier which constitutes one or more ingredients, in general, the formulations are prepared by uniformly and intimately bringing th". active compound in association with a liquid carrier, a waxy solid carrier or a finely uivided solid carrier, and then, if needed, shaping the product into the desired dosage torm.
Formulations of the present invention suitable for oral administration may be presented as tiisccte units such as capsules, cachets, tablets or lozenges, each

containing a predetermined amount of the active compound; as a powder or granules; or a su.spension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.
A tablci. .v.iy be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free flowing form, e.g., a powder or granules, optionally niixrMi with accessory ingredients, e.g., binders, lubricants, inert diluents, disintegrating agents or coloring agents. Molded tablets may be made by molding in a suilabk- machine a mixture of the active compound, preferably in powdered form, with ^i siiitable carrier. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl-ccliulose, polyethylen^j glycol, waxes and the like. Lubricants used in these dosage forms include, without i^mitation, sodium oleale, sodium stearate, magnesium stoarate. sodium benzoatc. sodiu.ii acetate, sodium chloride and the like. Disintegrators include, without limitation, slarcn, methyl cellulose, agar, bentonite, xanthan gum and the like.
Oral liqjid forms, such as syrups or suspensions in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth. acacia, mi"byl cellulose and the like, may be made by adding the active compound to the solut"-^n or suspension. Additional dispersing agents which may be employed include glycj:in and the like.
Formulations for vaginal or rectal administration may be presented as a suppository with a con ■.■ ^ntional carrier, i.e., a base that is nontoxic and nonirritating lo mucous membranes, compatible with a compound of structural formula I, and is stable in storage and docs ni.; bind or interfere with the release of the compound of structural formula 1. Suitable ba-^vS include: cocoa butter (theobroma oil), polyethylene glycols (such as carbowax y;;^ polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyclhylcne sorbitan fatty acid esters (such as Tween, Myrj, and Arlacel). glyccrinalcd gelatin, iM hydrogenated vegetable oils. When glycerinated gelatin suppositories are used, a preservative such as methylparaben or propylparaben may be employed.
Topical ."^reparations containing the active drug component can be admixed with a variety "tf carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel. allantoin. glycerine, vitamin A and E oils, mineral oil. PPG2 myristyl

propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin Intions, and shampoos in cream or gel formulations.
The compounds of ihe present invention can also be administered in the form of liposome dclivprry systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such af jholeslerol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodic: as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targctable drug carriers. Such polymers can include polyvinyl-pyrrolidonc, pyran copolymer, polyhydroxypropylmethacrylamide-phcnol, polyhydroxy-cthytaspartamidcphenf", or polyethylene-oxide polylyslne substituted with palmitoyi residues, furthermore, "he compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthocstcrs, polyactrtals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Formulations suitable for parenteral administration include formulations thai comprise a sterile aaucous preparation of the active compound which is preferably isotonic with the blooo of the recipient. Such forntulations suitably comprise a solution or suspension of a compound that is isotonic with the blood of the recipient subject. Such (brmulations may contain distilled water, 5% dextrose in distilled water or saline and the active compound. Often it is useful to employ a pharmaceuticatly and pharmacologically acceptable acid addition salt of the active compound that has appropriate solubility for the solvents employed. Useful formulations also comprise concentrated solutions or solids comprising the active compound which on dilution with an appropriate solvent give a solution suitable for parenteral administration.
The compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylaclic acid, polyen-Jilon caprolactone. polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans. polycyanoacrylates, and cross-linked or an^phipathic block copolymers of h.« lirogels.
The phh^maceulical composition and method of the present invention may further comprise other therapeutically active compounds usually applied in the

treatment of the abo-, r. mentioned conditions, including osteoporosis, periodontal disease, bone fracture, buiie damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hcmatopaiclic disorders, pancreatic cancer, arthritic conditions, such as inflammaVory arthritis, and joint repair.
For the reatment and prevention of osteoporosis, the compounds c>f the present invention may be administered in combination with a bone-strengthening agent selected from antiresorptive agents, osieoanabolic agents, and other agents beneficial for the skeleton through mechanisms which arc not precisely defined, such as calcium supplements, flavonoids, and vitamin D analogs. The conditions of periodontal disease, bone fracture, and bone damage following bone reconstructive surgery may also benefit from thes^: combined treatments. For example, the compounds of the instant invention ma> b:^ effectively administered in combination with effective amounts of other agents such as estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, avp3 integrin receptor antagonists, vacuolar ATPase inhibitors, the polypeptide ostcoprotegcrin, antagonists of VEGF, thiazolidinediones, calcitonin, protein kinase inhibitoi.s, parathyroid hormone (PTH) and analogs, calcium receptor antagonists, growth hormone secretagogues, growth hormone releasing hormone, insulin-like growth facior. bone morphogenetic protein (BMP), inhibitors of BMP antagonism, prostaglandin derivatives, fibroblast growth factors, vitamin D and derivatives thereof, vitamin K and derivatives thereof, soy isoflavones, calcium salts, and fluoride salts. "1 lie conditions of periodontal disease, bone fracture, and bone damage following bonij reconstructive surgery may also benefit from these combined treatments. In one embodiment of the present invention, a compound of the instant invention may be effctJv^ly administered in combination with an effective amount of a bone-strengthening agem selected from estrogen or an estrogen derivative, alone or in combination with a progestin or progestin derivative; a bisphosphonate; an antiestrogen or a selcclive estrogen receptor modulator; an av|33 integrin receptor antagonist; a cathepsin K inhibitor: an osteoclast vacuolar ATPase inhibitor; calcitonin; and osteoprotegerin.
In the ucatment of osteoporosis, the activity of the compounds of the present invention are distinct from that of the anti-resorptive agents: estrogens, bisphosphonates. SFlRMs. calcitonin, cathepsin K inhibitors, vacuolar ATPase

inhibitors, agents interfering with the RANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any other inhibitors of osteoclast generation or osteoclast activation. Rather than inhibiting bone resorption, the compounds of structural formula 1 stimulate bone Ibrmation. acting preferentially on cortical bone, which is responsible for a significant part of bene strength. The thickening of cortical bone substantially contributes to a reductioii in fracture risk, especially fractures of the hip. The combination of the tissue-selective androgen receptor modulators of structural formula I with anti-resorptive agents such as estrogen, bisphosphonatcs, anticstrogens, SERMs, calcitonin, «vp3 integrin receptor antagonists, MMG-CoA reductase inhibitors, vacuolar ATPasc inhibitors, and cathepsin K inhibitors is particularly useful because of the complementarity ofihe bone anabolic and antiresorptive actions.
Bone anlircsportive agents are those agents which are known in the art to inhibit the resorption of bone and include, for example, estrogen and estrogen derivatives which include steroidal compounds having estrogenic activity such as, for example. 1 7P-estradiol, estrone, conjugated estrogen (PREMARIN®), equine estrogen. 17p-ethynyl estradiol, and the tike. The estrogen or estrogen derivative may be employed alone or in cnmbination with a progestin or progestin derivative. Nonlimiting examples of progestin derivatives are norethindrone and medroxy-progesterone acetate.
Bisphosphonatcs are also bone anti-resorptive agents. Bisphosphonate compounds which may also be employed in combination with a compound of structural formula I of the present invention include:
(a) alendronic acid: (4-amino-l-hydroxybulylidene)-bis-phosphonic acid;
(b) alendronate (also Imown as alendronate sodium or monosodium trihydrate): (4-amino-l-hydroxybutylidcnc)-bis-phosphonate monosodium trihydrate (alendronic acid and alendronate arc described in U.S. Patents 4,922,007, to Kieczykowski et al., issued May 1. 1990. and 5,019,651, to Kieczykowski, issued May 28, 1991, both of which are incorporated by reference herein in their entirety);
(c) [(cycloheptylamino)-methylenel-bis-phosphonate (incadronatc), which is described in U.S. Patent 4,970.-^35. to Isomura et al., issued November 13, 1990, which is incorporated by reference herein in its entirety;
(d) {dichloromethylenc}-bis-phosphonic acid (clodronic acid) and the disodium salt (clodronate), which are described in Belgium Patent 672,205 (1966) and J. Org. Cheni 32.4\\\ (1967). both of which are incorporated by reference herein in their entirety;
(e) (I-hydroxy-3-(l-pyi.*olidInyl)-propylidene]-bis-phosphonate (EB-1053);

(0 (l-hydroxyethylidenc)-bis-phosphonatc (etidronate);
(g) [l-hydroxy-3-(methylpentylainino)propylidene]-bis-phosphonate (ibandronate),
which is described in U.S. Patent No. 4,927,814, issued May 22, 1990, which is
incorporated by reference herein in its entirety;
(h) {6-amino-l-hydroxyhc\ylidene)-bis-phosphonate(neridronate);
(i) [3-{dEmelhylaminoj-!-hydroxypropylidene]-bis-phosphonate(oipadronate);
G) (3-amino-l-hydroxynropylidene)-bis-phosphonate (pamidronate);
(k) [2-(2-pyridinyl)et!"i>!!dene]-bis-phosphonate (piridronate), which is described in
U.S. Patent No. 4,76l."106. which is incorporated by reference in its entirety;
(1) [ 1 -hydrosy-2-(3-pyi;dinyl)-ethyiidenc]-bis-phosphonate (risedronate);
(m) !|(4-chlorophenyl)thio]methylene}-bis-phosphonate (tiludronate), which is
described in U.S. Paicnt 4,876,248, to Breliere et al., October 24, 1989, which is
incorporated by reference herein in its entirety;
(n) f l-hydroxy-2-(lil-imidazol-l-yl)ethylideneJ-bis-phosphonate (zoledronate); and
(o) |l-hydroxy-2-imidazopyridin-(l,2-a)-3-ylethylidene]-bis-phosphonatc
(minodronate).
In one embodiment of the methods and compositions of the present invention, the bispho->phonate is selected from alendronate, clodronate, etidronate, ibandronate, ineadronate, minodronate, neridronate, olpadronate, pamidronate, piridronate. risedronatu, tiludronate, and zoledronate, and pharmaceutically acceptable salts thereof, and mixtures thereof. In a class of this embodiment, the bisphosphonate is selected from alendronate, risedronate, zoledronate, ibandronate, tiludronate. and clodronate. In a subclass of this class, the bisphosphonate is alendronate, pharmaceutically accC|nable salts and hydrates thereof, and mixtures thereof. A particular pharmaceutically acceptable salt of alendronate is alendronate monosodium. Pharmaceutically acceptable hydrates of alendronate monosodium include the monohydratc and the trihydrate. A particular pharmaceutically acceptable salt of riscdronatc is risedronate monosodium. Pharmaceutically acceptable hydrates of riscdronaie monosodium include the hemi-pentahydrate.
As usee" throughout this specification and claims, the term ""alendronic acid" includes the related bisphosphonic acid forms, pharmaceutically acceptable salt forms, and equilibrium mixtures of these. It includes crystalline, hydrated crystalline, and amorphous forms ol"alendronic acid and pharmaceutically acceptable salts thereof.

It specifically includes Linhydrous alendronate monosodium, alendronate monosodiuin monohydrate, and alendronate monosodium trihydratc.
Still further, antiestrogenic compounds such as raloxifene (see, e.g., U.S. Pat. No. 5,393,763), jlomiphene, zuclomiphcne, enclomiphene, nafoxidene, CI-680, CI-628. CN-55,945-27. Mer-25, U-II.555A, U-IOOA, and salts thereof, and the like (see, e.g., U.S. Patent Nus. 4,729,999 and 4,894,373) may be employed in combination with a compound of stiuctural formula I in the methods and compositions of the present invention. These ager.ls are also known as SERMs, or selective estrogen receptor modulators, agents known in the art to prevent bone loss by inhibiting bone resorption via pathways believed to be similar to those of estrogens. These agents may be used in combination with the compounds of the present invention to beneficially treat bone disorders including osteoporosis. Such agents include, for example, tamoxifen, raloxifene, lasoroxifeitc. toremifene, azorxifene, EM-800, EM-652. TSE 424, clomiphenc, droloxifcnc, idoxifene, and levormeloxifene [Goldstein, et al., ""A pharmacological review of selective estrogen receptor modulators," Human Reproduction Update. 6: 212-224 (2000), and Lufkin, et al., "The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis," Rheumatic Disease Cimies of North America. 27: 163-185(2001)]. SERMs arc also discussed in ""fargetin?, the Estrogen Receptor with SERMs," Ann. Rep. Med. Chem. 36: 149-158(2001).
ctvfB Integrin receptor antagonists suppress bone resorption and may be employed in combiniiuon with the tissue selective androgen receptor modulators of structural formula I for ^lie treatment of bone disorders including osteoporosis. Peptidyl as well as peptidomimetic antagonists of the avp3 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to W.J. Hoekstra and B.L Poulter, Curr. Med. Chem. 5: 195-204 (1998) and references cited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO 98/08840; WO 98/ir,460; WO 98/18461; WO 98/25892; WO 98/31359; WO 98/30542; WO 99/15506: WO 99/15507; WO 00/03973; EP 853084; EP 854140; EP 854145; US Patent Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796; 5,780.426; 5,929.120; 5,952.341: 6,017,925; and 6,048,861. Evidence of the ability of avp3 integrin receptor antagr.nists to prevent bone resorption in vitro and in vivo has been presented (see V.W. |-:ngleman et al.. ""A Peptidomimetic Antagonist of the avp3 Integrin Inhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vivo," J. Clin.

invest. 99: 2284-2292 (1997); S.B. Rodan et al., "A High Affinity Non-Peptide avp3 Ligand Inhibits Osteoclast Activity In Vitro and In Vivo," J. Bone Miner. Res, il: S289 (1996); J.F. Gourvcsi et al., "Trcvention of OVX-Induced Bone Loss With a Non-peptidic Ligand of the avp3 Vitronectin Receptor," Bone 23: 8612(1998); M.W, Lark ct al., "An Orally Active Vitronectin Receptor c(vp3 Antagonist Prevents Bone Resorption In Vitro and In Vivo in the Ovariectomized Rat," Bone 23-. S219 (1998)). Other avp3 antagonists are described in R.M. Keenan et al., "Discovery of Potent Nonpeptide Vitroncct"- Receptor (avp3) Antagonists," J. Med. Chem. 40: 2289-2292 (1997); R.M. Keenan ct al., "Benzimidazole Derivatives As Arginine Mimetics in 1,4-lienzodiazcpine Nonpeptide Vitronectin Receptor (avp3) Antagonists," Bioorg. Med. Chem. Lett. 8: 3165-3170 (1998); and R.M. Keenan ct al., "Discovery of an Imidazopyridinc-Containing 1,4-Benzodiazepine Nonpeptide Vitronectin Receptor (avp3) Antagonist With Efficacy in a Restenosis Model," Bioorg. Med. Chem. Lett. 8: 3171-3176 (1998). S"ill other benzazepinc, benzodiazepine and benzocycloheptenc avp3 integrin receptor antagonists are described in the following patent publications: WO 96/00574. WO ^6/00730. WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, WO 98/14192, WO 98/15278, WO 99/05107, WO 99/06049. WO 99/15170. WO 99/15178, WO 99/15506, and U.S. Patent No. 6,159,964, and WO 97/34865. avp3 integrin receptor antagonists having dibenzocycloheptenc, dibenzocyclohcptanc fnd dibenzoxazepine scaffolds have been described in WO 97/01540. WO 98/30542. WO 99/11626, WO 99/15508, WO 00/33838, U.S. Patent Nos- 6,008,213, and 6,069,158. Other osteoclast integrin receptor antagonists incorporating backbone conformational ring constraints have been described in the patent literature. Published patent applications or issued patents disclosing antagonists having a phenyl constraint include WO 98/00395, WO 99/32457. WO 99/37621. WO 99/44994. WO 99/45927, WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, HP 0 820.988, BP 0 820.991. U.S. Patent Nos. 5,741,796; 5,773,644; 5,773,646; 5.843.906; 5,852.210; 5.929,120; 5.952,381; 6,028,223; and 6,040.311. Published patent applications or issued patents disclosing antagonists having a monocyclic ring constraint include WO 99/26945. WO 99/30709, WO 99/30713. WO 99/31099, WO 99/59992. WO 00/00486. WO 00/09503. EP 0 796,855, EP 0 928.790, EP 0 928,793, Ij.S, Patent Nos. 5.710.159; 5.723,480: 5,981,546; 6.017,926: and 6,066,648. Published patent applications or issued patents disclosing antagonists having a bicyclic ring constraint include WO 98/23608, WO 98/35949, WO 99/33798, EP 0 853,084, U.S.

Patent Nos, 5.760.02:.. 5.919.792; and 5,925,655. Reference is also made to the following reviews for additional scientific and patent literature that concern alpha v intcgrin antagonists: ^": H. Duggan. et at., "Ligands to the integrin receptor avp3, Exp. Opjn, Iher. Patents, 10: 1367-1383 (2000); M. Gowen, et al., "Emerging therapies for osteoporosis." Emergin-" Drugs. 5: 1-43 (2000); J.S. Kerr, ct al., "Small molecule av intcgrin antagonists: novel anticancer agents," Exp. Opin. Invest. Drugs. 9: i27l"1291 (2000); and W.H. Mil"cr. ct al., "Identification and in vivo efficacy of small-molecule antagonists of integrin (r,"p3 (the vitronectin receptor)," Drug Discovery Today. 5: 397-408 (2000).
Cathepsin K. formerly known as cathepsin 02, is a cysteine protease and is described in PCT International Application Publication No. WO 96/13523, published May 9, 1996; U.S. Patent No. 5,501.969, issued March 3. 1996; and U.S. Patent No. 5.736,357. issued Apr" 7. 1998, all of which are incorporated by reference herein in their entirety. Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions. s>:ch as tumor metastasis, inflammation, arthritis, and bone remodeling. At acidic pH"s, cathepsins can degrade type-I collagen. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis.
Members of the class of HMG-CoA reductase inhibitors, known as the "statins," have been fp:md to trigger the growth of new bone, replacing bone mass lost as a result of osteoporosis (see The Wall Street Journal. Friday, December 3, 1999. page IJl). Therefore, the statins hold promise for the treatment of bone resorption. I"Aamplcs of HMG-CoA reductase inhibitors include statins in their lactonized or dihydroxy open acid terms and pharmaceutically acceptable salts and esters thereof including but not limited to lovastatin (see US Patent No. 4,342,767); simvastatin (see US Patent No. 4,4^"J,784); dihydroxy open-acid simvastatin, particularly the ammonium or calciun". -salts thereof; pravastatin, particularly the sodium salt thereof (see US Patent No, 4,346.227); fluvastatin, particularly the sodium salt thereof (see US Patent No. 5.354.772); atorva.statin, particularly the calcium salt thereof (see US Patent No. 5,273,995); ceriva"^tatin. particularly the sodium salt thereof (see US Patent No. 5,177.080), rosuvastatin. also known as ZD-4522 (see US Patent No. 5,260,440) and pitavastatin. also rcfirired to as NK-104, itavastatin, or nisvastatin (see PC"f international applicaiio;- publication number WO 97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pump inhibitors, may also be employed together with the tissue selective androgen receptor modulators of structural formula I. The proton ATPase which is found on the apical membrane of the osteoclast bas been reported to play a significant role in the bone resorption process. T"jreforc, this proton pump represents an attractive target for the design of inhibitors of bone resorption which are potentially useful for the treatment and prevention of osr:.oporosis and related metabolic diseases [see C. Farina el al., ■"Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents." F:»PT, 4: 163-172(1999)].
rhe angiogenic factor VEGF has been shown to stimulate the bone-resorbing activity of (■■ jlatcd mature rabbit osteoclasts via binding to its receptors on osteoclasts [see M. Nakagawa el al., "Vascular endothelial growth factor (VEGF) directly enhances oslcuclastic bone resorption and survival of mature osteoclasis," 1"1-:BS Letters. 473: 161-164 (2000)]. Therefore, the developmem of antagonists of V1;GF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1, may provide yet a further approach to the treatment or prevention of bone resorption.
Activators of the peroxisome proliferator-acttvated receplor-(PPAR ), such as the thiazolidinediones (TZD"s), inhibit osteoclast-like cell formation and bone resorption in vitro. Results reported by R. Okazaki et al. in l-indocrinoloiiv. 140: 6O60-5065 (1999) point to a local mechanism on bone marrow cells as well as a systemic one on glucose metabolism. Nonlimiling examples of PPAK activators include the glitazones, such as troglitazone, pioglilazone, rosiglilazonc, and BRl 49653.
Calcitonin may also be employed together with the tissue selective androgen receptor modulator of structural formula 1. Calcitonin is preferentially employed as salmon nasal spray (Azra el al.. Calcitonin. 1996. In: J. P. Bilezikian, et al.. hd., Principles of Bone, Biology, San Diego: Academic Press; and Silverman, ■"Calcitonin." Rheumatic Disease Clinics of North America, 27: 187-196, 2001)
Protein kinase inhibitors may also be employed together with the tissue selective androgen receptor modulators of structural formula I. Kinase inhibitors include those disclosed in WO 01/17562 and are in one embodiment selected from inhibitors of p38. Specific embodiments of p38 inhibitors useful in the present invention include SB 203580 [Badger et al., •Tharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal

models of arthritis, bone resorption, endotoxin shock, and immune function," J, Pharmacol. Exn. Thcr.. 279: I453-I46I (1996)].
OsteoanabcMc agents are those agents that are known in the art to build bone by increasing the production of the bone protein matrix. Such osteoanaboltc agcms include, for ex?iiple, the various forms of parathyroid hormone (PTH) such as naturally occurring TTH (1-84), PTH (1-34). analogs thereof, native or with substitutions and particularly parathyroid hormone subcutaneous injection. PTH has been found to increase the activity of osteoblasts, the cells that form bone, thereby promoting the synthesis of new bone (Modern Drup Discoverv. Vol. 3, No. 8, 2000), In studies reported at the lirst World Congress on Osteoporosis held in Chicago in June 2000, women in combined PTH-estrogen therapy exhibited a 12.8% increase in spinal bone mass and a 4.4% increase in total hip mass. Another study presented at the same meeting showed that PTl! could increase bone size as well as density. A clinical trial of the effect of the human parathyroid hormone 1-34 fragment [hPTH(l-34)] on postmenopausal osteoporotic women resulted in >65% reduction in spine fractures and a 54% reduction in noiivertebral fractures, al^er a median of 22 months of treatment [see J.M. Hock, Bone. 27: 467-469 (2000) and S. Mohan, et al.. Bone. 27: 471-478 (20QQ), and references cited therein]. Thus, PTH and fragments thereof, such as hPTH(l-34). may prove to be efficacious in the treatment of osteoporosis alone or in combination with other agents, such as the tissue selective androgen receptor modulators of the pre;.":nt invention. An injectable recombinant form of human PTH, Forteo (teriparatide). hn^ received regulatory approval in the U.S. for the treatment of osteoporosis.
Also usi.-ful in combination with the SARMs of the present invention are calcium receptor antagonists which induce the secretion of PTH as described by Gowen et al., in "Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion anu hone formation in osteopenic rats," J. Clin. Invest. 105: 1595-604 (2000).
Growth hormone secretagogues, growth hormone, growth hormone releasing hormone and the like are also osteoanabolic agents which may be employed with the compounds ac.-nrding to structural formula I for the treatment of osteoporosis. Representative growth hormone secretagogues are disclosed in U.S. Patent No. 3.239,345; U.S. Palciu No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5.206.235; U.S. Patent No. 5,283.241; U.S. Patent No. 5,284,841; U.S. Patent No.

5.310.737; U.S. Patent No. 5,3I7,0]7; U.S. Patent No. 5.374.721; U.S. Patent No. 5.430,144; U.S. Patcril No. 5,434,261; U.S. Patent No. 5,438,136; U.S. Patent No. 5.494.919; U.S. Patent No. 5,494.920; U.S. Patent No. 5,492,916; U.S. Patent No. 5.536,716; HI"O Patent Pub. No. 0,144.230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO 94/07480; PCT Patent Pub, No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. V"O 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598. PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO 95/34311: PCT Patent Pub. No. WO 96/02530; Science. 260. 1640-1643 (June 11, 1993); Ann. Rep. Med. Chem.. 28: 177-186 (1993); Bioorg. Med. Chcm. I..clt.. 4: 2709-2714 (19">4); and Proc. Natl. Acad, Sci. USA. 92: 7001-7005 (1995).
Insulin-like growth factor (IGF) may also be employed together with the tissue selective androgen receptor modulators of structural formula I. Insulin-like growth factors may be selec^ted from Insulin-like Growth Factor 1, alone or in combination with IGP binding protein 3 and IGF II [See Johannson and Rosen, "The IGFs as potential therapy for metabolic bone diseases," 1996, In: Bilezikian, et al.. Rd.. Principles of Bone Biology. San Diego: Academic Press; and Chiron et al., "Effects of recombinant insulin-like growth factor-l and growth hormone on bone turnover in ciderlv women." J, Bone Mine^Egg. 10: 1844-1852(1995)].
Bone morphogenetic protein (BMP) may also be employed together with the (issue selective androgen receptor modulators of structural formula I. lione morphogenetic protein includes BMP 2. 3. 5. 6. 7, as well as related molecules TGF beta and GDF 5 [Rosen et al,, "Bone morphogenetic proteins," 1996, In: J, P, Bilc/ikian. et al.. Hd.. l^rincijiles of Bone Biology. San Diego: Academic Press; and Wang EA. "Bone morpJiogenetic proteins (BMPs): therapeutic potential in healing bony defects." Trends Biotcchtiol-, 11: 379-383 (1993)].
Inhibitors of BMP antagonism may also be employed together with the tissue selective androgen receptor modulators of structural formula I. BMP antagonist inhibitors are in one embodiitient selected from inhibitors of the BMP antagonists SOST. noggin, chordin gremlin, and dan [Massague and Chen, "Controlling TGF-bcta signaling," Genes Dev.. i -1: 627-644, 2000; Aspenberg et al., "~The bone morphogenetic

proteins antagonist Noggin inhibits membranous ossification," J. Bone Miner. Res. 16: 497-500, 2001; Brunkow cl al., "Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein," Am. J. Hum. Genet. 68: 577-89(2001)].
fhe tissue-selective androgen receptor modulators of the present invention may also be combined with the polypeptide osteoprotegerin for the treatment of conditions associated with bone loss, such as osteoporosis. Preferably osteoprotegerin is riiammalian osteoprotegerin and more preferably human osteoprotegerin. 1"hc polypeptide osteoprotegerin, a member ot the tumor necrosis factor receptor supcrfaniily, is useful to treat bone diseases characterized by increased bone loss, such as osteoporosis. Reference is made to U.S. Patent No, 6,288,032, which is incorporated by reference herein in its entirety.
Prostaglandin derivatives may also be employed together with the tissue selective androgen receptor modulators of structural formula I. Prostaglandin derivatfvcs are in one embodiment selected from agonists of prostaglandin receptor liPl, IiP2, HP4, FP and IP or a derivative thereof [Pilbeam et al., "Prostaglandins and bone metabolism." 1996. In: Bilezikian, et al. Ed. Principles of Bone Biology, San Diego; Academic J"ress; \\"cinreb ct al., "E.xpre-ssion of the prostaglandin E(2) (PGK(2)) receptor subtype liP(4) lind its regulation by PGE(2) in osteoblastic cell lines and adult rat bone tissue."" Bone. 28: 275-281 (2001)],
Fibroblast growth factors may also be employed together with the tissue selective androgen receptor modulators of structural formula I. Fibroblast growth factors include aFGK. bFGF and related peptides with FGF activity [Hurley Florkiewicz, "Fibroblast growth factor and vascular endothelial growth factor families,"" 1996. In: J. P. Bilezikian, et al., Cd. Principles of Bone Biology, San Diego: Academic Press |.
In addiliun to bone resorption inhibitors and osteoanabolic agents, there are also other agents known to be beneficial for the skeleton through mechanisms which are not precisely defined. These agents may also be favorably combined wiih the tissue selective androgen receptor modulators of structural formula I.
Vitamin D and vitamin D derivatives may also be employed together with the tissue sclcciiv-; androgen receptor modulator of structural formula 1. Vitamin D and vitamin D derivatives include natural vitamin D, 25-OH-vitamin D3, I ,25(011)2 vitamin D3, I -OH-vitamin D3, I -OH-vitamin D2, dihydrolachysterol.

26.27-V6"{ ,25(Oli)2 wrMmin D3. (9-nor-I .25(OH)2 vitamin D3, 22-oxacaIcitriol, calcipotriol, 1 ,25(01 ij2-i6-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089. 20-epi-I ,25(011)2 vitamin D3. KH1060. ED71, 1 ,24(S)-(OH)2 vitamin D3, 1 ,24{R)-(OII)2 vitamin 03 fSce, Jones G., "Pharmacological mechanisms of therapeutics: vitamin D and analog,-." 1996. In: J. P. Bilezikian, et . al. Bd. Principles of Bone Biology, San Diego: A^ .>dcmic Press].
Vitamin K and vitamin K derivatives may also be employed together with the tissue selective androgen receptor modulators of structural formula I. Vitamin K and vitamin K derivatives include metialetretione (vitamin K2) [see Shiraki ct al., "Vitamin K2 (mcnatetrcnone) effectively prevents fractures and sustains lumbar bone mineral density in osteo"^orosis." J. Bone Miner. Res.. 15: 515-521 (2000)].
Soy isoTi^vones. including ipriflavone, may be employed together with the tissue selective androi^en receptor modulators of structural formula 1.
Fluoride salts, including sodium fluoride (NaF) and monosodium tluorophosphatc (MFP), may also be employed together with the tissue selective androgen receptor modulators of structural formula [. Dietary calcium supplements may also be employed "ugether with the tissue selective androgen receptor modulators of structural formula !. Dietary calcium supplements include calcium carbonate, calcium citrate, and naiui^l calcium salts [Heaney. Calcium. 1996. In: J. P, Bilezikian, et al., l:d.. Principles of Bone Biology, San Diego: Academic Press).
Daily dosage ranges for bone resorption inhibitors, osteoanaboHc agents and other agents whicn may be used to benefit the skeleton when used in combination with a compound of structural formula 1 are those which are known in the art. In such combinations, generally the daily dosage range for the tissue selective androgen receptor modulator of si,-;.;ctural formula I is 0.01 to 1000 mg per adult human per day, more preferably" from 0,1 LO 200 mg/day. However, adjustments to decrease the dose of each agent may be made due to the increased efficacy of the combined agent.
In particular, when a bisphosphonate is employed, dosages of 2.5 to 100 mg/day (measured as liic free bisphosphonic acid) are appropriate for treatment, more preferably 5 to 20 mg/day, especially about 10 mg/day. Prophylactically. doses of about 2.5 to about 10 mg/tiL; find especially about 5 mg/day should be employed. For reduction in sidc-effecis, it may be desirable to administer the combination of a compound of structural formula f and the bisphosphonate once a week. For once

weekly adminislralion. doses of about 15 mg to 700 mg per week of bisphosphonate and 0.07 to 7000 mg of a compound of structural formula I may be employed, either scparalcly. or in a coiribiiiexl dosage form. A compound of structural formula I may be favorably administered ir. a controlled-release delivery device, particularly for once weekly administration.
For th- treatment of atherosclerosis, hypercholesterolemia, and hyperlipidemia, the compounds of structural formula I may be effectively administered in combination with one or more additional active agents. The additional active agent or agents can be lipid-aliering compounds such as HMG-CoA reductase inhibitors, or agents having other pharmaceutical activities, or agents that have both lipid-altering effects and other pharmaceutical activities. Examples of HMG-CoA reductase inhibitors include sltims in their lactonized or dihydroxy open acid forms and pharmaccutically acccpable salts and esters thereof, including but not limited to lovastatin (see US Parent No. 4.342,767); simvastatin (see US Patent No. 4,444,784) dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof: pravastatin, particularly the sodium salt thereof (see US Patent No. 4,346,227) lluvastatin, particularly the sodium salt thereof (see US Patent No. 5,354,772) atorvastatin. particula, iv the calcium salt thereof (see US Patent No. 5.273,995) ccrivastatin. particularly the sodium salt thereof (see US Patent No. 5,177,080). and nisvaslatin, also rcfern.d to as NK-104 (see PCT international application publication number WO 97/23200). Additional active agents which may be employed in combination with a coninound of structural formula I include, but are not limited to, IIMG-CoA synthase inhibitors; squalenc epoxidase inhibitors; squalene synthetase inhibitors (also knowr. as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyllransferasc (ACAl"t inhibitors including selective inhibitors of ACAT-I or ACA"f-2 as well as dual inhibliors of ACAT-1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; cholesterol absorption inhibitors, such as SCII-58235, also known as e/etimibe and l-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, which is described in U.S. Patent Nos. 5,767,11-"^ and 5,846.966; bile acid sequestrants; LDL (low density lipoprotein) receptor indiicers; platelet aggregation inhibitors, for example glycoprotein lib/Ilia fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPAR ) agonists, including the compounds commonly referred to as glitazoncs, for example troglitazone, pioglitazone and rosiglitazone and,

including those cofpnounds lacluded within the structural class known as thiazolidincdioncs as wcil as those PPAR agonists outside the thiazolidinedione structural class; PPAR agonists, such as clofibrate, fenofibrate including micronizcd fciiofibrale, and gemfibrozil; PPAR dual / agonists; vitamin B6 (also known as pyridoxine) and the r"^armaceuticaliy acceptable salts thereof such as the HCI salt; vitamin Hj2 {also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or cste^" thereof such as the sodium salt and the methylglucamine salt; anli-oxidant vitamins such as vitamin C and E and beta carotene; beta-blockers; angiotensin II antagoni.is such as losartan; angiotensin converting enzyme inhibitors, such as enalapril and captopril; calcium channel blockers, such as nifedipine and dilliazem; endolhelin r,,itagonists; agents such as LXR ligands that enhance ABC I gene expression; bisphosphonate compounds, such as alendronate sodium; and cyclooxygcnasc-2 inhibitors, such as rofccoxib and celecoxib, as well as other agents known to be useful in the treatment of these conditions.
Daily ij^age ranges for HMG-CoA reductase inhibitors when used in combination with the compounds of structural formula I correspond to those which arc known in the an. Similarly, daily dosage ranges for the HMG-CoA synthase inhibitors; squalene cpoxidase inhihitors; squalene synthetase inhibitors (also known as squalenc synthase inhibitors), a".-vl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors of ACAT-I and -2; micn-jomal triglyceride transfer protein (MTP) inhibitors; probucol: niacin; cholesterol absorption inhibitors including ezetimibe; bile acid sequestranis; l,DL (low density hroprotein) receptor inducers; platelet aggregation inhibitors, including glycoprotein Iib/llIa fibrinogen receptor antagonists and aspirin; human peroxisome proliferate activated receptor gamma (PPAR ) agonists; PPAR agonists; PPAR dual / agonists; vitamin B^; vitamin B12; folic acid; anli-oxidant vitamins; beta-blocke--",, angiotensin 11 antagonists; angiotensin converting enzyme inhibitors; calcium channel blockers; endolhelin antagonists; agents such as LXR ligands that enhance ABCl gene expression; bisphosphonate compounds; and cyclooxygenasc-2 inhinuors also correspond to those which are known in the art, although due to the combined action with the compounds of structural formula I. the dosage may be somewhat lower when administered in combination.
One cm*"odiment of the invention is a method for effecting a bone turnover marker in a mammal comprising administering a therapeutically effective

amount of a compound according to formula i. Non-limiting examples of bone turnover markers can be selected from urinary C-telopeplide degradation products of type I collagen (CTXi. urinary N-telopeptide cross-links of type I collagen (NTX), DXA,andDPD.
In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy ;,i- concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternf;Ung treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating diseases caused by androgen deficiency or thai can be ameliorated by addition of androgen.
AbbreVialions Used in the Description of the Preparation of the Compounds of the
Present Invention;
AcOH Acetic aeid
BOP Benzotriazol-l-yioxytris(dimethylamino)phosphonium
hexafluorophosphate
Bu Butyl
calc. Calculated
ClbCI; Methylene chloride
CBZ (Cb/) Benzyloxycarbonyl
CS2CO3 Cesium carbonate
DDQ 2,3-Dichloro-5,6-dicyano-l.4-benzoquinone
DIiAD Diethyl azodicarboxylate
DIBAL Diisobutylaluminum hydride
Dll-A Diisopropylethylamine
DMAP 4-Dimcthylaminopyridine
DM)- N,>J-Dim ethyl formamide
DMSO Dimethyl sulfoxide
Hix: 1 -(3-Dimethylaminopropyl)3-ethylcarbodiimide HCi
i-;s-Ms f!lectron-spray mass spectroscopy

Ill ethyl
HtjO Diethyl ether
EtjN frielhylamine
h:tOAc Ethyl acetate
FAIi Fast atom bombardment
I"N(S02Phh N-Fluorobenzenesulfonimide
IIOAt 1 -I iydroxy-7-azabenzolriazole
1 lOBt ]^-hydroxybenzotriazole
IIPLC High-performance liquid chromatography
IIRMS High resolution mass spectrum
i-PrOH ijopropyl alcohol
LAII Lithium aluminum hydride
MM Lithium diisopropylamide
Mc Methyl
MF molecular formula
MgSO., Magnesium sulfate
MS mass spectrum
NMM N-methylmorpholine
NaaSO-i Sodium sulfate
Ph Phenyl
PhS(0)OMc Methyl benzenesulfinate
Pr Propyl
r.l. Room temperature
NaliCOj Sodium hydrogencarbonate
TIA Trifluoroacetic acid
TUF Tetrahydrofuran
■fLC Thin-layer chromatography.
Preparation of the Con. [pounds of the Invention
The com;iounds of the present invention can be prepared according to the procedures denonjd in the following reaction Schemes and Examples or modifications thereof using readily available starting materials, reagents, and conventional procedure:, ".T variations thereof well-known to a practitioner of ordinary skill in the art of synthetic organic chemistry. Specific definitions of variables in the


Allcrna"\ely the compounds of structural formula Jj:5 were prepared from intermediate JjO as shown in Scheme 2:






"I"he follo*ving examples are provided to further illustrate details for the preparation and use ot"thc compounds of the present invention. They are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed, rurlhcrmore, the compounds described in the following examples are not lo be construed as ionning the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.


Step_Ai 2a-riiJOii)-4-methyl-3-oxo-4-aza-5a-androstane-17p-carboxylic acid
methyl ester (1-21 „,.^_-^^__
To a soiulion ofl-I (7.5 g, 21.6 mmol) in THF (100 mL) at -78"C was added a solution of 1.5 M LDA in THh" (17.3 mL, 25.9 mmol) dropwise over 20 min and then stirred 1 h. A solution of FN(S02Ph)2 (10.2 g, 32.4 mmol) in THF (40 ml.) was then added over 20 min. After 30 min, the cooling bath was removed and the reaction was stirred for 14 h. EtjO was added, and the mixture was washed with water.

saturated aqueous soaium hydrogencarbonate, brine, dried (MgS04) and then concentrated. Chromat(igraphy on silica gel (hexanes to EtOAc as eluent) gave 1:2 (4,2 g) as a colorless solid. MS calculated M+H:3"^6. found 366.1.
Step B: 2-Fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-ene-l7p-carboxylic acid
methyl ester (1-3) ._.
To a solution of I^ (30 g, 82.1 mmol) in THF (400 mL) at -78"C was added a solution of 1.5 M LDA in THF (71.1 mL, 107 mmol) dropwise over 30 min and then stirred 1 h. Methyl benzenesulfinate (19.23 g. 123 mmol) was then added over 15 min. Aller 30 min. the cooling bath was removed and the reaction was stirred for I h. l-^tzO was addi d. and the mixture was washed with water, saturated aqueous sodium hydrogencarbonate, brine, dried (MgS04) and then concentrated. The residue was dissolved in toluene (200 mL) and heated at reflux for 2 h. Solvent evaporation and chromatography of the residue on silica gel (hexanes to 50% EtOAc/hexanes as eluent) gave Jjil (20.4 c) as a pale yellow solid. MS calculated MM I: 364. Ibund 364.1,
StepC: 2-Fluoro ■"-melhyl-3-oxo-4-aza-5a-androst-l-ene-17p-carboxylic acid
n-4)
To a solution of Jj:3 (2.4 g, 6.6 mmol) in 1,4-dioxane (50 ml.) was added a solution of lilhijm hydroxide (0.41 g, 9.9 mmol) in water (20 mL), and the mixture heated at I00°C tor 3 h. After cooling, the mixture was diluted with ethyl acetate and then washed with IN HCI. brine, dried (MgS04) and then concentrated to give J_-4 (2.2 g) as a paii. yellow solid. MS calculated M+11: 350, found 350.
Step D: N-(2-fluorophenylmethyl)-2-f]uoro-4-methyl-3-oxo-4-aza-5a-androst-J^
en-17p-carboxamide (5-1)
A mixture of _M (0.12 g. 0.34 mmol), EDC (0.079 g, 0.41 mmol). IIOAt (0,056 g. 0.41 iiimol). NMM (0.15 mL. L37 mmol) and 2-ftuorobenzylamine (0.52 g, 0.41 mmol) in OMF (2 mL) stirred for 14 h. The mixture was diluted with water, filtered, and the solids washed with water, then diethyl ether, and then dried under vacuum to give 5J. (0.12 g) as a pale yellow solid. MS calculated M-^H: 457.2661 found 457.2666.


Step A: S-{Pyridin-2-yl)-2-f]uoro-4-methyl-3>oxo-4-a/.a-5a-androst-l-en-l7p-
carbolh(Qate("2-J) .
A mixtLsre of M {0.80 g, 2.30 mniol), 2,2"-dithiopyridine (1.01 g. 4,6 mtnol) and lriphcnylph;"sphinc (1.2 g, 4.6 tnmol) in toluene (10 niL) was stirred 14 h. I"ollowing evaporation ot the solvent, the solids were suspended in toluene (5 mL) and diluted with diethyl ether. The solids were collected by filtration, washed with diethyl ether, and then dried under vacuum to give l-_i(0.12 g) as a pale yellow solid. MS calculated M (-H: 443. Tound 443.
SiepB: N-(2-"rr:*luoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-1 -en-17p-carboxaiiiide (6-1) ___^ _..
A mixture of 2^. (0.25 g, 0,57 mmol), S-trifluoromcthylaniline (0.18 g. 1-13 mmol) and silver(in Iriflate (0.15 g. 0.57 mmol) in dichloromelhane (3 mL) was

stirred 14 h. Followiny evaporation of the solvent, chromatography of the residue on silica gel (hexanes to RtOAc as eluent) gave 6J. (0.12 g) as a pale yellow solid. MS calculated M+H: 4^3.2473, found 493.2470.
I"^xamples 3-50 in Table 1 were prepared in a similar manner as (examples 1 and 2. but using the appropriate amine to generate the carboxamide.











Step A: 4-Mcthyl-3-oxo-4-aza-5a-andrQstane-l7p-carboxYlic acid (3-21



with toluene. The residue was dissolved in CH2CI2 and then washed with IN HCl, brine, dried (MgSOj) ar.d then concenlratcd to give 3^^ (2.1 g) as white solid. MS calculated M+l i: 3S2.5. found 352.2.


Utilizing ilie procedure described in Scheme 4, ±A_ was prepared from 3^ 5. MS calculated Mtli: 445, found 445.1.
Step B; N-(2-"rnlli::>rophenyl)-2 -tluoro-4-methyl-3-oxo-4-aza-5a-androstane-
jJB-carboxamide (H-\)
Utilizinf; llie procedure described in Scheme 4, 8J. was prepared from 4^ 1- MS found M+li:4:>i.:624.




Oral Composition
As a spccillc embodiment of an oral composition of a compound of this inveniion, 50 mg of a compound of the present invention is formatted with sufficient llnely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
h"xample 69
"fransdcrmal Patch KorTtulation
Ingrcdicm Amount
Compound of formuii" " 40 g
Silicone fluid 45 g
Colloidal silicone dioxi"."e 2.5 g
The silicone fluid and compound of structural formula I are mixed together and the
colloidal silicone dioxific is added to increase viscosity. The material is then dosed into
a subsequently heal sealed polymeric laminate comprised of the following: polyester
release liner, skin cont;^":t adhesive composed of silicone or acrylic polymers, a control
membrane which is a polyolefin (e.g. polyethylene, polyvinyl acetate or polyuretlianc).
and an impermeable lacking membrane made of a polyester mullilaminate. "Jhe
resulting laminated sheet is then cut into 10 cm^ patches. For 100 Patches.
lixamplc 70
Supppsilpry
Ingredient Amount
Compound of striicturai Tormula I 25 g
Polyethylene glycol 1000 1481 g
Polyethylene glycol 4000 494 g
rhe polyethylene glyco" 1000 and polyethylene glycol 4000 are mixed and melted. The
compound of structural formula 1 is mixed into the molten mixture, poured into molds
and allowed to cool. Per 1000 suppositories.
iixampie 71

Injectable solution
Ingredient Amount
Compound of structural formula 1 5 g
Buffering agents q.s.
Propylene glycol 400 mg
Water for injection 600 mL
fhc compound of structural formula 1 and buffering agents are dissolved in the
propylene glycol at about 50°C. The water for injection is then added with stirring and
the resulting solution is filtered, filled into ampules, sealed and sterilized by
autoclaving. For 1000 Ampules.
lixample 72
Injectable solution
Ingredient Amount
Compound of structural formula I 5 g
Buffering agents q.s.
Magnesium sulfate he;_:;-"hydrate 100 mg
Walcr for injection S80 mL
■fhc compound of structural formula 1, magnesium sulfate heplahydrate and buffering
agents are dissolved in the water for injection with stirring, and the resulting solution is
filtered, filled into ampoules, sealed and sterilized by autoclaving. For 1000 Ampoules.
The following assays were used to characterize the activity of the tissue selective androgen rccepiur modulators of the present invention.
in vitro and in vivo assays for identification of compounds with sarm activity
I. Hydroxy I apatite-based Radioligand Displacement Assay of Compound Affinity for
f^ndogenouslv Expres.^eu AR Materials:
Binding Buffer, fl-rnvi (10 mM Tris-HCI, 1 mM EDTA, 10% glycerol, 1 mM beta-
mccaptoethanol, 10 mivl ."odium Molybdate, pH 7,2)
50% I UP Slurry: Calbiochem I lydroxylapatite, Fast Flow, in 10 mM Tris, pH 8.0 and
I mM HDTA.
Wash Buffer: 40 mM "l j"is. pH7.5. 100 mM KCl, 1 mM RDTA and I mM EGTA.

95% FtOl I
Methyltricnolone. [I7r. methyPHI, {R1881*); NEN NET590 Methyllrienolone (Rl f-Xi). NEN NLP005 (dissolve in 95% EtOH) Dihydrotcstosterone (DIfi) [l,2,4,5,6,7-3n(N)] NEN NET453 I lydroxylapalite Fast Flow; Calbiochcm Cat#39l947 Molybdate^ Molybdic Acid (Sigma, Ml651) MDA-Mll-453 cell culture media:

glulamine

RPMI IMO (Gibco 11835-055) w/23.8 mM NaHCOs, 2 mM L-
In 500 ml. of complete media Final cone.
lOmL(lMHepes) 20 mM
5 mL (200 mM L-glu) 4 mM
0.5 mL (10 nig/mL human insulin) 10 g/mL
;.; 0.01 N HCI Calbiochem#407694-S)
50 mL r"»S (Sigma F2442) 10%
1 mL (10 mg/mLGentamicin 20 g/mL
G(bco#l5710-072)

Cell Passaging:
Cells (Hail R. E.. ct al., European Journal of Cancer. 30A: 484-490 (1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA is diluted in the same PBS 1:10. The cell layers are rinsed with IX Trypsin, extra Trypsin is poured out, and the cell layers are incubated at 37°C for - 2 min. The flask is tapped and checked for signs of cell detachment. Once the cells begin to slide off the flask, the complete media is added to kill the trypsin, "fhe cells are counted at this point, then diluted to the appropriate conccntralinn and split into flasks or dishes for further culturing (Usually 1:3 to 1:6 dilution).
Preparation of MDA-MB-453 Cell Lysate
When the MDA cells are 70 to 85% confluent, they arc detached as described above, and collected by centrifuging at 1000 g for 10 min at 4°C. The cell pellet is washed twice -viih TEGM (10 mM Tris-HCI, 1 mM EDTA. 10% glycerol. 1 mM bela-mercaptocth."innl, 10 mM Sodium Molybdate, pH 7.2). After the final wash.

the cells are rcsiispen,"•"H in TF.GM at a concentration of 107 cclls/mL. The cell suspension is snap froz-r. in liquid nitrogen or ethanol/dry ice bath and transferred to -80°C freezer on dry ice. Before setting up the binding assay, the frozen samples arc left on ice-water to jusl th iw (-1 hr). Then the samples are centrifuged at 12,500 g to 20,000 g for 30 min ct 4°C. The supernatant is used to set-up assay right away. If using 50 L of supernai^nt, the test compound can be prepared in 50 L of the TBGM buffer. Procedure^for Multiple Ccmpound Screening:
Ix TEGM buffer is prepared, and the isotope-containing assay mixture is prepared in the following order: EtOH (2% final concentration in reaction). ^Ij-RI881 or 3H-DHT (G : nM final Cone, in reaction) and Ix TEGM. [eg. For 100 samples. 200 L (100 x 2) of EtOH + 4,25 L of 1:10 3H-R1881 stock + 2300 L (100 X 23) Ix TEGM I. i I.e compound is serially diluted, e.g., if starting final cone, is 1 M. and the compound is in 25 L of solution, for duplicate samples, 75 L of 4x1 M solution is made and 3 L of 100 M is added to 72 L of buffer, and 1:5 serial dilution.
25 L o? -JH-RISSI trace and 25 L compound solution are first mixed together, followed by -iddition of 50 L receptor solution. The reaction is gently mixed, spun bricfiy at about 200 rpm and incubated at 4°C overnight. 100 L of 50% ilAP slurry is prepared and added to the incubated reaction which is then vortexed and incubated on ice for 5 to 10 minutes. The reaction mixture is vortexed twice more to resuspend HAI" while incubating reaction. The samples in 96-well format are then washed in wash buft""T using The FilterMate Universal Harvester plate washer (Packard). The washing process transfers HAP pellet containing ligand-bound expressed receptor to Unlfilter-96 GF/B filter plate (Packard). The HAP pellet on the filter plate is incubated with 50 L of MICROSCINT (Packard) scintillinl for 30 minutes before being counted on the TopCounl microscintillation counter (Packard). IC50S arc calculated using R1881 as a reference. Tissue selective androgen receptor modulators of the prcscni invention displayed IC50 values of 1 micromolar or less.
2, MMPl Promoter Supnression. Transient Transfection As-say (TRAMPS).
I icpG2 cells arc cultured in phenol red free MEM containing 10 % charcoal-treated FC:S at 37C with 5% CO?. For transfection. cells are plated at

10.000 cells/well in 96 well white, clear bottom plates. Twenty four hours later, cells are co-traiisfccled with a MMPI promoter-!uciferase reporter construct and a rhesus monkey expression coii-strucl (50 : 1 ratio) using FuGENR6 transfection reagent, following the protocol recommended by manufacturer. The MMPI promoter-luciferase reporter construct is gur.c""ated by insertion of a human MMPI promoter fragment (-179/1-63) into pGL2 luciferase reporter construct (Promega) and a rhesus monkey AR expression construct is generated in a CMV-Tag2B expression vector (Stratagenc). Cells are further cultuicd for 24 hours and then treated with test compounds in the presence of 100 nM ph(irbol-l2-myristate-13>acetate (PMA), used to increase the basal activity of MMPI promoter. The compounds are added at this point, at a range of iOOOnM to 0.03nM, I"l dilutions, at a concentration on lOX, l/lOth volume (cxamplc:IO microlitei^ of ligand at lOX added to 100 microliters of media already in the well). Cells arc further cultured for an additional 48 hours. Cells are then washed twice with PBS and ly^ jd by adding 70 L of Lysis Buffer (1 x, Promega) to the wells. The luciferase aciivity is measured in a 96-wcli format using a 1450 Microbcta Jet (Perkin l^lmer) luminoi,icler. Activity of test compounds is presented as suppression of luciferase signal from "hn PMA-s!imulated control levels. EC50 and Emax values arc reported. Tissue sclecL^."e androgen receptor modulators of the present invention activalc repression typically with submicromolar EC50 values and Emax values greater than about 50%. References;
a. Newberry EP. Willis i), |,atifi T, Boudreaux JM, Towler DA, "Fibroblast growth factor receptor ;iij,ialing activates the human interstitial collagcnase promoter via the bipartiLc Eis-APl element." Mol. Endocrinol. 11: 1129-44(1997).
b. Schncikert J. Pcterzi^l H. Defossez PA, Klockcr H, Launoit Y, Cato AC. ""Androgen receptor-lils protein interaction is a novel mechanism for steroid hormone-mediated down-modulation of matrix metalloproteinase expression," J.Biol.Chem. 271: 23907-23913(1996). 3. A Mammalian Two-I iybrid Assay for the Ligand-induced Interaction of N-Terminus
and C-"l"crminus Domains of the Androgen Receptor (Agonist Mode)
This as^ay assesses the ability of AR agonists to induce the interaction between the N-termin^! domain (NTD) and C-terminal domain (CTD) of rhAR that rcHecls Ihc in vivo v"n.lining potential mediated by activated androgen receptors. The

interaction of NTD sr.d CTD of rhAR is quantified as ligand induced association between a GaI4DB[)-rh^KCTD fusion protein and a VPI6-rhARNTD fusion protein as a mammalian iwo-hybrifl assay in CV-1 monkey Icidney cells.
The day before Iransfeetion, CV-1 cells are trypsinized and counted, and then plated at 20,000 cells/well in 96-weli plates or larger plates (scaled up accordingly) in I3M[-:M -f 10% FCS. The next morning, CV-1 cells are cotransfected with pCBIil (Gal4DBD-rhARLIJD lusion construct expressed under the SV40 early promoter), pCBB2 (VP16 -rhAR MID fusion construct expressed under the SV40 early promoter) and pFR {Gal4 responsive luciferase reporter, Promega) using LIP0FECTAM1NI-, PLUS reagent (GIBCO-BRL) following the procedure recommended by the vendor. Briefly. DNA admixture of 0.05 g pCBBl, 0.05 g pCBB2 and 0.1 ng of pFR is mixed in 3.4 ^il- OPTi-MEM (GIBCO-BRL) mixed with "PLUS Reagent" (1.6 L. (ilBCO-BRL) and inciiuaied at room temperature (RT) for 15 min to form the pre-complexed DNA.
I-or cacf, v/ell. 0.4 L I.IPOFECTAMINE Reagent (GiBCO-BRL) is diluted into 4.6 L OI"il-MlvM in a second tube and mixed to form the diluted LIPOFEC"IAMINI-. Reagent. The pre-complexed DNA (above) and the diluted LIPOl-"lvCTAMINE Reagent (above) are combined, mixed and incubated for 15 min at RT. The medium on ih^ cells is replaced with 40 L /well OPTI-MEM, and 10 L DNA-lipid complexes are added to each well. The complexes are mixed into the medium gently and inci;!?ated at 37°C at 5% CO2 for 5h. Following incubation, 200 I. /well D-MEM and BTO charcoal-.stripped FCS are added, followed by incubation at 37""C at 5% CO2. After 24 hours, the test compounds are added at the desired concenlralion(s) (1 nM 10 M). Forty eight hours later, luciferase activity is measured using LUC-"^creen system (TROPIX) following the manufacturer"s protocol. The assay is conducted directly in the wells by sequential addition of 50 L each of assay solution 1 follower by assay solution 2. Afler incubation for 40 minutes at room temperature, luminescence is directly measured with 2-5 second integration.
Activity of test compounds is calculated as the Emax relative to the activity obtained with 3 nM RI88I. Typical tissue-selective androgen receptor modulators of the prc"^"^nl invenlion display weak or no agonist activity in this assay with less than 50% agonist activity at 10 micromolar. Reference: I le B, Keinppaincn J A, Voegel JJ, Gronemeyer H, Wilson EM, ""Activation function

in the human androgen receptor ligand binding domain mediates inter-domain communication with the NH{2)-terminal domain," J. Biol. Chem. 274: 37219-37225 (1999).
4. A Mammalian l\vo-l ly^rid Assay l-"or Inhibition of Interaction between N-Terminus
and C-Tcrminus Homa"iis of Androgen Receptor (Antagonist Mode)
This asrqy assesses the ability of test compounds to antagonize the stimulatory effects of RiGSl on the interaction between NTD and CTD of rhAR in a mammalian two-hybrid assay in CV-l cells as described above.
forty eight hours after transfection, CV-l cells are treated with test compounds . typically at !0 M, 3.3 M, 1 M, 0.33 M, 100 nM, 33 nM. 10 nM. 3.3 nM and 1 nM final "-;oncentrations. After incubation at 37°C at 5% CO2 for 10 - 30 minutes, an AR agoni":! methyltrienolone (RI88I) is added to a fmal concentration of 0.3 nM and incubated ai 37""C. Forty-eight hours later, luciferase activity is measured using LLJC-Scrccn system (TROPIX) following the protoeol recommended by the manufacturer. The ability of test compounds to antagonize the action of R188I is calculated as the relative luminescence compared to the value with 0.3 nM RI88i alone.
SARM compounds of the present invention typically displayed antagonist activity in the ^resent assay with IC50 values less than 1 micromolar.
5. Trans-Activation Modulation of Androgen Receptor (TAMARl
This assay ussosscs the ability of test compounds to control transcription from the MMTV-LUC reporter gene in MDA-MB-453 cells, a human breast cancer cell line that naturally expresses the human AR, The assay measures induction of a modified MM"fV LTR/pjuinotcr linked to the LUC reporter gene.
20.000 to j0,000 cells/well are plated in a white, clear-bottom 96-well plate in "Exponential Growth Medium" which consists of phenol red-free RPMl 1640 containing ]0%FBS, 4inM L-glulamine, 20mM HEPES, \Oug/mL human insulin, and 20ug/ml. gcntamicin. Incubator conditions are 37""C and 5% CO2. The transfection is done in batch mode. "! he cells are trypsinized and counted to the right cell number in ihc proper amount o) i"/csh media, and then gently mixed with the Fugenc/DNA cocktail mix and plated onto the 96-well plate. All the wells receive 200 Tl of medium "- lipid/DNA complex and are then incubated at 37°C overnight. The transfection cocklail consists of ,scriim-free Opt"imem, Fugene6 reagent and DNA. The

manufacturer"s (Roche !3inchemical) protocol for cocktail setup is followed. The lipid (Ti) to DNA (Tg) ralic "ss approximately 3:2 and the incubation time is 20 min at room temperature. Sixtccii to 24 hrs after transfection, the ceils are treated with test compounds such that the final DMSO (vehicle) concentration is Activity -f test compounds is calculated as the Emax relative to the activity obtained wiih I ;J0 nM R1881. References:
R.B. Hall, et al.. "MDA-iviB-453, an androgen-responsive human breast carcinoma cell line with high androgen receptor expression," Eur. J. Cancer. 30A: 484-490 (1994). R.E. Hall, et al.. ""Re^jh"iion of androgen receptor gene expression by steroids and relinoicacid in human b-cast-cancer cells." Int. J. Cancer.. 52: 778-784 (1992).
6. In Vivo Prostate Asaa"
Male SpiufaUC-Dawley rats aged 9-10 weeks, the earliest age of sexual maturity, are used in prevention mode. The goal is to measure the degree to which androgen-like eompoui.ds delay the rapid deterioration (—85%) of the ventral prostate gland and semina] vcsiccs that occurs during a seven day period after removal of the testes (orchiectomy |OUX)),
Rats arc rrchieclomized (ORX). Each rat is weighed, then anesthetized by isofluranc gas that ia iTaintained to effect. A 1.5 cm anteroposterior incision is made in the scrotum. The right testicle is exteriorized. The spermatic artery and vas deferens are ligatcd with 4.0 sill 0.5cm proximal to the testicle. The testicle is freed by one cut of a small surgical scissors distal to the ligation site. The tissue stump is returned to the scrotum. The same i? repeated for the left testicle. When both stumps are returned to the scrotum, the scrotirr" and overlying skin are sutured closed with 4.0 silk. For Sham-ORX. all procedures -; "f^pling ligation and scissors cutting are completed. The rats fully recover consciousness and full mobility within 10-15 minutes.
A dose ■ .test compound is administered subcutaneously or orally to the rac immediatelv alter the surgical incision is sutured. Treatment continues for an additional six consccui"ve days.

Necropsy and l-.ndpoinLS:
The rat !-> Ilrst weighed, then anesthetized in a CO2 chamber until near death. Approximately 5ml whole blood is obtained by cardiac puncture. The rat is then examined for certain "gns of death and completeness of ORX. Next, the ventral portion of the prostate ,^jand is located and blunt dissected free in a highly stylized fashion. Ihe ventral r: jslale is blotted dry for 3-5 seconds and (hen weighed (VPW). Finally, the seminal vesitie is located and dissected free. The ventral seminal vesicle is blotted dry for 3-5 sccor"ds and then weighed (SVWT).
Primary data for this assay are the weights of the ventral prostate and seminal vesicle. Sccoriary data include serum LH (luteinizing hormone) and FSH {follicle stimulating hormone), and possible serum markers of bone formation and virilization. Data are :• -alyzed by ANOVA plus Fisher PLSD post-hoc test to identify intcrgroup differences, i lie extent to which test compounds inhibit ORX-induced loss of VPW and SVWT is f.^essed.
7. In Vivo Bone Formation Assav:
Female Sprague-Dawley rats aged 7-10 months are used in treatment mode to simulate aduli "luman females. The rats have been ovariectomized (OVX) 75-180 days previously, LU cause bone loss and simulate estrogen deficient, osteopenic adult human females. Pre-trcatment with a low dose of a powerful anti-resorptive. alendronate (0.0028mpk SC, 2X/wk) is begun on Day 0. On Day 15, treatment with test compound is started. Test compound treatment occurs on Days 15-31 with necropsy on Day 32. The goal is to measure the extent to which androgen-likc compounds increase ti.. amount of bone formation, shown by increased iluorochrome labeling, at the pcriost^-^jl surface.
In a typical assay, nine groups of seven rats each are studied.
On Days 19 and 29 (fifth and fifteenth days of treatment), a single subcutaneous injection of calcein (8mg/kg) is given to each rat.
Necropsy and Endpoint."
The rat i ■ I"lrst weighed, then anesthetized in a CO2 chamber until near death. Approximately 5mL whole blood is obtained by cardiac puncture. The rat is then examined for certain signs of death and completeness of OVX. First, the uterus is located, blunt dissected free in a highly stylized fashion, blotted dry for 3-5 seconds and

then weighed (UW). The uterus is placed in 10% neuiral-buffcred formalin. Next, the right leg is disarticulated at the hip. The femur and tibia are separated at the knee, substantially dcflcshed, and then placed in 70% ethanol.
A 1-cm .cgment of the central right femur, with the femoral proximal-dislal midpoini ats ceni-^:. is placed in a scintUiation vial and dehydrated and defatted in graded alcohols and acetone, then introduced to solutions with increasing concentrations of methyl methacrylate. It is embedded in a mixture of 90% methyl methacrylate :10% dibutyl phthalate, that is allowed to polymerize over a 48-72hr period. The bottle is cracked and the plastic block is trimmed into a shape that conveniently fits the \i.:e-like specimen holder of a Leica 1600 Saw Microtome, with the long axis of the bo-." prepared for cross-sectioning. Three cross-sections of 85)ini thickness are prepared and mounted on glass slides. One section from each rat that approximates the midpoint of the bone is selected and blind-coded. The periosteal surface of each section is assessed for total periosteal surface, single fluorochrome label, double fiuorochrome label, and interlabel distance.
Primary "lata for this assay are the percentage of periosteal surface bearing double label J"^d the mineral apposition rate (interlabel distance{^lm)/10d). scmi-independcnt marker^ of bone formation. Secondary data include uterus weight and histologic features. Tertiary endpoints may include serum markers of bone formation and virilization. Data are analyzed by ANOVA plus Fisher PI.SD post-hoc test to idcntiiy intergroup differences. The extent to which lest compounds increase bone formation endpoi-:! are assessed.
While tb"^ foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it is understood that the practice of the invention encompasses all of the usual variations, adoptions, or modifications, as being within the scope of the following claims and their equivalents.


PROPOSED CLAIM AMENDMENTS
1. A compound of structural formula 1:

a pharmaceutical ly acceptable salt, an enantiomer thereof; wherein n is 0, 1 or 2;
a-b represents CF=CH, CHFCH2, or CF2CH2;
Rl is hydrogen, hydroxymethyl, or C 1.3 alkyl, wherein alkyl is unsubstituted or
substituted with one to seven fluorine atoms; R2 is hydrogen R3 represents:
C1-4 alkyl,
(CH2)n-cycloheteroalkyl, and
(CH2)n-aryl! wherein aryl is selected from
(1) phenyl,
(2) naphthyl,
(3) benzimidazolyl,
(4) benzofuranyl,
(5) benzothiophenyl,
(6) benzoxazolyl,
(7) benzothiazolyl,
(8) benzodihydrofuranyl,
(9) 1,3-benzodioxolyl,
(10) 2,3-dihydro-l ,4-benzodioxinyl,
(U)indolyl,
(12) quinolyl,
(13) isoquinolyl.

(14) furanyl, (15)thienyl,
(16) imidazolyl,
(17) oxazolyl, (18)thiazolyl,

(19) isoxazolyl,
(20) isothiazolyl, (21)pyrazolyl,

(22) pyrrolyl,
(23) pyridyl,
(24) pyrimidyl,
(25) pyrazinyl.
(26) thiadiazolyl,
(27) oxadiazolyl,
(28) triazolyl,
(29) tetrazoiyl,
(30) indanyl, and
(31) azabenzimidazolyl;
wherein the alkyl group or the cycioheteroalkyi group is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, and Cj,4. alkoxy;
the aryl group as defined in items (1) to (30) is unsubstituted or substituted with one to three groups independently selected from halogen, phenyl, Cj-g alkyl, C3-8 cycloalkyl, C3-8 cycioheteroalkyi, phenyl-Ci-6 alkyl, amino-Co-6 alkyl, C|.6 alkylamino-Co-6 alkyl, (Cl-6 alkyl)2amino-Co-6 alkyl, phenyl-Co-6 alkylamino-Co-6 alkyl, (phenyl-Co-6 alkyl)2amino-Co-6 alkyl, C].^ alkylthio, phenyl-Co-6 alkylthio, Ci-6 alkylsulfinyl, phenyl-CO-6 alkylsulfinyl, Ci,6 alkylsulfonyl, phenyl-Co-6 alkylsulfonyl, Ci-6 alkoxy-Co-6 alkyl, phenyl-Co-6 alkoxy-Co-6 alkyl hydroxycarbonyl-Co-g alkyl, Ci-6 alkoxycarbonyl-Co-6 alkyl, phenyl-Co-6 alkoxycarbonyl-Co-6 alkyl, hydroxycarbonyl-C 1 . 6 alkyloxy, hydroxy-Co-6 alkyl, cyano, nitro, perfluoro-Ci-4 alkyl, perfluoro-C 1.4 aikoxy, 0x0, Ci-g alkylcarbonyloxy. phenyl-Co-6 alkylcarbonyloxy, Ci-6 alkylcarbonylamino, phenyl-Co.6 alkylcarbonylamino, Ci-6 alkylsulfonyIamino, phenyl-Co-6 alkylsulfonyl amino, Ci-6 alkoxycarbonylamino, phenyl-CO-6 alkoxycarbonylamino, Cl-6 alkylamino carbonylamino, phenyI-CO-6 alkyl aminocarbonyl amino, (Ci-6 alkyl)2 aminocarbony Iamino, (phenyl-CO-6 alkyl)2 aminocarbonyl amino, (Cl.6 alkyl)2 aminocarbonyloxy, and (phenyl-Co-6 alkyl)2 aminocarbonyloxy; and wherein any methylene (CH2) carbon atom

in (CH2)n is unsubstituted or substituted with one lo two groups independently selected
from halogen, hydroxy, and Ci-4 alkyl; or two substituents when on the same methylene
(CH2) group are taken together with the carbon atom to which they are attached to form a
cyclopropyl group;
or R2 and R3 together form a 5- or 6-membered saturated ring fused with a 5- or 6-
membered aromatic ring system having 0, 1, or 2 heteroatoms selected from the N, O,
andS.
2. The compound as claimed in claim 1 wherein Rl is hydrogen or
methyl.


(5) benzothiophenyl,
(6) benzoxazolyl,
(7) benzothiazolyl,
(8) benzodihydrofuranyl,
(9) 1,3-benzodioxolyl,
(10) 2,3-dihydro-l,4-benzodioxinyl,
(ll)indolyl,
(12) quinolyl,
(13) isoquinolyl, (14)furanyl, (15)thienyl,

(16) imidazolyl,
(17) oxazolyl. (18)thiazolyl,

(19) isoxazolyl,
(20) isothiazolyl,
(21) pyrazolyl,
(22) pyrrolyl,
(23) pyridyl,
(24) pyrimidyl,
(25) pyrazinyl,
(26) thiadiazolyl,
(27) oxadiazolyl,
(28) triazolyl,
(29) tetrazolyl.
(30) indanyl, and
(31) azabenzimidazolyl;
wherein the alky! group is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, and Ci-4 alkoxy; the aryl group as
defined in items (1) to (30) is unsubstituted or substituted with one to tliree groups independently selected from halogen, phenyl, Ci-g allfyl, C3.8 cycloalkyl, C3-8 cycloheteroalky!, phenyl-Ci-6 alkyl, amino-Co-6 alkyl, C\.s alkyiamino-CO-6 alkyl, (C].6 alkyl)2amino-Co-6 alkyl, phenyl-CO-6 alkylaraino-CO-6 alkyl, (phenyl-Co-6 alkyl)2amino-C0-6 alkyl, Ci-6 alkylthio, phenyl-Co-6 alkylthio, C\.s alkylsulfinyl, phenyl-CO-6 alkylsulfinyl, Cl-6 alkylsulfonyl, phenyl-CO-6 alkylsulfonyl, Ci-6 alkoxy-C0.6 alkyl, phenyI-Co-6 alkoxy-Co-6 alkyl, hydroxycarbonyl-Co-6 alkyl, C j .g

alkoxycarbonyl-Co-6 alkyl, phenyl-Co-6 alkoxycarbonyl-CO-6 alkyl, hydroxycarbonyl-Ci.6 alkyloxy, hydroxy-Co-6 alkyl, cyano, nitro, perfluoro-Ci-4 alkyl, perfluoro-Cl,4 alkoxy, 0x0, C]-6 alkylcarbonyloxy, phenyl-CO-6 alkylcarbonyloxy, Cl-6 alkylcarbonyl amino, phenyl-CO-6 alkylcarbonylamino, Cl.6 alkylsulfonylamino, phenyl-CO-6 ^^^Y^ sulfonylamino, Cl-6 aikoxycarbonyiamino, phenyl-CO-6 alkoxycarbonylamino, Ci-6 alkylaminocarbonylamino, phenyl-Co-6 alkyl aminocarbonylamino, (Cl.6 alkyl)2 aminocarbonylamino, (phenyl-CO-6 alkyl)2 aminocarbonylamino, (Cl-6 a"kyl)2 aminocarbonyloxy, and (phenyl-Co.6 a]kyl)2 aminocarbonyloxy; and wherein any methylene {CH2) carbon atom in (CH2)n "S unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyi group;
or R2 and R3 together form a 5- or 6-membered saturated ring fused with a 5- or 6-mcmbered aromatic ring system having 0, 1, or 2 heteroatoms selected from the N, O, andS.
4. The compound as claimed in claim 3, wherein Rl is hydrogen or methyl.
5. The compound as claimed in claim 1 wherein a-b represents CF=CH.
6. The compound as claimed in claim 1 wherein a-b represents CHFCH2.
7. The compound as claimed in claim 1 wherein R3 is (CH2)n-aryl-
8. The compound as claimed in claim 7 wherein n is 0 or 1.
9. The compound as claimed in claim 1 wherein Rl is methyl, a-b represents CF=CH, and R3 is (CH2)n-aryl.
10. The compound as claimed in claim 9 wherein n is 0 or 1.
11. The compound as claimed in claim 1 wherein Rl is methyl, a-b represents CHFCH2, and R3 is (CH2)n-aryl.
12. The compound as claimed in claim 11 wherein n is 0 or 1.

13. The compound as claimed in claim 1 wherein R1 is methyl, a-b represents CF=CH, and R3 is (CH2)n-cycloheteroalkyl.
14. The compound as claimed in claim 13, wherein n is 0 or 1.
15. The compound as claimed in claim 1 wherein Rl is methyl, a-b represents CHFCH2, and R3 is (CH2)n-cycIoheteroatkyl.
16. The compound as claimed in claim 15, wherein n is 0 or 1.
17. The compound as claimed in claim 2 is preferably represented by -N-(2,2,2-trifluoroethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(2-f]uorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-1 -en-17p-
carboxamide; N-(3-fIiiorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-1 -en-17p-
carboxamide; N-(2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-
carboxamide; N-{2-chlorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-carboxamide; N-(4-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamidc; N-(3-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamide; N-(2-methy(phenyi)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-1 -en-17p-carboxamide; N-(3-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-I73-carboxamide; N-(2-fluorophenyl)-2-f]uoro-4-methyl-3-oxo-4-aza-5a-androst-]-en-17P-carboxamide; N-(3-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-carboxamide; N-{4-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-carboxamide; N-(4-chloro-2-fluorophenyl)-2-tluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(2,4-difluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-!7p-
carboxamide: N-(a-methy]phenyimethy])-2-flijoro-4-methy)-3-oxo-4-aza-5a-androst-)-en-!7p-
carboxamide; N-(phenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-!-en-l7p-carboxamide; N-(4-chloro-2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo>4-aza-5a-androst-l-en-
17p-carboxamidc;

N-(5-methylpyridin-2-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamide;
N-(thiophen-2-y]methy])-2-nuoro-4-methyl-3-o.\o-4-aza-5a-androst-l-en-]7p-carboxamide;
N-{thiophen-3-ylmethyl)-2-nuoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamide;
N-(2-trifluoromethylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-
carboxamide; N-(benzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androsl-l-en-17|3-
carboxamide; N-(i-methylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carboxamide; N-(l-methyl-5-trifluoromethy!benzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-
5a-androst-l -en-17p-carboxamide; N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carboxamide; N-(5-methoxybenzimida2o!-2-ylmethyl}-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-
en-17[3-carboxamide: N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17ji-
carboxamidc; N-(2,3-dihydro-l,4-benzodioxin-2-yImethyI)-2-fluoro-4-methyi-3-oxo-4-aza-5a-androst-
1 -en-17p-carboxaniide; N-(thiazoi-2-ylmethyi)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-{4-methy]th)azol-2-y]methyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-J7P-
carboxamide; N-(thiazo!-4-ylmethyi)-2-tluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(!-methylimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(tetrahydro-2//-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carboxamide; N-(letrahydro-2//-pyran-2{R)-ylinethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carbo\"amide; N-(2,3-dihydro-l,4-bcnzodioxin-2(R)-ylmelhyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-l-en-!7p-carboxamide;

N-(2,3-dihydro-l,4-ben2odioxin-2(S)-ylmelhy!)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-1 -en-17P-carboxamide; N-(letraliydrofurar)-2(S)-ylmethy])-2-fliJoro-4-methy]-3-oxo-4-aza-5a-androst-l-en-17p-
carbox amide; N-(letrahydrofuran-2{R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(3//-imidazo[4,5-ft]pyridin-2-ylmethyl)-2-fluoro-4-inethyl-3-oxo-4-aza-5a-androsl-!-
en-17p-carboxamide; N-(2-fluorophenylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17(J-
carbox amide; N-(2-trifluoromethylphenylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-I7f!-
carboxamide; N-(3-methoxyphenyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17P-carboxamide; N-(4-methoxyphenyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-carboxamide; N-(2-trifluoromethylphenyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-iindrostan-17p-
carboxamide; N-(2-chlorophenyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17P-carboxamide; N-(2-fluorophenylmelhyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-]7p-
carboxamide; N-{ben2imidazol-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androslan-17p-
carboxamide; N-(l-melhylbenzimidazol-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-
17p-carboxamide; N-(thiazol-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androsian-17p-carboxamide; N-(furan-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17P-carboxamide;
and N-(thiophen-2-yImethyi)-2a-fluoro-4-metIiyi-3-oxo-4-aza-5a-androstan-I7[3-
carboxamide; pharmaceutically acceptable salts and enanliomers thereof.
18. The compound as claimed in ciaim 17 is further chosen from; N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-]-en-I7P-
carboxamide; N-(3-fluoropheny[methyl)-2-f[uoro-4-methyI-3-oxo-4-aza-5a-androst-I-en-I7p-
carboxamide;

N-(5-chloroben2imidazol-2-ylmcthyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17p-carboxamide; N-(5-melhoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-
en-17p-carboxamide; N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androsl-l-en-17j3-
carboxamide; N-(tetrahydro-2//-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
]7p-carboxamide; N-(tetrahydro-2//-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
IVP-carboxamide; N-(2,3-dihydro-l,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androsi-1 -en-17p-carboxamide; N-(2,3-dihydro-l,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-l-en-17P-carboxamide; N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(tetrahydrofuran-2(R)-ylmethyl)-2-f]uoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-
carboxamide; N-{3//-imidazo[4,5-6]pyridin-2-ylmelhyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-
en-17p-carboxamide: N-(2-fluorophenylmetbyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-]7p-
carboxamide; N-(thiazol-2-ylmelhyl)-2a-{luoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-carboxamide; N-(furan-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17P-carboxamide;
and N-(lhiophen-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-
carboxamide; pharmaceutical iy acceptable salts and enantiomers thereof.
19. The compound as claimed in claim 18 is still ftirther chosen from: N-ftetrahydro-2/y-pyraji-2(S)-y]methyl)-2-nuoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17P-carboxamide; N-(letrahydro-2//-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
17P-carboxamide; N-(2,3-dihydro-l,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-1 -en-17B>carboxamide;

N-(2,3-dihydro-l,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-
androst-l-en-17p-carboxamide; N-(tetrahydrofaran-2(S)-ylmcthyl)-2-fluoro-4-methyl-3-oxo-4-a2a-5a-androst-l-en-17|3-
carbox amide; N-(letrahydrofuran-2{R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(3//-imidazo[4,5-/>]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-
en-17p-carboxamide; pharmaceutically acceptable salts and enantiomers thereof,
20. The compound as claimed in claim 18 is still further selected from: N-{2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-
carboxamide; N-{5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-
!7p-carboxamide; N-(5-methoxybenzJmidazol-2-ylmethyl)-2-fluDro-4-methyl-3-oxo-4-aza-5a-androst-l-
cn-17p-carboxamide; N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-t7p-
carboxamide; N-{2-fluorophenylmethyl)-2a-nuoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-
carboxamide; N-(thiazol-2-y!methyl)-2a-fluorQ-4-methyl-3-oxo-4-aza-5a-androstan-17p-carboxamide; N-(furan-2-ylmethyl)-2a-fluoro-4-methyl-3-Dxo-4-aza-5a-androstan-I7p-carboxamide;
and N-(thiophen-2-ylmethyl)-2a-fluoro-4-methyl-3-oxo-4-aza-5a-androstan-17p-
carboxamide; pharmaceutically acceptable salts and enantiomers thereof.
21. The preferred compounds as claimed in preceding claims are still further represented by:
N-(2,2,2-trifluoroethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17P-carboxamide;

N-(2-fluorophenyImethyl)-2-fluoro.4-methyi-3-oxo-4-aza-5a-androst-i-en-17p-carboxamide;
N-{2-trifluoromethylphenylinethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamide;
N-(benzimidazoI-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-carboxamidc;
N-(l-methylimidazol-2-yImethyl)-2-fluoro-4-inethyl-3-oxo-4-aza-5cx-androsM-en-17p-carboxamide;
N-(3//-imidazo|;4,5-6]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androsl-]-en-17p-carboxamide; more preferably from
N-(2,2,2-trifluoroethyI)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide; N-(benzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5a-androst-l-en-17p-
carboxamide;and N-{3//-imidazo[4,5-6]pyridin-2-ylmethyI)-2-fluoro-4-methyl-3-oxo-4-a2a-5a-androsl-l-
en-I7p-carboxamide; and pharmaceutically acceptable salts and enantiomers
thereof,
22. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim I including preferred compounds, a pharmaceutical ly acceptable salt and/or an enantiomer thereof as claimed in any preceding claims optionally in combination with other therapeutic agent such as herein described.
23. A composition as claimed in claim 22 optionally contains other therapeutic agent such as herein described and preferably selected from :
(a) an estrogen or an estrogen derivative, alone or in combination with a progestin or progestin derivative,
(b) a bisphosphonate,
(c) an antiestrogen or a selective estrogen receptor modulator,
(d) an avp3 integrin receptor antagonist,
(e) a cathepsin K inhibitor,
(f) an osteoclast vacuolar ATPase inhibitor,
(g) an antagonist of VEGF binding to osteoclast receptors,
(h) calcitonin,
(i) ostoprotegrin, and

(j) parathyroid hormone or analog thereof more preferably selected from
bis phosphonate exemplified by alendronet monosodium mono or triphosphate and is capable of (i) modulating a fjunction mediated by the androgen receptor; (ii) activating the function of the androgen receptor in at least one of bone and muscle tissue and the one blocked in the prostate or the uterus; (iii) treating or ameliorating a condition with regard to bone related diseases such as rheumatoid arthritis and osteoarthritis; male hypogonadism, and prostate cancer preferably osteoporosis and or prostate cancer; caused by androgen deficiency by androgen replacement, or increasing androgen replacement.
24. A process for making a pharmaceutical composition comprising combining, in a conventional manner such as herein described, a compound as claimed in claim 1 including preferred compounds or a pharmaceutically acceptable salt or an enantiomer thereof as claimed in any preceding claims optionally in combination with other agent such as herein described and a pharmaceutically acceptable carrier.
25. A compound as claimed in claim 1 including preferred compounds or a pharmaceutically acceptable salt or an enantiomer thereof, composition thereof, process therefore and use thereof substantially as herein described with reference to examples.

Documents:

2007-chenp-2004 abstract duplicate.pdf

2007-chenp-2004 abstract.pdf

2007-chenp-2004 assignment.pdf

2007-chenp-2004 claims duplicate.pdf

2007-chenp-2004 claims.pdf

2007-chenp-2004 correspondence others.pdf

2007-chenp-2004 correspondence po.pdf

2007-chenp-2004 description (complete) duplicate.pdf

2007-chenp-2004 description (complete).pdf

2007-chenp-2004 form-1.pdf

2007-chenp-2004 form-13.pdf

2007-chenp-2004 form-18.pdf

2007-chenp-2004 form-26.pdf

2007-chenp-2004 form-3.pdf

2007-chenp-2004 form-5.pdf

2007-chenp-2004 pct.pdf

2007.jpg


Patent Number 205696
Indian Patent Application Number 2007/CHENP/2004
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 09-Apr-2007
Date of Filing 08-Sep-2004
Name of Patentee M/S. MERCK & CO ., INC.
Applicant Address 126 EAST LINCOLN AVENUE, RAHWAY, NJ 07065-0907
Inventors:
# Inventor's Name Inventor's Address
1 PERKINS,JAMES,J, 126 EAST LINCOLIN AVENUE RAHWAY NJ 07065-0907
2 MEISSNER, ROBERT,S 126 EAST LINCOLN AVENUE, RAHWAY, NJ 07065-0907
PCT International Classification Number A61K 31/473
PCT International Application Number PCT/US03/08277
PCT International Filing date 2003-03-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/363,822 2002-03-13 U.S.A.