WO2006060108A1

WO2006060108A1 - N-(pyridin-3-yl)-2-phenylbutanamides as androgen receptor modulators

Info

Publication number: WO2006060108A1
Application number: PCT/US2005/039931
Authority: WO
Inventors: Yuntae Kim; Joshua Close; Mark E. Duggan; Barbara Hanney; Robert S. Meissner; Jeffrey Musselman; James J. Perkins; Jiabing Wang
Original assignee: Merck & Co., Inc.
Priority date: 2004-10-29
Filing date: 2005-10-25
Publication date: 2006-06-08
Also published as: CN101052398A; JP2008518968A; US20080124402A1; CA2585276A1; AU2005310238A1; EP1807076A1; EP1807076A4

Abstract

Compounds of structural formula (I) are modulators of the androgen receptor (AR) in a tissue selective manner. These compounds are useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), abdominal adiposity, metabolic syndrome, type II diabetes, cancer cachexia, Alzheimer’s disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

Description

TITLE OF THE INVENTION

N-(PYRIDIN-3-YL)-2-PHENYLBUTANAMIDES AS ANDROGEN RECEPTOR MODULATORS

FIELD OF THE INVENTION The present invention relates to N-(pyridin-3-yl)-2-phenylbutanamide derivatives, their synthesis, and their use as androgen receptor modulators. More particularly, the compounds of the present invention are tissue-selective androgen receptor modulators (SARMs) and are thereby useful for 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. Additionally, the SARMs of the present invention can be used to treat mental disorders associated with low testosterone, such as depression, sexual dysfunction, and cognitive decline. SARMs, being antagonists in specific tissues, are also useful in conditions where elevated androgen tone or activity causes symptoms, such as benign prostate hyperplasia and sleep apnea.

BACKGROUND OF THE INVENTION

The androgen receptor (AR) belongs to the superfamily of steroid/thyroid hormone nuclear receptors, whose other members include the estrogen receptor, the progesterone receptor, the glucocorticoid receptor, and the mineralocorticoid receptor. The AR is expressed in numerous tissues of the body and is the receptor through which the physiological as well as the pathophysiological effects of androgens, such as testosterone (T) and dihydrotestosterone (DHT), are mediated. Structurally, the AR is composed of three functional domains: the ligand binding domain (LBD), the DNA-binding domain, and amino-terminal domain. A compound that binds to the AR and mimics the effects of an endogenous AR ligand is referred to as an AR agonist, whereas a compound that inhibits the effects of an endogenous AR ligand is termed an AR antagonist. Androgen ligand binding to the AR induces a ligand/receptor complex, which, after translocation into the nucleus of the cell, binds to regulatory DNA sequences (referred to as androgen response elements) within the promoter or enhancer regions of the target genes present in the nucleus. Other proteins termed cofactors are next recruited, which bind to the receptor leading to gene transcription. Androgen therapy has been 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 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, are used to treat prostate cancer. It would therefore be useful to have available compounds that can activate ("agonize") the function of the AR in a tissue-selective manner that would produce the desired osteo- and myoanabolic effects of androgens without the negative androgenic properties, such as virilization and repression of high density lipoprotein cholesterol (HDL).

The beneficial effects of androgens on bone in postmenopausal osteoporosis were documented in recent studies using combined testosterone and estrogen administration [Hofbauer, et al., Eur. J. Edocrinol. 140: 271-286 (1999)]. In a large 2-year, double-blind comparison study, oral conjugated estrogen (CEE) and methyltestosterone combinations were demonstrated to be effective in promoting accrual of bone mass in the spine and hip, while conjugated estrogen therapy alone prevented bone loss FJ. Reprod. Med.. 44: 1012-1020 (1999)].

Additionally, there is evidence that hot flushes decrease in women treated with CEE and methyltestosterone; however, 30% of the treated women suffered from significant increases in acne and facial hair, a complication of all current androgen pharmacotherapies [Watts, et al., Obstet. Gynecol., 85: 529-537 (1995)]. It was also found that the addition of methyltestosterone to CEE decreased HDL levels, as seen in other studies. Thus, the virilizing potential and effects on lipid profile of current androgen therapies provide a rationale for developing tissue-selective androgen receptor agonists. Androgens play an important role in bone metabolism in men [Anderson, et al.,

"Androgen supplementation in eugonadal men with osteoporosis — effects of six months of treatment on bone mineral density and cardiovascular risk factors," Bone, 18: 171-177 (1996)]. Even in eugonadal men with osteoporosis, the therapeutic response to testosterone treatment reveals that androgens exert important osteoanabolic effects. Mean lumbar BMD increased from 0.799 gm/cm2 to 0.839 g/cm2, in 5 to 6 months in response to 250 mg of testosterone ester administered intramuscularly. SARMs can thus be used to treat osteoporosis in men.

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 AR antagonists. In response to hormonal deprivation, these men suffered from hot flushes, significant bone loss, weakness, and fatigue. In a 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 ADT for greater than one year than the patients who did not undergo ADT [Wei, et al., Urology, 54: 607-611 (1999)]. Lumbar spine BMD was significantly lower in men who had undergone ADT. Thus tissue selective AR antagonists in the prostate that lack antagonistic action in bone and muscle can be useful agents for the treatment of prostate cancer, either alone or as an adjunct to traditional ADT [See also A. Stoch, et al., J. Clin. Endocrin. Metab.. 86: 2787-2791 (2001)].

Tissue-selective AR antagonists can also treat polycystic ovarian syndrome in postmenopausal women. See CA. Eagleson, et al., "Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone," J. Clin. Endocrinol. Metab., 85: 4047-4052 (2000). SARMs can also treat certain hematopoietic disorders as androgens stimulate renal hypertrophy and erythropoietin (EPO) production. Prior to the introduction of recombinant human EPO, androgens were employed to treat anemia caused by chronic renal failure. In addition, androgens increase serum EPO levels in anemic patients with non-severe aplastic anemia and myelodysplastic syndromes. Treatment for anemia will require selective action such as can be provided by SARMs. SARMs can also have clinical value as an adjunct to the treatment of obesity. This approach to lowering body fat is supported by published observations that androgen administration reduced subcutaneous and visceral fat in obese patients [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)], [J.C. Lovejoy, et al., "Exogenous Androgens Influence Body Composition and Regional Body Fat Distribution in Obese Postmenopausal Women — A Clinical Research Center Study," J. Clin. Endocrinol. Metab.. 81: 2198-2203 (1996)]. Therefore, SARMs devoid of unwanted androgenic effects can be beneficial in the treatment of obesity.

Androgen receptor agonists can also have therapeutic value against metabolic syndrome (insulin resistance syndrome, syndrome X), particularly in men. Low levels of total and free testosterone and sex hormone-binding globulin (SHBG) in men have been associated with type 2 diabetes, visceral obesity, insulin resistance (hyperinsulinemia, dyslipidemia) and metabolic syndrome. D. Laaksonen, et al., Diabetes Care. 27 (5): 1036-1041(2004); see also D. Laaksonen, et al. Euro. J Endocrin. 149: 601- 608 (2003); P. Marin, et al. Int. J. Obesity. 16: 991-997 (1992), and P. Marin, et al. Obesity Res.. 1(4): 245-251 (1993).

Androgen receptor agonists can also have therapeutic value against neurodegenerative diseases such as Alzheimer's disease (AD). The ability of androgens to induce neuroprotection through the androgen receptor was reported by J. Hammond, et al., "Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons," J. Neurochem., 77: 1319-1326 (2001). Gouras et al. reported that testosterone reduces secretion of Alzheimer's β-amyloid peptides and can therefore be used in the treatment of AD ITProc. Nat. Acad. ScL. 97: 1202-1205 (2000)]. A mechanism via inhibition of hyperphosphorylation of proteins implicated in the progression AD has also been described [S. Papasozomenos, "Testosterone prevents the heat shock-induced over activation of glycogen synthase kinase-3β but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of τ: Implications for Alzheimer's disease," Proc. Nat. Acad. Sci.. 99: 1140-1145 (2002)].

Androgen receptor agonists can also have a beneficial effect on muscle tone and strength. Recent studies have demonstrated that "physiologic androgen replacement in healthy, hypogonadal men is associated with significant gains in fat-free mass, muscle size and maximal voluntary strength," [S. Bhasin, et al., J. Endocrin.. 170: 27-38 (2001)].

Androgen receptor modulators can be useful in treating decreased libido in both men and women. Androgen deficiency in men is related to diminished libido. S. Howell et al., Br. J. Cancer. 82: 158-161. Low androgen levels contribute to the decline in sexual interest in many women during their later reproductive years. S. Davis, J. Clin. Endocrinol. Metab., 84: 1886-1891 (1999). In one study, circulating free testosterone was positively correlated with sexual desire. Id. In another study, women with primary or secondary adrenal insufficiency were provided physiological DHEA replacement (50 mg/day). Compared with women taking placebo, DHEA-administered women showed an increase in the frequency of sexual thoughts, interest, and satisfaction. W. ArIt, et al., N Engl. J. Med. 341: 1013-1020 (1999), see also, K. Miller, J. Clin. Endocrinol. Metab., 86: 2395-2401 (2001).

Additionally, androgen receptor modulators may also be useful in treating cognitive impairment. In a recent study, high-dose oral estrogen either alone or in combination with high-dose oral methyltestosterone was given to postmenopausal women for a four-month period. Cognitive tests were administered before and after the four-month hormone treatment. The investigation found that women receiving a combination of estrogen (1.25 mg) and methyltestosterone (2.50 mg) maintained a steady level of performance on the Building Memory task, but the women receiving estrogen (1.25 mg) alone exhibited decreased performance. A. Wisniewski, Horm. Res. 58:150-155 (2002).

SUMMARY OF THE INVENTION

The present invention relates to compounds of structural formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, their uses, and pharmaceutical compositions.

These compounds are effective as androgen receptor agonists and are particularly effective as SARMs. They are therefore useful for the treatment 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 pharmaceutically acceptable carrier.

In this invention, we have identified compounds that function as SARMs using a series of in vitro cell-assays that profile ligand mediated activation of AR, such as (i) N-C interaction, (ii) transcriptional repression, and (iii) transcriptional activation. SARM compounds in this 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 effects on prostate growth 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 conditions 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 as bisphosphonates, estrogens, SERMs, cathepsin K inhibitors, αvβ3 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 can also be employed, either alone or in combination, for treatment of prostate disease, such as prostate cancer and benign prostatic hyperplasia (BPH). Moreover, compounds of this invention exhibit minimal effects on skin (acne and facial hair growth) and can be useful for treatment of hirsutism. Additionally, compounds of this invention can stimulate muscle growth and can be useful for treatment of sarcopenia and frailty. They can be employed to reduce visceral fat in the treatment of obesity. Moreover, compounds of this invention can exhibit androgen agonism in the central nervous system and can be useful to treat vasomotor symptoms (hot flush) and to increase energy and libido. They can be used in the treatment of Alzheimer's disease. The compounds of the present invention can also be used in the treatment of prostate cancer, either alone or as an adjunct to GnRH 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 prostate, and minimize bone depletion. Further, the compounds of the present invention can be used for their ability to restore bone in the treatment of pancreatic cancer as an adjunct to treatment with antiandrogen, or as monotherapy for their antiandrogenic properties, offering the advantage over traditional antiandrogens of being bone-sparing. Additionally, compounds of this invention can increase the number of blood cells, such as red blood cells and platelets, and can be useful for the treatment of hematopoietic disorders, such as aplastic anemia. Thus, considering their tissue selective androgen receptor agonism listed above, the compounds of this invention are ideal for hormone replacement therapy in hypogonadic (androgen deficient) men.

This invention is also concerned with safely and specifically treating a male subject with abdominal adiposity, metabolic syndrome (also known as the 'insulin resistance syndrome', and 'Syndrome X'), and type π diabetes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are useful as androgen receptor modulators, in particular, as selective androgen receptor modulators (SARMs). Compounds of the present invention are described by structural formula I:

a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: R³ R² Λ

W is _\ τ__y ^u__ //_ or Λ *-IΛ <? L ; n is 0, 1, 2, or 3; m is O, 1, or 2; Z is OR6, orNR7R8 R2 and R3 are each independently chosen from hydrogen, halogen, hydroxyl, Ci^alkyl, Ci-

4cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more fluorine atoms, and provided that at least one of R^ or R3 is other than hydrogen, and further provided that when R2 is OH, then R3 is other than OH; Rl, R7, and R^ are each independently chosen from hydrogen, halogen, perfluoroCi-6alkyl, perfluoroCi-βalkoxy, Ci-io alkyl, C2-10 alkenyl,

C2-10 alkynyl, aryl Co-10 alkyl, C3.8 cycloalkyl Cθ-10 alkyl, C3-8 heterocyclyl Co-10 alkyl, (Cθ-10 alkyl) i_2aminocarbonyl Co-10 alkyl,

(aryl Co-10 alkyl) i-2aminocarbonyl Cθ-10 alkyl, C3-8 cycloalkyl Q)-IO alkyl aminocarbonyl Cθ-10 alkyl, C3-8 heterocyclyl Co-10 alkyl aminocarbonyl Cθ-10 alkyl, Cθ-10 alkyl carbonylamino Ci-io alkyl, C3-8 cycloalkyl Cθ-10 alkyl carbonylamino Ci_io alkyl,

C3-8 heterocyclyl Co-10 alkyl carbonylamino Ci-io alkyl, aryl Q)-10 alkyl carbonylamino Ci-io alkyl, Cθ-10 alkyloxy carbonylamino Cχ-io alkyl, C3-8 cycloalkyl Co-10 alkyloxy carbonylamino Ci-io alkyl, C3-8 heterocyclyl Co-10 alkyloxy carbonylamino Ci_io alkyl, aryl Q)-IO alkyloxy carbonylamino Cχ-io alkyl, Ci-io alkoxy (carbonyl)θ-lCθ-lO alkyl, Co-10 alkyloxy carbonylCθ-10 alkyl, C3-8 cycloalkyl Co-10 alkyloxy carbonylCo-lO alkyl, C3-8 heterocyclyl Cθ-10 alkyloxy carbonylCθ-lθ alkyl, aryl Q)-10 alkyloxy carbonylCθ-10 alkyl, hydroxycarbonyl Ci_lθ alkyl, hydroxycarbonyl C2-10 alkenyl, hydroxycarbonyl C2-10 alkynyl, and hydroxy Co-ioalkyl, provided that when one carbon of the phenyl ring is directly substituted with an oxygen as an linker, then any carbon of the phenyl ring adjacent to this oxygen substituted carbon is substituted with other than an oxygen linker; ach independently chosen from hydrogen, halogen, perfluoroCi-6alkyl, perfluoroC 1 -βalkoxy ,

Ci-io alkyl,

C2-IO alkenyl,

C2-10 alkynyl, Ci_io alkylthio, aryl Q)-10 alkyl,

C3-8 cycloalkyl Co-10 alkyl,

C3-8 heterocyclyl Q)-10 alkyl,

(Co-10 alkyl)i-2amino Cθ-10 alkyl, (aryl Cθ-10 ^alkyl)l-2amino Cθ-10 alkyl

(C3_8 cycloalkyl Co-10 alkyl) i-2amino Q)-l0 alkyl,

(C3_8 heterocyclyl Q)-IO alkyl) i_2amino Co-10 alkyl,

(Co-10 alkyl) i-2aminocarbonylamino Co-10 alkyl,

(aryl Cθ-10 alkyl) i_2aminocarbonylamino Q)-IO alkyl, C3_8 heterocyclyl Q)-IO alkyl aininocarbonylamino Co-10 alkyl,

C3-8 cycloalkyl Co-10 alkyl aminocarbonylamino Co-10 alkyl,

(Co-10 alkyl) i-2aminocarbonyl Q)-IO alkyl,

(aryl Cθ-10 alkyl) i_2aminocarbonyl Co-10 alkyl,

C3-8 cycloalkyl Co-10 alkyl aminocarbonyl Co-10 alkyl, C3-8 heterocyclyl Co-10 alkyl aminocarbonyl Co-10 alkyl,

Co-10 alkyl carbonylamino Co-10 alkyl,

C3-8 cycloalkyl Co-10 alkyl carbonylamino Co-10 alkyl,

C3-8 heterocyclyl Co-10 alkyl carbonylamino Co-10 alkyl, aryl Co-10 alkyl carbonylamino Q)-IO alkyl, Q)-IO alkyloxy carbonylamino Q)-IO alkyl,

C3-8 cycloalkyl Q)-IO alkyloxy carbonylamino Co-10 alkyl,

C3_8 heterocyclyl Co-10 alkyloxy carbonylamino Co-10 alkyl, aryl Cø-lO alkyloxy carbonylamino Q)-IO alkyl,

Cθ-10 alkyloxy carbonyloxy Co-10 alkyl,

C3_8 cycloalkyl Cθ-10 alkyloxy carbonyloxy Cθ-10 alkyl,

C3-8 heterocyclyl Cθ-10 alkyloxy carbonyloxy Cθ-10 alkyl, aryl Q)-IO alkyloxy carbonyloxy Cθ-10 alkyl,

Ci-io alkoxy (carbonyl)θ-lCθ-lO alkyl,

Co-10 alkylcarboxy Cθ-10 alkylamino, hydroxycarbonyl Ci-io alkyl, hydroxycarbonyl C2-10 alkenyl, hydroxycarbonyl C2-10 alkynyl,

Ci-io alkoxy,

Ci-ioalkyloxy Co-lOalkyl, aryloxy Cθ-10 alkyl,

C3-8 cycloalkyloxy Co-10 alkyl Cθ-10 alkyl, C3-8 heterocyclyl Q)-10^alkyl ^oχy Q)-IO alkyl,

Ci_io alkylcarbonyloxy Cθ-10 alkyl,

(Cθ-10 alkyl) i_2aminosulfonyl Cθ-10 alkyl,

(aryl Cθ-10 alkyl) i-2aminosulfonyl Co-10 alkyl,

C3-8 cycloalkyl Cθ-10 alkyl aminosulfonyl Cθ-10 alkyl, C3-8 heterocyclyl Cθ-10 alkyl aminosulfonyl Co-10 alkyl,

Cθ-10 alkyl sulfonylamino Co-10 alkyl,

C3-8 cycloalkyl Cθ-10 alkyl sulfonylamino Q)-IO alkyl,

C3-8 heterocyclyl Q)-IO alkyl sulfonylamino Cθ-10 alkyl, aryl Cθ-10 alkyl sulfonylamino Cθ-10 alkyl, Ci-io alkyloxy(carbonyl)θ- 1 Co- 10 alkylamino,

C3-8 heterocyclyl Cθ-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino,

C3-8 cycloalkyl Cθ-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, aryl Cθ-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino,

(Cθ-10 alkyl) i_2aminocarbonyloxy, (aryl Q)-IO alkyl) i_2aminocarbonyloxy,

(C3-8 heterocyclyl Q)-IO alkyl) i-2aminocarbonyloxy,

(C3-8 cycloalkyl Cθ-ioalkyl)i-2aminocarbonyloxy, and hydroxy Cθ-lθalkyl;

R6 is chosen from hydrogen, Ci_5alkyl, Ci-5cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more fluorine atoms; and wherein in Rl, R2, R3, R4_? R5, R6_; R7_; and R8, said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more groups chosen from hydroxy, Ci-β alkyl, Ci-6 alkoxy, halogen, CO2H, cyano, O(C=O)Ci-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, -0(θ-l)(Ci-io)perfluoroalkyl, Co-10 alkylaminocarbonylamino, Ci_io alkyloxycarbonylamino, Ci-io alkylcarbonylamino, Co-10 alkylaminosulfonylamino, C140 alkylsulfonylamino, Ci- 10 alkylsulfonyl, Co-10 alkylaminosulfonyl, Co-10 alkylaminocarbonyl and NH2.

Illustrative but nonlimiting examples of compounds of the present invention are the following:

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-phenylbutanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3,4-dichlorophenyl)butanamide; 2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-fluorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-fluorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3,4-difluorophenyl)propanamide; 2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3,4-difluorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-chlorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-chlorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-bromoρhenyl)butanamide;

2-(S)-N-[(5-cycloρropyl-2-methoxypyridin-3-yl)methyl]-2-(3-trifluoromethylphenyl)butanamide; 2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluoro-4-chlorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluoro-4-chlorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-fluoro-3-chlorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-fluoro-3-chlorophenyl)butanamide;

N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-3,3,3-trifluoro-2-hydroxy-2-phenylpropanamide; (2R)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-3,3₅3-trifluoro-2-hydroxy-2-phenylpropanamide;

N-tCS-cyclopropyl^-methoxypyridin-S-y^methyll-S^^^^-pentafluoro^-hydroxy^-phenylbutanamide;

N-tCS-cyclopropyl^-methoxypyridin-S-yOmethyll-S^^-trifluoro^-phenylpropanamide;

(2S)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl } -2-phenylbutanamide;

(2S)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-(3,4-dichlorophenyl)butanamide; N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-l-phenylcyclopropanecarboxamide;

(lR,2R)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylcyclopropanecarboxamide;

2-(4-fluorophenyl)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}cyclopropanecarboxamide;

(lS,2S)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylcyclopropanecarboxamide;

(2S)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-(3-chlorophenyl)butanamide; (2S)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl }-2-(3-trifluoromethyl phenyl)butanamide;

(2S)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl } -2-(4-trifluoromethyl phenyl)butanamide;

3,3,3-trifluoro-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylpropanamide; (2R)-3,3,3-trifluoro-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2- phenylpropanamide;

3,3,3-trifluoro-N-{[2-methoxy-5-(trifluoromethyl)pyridm-3-yl]methyl}-2-phenylpropanamide; 3,3,4,4,4-pentafluoro-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2- phenylbutanamide;

(2R)-3,3,4,4,4-pentafluoro-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2- phenylbutanamide;

(2R)-2-(3-fluorophenyl)-2-hydroxy-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}butanamide; 2R)-2-(4-fluorophenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}butanamide; 2R)-2-(3,4-dichlorophenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3- yljmethyl jbutanamide; 2R)-2-(4-trifluoromethylphenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3- yl]methyl }butanamide;

2R)-2-phenyl-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}butanamide; 2R)-2-phenyl-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3-yl]methyl}butanamide; 2R)-2-phenyl-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3-yl]methyl}propanamide; 2R)-2-(3,4-dichlorophenyl)-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3-yl]methyl}butanamide; 2R)-2-(4-trifluoromethylphenyl)-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3- yl]methyl Jbutanamide; 2R)-2-(3-fluorophenyl)-2-hydroxy-N-{ [2-methoxy-5-( cyclopropyl)pyridin-3-yl]methyl Jbutanamide; (2S)-N-{[2-(Methylamino)-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylbutanamide; Benzyl (2-{ [3-({ [(2S)-2-phenylbutanoyl]amino}methyl)-5-(trifluoromethyl)pyridin-2- yl]amino}ethyl)carbamate; and pharmaceutically acceptable salts and stereoisomers thereof. The compounds of the present invention can have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the 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, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term "Co alkyl" (as in "Cθ-8 alkylaryl") shall refer to the absence of an alkyl group.

The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range. The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds can be present. Thus, "C2-C6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on. The straight, branched or cyclic portion of the alkynyl group can contain triple bonds and can be substituted if a substituted alkynyl group is indicated.

"Cycloalkyl" as used herein is intended to include non-aromatic cyclic hydrocarbon groups, having the specified number of carbon atoms, which may or may not be bridged or structurally constrained. Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl, tetrahydro-naphthalene, methylenecylohexyl, and the like. As used herein, examples of "C3 - CJQ cycloalkyl" can include, but are not limited to:

" Alkoxy" represents either a cyclic or non-cyclic alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Alkoxy" therefore encompasses the definitions of alkyl and cycloalkyl above.

"Perfluoroalkyl" represents alkyl chains of up to 10 carbon atoms having exhaustive substitution of their corresponding hydrogens with fluorine atoms.

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include, but are not limited to, phenyl, naphthyl, tetrahydro-naphthyl, indanyl, or biphenyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms chosen from O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: azabenzimidazole, acridinyl, carbazolyl, cinnolinyl benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzodihydrofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, indolyl, quinolyl, quinoxalinyl, isoquinolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, piridazinyl, tetrahydroquinolinyl, thiadiazolyl, oxadiazolyl, triazolyl, imidizopyridinyl, tetrazolyl, and indanyl. As with the definition of heterocycle below, "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen- containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. Whenever the term "alkyl" or "aryl" or either of their prefix roots appears in a name of a substituent (e.g., aryl Cθ-8 alkyl), it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cθ-8) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

As appreciated by those of skill in the art, "halo" or "halogen" as used herein is intended to include chloro, fluoro, bromo and iodo.

The term "heterocycle" or "heterocyclyl" as used herein is intended to mean a 5- to 14- membered aromatic or nonaromatic ring system containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. "Heterocyclyl" therefore includes the above mentioned heteroaryls, as well as dihydro and tetrathydro analogs thereof. Further examples of "heterocyclyl" include, but are not limited to the following: azabenzimidazole, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and include an aryl portion where aryl is as defined above. Examples of arylalkyl include, but are not limited to, benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine and butylpyridine.

The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom. The term "oxo" means "=O". The term "carbonyl" means "C=O."

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. 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 that the (two or more) substituents can be the same or different.

When any variable (e.g., Rl, R4, etc.) occurs more than one time in any substituent or in formula I, its definition in each occurrence is independent of its definition at every other 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 designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C 1.5 alkylcarbonylamino Ci-6 alkyl substituent is equivalent to O

Jl -C_1-6 alkyl- HN ^{^}C_1-5 alkyl.

Li choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. Rl, R^, R3, R4, R5 _et_c., are to be chosen in conformity with well-known principles of chemical structure connectivity.

Lines drawn into the ring systems from substituents indicate that the indicated bond can be attached to any of the substitutable ring atoms. If the ring system is polycyclic, it is intended that the bond be attached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results. The phrase "optionally substituted with one or more substituents" should be taken to be equivalent to the phrase "optionally substituted with at least one substituent" and in such cases one embodiment will have from zero to three substituents.

In one embodiment of the invention, W is X ^-— V In another embodiment, W is

In one embodiment of the invention, Z is OR6. In yet another embodiment, Z is NR7R8. In one embodiment, R6 is chosen from hydrogen and Cχ_5alkyl optionally substituted with one or more fluorine atoms. In one variant of this embodiment, R6 is chosen from hydrogen, methyl, ethyl and propyl.

In another embodiment, R6 is chosen from hydrogen and Ci_5cycloalkyl optionally substituted with one or more fluorine atoms. In one variant of this embodiment, R^ is cyclopropyl or cyclopentyl optionally substituted with one or more flurine atoms. In one embodiment, R.2 and R3 are each independently chosen from hydrogen, hydroxyl, Ci_4alkyl optionally substituted with one or more fluorine atoms, and provided that at least one of R.2 or

R.3 is other than hydrogen, and further provided that when R^ is OH, then R3 is other than OH.

In another embodiment of the invention, R^ is OH and R^ is chosen from hydrogen and Ci_4alkyl optionally substituted with one or more fluorine atoms.

In one embodiment of the invention, Rl, R^, and R^§ are each independently chosen from: hydrogen, halogen, perfluoroCi-βalkyl, aryl Cθ-10 alkyl, C3-8 cycloalkyl C()-10 alkyl, C3-8 heterocyclyl Cθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyl aminocarbonyl Co-10 alkyl,C3_g heterocyclyl Cθ- 10 alkyl aminocarbonyl Q)-IO alkyl, Co-io alkyl carbonylamino Ci-io alkyl, C3-8 cycloalkyl Co-10 alkyl carbonylamino Ci-io alkyl, C3-8 heterocyclyl Cθ-10 alkyl carbonylamino Ci-io alkyl, aryl Q)-IO alkyl carbonylamino Cl-io alkyl, Cθ-10 alkyloxy carbonylamino Ci-io alkyl, C3-8 cycloalkyl Q)-IO alkyloxy carbonylamino Ci_io alkyl, C3-8 heterocyclyl Cθ-10 alkyloxy carbonylamino Ci-io alkyl, aryl Co-10 alkyloxy carbonylamino Ci-io alkyl, Ci_io alkoxy (carbonyl)θ-lCθ-lO alkyl, Cθ-10 alkyloxy carbonylCθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyloxy carbonylCθ-10 alkyl, C3-8 heterocyclyl Q)-IO alkyloxy carbonylCθ-10 alkyl, aryl Co-10 alkyloxy carbonylCθ-10 alkyl, hydroxycarbonyl Ci- 10 alkyl, and hydroxy Q)-10^alkyl.

In one variant of this embodiment Rl, R7, and R^ are each independently chosen from: hydrogen, halogen, perfluoroCi_6alkyl, aryl Co-10 alkyl, C3_8 cycloalkyl Cθ-10 alkyl, C3-8 heterocyclyl Co-10 alkyl, C3-8 cycloalkyl Q)-IO alkyl aminocarbonyl Q)-IO alkyl, C3-8 heterocyclyl Cθ-10 alkyl aminocarbonyl Cθ-10 alkyl, Co-10 alkyl carbonylamino Ci-io alkyl, C3-8 cycloalkyl Co-10 alkyl carbonylamino Ci-io alkyl, C3-8 heterocyclyl Q)-IO alkyl carbonylamino Ci-io alkyl, aryl Cθ-10 alkyl carbonylamino Ci-io alkyl, Cθ-10 alkyloxy carbonylamino Ci-io alkyl, C3-8 cycloalkyl Cθ-10 alkyloxy carbonylamino Ci-io alkyl, C3-8 heterocyclyl Co-10 alkyloxy carbonylamino Ci-io alkyl, aryl Co-10 alkyloxy carbonylamino C140 alkyl, and hydroxy Q)_ioalkyl. In another variant, Rl, R7, and R^ are each independently chosen from: hydrogen, halogen, perfluoroCi-6alkyl, aryl Q)-IO alkyl, C3-8 cycloalkyl Q)-IO alkyl, C3-8 heterocyclyl Q)-IO alkyl, Q)-IO alkyloxy carbonylamino Ci_io alkyl, C3-8 cycloalkyl Co-10 alkyloxy carbonylamino Ci-io alkyl, C3-8 heterocyclyl Cθ-10 alkyloxy carbonylamino Ci-io alkyl, aryl Co-10 alkyloxy carbonylamino Ci-io alkyl, and hydroxy Cθ-10^alkyl. In one embodiment of the invention, R4 and R5 are each independently chosen from hydrogen, halogen, perfluoroCi_6alkyl, perfluoroCi_6alkoxy, Ci-io alkyl, aryl Cθ-10 alkyl, C3_8 cycloalkyl Cθ-10 alkyl, C3-8 heterocyclyl Cθ-10 alkyl, (aryl Co-10 alkyl) i_2aminocarbonyl Q)-IO alkyl, C3-8 cycloalkyl Q)-IO alkyl aminocarbonyl Q)-IO alkyl, C3_8 heterocyclyl Q)-IO alkyl aminocarbonyl Q)-IO alkyl, Co-10 alkyl carbonylamino Q)-IO alkyl, C3-8 cycloalkyl Q)-IO alkyl carbonylamino Q)-IO alkyl, C3-8 heterocyclyl Q)-IO alkyl carbonylamino Q)-IO alkyl, aryl Co-10 alkyl carbonylamino Q)-IO alkyl, Cθ-10 alkyloxy carbonylamino Cθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyloxy carbonylamino Cθ-10 alkyl, C3-8 heterocyclyl Cθ-10 alkyloxy carbonylamino Cθ-10 alkyl, aryl Co-10 alkyloxy carbonylamino Co-10 alkyl, Co-10 alkyloxy carbonyloxy Cθ-10 alkyl, Q$_8 cycloalkyl Cθ-10 alkyloxy carbonyloxy Co- 10 alkyl, C3-8 heterocyclyl Cθ-10 alkyloxy carbonyloxy Co-10 alkyl, aryl Cθ-10 alkyloxy carbonyloxy Co-10 alkyl, Ci_io alkoxy (carbonyl)θ-lCθ-lO alkyl, Co-10 alkylcarboxy Cθ-10 alkylamino, hydroxycarbonyl Ci- 10 alkyl, hydroxy carbonyl C2-10 alkenyl, hydroxycarbonyl C2-10 alkynyl, Ci-io alkoxy, Ci-ioalkyloxy Co-ioalkyl, aryloxy Q)-IO alkyl, C3_8 cycloalkyloxy Co-10 alkyl Q)-IO alkyl, C3-8 heterocyclyl Q)_ioalkyl ^oχy Co-10 alkyl, Ci-io alkylcarbonyloxy Q)-10 alkyl, Ci-io alkyloxy(carbonyl)θ-lQ)-10 alkylamino, C3-8 heterocyclyl Co-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, C3-8 cycloalkyl Co-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, aryl Co-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, (Co-10 alkyl) i-2aminocarbonyloxy, (aryl Cθ-10 alkyl)i_ 2aminocarbonyloxy, (C3-8 heterocyclyl Co-10 alkyl) i-2aminocarbonyloxy, (C3-8 cycloalkyl Co- 10alkyl)i_2aminocarbonyloxy, and hydroxy Cθ-lθalkyl.

Pn a variant of this embodiment, R.4 and R^ are each independently chosen from hydrogen, halogen, perfluoroCi-βalkyl, perfluoroCi_6alkoxy, Ci-io alkyl, aryl Cθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyl, C3-8 heterocyclyl Cθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyl aminocarbonyl Q). 10 alkyl, C3-8 heterocyclyl Cθ-10 alkyl aminocarbonyl Co-10 alkyl, Co-10 alkyl carbonylamino Co-10 alkyl, C3-8 cycloalkyl Q)-IO alkyl carbonylamino Cθ-10 alkyl, C3_8 heterocyclyl Co-10 alkyl carbonylamino Cθ-10 alkyl, aryl Cθ-10 alkyl carbonylamino Cθ-10 alkyl, Co-10 alkylcarboxy Cθ-10 alkylamino, hydroxycarbonyl Ci_io alkyl, Ci-io alkoxy, Ci-ioalkyloxy Co-ioalkyl, aryloxy Co-10 alkyl, C3-8 cycloalkyloxy Cθ-10 alkyl Cθ-10 alkyl, C3-8 heterocyclyl Co-ioalkyl oxy Cθ-10 alkyl,' Ci_ 10 alkylcarbonyloxy Cθ-10 alkyl, Ci-io alkyloxy(carbonyl)θ-lCθ-10 alkylamino, C3.8 heterocyclyl Cθ- 10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, C3-8 cycloalkyl Co-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, aryl Cθ-10 alkyloxy(carbonyl)θ-lCθ-lθ alkylamino, (Cθ-10 alkyl) i-2aminocarbonyloxy, (aryl Cθ-10 alkyl) i-2aminocarbonyloxy, (C3.8 heterocyclyl Q)-IO alkyl) i-2aminocarbonyloxy, (C3-8 cycloalkyl Cθ-10^alkyl)i-2aminocarbonyloxy, and hydroxy Co-lOalkyl. In yet another variant, R4 and R.5 are each independently chosen from hydrogen, halogen, perfluoroCi-6alkyl, perfluoroCi_6alkoxy, Ci_io alkyl, aryl Co-10 alkyl, C3-8 cycloalkyl Cθ- 10 alkyl, C3_8 heterocyclyl Cθ-10 alkyl, and hydroxy Co-ioalkyl.

In another embodiment of the invention, R.4 and R^ are each independently chosen from hydrogen, halogen, perfluoroCi-βalkyl, perfluoroCi-galkoxy, Ci-io alkyl, C2-IO alkenyl, C2-IO alkynyl, Ci-io alkylthio, (Co-10 alkyl) i_2amino Cθ-10 alkyl, (aryl Co-10 alkyl) i_2amino Co-10 alkyl, (C3_8 cycloalkyl Co-10 alkyl) i-2amino Cθ-10 alkyl, (C3-8 heterocyclyl Co-10 alkyl) i-2amino Co-10 alkyl, (Q)-IO alkyl) i-2aminocarbonylamino Cθ-10 alkyl, (aryl Q)-IO alkyl) i-2aminocarbonylamino Q)- 10 alkyl, (Q)-IO alkyl) i-2aminocarbonyl Q)-IO alkyl, (aryl Q)-IO alkyl) i-2aminocarbonyl Cθ-10 alkyl, (Q)-IO alkyl) i_2aminosulfonyl Cθ-10 alkyl, (aryl Q)-IO alkyl) i_2aminosulfonyl Co-10 alkyl, C3-8 cycloalkyl Q)-IO alkyl aminosulfonyl Cθ-10 alkyl, C3_8 heterocyclyl Co-10 alkyl aminosulfonyl Co-10 alkyl, CQ-10 alkyl sulfonylamino CQ-10 alkyl, C3-8 cycloalkyl CQ-10 alkyl sulfonylamino CQ-10 alkyl, C3-8 heterocyclyl Q)-IO alkyl sulfonylamino Co-10 alkyl, aryl Cθ-10 alkyl sulfonylamino Cθ-10 alkyl, and hydroxy Cθ-lθ^alkyl-

As should be noted in the substituents Rl, R2, R3, R4, R5, R6, R7, and R8, said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more groups chosen from hydroxy, Cχ-6 alkyl, Q-6 alkoxy, halogen, CO2H, cyano, O(C=O)Cχ-C6 alkyl,

NO2, trifluoromethoxy, trifluoroethoxy, -0(θ-l)(Ci_io)perfluoroalkyl, Cθ-10 alkylaminocarbonylamino, Cl-10 alkyloxycarbonylamino, Ci-io alkylcarbonylamino, Co-10 alkylaminosulfonylamino, Ci_io alkylsulfonylamino, Ci_io alkylsulfonyl, Cθ-10 alkylaminosulfonyl, Co-10 alkylaminocarbonyl and NH2. Compounds of the present invention have been found to be tissue-selective modulators of the androgen receptor (SARMs). In one aspect, compounds of the present invention can be useful to activate the function of the androgen receptor in a mammal, and in particular 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 of a male individual or in the uterus of a female individual. A further aspect of the present invention is the use of compounds of formula I to attenuate or block the function of the androgen receptor in the prostate of a male individual or in the 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). Representative compounds of the present invention typically display submicromolar binding affinity for the androgen receptor. Compounds of this invention are therefore useful in treating mammals suffering from disorders related to androgen receptor function. Therapeutically effective amounts of the compound, including the pharmaceutically acceptable salts thereof, are administered to the mammal, to treat disorders related to androgen receptor function, such as, androgen deficiency, disorders which can be ameliorated by androgen replacement, or which can be improved by androgen replacement, including: enhancement of weakened muscle tone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture (for example, vertebral and non- vertebral fractures), bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, pancreatic cancer, inflammatory arthritis and joint repair, HTV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), cancer cachexia, Alzheimer's disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease. Treatment is effected by administration of a therapeutically effective amount of a compound of structural formula I to a mammal in need of such treatment. In addition, these compounds are useful as ingredients in pharmaceutical compositions alone or in combination with other active agents. In one embodiment, the compounds of the present invention can be used to treat conditions in a male 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, periodontal disease, HTV-wasting, prostate cancer, cancer cachexia, obesity, arthritic conditions, anemias, such as for example, aplastic anemia, muscular dystrophies, and Alzheimer's disease, cognitive decline, sexual dysfunction, sleep apnea, depression, benign prostatic hyperplasia (BPH), abdominal obesity, metabolic syndrome, type π diabetes, and atherosclerosis, alone or in combination with other active agents. Treatment is effected by administration of a therapeutically effective amount of a compound of structural formula I to a male individual in need of such treatment. "Arthritic condition" or "arthritic conditions" refers to a disease wherein inflammatory lesions are confined to the joints or any inflammatory conditions of the joints, most notably osteoarthritis and rheumatoid arthritis (Academic Press Dictionary of Science Technology; Academic Press; 1st edition, January 15, 1992). The compounds of Formula I 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; inflammatory 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 arthritic condition which comprises administering a therapeutically effective amount of a Compound of Formula I. A subembodiment is the treatment or prevention of osteoarthritis, which comprises administering a therapeutically effective amount of a Compound of Formula I. See: Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Ann. N. Y. Acad. ScL 2002 Jun;966:131-42; Cutolo, M. Rheum Pis Clin North Am 2000 Nov;26(4):881-95; Bijlsma JW, Van den Brink HR. Am J Reprod Immunol 1992 Oct-Dec;28(3-4):231-4; Jansson L, Holmdahl R.;

Arthritis Rheum 2001 Sep;44(9):2168-75; and Purdie DW. Br Med Bull 2000; 56(3):809-23. Also, see Merck Manual, 17th edition, pp. 449451.

When used in combination to treat arthritic conditions, the compounds of Formula I can be used with any of the drugs disclosed herein as useful for combination therapy, or can be used with drugs known to treat or prevent arthritic conditions, such as corticosteroids, cytoxic drugs (or other disease modifying or remission inducing drugs), gold treatment, methotrexate, NSAIDs, and COX-2 inhibitors.

In another embodiment, the compounds of the present invention can 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, aging skin, glucocorticoid-induced osteoporosis, postmenopausal symptoms, periodontal disease, HTV-wasting, cancer cachexia, obesity, anemias, such as for example, aplastic anemia, muscular dystrophies, Alzheimer's disease, premature ovarian failure, cognitive decline, sexual dysfunction, depression, inflammatory arthritis and joint repair, atherosclerosis, and autoimmune disease, alone or in combination 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 formula I are also useful in the enhancement of muscle tone in mammals, such as for example, humans. The compounds of structural formula I can also be employed as adjuncts to traditional androgen depletion therapy in the treatment of prostate cancer to restore bone, minimize bone loss, and maintain bone mineral density. In this manner, they can be employed together with traditional androgen deprivation therapy, including GnRH agonists/antagonists, such as those disclosed in P. Limonta, et al., Exp. Opin. Invest. Drugs, 10: 709-720 (2001); HJ. Strieker, Urology, 58 (Suppl. 2A): 24-27 (2001); R.P. Millar, et al., British Medical Bulletin, 56: 761-772 (2000); and A.V. Schally et al., Advanced Drug Delivery Reviews, 28: 157-169 (1997). The compounds of structural formula I can be used in combination with antiandrogens, such as flutamide, 2-hydroxyflutamide (the active metabolite of flutamide), nilutamide, and bicalutamide (Casodex™) in the treatment of prostate cancer.

Further, the compounds of the present invention can also be employed in the treatment of pancreatic cancer, either for their androgen antagonist properties or as an adjunct to an antiandrogen, such as flutamide, 2-hydroxyflutamide (the active metabolite of flutamide), nilutamide, and bicalutamide (Casodex™). The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.

Compounds of structural formula I can minimize the negative effects on lipid metabolism. Therefore, considering their tissue selective androgen agonistic properties, the compounds of this invention exhibit advantages over existing approaches for hormone replacement therapy in hypogonadic (androgen deficient) male individuals.

Additionally, compounds of the present invention can increase the number of blood cells, such as red blood cells and platelets, and can be used for treatment of hematopoietic disorders, such as aplastic anemia.

In one embodiment of the invention, therapeutically effective amounts of the compound of Formula I, are administered to the mammal, to treat or improve disorders selected from enhancement of weakened muscle tone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, pancreatic cancer, inflammatory arthritis and joint repair, HTV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), cancer cachexia, Alzheimer's disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease.

In another embodiment, therapeutically effective amounts of the compound can be used to treat or improve a disorder selected from weakened muscle tone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, Alzheimer's disease, and frailty.

In another embodiment, the compound in accordance with the invention can be used to treat or improve a disorder such as male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, pancreatic cancer, inflammatory arthritis and joint repair, HTV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), cancer cachexia, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease.

The compounds of the present invention can be administered in their enantiomerically pure form. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

As used 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 that mimics the action of a natural ligand in some tissues but not in others. A "partial agonist" is an agonist which is unable to induce maximal activation of the receptor population, regardless of the amount of compound applied. A "full agonist" induces full activation of the androgen receptor population at a given concentration. A compound of the present 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 induced by a natural androgen receptor ligand.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Non-limiting representive salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. In one variant of the invention, the salts are chosen from the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Non-limiting examples of salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids which can be employed include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like, hi one variant, the acids are selected from citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et ah, "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19.

It would also be noted that the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.

The term "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 clinician.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient 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 understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

By the term "modulating a function mediated by the androgen receptor in a tissue selective manner" it is meant modulating a function mediated by the androgen receptor selectively (or discriminately) in anabolic (bone and/or muscular) tissue (bone and muscular) in the absence of such modulation at androgenic (reproductive) tissue, such as the prostate, testis, seminal vesicles, ovary, uterus, and other sex accessory tissues. In one embodiment, the function of the androgen receptor in anabolic tissue is activated whereas the function of the androgen receptor in androgenic tissue is blocked or suppressed. In another embodiment, the function of the androgen receptor in anabolic tissue is blocked or suppressed whereas the function of the androgen receptor in androgenic tissue is activated. The administration of a compound of structural formula I in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural formula I to the patient in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of well-known risk factors. The effective amount of an individual 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 administration, other drugs and treatments which the patient can concomitantly require, and other factors in the physician's judgment. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

Generally, the daily dosage of a compound of structural formula I can be varied over a wide range from about 0.01 to about 1000 mg per adult human per day. For example, dosages range from about 0.1 to about 200 mg/day. For oral administration, the compositions can be provided in the form of tablets containing from about 0.01 to about 1000 mg, such as for example, 0.01, 0.05, 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, 200, 225, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the mammal to be treated. The dose can be administered in a single daily dose or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose can be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration. When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through an intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any 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 with an acceptable carrier thereof and optionally other therapeutically active ingredients. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not being deleterious to the recipient subject of the formulation.

The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of structural formula I together with a pharmaceutically acceptable carrier thereof. The formulations include those suitable for oral, rectal, intravaginal, intranasal, topical and parenteral (including subcutaneous, intramuscular and intravenous administration). In one embodiment, the formulations are those suitable for oral administration.

Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to about 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art.

The formulations can be presented in a unit dosage form and can be prepared by any of the 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 the active compound in association with a liquid carrier, a waxy solid carrier or a finely divided solid carrier, and then, if needed, shaping the product into the desired dosage form. Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or nonaqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active compound in a free flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, disintegrating agents or coloring agents. Molded tablets can be made by molding in a suitable machine a mixture of the active compound, preferably in powdered form, with a suitable 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-cellulose, polyethylene glycol, waxes and the like. Non-limiting representative lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl cellulose and the like, can be made by adding the active compound to the solution or suspension. Additional dispersing agents which can be employed include glycerin and the like.

Formulations for vaginal or rectal administration can be presented as a suppository with a conventional carrier, i.e., a base that is nontoxic and nonirritating to mucous membranes, compatible with a compound of structural formula I, and is stable in storage and does not bind or interfere with the release of the compound of structural formula I. Suitable bases include: cocoa butter (theobroma oil), polyethylene glycols (such as carbowax and polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acid esters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, and hydrogenated vegetable oils. When glycerinated gelatin suppositories are used, a preservative such as methylparaben or propylparaben can be employed.

Topical preparations containing the active drug component can be admixed with a variety of 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 lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Compounds of the present invention can also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can 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, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulations that comprise a sterile aqueous preparation of the active compound which can be isotonic with the blood of the recipient. Such formulations suitably comprise a solution or suspension of a compound that is isotonic with the blood of the recipient subject. Such formulations can contain distilled water, 5% dextrose in distilled water or saline and the active compound. Often it is useful to employ a pharmaceutically 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 pharmaceutical composition and method of the present invention can further comprise other therapeutically active compounds usually applied in the treatment of the above mentioned conditions, including osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, hematopoietic disorders, such as for example, aplastic anemia, pancreatic cancer, Alzheimer's disease, inflammatory arthritis, and joint repair.

For the treatment and prevention of osteoporosis, the compounds of the present invention can be administered in combination with at least one bone-strengthening agent selected from antiresorptive agents, osteoanabolic agents, and other agents beneficial for the skeleton through mechanisms which are 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 can also benefit from these combined treatments. For example, the compounds of the instant invention can be effectively administered in combination with effective amounts of other agents such as estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, αvβ3 integrin receptor antagonists, vacuolar ATPase inhibitors, the polypeptide osteoprotegerin, antagonists of VEGF, thiazolidinediones, calcitonin, protein kinase inhibitors, parathyroid hormone (PTH) and analogs, calcium receptor antagonists, growth hormone secretagogues, growth hormone releasing hormone, insulin-like growth factor, 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. The conditions of periodontal disease, bone fracture, and bone damage following bone reconstructive surgery can also benefit from these combined treatments.

In one embodiment of the present invention, a compound of the instant invention can be effectively administered in combination with an effective amount of at least one bone-strengthening agent chosen from estrogen, and estrogen derivatives, alone or in combination with progestin or progestin derivatives; bisphosphonates; antiestrogens or selective estrogen receptor modulators; αvβ3 integrin receptor antagonists; cathepsin K inhibitors; osteoclast vacuolar ATPase inhibitors; calcitonin; and osteoprotegerin. In the treatment of osteoporosis, the activity of the compounds of the present invention are distinct from that of the anti-resorptive agents: estrogens, bisphosphonates, SERMs, 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 I aid in the stimulation of bone formation, acting, for example, on cortical bone, which is responsible for a significant part of bone strength. The thickening of cortical bone substantially contributes to a reduction in fracture risk, especially fractures of the hip. The combination of the tissue-SARMs of structural formula I with anti-resorptive agents such as for example estrogen or estrogen derivatives, bisphosphonates, antiestrogens, SERMs, calcitonin, αvβ3 integrin receptor antagonists, HMG-CoA reductase inhibitors, vacuolar ATPase inhibitors, and cathepsin K inhibitors is particularly useful due to the complementary effect of the bone anabolic and antiresorptive actions. Non-limiting representatives of estrogen and estrogen derivatives include steroidal compounds having estrogenic activity such as, for example, 17β-estradiol, estrone, conjugated estrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol, and the like. The estrogen or estrogen derivative can be employed alone or in combination with a progestin or progestin derivative. Nonlimiting examples of progestin derivatives are norethindrone and medroxy-progesterone acetate. Non-limiting examples of bisphosphonate compounds which can also be employed in combination with a compound of the present invention include:

(a) alendronate (also known as alendronic acid, 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid, alendronate sodium, alendronate monosodium trihydrate or 4-amino-l- hydroxybutylidene-l,l-bisphosphonic acid monosodium trihydrate. Alendronate is described in U.S. Patents 4,922,007, to Kieczykowski et al., issued May 1, 1990;

5,019,651, to Kieczykowski, issued May 28, 1991; 5,510,517, to Dauer et al., issued April 23, 1996; 5,648,491, to Dauer et al., issued July 15, 1997;

(b) [(cycloheptylamino)-methylene]-bis-phosρhonate (incadronate), which is described in U.S.

Patent 4,970,335, to Isomura et al., issued November 13, 1990; (c) (dichloromethylene)-bis-phosphonic acid (clodronic acid) and the disodium salt (clodronate), which are described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967);

(d) [l-hydroxy-3-(l-pyrrolidinyl)-propylidene]-bis-phosphonate (EB-1053);

(e) ( 1 -hydroxyethylidene)-bis-phosphonate (etidronate) ; (f) [l-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate (ibandronate), which is described in U.S. Patent No. 4,927,814, issued May 22, 1990;

(g) (6-amino-l-hydroxyhexylidene)-bis-phosphonate (neridronate);

(h) [3-(dimethylamino)-l-hydroxypropylidene]-bis-phosphonate (olpadronate);

(i) (3-amino-l-hydroxypropylidene)-bis-phosphonate (pamidronate); Q) [2-(2-pyridinyl)ethylidene]-bis-phosphonate (piridronate), which is described in U.S. Patent No. 4,761,406;

(k) [l-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate (risedronate);

(1) { [(4-chlorophenyl)thio}methylene}-bis-phosphonate (tiludronate), which is described in U.S.

Patent 4,876,248, to Breliere et al., October 24, 1989; (m) [l-hydroxy-2-(lH-imidazol-l-yl)ethylidene]-bis-phosphonate (zoledronate); and

(n) [l-hydroxy-2-imidazopyridin-(l,2-a)-3-ylethylidene]-bis-phosphonate (minodronate). In one embodiment of the methods and compositions of the present invention, the bisphosphonate is chosen from alendronate, clodronate, etidronate, ibandronate, incadronate, minodronate, neridronate, olpadronate, pamidronate, piridronate, risedronate, tiludronate, zoledronate, pharmaceutically acceptable salts of these bisphosphonates, and mixtures thereof. In one variant, the bisphosphonate is selected from alendronate, risedronate, zoledronate, ibandronate, tiludronate, and clodronate. In a subclass of this class, the bisphosphonate is alendronate, pharmaceutically acceptable 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 monohydrate and the trihydrate. A particular pharmaceutically acceptable salt of risedronate is risedronate monosodium. Pharmaceutically acceptable hydrates of risedronate monosodium include the hemi-pentahydrate.

Still further, antiestrogenic compounds such as raloxifene (see, e.g., U.S. Patent No. 5,393,763), clomiphene, zuclomiphene, enclomiphene, nafoxidene, CI-680, CI-628, CN-55,945-27, Mer- 25, U-11,555A, U-100A, and salts thereof, and the like (see, e.g., U.S. Patent Nos. 4,729,999 and 4,894,373) can be employed in combination with a compound of structural formula I in the methods and compositions of the present invention. These agents 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.

Non-limiting representatives of SERMs include, for example, tamoxifen, raloxifene, lasofoxifene, toremifene, azorxifene, EM-800, EM-652, TSE 424, clomiphene, droloxifene, idoxifene, and levormeloxifene [Goldstein, et al., "A pharmacological review of selective estrogen receptor modulators," Human Reproduction Update. 6: 212-224 (2000); Lufkin, et al., Rheumatic Disease Clinics of North America, 27: 163-185 (2001), and "Targeting the Estrogen Receptor with SERMs," Ann. Rep. Med. Chem. 36: 149-158 (2001)]. αvβ3 Integrin receptor antagonists suppress bone resorption and can be employed in combination with the SARMs of structural formula I for the treatment of bone disorders including osteoporosis. Peptidyl as well as peptidomimetic antagonists of the αvβ3 integrin receptor have been described both in the scientific and patent literature. For example, reference is made to WJ. 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 98/18460; 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.

Other αvβ3 antagonists are described in R.M. Keenan et al., J. Med. Chem. 40: 2289- 2292 (1997); R.M. Keenan et al., Bioorg. Med. Chem. Lett. 8: 3165-3170 (1998); and R.M. Keenan et al., Bioorg. Med. Chem. Lett. 8: 3171-3176 (1998). Other non-limiting representative examples of published patent and patent applications that describe various αvβ3 integrin receptor antagonists include: those comprising benzazepine, benzodiazepine and benzocycloheptene— PCT Patent Application Nos. WO 96/00574, WO 96/00730, 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 97/34865,WO 99/15506, and U.S. Patent No. 6,159,964; those comprising dibenzpcyclopheptene, and dibenzoxapine -PCT Patent Application Nos. WO 97/01540, WO 98/30542, WO 99/11626, WO 99/15508, and U.S. Patent Nos. 6,008,213 and 6,069,158; those having a phenol constraint — PCT Patent Application Nos. 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, European Patent Nos. EP 0 820,988, EP 0 820,991, and U.S. Patent Nos. 5,741,796, 5773,644, 5,773,646, 5,843,906, 5,852,210, 5,929,120, 5,952,281, 6,028,223 and 6,040,311; those having a monocyclic ring constraint -PCT Patent Application Nos. WO 99/26945, WO 99/30709, WO 99/30713, WO 99/31099, WO 99/59992, WO 00/00486, WO 00/09503, European Patent Nos. EP 0 796,855, EP 0 928,790, EP 0 928,793, and U.S. Patent Nos. 5,710,159, 5,723,480, 5,981,546, 6,017,926, and 6,066,648; and those having a bicyclic ring constraint -PCT Patent Application Nos. WO 98/23608, WO 98/35949, and WO 99/33798, European Patent No. EP 0 853,084, and U.S. Patent Nos. 5,760,028, 5,919,792, and 5,925,655.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease and is described in PCT International Application Publication No. WO 96/13523; U.S. Patent Nos. 5,501,969 and 5,736,357. Cysteine proteases, specifically cathepsins, are linked to a number of disease conditions, such 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. Non-limiting examples of cathespin K inhibitors can be found in PCT International Publications WO 01/49288 and WO 01/77073.

Members of the class of HMG-CoA reductase inhibitors, known as the "statins," have been found 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 B 1). Therefore, the statins hold promise for the treatment of bone resorption. Examples of HMG-CoA reductase inhibitors include statins in their lactonized or dihydroxy open acid forms 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. 4,444,784); dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof (see US Patent No. 4,346,227); fluvastatin, particularly the sodium salt thereof (see US Patent No. 5,354,772); atorvastatin, particularly the calcium salt thereof (see US Patent No. 5,273,995); cerivastatin, 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 referred to as NK- 104, itavastatin, or nisvastatin (see PCT international application publication number WO 97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pump inhibitors, can be employed together with the SARMs of structural formula I. The proton ATPase which is found on the apical membrane of the osteoclast has been reported to play a significant role in the bone resorption process. Therefore, 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 osteoporosis and related metabolic diseases [see C. Farina et al., DDT, 4: 163-172 (1999)].

The angiogenic factor VEGF has been shown to stimulate the bone-resorbing activity of isolated mature rabbit osteoclasts via binding to its receptors on osteoclasts [see M. Nakagawa et al., FEBS Letters, 473: 161-164 (2000)]. Therefore, the development of antagonists of VEGF binding to osteoclast receptors, such as KDR/Flk-1 and FlM, can provide yet a further approach to the treatment or prevention of bone resorption.

Activators of the peroxisome proliferator-activated receptor-γ (PPARγ), such as the thiazolidinediones (TZD' s), inhibit osteoclast-like cell formation and bone resorption in vitro. Results reported by R. Okazaki et al. in Endocrinology, 140: 5060-5065 (1999) point to a local mechanism on bone marrow cells as well as a systemic one on glucose metabolism. Nonlimiting examples of PPARγ, activators include the glitazones, such as troglitazone, pioglitazone, rosiglitazone, and BRL 49653. Calcitonin can also be employed together with the SARMs of structural formula I. Calcitonin is preferentially employed as salmon nasal spray (Azra et al., Calcitonin. 1996. In: J. P. Bilezikian, et al., Ed., Principles of Bone Biology, San Diego: Academic Press; and Silverman, "Calcitonin," Rheumatic Disease Clinics of North America. 27: 187-196, 2001)

Protein kinase inhibitors can also be employed together with the SARMs of structural formula I. Kinase inhibitors include those disclosed in WO 01/17562 and are in one embodiment selected from inhibitors of p38. Non-limiting examples of p38 inhibitors useful in the present invention include SB 203580 [Badger et al., J. Pharmacol. Exp. Ther.. 279: 1453-1461 (1996)].

Osteoanabolic agents are those agents that are known to build bone by increasing the production of the bone protein matrix. Such osteoanabolic agents include, for example, parathyroid hormone (PTH) and fragments thereof, such as naturally occurring PTH (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 Drug Discovery, Vol. 3, No. 8, 2000). An injectable recombinant form of human PTH, Forteo (teriparatide), has received regulatory approval in the U.S. for the treatment of osteoporosis. Also useful 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., J. Clin. Invest. 105: 1595-604 (2000). Additional osteoanabolic agents include growth hormone secretagogues, growth hormone, growth hormone releasing hormone and the like can be employed with the compounds according to structural formula I for the treatment of osteoporosis. Representative growth hormone secretagogues are disclosed in U.S. Patent Nos. 3,239,345, 4,036,979, 4,411,890, 5,206,235, 5,283,241, 5,284,841, 5,310,737, 5,317,017, 5,374,721, 5,430,144, 5,434,261, 5,438,136, 5,494,919, 5,494,920, 5,492,916 and 5,536,716; European Patent Pub. Nos. 0,144,230 and 0,513,974; PCT Patent Pub. Nos. WO 94/07486, WO 94/08583, WO 94/11012; WO 94/13696, WO 94/19367, WO 95/03289, WO 95/03290, WO 95/09633, WO 95/11029, WO 95/12598, WO 95/13069, WO 95/14666, WO 95/16675, WO 95/16692, WO 95/17422, WO 95/17423, WO 95/34311, and WO 96/02530; articles, Science, 260. 1640-1643 (June 11, 1993); Ann. Rep. Med. Cherα. 28: 177-186 (1993); Bioorg. Med. Cherα Lett.. 4: 2709-2714 (1994); and Proc. Natl. Acad. Sd. USA. 92: 7001-7005 (1995).

Insulin-like growth factor (IGF) can also be employed together with the SARMs of structural formula I. Insulin-like growth factors can be selected from Insulin-like Growth Factor I, alone or in combination with IGF binding protein 3 and IGF II [See Johannson and Rosen, "The IGFs as potential therapy for metabolic bone diseases," 1996, In: Bilezikian, et al., Ed., Principles of Bone Biology. San Diego: Academic Press; and Ghiron et al., J. Bone Miner. Res. 10: 1844-1852 (1995)].

Bone morphogenetic protein (BMP) can also be employed together with the SARMs of structural formula I. Bone 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. Bilezikian, et al., Ed., Principles of Bone Biology. San Diego: Academic Press; and Wang EA, Trends Biotechnol.. 11: 379-383 (1993)].

Inhibitors of BMP antagonism can also be employed together with the SARMs of structural formula I. In one embodiment, BMP antagonist inhibitors are chosen from inhibitors of the BMP antagonists SOST, noggin, chordin, gremlin, and dan [see Massague and Chen, "Controlling TGF- beta signaling," Genes Dev.. 14: 627-644, 2000; Aspenberg et al., J. Bone Miner. Res. 16: 497-500, 2001; and Brunkow et al., Am. J. Hum. Genet. 68: 577-89 (2001)].

The tissue-selective androgen receptor modulators of the present invention can also be combined with the polypeptide osteoprotegerin for the treatment of conditions associated with bone loss, such as osteoporosis. The osteoprotegerin can be selected from mammalian osteoprotegerin and human osteoprotegerin. The polypeptide osteoprotegerin, a member of the tumor necrosis factor receptor super- family, 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.

Prostaglandin derivatives can also be employed together with the SARMs of structural formula I. Non-limiting representatives of prostaglandin derivatives are selected from agonists of prostaglandin receptors EPl, EP2, EP4, FP, IP and derivatives thereof [Pilbeam et al., "Prostaglandins and bone metabolism," 1996. In: Bilezikian, et al. Ed. Principles of Bone Biology, San Diego: Academic Press; Weinreb et al., Bone. 28: 275-281 (2001)]. Fibroblast growth factors can also be employed together with the SARMs of structural formula I. Fibroblast growth factors include aFGF, 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., Ed. Principles of Bone Biology, San Diego: Academic Press]. In addition 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 can also be favorably combined with the SARMs of structural formula I.

Vitamin D, vitamin D derivatives and analogs can also be employed together with the SARMs of structural formula I. Vitamin D and vitamin D derivatives include, for example, D3 (cholecaciferol), D2 (ergocalciferol), 25-OH-vitamin D3, lα,25(OH)2 vitamin D3, lα-OH-vitamin D3, lα-OH-vitamin D2, dihydrotachysterol, 26,27-F6-lα,25(OH)2 vitamin D3, 19-nor-lα,25(OH)2 vitamin D3, 22-oxacalcitriol, calcipotriol, lα,25(OH)2-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB 1089, 20-epi- lα,25(OH)2 vitamin D3, KH1060, ED71, lα,24(S)-(OH)2 vitamin D3, lα,24(R)-(OH)2 vitamin D3 [See, Jones G., "Pharmacological mechanisms of therapeutics: vitamin D and analogs," 1996. In: J. P. Bilezikian, et al. Ed. Principles of Bone Biology, San Diego: Academic Press].

Vitamin K and Vitamin K derivatives can also be employed together with the SARMs of structural formula I. Vitamin K and vitamin K derivatives include menatetrenone (vitamin K2) [see Shiraki et al., J. Bone Miner. Res.. 15: 515-521 (2000)].

Soy isoflavones, including ipriflavone, can be employed together with the SARMs of structural formula I.

Fluoride salts, including sodium fluoride (NaF) and monosodium fluorophosphate (MFP), can also be employed together with the SARMs of structural formula I. Dietary calcium supplements can also be employed together with the SARMs of structural formula I. Dietary calcium supplements include calcium carbonate, calcium citrate, and natural calcium salts (Heaney. Calcium. 1996. In: J. P. Bilezikian, et al., Ed., Principles of Bone Biology, San Diego: Academic Press).

The tissue-selective androgen receptor modulators of the present invention can also be combined with an alpha- 1 adrenergic blocking agent or a 5 alpha reductase inhibitor for the treatment of benign prostatic hyperplasia (BPH). Nonlimiting examples of alpha- 1 adrenergic blocking agents include: Doxazosin (Pfizer), Terazosin HCl (Abbott), Tamsulosin HCl (Boehringer Ingelheim), and Alfuzosin HCl (Sanofi-Synthelabo). Nonlimiting examples of 5 alpha reductase inhibitors include the compound of structural formula I:

wherein R is selected from: (a) Ci-IO alkyl, unsubstituted or substituted with one to three halogen substituents, and (b) phenyl, unsubstituted or substituted with one to three substituents independently selected from halogen, methyl, and trifluoromethyl; for instance, Finasteride (Merck & Co., Inc.), dutasteride (AVODART, GlaxoSmithKline), and epristeride. Daily dosage ranges for bone resorption inhibitors, osteoanabolic agents and other agents which can be used to benefit the skeleton when used in combination with a compound of structural formula I are those which are known in the art. In such combinations, generally the daily dosage range for the SARMs of structural formula I ranges from about 0.01 to about 1000 mg per adult human per day, such as for example, from about 0.1 to about 200 mg/day. However, adjustments to decrease the dose of each agent can be made due to the increased efficacy of the combined agent.

In particular, when a bisphosphonate is employed, dosages from about 2.5 to about 100 mg/day (measured as the free bisphosphonic acid) are appropriate for treatment, such as for example ranging from 5 to 20 mg/day, or about 10 mg/day. Prophylactically, doses of about 2.5 to about 10 mg/day and especially about 5 mg/day should be employed. For reduction in side-effects, it can be desirable to administer the combination of a compound of structural formula I and the bisphosphonate once a week. For once weekly administration, doses ranging from about 15 mg to about 700 mg per week of bisphosphonate and from about 0.07 to about 7000 mg of a compound of structural formula I can be employed, either separately, or in a combined dosage form. A compound of structural formula I can be favorably administered in a controlled-release delivery device, particularly for once weekly administration.

For the treatment of atherosclerosis, hypercholesterolemia, and hyperlipidemia, the compounds of structural formula I can be effectively administered in combination with one or more additional active agents. The additional active agent or agents can be chosen from lipid-altering compounds such as HMG-CoA reductase inhibitors, agents having other pharmaceutical activities, and agents that have both lipid-altering effects and other pharmaceutical activities. Non-limiting examples of HMG-CoA reductase inhibitors include statins in their lactonized or dihydroxy open acid forms 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. 4,444,784); dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof; pravastatin, particularly the sodium salt thereof (see US Patent No. 4,346,227); fluvastatin, particularly the sodium salt thereof (see US Patent No.

5,354,772); atorvastatin, particularly the calcium salt thereof (see US Patent No. 5,273,995); cerivastatin, particularly the sodium salt thereof (see US Patent No. 5,177,080), and nisvastatin, also referred to as NK-104 (see PCT international application publication number WO 97/23200).

Additional active agents which can be employed in combination with a compound of structural formula I include, but are not limited to, HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACAT-I and -2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; cholesterol absorption inhibitors, such as SCH-58235, also known as ezetimibe and 1- (4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, which is described in U.S. Patent Nos. 5,767,115 and 5,846,966; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein Hb/πia fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPARγ), agonists, including the compounds commonly referred to as glitazones, for example troglitazone, pioglitazone and rosiglitazone and, including those compounds included within the structural class known as thiazolidinediones as well as those PPARγ, agonists outside the thiazolidinedione structural class; PPARα agonists, such as clofibrate, fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin Bβ (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin B 12 (also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; anti-oxidant vitamins such as vitamin C and E and beta carotene; beta- blockers; angiotensin II antagonists such as losartan; angiotensin converting enzyme inhibitors, such as enalapril and captopril; calcium channel blockers, such as nifedipine and diltiazem; endothelin antagonists; agents such as LXR ligands that enhance ABCl gene expression; bisphosphonate compounds, such as alendronate sodium; and cyclooxygenase-2 inhibitors, such as rofecoxib and celecoxib, as well as other agents known to be useful in the treatment of these conditions. Daily dosage ranges for EOvIG-CoA reductase inhibitors when used in combination with the compounds of structural formula I correspond to those which are known in the art. Similarly, daily dosage ranges for the HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-I or ACAT-2 as well as dual inhibitors of ACAT-I and -2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; cholesterol absorption inhibitors including ezetimibe; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, including glycoprotein nb/IHa fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPARγ) agonists; PPARα agonists; PPAR dual α/γ agonists; vitamin B6; vitamin B 12; folic acid; anti-oxidant vitamins; beta- blockers; angiotensin II antagonists; angiotensin converting enzyme inhibitors; calcium channel blockers; endothelin antagonists; agents such as LXR ligands that enhance ABCl gene expression; bisphosphonate compounds; and cyclooxygenase-2 inhibitors 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 can be somewhat lower when administered in combination. One embodiment of the invention is a method for affecting 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-telopeptide degradation products of type I collagen (CTX), urinary N-telopeptide cross-links of type I collagen (NTX), osteocalcin (bone GIa protein), dual energy x-ray absorptionmetry (DXA), bone specific alkaline phosphatase (BSAP), quantitative ultrasound (QUS), and deoxypyridinoline (DPD) crosslinks.

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 or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating 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 that can be ameliorated by addition of androgen. Abbreviations Used in the Description of the Preparation of the Compounds of the Present Invention:

AcOH Acetic acid

AD-mix-β Sharpless asymmetric oxidant, beta form BuOH Butyl alcohol

Diisobutylaluminum hydride

DDBAL

DIPEA diisopropylethylamine

DHT Dihydrotestosterone

DMAP 4-Dimethylaminopyridine DMEM Dulbecceo modified eagle media

DMSO Dimethyl sulfoxide

DMF N,N-Dimethylformamide

EA Ethyl acetate EDC 1 -(3-Dimethylaminopropyl)3-ethylcarbodiimide HCl

EDTA Ethylenediaminetetraacetic acid

EtOAc Ethyl acetate

EtOH Ethanol

Et₂O ethanol

Et₃N Triethylamine

FCS Fetal calf serum

HBTU O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HEPES (2-Hydroxyethyl)- 1 -piperazineethanesulf onic acid

HOAt 1 -hydroxy-7-azabenzotriazole

HOBT

HPLC High-performance liquid chromatography

KHMDS Potassium bistrimethylsilylamide

LCMS Liαuid chromotottraphv/mass spectroscopy LDA Lithium diisopropylamide

MeOH Methanol

NBS N-bromosuccinimide

Net3 triethylamine n-Bu4NI Tetra-n-butylammonium iodide

PMBCL p-Methoxybenzyl chloride

P(cHex)3 tricyclohexylphosphine

Pd₂(dba)3 tris(dibenzylideneacetone)dipalladium (0)

P(tertBu)3 tri-(tert-butyl)phosphine

Pd(OAc)2 Palladium acetate

Ti(OEt)4 titaniumethoxide p-TosCl p-Toluenesulfonyl chloride

PyBop benzotriazol- 1 -yloxytripyrrolidinophc hexafluorophosphate

Rt or rt Room temperature

TFA Trifluoroacetic acid

TLC Thin-laver chromatoerat>hv

The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. The illustrative schemes below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound in place of multiple substituents which are allowed under the definitions of Formula I defined previously.

Scheme 1

Scheme 1 is a general depiction of the synthesis of compounds of formula I through the coupling of a substituted phenyl acetic acid or a substituted phenyl cyclopropyl carbocylic acid with a substituted 3-aminomethyl pyridine. The compounds may be prepared utilizing appropriately substituted commercially available pyridines.

EXAMPLEl

1-C

A mixture of 3,4-dichlorophenylacetic acid (KA, 50 g, 244 mmol), (lS,2S)-(+)- pseudoephedrine (KB, 44.3 g, 268 mmol), HOBT (37.3 g, 244 mmol), EDC (51.4 g, 268 mmol), and diisopropylethylamine (31.5 g, 244 mmol) in DMF (400 mL) was stirred 18 hours followed by azeotroping with toluene. The resulting residue was dissolved in EtOAc (400 mL), washed with saturated NaHCO₃ solution (2 X 200 mL) and IN HCl (3 X 300 mL), and dried over MgSO₄. Evaporation of the solvent gave the product 1-C as a thick, pale-yellow oil. MS calculated M+H: 352, found 352.

Step B: 1-D

To a mixture of lithium chloride (25.8 g, 608 mmol) and LDA (152 mL of a 1.5M solution in cyclohexane) in THF (75 mL) at -78°C was slowly added a solution of I₁C (35.7 g, 101 mmol) in THF (50 mL). This mixture was stirred for one hour at -78°C, then 15 minutes at O⁰C. After re-cooling to -78°C, ethyl iodide (23.7 g, 152 mmol) was slowly added, followed by stirring at 0⁰C for 45 minutes and quenching with saturated NH₄Cl solution (150 mL). This mixture was extracted with ether (2 X 100 mL), and the combined extracts dried over MgSO₄. After evaporation of the solvents, the residue was chromatographed on silica gel, eluting with 66% to 0% hexanes in ethyl acetate to give the product 1-D as a pale yellow solid. MS calculated M+H: 380, found 380.

Step C: 1-E

To a solution of 1-D (14.1 g, 37.1 mmol) in dioxane (90 mL) was slowly added 18N H₂SO₄ (90 mL). The reaction mixture was heated to reflux for two hours, poured over ice (-300 g), and extracted with EtOAc. The organic layer was dried over MgSO₄ and azeotroped with toluene to give the product IrE as a pale yellow solid. ¹H NMR (CDCl₃): δ 7.41 (IH, d), 7.39 (IH, s), 7.16 (IH, d), 3.49 (IH, m), 2.08 (IH, m), 1.79 (IH, m), 0.91 (3H, m).

Step D: 1-G

To a solution of in methyl 5-bromo-2-chloronicotinate (KF, Ryan Scientific, 20 g, 79.8 mmol) in 20 mL methanol was added 15.8 g of a solution of sodium methoxide in methanol (30% w/w, 87.8 mmol). The resulting mixture was stirred at 5O⁰C for 1 hour, then evaporated to dryness. The residue was diluted with 200 mL ethyl acetate, washed with water, and dried over MgSO₄. Evaporation of the solvent gave the product 1-G as an off-white solid. MS calculated M+H: 246, found 246. Step E: 1-H

A mixture of 1-G (40 g, 163 mmol), cyclopropylboronic acid (16.7 g, 195 mmol), tripotassium phosphate (121 g, 569 mmol), tricyclohexylphosphine (4.6 g, 16.3 mmol), palladium acetate (1.8 g, 8.1 mmol), toluene (500 mL) and water (45 mL) was degassed with a stream of nitrogen for 10 minutes and then heated at reflux for 3 hours. 40 mL of water was then collected by azeotropic distillation in a Dean-Stark trap, and the mixture cooled to ambient temperature. MgSO4 (60 g) was added, and the resulting mixture filtered through a pad of CELITE, washing with ethyl acetate. The filtrate was evaporated to dryness, and the residue chromatographed on silica gel, eluting with 3% to 10% ethyl acetate in hexanes to give the product 1-H as an oil. MS calculated M+H: 208, found 208.

Step F: JA

To a mixture of JJH (24 g, 115 mmol) and dichloromethane (200 mL) at -78°C was added a solution of DEBAL (290 mL of 1 M in dichloromethane) over 30 minutes. The resulting mixture was stirred for 30 minutes and then quenched by the slow addition of ethanol (16 g). A solution of potassium sodium tartrate (85 g, 405 mmol) in 400 mL water was added, followed by ether (700 mL), and the mixture allowed to warm to RT and stirred for 40 minutes. The layers were separated, and the aqueous layer extracted with 300 mL ether. The combined organics were dried over MgSO₄ and the solvents evaporated to give the product hi as a light brown oil. MS calculated M+H: 180, found 180.

Step G: _M

To a mixture of oxalyl chloride (20.1 g, 159 mmol) and dichloromethane (400 mL) at - 78°C was added DMSO (16.6 g, 212 mmol) in 20 mL dichloromethane over 10 minutes. After an additional 10 minutes, a mixture of the alcohol IΛ (19 g, 106 mmol) in 70 mL dichloromethane was added over 15 minutes, and the resulting mixture stirred for 30 minutes. Triethylamine (54g, 530 mmol) was added rapidly, and the bath was then removed and replaced with a warm water bath. After 30 minutes, the mixture was diluted with ether (600 mL) and water (300 mL). The layers were separated, and the aqueous layer extracted with 300 mL ether. The combined organics were dried over MgSO₄ and the solvents evaporated to give the product LJ as a dark brown oil. MS calculated M+H: 178, found 178.

Step H: 1-K

A mixture of tert-butane sulfmamide (12.8 g, 105 mmol), titanium ethoxide (109 g, 480 mmol) and the aldehyde LJ (17 g, 96 mmol) and 100 mL THF was stirred at 5O⁰C for 1 hour. Cooled to O⁰C, and NaBH₄ (14.5 g, 384 mmol) was added in 4 portions over 5 min. Moderate bubbling ensued, and the bath was removed. The solution was stirred for 1 hr. The solution was re-cooled to 0⁰C, and methanol (70 mL) was added slowly over 1 hr, producing a gentle gas evolution until quenched, about 1 hr. With vigorous stirring, 250 mL brine was added, producing a white precipitate. Two cups of CELITE were added, followed by 100 mL THF, and the mixture was filtered through a pad of CELITE. The filter cake was washed two 300 mL portions of ethyl acetate, stirring the cake in solvent each time. Evaporated to 1/4 volume, diluted with 150 mL water, and extracted with 2 X 400 mL EtOAc. The organics were then dried over MgSO₄. After evaporation of the solvents, the residue was chromatographed on silica gel, eluting with 0% to 75% ethyl acetate in hexanes to give the product 1-K as a colorless solid. MS calculated M+H: 283, found 283.

1-L To a mixture of K[ (4.5 g, 15.9 mmol) in chloroform (41 mL) at 0⁰C was added a solution of HCl in dioxane (4N, 12 mL, 48 mmol). After an additional 2 hours at O⁰C, the solvents were evaporated in vacuo without heating to give the product amine bis-hydrochloride salt JJL as a colorless solid. MS calculated M+H: 179, found 179.

Step J: 2-(S)-N-l(5-cvclopropyl-2-methoxypyridin-3-yl)methyll-2-(3,4- dichlorophenvDbutanamide (1-2)

To a stirred solution of carboxylic acid hΕ (1.4 grams, 6.00 mmol), amine, IjL, (1.43 grams, 5.71 mmol), NMM (2.43 grams, 24.02 mmol, 2.64 ml), and CH₃CN (20 ml) was added HBTU

(2.51 grams, 6.61 mmol). After 1.0 hour, the reaction was diluted with EtOAc and then washed with H₂O, sat NaHCO₃, brine, dried (MgSO₄) and concentrated. Chromatography on silica gel, eluting with

0% to 30% EtOAc/hexanes, gave 1^2 as a colorless solid.

MS calculated M+H: 393.1131, found 393.1140

Examples 1^2 through 1-16 were prepared utilizing analogous chemistry to that shown in

Example IA.. The carboxylic acid portion of examples of 1-17 through 1-18,¹ 1-19,² and 1-20³ in Table

1 were prepared by a known synthetic methods (1. Mosher, H. S. et al. J. Org. Chem. 1969, 34, 2543; 2.

Prakash, G. K. S. et al. J. Org. Chem. 1991, 56, 984; 3. Simig, G. et al. J. Fluorine Chem. 1996, 76, 91).

EXAMPLE 2

2-B

To a solution of 2-chloro-3-cyano-5-trifluoromethylpyridine (prepared as described by Jiao, et al. WO 03/093266, 7.7g, 37.4 mmol) in 200 mL MeOH at 0⁰C was added a solution of sodium methoxide in methanol (7.06 g of 30% by weight, 39.3 mmol). The mixture was allowed to warm to room temperature. After 3 hours, the solvents were removed by evaporation. The residue was diluted with EtOAc and then washed with H₂O, brine, and dried (MgSO₄) and concentrated to give the product 2-B as an oil. MS calculated M+H: 203, found 203. 2-C

A mixture of 2-B (7.6 g, 38 mmol), Raney nickel (7 ml of a slurry in water) and 50 mL 2M ammonia in methanol was stirred under a balloon of hydrogen for 8 hours. The mixture was filtered though a pad of CELITE, evaporated, than evaporated from 100 mL dioxane to give an oil. The oil was dissolved in 40 mL dioxane, cooled to 0⁰C, and a solution of 4N HCl in dioxane (50 mL) was added. The resulting residue was evaporated to give the product hydrochloride salt 2C as a colorless solid. MS calculated M+H: 203, found 203.

Step C: 2-1 Utilizing the procedure described in Example 1, 2Λ_ was prepared from 2-C and (2S)-2- phenylbutanoic acid. MS calculated M+H: 353.1472, found 353.1476.

The carboxylic acid portion of examples of 2-10 through 2-11,¹ 2-12,² and 2-13³ in Table

2 were prepared by a known synthetic methods (1. Mosher, H. S. et al. J. Org. Chem. 1969, 34, 2543; 2, Simig, G. et al. J. Fluorine Chem. 1996, 76, 91; 3, Prakash, G. K. S. et al. J. Org. Chem. 1991, 56, 984;). The ethyl ester of the carboxylic acid portion of example 2-14 was resolved (with ChiralPak AD column) and then hydrolyzed (KOH in aqueous MeOH at the ambient temperature) to be coupled to the amine portion.

EXAMPLE 3

3-B

A stirred suspension of 3-fluorophenyl boronic acid (2.0 grams, 14.29 mmol), 2-bromo- 1-butene (2.12 grams, 15.72 mmol), KF (2.74 grams, 47.17 mmol) and THF (25 ml) was purged with N₂ for 5 minutes. Added P(tertBu)₃ followed by Pd₂(dba)₃. The mixture was stirred overnight. The reaction was diluted with Et₂O (100 ml) and then filtered through a pad of silica gel. The silica gel was washed with Et₂O (100 ml) and then the combined organics were concentrated to provide the olefin 3-B. The olefin was used as-is in the next reaction step.

Step B: 3-C

To a solution of AD-mix-β in 1:1 ¹BuOHZH₂O (80 ml) at O⁰C was added the olefin 3^B (1.5 gram, 9.99 mmol) dissolved in ¹BuOH. The mixture was stirred at O⁰C for 8 hours. Sodium sulfite (15 gram) was added and the mixture was stirred for 1 hour. The mixture was extracted with EtOAc and then the organic portion was washed with brine, dried (MgSO₄) and concentrated in vacuo to provide the crude diol 3-C. MS calculated M+H: 185.21, found 185.2.

3-D To a solution of the diol (1.5 gram, 8.14 mmol) in acetone (10 ml) was added H₂O (50 ml), NaHCO₃ (1 gram) and 10% Pt/C (2 gram). The mixture was heated to 90⁰C and air was gently bubbled through the mixture. After 8 hours, the reaction was allowed to cool to ambient temperature. The reaction was filtered through the CELITE pad and the resulting solution was concentrated. The residue was dissolved in IN HCl and then extracted with EtOAc. The organic portion was washed with brine, dried (MgSO₄) and concentrated to provide the crude acid. IH NMR (CDCl₃): 7.26-7.41 (3H, m), 6.97 (IH, m), 2.23 (IH, m), 2.05 (IH, m), 0.94 (3H, t, J=7Hz).

3-1

Utilizing the procedure described in Example 1, 3-1 was prepared. MS calculated M+H: 387.1327, found 387.1335.

EXAMPLE 4

2-A 4-A

(2S)-Phenylbutanoic acid

PyBop, 'Pr₂NEt, DMF

Step A: 4-A A solution of the chloride (2-A, 99 mg, 0.48 mmol) in CH₂Cl₂ (5 mL) was treated at the ambient temperature with CH₃NH₂ (2N in methanol, 0.5 mL) and stirred for 2 h. The reaction mixture was partitioned between CH₂Cl₂ and water, filtered through a hydrophobic fritted cartridge. The filtrated solution was concentrated in vacuo to give desired product, 4-A, as a white solid.

Step B: 4-B

A stirred solution of the nitrile (4-A, 90 mg, 0.45 mmol) in methanol (10 mL) was treated at 0 ⁰C with di-tert-butyl dicarbonate (293 mg, 1.34 mmol) and NiCl₂-OH₂O (11 mg, 0.05 mmol). After the reaction mixture became homogeneous, solid NaBH4 was added to the reaction mixture in portions until all the nitrile (4-A) disappeared on TLC. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO₄) and concentrated in vacuo. The solid residue was purified by chromatography (SiO₂, 0 to 50% ethyl acetate in hexanes) to obtain 4J3; ¹H-NMR (CDCl₃, 500 MHz) δ 8.34 (s, 1 H), 7.32 (s, 1 H), 6.40 (bs, 1 H), 4. 80 (bs, 1 H), 4.20 (d, 2 H, J = 6.5 Hz), 3.02 (d, 3 H, J = 5.0 Hz), 1.46 (s, 9 H).

Step C: 4-C

A solution of the tert-butyl carbamate (4-B, 70 mg, 0.23 mmol) in ethanol (3 mL) was treated at the ambient temperature with ethanol saturated with HCl (5 mL). After 30 min stirring, the reaction mixture was concentrated in vacuo to afford the desire compound (4-C) which was used without further characterization.

Step D: 4-1

A stirred solution of (2S)-phenylbutyric acid (53 mg, 0.32 mmol) in N,N- dimethylformamide (3 mL) was treated at the ambient temperature subsequently with N,N-diisopropyl-N- ethylamine (126 μL, 0.94 mmol) and PyBop (167 mg, 0.32 mmol). After 30 min stirring, the amine (4-C, 70 mg, 0.29 mmol) was added to the reaction mixture, stirred for 1.5 h, concentrated in vacuo. The residue was chromatographed (SiO₂, ethyl acetate / hexanes = 0 to 50 %) to afford the desired product as a white solid 44; ¹H-NMR (CDCl₃, 500 MHz) δ 8.29 (s, 1 H), 7.34 - 7.244 (m, 6 H), 6.41 (d, 1 H, J = 3.5 Hz), 5.85 (t, 1 H, J = 5.8 Hz), 4.34 (dd, I B, J= 15.3, 6.8 Hz), 4.22 (dd, I H, J= 15.3, 6.3 Hz), 3.23 (t, 1 H, J = 7.5 Hz), 2.94 (d, 3 H, J = 4.5 Hz), 2.19 (m, 1 H), 1.81 (m, 1 H), 0.88 (t, 3 H, J = 7.5 Hz).

Table 4

1-a 1-b 1-c

[* = racemic or (S)]

EXAMPLE 5 Pharmaceutical Composition

As a specific embodiment of this invention, 100 mg of (2R)-2-(3-fluorophenyl)-2- hydroxy-N-{ [2-methoxy-5-( cyclopropyl)pyridin-3-yl]methyl}butanamide, is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0, hard gelatin capsule.

While the 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.

ASSAYS

In Vitro and In Vivo Assays for SARM Activity Identification of Compounds The compounds exemplified in the present application exhibited activity in one or more of the following assays.

Hydroxylapatite-based Radioligand Displacement Assay of Compound Affinity for Endogenously Expressed AR

Materials:

Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)

50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM Tris, pH 8.0 and 1 mM EDTA. Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.

95% EtOH

Methyltrienolone, [17α-methyl-3H], (R1881*); NEN NET590

Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)

Dihydrotestosterone (DHT) [1,2,4,5,6,7-3H(N)] NEN NET453 Hydroxylapatite Fast Flow; Calbiochem Cat#391947

Molybdate = Molybdic Acid (Sigma, M 1651)

MDA-MB-453 cell culture media:

RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCθ3, 2 mM L-glutamine in 500 mL of complete media Final cone.

10 mL (IM Hepes) 20 mM

5 mL (200 mM L-glu) 4 mM

0.5 mL (10 mg/mL human insulin) 10 μg/mL in 0.01 N HCl Calbiochem#407694-S)

50 mL FBS (Sigma F2442) 10%

1 mL (10 mg/mL Gentamicin 20 μg /mL

Gibco#15710-072) Cell Passaging Cells (Hall R. E., et 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. The cells are counted at this point, then diluted to the appropriate concentration and split into flasks or dishes for further culturing (Usually 1:3 to 1:6 dilution).

Preparation of MDA-MB-453 Cell Lvsate When the MDA cells are 70 to 85% confluent, they are detached as described above, and collected by centrifuging at 1000 g for 10 minutes at 4°C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate, pH 7.2). After the final wash, the cells are resuspended in TEGM at a concentration of Iθ7 cells/mL. The cell suspension is snap frozen in liquid nitrogen or ethanol/dry ice bath and transferred to -8O⁰C freezer on dry ice. Before setting up the binding assay, the frozen samples are left on ice-water to just thaw (~1 hr). Then the samples are centrifuged at 12,500 g to 20,000 g for 30 min at 4⁰C. The supernatant is used to set-up assay right away. If using 50 μL of supernatant, the test compound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening

Ix TEGM buffer is prepared, and the isotope-containing assay mixture is prepared in the following order: EtOH (2% final concentration in reaction), 3H-R1881 or 3H-DHT (0.5 nM final Cone, in reaction) and Ix TEGM. [eg. For 100 samples, 200 μL (100 x 2) of EtOH + 4.25 μL of 1:10 3H- R1881 stock + 2300 μL (100 x 23) Ix TEGM]. The compound is serially diluted, e.g., if starting final cone, is 1 μM, and the compound is in 25 μL of solution, for duplicate samples, 75 μL of 4x1 μM solution is made and 3 μL of 100 μM is added to 72 μL of buffer, and 1:5 serial dilution.

25μL of 3H-R1881 trace and 25 μL compound solution are first mixed together, followed by addition of 50 μL receptor solution. The reaction is gently mixed, spun briefly at about 200 rpm and incubated at 4°C overnight. 100 μL of 50% HAP 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 HAP while incubating reaction. The samples in 96-well format are then washed in wash buffer using The FilterMate™ Universal Harvester plate washer (Packard). The washing process transfers HAP pellet containing ligand-bound expressed receptor to Unifilter-96 GF/B filter plate (Packard). The HAP pellet on the filter plate is incubated with 50 μL of MICROSCINT (Packard) scintillint for 30 minutes before being counted on the TopCount microscintillation counter (Packard). IC50S are calculated using Rl 881 as a reference.

The compounds, Examples 1-1 through 1-19, and Examples 2-1 through 2-15, found in Tables 1 and 2, were tested in the above assay and found to have an IC50 value of 1 micromolar or less.

Mammalian Two-Hybrid Assay for the Ligand-induced Interaction of N-Terminus and C-Terminus

Domains of the Androgen Receptor (Agonist Mode: VIRCON)

This assay assesses the ability of AR agonists to induce the interaction between the N- terminal domain (NTD) and C-terminal domain (CTD) of rhAR that reflects the in vivo virilizing potential mediated by activated androgen receptors. The interaction of NTD and CTD of rhAR is quantified as ligand induced association between a Gal4DBD-rhARCTD fusion protein and a VP 16- rhARNTD fusion protein as a mammalian two-hybrid assay in CV-I monkey kidney cells. The day before transfection, CV-I cells are trypsinized and counted, and then plated at 20,000 cells/well in 96-well plates or larger plates (scaled up accordingly) in DMEM + 10% FCS. The next morning, CV-I cells are cotransfected with pCBBl (Gal4DBD-rhARLBD fusion construct expressed under the SV40 early promoter), pCBB2 (VP16 -rhAR NTD fusion construct expressed under the SV40 early promoter) and pFR (Gal4 responsive luciferase reporter, Promega) using

LIPOFECTAMINE PLUS reagent (GIBCO-BRL) following the procedure recommended by the vendor. Briefly, DNA admixture of 0.05 μg pCBBl, 0.05 μg pCBB2 and 0.1 μg of pFR is mixed in 3.4 μL OPTI- MEM (GIBCO-BRL) mixed with "PLUS Reagent" (1.6 μL, GIBCO-BRL) and incubated at room temperature (RT) for 15 min to form the pre-complexed DNA. For each well, 0.4 μL LIPOFECTAMINE Reagent (GIBCO-BRL) is diluted into 4.6 μL

OPTI-MEM in a second tube and mixed to form the diluted LIPOFECTAMINE Reagent. The pre- complexed DNA (above) and the diluted LIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15 minutes at room temperature. The medium on the cells is replaced with 40 μL /well OPTI-MEM, and 10 μL DNA-lipid complexes are added to each well. The complexes are mixed into the medium gently and incubated at 37°C at 5% CO2 for 5 hours. Following incubation, 200 μL /well D- MEM and 13% 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 concentration(s) (1 nM - 10 μM). Forty eight hours later, luciferase activity is measured using LUC-Screen system (TROPIX) following the manufacturer's protocol. The assay is conducted directly in the wells by sequential addition of 50 μL each of assay solution 1 followed by assay solution 2. After 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 R1881. Typical tissue-selective androgen receptor modulators of the present invention display weak or no agonist activity in this assay with less than 50% agonist activity at 10 micromolar. See He B, Kemppainen JA, 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).

Trans-Activation Modulation of Androgen Receptor (TAMAR) This assay assesses 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 MMTV LTR/promoter linked to the LUC reporter gene.

20,000 to 30,000 cells/well are plated in a white, clear-bottom 96-well plate in "Exponential Growth Medium" which consists of phenol red-free RPMI 1640 containing 10%FBS, 4mM L-glutamine, 2OmM HEPES, 10ug/mL human insulin, and 20ug/mL gentamicin. Incubator conditions are 37⁰C and 5% CO2. The transfection is done in batch mode. The cells are trypsinized and counted to the right cell number in the proper amount of fresh media, and then gently mixed with the Fugene/DNA cocktail mix and plated onto the 96-well plate. All the wells receive 200 Η of medium + lipid/DNA complex and are then incubated at 37°C overnight. The transfection cocktail consists of serum-free Optimem, Fugeneό reagent and DNA. The manufacturer's (Roche Biochemical) protocol for cocktail setup is followed. The lipid (Tl) to DNA (Tg) ratio is approximately 3:2 and the incubation time is 20 minutes at room temperature. Sixteen to 24 hrs after transfection, the cells are treated with test compounds such that the final DMSO (vehicle) concentration is <3%. The cells are exposed to the test compounds for 48 hours. After 48 hours, the cells are lysed by a Promega cell culture lysis buffer for 30- 60 minutes and then the luciferase activity in the extracts is assayed in the 96-well format luminometer. Activity of test compounds is calculated as the Emax relative to the activity obtained with 100 nM R1881.

See R.E. Hall, et al., "MDA-MB-453, an androgen-responsive human breast carcinoma cell line with high androgen receptor expression," Eur. J. Cancer, 3OA: 484-490 (1994) and R.E. Hall, et al., "Regulation of androgen receptor gene expression by steroids and retinoic acid in human breast- cancer cells," Int. J. Cancer.. 52: 778-784 (1992).

Activity of test compounds is calculated as the E_maχ relative to the activity obtained with R1881. The exemplified tissue selective androgen receptor modulators of the present invention display partial agonist activity in this assay of greater than 10%.

In Vivo Prostate Assay

Male Sprague-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 compounds delay the rapid deterioration (~-85%) of the ventral prostate gland and seminal vesicles that occurs during a seven day period after removal of the testes (orchiectomy [ORX]). Rats are orchiectomized (ORX). Each rat is weighed, then anesthetized by isoflurane gas that is maintained 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 ligated with 4.0 silk 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 is repeated for the left testicle. When both stumps are returned to the scrotum, the scrotum and overlying skin are sutured closed with 4.0 silk. For Sham-ORX, all procedures excepting ligation and scissors cutting are completed. The rats fully recover consciousness and full mobility within 10-15 minutes.

A dose of test compound is administered subcutaneously or orally to the rat immediately after the surgical incision is sutured. Treatment continues for an additional six consecutive days.

Necropsy and Endpoints The rat is first 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 ORX. Next, the ventral portion of the prostate gland is located and blunt dissected free in a highly stylized fashion. The ventral prostate is blotted dry for 3-5 seconds and then weighed (VPW). Finally, the seminal vesicle is located and dissected free. The ventral seminal vesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate and seminal vesicle. Secondary data include serum LH (luteinizing hormone) and FSH (follicle stimulating hormone), and possible serum markers of bone formation and virilization. Data are analyzed by ANOVA plus Fisher PLSD post-hoc test to identify intergroup differences. The extent to which test compounds inhibit ORX- induced loss of VPW and SVWT is assessed.

In Vivo Bone Formation Assay:

Female Sprague-Dawley rats aged 7-10 months are used in treatment mode to simulate adult human females. The rats have been ovariectomized (OVX) 75-180 days previously, to cause bone loss and simulate estrogen deficient, osteopenic adult human females. Pre-treatment 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-like compounds increase the amount of bone formation, shown by increased fluorochrome labeling, at the periosteal 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 Endpoints

The rat is first 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% neutral-buffered formalin. Next, the right leg is disarticulated at the hip. The femur and tibia are separated at the knee, substantially defleshed, and then placed in 70% ethanol.

A 1-cm segment of the central right femur, with the femoral proximal-distal midpoint ats center, is placed in a scintillation 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 48-72 hours period. The bottle is cracked and the plastic block is trimmed into a shape that conveniently fits the vice-like specimen holder of a Leica 1600 Saw Microtome, with the long axis of the bone prepared for cross-sectioning. Three cross-sections of 85μm 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 fluorochrome label, and interlabel distance. Primary data for this assay are the percentage of periosteal surface bearing double label and the mineral apposition rate (interlabel distance (μm)/10d), semi-independent markers of bone formation. Secondary data include uterus weight and histologic features. Tertiary endpoints can include serum markers of bone formation and virilization. Data are analyzed by ANOVA plus Fisher PLSD post- hoc test to identify intergroup differences. The extent to which test compounds increase bone formation endpoint are assessed.

In Vivo Lean Body Mass Assay:

The goal is to measure the extent to which SARM compounds change lean body mass (LBM), shown by change in LBM during a 24 day treatment period. In a typical assay, seven groups of nine rats each are studied. Female Sprague-Dawley rats aged 7-10 months are used. They have been ovariectomized (OVX) 75-180 days previously, to cause bone loss and simulate the hormonal condition of estrogen deficient, osteopenic adult human females. On Day 0, lean body mass (LBM) is measured non-invasively in each rat (dual energy x-ray absorptiomtery; DXA; Hologic Corporation; or EchoMRI- 700; Echo Medical Systems; Houston, TX). On Day 1, treatment with test compound is started and continued for 24 days. On Day 24, lean body mass is non-invasively remeasured in each rat. Primary data for this LBM assay is "change in LBM (g)" during treatment. Data are analyzed by ANOVA plus Fisher PLSD post-hoc test to identify intergroup differences. The extent to which test compounds change LBM is assessed. An efficacious SARM increases LBM by 20-3Og (5-7% increase) greater than control (P<.02).

Rats studied for LBM in vivo may also be studied for other endpoints likely to be affected by SARMs, such as uterine weight, sebaceous gland hypertrophy, and bone formation rate.

Claims

WHAT IS CLAIMED IS:

1. A compound of structural formula I:

a pharmaceutically acceptable salt or a stereoisomer thereof,

n is 0, 1, 2, or 3; m is 0, 1, or 2; Z is OR6, or NR7R8_;

R.2 and R^ are each independently chosen from hydrogen, halogen, hydroxyl, Ci-4alkyl, Ci-

4cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more fluorine atoms, and provided that at least one of R^ or R3 is other than hydrogen, and further provided that when R^ is OH, then R3 is other than OH; Rl, R7, and R^ are each independently chosen from hydrogen, halogen, perfluoroC i .galkyl, perfluoroC i .βalkoxy , Ci-io alkyl,

C2-10 alkenyl, C2-IO alkynyl, aryl Co-10 alkyl, C3-8 cycloalkyl Co-10 alkyl, C3-8 heterocyclyl Co-10 alkyl,

(Co-10 alkyl) i-2aminocarbonyl Co-10 alkyl, (aryl Co-10 alkyl) i_2aminocarbonyl Co-10 alkyl, C3-8 cycloalkyl Q)-IO alkyl aminocarbonyl Co-10 alkyl, C3_8 heterocyclyl Co-10 alkyl aminocarbonyl Q)-IO alkyl, Ci-io alkoxy (carbonyl)θ-lQ)-10 alkyl,

Co-10 alkyloxy carbonylCo-10 alkyl, C3-8 cycloalkyl Co-10 alkyloxy carbonylCo-10 alkyl, C3-8 heterocyclyl Q)-IO alkyloxy carbonylCo-10 alkyl, Co-io alkyl carbonylamino Ci_io alkyl, C3-8 cycloalkyl Q)- 10 alkyl carbonylamino Ci_io alkyl,

C3-8 heterocyclyl Cθ-10 alkyl carbonylamino Ci-io alkyl, aryl Cθ-10 alkyl carbonylamino Ci-io alkyl,

Cθ-10 alkyloxy carbonylamino Ci- 10 alkyl, C3-8 cycloalkyl Q)-IO alkyloxy carbonylamino Ci-io alkyl,

C3-8 heterocyclyl Cθ-10 alkyloxy carbonylamino Ci-io alkyl, aryl Cθ-10 alkyloxy carbonylamino Ci-io alkyl, aryl Q)-IO alkyloxy carbonylCo-lO alkyl, hydroxycarbonyl Ci-io alkyl, hydroxycarbonyl C2-IO alkenyl, hydroxycarbonyl C2-IO alkynyl, and hydroxy Q)-10alkyl, provided that when one carbon of the phenyl ring is directly substituted with an oxygen as an linker, then any carbon of the phenyl ring adjacent to this oxygen substituted carbon is substituted with other than an oxygen linker; ach independently chosen from hydrogen, halogen, perfluoroC 1 -6alkyl, perfluoroC 1.βalkoxy , Ci-10 alkyl,

C2-10 alkenyl,

C2-IO alkynyl,

Ci-io alkylthio, aryl Cθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyl,

C3-8 heterocyclyl Cθ-10 alkyl,

(Q)-IO alkyl) i-2amino Q)-IO alkyl,

(aryl Q)-IO alkyl) i-2amino Cθ-10 alkyl,

(C3-8 cycloalkyl Q)-IO alkyl) i-2amino Q)-IO alkyl, (C3-8 heterocyclyl Q)- 10 alkyl) 1 -2amino Q)- 10 alkyl,

(Co-10 alkyl) i_2aminocarbonylamino Co-10 alkyl,

(aryl Q)-IO alkyl) i-2aminocarbonylamino Cθ-10 alkyl,

C3_8 heterocyclyl Cθ-10 alkyl aminocarbonylamino Cθ-10 alkyl,

C3-8 cycloalkyl Q)-IO alkyl aminocarbonylamino Cθ-10 alkyl, (Q)- 10 alkyl) 1 _2aminocarbonyl Q)- 10 alkyl,

(aryl Cθ-10 alkyl) l-2aminocarbonyl Cθ-10 alkyl,

C3-8 cycloalkyl Co-10 alkyl aminocarbonyl Co-10 alkyl, C3-8 heterocyclyl Cθ-10 alkyl aminocarbonyl Cθ-10 alkyl,

Q)-IO alkyl carbonylamino Cθ-10 alkyl,

C3-8 cycloalkyl Cθ-10 alkyl carbonylamino Cθ-10 alkyl,

C3-8 heterocyclyl Cø-lO alkyl carbonylamino Cθ-10 alkyl, aryl Cθ-10 alkyl carbonylamino Co-10 alkyl,

Q)- 10 alkyloxy carbonylamino Co-10 alkyl,

C3-8 cycloalkyl Cθ-10 alkyloxy carbonylamino Co-10 alkyl,

C3.8 heterocyclyl Co-10 alkyloxy carbonylamino Co-10 alkyl, aryl Cθ-10 alkyloxy carbonylamino Cθ-10 alkyl, Cθ-10 alkyloxy carbonyloxy Q)-IO alkyl,

C3-8 cycloalkyl Cθ-10 alkyloxy carbonyloxy Q)-IO alkyl,

C3-8 heterocyclyl Co-10 alkyloxy carbonyloxy Q)-IO alkyl, aryl Cθ-10 alkyloxy carbonyloxy Q)-IO alkyl,

Ci-io alkoxy (carbonyl)θ-lQ)-10 alkyl, Q)- 10 alkylcarboxy Q)- 10 alkylamino, hydroxycarbonyl Ci-io alkyl, hydroxycarbonyl C2-10 alkenyl, hydroxycarbonyl C2-10 alkynyl,

Ci-io alkoxy, Ci_ioalkyloxy Co-ioalkyl, aryloxy Cθ-10 alkyl,

C3-8 cycloalkyloxy Q)-IO alkyl Q)-IO alkyl,

C3_8 heterocyclyl Co-ioalkyl oxy Cθ-10 alkyl,

Ci_io alkylcarbonyloxy Co-10 alkyl, (Q)- 10 alkyl) 1 -2aminosulfonyl Q)- 10 alkyl,

(aryl Cθ-10 alkyl) i-2aminosulfonyl Cθ-10 alkyl,

C3-8 cycloalkyl Cθ-10 alkyl aminosulfonyl Q)-IO alkyl,

C3-8 heterocyclyl Co-10 alkyl aminosulfonyl Cθ-10 alkyl,

Co-10 alkyl sulfonylamino Cθ-10 alkyl, C3-8 cycloalkyl Cθ-10 alkyl sulfonylamino Q)-IO alkyl,

C3-8 heterocyclyl Co-10 alkyl sulfonylamino Cθ-10 alkyl, aryl Q)-IO alkyl sulfonylamino Q)-IO alkyl,

Ci-io alkyloxy(carbonyl)θ-lQ)-10 alkylamino,

C3-8 heterocyclyl Q)-IO alkyloxy(carbonyl)θ-lQ).-lθ alkylamino, C3-8 cycloalkyl Cθ-10 alkyloxy(carbonyl)θ-lCθ-10 alkylamino, aryl Q)-IO alkyloxy(carbonyl)θ-lQ)-10 alkylamino,

(Q)-IO alkyl) i-2aminocarbonyloxy, (aryl Cø-lO alkyl)i_2aminocarbonyloxy, (C3_8 heterocyclyl Cθ-10 alkyl)i_2aminocarbonyloxy, (C3-8 cycloalkyl Cθ40^alkyl)l-2^ami^nocarbonyloxy, ^and hydroxy Cθ-lθ^alkyl; R6 is chosen from hydrogen, Ci_5alkyl, Ci-Scycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one or more fluorine atoms; and wherein in Rl, R2, R3, R4, R5, R6, R7, and KB, said alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and cycloalkyl are each optionally substituted with one or more groups chosen from hydroxy, Cχ-6 alkyl, Ci -6 alkoxy, halogen, CO2H, cyano, 0(C=O)Ci-Cg alkyl, NO2, trifluoromethoxy, trifluoroethoxy, -0(θ-l)(Ci_io)perfluoroalkyl, Co-10 alkylaminocarbonylamino, Ci-io alkyloxycarbonylamino, Ci-io alkylcarbonylamino, Co-10 alkylaminosulfonylamino, Ci-io alkylsulfonylamino, Ci_io alkylsulfonyl, Co-10 alkylaminosulfonyl, Co-10 alkylaminocarbonyl and NH2-

2. A compound of Claim 1, chosen from:

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-phenylbutanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3,4-dichlorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluorophenyl)butanamide; 2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-fluorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3,4-difluorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3,4-difluorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-chlorophenyl)butanamide; 2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-chlorophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-bromophenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-trifluoromethylphenyl)butanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluoro-4-chlorophenyl)propanamide;

2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(3-fluoro-4-chlorophenyl)butanamide; 2-(S)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-2-(4-fluoro-3-chlorophenyl)propanamide;

N-tCS-cyclopropyl^-methoxypyridin-S-y^methyll-S^^-trifluoro^-hydroxy^-phenylpropanamide;

(2R)-N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-3,3,3-trifluoro-2-hydroxy-2-phenylpropanamide;

N-tCS-cyclopropyl^-methoxypyridin-S-y^methyll-S^^^^-pentafluoro^-hydroxy^-phenylbutanamide; N-[(5-cyclopropyl-2-methoxypyridin-3-yl)methyl]-3,3,3-trifluoro-2-phenylpropanamide;

(2S)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylbutanamide;

(lR,2R)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylcyclopropanecarboxamide;

2-(4-fluorophenyl)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}cyclopropanecarboxamide;

(lS,2S)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylcyclopropanecarboxamide; (2S)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-(3-chlorophenyl)butanamide;

(2S)-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl } -2-(3-trifluoromethyl phenyl)butanamide;

(2S)-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-(4-trifluoromethyl phenyl)butanamide;

3,3,3-trifluoro-2-hydroxy-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2-phenylpropanamide;

(2R)-3,3,3-trifluoro-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2- phenylpropanamide;

3,3,3-trifluoro-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl } -2-phenylpropanamide;

3,3,4,4,4-pentafluoro-2-hydroxy-N-{ [2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}-2- phenylbutanamide;

(2R)-2-(3-fluorophenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}butanamide;

2R)-2-(4-fluorophenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}butanamide;

2R)-2-(3,4-dichlorophenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3- yl]methyl }butanamide; 2R)-2-(4-trifluoromethylphenyl)-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3- yl]methyl Jbutanamide;

2R)-2-phenyl-2-hydroxy-N-{[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]methyl}butanamide;

2R)-2-phenyl-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3-yl]methyl}butanamide;

2R)-2-phenyl-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3-yl]methyl}propanamide; 2R)-2-(3,4-dichlorophenyl)-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3-yl]methyl}butanamide;

2R)-2-(4-trifluoromethylphenyl)-2-hydroxy-N-{[2-methoxy-5-(cyclopropyl)pyridin-3- yl]methyl }butanamide;

2R)-2-(3-fluorophenyl)-2-hydroxy-N-{ [2-methoxy-5-( cyclopropyl)pyridin-3-yl]methyl}butanamide;

(2S)-N-{ [2-(MethylanLiino)-5-(trifluoromethyl)pyridin-3-yl]methyl } -2-phenylbutanamide; Benzyl (2-{ [3-({ [(2S)-2-phenylbutanoyl]amino}methyl)-5-(trifluoromethyl)pyridin-2- yl] amino } ethyl)carbamate; and pharmaceutically acceptable salts and stereoisomers thereof.

3. The use of the compound of any one of Claims 1-2 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for the treatment or prevention of a condition selected from: weakened muscle tone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia, hematopoietic disorders, arthritic condition and joint repair, HTV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, Alzheimer's disease, cognitive decline, sexual dysfunction, sleep apnea, benign prostate hyperplasia, abdominal adiposity, metabolic syndrome, type II diabetes, depression, premature ovarian failure, and autoimmune disease, in a mammal in need thereof.

4. The use of Claim 3, wherein said condition is osteoporosis.

5. A pharmaceutical composition comprising a compound of any one of Claims 1-2 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

6. A composition of Claim 5, further comprising an active ingredient selected from: an estrogen or an estrogen derivative, alone or in combination with a progestin or progestin derivative, a bisphosphonate, an antiestrogen or a selective estrogen receptor modulator, an αvβ^'3 integrin receptor antagonist, a cathepsin K inhibitor, n HMG-CoA reductase inhibitor, an osteoclast vacuolar ATPase inhibitor, an antagonist of VEGF binding to osteoclast receptors, an activator of peroxisome proliferator- activated receptor γ, calcitonin, a calcium receptor antagonist, parathyroid hormone or analog thereof, a growth hormone secretagogue, human growth hormone, insulin-like growth factor, a p38 protein kinase inhibitor, bone morphogenetic protein, an inhibitor of BMP antagonism, a prostaglandin derivative, vitamin D or vitamin D derivative, vitamin K or vitamin K derivative, ipriflavone, fluoride salts, dietary calcium supplements, osteoprotegerin, an alpha-1 adrenergic blocking agent, and a 5 alpha reductase inhibitor.

7. A composition of Claim 6, wherein said bisphosphonate is alendronate.

8. A process for making a pharmaceutical composition comprising combining a compound according to any one of Claims 1 to 2 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

9. A use of Claim 3, wherein the arthritic condition is selected from rheumatoid arthritis and osteoarthritis.

10. The use of Claim 3, wherein said condition is selected from sarcopenia or cancer cachexia.