WO2010118287A1 - Selective androgen receptor modulators - Google Patents

Abstract

This invention provides compounds of formula I, Ia, Ib or Ic, or salts thereof, pharmaceutical compositions comprising a compound of formula I, Ia, Ib or Ic, and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) and processes for making compounds of formula I and intermediates useful in the preparation of same.

Description

SELECTIVE ANDROGEN RECEPTOR MODULATORS

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 61/212,399, filed on April 10, 2009. The entire teachings of the above application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Androgen signaling is mediated through the androgen receptor (AR) and is a nuclear signaling pathway of tremendous importance in mammals. In addition to its primary role in sexual development, maturation and maintenance of sexual function in both males and females, this critical hormone signaling pathway affects a large number of non-sexual tissues including, bone, muscle, CNS, liver, etc. In humans, testosterone and dihydrotestosterone are the primary ligands that mediate AR- signaling. Both are high affinity ligands for AR, with dihydrotestosterone having somewhat higher affinity. Testosterone is converted to dihydrotestosterone through the action of 5α-reductase enzymes and is converted to 17β-estradiol (potent endogenous estrogen) through the action of P-450 aromatase enzymes. AR signaling is mediated by binding of an AR ligand to AR in the cellular cytosol, homodimerization of two AR receptors and nuclear location of the ligand bound dimer to the cell nucleus where the complex associates with various coactivators as well as Androgen Response Elements (palindrome-like sequences of DNA) which serve as activation sites for certain AR-mediated genes. Due to the very large number of AR target tissues, both sexual and non-sexual, androgens such as testosterone and dihydrotestosterone have a number of potentially desirable actions as well as non-desirable actions depending on the particular individual's age, sex, therapeutic need, etc. In the adult male and female, certain positive consequences of AR-agonist signaling can be generalized as including increased bone mineral density and a corresponding reduction of risk of bone fractures. Accordingly, androgen supplementation can be very valuable in the prevention or treatment of osteoporosis where the osteoporosis might originate from any number of different causes, such as corticosteroid induced osteoporosis and age-related osteoporosis (e.g. postmenopausal). Likewise, males and females respond to agonist supplementation with an increase in muscle mass and very often a decrease in fat mass. This is beneficial in a very large number of treatment modalities. For example, there are many wasting syndromes associated with different disease states where the therapeutic goal is for a patient to maintain weight and function, such as the treatment of cancer associated cachexia, AIDs-related cachexia, anorexia and many more. Other muscle- wasting disorders such as muscular dystrophy in its many forms as well as related disorders can also be treated to advantage with androgens. The increase in muscle mass with concomitant reduction in fat mass associated with anabolic androgen action has additional health benefits for many men and women including potentially increased sensitivity to insulin. Androgen supplementation is also associated with reduction of high triglycerides, though there is a general correlation with androgen use and decreased HDL levels and in some cases, increased LDL levels. In the CNS, numerous laudatory benefits have been associated with androgen supplementation including improved sexual desire and functioning, increased cognition, memory, sense of well being and possible decrease in risk of Alzheimer's disease. Androgen antagonists have been used in treating prostate cancer, where blockade of androgen signaling is desired whereas some androgens agonists (e.g. dihydrotestosterone) stimulate the hypertrophy of prostate tissue and may be a causative factor in prostate cancer. Androgen agonist activity is often associated with stimulation of benign prostate hyperplasia, a disease characterized by an enlarged prostate often accompanied by discomfort and difficulty in urination due to blockage of the urethra. As a result, androgen antagonists have efficacy in the reduction of the size of the prostate and the corresponding symptoms of benign prostate hyperplasia, though it is much more common to use a 5α-reductase inhibitor (e.g. finasteride) as such inhibitors do not decrease androgen signaling systemically to the same extent as a typical anti-androgen (e.g. bicalutamide), but rather reduce androgen drive more site specifically to where testosterone to DHT conversion occurs such as the prostate and scalp. Androgen antagonists also find utility in the treatment of hirsutism in women as well as the treatment of acne. Androgens are generally contraindicated in conditions that are treated with androgen antagonists since they can exacerbate the symptoms that are being treated.

Ideally, an androgen would retain the benefits of androgen agonists while minimizing the stimulatory effects on the prostate in males as well as some of the other untoward effects of androgens including masculinization of women and increase in acne in both sexes. Androgens that demonstrate tissue selective effects compared to the benchmarks testosterone and/or dihydrotestosterone are typically referred to as androgen receptor modulators or more often, selective androgen receptor modulators (SARMs). At the far end of potential selectivity, an ideal SARM would demonstrate no prostate stimulation while maintaining or growing muscle sufficient to effectively mimic the effects of testosterone or dihydrotestosterone. The growing appreciation of the positive contribution that SARMs can make in the many therapeutic areas where androgen activity is desirable has led to a large amount of research into this important area. Due to a compelling need for novel and effective androgen therapies with potentially reduced side effects, novel and effective SARM compounds are urgently needed.

SUMMARY OF THE INVENTION In certain embodiments, this invention describes a compound of formula I

I wherein: R_x is CN, Cl, Br, NO₂ or R_xl ;

R_y is hydrogen, CH₃, CF₃, or halogen;

R_xI is a 5 member heteroaryl, said heteroaryl selected from ςr O o-V

R'- R¹- 3cr .

^ J R- s-^

^

N N N

R' is hydrogen or optionally Ci-C₂ alkyl, CF₃, or halogen; or R_x and R_y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from:

wherein: each R" is independently hydrogen or optionally CF₃, or C)-C₂ alkyl; A is a bond or a 5- or 6- member heteroaryl group wherein said 5- or 6- member heteroaryl is substituted with hydrogen and optionally up to two substituents independently selected from Ci_-3 alkyl, CN, Ci_-3 haloalkyl or halogen;

B is a phenyl, Ci_-6 alkyl, Ci_-6 haloalkyl, 5- or 6-member heteroaryl or bicyclic heteroaryl; each R_a is independently selected from Ci_-4 alkyl (optionally substituted with from 1-2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(0)0Ci_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C_]-3 alkyl, and OCi.₃ alkyl), - N(R_b)C(0)Ci_₆ alkyl, - N(R_b)C(O)phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C]_-3 alkyl, and OCi_-3 alkyl), NR_bR_b', Ci_-4 haloalkyl, halogen, OH, OCi_-3 alkyl, OCi_-3 haloalkyl, OC(O)Ci- i₂ alkyl, OC(O)phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C ₁.₃ alkyl, and OCi_-3 alkyl), OC(O)OCi_-I2 alkyl, OC(O)Ophenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, C ₁-₃ alkyl, and OCi_-3 alkyl), 0S0₂-phenyl, (wherein said phenyl is optionally substituted with 1-3 substituents independently selected from halogen, Ci_-3 alkyl or Ci.₃ haloalkyl), OSO₃-, OPO₃-, OSO₂NR_bR_b-, S(O)_0-2phenyl, and S(O)_0-2Ci_-3 alkyl; each R_b and R_b' is independently selected from hydrogen, Ci_-3 alkyl and Ci_-3 haloalkyl; n is O, 1, 2, or 3; n' is O or l ; n" is O or 1 ;

Ri, R₂, R₅, R₆, R₇ and Rg are each independently selected from hydrogen, Ci_-3 alkyl, Ci_-3 haloalkyl, OR₃ and phenyl;

R₉ is hydrogen, Ci_-3 alkyl or OR₃; provided that at least one of Ri , R₂, R₅, R₆, R₇, R₈ or R₉ is OR₃ ; each R₃ is independently selected from hydrogen, Ci_-4 alkyl, Ci_-4 haloalkyl, C_2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from halogen, Ci_-3 alkyl, S(O)_0-2Ci_-3 alkyl, S(O)_0-2phenyl, 0-C_1-6 alkyl, OCF₃), C(O)-Ci-I₀ alkyl, SO₃-, PO₃-, SO₂NRbRb' and C(O)phenyl;

D and E are each independently C or N;

Rio and Rn are at each and every occurrence independently selected from hydrogen, Cj_-3 alkyl, Ci_-3 haloalkyl, CN or halogen; p is O, 1 or 2; q is O, 1 or 2; and

R₄ is H, C]_-4 alkyl or Ci_-4 haloalkyl; or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION In certain embodiments, this invention describes a compound of formula I

wherein:

R_x is CN, Cl, Br, NO₂ or R_xl;

Ry is hydrogen, CH₃, CF₃, or halogen;

R_x] is a 5 member heteroaryl, said heteroaryl selected from

R' is hydrogen or optionally Ci-C₂ alkyl, CF₃, or halogen; or

R_x and R_y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from:

wherein: each R" is independently hydrogen or optionally CF₃, or Ci-C₂ alkyl; A is a bond or a 5- or 6- member heteroaryl group wherein said 5- or 6- member heteroaryl is substituted with hydrogen and optionally up to two substituents selected from Ci_-3 alkyl, CN, Ci_-3 haloalkyl or halogen; B is a phenyl, Ci_-6 alkyl, Ci_-6 haloalkyl, 5- or 6-member heteroaryl or bicyclic heteroaryl; each R_a is independently selected from Ci_-4 alkyl (optionally substituted with from 1-2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(O)OCi_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C_{1 -3} alkyl, and OC_1-3 alkyl), - N(R_b)C(O)Ci_-6 alkyl, - N(R_b)C(O)phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCj_-3 alkyl), NR_bR_b-, C _M haloalkyl, halogen, OH, OCi_-3 alkyl, OCi_-3 haloalkyl, OC(O)C,. ₁₂ alkyl, OC(O)phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCj_-3 alkyl), OC(O)OCi-I₂ alkyl, OC(O)Ophenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), OSO₂-phenyl, (wherein said phenyl is optionally substituted with 1-3 substituents independently selected from halogen, Ci_-3 alkyl or Ci_-3 haloalkyl), OSO₃-, OPO₃-, 0S0₂NR_bR_b>, S(O)_0-2phenyl, and S(O)_0-2Ci_-3 alkyl; each R_b and R_b- is independently selected from hydrogen, Ci_-3 alkyl and Cj_-3 haloalkyl; n is O, 1, 2, or 3; n' is O or 1 ; n" is O or l ;

R], R_2, R_5, R_6, R_? and Rg are each independently selected from hydrogen, Ci_-3 alkyl, Ci_-3 haloalkyl, OR₃ and phenyl;

R₉ is hydrogen, Ci_-3 alkyl or OR₃; provided that at least one of Ri, R₂, R₅, R₆, R₇, Rs or R₉ is OR₃; each R₃ is independently hydrogen, Cj_-4 alkyl, Ci_-4 haloalkyl, C_2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from halogen, Ci_-3 alkyl, S(O)_0-2Ci_-3 alkyl,

S(0)o-₂phenyl, 0-Ci_-6 alkyl, OCF₃), C(O)-Ci₀ alkyl, SO₃-, PO₃-, SO₂NR_bR_b> and C(O)phenyl; D and E are each independently C or N;

Rio and Ri i are at each and every occurrence independently selected from hydrogen, Ci_-3 alkyl, Ci_-3 haloalkyl, CN or halogen;p is O, 1 or 2; q is O, 1 or 2; and

R₄ is H, C₁₄ alkyl or C]_-4 haloalkyl; or pharmaceutically acceptable salts thereof.

In certain embodiments of this invention, for the compound of formula I, R_x is CN.

In certain embodiments of this invention, for the compound of formula I, R_y is CF₃ or Cl. In some embodiments of this invention, for the compound of formula I, D is

C.

In some embodiments of this invention, for the compound of formula I, E is C.

In certain embodiments of this invention, for the compound of formula I, both D and E are C.

In some embodiments of this invention, for the compound of formula I, both D and E are C and are connected by a double bond.

In certain embodiments of this invention, for the compound of formula I, both D and E are C and are connected by a single bond. In some embodiments of this invention, for the compound of formula I, Rio and Ri i are hydrogen at each occurrence.

In some embodiments of this invention, for the compound of formula I, Rio is hydrogen at each occurrence and Ri i is CH₃ or CF₃ at least at one occurrence.

In certain embodiments of this invention, for the compound of formula I, R_x is CN and R_y is CF₃ or Cl.

In some embodiments of this invention, for the compound of formula I, R₄ is hydrogen or CH₃. In certain embodiments of this invention, for the compound of formula I, R₄ is hydrogen.

In some emdodiments of this invention, for the compound of formula I, R_x is CN, R_y is CF₃ or Cl and R₄ is hydrogen. In certain aspects of this invention, for the compound of formula I, A is a 5 member heteroaryl.

In certain aspects of this invention, for the compound of formula I, A is a 5 member heteroaryl selected from the following group of 5 member heteroaryls:

wherein each R" is independently hydrogen, CF₃, or Ci -C₂ alkyl;

In some embodiments of this invention, for the compound of formula I, A is

In certain embodiments of this invention, for the compound of formula I, R_x

is CN, R_y is CF₃ or Cl, R₄ is hydrogen and A is

.

In some embodiments, for the compound of formula I, B is phenyl.

In certain embodiments of this invention, for the compound of formula I, R_x

is CN, R_y is CF₃ or Cl, R₄ is hydrogen, A is

and B is

wherein R_a is as defined previously in I.

In some embodiments of this invention, for the compound of formula I, R_x is

CN, Ry is CF₃ or Cl, R₄ is hydrogen, A is

and B is

or wherein R_a is CN, OH, F or Cl.

In some embodiments of this invention, for the compound of formula I, B is

In some embodiments of this invention, for the compound of formula I, R_x is

CN, Ry is CF₃ or Cl, R₄ is hydrogen, A is

and B

In some embodiments of this invention, for the compound of formula I, R_x is

CN, R₄ is hydrogen, A is

and B is

or , wherein R_a is CN, OH, F or Cl.

In certain aspects of this invention, for the compound of formula I, either Ri or R₂ is OR₃. In certain aspects of this invention, for the compound of formula I, either R₅ or R₆ is OR₃.

In certain aspects of this invention, for the compound of formula I, either R₇ or Re is OR₃ and R₉ is hydrogen. In certain aspects of this invention, for the compound of formula I, either R| or R₂ is OR₃, either Ri or R₂ is methyl and n' and n' ' are each O and R₉ is hydrogen or methyl.

In certain aspects of this invention, for the compound of formula I, Ri is OR₃, R₂ is hydrogen, n' is O and n" is O and R₉ is hydogen. In some embodiments of this invention, for the compound of formula I, Ri and R₂ are each hydrogen, R₅ is OR₃ and R₆ is hydrogen, R₉ is hydrogen and n' ' is 0.

In certain embodiments of this invention, for the compound of formula I, R₃ is hydrogen. In certain embodiments of this invention, for the compound of formula I, R_x

is CN, R_y is CF₃ or Cl, R₄ is hydrogen, A is ' -J °¹T ''" , B i is a

, wherein R_a is CN, OH, F or Cl and R₁ or R₂ is OR₃, either R] or R₂ is methyl, n' and n" are each 0 and R9 is hydrogen or methyl. In certain embodiments of this invention, for the compound of formula I, R_x

is CN, R_y is CF₃ or Cl, R₄ is hydrogen, A is

, B is

or , wherein R_a is CN, OH, F or Cl and R₁ or R₂ is OR₃, either R₁ or R₂ is methyl, n' and n" are each 0 and R₉ is hydrogen or methyl and R₃ is hydrogen. In some embodiments of this invention, for the compound of formula I, R_x is

is, CN, OH, F or Cl and Ri or R₂ is OR₃, either Ri or R₂ is methyl, n' and n" are each O, R₉ is hydrogen or methyl and R₃ is hydrogen.

The invention described herein relates to compounds of formula Ia:

Ia wherein: R_x is CN, Cl, Br, NO₂ or R_x] ;

R_y is CH₃, CF₃, or halogen; R_xi is a 5 member heteroaryl, said heteroaryl selected from

ςr c^'V-'

R'- R R'-jr "N R'- N l5S

N N

R' is hydrogen, Ci-C₂ alkyl, CF₃, or halogen; or

R_x and R_y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from:

wherein: each R" is independently hydrogen, CF₃, or C]-C₂ alkyl;

A is a bond or a 5- or 6- member hetεroaryl group; each R_a is independently selected from Ci_-4 alkyl (optionally substituted with from 1-2 CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(O)OC_1-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OC_1-3 alkyl), - N(R_b)C(O)C_1-6 alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C_1-3 alkyl, and OCj_-3 alkyl), NRbRb-, Ci_-4 haloalkyl, halogen, OH, OCi_-3 alkyl, OCi_-3 haloalkyl, OSO₂-phenyl, (wherein said phenyl is optionally substituted with 1 -3 substituents independently selected from halogen, Ci_-3 alkyl or Ci_-3 haloalkyl), S(0)o-₂phenyl, and S(O)_O-2Ci_-3 alkyl; each R_b and R_b> is each independently selected from hydrogen, Ci_-3 alkyl and

Ci_-3 haloalkyl; n is O, 1, 2, or 3;

Ri and R₂ are each independently selected from hydrogen, Ci_-3 alkyl, C_1-3 haloalkyl and phenyl; R₃ is hydrogen, Ci_-4 alkyl, Ci_-4 haloalkyl, C_2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from: halogen, Ci_-3 alkyl, S(O)_O-2C]_-3 alkyl, S(O)_0-2phenyl, 0-C_1-6 alkyl, OCF₃), C(O)-C_1-6 alkyl and C(O)Phenyl;

D and E are each independently C or N; R_1O and R₁₁ are at each and every occurrence independently selected from hydrogen, C_1-3 alkyl, C_1-3 haloalkyl, CN or halogen; and

R₄ is H, Ci_-4 alkyl or Ci_-4 haloalkyl; or pharmaceutically acceptable salts thereof.

In certain embodiments of this invention, for the compound of formula Ia, A is a 5 member heteroaryl group;

In some embodiments of this invention, for the compound of formula Ia, A is a 5 member heteroaryl group selected from the group consisting of:

' I Ti > \r ' , L π £ Vi , ^

>r i

wherein each R" is independently hydrogen, CF₃, or Ci-C₂ alkyl.

In certain embodiments of this invention, for the compound of formula Ia, R_x may be CN.

In some embodiments, for the compound of formula Ia, R_y is CF₃ or Cl. In some embodiments, for the compound of formula Ia, R_x is CN and R_y is Cl.

In certain embodiments of this invention, for the compound of formula Ia, A

In certain embodiments, for the compound of formula I, D and E are both C.

In some embodiments, for the compound of formula I, D and E are both C, p and q are each 2 and each Rio and Rn are independently at each occurrence selected from hydrogen, CH₃ or CF₃. In some embodiments, for the compound of formula I, D and E are both C and connected by a double bond, p and q are each 1, and each Rio and Rn are independently at each occurrence selected from hydrogen, CH₃ or CF₃.

In some embodiments of this invention, for the compound of formula Ia, R₈ is OH, OMe, OCF₃, CN, SO₂CH₃, or halogen and n is 1. In certain embodiments of this invention, for the compound of formula Ia, R_a is 4'-Fl or 4'-Cl. In certain embodiments of this invention, for the compound of formula Ia, R_a is 4'-OH.

In certain embodiments of this invention, for the compound of formula Ia, R₈ is 4'-CN. In certain embodiments of this invention, for the compound of formula Ia, n is O.

In some embodiments, for the compound of formula Ia, R₄ is H, CH₃ or CH₂CF₃.

In some embodiments of this invention, for the compound of formula Ia, R₄ is H.

In certain embodiments of this invention, for the compound of formula Ia, Ri and R₂ are each independently H, CH₃, or CF₃, and at least one of Ri and R₂ is not H.

In other embodiments of this invention, for the compound of formula Ia, Ri is H and R₂ is CH₃.

In some embodiments of this invention, for the compound of formula Ia, Rj is CH₃ and R₂ is H.

In certain embodiments of this invention, for the compound of formula Ia, Ri is H, R₂ is CF₃. In some embodiments of this invention, for the compound of formula Ia, Rj is CF₃ and R₂ is H.

In certain embodiments of this invention, for the compound of formula Ia, R₃ is H.

In some embodiments of this invention, for the compound of formula Ia, Ri = R₂ = CH₃.

In some embodiments of this invention, for the compound of formula Ia, R_x

is CN, R_y is CF₃ or Cl, A is ^"N ' ₅ D and E are both C, R_a is selected from halogen, CN, OCH₃, SO₂CH₃ and OH, n is O or 1, Ri is CH₃, CF₃ or H, R₂ is CH₃, CF₃ or H, R₃ is H, R₄ is H, CH₃, CH₂CH₃, or CH₂CF₃. In certain embodiments of this invention, for the compound of formula Ia,

R_x is CN, R_y is Cl, A is

D and E are both C, p and q are each 2, and each Rio and Rn are independently at each occurrence selected from hydrogen, CH₃ or CF₃. R_a is selected from halogen, CN, OCH₃ and OH, n is 0 or 1, Ri is H or CH₃, R₂ is H or CH₃, R₃ is H, R₄ is H, wherein at least one of Ri and R₂ is not H. In certain embodiments of this invention, for the compound of formula Ia,

R_x is CN, R,, is CL A is

, D and E are both C and connected by a double bond, p and q are each 1, and each Rio and Rn are independently at each occurrence selected from hydrogen, CH₃ or CF₃. R_a is selected from halogen, CN, OCH₃ and OH, n is O or 1 , Ri is H or CH₃, R₂ is H or CH₃, R₃ is H, R₄ is H, wherein at least one of Rj and R₂ is not H.

In certain embodiments, this invention describes a compound of formula Ib or Ic

Ib Ic wherein:

R_y is hydrogen, CF₃ or Cl; each R₈ is independently selected from Ci^ alkyl (optionally substituted with from 1-2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(O)OCi_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C1.₃ alkyl, and OQ.₃ alkyl), - N(Rb)C(O)Cj_-6 alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Cj_-3 alkyl, and OCi_-3 alkyl), NR_bR_b., Ci_-4 haloalkyl, halogen, OH, OCi_-3 alkyl, OC_1-3 haloalkyl, S(O)_{0- 2}phenyl, and S(O)_0-2C i-₃ alkyl; each Rb and Ry is independently selected from hydrogen, Cj_-3 alkyl and Ci_-3 haloalkyl; n is O, 1, 2, or 3;

Ri and R₂ are each independently selected from hydrogen, C]_-3 alkyl, Ci_-3 haloalkyl and phenyl;

R₃ is hydrogen, C]_-4 alkyl, Ci_-4 haloalkyl, C_2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1 -3 substituents independently selected from: halogen, Cj_-3 alkyl, S(0)o-₂Ci_₃ alkyl, S(0)o-₂phenyl, O-Ci-₆ alkyl, OCF₃), Ci_-6 acyl, and benzoyl;

R₄ is H, C i-₄ alkyl or Ci_-4 haloalkyl;

Rio and Rn are at each and every occurrence independently selected from hydrogen, Cj_-3 alkyl, Ci_-3 haloalkyl, CN or halogen; or pharmaceutically acceptable salts thereof.

In certain embodiments, for a compound of formula Ib or Ic, R_y is CF₃ or Cl.

In some embodiments, for a compound of formula Ib or Ic, Rio and Rn are each independently selected from hydrogen, CH₃ or CF₃.

In certain embodiments, for a compound of formula Ib or Ic, Ri and R₂ are each independently selected from hydrogen and CH₃.

In some embodiments, for a compound of formula Ib or Ic, R₄ is hydrogen.

In certain embodiments, for a compound of formula Ib or Ic, each R_a is independently selected from 5-member heteroaryl, CN, - N(R_b)C(O)OCi_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), - N(R_b)C(O)Cj_-6 alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), C _M haloalkyl, halogen, OH, OC_1-3 alkyl, OC_1-3 haloalkyl and S(O)_0-2Ci_-3 alkyl; R_b and R_b- are each independently selected from hydrogen, Ci_-3 alkyl and C_1-

₃ haloalkyl; and n is O, 1 or 2. In some embodiments, for a compound of formula Ib or Ic, R₃ is hydrogen.

In certain embodiments, for a compound of formula Ib or Ic, R_y is CF₃ or Cl, Rio and Rn are each independently selected from hydrogen, CH₃ or CF₃.

In certain embodiments, for a compound of formula Ib or Ic, R_y is CF₃ or Cl, Rio and Rn are each independently selected from hydrogen, CH₃ or CF₃ and R₄ is hydrogen.

In certain embodiments, for a compound of formula Ib or Ic, R_y is CF₃ or Cl, Rio and Rn are each independently selected from hydrogen, CH₃ or CF₃, R₄ is hydrogen and each R_a is independently selected from 5 -member heteroaryl, CN, - N(R_b)C(O)OCi_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OC_1-3 alkyl), - N(R_b)C(O)Ci_₆ alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), Ci_-4 haloalkyl, halogen, OH, OCi_-3 alkyl, OC_L3 haloalkyl and S(O)_0-2Ci_-3 alkyl;

R_b and R_b> are each independently selected from hydrogen, Ci_-3 alkyl and Ci- ₃ haloalkyl; and n is O, 1 or 2.

In some embodiments, for a compound of formula Ib or Ic, R₃ is hydrogen. In some embodiments of this invention, the compound of formula I, Ia, Ib or

Ic, is selected from the following list. (The compound names in the list were generated with the assistance of ChemDraw^® versions 8.0, 9.0 and/or 11.0 (CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, MA 02140 USA)). When the stereochemistry at a chiral center is not defined in the compound name this indicates that the sample prepared contained a mixture of isomers at this center.

In certain embodiments, this invention describes a compound selected from one of the following:

4-chloro- 1 -(( 1 R, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)- 1 H-indole-5-carbonitrile; 4-chloro- 1 -(( 1 S, 2S)- 1 -(5-(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)-lH-indole-5-carbonitrile;

4-chloro- 1 -(( 1 R, 2S)- 1 -(5-(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)indoline-5 -carbonitrile; and 4-chloro-l-((15, 25)-l-(5-(4-cyanophenyl)-l ,3,4-oxadiazol-2-yl)-2- hydroxypropyl)indoline-5-carbonitrile; or a pharmaceutically acceptable salt of any of the foregoing.

The invention also relates to pharmaceutical compositions comprising a compound of formula I, Ia, Ib or Ic, or any of the structural embodiments described herein and at least one pharmaceutically acceptable excipient.

The invention also provides a method of modulating an androgen receptor in a cell, comprising the administration of a compound to said cell wherein said compound has structural formula I, Ia, Ib or Ic, or any of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof. This invention provides a method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to formula I, Ia, Ib or Ic, and monitoring the effect of the compound on the cell.

This invention also provides a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) a disease, syndrome, illness, or symptom associated with insufficient androgen levels in a mammal in need thereof, wherein said method comprises the administration to said mammal of an effective amount of a compound of formula I, Ia, Ib or Ic, or any one of the structural embodiments described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In a particular embodiment, the mammal is a human. In some embodiments, this invention provides a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, cachexia, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders, Alzheimer's dementia, attention deficit disorder, senile dementia, coronary artery disease, hirsutism, pain, myalgia, myocardial infarction, stroke, clotting disorders, thromboembolisms, congestive heart disorder, low insulin sensitivity, low glucose utilization, high blood sugar, organ transplant, metabolic syndrome, diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, tooth injury, tooth disease, periodontal disease, liver disease, thrombocytopenia, fatty liver conditions, endometriosis, hot flushes, hot flashes, vasomotor disturbance, stress disorders, dwarfism, dyslipidemia, cardiovascular disease, coronary artery disease, renal disease, thin skin disorders, lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn's disease, Paget' s disease, osteoarthritis, connective tissue disease or disorders, injury, burns, trauma, wounds, bone fracture, atherosclerosis, cachexia, cancer cachexia, and obesity, in a mammal in need thereof comprising the administration to said mammal of an effective amount of a compound according to a structure of formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of structural formula I, Ia, Ib or Ic, or one of the structural embodiments described herein including pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. In a particular embodiment, the mammal is a human.

In certain aspects, this invention describes a method of treating (e.g., preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of) prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need thereof comprising the administration to said mammal of a compound according to a structure of formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of structural formula I, Ia, Ib, or Ic, or one of the structural embodiments described herein including pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. In a particular embodiment, the mammal is a human.

The term "alkenyl" as used herein refers to a hydrocarbon backbone radical, having the number of carbon atoms falling within the specified range. For example, C_2-3 alkenyl means that a hydrocarbon radical is attached that may contain anywhere from 2 to 3 carbon atoms with the remaining valence filled in by hydrogen atoms unless specified otherwise. The term also includes each permutation as though it were separately listed. Thus, C_2-3 alkenyl includes ethenyl, 1-propenyl and 2- propenyl.

The term "alkyl" as used herein refers to both straight and branch chain hydrocarbon radicals, having the number of carbon atoms falling within the specified range. For example, Ci_-4 alkyl means that a hydrocarbon radical is attached that may contain anywhere from 1 to 4 carbon atoms with the remaining valence filled in by hydrogen atoms. The definition also includes separately each permutation as though it were separately listed. Thus, Ci_-2 alkyl includes methyl and ethyl. The term Ci_-3 alkyl includes methyl, ethyl, propyl and 2-propyl. The term Cj. ₄ alkyl includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl and tert- butyl. The term C₁-₅ alkyl includes methyl, ethyl, 2-propyl, n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pentan-2-yl, pentan-3-yl, and tert-pentyl, iso-pentyl.

The term "halogen" as used herein refers to a fluorine, chlorine, bromine or iodine radical.

The term "haloalkyl" refers to an alkyl radical wherein said alkyl radical is the same as defined for the term "alkyl" except that the alkyl radical additionally has from 1 to 5 halogen atoms attached to the alkyl chain. For example, Ci haloalkyl includes

-CH₂F, -CHF₂, -CF₃ and the like, C₂ haloalkyl includes -CH₂F, CHF₂, CF₃, - CH₂CH₂F, -CH₂CHF₂, -CH₂CF₃, -CF₂CHF₂, -CF₂CF₃ and the like. C_1-3 haloalkyl is defined to include -CH₂F, -CHF₂, -CF₃, -CH₂CF₃, -CHFCF₃, -CF₂CF₃, -CHClCH₃, - CH₂CH₂Cl, -CH₂CH₂CF₃, and the like. Ci_-4 haloalkyl is defined to include -CH₂F, - CHF₂, -CF₃, -CH₂CF₃, -CHFCF₃, -CF₂CF₃, -CHClCH₃, -CH₂CH₂Cl, -CH₂CH₂CF₃, - CH₂CH₂CH₂CF₃, CFICICF₂CH₂CH₃, CF₂CH₂CH₂CHF₂, CH₂CFI₂CH₂CH₂F, CH₂CH₂CH₂CH₂Cl, and the like. The term "hydroxy alkyl" refers to an alkyl radical wherein said alkyl radical is the same as defined for the term "alkyl" except that the alkyl radical additionally has from 1 or 2 hydroxyl groups attached to the alkyl chain. For example, C_{2- 4}hydroxyalkyl includes 2-hydroxyethyl, 2-hydroxypropyl, 2,4-dihydroxybutyl and the like. The term "5-member heteroaryl" refers to a heteroaryl ring system radical wherein said heteroaryl contains at least one heteroatom selected from the groups consisting of N, O and S and up to 3 additional heteroatoms selected from the group consisting of N, O and S. If not otherwise defined, the 5-member rings system is optionally substituted with 1-2 substituents selected from halogen, Ci_-2 alkyl, Ci_-2 haloalkyl, or CN. The points of attachment of the optional substituent(s) as well as the rest of the molecule maybe selected from any position wherein there is an open valence. Some examples of 5-member heteroaryls include:

s Λ Λ. o, .^»■

The term "6-member heteroaryl" refers to a heteroaryl ring system radical wherein said heteroaryl contains at least one heteroatom selected from N and up to two additional Ns. If not otherwise specified, the 6-member heteroaryl ring is optionally substituted with 1-2 substituents selected from halogen, Ci_-2 alkyl, Ci_-2 haloalkyl, or CN. The points of attachment of the optional substituent(s) as well as the rest of the molecule maybe selected from any position wherein there is an open valence. Some examples of 6-membered heteroaryls include:

The term "bicyclic heteroaryl" as used herein refers to a bicyclic fused-ring system wherein at least one of the two rings is substituted with at least one heteroatom selected from N, O and S. The bicyclic heteroaryl ring system contains from 8 to 12 backbone atoms and may contain a total of up to 4 heteroatoms in the backbone. The bicylic heteroaryl ring systems of this invention require that at least one of the two rings is aromatic but the two rings together may be aromatic as well (e.g. quinoline). Some non-limiting examples of bicyclic heteroaryl ring systems are provided below:

and

The compounds of this invention may be present as solids and when so present, may be in an amorphous form or they may be crystalline. When the compounds of this invention are in the crystalline form, they might be present as a single polymorph or a mixture of polymorphs or even as a mixture of amorphous material together with one or more distinct polymorphs - the invention is not limited according to any particular solid or liquid state form.

The compounds of this invention contain at least one stereocenter and therefore, exist in various stereoisomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. "/?" and "S" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "i?" and "S"' denote the relative configurations of substituents around one or more chiral carbon atoms When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.

The compounds of the invention may be prepared as individual isomers by incorporating or starting with a specific isomer, isomer-specific synthesis or resolution from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

Where compounds of this invention include one or more basic sites such as amines, acid addition salts can be made and this invention includes such acid addition salts. Some representative (non-limiting) acid addition salts include hydrochloride, hydrobromide, hydroiodide, acetate, benzenesulfonate, mesylate, besylate, benzoate, tosylate, citrate, tartrate, sulfate, bisulfate, lactate, maleate, mandelate, valerate, laurate, caprylate, propionate, succinate, phosphate, salicylate, napsylate, nitrate, tannate, resorcinate and the like, including multiprotic salts as well as mixtures of the acid addition salts. In cases where an amine is present, this invention also embraces quaternized ammonium salts of those amines. It should be appreciated that N-oxides of amines are also embraced within the definition of the compounds of this invention. Likewise, where compounds of this invention include one or more acid sites such as carboxylic acids, phenols and the like, basic addition salts can be made and this invention includes such basic addition salts. For example, some representative (non-limiting) acidic compounds of this invention may be present as their lithium, sodium, potassium, ammonium, trialkyammonium, calcium, magnesium, barium and the like.

The compounds of this invention can also be present as solvates and such solvates are embraced within the scope of this invention even where not explicitly described. Such solvates are preferably hydrates but can be solvates comprised of other solvents, preferably where those solvents are considered to be non-toxic or at least acceptable for administration to mammals, preferably humans. The solvates can be stoichiometric or non-stoichiometric, singular or in combination. Some exemplary solvates include water, ethanol, acetic acid and the like.

The therapeutic utility of these compounds includes "treating" a mammal, preferably a human where treating is understood to include treating, preventing, or ameliorating the symptoms associated with, or reducing the incidence of, reducing the pathogenesis of, facilitating the recovery from or delaying the onset of the syndrome, illness, malady or condition being considered. The compounds of this invention can also be useful in states or conditions where no clear deficit, illness or malady per se is perceived but rather, where a preferred condition, sensation, performance, capability or state is obtainable through therapeutic intervention with a compound of this invention.

The compounds of this invention, when used as therapeutics can be administered by any method known to one of skill in the art such as orally, bucally, intravenously, subcutaneously, intramuscularly, transdermally, intradermally, intravascularly, intranasally, sublingually, intracranially, rectally, intratumorally, intravaginally, intraperitonealy, pulmonary, ocularly and intratumorally.

As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

When administered, the compounds and compositions of this invention maybe given once daily or with multiple daily doses such as twice per day, three times per day and four times per day.

In one embodiment of this invention, the compound is administered orally where it can be formulated for solid dosage administration or liquid dosage administration. Solid dosage administration can be in the form of a tablet, granule, capsule, pill, pellet, powder and the like. Liquid dosage formulations include syrups, solutions, gels, suspensions, elixirs, emulsions, colloids, oils, and the like.

As mentioned previously, the compounds of this invention may be solids and when present as solids, they maybe of defined particle size. Where the compound of this invention is not particularly water soluble, it is sometimes preferable to administer the compound with a certain particle size - a particle size with a preferred range where the average mean particle size diameter is under 100 microns, or 75 microns, or 50 microns, or 35 microns, or 10 microns or 5 microns. Solid dosage formulations will comprise at least one compound of this invention together with one or more pharmaceutical excipients. Those excipients are known to one of skill in the art and include, by way of non-limiting example diluents (monosaccharides, disaccharides and polyhydric alcohols including starch, mannitol, dextrose, sucrose, microcrystalline cellulose, maltodextrin, sorbitol, xylitol, fructose and the like), binders (starch, gelatin, natural sugars, gums, waxes and the like), disintegrants (alginic acid, carboxymethylcellulose (calcium or sodium), cellulose, crocarmellose, crospovidone, microcrystalline cellulose, sodium starch glycolate, agar and the like), acidic or basic buffering agents (citrates, phoshphates, gluconates, acetates, carbonates, bicarbonates and the like), chelating agents (edetic acid, edetate calcium, edetate disodium and the like), preservatives (benzoic acid, chlorhexidine gluconate, potassium benzoate, potassium sorbate, sorbic acid, sodium benzoate and the like), glidants and lubricants (calcium stearate, oils, magnesium stearate, magnesium trisilicate, sodium fumarate, colloidal silica, zinc stearate, sodium oleate, stearic acid, and the like), antioxidants and/or preservatives (tocopherols, ascorabtes, phenols, and the like) and acidifying agents (citric acid, fumaric acid, malic acid, tartaric acid and the like) as well as coloring agents, coating agents, flavoring agents, suspending agents, dessicants, humectants and other excipients known to those of skill in the art. The solid dosage formulations of this invention can be prepared in different forms including most commonly, tablets and capsules. The tablets can be formulated by a wide variety of methods known to one of skill in the art including, for example, preparing a dry powder mixture of the drug substance in combination with one or more of the excipients granulating the mixture and pressing to together into a tablet and optionally coating the tablet with an enteric or non-enteric coating. The final coat typically includes a light protective pigment such as titanium oxide and a shellac or wax to keep the tablet dry and stable. While not intending to be limited by theory or example, in some instances it might be preferred to prepare the tablets by wet granulating the drug with one or more of the excipients and then extruding the granulated material.

The solid dosage forms of this invention also include capsules wherein the drug is enclosed inside the capsule either as a powder together with optional excipients or as granules containing usually including one or more excipients together with the drug and wherein the granule in turn can be optionally coated, for example, enterically or non-enterically.

In certain embodiments of this invention, the solid dosage formulations of this invention are formulated in a sustained release formulation. Such formulations are known to those of skill in the art and generally rely on the co-formulation of the drug with one or more matrix forming substances that slow the release of the androgen receptor modulator thus extending the compound's lifetime in the digestive track and thereby extend the compounds half-life. Some non-limiting matrix forming substances include hydroxypropyl methylcellulose, carbopol, sodium carboxymethylcellulose and the like.

In some embodiments of this invention, the compounds are formulated for delivery other than via a solid oral dosage form. For example, in certain instances it might be preferable to deliver a compound of this invention by a pulmonary route. A pulmonary route of administration typically means that the compound of this invention is inhaled into the lung where it is absorbed into the circulation. Such a route of administration has the advantage of avoiding a first pass liver effect thereby possibly increasing bioavailability as well as decreasing or eliminating undesirable androgen agonist effects on the liver such as increasing liver enzymes and/or decreasing HDL. Formulating a compound of the invention for pulmonary delivery can be accomplished by micronizing the compound of the invention to a very fine size particle, typically with a mean average diameter of less than 20 microns, or less than 10 microns or between 2 and 5 microns. The powder may then be inhaled by itself or more likely mixed with one or more excipients such as lactose or maltose. The powder can then be inhaled in a dry powder inhaling device either once or multiple times per day depending on the particular compound and the patients need. Other types of pulmonary dosage forms are also embraced by this invention. In an alternative to the dry powder delivery, the compound of this invention may be suspended in an aerosolizing medium and inhaled as a suspension through a meter dosed inhaler or a nebulizer.

The compounds of this invention can be formulated for transdermal delivery. Effective advantage of these compounds can be taken through a wide variety of transdermal options. For example, the compounds of this invention maybe formulated for passive diffusion patches where they are preferably embedded in a matrix that allows for slow diffusion of the compound into the treated subject's circulation. For this purpose, the compound is preferably dissolved or suspended in solvents including by way of non-limiting examples one or more of ethanol, water, propylene glycol, and Klucel HF. In some instances, a polymer matrix (e.g. acrylate adhesive) will comprise the bulk of the transdermal formulation. In some instances, the transdermal formulations maybe designed to be compatible with alternate transdermal delivery technologies. For example, some transdermal technologies achieve greater and/or more consistent delivery by creating micropores in the skin using radio frequency, heat, ultrasound or electricity. In some cases, the compounds of this invention can be used with microneedle technology wherein the compound is loaded into or on top of very small needles which due not need to penetrate the dermis to be effective. The compounds of this invention may be employed alone or in combination with other therapeutic agents. By way of non-limiting example, the compounds of this invention can be used in combination with anti-lipidemics (statins, fibrates, omega-3 oils, niacinates and the like), bone anti-resorptives (bisphosponates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin, and the like), bone anabolic agents (PTH and fragments e.g teriparatide, PTHRP and analogues e.g. BaO58), anti-diabetics (e.g. insulin sensitizers, glucose absorption and synthesis inhibitors (e.g. metformin)), anti-anxiety agents, antidepressants, anti-obesity agents, contraceptive agents, anti-cancer agents, PPARγ agonists (e.g. pioglitazone), and the like. When used in combination, the compounds of this invention may be co- formulated or co-administered wherein said co-administration does not require dosing at exactly the same time but rather indicates that the patient is undergoing treatment with one or more of the additional agents during the timeframe of treatment with the selective androgen modulators of this invention. Thus, the additional drug(s) for combination treatment can be administered concomitantly, sequentially or separately from the compounds of this invention.

The compounds of this invention may be administered according to different dosage scheduling and the dosage may be adjusted as deemed necessary by the subject or preferably by the subject in consultation with a qualified practitioner of medicine. Dosing of the compounds of this invention can take place by multiple routes and consequently, the dosing schedule and amounts are dependent not only on the particular subject's weight, sex, age, therapy contemplated, etc but also by the route of the drug chosen.

By way of non-limiting example, the compounds of this invention may be dosed by the oral route in a once daily, twice daily, three times daily or more than three times per day depending on the particular needs of that subject, the formulation of the drug, etc. The dosage will typically be from about 0.01 mg to 500 mg of drug per daily dosage, for example from about 0.1 mg to about 10 mg, such as from about 0.1 mg to about 3 mg, or from about 0.1 mg to about 250 mg of drug per daily dosage, or from about 1 mg to about 150 mg of drug per daily dosage, or from aobut 5 mg to about 100 mg of drug per daily dosage.

It is understood that the amount of compound dosed per day can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc. For example, with every other day administration, a 5 mg per day dose can be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, etc. In one embodiment, a compound of this invention is dosed once every seven days.

The compounds of this invention can also be dosed on a monthly basis meaning that administration is done once per month. In addition, the compounds of this invention can be dosed on a weekly basis (once a week), every other week, every three weeks or every four weeks for a single day or multiple days. The compounds of this invention can also be dosed on an as needed or "pro re nata" "prn" schedule, and "on demand". In this type of dosing, the compouonds of this invention are administered in a therapeutically effective dose at some time prior to commencement of an activity wherein the therapeutic effect of the compounds of this invention is desirable. Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation.

The compounds of this invention can be prepared by a variety of synthetic routes and techniques known to those of skill in the art. The processes disclosed herein should not be construed as limiting the examples or scope of the invention in any way but rather are provided as just some of the representative ways that the compounds of this invention can be or were prepared.

In some cases, protective groups are employed in the synthesis of the compounds of this invention and it should be appreciated that there are a diverse array of protective groups and strategies that can be employed in organic synthesis (T.W.Green and P.G.M.Wuts (2006) Greene's Protective Groups in Organic Synthesis, herein incorporated by reference in its entirety) and that where a protective group is referred to generically, any appropriate protective group should be considered. In some instances, leaving groups are employed in the synthesis of compounds of this invention. Where a specific leaving group is referred to, it should be appreciated that other leaving groups might also be used. Leaving groups typically include those groups that can stabilize an anion. In the case of nucleophilic aromatic substitutions, the leaving group may be an anion or a neutrally charged group. In some cases, the leaving group for nucleophilic aromatic substitution may be a group that is not typically considered to be a stabilized anion (e.g. fluoride or hydride). While not intending to be bound by theory or the examples, some typical nucleophilic leaving groups include halogens, sulfonates (O-mesylates, O-tosylates, etc), hydrides, quaternized amines, nitro, and the like. Additional discussion and examples can be found in leading textbooks on organic chemistry including, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th Edition, which is herein incorporated in its entirety.

In scheme 1, a method for preparing certain embodiments of the invention is described. In particular, the method is carried out for the synthesis of certain indole embodiments of the invention. Scheme 1

In scheme 2, a method for preparing certain embodiments of the invention is described. In particular, the method is carried out for the synthesis of certain dihydroindole embodiments of the invention. Scheme 2

DETERMINATION OF BIOLOGICAL ACTIVITY

In order to demonstrate the utility of the compounds of this invention, an androgen receptor binding assay was performed. The compounds of this invention are shown to demonstrate affinity for the androgen receptor. The assay was performed as specified by the manufacturer (Invitrogen, Madison, WI). Briefly, 1 μl of 1OmM compound was added to 500μl of AR screening buffer in a 1.5ml eppendorf tube to make a 2x10^"5M stock. 10-fold serial dilutions of the test compounds were prepared ranging in concentration from 10^"5M to 10^"12M. Each dilution was added in triplicate to a black 384-microtiter plate. The test compounds will be diluted 2-fold in the final reaction. 2x AR-Fluormone™ complex was prepared with 2nM Flourmone AL Green™ and 3OnM AR. 25 μl of 2x complex was aliquoted to each reaction well, such that the final reaction volume was 50μl per well. Plate was sealed with a foil cover and incubated in the dark at room temperature for 4 h. Polarization values for each well were measured. The polarization values were plotted against the concentration of the test compound. The concentration of the test compound that results in half-maximum shift equals the IC₅₀ of the test compound. As a control, a competition curve for Rl 881 ( methyltrienolone) was performed for each assay. Curve Fitting was performed using GraphPad Prism® software from GraphPad™ Software Inc.

Binding data are reported as a single determination if the experiment was run once only and as the average of experiments if the binding experiment was performed two or more times with that compound. Results are set forth in Table 1.

IN VIVO RAT MODEL OF ANDROGEN AND ANABOLIC ACTIVITY-RAT HERSCHBERGER ASSAY

The following is a typical procedure of the in vivo evaluation of the selective androgens of this invention. In particular, this assay looks primarily at the ability of the selective androgens of this invention to increase muscle size in an immature, castrated rat. In addition, androgenic effects are looked at primarily by weighing the prostate and seminal vesicles. Selective compounds will show a greater increase in the levator ani relative to the prostate and seminal vesicles when compared to testosterone treated, castrated animals or to intact animals that have not been treated. Immature Sprague Dawley male rats were obtained Charles River Laboratories (Stoneridge, NY). All animals were maintained in a temperature and humidity controlled room with a 12hr light: 12 hr dark cycle, with ad lib access to food (TD 291615, Teklad, Madison, WI) and water. Rats were anesthetized and orchidectomized (GDX) or sham surgery (SHAM) was performed. After a 7-day recovery period, the animals were randomized according to weight and assigned to treatment groups (n=5), SHAM, OVX + vehicle, OVX + Cpd treated. Testosterone propionate (TP 1 mg/kg in 5% DMSO/95% corn oil) was administered by once daily subcutaneous injections, while the tested compounds of the invention were dosed in vehicle (typically 20% cyclodextrin or 0.5% carboxymethylcellulose) and administered by once daily oral gavage. The rats were then dosed once daily for 4 days. All animals were euthanized via carbon dioxide inhalation 24 hs after the last dose. The prostate, seminal vesicle and levator ani and bulba cavernous (LABC) tissues were removed, weighed and recorded. Body weights were recorded for each animal at baseline and at sacrifice. Results are set forth in Table 2. IN VIVO MODELS OF BONE LOSS AND PREVENTION

Compounds of this invention may also be assayed in vivo to determine their effect on preventing bone loss in animal models of bone loss. Animal models of bone loss are well-known to those of ordinary skill in the art. Examples of bone loss models include the rat and mouse ovariectomized models. Examples of such models are replete in the art, some non-limiting methods and examples are provided in Cesnjaj, et al European Journal of Clinical Chemistry and Clinical Biochemistry (1991), 29(4), 211-219; Y.L. Ma et al., Japanese Journal of Bone and Mineral Research 23 (Suppl.):62-68 (2005); Ornoy, et al, Osteoporosis: Animal Models for the Human Disease; Animal Models of Human Related calcium Metabolic Disorders (1995), 105-126.

COMPOUND CHARACTERIZATION All solvents were commercially available and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (60 F254; EMD Chemicals) which were visualized using ultraviolet light, iodine vapor, or vanillin stain. Flash chromatography was performed on silica gel (230-400 mesh, Silicycle) using commercially available high purity solvents. ¹H and ¹³C NMR spectra were determined in CDCI₃, MeOH-^, DMSO-t/g, or acetone- d(, using either a Varian Unity 400 MHz spectrometer or a Varian Unity 500 MHz spectrometer. Proton chemical shifts (δ) are relative to the residual solvent peaks for each deuterated solvent and expressed in ppm. Coupling constants (J) are expressed in hertz. Mass spectra were obtained on a Waters HQH Quattro II mass spectrometer. All melting points were obtained on a Tottoli melting point apparatus manufactured by Bϋchi and are uncorrected. All hydrazides were either purchased or prepared according to procedures described in the literature. All chemical reagents are commercially available and were used without further purification unless stated otherwise.

Example 1

4-chloro-l-((li?, 2S)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)-2-hydroxypropyl)-

1 H-indole-5-carbonitril

Intermediate 1

To a solution of 2-chloro-4-fluorobenzonitrile (20.0 g, 128.6 mmol) in THF (200 mL) was added LDA (28% wt in THF, 71.0 mL, 142.0 mmol) at -78 ⁰C. After addition, the mixture was stirred at the same temperature for 5 h, and then ethylene oxide (9.7 ml, 194.2 mmol) was added. The reaction mixture was allowed to warm to R. T. gradually and stirred overnight. The reaction was quenched by adding saturated aqueous NH₄Cl solution and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na₂SO₄. After the solvent was removed, the residue was purified by SiO₂ column to give 2-chloro-4-fluoro-3-(2- hydroxyethyl)benzonitrile (17.0 g, 66%). ¹H NMR (400 MHz, CDCl₃, δ in ppm) 7.58 (dd, J = 5.5, 8.6 Hz, IH), 7.10 (t, J= 8.6 Hz, IH), 3.88 (m, 2H), 3.13 (t, J= 6.8 Hz, 2H).

Intermediate 2

To a solution of 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (1.58 g, 7.92 mmol) in CH₂Cl₂ (80 mL) was added DMP (5.39 g, 12.7 mmol) at 0 ⁰C. The mixture was stirred at 0 ⁰C for 2 h and room temperature for overnight. The reaction was quenched by adding saturated aqueous Na₂S₂O₃ (50 mL) and saturated Na₂CO₃ (100 mL) and extracted with EtOAc : Hexanes (1 : 1) (2 x 200 mL). The combined organic layer was washed with saturated aqueous Na₂CO₃ solution, water, brine and dried over Na₂SO₄. Removal of the solvent gave the crude 2-chloro-4-fluoro-3-(2- oxoethyl)benzonitrile as a brown solid (1.6 g), which was used directly for the following reaction. ¹H NMR (400 MHz, CDCl₃, δ in ppm) 9.77 (s, IH), 7.67 (dd, J = 5.6, 8.8 Hz, IH), 7.16 (t, J= 8.8 Hz, IH), 4.02 (s, 3H).

Intermediate 3

To a mixture of 2-chloro-4-fluoro-3-(2-oxoethyl)benzonitrile (0.92 g, 4.7 mmol), D-threonine (0.555 g, 4.7 mmol) and anhydrous methanol (25 mL) was added Et₃N (0.75 mL, 5.4 mmol) at room temperature. The resulted mixture was stirred at room temperature for overnight. After removal of the solvent, the residue was dissolved in EtOAc (300 mL) and washed with acidified water. The EtOAc extracts were concentrated to give a residue, which was purified by SiO₂ column to provide the title compound QR, 3S)-2-(4-chloro-5-cyano-lH-indol-l-yl)-3- hydroxybutanoic acid (0.83 g, 65% yield in two steps). ¹H NMR (400 MHz, Methanol-d₄, δ in ppm) 7.79 (d, J= 3.5 Hz, IH), 7.58 (d, J= 8.4 Hz, IH), 7.44 (d, J = 8.4 Hz, IH), 6.71 (d, J= 3.5 Hz, IH), 5.23 (d, J= 3.9 Hz, IH), 4.72 (m, IH), 1.00 (d, J= 6.4 Hz, 3H).

Intermediate 4

To a mixture of (2R, 35)-2-(4-chloro-5-cyano-lH-indol-l-yl)-3- hydroxybutanoic acid (0.52 g, 1.87 mmol), 4-cyanobenzhydrazide (305 mg, 1.89 mmol), HOBt (256 mg, 1.89 mmol) in THF : DMF (1 : 1) (40 mL) were added EDC (545 mg, 2.84 mmol) and Et₃N (0.45 mL, 3.23 mmol) at 0 ⁰C. The mixture was stirred at 0 ⁰C for 30 min., then room temperature for overnight. The reaction was quenched by adding water and extracted with EtOAc (200 mL). The EtOAc extracts were washed with water, brine and dried over Na₂SO₄. Removal of the solvent and purification of the residue gave the title compound N'-((2i?, 35^)-2-(4-chloro-5- cyano-lH-indol-l-yl)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.51 g, 65%). ¹H NMR (400 MHz, Acetone-d₆, δ in ppm) 8.08 (d, J= 8.6 Hz, 2H), 7.93 (d, J= 8.6 Hz, 2H), 7.92 (d, J= 3.7 Hz, IH), 7.76 (d, J= 8.8 Hz, IH), 7.55 (d, J= 8.8 Hz, IH), 6.75 (d, J = 3.7 Hz, IH), 5.30 (d, J= 7.4 Hz, IH), 4.67 (m, IH), 1.34 (d, J= 6.2 Hz, 3H). Intermediates 5 and 6

TBSCI

Imidazole

To a solution of N'-((2i?, 35)-2-(4-chloro-5-cyano-lH-indol-l-yl)-3- hydroxybutanoyl)-4-cyanobenzohydrazide (0.51 g, 1.21 mmol) in DMF (15 mL) were added imidazole (329 mg, 4.83 mmol) and TBSCl (365 mg, 2.42 mmol) at 0 ⁰C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na₂SO₄. Removal of the solvent gave a residue, which was purified by SiO₂ column to afford N'-((25', 35)-3-(tert-butyldimethylsilyloxy)-2-(4-chloro-5-cyano- 1 H-indol- 1 - yl)butanoyl)-4-cyanobenzohydrazide (58 mg, 9%) and N'-((2i?, 35)-3-(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyano-l H-indol- 1 -yl)butanoyl)-4- cyanobenzohydrazide (300 mg, 46%). N'-((25, 35)-3-(tert-butyldimethylsilyloxy)-2- (4-chloro-5-cyano-l H-indol- l-yl)butanoyl)-4-cyanobenzohydrazide: ¹H NMR (400 MHz, CDCl₃, δ in ppm) 7.91 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.4 Hz, 2H), 7.63 (d, J = 3.3 Hz, IH), 7.32 (d, J= 9.0 Hz, IH), 7.25 (d, J= 9.0 Hz, IH), 6.74 (d, J= 3.3 Hz, IH), 4.87 (d, J= 7.4 Hz, IH), 4.56 (m, IH), 1.08 (d, J= 6.2 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H). N'-((2i?, 35)-3-(tert-butyldimethylsilyloxy)-2-(4-chloro-5- cyano-1 H-indol- l-yl)butanoyl)-4-cyanobenzohydrazide: ¹H NMR (400 MHz, CDCl₃, δ in ppm) 7.90 (d, J= 8.6 Hz, 2H), 7.89 (d, J= 3.3 Hz, IH), 7.81 (d, J= 8.6 Hz, 2H), 7.50 (d, J= 8.6 Hz, IH), 7.33 (d, J= 8.6 Hz, IH), 6.91 (d, J= 3.3 Hz, IH), 5.03 (d, J= 4.5 Hz, IH), 4.82 (m, IH), 1.20 (d, J= 6.2 Hz, 3H), 0.88 (s, 9H), 0.14 (s, 3H), 0.00 (s, 3H). Intermediate 7

To a solution of trinhenylphosphine (293 mg, 1.12 mmol) in DCM (20 mL) was added I₂ (283 mg, 1.12 mmol) at 0 ⁰C. After I₂ was dissolved completely, Et₃N (0.31 mL, 2.23 mmol) was added, followed by a solution of N'-((2i?, 3S)-3-(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyano-lH-indol-l-yl)butanoyl)-4- cyanobenzohydrazide (300 mg, 0.56 mmol) in DCM (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min.. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na₂SO₄. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound \-((\R, 25)-2-(tert- butyldimethylsilyloxy)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4-chloro- lH-indole-5-carbonitrile (250.0 mg, 86%). ¹H NMR (400 MHz, CDCl₃, δ in ppm) 8.46 (d, J= 8.6 Hz, 2H), 8.15 (d, J = 8.6 Hz, 2H), 8.13 (d, J= 3.2 Hz, IH), 7.82 (d, J = 8.6 Hz, IH), 7.76 (d, J= 8.6 Hz, IH), 7.18 (d, J= 3.2 Hz, IH), 6.05 (d, J- 5.9 Hz, IH), 5.15 (m, IH), 1.59 (d, J= 6.0 Hz, 3H), 1.04 (s, 9H), 0.36 (s, 3H), 0.00 (s, 3H). Example 1

4-chloro- 1 -(( 1 R, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2-hydroxypropyl)-

1 H-indole-5-carbonitrile

To a solution of l-((\R, 2S>2-(tert-butyldimethylsilyloxy)-l-(5-(4- cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4-chloro-lH-indole-5-carbonitrile (40 mg, 0.08 mmol) in THF (3 mL) was added 48% aqueous HF solution (2 mL) at 0 ⁰C. The mixture was stirred at R. T. for 2 h. Then, the reaction mixture was poured into saturated aqueous NaHCO₃ solution (100 mL), which was extracted with EtOAc (2 x 70 mL). The combined EtOAc extracts were washed with water, brine and dried over Na₂SO₄. After concentration, the residue was purified by silica gel column to give the title compound 4-chloro-l-((li?, 25)-l-(5-(4-cyanophenyl)-l,3,4- oxadiazol-2-yl)-2-hydroxypropyl)-lH-indole-5-carbonitrile (29 mg, 94%). ¹H NMR (400 MHz, Acetone-de, δ in ppm) 8.21 (d, J= 8.6 Hz, 2H), 8.05 (d, J = 3.4 Hz, IH), 7.99 (d, J= 8.6 Hz, 2H), 7.88 (d, J = 8.4 Hz, IH), 7.58 (d, J= 8.4 Hz, IH), 6.81 (d, J = 3.4 Hz, IH), 6.26 (d, J- 5.3 Hz, IH), 4.98 (m, IH), 1.23 (d, J= 6.4 Hz, 3H).

Intermediate 8

To a solution of triphenylphosphine (78 mg, 0.30 mmol) in DCM (6 mL) was added I₂ (75 mg, 0.30 mmol) at 0 ⁰C. After I₂ was dissolved completely, Et₃N (0.082 mL, 0.59 mmol) was added, followed by a solution of N'-((25', 35)-3-(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyano-lH-indol-l-yl)butanoyl)-4- cyanobenzohydrazide (79 mg, 0.15 mmol) in DCM (3 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 5 min.. The reaction was quenched with saturated sodium thiosulfate (2 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na₂SO₄. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound 1-((I₁S, 25)-2-(tert- butyldimethylsilyloxy)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4-chloro- lH-indole-5-carbonitrile (55.5 mg, 73%). ¹U NMR (400 MHz, CDCl₃, δ in ppm) 8.24 (d, J= 8.6 Hz, 2H), 7.90 (d, J= 8.6 Hz, 2H), 7.76 (d, J= 3.5 Hz, IH), 7.65 (d, J = 8.6 Hz, IH), 7.59 (d, J= 8.6 Hz, IH), 6.90 (d, J= 3.5 Hz, IH), 5.68 (d, J= 8.6 Hz, IH), 4.89 (m, IH), 1.19 (d, J= 6.0 Hz, 3H), 0.83 (s, 9H), 0.18 (s, 3H), 0.00 (s, 3H).

Example 2

4-chloro-l-((15', 2S)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)-2-hydroxypropyl)- lH-indole-5-carbonitrile

To a solution of 1-((1S, 25)-2-(tert-butyldimethylsilyloxy)-l-(5-(4- cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4-chloro-lH-indole-5-carbonitrile (56 mg, 0.11 mmol) in THF (3 mL) and CH₃CN (1 mL) was added 48% aqueous HF solution (3 mL) at 0 ⁰C. The mixture was stirred at room temperature for 2 h. Then, the reaction mixture was poured into saturated aqueous NaHCO₃ solution (100 mL), which was extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with water, brine and dried over Na₂SO₄. After concentration, the residue was purified by silica gel column to give the title compound 4-chloro-l-((lS', 2S)-I- (5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)-2-hydroxypropyl)-lH-indole-5- carbonitrile (43.0 mg, 99%). ¹H NMR (400 MHz, Acetone-d₆, δ in ppm) 8.23 (d, J= 8.6 Hz, 2H), 8.07 (d, J= 3.2 Hz, IH), 7.99 (d, J= 8.6 Hz, 2H), 7.98 (d, J= 8.6 Hz, IH), 7.61 (d, J= 8.6 Hz, IH), 6.82 (d, J= 3.2 Hz, IH), 6.1 1 (d, J= 7.4 Hz, IH), 4.92 (m, IH), 1.24 (d, J= 6.3 Hz, 3H). Example 3 4-chloro- 1 -(( 1 R, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)indoline-5-carbonitrile

Intermediate 9

To a solution of 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (2.96 g, 14.87 mmol) and D-Threonine (2.66 g, 22.31 mmol) in DMSO (30 mL) was added K₂CO₃ (4.11 g, 29.75 mmol) at room temperature. The reaction mixture was heated to 80 ⁰C and maintained for 72 h. After which the reaction mixture was cooled to room temperature, diluted with H₂O (200 mL) and extracted with MTBE (3 x 100 mL). The MTBE extracts were discarded and the aqueous layer was acidified with solid citric acid (15 g). The resulting aqueous solution was extracted with EtOAc (3 x 150 mL) and the combined organic extracts were washed with brine (200 mL), dried (Na₂SO₄), filtered and concentrated to provide a brown oil. The resulting oil was purified by flash chromatography over silica gel (EtOAc :hexanes; 1 :3 then 1 :1 and finally EtOAc) to provide the title compound (3.25 g, 73%): ¹H NMR (400 MHz, Acetone-d₆, δ in ppm) 7.48 (d, J= 8.6 Hz, IH), 6.68 (d, J= 8.6 Hz, IH), 6.15 (d, J= 8.2 Hz, IH), 4.50-4.37 (m, IH), 4.18 (dd, J= 3.1, 8.2 Hz, IH), 3.83 (t, J= 6.7 Hz, 2H), 3.07 (t, J= 6.7 Hz, 2H), 1.31 (d, J= 6.4 Hz, 3H). Intermediate 10

To a vigorously stirred solution of (2R, 3/S)-2-(3-chloro-4-cyano-2-(2- hydroxyethyl)phenylamino)-3-hydroxybutanoic acid (2.7 g, 9.0 mmol) in methanol : toluene (1 : 1) (150 mL) was added (trimethylsilyl)diazomethane (2.0 M in ethyl ether) until the solution turned into yellowish. Then, the mixture was stirred at room temperature for 20 min., After the solvent was removed, the residue was purified by silica gel column to provide (2R, 35)-methyl 2-(3-chloro-4-cyano-2-(2- hydroxyethyl)phenylamino)-3-hydroxybutanoate (1.82 g, 65%). ¹H NMR (400 MHz, Acetone-d₆, δ in ppm) 7.47 (d, J= 8.6 Hz, IH), 6.63 (d, J= 8.6 Hz, IH), 6.18 (d, J= 9.2 Hz, IH), 4.28 (m, IH), 4.22 (dd, J= 2.7, 9.2 Hz, IH), 3.84 (m, 2H), 3.68 (s, 3H), 3.07 (t, J= 6.4 Hz, 2H), 1.29 (d, J= 6.1 Hz, 3H).

Intermediate 1 1

To a solution of (2R, 3<S)-methyl 2-(3-chloro-4-cyano-2-(2- hydroxyethyl)phenylamino)-3-hydroxybutanoate (2.10 g, 6.7 mmol) in THF (110 mL) were added PPh₃ (2.12 g, 8.1 mmol) and DIAD (1.86 mL, 9.1 mmol). The resulting mixture was heated at 70 ⁰C for 6 h. Then, the solvent was removed, the residue was purified by silica gel column to give (2R, 35)-methyl 2-(4-chloro-5- cyanoindolin-l-yl)-3-hydroxybutanoate (1.41 g, 71%). ¹H NMR (400 MHz, CDCl₃, δ in ppm) 7.31 (d, J= 8.2 Hz, IH), 6.27 (d, J= 8.2 Hz, IH), 4.41 (m, IH), 4.01 (d, J = 6.2 Hz, IH), 3.95 (m, IH), 3.74 (m, IH), 3.71 (s, 3H), 3.04-3.13 (m, 2H), 2.52 (b, IH), 1.28 (d, J = 6.2 Hz, 3H). Intermediate 12

To a mixture of (22?, 35)-methyl 2-(4-chloro-5-cyanoindolin-l-yl)-3- hydroxybutanoate (0.64 g, 2.17 mmol) in THF (25 mL) and water (5 mL ) was added 2N LiOH (2.0 mL, 4.0 mmol) at 0 ⁰C. The mixture was stirred at 0 ⁰C for 2 h, then acidified to pH =2-3 with 2N HCl and extracted with EtOAc (200 mL). The EtOAc extracts was washed with water and concentrated to give the crude (22?, 3S)- 2-(4-chloro-5-cyanoindolin-l-yl)-3-hydroxybutanoic acid (0.65 g), which contained about 10-15% epimer at the 2-position and was used directly for the following reactions without further purification. ¹H NMR (400 MHz, Methanol-d^ δ in ppm) 7.37 (d, J= 8.4 Hz, IH), 6.43 (d, J= 8.4 Hz, IH), 4.40 (m, IH), 4.16 (d, J= 6.2 Hz, IH), 3.88-3.90 (m, 2H), 3.02-3.11 (m, 2H), 1.27 (d, J= 6.4 Hz, 3H).

Intermediate 13

To a mixture of (22?, 3S)-2-(4-chloro-5-cyanoindolin-l-yl)-3- hydroxybutanoic acid (0.65 g, 2.17 mmol), 4-cyanobenzhydrazide (350.0 mg, 2.17 mmol), HOBt (294.0 mg, 2.17 mmol) in THF : DMF (1 : 1) (40 mL) were added EDC (626 mg, 3.27 mmol) and Et₃N (0.50 mL, 3.59 mmol) at 0 ⁰C. The mixture was stirred at 0 ⁰C for 30 min., then room temperature for overnight. The reaction was quenched by adding water and extracted with EtOAc (200 mL). The EtOAc extracts were washed with water, brine and dried over Na₂SO₄. After removal of the solvent, the residue was purified by silica gel column washed with 80% EtOAc in hexanes to give the title compound N'-((2i?, 35)-2-(4-chloro-5-cyanoindolin-l-yl)-3- hydroxybutanoyl)-4-cyanobenzohydrazide (0.56 g, 61%). ¹H NMR (400 MHz, Acetone-d_ό, δ in ppm) 8.08 (d, J= 8.4 Hz, 2H), 7.93 (d, J= 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, IH), 6.64 (d, J= 8.4 Hz, IH), 4.40 (m, IH), 4.26 (d, J= 8.2 Hz, IH), 4.02-4.10 (m, 2H), 3.08 (t, J= 9.0 Hz, 2H), 1.34 (d, J = 6.0 Hz, 3H).

Intermediates 14 and 15

TBSCI Imidazole

To a solution of K-((2R, 35)-2-(4-chloro-5-cyanoindolin-l-yl)-3- hydroxybutanoyl)-4-cyanobenzohydrazide (0.55 g, 1.30 mmol) in DMF (15 mL) were added imidazole (260 mg, 3.82 mmol) and TBSCl (390 mg, 2.59 mmol) at 0 ⁰C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na₂SO₄. Removal of the solvent gave a residue, which was purified by SiO₂ column to provide N'-((25^*, 35')-3-(tert-butyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l- yl)butanoyl)-4-cyanobenzohydrazide (110 mg, 16%) and N'-((2Λ, 35)-3-(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l-yl)butanoyl)-4- cyanobenzohydrazide (410 mg, 59%). N'-((25^r, 3S>3-(tert-butyldimethylsilyloxy)-2- (4-chloro-5-cyanoindolin-l-yl)butanoyl)-4-cyanobenzohydrazide: ¹H NMR (400 MHz, CDCl₃, δ in ppm) 9,36 (b, IH), 8.89 (b, IH), 7.83 (d, J= 8.6 Hz, 2H), 7.70 (d, J= 8.6 Hz, 2H), 7.28 (d, J= 8.4 Hz, IH), 6.25 (d, J= 8.4 Hz, IH), 4.34 (m, IH), 3.90 (m, IH), 3.83 (d, J= 7.6 Hz, IH), 3.69 (m, IH), 2.96-3.11 (m, 2H), 1.25 (d, J = 6.2 Hz, 3H), 0.82 (s, 9H), 0.07 (s, 3H), 0.00 (s, 3H). N'-((2/?, 3S)-3-(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l-yl)butanoyl)-4- cyanobenzohydrazide: ¹H NMR (400 MHz, CDCl₃, δ in ppm) 9.09 (b, IH), 8.79 (b, IH), 7.89 (d, J= 8.6 Hz, 2H), 7.75 (d, J= 8.6 Hz, 2H), 7.30 (d, J= 8.2 Hz, IH), 6.27 (d, J= 8.2 Hz, IH), 4.58 (m, IH), 4.12 (d, J= 5.0 Hz, IH ), 3.96 (m, 2H), 3.13 (m, 2H), 1.29 (d, J= 6.2 Hz, 3H), 0.80 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H).

Intermediate 16

To a solution of triphenylphosphine (400 mg, 1.53 mmol) in DCM (20 mL) was added I₂ (387 mg, 1.52 mmol) at 0 ⁰C. After I₂ was dissolved completely, Et₃N (0.43 mL, 3.09 mmol) was added, followed by a solution of N'-((2i?, 3S)-3-(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l-yl)butanoyl)-4- cyanobenzohydrazide (410 mg, 0.76 mmol) in DCM (10 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min.. The reaction was quenched with saturated sodium thiosulfate (5 mL) and diluted with DCM (200 mL). The organic layer was separated and washed with water, brine and dried over Na₂SO₄. After the solvent was removed, the residue was purified by flash chromatography to give the title compound l-((\R, 25)-2-(tert- butyldimethylsilyloxy)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)propyl)-4- chloroindoline-5-carbonitrile (395 mg, -100%). ¹H NMR (400 MHz, CDCl₃, δ in ppm) 8.26 (d, J= 8.2 Hz, 2H), 7.95 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.4 Hz, IH), 6.49 (d, J= 8.4 Hz, IH), 4.98 (d, J= 5.9 Hz, IH ), 4.82 (m, IH), 4.06-4.20 (m, 2H), 3.22-3.31 (m, 2H), 1.48 (d, J= 6.0 Hz, 3H), 0.87 (s, 9H), 0.21 (s, 3H), 0.00 (s, 3H). Example 3

To a solution of 1-((U?, 2S)-2-(tert-butyldimethylsilyloxy)-l-(5-(4- cyanophenyl)-l ,3,4-oxadiazo!-2-yl)propyl)-4-chloroindoline-5-carbonitrile (110 mg, 0.21 mmol) in MeCN (6 niL) was added 48% aqueous HF solution (3 mL) at 0 ⁰C. The mixture was warmed to room temperature and stirred for 2 h. Then, the reaction mixture was poured into saturated aqueous NaHCO₃ solution (100 mL), which was extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with water, brine and dried over Na₂SO₄. After concentration, the residue was purified by silica gel column to give the title compound 4-chloro-l-((li?, 25)- 1 -(5- (4-cyanophenyl)-l,3,4-oxadiazol-2-yl)-2-hydroxypropyl)indoline-5-carbonitrile (84 mg, 99%). ¹H NMR (400 MHz, Acetone-d₆, δ in ppm) 8.21 (d, J= 8.8 Hz, 2H), 7.99 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.4 Hz, IH), 6.76 (d, J= 8.4 Hz, IH), 5.18 (d, J = 7.2 Hz, IH ), 4.70 (m, IH), 4.17 (m, IH), 3.95 (m, IH), 3.12 (t, J= 8.6 Hz, 2H), 1.34 (d, J= 6.2 Hz, 3H).

Intermediate 17

To a solution of triphenylphosphine (108 mg, 0.41 mmol) in DCM (8 mL) was added I₂ (104 mg, 0.41 mmol) at 0 ⁰C. After I₂ was dissolved completely, Et₃N (0.12 mL, 0.86 mmol) was added, followed by a solution of N'-((2S, 35)-3 -(tert- butyldimethylsilyloxy)-2-(4-chloro-5-cyanoindolin-l-yl)butanoyl)-4- cyanobenzohydrazide (1 10 mg, 0.20 mmol) in DCM (4 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 5 min.. The reaction was quenched with saturated sodium thiosulfate (5 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na₂SO₄. After the solvent was removed, the residue was purified by flash chromatography to give the title compound 1-((1(S¹, 25)-2-(tert- butyldimethylsilyloxy)-l-(5-(4-cyanophenyl)-l,3,4-oxadiazol-2-yl)propyl)-4- chloroindoline-5-carbonitrile (100 mg, 96%). ¹H NMR (400 MHz, CDCl₃, δ in ppm) 8.28 (d, J= 8.4 Hz, 2H), 7.97 (d, J- 8.4 Hz, 2H), 7.55 (d, J= 8.2 Hz, IH), 6.70 (d, J = 8.2 Hz, IH), 4.90 (d, J= 9.3 Hz, IH ), 4.72 (m, IH), 4.08 (m, IH), 3.96 (m, IH), 3.26 (m, 2H), 1.55 (d, J= 6.1 Hz, 3H), 0.84 (s, 9H), 0.23 (s, 3H), 0.00 (s, 3H).

Example 4

To a solution of 1-((15, 25)-2-(tert-butyldimethylsilyloxy)-l-(5-(4- cyanophenyl)-l ,3,4-oxadiazol-2-yl)propyl)-4-chloroindoline-5-carbonitrile (90 mg, 0.17 mmol) in MeCN (6 mL) was added 48% aqueous HF solution (3 mL) at 0 ⁰C. The mixture was warmed to room temperature and stirred for 2 h. Then, the reaction mixture was poured into saturated aqueous NaHCO₃ solution (100 mL), which was extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were washed with water, brine and dried over Na₂SO₄. After concentration, the residue was purified by silica gel column to give the title compound 4-chloro-l-((lS, 2S)-I-(S- (4-cyanophenyl)-l,3,4-oxadiazol-2-yl)-2-hydroxypropyl)indoline-5-carbonitrile (62 mg, 89%). ¹H NMR (400 MHz, Acetone-d₆, δ in ppm) 8.20 (d, J= 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.4 Hz, IH), 6.84 (d, J = 8.4 Hz, IH), 5.03 (d, J = 8.6 Hz, IH ), 4.66 (m, IH), 3.99 (m, IH), 3.95 (m, IH), 3.10 (t, J = 8.2 Hz, 2H), 1.44 (d, J= 6.0 Hz, 3H).

The binding data shown in table 1 (below) is from the result of a single or multiple determinations based on the same compound. Where multiple data points have been taken, the value reported is the average of the multiple determinations.

Table 1 Compound AR-Binding Affinity

In vivo activity - Rat Herschberger Assay

In vivo utility of the compounds of this invention may be demonstrated through use of various in vivo animal models including the Herschberger assay. Data from example 4 is shown in Table 2 below:

Table 2 Rat Herschberger Assay

Prostate, seminal vesicle and levator ani bulbus cavernosus (LABC) are all represented as % relative to sham. After sacrifice, organ weights of young, orchidectomized rats treated with compound for 4 days are compared to sham operated animals. Preferred compounds of this invention demonstrate increased levator ani stimulation relative to prostate and/or seminal vesicles

Claims

What is claimed is: 1. A compound according to the formula I

wherein:

R_x is CN, Cl, Br, NO₂ or Rχi ;

R_y is hydrogen, CH₃, CF₃, or halogen;

R_xI is a 5 member heteroaryl, said heteroaryl selected from

R' is hydrogen or optionally Cj-C₂ alkyl, CF₃, or halogen; or R_x and R_y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from'

wherein: each R" is independently hydrogen or optionally CF₃, or Ci-C₂ alkyl;

A is a bond or a 5- or 6- member heteroaryl group wherein said 5- or 6- member heteroaryl is substituted with hydrogen and optionally up to two substituents independently selected from Cj_-3 alkyl, CN, C ₁.₃ haloalkyl or halogen;

B is a phenyl, C_1-6 alkyl, Ci_-6 haloalkyl, 5- or 6-member heteroaryl or bicyclic heteroaryl; each R_a is independently selected from Ci_-4 alkyl (optionally substituted with from 1 -2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(O)OC]_-6 alkyl,

- N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), - N(Rb)C(O)C 1-6 alkyl, - N(R_b)C(O)phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OC]_-3 alkyl),

NR_bR_b', C_1-4 haloalkyl, halogen, OH, OC_1-3 alkyl, OC,.₃ haloalkyl, OC(O)Ci- ₁₂ alkyl, OC(O)phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Cj_-3 alkyl, and OCi_-3 alkyl), OC(O)OC_M2 alkyl, OC(O)Ophenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, C_]-3 alkyl, and OCi_-3 alkyl), OSO₂-phenyl, (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from halogen, Ci_-3 alkyl or Ci_-3 haloalkyl), OSO₃-, OPO₃-, OSO₂NRbR_b-, S(0)o_-2phenyl, and S(O)_0-2C]_-3 alkyl; each R_b and R_b- is independently selected from hydrogen, Ci_-3 alkyl and Ci_-3 haloalkyl; n is O, 1, 2, or 3; n' is O or 1 ; n" is O or 1; Ri, R₂, R5, R₆, R₇ and Rs are each independently selected from hydrogen, Ci_-3 alkyl, Ci_-3 haloalkyl, OR₃ and phenyl;

R₉ is hydrogen, C ₁.₃ alkyl or OR₃; provided that at least one of R₁, R₂, R₅, R₆, R₇, Rs or R9 is OR₃; each R₃ is independently hydrogen, Ci_-4 alkyl, Ci_-4 haloalkyl, C_2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1 -3 substituents independently selected from halogen, C_1-3 alkyl, S(O)_0-2C_1-3 alkyl, S(O)_0-2phenyl, 0-C_1-6 alkyl, OCF₃), C(O)-C_1-10 alkyl, SO₃-, PO₃-, SO₂NR_bR_b' and C(O)phenyl;

D and E are each independently C or N;

Rio and Rn are at each and every occurrence independently selected from hydrogen, C_{1 -3} alkyl, Ci_-3 haloalkyl, CN or halogen; p is O, 1 or 2; q is O, 1 or 2; and

R₄ is H, C i_-4 alkyl or Ci_-4 haloalkyl; or a pharmaceutically acceptable salt thereof. A compound according to formula Ia

Ia wherein:

R_x is CN, Cl, Br, NO₂ or R_xi;

R_y is CH₃, CF₃, or halogen;

R_x] is a 5 member heteroaryl, said heteroaryl selected from

R' is hydrogen, Ci-C₂ alkyl, CF₃, or halogen; or R_x and R_y together with the phenyl group to which they are attached form a 5 member aromatic ring selected from:

^R11

wherein: each R" is independently hydrogen, CF₃, or Ci-C₂ alkyl;

A is a bond or a 5- or 6- member heteroaryl group; each R_a is independently selected from Ci_-4 alkyl (optionally substituted with from 1 -2 substituents independently selected from CN, OH or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(O)OCi_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), - N(Rb)C(O)C i.₆ alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), NR_bR_b>, C_1-4 haloalkyl, halogen, OH, OCi_-3 alkyl, OCi_-3 haloalkyl, OSO₂- phenyl, (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from halogen, Ci_-3 alkyl or Ci_-3 haloalkyl), S(O)_0-2phenyl, OSO₃-, OPO₃-, 0S0₂NR_bR_b', and S(O)_0-2C_1-3 alkyl; each R_b and R_b- is independently selected from hydrogen, Ci_-3 alkyl and Ci_-3 haloalkyl; n is O, 1, 2, or 3; p is O, 1 or 2; q is O, 1 or 2; Ri and R₂ are each independently selected from hydrogen, Ci_-3 alkyl, C i-₃ haloalkyl and phenyl;

R₃ is hydrogen, C₁.₄ alkyl, Ci_-4 haloalkyl, C_2-4 hydroxylalkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from: halogen, C₁.₃ alkyl, S(0)o_-2Ci-₃ alkyl, S(0)o-₂phenyl, 0-C_1-6 alkyl, OCF₃), C(O)-Ci_-6 alkyl and C(O)Phenyl;

D and E are each independently C or N;

Rio and Rn are at each and every occurrence independently selected from hydrogen, Ci_-3 alkyl, Ci_-3 haloalkyl, CN or halogen; and

R₄ is H, C]_-4 alkyl or Ci_-4 haloalkyl; or a pharmaceutically acceptable salt thereof. A compound according to formula Ib or Ic

Ib Ic

wherein:

R_y is hydrogen, CF₃ or Cl; each R_a is independently selected from Ci_-4 alkyl (optionally substituted with from 1 -2 substituents independently selected from CN, OFI or 5 member heteroaryl), 5-member heteroaryl, CN, - N(R_b)C(O)OCj_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Cj_-3 alkyl, and 0C,_-3 alkyl), - N(R_b)C(O)C_-6 alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), NR_bR_b', Ci_₄ haloalkyl, halogen, OH, 0C_!-3 alkyl, OCi_-3 haloalkyl, OSO₃-, OPO₃-, OSO₂NRbRb', S(0)o-2phenyl, and S(O)_0-2C_{1 -3} alkyl; each R_b and R_b' is independently selected from hydrogen, Ci_-3 alkyl and Ci_-3 haloalkyl; n is O, 1, 2, or 3;

Ri and R₂ are each independently selected from hydrogen, Ci_-3 alkyl, Cμ₃ haloalkyl and phenyl;

R₃ is hydrogen, Ci_-4 alkyl, Cm haloalkyl, C_2-4 hydroxylalkyl, benzyl, wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substituents independently selected from: halogen, Ci_-3 alkyl, S(O)_O-2Ci_-3 alkyl, S(O)₀.₂phenyl, 0-Ci_-6 alkyl, OCF₃), Ci_-6 acyl, and benzoyl;

R₄ is H, Ci_-4 alkyl or Ci_-4 haloalkyl;

Rio and Rn are at each and every occurrence independently selected from hydrogen, Ci_-3 alkyl, Ci_-3 haloalkyl, CN or halogen; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3, wherein R_y is CF₃ or Cl.

5. A compound according to claim 3, wherein Rj o and Ri _\ are each independently selected from hydrogen, CH₃ or CF₃.

6. A compound according to claim 3, wherein Ri and R₂ are each independently selected from hydrogen and CH₃.

7. A compound according to claim 3, wherein R₄ is hydrogen.

8. A compound according to claim 3, wherein each R_a is independently selected from 5-member heteroaryl, CN, - N(R_b)C(0)0Ci_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1-3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OCi_-3 alkyl), - N(R_b)C(O)Ci_-6 alkyl, - N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and OC₁-₃ alkyl), Ci_-4 haloalkyl, halogen, OH, Od_-3 alkyl, OCi_-3 haloalkyl and S(O)_0-2Ci_-3 alkyl; R_b and R_b' are each independently selected from hydrogen, Ci_-3 alkyl and Ci- ₃ haloalkyl; and n is O, 1 or 2.

9. A compound according to claim 3, wherein R₃ is hydrogen.

10. A compound according to claim 3, wherein R_y is CF₃ or Cl, Rio and Ri ₁ are each independently selected from hydrogen, CH₃ or CF₃.

1 1. A compound according to claim 3, wherein R_y is CF₃ or Cl, Rj ₀ and R] ₁ are each independently selected from hydrogen, CH₃ or CF₃ and R₄ is hydrogen.

12. A compound according to claim 3, wherein: Ry is CF₃ or Cl, Rio and Rn are each independently selected from hydrogen, CH₃ or

CF₃;

R₄ is hydrogen; and each R_a is independently selected from 5-member heteroaryl, CN, -

N(R_b)C(O)OCi_-6 alkyl, - N(R_b)C(O)OPhenyl (wherein said phenyl is optionally substituted with from 1 -3 substituents independently selected from

CN, halogen, OH, C_1-3 alkyl, and OCi_-3 alkyl), - N(R_b)C(O)Q_-6 alkyl, -

N(R_b)C(O)Phenyl (wherein said phenyl is optionally substituted with from 1- 3 substituents independently selected from CN, halogen, OH, Ci_-3 alkyl, and

OCi_-3 alkyl), Ci_-4 haloalkyl, halogen, OH, OC_1-3 alkyl, 0C_]-3 haloalkyl and

S(O)_0-2Ci_-3 alkyl; each R_b and R_b' is independently selected from hydrogen, C_{1 -3} alkyl and C_1-3 haloalkyl; and n is O, l or 2 or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 12, wherein R₃ is hydrogen.

14. A compound selected from one of the following: a) 4-chloro- 1 -(( 1 R, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)-lH-indole-5-carbonitrile; b) 4-chloro- 1 -(( 1 S, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)-lH-indole-5-carbonitrile; c) 4-chloro- 1 -(( 1 R, 2S)- 1 -(5 -(4-cyanophenyl)- 1 ,3 ,4-oxadiazol-2-yl)-2- hydroxypropyl)indoline-5-carbonitrile; and d) 4-chloro-l-((lS, 2S)- 1 -(5 -(4-cyanophenyl)- 1,3, 4-oxadiazol-2-yl)-2- hydroxypropyl)indoline~5-carbonitrile; or a pharmaceutically acceptable salt of any of the foregoing.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 - 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

16. A method of modulating an androgen receptor in a cell, comprising the administration of a compound according to any one of claims 1-14 or the composition of claim 15, or a pharmaceutically acceptable salt thereof.

17. A method of identifying a compound capable of modulating an androgen receptor comprising contacting a cell expressing an androgen receptor with a compound according to any one of the claims 1-14, and monitoring the effect of the compound on the cell.

18. A method of treating sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, cachexia, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders, Alzheimer's dementia, attention deficit disorder, senile dementia, coronary artery disease, hirsutism, pain, myalgia, myocardial infarction, stroke, clotting disorders, thromboembolisms, congestive heart disorder, low insulin sensitivity, low glucose utilization, high blood sugar, organ transplant, metabolic syndrome, diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, tooth injury, tooth disease, periodontal disease, liver disease, thrombocytopenia, fatty liver conditions, endometriosis, hot flushes, hot flashes, vasomotor disturbance, stress disorders, dwarfism, dyslipidemia, cardiovascular disease, coronary artery disease, renal disease, thin skin disorders, lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn's disease, Paget' s disease, osteoarthritis, connective tissue disease or disorders, injury, burns, trauma, wounds, bone fracture, atherosclerosis, cachexia, cancer cachexia, and obesity in a mammal in need thereof, comprising the administration to said mammal of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 through 14, or a pharmaceutical composition of claim 15.

19. A method of treating prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need thereof, comprising the administration to said mammal of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 through 14, or a pharmaceutical composition of claim 15,

20. The use of a compound according to claims 1-14, or a pharmaceutically acceptable salt thereof, or the composition of claim 15, in the manufacture of a medicament for the treating sarcopenia, frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment, cachexia, muscular dystrophy, weak appetite, low body weight, anorexia nervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting, chronic fatigue syndrome, short stature, low testosterone levels, diminished libido, benign prostate hypertrophy, infertility, erectile dysfunction, vaginal dryness, premenstrual syndrome, postmenopausal symptoms, female hormone replacement therapy, male hormone replacement therapy, depression, Type II diabetes, mood disorders, sleep disorders, memory disorders, neurodegenerative disorders, Alzheimer's dementia, attention deficit disorder, senile dementia, coronary artery disease, hirsutism, pain, myalgia, myocardial infarction, stroke, clotting disorders, thromboembolisms, congestive heart disorder, low insulin sensitivity, low glucose utilization, high blood sugar, hypercholesterolemia, organ transplant, metabolic syndrome, diabetes, glucose intolerance, hyperinsulinemia, insulin resistance, tooth injury, tooth disease, periodontal disease, liver disease, thrombocytopenia, fatty liver conditions, endometriosis, hot flushes, hot flashes, vasomotor disturbance, stress disorders, dwarfism, dyslipidemia, cardiovascular disease, coronary artery disease, renal disease, thin skin disorders, lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn's disease, Paget's disease, osteoarthritis, connective tissue disease or disorders, injury, burns, trauma, wounds, bone fracture, atherosclerosis, cachexia, cancer cachexia, and obesity.

21. The use of a compound according to any one of claims 1 - 14, or a pharmaceutically acceptable salt thereof, or the composition of claim 15, in the manufacture of a medicament for the treating prostate cancer, breast cancer, endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer.