TW200307661A - Multi-substituted selective androgen receptor modulators and methods of use thereof - Google Patents

Abstract

This invention provides androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for (a) male contraception; (b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; (c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; (d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; (e) preventing and/or treating dry eye conditions; (f) oral androgen replacement therapy; and/or (g) decreasing the incidence of, halting or causing a regression of prostate cancer.

Description

(i) (i) 200307661 Description of the invention (The description of the invention should state the technical field, prior art, content, implementation, and drawings of the invention. Brief description of the government's rights and interests. This invention belongs to the National Cancer Institute. , Under the grant certificate number R29 CA0680% granted by the National Institutes of Health, and under the grant certificate number R15 HD35329 awarded by the National Institute of Child Health and Human Development, National Institute of Health Implemented with government support. The government may have certain rights in the invention. TECHNICAL FIELD The present invention relates to an androgen receptor-targeted agent (ARTA), which confirms the antiandrogenic activity of a non-steroidal ligand to the androgen receptor. These medicaments are a novel subgroup of the world's foot compounds, which are selective androgen receptor modulators (SARMs) that can be used for a) male contraception; b) treatment of multiple hormone-related symptoms, such as androgens in aging men Symptoms associated with a decrease in ADAM, c) treatment of symptoms associated with a decline in androgen in women (ADIF); treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or treatment of dry eyes Symptoms; f) Oral androgen replacement therapy; and / or a decrease in the incidence of leg cancer, stopping it or causing it to recover. Pre-A technology Quasi-hormone receptor (AR ") is a ligand-activated transcription-regulating protein that is induced by its sexual development and function in males through its activity with endogenous androgens. Androgens-like sex hormones for men. # Hormones are steroids, which are produced in the body by testes and the adrenal cortex, or can be synthesized in experiments. Androgenic steroids play an important role in many physiological processes, including the development and maintenance of male sexual characteristics, such as: 肉 与 200307661 (2) bone skeletal ridges, sacral growth, spermatogenesis, and male hair (Matsumoto,

Endocrinol Met Clin N Am. 23: 857-75 (1994)). Endogenous steroid androgens include testosterone and dihydrotestosterone (" DHT "). Testosterone is the main steroid secreted by testis' and is the main circulating androgen found in male plasma. Testosterone is 5 alpha in many peripheral tissues. -Reductase is converted to DHT. Therefore, DHT is considered to act as an intracellular mediator for most androgenic effects (zhou et al. Mole. Endocrinol 9: 208-18 (1995)). Others Steroids androgens include esters of fluorenone, such as Cypionate, Propionate, Phenylpropionate, Cyclopentylpropionate, Isohexanoate, Heptanoate and Caprate Esters, and other synthetic androgens, such as 7-methyl-normethylone (" MENT) and its acetate (Sundaram et al., &Quot; 7 α-methyl-normethylone (MENT): male contraceptives The most suitable androgen ", Arm. Med ·, 25: 199-205 (1993) (,, Sxmdaram ,,)). Since AR is involved in male sexual development and function, AR is to achieve male contraception or other hormone replacement Possible targets for the form of therapy. Social alertness of population growth and family planning worldwide has stimulated Most researches on contraception. Contraception is a difficult topic in any case. It is full of cultural and social stigma, religious implication, and most importantly, 'important health concerns. When this topic focuses on This situation will only worsen when men are contraceptive. Despite the effectiveness of appropriate contraceptive devices, historically, 'society has been counting on women to take responsibility for contraceptive decisions and their consequences. Although concerns over sexually transmitted diseases have made men more aware To the need to develop safe and responsible habits, but women are still often the number one choice for contraception. Women have many options, ranging from temporary mechanical devices such as sponges and diaphragms to temporary chemical devices such as spermicide. Women also follow The meaning is more than 200307661

(3) Permanent choices, such as physical devices, including IUDs and cervical caps, and more permanent chemical treatments, such as birth control pills and subcutaneous implants. But the only options available to date for men include condom use and vasectomy. However, condom use is not preferred by many men because of reduced sexual sensitivity, spontaneous disruption of sex, and the significant likelihood of pregnancy due to rupture or misuse. Vasectomy was not recommended either. Right, there are more convenient methods of birth control that can be used by men, especially long-term methods. ”Just before sex, it does not require preparatory activities. This method can significantly increase the possibility that men are more expensive for contraception. In this regard, the administration of male sex steroids (such as fluorenone and its derivatives) has been shown to be particularly promising due to the combined gonadotropin-inhibiting and androgen-substituting properties of these compounds (Steinberger et al. "Sex dosing of fluorenone enanthate, effects on sperm production and plasma acetone, maturation-stimulating hormone, and luteinizing hormone content: possible preliminary assessment of male contraceptives, fertility, and infertility 28: 1320-28 ( 1977)). Chronic administration of high-dose fluorenone will completely abolish sperm production (azoospermia) or reduce it to very low levels (too few sperm). The extent to which sperm production is necessary to produce infertility is not clearly understood. However, a recent report by the World Health Organization has shown that weekly intramuscular injection of fluorenone enanthate results in azoospermia or severe hypospermia (meaning, less than 3 million sperm per ml), and 98% of men treated Cause infertility (Methods and Regulations of Men's Fertility by the Task Force of the World Health Organization, Contraceptive Effects of Azoospermia and Too-Spermia Induced by π 睪 one in Normal Men ", Fertility and Infertility 65: 821-29 (1996) ). A variety of fluorenone esters have been developed which are absorbed more slowly after intramuscular injection 200307661

(4) 'This will cause a greater androgenic effect. The fluorenone enanthate is widely used by these brewers. Although from the viewpoint of establishing the feasibility of hormonal agents for male contraception, fluorenone enanthate is already valuable, but it has several disadvantages, including the necessity of weekly injections, and the superphysiological effects immediately following intramuscular injections. The peak content of fluorenone exists (Wu, "The role of fluorenone enanthate in normal men: experience from the efficacy of multicenter contraceptive studies", fertility and infertility: 626-36 (1996)). Steroid ligands that combine AR and act as androgens (such as acetoenanthionate) or as antiandrogens (such as cyproterone acetate) have been known for many years and are used clinically (Wul988 ). Although nonsteroidal antiandrogens are clinically used for hormone-dependent prostate cancer, nonsteroidal androgens have not been reported. Therefore, research on male contraceptives has focused entirely on steroids. Prostate cancer is one of the most frequently occurring cancers in American men, with hundreds of thousands of novel diseases being diagnosed every year. Unfortunately, more than ten percent of newly diagnosed cases of prostate cancer have been identified pathologically, and they have a cure, and the prognosis of sorrow and sorrow. One way to deal with this problem is to detect prostate cancer early after screening procedures to reduce the number of adenocarcinomas that have progressed in the past Φ > r ^ 0. However, another strategy is to develop a head cancer that prevents the prevention of spleen adenocarcinoma. One-third of all men over the age of 50 have "prostate cancer, which can be activated into a life-threatening form of clinical prostate cancer. The frequency of tumors printed on paper and printed on the glenoid glands has been shown to increase substantially with the life of Λ * soldiers, from 50 years old (5 less 14%) to 90 years old (4〇_80% have Potential forefront 臆 # cancer < number of people, across all cultures, ethnic groups and ethnic groups 200307661 (5)

The same ', but the frequency of clinically strong cancers is significantly different. This suggests that environmental factors can play a role in activating potential prostate cancer. Therefore, the development of treatment and prevention strategies against prostate cancer can have the greatest overall impact on both the medicine and the economy against prostate cancer. Osteoporosis is a systemic skeletal disease characterized by low bone mass and bone tissue degradation, which results in increased bone fragility and susceptibility to fractures. In the United States, this symptom affects more than 25 million people and causes fractures in more than 1-3 million people each year, including vertebrae of 50,000 people, hips of 250,000 people and A wrist fracture occurred in 240,000 people. Hip fractures are the most severe result of osteoporosis, with 5-20% of patients dying within a year and more than 50% of survivors becoming disabled. The elderly are at great risk of osteoporosis, so the problem is expected to increase significantly as the population ages. The incidence of fractures worldwide is predicted to triple in the next 60 years. A study estimates that 45 million people worldwide will have hip fractures by 2050. Women are at greater risk of osteoporosis than men. During the five years following menopause, women experience sharp acceleration of bone loss. Other factors that increase this risk include smoking, alcohol abuse, sedentary lifestyles, and low calcium intake. However, osteoporosis also often occurs in men. It is fully confirmed that the bone mineral density of men will decrease with age. The decrease in bone mineral content and density is related to the reduced bone strength, and 1 is susceptible to fractures. In non-reproductive tissues, the molecular mechanisms underlying the pro-organic effects of sex hormones are only beginning to be understood, but it is clear that the physiological concentrations of androgens and estrogen throughout the life cycle (6) (6) 200307661

In the ring, to maintain the bones and so on, the μ condition ±%, up plays an important role. Therefore, when androgen or estrogen reserve + η soil-culturin loss occurs, there is an increase in the rate of bone reformation, which will cause bismuth to induce you to consume and form < balance skewed to Conducive to wear, it will promote the loss of bone mass, Kelvin. In men, the natural decline in sex hormones during the maturation period (direct decline in androgens, and the lower levels of "estrogens" are derived from the androgen's peripheral aromatization) are accompanied by bone fragility. This effect is also found in men who have had their testicles circumcised. Decreased androgen in aging men (ADAM) refers to a gradual decrease in androgen production, usually in men after middle age. This symptom is characterized by changes in the physical and intellectual range, which are related to the androgen environment, and can be corrected by the manipulation of the androgen environment. ADAM's biochemical characteristics are not only a decrease in serum androgens And it is reduced on other hormones, such as growth hormone, melatonin and exo-androsterone. Clinical phenomena include fatigue, depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, osteopenia <, benign prostatic hyperplasia, anemia, mood and mood Cognitive changes and prostate cancer. Androgen deficiency (ADIF) in women refers to a variety of hormone-related symptoms, including those commonly seen in women after middle age. This symptom is characterized by sexual dysfunction, hyposexuality, hypogonadism, oligosarcoma, osteoporosis, osteoporosis, cognitive and mood changes, anemia, depression, hair loss, obesity, endometrium Ectopic tissue formation, breast cancer, uterine cancer and ovarian cancer. Muscle exhaustion refers to a progressive loss of muscle mass and / or a progressive loss of muscle 200307661

(7) Weakness and degeneration 'include skeletal or voluntary muscles that control movement, myocardium that controls the heart (cardiomyopathy), and smooth muscles. Chronic muscle wasting is a chronic condition (that is, lasting for a long time) and is characterized by a progressive loss of muscle mass, weakening and degeneration of muscle. Muscle mass loss' that occurs during muscle wasting can be characterized by muscle protein breakdown or degradation. The occurrence of protein degradation is due to an unusually high rate of protein degradation, an unusually low rate of protein synthesis' or a combination of both. Protein degradation, whether caused by a high degree of protein degradation or a low degree of protein synthesis, can lead to a decrease in muscle mass and muscle consumption. Muscle wasting is accompanied by a chronic, neuropathic, transmission, or infectious pathological disease, disorder, or condition. It includes muscular dystrophy, such as Duchenne muscular dystrophy and myotonic dystrophy, muscular atrophy, such as gray matter post muscular atrophy (PPMA); cachexia, such as cardiac cachexia, AIDS cachexia, and cancer cachexia, malnutrition, leprosy, diabetes, kidney disease , Chronic obstructive pulmonary disease (Copd), cancer, end-stage renal failure, emphysema, osteomalacia, HIV infection, AIDS, and cardiomyopathy. In addition, other conditions and symptoms are linked to and may cause muscle wasting. It includes lower back pain, progressive aging, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, burns, and when the limbs are Disuses for conditioning during fixation, long-term hospitalization due to illness or injury, and alcoholism. If muscle exhaustion remains undiminished, it can have dire health effects. For example, changes that occur during muscle depletion may lead to a weakened state of the body, which is harmful to the health of the individual, causing increased susceptibility to infection, and poor performance 200307661

(8) State and susceptibility to damage. Both basic science and clinical levels need new and innovative research approaches to develop compounds that can be used for a) male contraception; b) treatment of multiple hormone-related symptoms, such as androgen decline in aging men (ADAM ) Related symptoms, such as fatigue, depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, oligosomyopathy, osteoporosis, osteoporosis, benign Benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; c) treatment of symptoms associated with ADIF, such as sexual dysfunction, hyposexuality, hypogonadism, oligosarcoma, osteoporosis, osteoporosis, cognition Changes in strength and mood, depression, anemia, hair loss, obesity, endometrial tissue formation, breast cancer, uterine cancer and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e ) Prevent and / or treat dry eye symptoms; f) oral androgen replacement therapy; and / or g) reduce the incidence of prostate cancer and stop or cause it Its recovery. SUMMARY OF THE INVENTION In a specific embodiment, the present invention provides an androgen receptor-targeted agent (ARTA). This agent defines a novel subgroup of compounds that are selective androgen receptor modulators (SARMs). Several secondary compounds have been found to have surprising androgenic and anabolic activity of androgen receptors by non-steroidal ligands. 6 found that other SARM compounds have non-steroidal ligands for androgenic + # "〃 素 又 姐 <surprising anti-androgenic activity. SARM chemotherapy can be used for a) male contraception; b) treatment of a variety of hormone-related symptoms J ^ Strength in `` androgen decline (9) (9) 200307661

(= DAM) I-related symptoms, such as fatigue, depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, oligosomyopathy, #quality deficiency , Osteoporosis, benign disease, glandular enlargement, changes in mood and cognition, and prostate cancer; 0 treatment of symptoms associated with androgen decline in women (ADIF), such as sexual dysfunction, sexual desire Decrease, hypogonadism, oligosarcoma, osteopenia, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity, endometrial tissue formation, breast cancer, uterine cancer and ovaries Cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms, e) prevention and / or treatment of dry eye symptoms; o oral androgen replacement therapy 'and / or g) reduce the incidence of prostate cancer, making it Stop or cause it to recover. In a specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I:

Where X is a bond, 0, CH2, NH, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR;

R is alkyl, salkyl, di || alkyl, tri-1,2-alkyl, CH2F chf2, cf3, cf2cf3; aryl, phenyl, halogen, alkenyl, or oh; 1 is CH3, CH2F, chf2, CF3 , CH2CH3 or CF2CF3; 200307661

R2 is F, α, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure:

Z is N02, CN, COR, COOH or CONHR; Y is CF3, F, Bi *, Cl, I, CN or SnR3; Q is fluorene, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, SO5R, SR; or Q and the benzene ring connected to it are a fused ring System, represented by structure A, B or C:

n is an integer of 1-4; and m is an integer of 1-3. In another specific embodiment, the present invention provides analogs, derivatives, isomers, metabolites, pharmaceutically acceptable (11) (11) 200307661 salts, hydrates or N-oxidation of compounds of formula I Or any combination thereof. ^ In a specific embodiment, X in compound J is 0. In another specific embodiment, compounds! In C ^ O. In another embodiment: in the specific embodiment of the stomach, Z in Compound I is No. 02. In another embodiment, Z in compound J is CN. In another embodiment, γ in Compound! Is%. : In a wide range of specific examples, Q4nhcocH3 in Compound !. In another specific embodiment, (^ is! ^ In compound). In another specific embodiment, T is 0H in compound !. In another specific embodiment; R1 is CHS. In another embodiment, Q in compound I is F, and R2 is CH3. In another embodiment, Q in compound J is F, and 112 is α. In a specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula π:

Π where P is an integer of 2-5, and the remaining substituents are as defined above for compound J. In a specific embodiment, p is 5. In another specific embodiment, the present invention provides analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, hydrates or N-oxides or any combination thereof, of a compound of formula II. In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula V: 200307661 (12)

Where R2 is F, Cl, Br, I, CH3, CF3, OH, CN, No2, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure:

R is alkyl, i-alkyl, dihaloalkyl, tridentyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl, or OH; Z is No2, CN, COR, COOH or CONHR; Y is CF3, F, Br, Cl, I, CN or SnR3; Q is H, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR , CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring to which it is connected is a fused ring system with structure A, 200307661

B or C means:

n is an integer of 1-4; and m is an integer of 1-3. In another embodiment, the present invention provides analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, hydrates or N-oxides or any combination thereof of a compound of formula V. In another embodiment, z in compound v is No. In another embodiment, z in compound V is CN. In another specific embodiment, Y in 'compound V is CF3. In another embodiment, Q in compound V is NHCOCH3. In another embodiment, the compound is F, and &amp; is CH3. In another embodiment, Q in compound v is F, and r2 is C1. In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the formula:

Where P * is the definition of the integer V of 1-4. In one term &lt; positive, and the remaining substituents are as described above for a specific embodiment of the compound, p is 5. (14) 200307661 In another specific embodiment, the analog t invention provides a compound of formula VI or the like

In a specific embodiment, SARM is represented by the following structure:

In another specific embodiment, SARM is represented by the following structure

In another specific embodiment, SARM is represented by the following structure

The compound is an androgen receptor antagonist. In another embodiment, any SARM compound of Formula I-VI irreversibly binds to an androgen receptor. In another embodiment, 'any SARM compound of formula I-VI is reversibly bound to the androgen receptor. In a specific embodiment, the present invention provides a composition comprising the selective androgen receptor modulator compound of the present invention and its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable Sleep, pharmaceutical products, hydrates or N-oxides or any combination thereof. In another embodiment, the present invention provides a pharmaceutical composition-21- (15) 200307661, which comprises the selective androgen analog, derivative, isomer hydrate or N-oxide of the present invention. Or in any other specific embodiment, the androgen receptor modulator compound to the next step, the androgen receptor and the compound and / or its analogs, substances, pharmaceutically acceptable salts, medical Any combination thereof may be contacted in an amount that can have a compound to the androgen receptor. In another embodiment, a method for spermatogenesis comprises the production of selective androgen receptor modulators, isomers, metabolites, hydrates or N-oxides, or spermatozoa. In another specific embodiment, a method of intermediate contraception, which includes the following selective androgen receptor modulators, isomers, metabolites, hydrates, or N-oxides or any of their sperm, In order to achieve disease in another specific embodiment, the method includes the steps of using a hormone receptor modulator compound and / or, a metabolite, a medicinal product, a combination; and an appropriate carrier or diluent. The present invention provides a method for binding a selective androgen receptor, which comprises a selective androgen receptor modulating derivative, an isomer, a metabolic medicinal product, a hydrate or an N-oxide or a potent binding selection with the invention. Sexual Androgen Receptor Modulation The present invention provides a method for inhibiting a patient's androgen receptor in contact with a compound of the present invention and / or its analog, a derivative, a pharmaceutically acceptable salt, or any combination of medicinal products. The amount is effective for inhibiting the present invention to provide a method for administering the compound of the present invention and / or its analogs, derivatives, pharmaceutically acceptable salts, and pharmaceutical products to male patients. Can effectively inhibit contraception in patients. The present invention provides an androgen receptor for any hormone treated patient and any

(16) Selective androgen receptor modulator compounds and / or their analogs, derivatives, isomers, metabolism products, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or In any combination, the amount is effective · Achieve changes in androgen-dependent symptoms. In another specific embodiment, the present invention provides a method of hormone replacement therapy, which includes the following steps, the patient's androgen receptor and the present invention and a selective androgen receptor modulator compound and / or Its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical beta products, hydrates or N-oxides or any combination thereof are contacted in amounts effective to achieve androgen-dependent symptoms The change. In another specific embodiment, the present invention provides a method for treating a patient with hormone-related symptoms, comprising the steps of administering to the patient a selective androgen receptor modulator compound of the present invention and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable positions, medicinal products, hydrates or N-oxides, or any of their crude forms, in amounts effective to achieve androgen-dependent symptoms Variety. _ In another embodiment, the present invention provides a method for treating a patient with prostate cancer, which includes the steps of administering to the patient a selective androgen receptor modulator compound of the present invention and / Or its analogs, derivatives, isomers, metabolism products, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat the prostate cancer. In another specific embodiment, the present invention provides a method for preventing prostate cancer in a patient, which comprises the following steps: administering the disease to the patient (17) 200307661

Ming's selection of organisms, foreign products, and water is effective in preventing the disease of another adenocarcinoma, and the amount of the disease and / or its acceptable combination is the disease of another adenocarcinoma. Conjugation, the amount of which is in the course of another adenocarcinoma, the substance and / or the scientifically acceptable combination, and the neutral androgen dimorphin modulator compound and / or its analogue, structure in another patient , Metabolites, pharmaceutically acceptable: compounds or N-oxides or any combination thereof, the amount of which can be in the disease of prostate cancer. ^ Item t. The present invention provides a method for delaying the progression of prostate cancer in patients with prostatic diseases, which comprises the steps of administering the selective androgen receptor modulator compound analogs and derivatives of the invention , Isomers, metabolites, pharmacological salts, medicinal products, hydrates or N_oxides or any group thereof can effectively delay the progression of prostate cancer in patients. In a specific embodiment, the present invention provides a method for preventing the recurrence of prostatic adenocarcinoma in patients with prostatic disease, which comprises the step of administering to the patient the selective androgen receptor modulator of the present invention and combining the analog thereof. , Derivatives, isomers, metabolites, medicinal salts, medicinal products, hydrates or oxides, or any group thereof, can effectively prevent the recurrence of prostate cancer in patients. In a specific embodiment, the present invention provides a method for treating recurrence of prostate cancer in a patient suffering from a forefront, which comprises the step of administering to the patient the selective androgen receptor modulator of the present invention, combining an analog thereof, and derivatizing the same. Substances, isomers, metabolites, medicated salts, medicinal products, hydrates or N-oxides or any amount thereof can effectively treat the recurrence of prostate cancer in a patient. In a specific embodiment, the present invention provides a method for treating dry eye symptoms in a patient with dry eye, comprising the steps of treating the disease -94. (18) (18) 200307661

Suffer from administration of a selective androgen receptor modulator compound and / or its analogs, derivatives, isomers' metabolites, pharmaceutically acceptable, salts, pharmaceutical products, hydrates, or N • oxides Or any combination thereof in an amount effective to treat dry eye in a patient. In another specific embodiment, the present invention provides a method for preventing dry eye symptoms in a patient, which includes the steps of administering to the patient a selective androgen receptor modulator compound of the present invention and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent dry eyes in patients. · In another embodiment, the present invention provides a method for preparing a selective androgen-receptor modulator (SARM) compound, which is represented by the structure of Formula I:

Where X is 〇, NH, S, Se, PR, or NR; G is 〇 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkynyl, i-alkynyl, two-halfyl, three-halfyl , CH2 F, chf2, cf3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; ~ CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; 200307661

R2 is F, α, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br , I, CN, N02, COR, COOH, CONHR, CF3, SnR3 'or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure:

Z is No2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is fluorene, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO? CH3, NHS02R, OH, OR, COR, OCOR, 0S02R, S02rSR; or Q and the benzene ring to which it is connected is a fused Ring system, represented by structure A, B or C:

η is an integer of 1-4; and m is an integer of 1-3; This method includes the following steps to make a compound of formula VII: 200307661 (20)

Where Z, Y, G, R !, T, R3 and m are as defined above, and L is a releasing group, which is coupled with a compound of formula VIII:

Wherein Q, X, R2 &amp; n are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula VII is prepared in the following manner: a) The compound of formula IX is prepared by the ring-opening action of a cyclic compound of formula X

G

Rfy X IX. Where L, Ri, G and T are as defined above and Ti is 0 or NH; and b) make the amine of formula XI:

-01 _ 200307661

(21) wherein z, γ, R3 and m are as defined above, and react with a compound of formula IX in the presence of a coupling reagent to produce a compound of formula VII.

In a specific embodiment, step XI is performed in the presence of HBr. In another specific embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. The novel selective androgen receptor modulator compound of the present invention, whether alone or as a pharmaceutical composition, can be used for a) male contraception; b) treatment of a variety of hormone-related symptoms, such as symptoms associated with ADAM, such as fatigue, Depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, oligosarcoma, bone deficiency, benign prostatic hyperplasia, and changes in mood and cognition; c) treatment Symptoms associated with ADIF, such as sexual dysfunction, hyposexuality, hypogonadism, sarcopenia, osteoporosis, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity, uterus Endometriosis, breast, uterine and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or treatment of dry eye symptoms; f) oral androgen replacement therapy; And / or g) reduce the incidence of prostate cancer, stop it or cause it to recover. -28- (22) 200307661

The steroids androgen receptor receptor modulators of the present invention lack the and other advantages of androgen and inconvenient administration of androgen receptor androgen receptor modulators. In a specific agent (ARTA) &lt; Selective androgen has non-steroidal metabolic activity. The body androgen is affected by symptoms related to androgen alone, or related to hormones, erectile dysfunction, anemia, obesity, hyperplasia of obesity, androgen disorders in women, and libido androgenic androgen receptor modulation paint. Compounds provide important advances in overcoming therapies, because the present invention &lt; selective androgen compounds have been described in the method &amp; θ ', androgen and synthetic partners with non-steroidal ligands Also, industrial wind metabolic activity. Therefore, selective dosing compounds have non-facet-like cheek ligands that are subject to anabolic activity against androgens, and are not prepared for war and are not accompanied by severe side effects, patterns or high costs. With oral bioavailability, cross-reactivity of sterol receptors, and long biological half-life inventions, the invention provides androgen receptors as the target. This agent is a novel subgroup of defined compounds, which It is a receptor modulator (SARM). Several SARM compounds have been found to have surprising androgen synergy with androgen receptors. Other SARM compounds have been found to have surprisingly androgenic activity with non-steroidal ligands. SARM compound is used as a composition, T is used for a) male contraception; b) treatment of multiple symptoms, such as constipation and redness in aging men τ &lt; androgen decline (ADAM) 'such as fatigue, depression, sexual decline, sexual decline Dysfunction, hypogonadism, osteoporosis, osteoporosis, hair loss, hair loss, oligosarcoma, osteoporosis, temporary bone loss ^ _ Dan for osteoporosis, benign heart and changes in cognition And poorly treated adenocarcinoma; c) treatment of hormonal decline (ADIF) is associated with # & I, P &lt; 痖, such as hypogonadism, hypogonadism, oligomuscular #, & ^ prostitute, bone Lack, bone 200307661

(23) osteoporosis, cognitive and mood changes, ginseng suppression, anemia, hair loss, obesity, endometrial tissue formation, breast cancer, uterine cancer and ovarian cancer; d) treatment and / or prevention Symptoms of acute and / or chronic muscle wasting; e) prevention and / or treatment of dry eye symptoms; o oral androgen replacement therapy; and / or g) reducing the incidence of prostate cancer, stopping it or causing it to recover. In a specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I:

Where X is a bond, 0, CH2, NH, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, bidentane Group, trisalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, functional element, fluorenyl or OH; CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, a, Br , I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 forms a fused ring system with the benzene ring to which it is connected, and is represented by the following structure: 200307661

Z is N02, CN, COR, COOH or CONHR;

Y is CF3, F, Br, Cl, I, CN or SnR3; Q is H, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3 , NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring to which it is connected is a fused ring system, represented by the structure A, B or C:

η is an integer of 1-4, and m is an integer of 1-3. In a specific embodiment, the invention provides analogs of a compound of formula I. In another embodiment, the invention provides derivatives of compounds of formula I. In another embodiment, the present invention provides an isomer of a compound of formula I. In another embodiment, the present invention provides a metabolic product of a compound of formula I. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of Formula I. In another embodiment, the invention provides a pharmaceutical product of a compound of formula I. In another embodiment, the present invention provides a hydrate of a compound of formula I. On 2003200361

(25) In a specific embodiment, the present invention provides an N-oxide of a compound of formula I. In another embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide combination of a compound of formula . In a specific embodiment, the present invention provides a compound of formula I, wherein X is 0. In another specific embodiment, the present invention provides a compound of formula I, wherein G is 0. In another embodiment, the present invention provides a compound of formula I, wherein Z is N02. In another embodiment, the invention provides a compound of formula I, wherein Z is CN. In another embodiment, the present invention provides a compound of formula I, wherein Y is CF3. In another embodiment, Q is NHCOCH3. In another embodiment, the invention provides a compound of formula I, wherein Q is F. In another embodiment, the present invention provides a compound of formula I, wherein T is OH. In another embodiment, the present invention provides a compound of formula I, wherein &amp; is CH3. In another specific embodiment, the present invention provides a compound of formula I, wherein Q is F and R2 is ch3. In another embodiment, the present invention provides a compound of formula I, wherein Q is F and R2 is C1. The substituents Z, Y, and R3 may be at any position on the ring bearing these substituents (hereinafter referred to as the "A ring"). In a specific embodiment, the substituent Z is in the para position of the A ring. In another embodiment, the substituent Y is in the position between the A ring. In another embodiment, the substituent Z is in the para position of the A ring, and the substituent Y is in the inter position of the A ring. The substituents Q and R2 may be in any position on the ring with these substituents (hereinafter referred to as &quot; B ring "). In a specific embodiment, the substituent Q is on the B ring 200307661

(26) in opposition. In another embodiment, the substituent Q is in the ____ para position. In another specific embodiment, the substituent Q is NJJCOCH3, and is in the para position of the B ring. As intended to be included herein, when the integers 111 and 11 are greater than one, the substituents and &amp; are not limited to one particular substituent, and may be any combination of the substituents listed above. In the embodiment of the gastric λ body, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the formula:

(F) P, where p is an integer of 2-5, H and the other substituents are as defined above for compound I.

In a specific embodiment, Taishuangnn L The present invention provides a compound of formula II, wherein p is 2. In a specific embodiment, the present invention provides a compound of formula II, wherein p is 3. In a specific example, a, I, the present invention provides a compound of formula II, where p is 4. In a spirit of excitement

In the embodiment, the present invention provides a compound of formula II, wherein ρ is 5. In one embodiment, the invention provides analogs of the compound of formula II; in another embodiment of the invention, the invention provides compounds of the formula engineering compound

derivative.彡 In another embodiment, the present invention provides isomers of compounds of formula II. In another—item ~ IL

^ In the examples, the present invention provides Formula II

Metabolites of compounds. In another _ 3 ^. Y.,. ^ 0EI and another specific embodiment, the present invention 200307661 (27) provides a pharmaceutically acceptable salt of a compound of formula II. In another embodiment, the invention provides a pharmaceutical product of a compound of formula II. In another embodiment, the present invention provides a hydrate of a compound of formula II. In another embodiment, the present invention provides an N-oxide of a compound of Formula II. In another embodiment, the invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, medicinal product, hydrate, or N-oxide combination of a compound of Formula II . In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, represented by the structure of formula III:

ΙΠ where X is a bond, 0, CH2, NH, Se, PR, NO, or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihalo Alkyl, trihalo, CH2 F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl or OH; CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, C Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR;

R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR 200307661

(28), CF3, SnR3, or R3 together with the benzene ring to which they are attached form a fused ring system, which is represented by the following structure:

Z is No2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is fluorene, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02 CH3, NHS02R, OH, OR, COR, OCOR, 0S02R, S02R, SR; or Q and the benzene ring connected to it are a thick Closed loop system, represented by structure A, B or C:

A B

n is an integer of 1-4; and m is an integer of 1-3. In a specific embodiment, the invention provides analogs of compounds of formula III. In another embodiment, the invention provides derivatives of compounds of formula III. In another embodiment, the present invention provides an isomer of a compound of formula III. In another embodiment, the present invention provides a metabolic product of a compound of formula III. In another specific embodiment, the present invention is 200307661

(29) is a pharmaceutically acceptable salt that provides a compound of formula III. In another embodiment, the invention provides a pharmaceutical product of a compound of formula III. In another embodiment, the present invention provides a hydrate of a compound of formula III. In another embodiment, the present invention provides an N-oxide of a compound of formula III. In another specific embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide combination of a compound of Formula III . In a specific embodiment, the present invention provides a compound of formula III, wherein X is 0. In another embodiment, the present invention provides a compound of formula m wherein G is 0. In another specific embodiment, the present invention provides a compound in which z is NO2i. In another embodiment, the present invention provides a compound of formula III wherein 2 is CN. In another embodiment, the present invention provides a compound of formula M wherein Y is CF3. In another embodiment, the present invention provides a compound of formula III wherein Q is NHCOCH3. In another embodiment, Q is F. In another embodiment, the present invention provides a compound of formula m with τ being 0H. In another embodiment, the present invention provides a compound of formula III &amp; is Ch3. In another specific embodiment, 9 is? And R2 * ch3. In another embodiment, the present invention provides a compound of formula III wherein 9 is F and &amp; is α.糸 In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula IV.

200307661 (30) where p 'is 1-4 &lt; integer &quot; and the remaining substituents are as defined above for compound m. -In a specific embodiment, the present invention provides a compound of formula IV, wherein p is 1. In a specific embodiment, the present invention provides a compound of formula IV, wherein P 'is 2. In a specific embodiment, the present invention provides a compound of formula jy 'wherein P1 is 3. In a specific embodiment, the present invention provides a compound of formula IV, wherein p 'is 4. | In a specific embodiment, the present invention is provided! Analogs of compound V. In another embodiment, the invention provides derivatives of compounds of formula IV. In another embodiment, the present invention provides a compound of formula IV.

Isomers of things. In another specific embodiment, the present invention is provided! V. Metabolites of compounds. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of Formula IV. In another embodiment, the invention provides a pharmaceutical product of a compound of formula IV. In another embodiment, the present invention provides a hydrate of a compound of formula IV. In another embodiment, the present invention provides an N-oxide I of a compound of formula IV. In another embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide combination of a compound of Formula IV . In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula V:

-T7- 200307661

(31) where R2 is F, α, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR x NR2 'SR &gt; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, S11R3 'or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure:

YYR is alkyl, alkyl, dialkyl, trialkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl or OH; Z is N02, CN, COR, COOH or CONHR ; Y is CF3, F, Br, Cl, I, CN or SnR3-; Q is H, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR , NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, 〇〇〇2r, S02R, SR; or Q and the benzene ring to which it is connected as a fused ring system, with structure A, B or C means:

(32) (32) 200307661 n is an integer from 1-4; and m is an integer from 1-3. In one embodiment, the invention provides analogs of a compound of formula v. In another embodiment, the invention provides derivatives of compounds of formula vt. In another embodiment, the present invention provides an isomer of a compound of formula V. #In another specific embodiment, the present invention provides a metabolic product of a compound of formula V. In another embodiment, the invention provides a pharmaceutically acceptable salt of a compound of formula V. In another specific embodiment, the invention provides a pharmaceutical product of a compound of formula v. In another embodiment, the present invention provides a hydrate of a compound of formula (I). In another embodiment, the present invention provides N-oxides of compounds of formula V. In another embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, medicinal product, hydrate or N_oxide combination of a compound of formula V . In another embodiment, the present invention provides a compound of formula V, wherein Z is No. In another embodiment, the present invention provides a compound of formula V, wherein Z is CN. In another embodiment, the present invention provides a compound of formula V, wherein γ is eh. In another specific embodiment / the present invention provides a compound of formula V, wherein (^ is nhcqcH3. In another specific embodiment, the present invention provides a compound of formula V, wherein 卩 is 17. In an embodiment, the present invention provides a compound of formula v, wherein 卩 is 1 ?, and &amp; is 0¾. In another specific embodiment, the present invention provides a compound of formula v, wherein Q is F, and &amp; is C1. In another specific embodiment, the present invention provides a selective male stimulation 200307661

(33) A compound of a receptor receptor modulator (SARM), represented by the formula VI structure ...

Where pf is an integer from 1 to 4 and the remaining substituents are as defined above for compound V. In a specific embodiment, the present invention provides a compound of formula VI, wherein P * is 1. In a specific embodiment, the present invention provides a compound of formula VI, wherein p 'is 2. In a specific embodiment, the present invention provides a compound of formula VI, wherein "is 3. In a specific embodiment, the present invention provides a compound of formula VI, wherein p 'is 4. In a specific embodiment, The present invention provides analogs of compounds of formula VI. In another specific embodiment, the present invention provides derivatives of compounds of formula VI. In another specific embodiment, the present invention provides differences in compounds of formula VI In another embodiment, the present invention provides a metabolic product of a compound of formula VI. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula VI. In another embodiment, In one embodiment, the present invention provides a pharmaceutical product of a compound of Formula VI. In another embodiment, the present invention provides a hydrate of a compound of Formula VI. In another embodiment, the present invention provides N-oxide of a compound of formula VI. In another embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt of a compound of formula VI A combination of a pharmaceutical product, a hydrate, or an N-oxide. In one embodiment, the SARM compound is any compound of formula i-vi 200307661 (34), where Han 2 is F. In another embodiment, A SARM compound is any compound of formula I vi 'where &amp; is a. In a specific embodiment, the s compound is any compound of formula IΛα, where &amp; is 玢. In a specific embodiment, the SARM compound is any formula ] [_ VI compound, where &amp; is I. In another specific embodiment, the SARM compound is any compound of formula μνι, where R2 is CH3. In another specific embodiment, the SARM compound is any formula I-VI In another embodiment, the SARM compound is any compound of formula I-VI, wherein &amp; is ο. In another embodiment, the SARM compound is any formula i -vi compound, wherein r2 is 0H. In another specific embodiment, the SARM compound is any of the formula IΛαα ', where is CN ^ In another specific embodiment, the jgARM compound is any compound of formula I-VI Where &amp; is No. 02. In another specific embodiment, the 'SARM compound is any compound of Formula I-VI, which is NHCOCH3. In another specific embodiment, the SARM compound is any compound of Formula i_VI, wherein R2 is NHCOCF3. In another specific implementation In the example, the 3-compound is any compound of formula I-VI, wherein R2 is NHCOR. In another specific embodiment, the SARM compound is any compound of formula I-VI, wherein r2 is a aryl group. In another specific implementation In the example, the SARM compound is any of the compounds of formula IΛ ′, where Chi 2 is a aryl group. In another specific embodiment, the s arm compound is any compound of Formula I-VI, wherein R2 is OR. In another specific embodiment, the SARM compound is any compound of Formula I-VI, wherein r2 is nh2. In another specific embodiment, the SARM compound is a compound of any formula, wherein &amp; is NHR. In another specific embodiment, the SARM compound is any compound of Formula I-VI, wherein &amp; is NR ?. In another embodiment, 200307661 (35) &apos; SARM compound is any compound of Formula I-VI, wherein r2 is SR. In a specific embodiment, the SARM compound is any compound of Formula IΛα, wherein &amp; is F. In another specific embodiment, the SARM compound is any compound of formula ι-νι, wherein% is α. In another specific embodiment, the sarm compound is any compound of Formula I_VI, wherein% is Br. In another specific embodiment, the 'SARM compound is any compound of formula i-vi, wherein &amp; is I. In another embodiment, the SARM compound is any compound of Formula I-VI, wherein &amp; is CN. In another specific embodiment, the sARM compound is any compound of formula ι-νι, and its center is No 2. In another specific embodiment, the SARM compound is any compound of formula IΛα, wherein% is COR. In another embodiment, the SARM compound is any compound of formula IΛα, wherein R3 is COOH. In another embodiment of the sulfonic acid, the sarm compound is any compound of Formula VI, where is CONHR. In another embodiment, the SARM compound is any compound of Formula I-VI, wherein &amp; is cf3. In another specific embodiment, the SARM compound is any compound of Formula IΛΊ, and its center is SnR3. In another specific embodiment, the SARM compound is a compound of any formula, wherein Rs forms a compound together with the benzene ring to which it is attached, and is represented by the following structure:

In a specific embodiment, the SARM compound is any compound of Formula IΛα where m is 1. In another embodiment, the compound is Ren 200307661

(36) A compound of formula I-VI, wherein m is 2. In another specific embodiment, the sarm compound is any compound of Formula I-VI, where m is 3. In a specific embodiment, the 'SARM compound is any compound of Formula I-Vi, wherein n is 1. In another embodiment, the SARM compound is any compound of Formula I-Vi, wherein n is 2. In another specific embodiment, the sarm compound is any compound of formula I_VI, where n is 3. In another embodiment, the compound is a compound of any formula, wherein n is 4. In another specific embodiment, SARM is represented by the following structure

In another specific embodiment, SARM is represented by the following structure

In another specific embodiment, SARM is represented by the following structure

The substituent R is defined herein as alkyl, haloalkyl, dihaloalkyl, dihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, fluorenyl, or hydroxyl (OH) . π alkyl refers to saturated aliphatic hydrocarbons, including straight chain, branched chain and cycloalkyl. In a specific embodiment, the alkyl group has 1-12 carbons. In another embodiment, the &apos; alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another specific embodiment, the alkyl group has M 200307661

(37) Carbon. The alkyl group may be unsubstituted or substituted by one or more base groups, and the substituent is selected from the group consisting of haloyl, alkynyl, alkoxycarbonyl, amido, alkyl, amido, and diamino. , Nitro, amino, alkylamino, dialkylamino, carboxyl, thio, and thioalkyl. &Quot; 'Haloalkyl &quot; means an alkyl group, as defined above, which is substituted by-or more halogen atoms', e.g. F, Cl, Br or I. `` Aryl '' refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted with one or more groups. Selected from the group consisting of halogen, sulfonyl, sulfonyl, alkynyl, amine, alkyl, amino, dialkyl, amino, alkyl, alkyl, dialkyl, Radical or thio radical or thio radical. Non-limiting examples of aryl rings are phenyl, succinyl, sulfanyl, pyrhyl, pyrimyl, pyrimidinyl, pyrazolyl, pyridyl, furyl, thiophenyl, sideazolyl, imidazolyl "Isoxazolyl" means "hydroxyl". "Hydroxy" refers to a group having at least ^ carbon-to-carbon double bonds. Halo refers to F, Cl, Br, or I. &quot; The "group" refers to a grafting group bonded to an aryl group, wherein the alkyl group and the aryl group are as defined above. An example of an aralkyl group is a hexyl group. As intended to be included herein, the present invention relates to SARM compounds and / or The use of analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or combinations thereof. In a specific embodiment, the present invention relates to SARM Use of analogues of compounds. In another embodiment, the present invention relates to the use of derivatives of SARM compounds. In another embodiment, 200307661

(38) The present invention relates to the use of isomers of SARM compounds. In another specific embodiment, the present invention relates to the use of metabolic products of SARM compounds. In another embodiment, the present invention relates to the use of a pharmaceutically acceptable salt of a SARM compound. In another embodiment, the present invention relates to the use of pharmaceutical products of SARM compounds. In another embodiment, the present invention relates to the use of a hydrate of a SARM compound. In another embodiment, the present invention relates to the use of N-oxides of SARM compounds. As defined herein, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, configurational isomers and analogs, and the like. In a specific embodiment, the present invention covers the use of various optical isomers of SARM compounds. Those skilled in the art should understand that the SARM of the present invention contains at least one palm center. Therefore, the SARM used in the method of the present invention may exist in optically active or racemic form and be isolated. Some compounds can also show polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, which has properties useful in the treatment of androgen-related symptoms described herein. In a specific embodiment, the SARM is a pure (R) -isomer. In another embodiment, SARM is a pure (s) -isomer. In another embodiment, SARM is a mixture of (R) and hydrazone isomers. In another specific embodiment, SARM is a racemic mixture comprising equal amounts of (R) and a hydrazone isomer. In this technique, it is known how to prepare optically active forms (for example, through the analysis of racemic forms, by recrystallization techniques' synthesized from optically active starting materials in 200307661 (39), by synthesizing by palm or using The stationary phase is separated by chromatography).

The present invention includes amine-substituted compounds and pharmaceutically acceptable salts of organic and inorganic acids (e.g., baric acid and hydrochloric acid). The invention also includes N-oxides of the amine substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with an inorganic base such as sodium hydroxide. Desirable esters can also be made from aliphatic and aromatic carboxylic acids such as acetic acid and benzoates. The invention further includes derivatives of sARM compounds. The term "derivative" includes, but is not limited to, ether derivatives, acid derivatives, amidine derivatives, and derivatives. In addition, the present invention further includes a hydrate of a SARM compound. &quot; Hydrate &quot; includes, but is not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, etc. The present invention further includes metabolites of 8-compounds. &quot; xinchen

The term "metabolite" means any substance produced by another substance through metabolism or metabolic processes. Drug product. "Pharmaceutical products, compositions for medicinal use (the present invention further includes medical compounds of SARM compounds ^ 'means suitable for a pharmaceutical composition as defined herein). In another-specific embodiment, the standard touch and eight points According to the method of Selenium Compound (SARM) compound, the person expresses the following formula: σ

200307661,

(40) where X is 0, NH, S, Se, PR or NR; G is O or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, #alkyl, di-alkyl, tri Alkyl, CH2F, CHF2, CF3, CF2 CF3, aryl, phenyl, halogen, alkenyl or OH; &amp; CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, Cl, Br, I , CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, 〇R ,, NHR-NR2 'SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 forms a fused ring system with the benzene ring to which it is connected, and is represented by the following structure:

Z is No2, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is fluorene, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02 CH3, NHS02R, OH, OR, COR, OCOR, 0S02R, S02R, SR; or Q and the benzene ring connected to it are a thick one Closed loop system, represented by structure A, B or C: 200307661 (41)

n is an integer of 1-4; and m is an integer of 1-3; This method includes the following steps to make a compound of formula VII:

ΥΠ where Z, Y, G, R !, T, R3, and m are as defined above, and L is a leaving group, which is coupled with a compound of formula VIII:

Wherein Q, X, R2 and η are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, a compound of formula VII is prepared in the following manner: a) A compound of formula IX is prepared by the ring-opening action of a cyclic compound of formula X

X IX 200307661 (42) where L, h, G, and T are as defined above, and 1 \ is 0 or NH; and b) make the amine of formula XI:

Z, Y, R3 and m are all as defined above, and react with a compound of formula IX in the presence of a coupling reagent to produce a compound of formula VII.

Those skilled in the art should understand that when A is 0 or NH, T in compound VIII is 0 or NH2. Therefore, when T in compound I is QR, the reaction will involve another step of converting OH to OR via reaction with, for example, an alkyl halide R-X. When T in compound I is NHCOR, NHCOCH3, the reaction will involve another step of converting NH2 to NHCOR or NHCOCH3 by reacting with, for example, its corresponding hafnium chloride C1COR or C1C0CH3. In a specific embodiment, step VII is performed in the presence of HBr. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. 200307661 (43) In a specific embodiment, the coupling step defined above is performed in the presence of a base. Any suitable base that deprotonates the hydrogen of the -XH moiety (eg, a phenol moiety when X is 0) and allows coupling can be used. Non-limiting examples of bases are carbonates, such as alkali metal carbonates, such as sodium carbonate (Na2C03), bell carbonate (K2 C03), and cesium carbonate (Cs2 C03); bicarbonates, such as alkali metal bicarbonates, such as Sodium bicarbonate (NaHC03), bicarbonate bell (KHCO3), test metal hydride, such as sodium hydride (NaH), hydrogenated (KH) and lithium hydride (LiH). The leaving group L is defined herein as any removable group that is conventionally considered for chemical reactions, as known to those skilled in the art ^ Suitable leaving groups are halogens, such as F, Cl, Br and I ; Alkyl esters (_〇s〇2R), where R is an alkyl group, such as methanesulfonate (methanesulfonate), trifluoromethanesulfonate, ethanesulfonate, 2,2, 2-trifluoroethane sulfonate, perfluorobutane sulfonate; aryl sulfonates (-0SO2 Ar), where Ar is aryl, such as p-toluenemethylsulfonic acid ( Tosylate), benzenesulfonate, which may be unsubstituted or substituted with methyl, chlorine, bromine, nitro, etc .; No3, No2 or sulfate, sulfite, phosphate , Phosphite, carboxylate, imide, K or urethane. This reaction is conveniently carried out in a suitable inert solvent or diluent, such as tetrahydrofuran, diethyl ether, aromatic amines, such as pyridine; aliphatic and aromatic hydrocarbons, such as benzene, toluene, and xylene; DMS (DMS) 〇), dimethylformamide (DMF) and dimethylacetamide (DMAC). This reaction is suitably performed at a temperature ranging from, for example, μ to 120C, for example, at or near ambient temperature. The above-mentioned I coupling reagent is a carboxylic acid / thio-50-(44) (44) 200307661 carboxylic acid of the formula χ which can be converted into its reactive derivative, so it can be combined with individual amines. Amine / thiamine bonding reagent. Carboxylic acid / thiocarboxylic acid, saccharin / sulfonate, and other organisms are, for example, sulfonium sulfonium / sulfonated sulfonium, such as bismuth *, bismuth *, sulfonate, and sour gas (eg, Dithionyl dichloride), in turn, to form fluorenyl / thiosulfenyl chloride; mixing, for example, an acid anhydride formed by the reaction of acid spot-like, phenolic acid such as isobutyl chloroformate; active esters &quot; A where Θ day, for example, formed by the reaction of phthalic acid / thio acid with phenol, ester / thioester or alcohol, such as methyl ^ isopropanol, butanol or N-hydroxybenzotriazole, ~ / thiopyridine; Fluorenyl / thiofluorenyl azide, for example azide A 1G formed by the reaction of an acid / thiophosphonium & with a azide such as diphenylphosphine diphenylphosphonium, fluorenyl cyanide / thiosulfide Cyanide, such as a cyanide formed by the reaction of an acid with a cyanide, such as diethylphosphonium cyanide; or a reaction of an acid / thio acid with a carbodiimide, such as dicyclohexylcarbodiimide product. The reaction is conveniently carried out in a suitable inert solvent or diluent as described above, suitably in the presence of a base, such as triethylamine, and in a temperature range such as described above. Biological Methods of Selective Androgen J Substance Compounds: The compounds provided herein are selective androgen receptor modulator (SARM) compounds that can be used for oral fluorenone replacement therapy, which has a non-steroidal ligand pair Androgenic and anabolic activity of the androgen receptor is surprisingly in vivo. Furthermore, appropriately substituted compounds are effective in treating stigma adenocarcinoma 'and can be used for imaging of prostate cancer. SARM compounds demonstrate in vivo androgen and anabolic metabolism of nonsteroidal ligands to androgen receptors 200307661 (45) As intended herein, appropriately substituted SARM compounds of the invention may be used for a) male contraception; b ) Treatment of various hormone-related symptoms, such as those associated with ADAM in aging men, such as fatigue, depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss Fall, anemia, obesity, oligosarcoma, osteoporosis, osteoporosis, benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; c) treatment of symptoms associated with ADIF, such as sexual dysfunction, hyposexuality , Hypogonadism, sarcopenia, osteoporosis, osteoporosis, changes in cognition and mood, depression, anemia, hair loss, obesity, endometrial tissue formation, breast cancer, uterine cancer and ovarian cancer D) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or treatment of dry eye symptoms; f) oral male Hormone replacement therapy; and / or g) reduce the incidence of prostate cancer, stop it or cause it to recover. As used herein, receptors for extracellular signaling molecules are collectively referred to as π-cell signaling receptors. "Many cellular signaling receptors are transmembrane proteins on the surface of cells; when they bind to cells, When a signaling molecule (ie, a ligand) is sent out, it becomes activated so that it can produce a step response of intracellular messages that alters cell behavior. In contrast, in some cases, the receptor system is inside the cell, And the signaling ligand must enter the cell to activate it; therefore, these signaling molecules must be small enough and hydrophobic to diffuse across the plasma membrane of the cell. Steroid hormones are an example of small hydrophobic molecules It directly diffuses across the plasma membrane of the target cells and binds to intracellular cells to send messages to the receptor -52- (46) 200307661. These systems are structurally related and form the intracellular receptor superfamily (or steroid- Hormonal receptor superfamily). Steroid hormone receptors include progesterone receptor, estrogen receptor, androgen receptor, glucocorticoid receptor and mineral corticoid receptor The invention is specifically directed to the androgen receptor. In addition to the ligand binding to the receptor, the receptor can be blocked to prevent ligand binding. When a substance is bound to the receptor, the three-dimensional structure of the substance It fits into the space created by the three-dimensional structure of the acceptor, and it is in the form of a ball and a sleeve. The better the ball fits into the sleeve, the more it is kept unknown. This phenomenon is called Affinity. If the substance has a greater affinity than the original hormone, it will compete with the hormone and bind this binding site more frequently. Once bound, the message can be transmitted to the cell through the receptor, causing the cell to respond in some way. This system is called activation. During activation, the activated receptor system then directly regulates the transcription of specific genes. However, the substance and the receptor may have certain traits other than affinity to activate the cell. The atoms and receptors of this substance A chemical bond between the atoms of the body can be formed. In some cases, this can lead to a change in the style of the stylus that is sufficient to begin the activation process (called message transduction).

And make it active. In a specific embodiment,. The receptor activator is, in a specific embodiment, to the steroid hormone receptor, the activator compound of the present invention is an activator that binds to the androgen receptor. In another specific embodiment, the compound has a high affinity for the androgen receptor. On another -53- 200307661

(47) In a specific embodiment, the activator compound also has anabolic activity. In another specific embodiment +, the present invention provides a selective androgen modulator compound, which has a stimulant and anabolic activity of a nonsteroidal compound on the androgen receptor. In another specific example, the present invention is directed to the compound and @, a selective androgen receptor modulator, which is an antagonist compound. A receptor antagonist is a substance that binds to and inactivates a receptor. Therefore, in a specific embodiment, the SARM compounds of the present invention can be used to bind to and inactivate the steroid hormone receptor m '. In a specific embodiment, the antagonist compound of the present invention is an antagonist that binds to an androgen receptor. In another embodiment, the compound has a high affinity for the androgen receptor. In yet another specific embodiment, the SARM compound of the present invention can be classified as a partial AR activator / cumin inhibitor. In some tissues, SA is a secondary activator that causes an increase in AR-responsive genes to turn green (such as muscle synthesis metabolism). In other tissues, these compounds act as inhibitors at M to prevent the stimulating effect of natural androgens. The detection of whether the compound of the present invention is an AR activator or antagonist is well known to those skilled in the art. For example, 'AR stimulating activity can be measured by monitoring the ability of a SARM compound to maintain and / or stimulate the growth of AR-containing tissues such as the prostate and seminal vesicles', which is measured by weight. AR antagonistic activity can be measured by monitoring the ability of SARM compounds to inhibit the growth of AR-containing tissues. The compounds of the invention bind reversibly or irreversibly to the androgen receptor. In a specific embodiment, the androgen receptor is an androgen receptor in a mammal. In another specific embodiment, the androgen receptor is human androgenic 200307661

(48) hormone receptor. In a specific embodiment, the SARM compound is reversibly bound to an androgen receptor in a mammal, such as a human. The reversible binding of a compound to a receptor means that the compound can detach from the receptor after binding. In another embodiment, a SARM compound irreversibly binds to an androgen receptor in a mammal, such as a human. Therefore, in a specific embodiment, 'the compound of the present invention may contain a functional group (e.g., an affinity marker)' which allows the alkylation of the androgen receptor (meaning covalent bond formation). Therefore, in this case, the sense compound is an alkylating agent, which is irreversibly bound to the receptor 'and therefore cannot be replaced with steroids such as the endogenous ligand DHT and 睪. "Alkylating agent, is defined herein as an agent that forms alkylates (forming covalent bonds) with cellular components such as DN A, RN A, or enzymes. It is a highly reactive chemical substance, It will introduce alkyl groups to biological living knives in order to prevent its inherent function. The part of the alkynyl group is a kind of parent-child base ring, which will interact with the nucleophilic part of the cell components. According to a specific embodiment of the present invention, a method for combining a SARM compound to an androgen receptor according to the present invention is provided by combining the receptor with a SARM compound and its or its analogs, derivatives, isoforms Structures, metabolisms: compounds, pharmaceutically acceptable salts, I drug products, hydrates or N-oxides, or any of these, and are effective in causing selective androgen receptor modulators to combine: binding to androgens Contact under the condition of a receptor. Selective androgen receptor modulation means that the combination of a compound and the androgen receptor allows the compound of the present invention to be used as a male contraceptive, and used in a variety of hormone treatment towels. Activator mouthpiece ... He Zhixiong Receptor and activating it. Antagonist compound will -55-200307661

Binding to androgen receptor I inactivates it. The combination of agonist or antagonist compounds' is either &lt; reversible or irreversible. According to an allogeneic embodiment of the present invention, a method for inhibiting spermatogenesis in a patient is provided by combining a patient's androgen receptor with the SARM compound and / or its analog, derivative, Structures, metabolism products, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof in an amount effective to bind a selective androgen receptor modulator compound to the androgen receptor, And inhibit spermatogenesis. According to another embodiment of the present invention, a method for contraception in a male patient is provided, which comprises the steps of administering to the patient a SARM compound and / or its analog, derivative, Structures, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides, or any combination thereof, in an amount effective to inhibit sperm production in the patient, thereby achieving contraception in the patient. According to another embodiment of the present invention, a method for hormonal treatment in a patient (ie, a person suffering from androgen-dependent symptoms) is provided, which comprises combining the patient's androgen receptor with the SARM of the present invention. Compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N_oxides, or any combination thereof are contacted in an amount effective to bind selective androgens Receptor modulator compounds to the androgen receptor and achieve changes in androgen-dependent symptoms. According to another embodiment of the present invention, there is provided a method of hormone replacement therapy in a patient (ie, a person suffering from androgen-dependent symptoms), which comprises combining the patient's androgen receptor with the SARM compounds and / (50) (50) 200307661

Or its analogs, derivatives, lipases, amylases, metabolites, pharmaceutically acceptable salts, medicinal products *, hydrates or n-oxides, or any combination thereof, in an amount effective to bind a selective male Hormone receptor modulator compounds to the androgen receptor and achieve changes in androgen-dependent symptoms. According to another embodiment of the present invention, a method for treating a patient with hormone-related symptoms is provided, which comprises administering to the patient a SARM compound and / or an analog, derivative, or isomer thereof according to the present invention. Substances, metabolism products, pharmaceutically acceptable salts, pharmaceutical products hydrates or n-oxides, or any combination thereof, in an amount effective to bind the SARM compound to the androgen receptor and achieve changes in androgen-dependent symptoms. Androgen-dependent symptoms that can be treated in accordance with the present invention include those associated with aging, such as hypogonadism, oligosarcoma, erythropoiesis, osteoporosis, and any other later measured low-androgen-dependent (eg, ) Symptoms of content. According to another specific embodiment of the present invention, there is provided a method for treating a patient suffering from spleen adenocarcinoma, which comprises the steps of administering the SARM compound and / or the like of the present invention to the patient. Substances, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat prostate cancer in a patient. 0 According to the invention Another specific embodiment is to provide a method for preventing prostate cancer in a patient, comprising the steps of administering to the patient a SARM compound and / or an analog, derivative, or isomer thereof according to the present invention. , Metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N_200307661 (51) oxides or any combination thereof, the amount of which is effective in preventing and treating prostate cancer in patients. According to another specific embodiment of the present invention, a method for delaying the progression of prostate cancer in a patient with prostate cancer is provided, which comprises the steps of administering the SARM compound and / or the SARM compound of the present invention to the patient. Analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates, or N-oxides, or any combination thereof, are in amounts effective to delay the progression of prostate cancer in a patient. According to another specific embodiment of the present invention, a method for preventing the recurrence of prostate cancer in a patient with prostate cancer is provided, which comprises the steps of administering the SARM compound of the present invention to the patient and / or Its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, are effective in preventing the recurrence of prostate cancer in patients. . According to another specific embodiment of the present invention, a method for treating recurrence of prostate cancer in a patient with prostate cancer is provided, which comprises the following steps: administering the SARMt compound of the present invention to the patient and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat prostate cancer in a patient Happen again. Furthermore, the stimulating effect of the 'androgen stylistic' can stimulate the production of tears, so the SARM compounds of the present invention can be used to treat dry eye symptoms. Therefore, according to another specific embodiment of the present invention, a method for treating dry eye symptoms in a patient with dry eye is provided. The method includes the following steps.

(52) a selective androgen receptor modulator compound of formula IV and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medical products, hydrates or N-oxidation Or any combination thereof in an amount effective to treat dry eye in a patient. According to another embodiment of the present invention, a method for preventing dry eye symptoms in a patient is provided, which comprises the steps of administering to the patient a selective androgen receptor modulator compound of formula IV and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent dry eyes in patients. When defined herein, &quot; contact &quot; means that the sarm compound of the invention is introduced into a sample containing an enzyme, 'placed in a test tube, flask, tissue culture, wafer, p-row, plate, microplate. , Capillaries, or the like +, and cultured at a temperature and time sufficient to allow SARM to bind to the enzyme. The method used to bring the sample into contact with noodles or other specific binding ingredients is familiar to the artist ... and can be selected according to the type of test plan to be operated. The cultivation methods are also standard and known to those skilled in the art. The term means in the context of the present invention that a SARM is compounded in another specific embodiment, &quot; contact, and a SARM compound is introduced into a patient to be treated for contact with an androgen receptor in vivo. Includes prevention and remission of the disease. The term "pi treatment" as used herein, "repression," and "inhibition" term, has treatment. "Reduction" as used herein has its general meaning of reducing or decreasing. The word "progress" used in this article means to increase the scope or severity, advance, grow, or become 200307661

(53) Worse. The term "recurrence" as used herein means the recovery of the disease after remission. As used herein, the term "administration" refers to bringing a patient into contact with a SARM compound of the invention. When As used herein, administration can be achieved in vitro, meaning in a test tube, or in vivo, meaning in a living organism, such as a cell or tissue of a human. In a specific embodiment, the invention encompasses The compound of the present invention is administered to a patient. The term "sexual desire" as used herein means sexual need. The term "erection" used herein means that it can be erect. An erection tissue is a tissue that can be greatly expanded and become hard by the expansion of many of the blood vessels it contains. &quot; Hypogonadism "is a symptom characterized by abnormality of the gonads that reduces functional activity and retards growth or sexual development, or the symptoms caused by it." Bone deficiency refers to reducing the calcification or density of bone. It is a term covering all skeletal systems in which such symptoms are found. "Osteoporosis" refers to the thinning of bones as bone mass decreases. This is caused by the depletion of calcium and bone proteins. Osteoporosis makes people susceptible to fractures. It is often a slow healing and bad Healed. Untreated osteoporosis may cause posture changes, physical deformities, and reduced mobility. BPH (benign prostatic hyperplasia) is a non-malignant enlargement of the prostate and is the most commonly found in any internal organ Common non-malignant hyperplasias and the main cause of adult men's disease. BPH occurs in more than 75% of men over the age of 50 'and reaches 88% infection rate during the age of 90. BPH will continue to make 200307661 (54) into horizontal The urethra (prostatic urethra) part of the prostate slowly squeezes. This will cause the patient to experience continuous urinating due to the incomplete emptying of the bladder and the urgency of urination. Blocking of urine flow may also cause urination. There is generally a lack of control, including difficulty in inducing urination when needed, and difficulty in preventing urine flow, as the inability to empty urine from the bladder is a condition known as Overflow incontinence of symptoms, which may lead to urinary obstruction and music exhaustion &quot;. Cognition "refers to the process of understanding, clear words, to perceive, understand, think, learn and judge the process. Cognition is the field of psychology, linguistics, computer science, neuroscience, mathematics, ethnography, and philosophy. The term “π mood” refers to the temperament or state of mind. As intended in this context, change means any positive or negative change in cognition and / or mood. &quot; Depression 'refers to physical, The diseases of mood and thinking affect the way people eat, sleep, and the way one feels and thinks about themselves. Signs and symptoms of depression include loss of fun, loss of appetite or overeating, loss of emotional expression, feeling empty, hopeless, pessimistic, feelings of guilt or helplessness, social disengagement, fatigue, sleep disorders, concentration, recall or decision making Difficulty can't sleep, irritating, headache, digestive disorders or chronic pain. &quot; Hair Dropping &quot; —The word, medically called baldness, refers to baldness, as in the very common type of male pattern baldness. The baldness is typically caused by small pieces of hair falling off the scalp, and sometimes progresses to complete baldness, and even loses body hair. Hair fall affects both men and women. "Anemia 1" refers to the symptoms in the blood that you think τ ^ 3 ^ 丄 from the nails, ears are lower than normal red blood cells or lower than the normal 200307661 (55) amount of hemoglobin. The oxygen-carrying capacity of blood is therefore Decreased. People with anemia may easily feel tired and fatigued, appear pale, develop palpitations, and often become short of breath. Anemia is caused by four basic factors: a) bleeding (bleeding); b) red blood cell dissolution (of red blood cells) Excessive destruction); c) insufficient production of red blood cells; and d) insufficient normal hemoglobin. Anemia can take many forms, including aplastic anemia, benzene poisoning, Fanconi anemia, neonatal hemolytic disease, hereditary spherocytosis, iron deficiency Anemia, oste petrochemical disease, malignant anemia, sickle cell disease, thalassemia, spinal dysplasia syndrome and various bone marrow diseases. As intended to be included herein, the SARM compounds of the present invention can be used to prevent and / or treat the above Any one or more of the forms of anemia listed. Π Obesity refers to a state much higher than a person's normal weight. Traditionally, if people exceed their Think about 20% of body weight, which is considered to be obese. Obesity has been more clearly defined by the National Institutes of Health (NI) as a body-to-mass index (BMI) of 30 or more. Obesity is often multifactorial. Behavioural factors-based. Overweight due to obesity is an important contributing factor to health problems. It increases the risk of developing many diseases, including: type 2 (adult onset) diabetes; hypertension (hypertension); stroke (Cerebral vascular accident or CVA); heart attack (myocardial infarction or MI); heart failure (campaign heart failure) 'cancer (some forms, such as prostate cancer, and colon and rectal cancer); gallstones and Gallbladder Disease (Cholecystitis); Gout and Gouty Arthritis; Osteoarthritis of the Knee, Hip, and Lower Back (Degenerative Arthritis); Sleep Apnea (Failure to Breathe Normally While Sleeping, Reduce Blood Oxygen); and Pickwic ] dan's symptoms (obesity, red face, hypoventilation, and sleepiness). As intended to cover 200307661

(56) As used herein, the term "obesity" includes any of the obesity-related symptoms and diseases listed above. Therefore, the SARM compounds of the present invention can be used to prevent and / or treat obesity and any one or more of them. The obesity-related symptoms and diseases listed here are: • Prostate cancer ”is one of the most common cancers among men in the United States, with hundreds of thousands of new cases diagnosed each year. It has been found that more than sixty percent of newly diagnosed prostate cancer cases have been pathologically progressed without cure and prognosis for depression. One-third of all men over 50 years of age have a potential form of prostate cancer that can be activated into a life-threatening clinical form such as prostate cancer. The frequency of potential prostate tumors has been shown to increase substantially with every ten years of life, from 50 years (5.3-14%) to 90 years (40-80%). The number of people with potential prostate cancer is the same across all cultures, ethnic groups, and races, but the frequency of clinically strong cancers is significantly different. This suggests that environmental factors can play a role in activating potential prostate cancer. In a specific embodiment, the method of the invention comprises administering the SARM compound as a separate active ingredient. However, it is also encompassed within the scope of the present invention are methods relating to hormone therapy, to treating prostate cancer, to delaying the progression of prostate cancer, and to preventing and / or treating the recurrence of prostate cancer, which include administering a SARM compound and using a combination of Or multiple therapeutic agents. These agents include, but are not limited to: LHRH analogs, reversible antiandrogens, antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, lutein preparations, and other nuclear hormone receptors Agents, selective estrogen receptor modulators (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine, (57) (57) 200307661

Bisphosphonates and one or more other SARMs. Therefore, in a specific embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound, and using 1hrh analogs in combination. In another embodiment, the method of the present invention comprises administering a selective androgen stylistic modulator compound and using a reversible antiandrogen. In another specific embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using an anti-estrogen. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using an anticancer drug in combination. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound, and using a 5- "reductase inhibitor. In another embodiment, the method of the present invention comprises administering A selective androgen receptor modulator compound is used in combination with an aromatase inhibitor. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and used progesterone in combination. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using an agent that acts through other nuclear hormone receptors. In another specific embodiment, the present invention The method comprises administering a selective androgen receptor modulator compound in combination with a selective estrogen receptor modulator (SERM). In another embodiment, the method of the invention comprises administering a selective androgen receptor modulator Body modulator compounds, and the same use of the corpus luteum §. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound, and Concomitant use of estrogen. In another embodiment, the method of the present invention includes administering a selective androgen receptor modulator compound in combination with a PDE5 inhibitor. In another embodiment, the present invention 200307661 (58 )

The method involves administering a selective androgen receptor modulator compound and using apomorphine in combination. In another embodiment, the method of the present invention comprises a selective androgen receptor modulator compound and a bisphosphonate. In another specific embodiment, the method of the invention comprises administering a selective androgen receptor modulator compound and using one or more other SARMs. In a specific embodiment, the present invention provides a composition and a pharmaceutical composition comprising any selective androgen receptor modulator compound of the formula [Λα], and / or its analogs, derivatives, isomers Acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof; and appropriate carriers or diluents. "Pharmaceutical composition" as used herein means a therapeutically effective amount of SARM, accompanied by appropriate diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers. &Quot; Used herein &quot; "Therapeutically effective amount" means an amount that provides a therapeutic effect on a specific symptom and administration of a medication. This composition is a liquid or lyophilized or otherwise dried formulation and contains various buffering diluents (such as Tris-HCl, acetate, phosphate), ρΗ and ionic strength additives, such as albumin or Gelatin to prevent absorption to the surface, cleaners (such as Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizers (such as glycerol, polyvinyl glycerol), antioxidants (such as ascorbic acid, sodium metabisulfite), Preservatives (such as thimerosal, methyl alcohol, parabens), bulking substances or osmotic modifiers (such as lactose, mannitol) 'polymers such as polyethylene glycol covalently linked to proteins, Incorporation with metal ions, or incorporation of this substance into or on microparticle formulations of polymer compounds such as polylactic acid, polyglycolic acid, hydrogel, etc., or in microfat 200307661 (59) particles, microemulsions , Cells, monolayer or multilayer vesicles, pseudo red blood cells or spheroids. Such a composition will affect the physical state, solubility, stability, release rate in vivo and clearance rate in vivo. Controlled or sustained release compositions include formulations in lipophilic reservoirs (eg fatty acids, waxes, oils). Also encompassed by the present invention are microparticle compositions that have been coated with a polymer, such as poly (poloxamer) or polyoxamine. Other specific embodiments of the human group of the present invention incorporate protective coatings in the form of microparticles, protease inhibitors or penetration enhancers for various administration routes, including non-intestinal, lung, nasal and oral cavity. In a specific embodiment, the pharmaceutical composition is parenteral, anticancer, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intravaginal, intraperitoneal, indoor, intracranial or Intratumoral methods are used for one person to privatize, which is known to the artist, and includes but is not limited to 〇001_〇1M, and preferably a phosphate buffer of ⑽ $, or 0.8% saline . In addition, such pharmacologically acceptable (carriers can be aqueous or non-aqueous solutions, suspensions and emulsifications: lozenges &lt; examples are propylene glycol, polyalcohols, phospholipids, such as pepper, hydrazone and injectable organic ester See you,

Aqueous / water-based, 9 aqueous vehicles include water, I / aqueous solution, emulsions, or suspensions, including non-menstrual β A β β 1 water and buffered media. The medium sword C includes emulsified sodium solution, lindrin chloride, lactic acid 蚨 &amp; &lt; 'stone dextrose, dextrose:, ... Ringer's solution and non-volatile oil. The veins ... h fluids and camps. Mangu's veins. Intravenous media packs: Lv Yangbuwu, electrolyte supplements, 嬖 are basic squats, Fenshi &quot; Preservatives and other additives can also be present 200307661 () such as antimicrobials, antioxidants, collectors, inert gases, etc. Controlled or sustained release compositions include formulations in lipophilic reservoirs (eg fatty acids, waxes, oils). Also encompassed by the present invention are microparticle compositions that have been coated with a polymer (such as polyoxygen or polyoxyamine), and antibodies coupled to a tissue-specific receptor, ligand, or antigen, or coupled to tissue A compound that is a ligand for a specific receptor. Other specific embodiments of the composition of the present invention are incorporated in the form of microparticles, protective coatings, protease inhibitors or penetration enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral cavity. It is known to use water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyethylene tetrahydroe The modified compound covalently linked to proline after intravenous injection will show a substantially longer half-life in blood compared to its corresponding unmodified compound (Abuchowski et al., 1981; Newmark et al. (1982, and Katre et al., 1987). Such modification can also increase the solubility of the compound in the aqueous solution, eliminate the aggregation effect, improve the physical and chemical footing of the compound 'and greatly reduce the immunogenicity and reactivity of the compound. Therefore, 'the desired biological activity in vivo can be achieved less frequently or at lower doses compared to the use of unmodified compounds' by administering such polymer_ compound adducts. In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, 'the drug can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, microlipids, or other modes of administration. In a specific embodiment, the pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. 200307661

(61)

Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. J. Med. 321: 574 (1989)). In another embodiment, a polymeric substance may be used. In yet another embodiment, the controlled release system can be placed near the target of treatment (meaning the brain), so only a portion of the system dose is required (see, for example, Goodson, Controlled Release Medical Applications) , Ibid., Vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in Langer's review (Science, 249: 1527-1533 (1990)). The pharmaceutical preparation may contain a SARM agent alone, or may further include a pharmaceutically acceptable carrier, and may be in a solid or liquid form such as a tablet, powder, capsule, column, solution, suspension, naval agent, emulsion, Gels, creams or suppositories, including rectal and urethral suppositories. Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof. A pharmaceutical preparation containing a SARM agent can be administered to a patient by, for example, subcutaneous implantation of spherules. In a further specific embodiment, this stem particle provides controlled release of the SARM agent over a period of time. This preparation can also be administered intravenously, intra-arterially or intramuscularly from liquid leftovers, orally administered liquid or solid preparations, or by local application. The administration can also be achieved by using guzhi suppositories or urethral suppositories. The medicinal preparation of the present invention can be 0 4,,, ^^ I and Table M. It can be obtained from the known <degradation, mixing, granulation or tablets

Agent formation method. The counterpart Shanghai iridium .. ^ OA has oral gambling, which is based on the SARM agent or its physiologically acceptable derivative, such as 躏 龆, fine χτ ^, -Ge dish cheek 酉 day class, N-lice compounds, etc. Additive blends used in this project, such as vehicles, stabilizers or inert diluents, and refined methods to convert into appropriate dosage forms such as tablets, coatings

Tablets, hard or soft gelatin swelled, ^ a _ R gelatin capsules, aqueous, drunk or oily solution. Appropriate inert vehicle "example is a conventional tablet base, ^ ^ ^ ^ ^ ^ ^ 0 7-hole sugar, sugar or corn starch 200307661 (62)

Powder, and 'combined with the disintegrant and lubricant suitable oily flower oil or cod liver (subcutaneous'), physiologically, it is transformed into a bacterial liquid that dissolves this item, for example, he can be pharmacologically or synthetically, Water, salts, such as propylene glycol injectable solutions, are active, and are clear. They are transferred to nasal suspensions; but the solids and liquid active ingredients in the liquid are oil, ethanol, or, in addition, group 1 adhesives, such as gum arabic , Corn starch, gelatin, such as corn curd, potato curd, alginic acid, or companion, such as stearic acid or magnesium stearate. Examples of vehicles or solvents are vegetable or animal oils, such as sunflower oil . The formulation can be achieved with dry and moist granules. For parenteral intravenous, intra-arterial or intramuscular injection), SARM agents or permitted derivatives such as salts, esters, N_oxide and other liquids and suspensions can be used. Or emulsion, if necessary, use conventional and suitable substances, such as solubilizers or other adjuvants. Examples are non-K people / with or without added surfactants, and adjuvants that they accept. Illustrative oils are petroleum / animal / vegetables such as peanut oil, soybean oil or mineral oil. Generally, water, aqueous dextrose and related sugar solutions, and glycol alcohols or polyethylene glycols are the preferred liquid carriers, especially for use. The preparation of a pharmaceutical composition of ingredients is very typical in this technology. This composition is made into an aerosol of a polypeptide, a pharynx, or an injectable, whether it is a liquid solution or a 'suitable preparation. Dissolve or suspend in bulk form before injection. This formulation can also be emulsified 'the active therapeutic sword is often mixed and the excipient is pharmaceutically acceptable and compatible. Suitable thieves are, for example, water, saline, dextrose, analogues, or any combination thereof. May contain small amounts of auxiliary substances, such as wetting or emulsifying agents 200307661

(63) 'pH buffering agent, which enhances the effectiveness of the active ingredient. The active ingredient can be formulated into the composition in the form of a neutralized pharmaceutically acceptable salt. Pharmaceutically acceptable salts, including acid addition salts (formed with the free-state amine groups of a polypeptide or antibody molecule), with inorganic acids, such as hydrochloric acid or phosphoric acid, or organic acids, such as acetic acid, oxalic acid, tartaric acid, phenylethanol Acids are formed together. Salts formed from free-state carboxyl groups can also be derived from inorganic compounds such as sodium, potassium, ammonium, calcium, or iron hydroxides, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, and histamine , Procaine, etc. For the topical administration of body creams such as creams, gels, drops, etc., SARMs or their physiologically acceptable derivatives, such as salts, esters, N-oxides, etc. The scientifically acceptable diluent is prepared and administered as a solution, suspension or emulsion with or without a pharmaceutical carrier. In another embodiment, the active compound can be delivered via vesicles, particularly microlipids (see Langer, Science 249: 1527-15; 33 (1990); Treat et al., For the treatment of infectious diseases and cancer Lipids, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353_365 (1989); Lopez-Berestein, supra, pp. 317-327; see cit. For pharmaceutical use, SARM salts are pharmaceutically acceptable salts. However, other salts can be used to prepare the compound according to the present invention or a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of a compound according to the present invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, Methanesulfonic acid, fumaric acid, maleic acid, succinic acid 200307661

(64), acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Embodiments The following examples are presented to more fully illustrate preferred specific embodiments of the present invention. However, it should never be interpreted as limiting the broad scope of the invention. Experimental Details Paragraph Example 1-Binding Affinity Binding Affinity is as described in He et al., Eur. J. Med. Chem. (2002), 619-634; Measured as described. Identification number Molecular weight Structure Ki _ RBA (%) 1 420.29 3.4 ± 0.56 17.6 2 CnHi〇FgN2〇5 474.26 1.37 ± 0.34 13.3 3 C17H12F6N2O5 438.28:; Ac. Fen · 11.3 Soil 1.1 3.1 4 Cl7H16F4N205 418.3 6.〇i0.7 7 5.8 5 C17H13F5N2O3 420.29 3.2 ± 0.3 10.9 6 Ci7Hi2F6N2 05 5 438 * 28 :; ^^. Thai 9.1 ± 0.6 3.4 7 C17H13C1F4N205 436.74 ^ OJUOC1 / OH 4.9 ± 0.3 9.1 8 C17H13C1F4N205 436.74 10.3 ± 2.0 4.3 200307661

(65) 9 C17H J3CI2F3N2O5 453.2 1.0i0.09 20.2 10 Cl7Hl4F4N205 402.3 3.4 ± 0.34 5.9 11 Ci7Hi2F5N2〇5 438.28 〇2N &quot; T ^ i 0 &quot; ΥΎ 10.3 soil 2.0 5.0 12 C17H10ClF7N2O5 490.71 NR experimental method Male Sprague-Dawley rats, weighing 90 to 100 grams, were purchased from Harlan Biotechnology (Indianapolis, IN). Keep the animals in a 12-hour light-dark cycle, with unlimited food and water access. This animal proposal was reviewed and approved by the Public Animal Laboratory Animal Care and Use Committee. Researchers randomly assigned rats into several treatment groups. One day before the start of drug treatment, the animals were individually removed from the cages, weighed, and anesthetized with an intraperitoneal dose of ketamine / toluene (87/13 mg / kg; approximately 1 ml per kg). When properly anesthetized (meaning there is no response to toe pinch), the animal's ears are marked for identification purposes. The animals were then placed on sterile pads and their abdomen and scrotum were washed with betadine and 70% alcohol. The testicles were removed via midline scrotal incision, in which the sutures were ligated with a sterile suture before surgical removal of each testicle 200307661

(66) Pill tissue. The surgical wound site was closed with a sterile stainless steel wound center, and this site was cleaned with Bedatin. Return the animal to a sterile pad (until it is able to stand) ’and return it to the cage. Twenty-four hours later, the animals were reanaesthetized with ketamine / toxidine, and the Alzet osmotic pump (type 2002) was placed subcutaneously in the scapular area. In this case ’, the scapular area was shaved and cleaned (Bedatin and alcohol), and a small incision (1 cm) was performed using a sterile scalpel ^ The osmotic pump was inserted and the wound was closed with a sterile stainless steel wound clip. The animal was allowed to recover and returned to the gardenia. The osmotic pump contained the appropriate therapeutic drug which had been dissolved in polyethylene glycol 300 (PEG 300). The osmotic pump is filled with the appropriate solution one day before implantation. Monitor animals daily for signs of acute toxicity to medication (eg, sleepiness, rough outer membranes). Fourteen days after drug treatment, rats were anesthetized with ketamine / toxidine. The animals were then sacrificed by exsanguination under anesthesia. Blood samples were collected by venipuncture of the abdominal aorta and subjected to complete blood cell analysis. Place a portion of the blood in individual test tubes, leave for 1 minute at 12,000 grams, remove the plasma layer, and freeze at -2 ° C. ^ The abdominal prostate, seminal vesicles, anus muscle, liver, kidney Remove the spleen, lungs, and heart, remove the external tissues, weigh them, place them in a vial containing neutral buffered formalin, and send the saved tissues to GTx for histopathological analysis. Data analysis, the weight of all organs are normalized into body weight, and any statistically significant difference is analyzed by single factor ANOVA '. The weight of the prostate and seminal vesicles is used as an index of male and female evaluation ^ 京 ^ f juice evaluation index The weight of the anal muscle is used to evaluate anabolic activity. 200307661

Results The androgenic and anabolic activities of compounds 1 and 1 and 2 were tested in castrated rat model 14 days after administration. The original control group (uncasted, untreated) and the castrated control group (castrated, untreated) were used as control groups. As shown in Table 1 and Figure 1, the weights of the prostate, seminal vesicles, and anal muscles were significantly reduced in castrated &lt; rats due to endogenous androgen production &lt; elimination. Treatment with 1 mg / day of compounds 丨 and 2 increased the weight of the gonioblasts, seminal vesicles, and seminal vesicles. Compounds 1 and 2 showed lower efficacy and intrinsic activity in increasing the weight of the prostate and seminal vesicles, but showed greater efficacy and intrinsic activity in increasing the weight of the anal muscle. In particular, 'Compound 1 is able to maintain the anal muscle weight I of castrated animals to the same extent as the original animals. Therefore, Compound 1 is an effective non-steroidal anabolic agent. This is a significant improvement over previous compounds' because this compound selectively stimulates muscle growth and other anabolic effects, while having less effect on the prostate and seminal vesicles. This may be particularly relevant in aging men with concerns about the development or progression of prostate cancer. Table 1 Castrated compound 1 (pumped) Compound 1 (daily injection) Compound 2 (daily injection) Prostate 100 ± 14.3 6.2 ± 2.5 40.3 ± 10.0 33.1 ± 8.5 7.2 ± 1.4 Seminal vesicle 101 + 26.8 8.1 + 1.8 30.9 + 5.7 23.6 ± 8.8 7.2 ± 0.9 ^ portal muscle 102 ± 8.1 40.9 ± 9.4 122.5 ± 10.4 112.8 ± 9.4 55.83 ± 2.84 200307661

(68) * Reference group was treated with 1 mg / day of Compound 1 via an osmotic pump. The androgenic and anabolic activities of the compound #j; compound 7 are in castrated rat mode and examined 14 days after administration. The original control group (uncasted, untreated) and the castrated control group (castrated, untreated) were used as control groups. Rats were castrated on day 0 and received daily subcutaneous doses (0.05 to 3 mg / day) of compound 7 in a DMSO / PEG vehicle. On the last day, rats were sacrificed, and the wet weights of androgen (prostate and seminal vesicles) and anabolic (anal lifting) organs were measured. As shown in Figure 2, treatment with increasing doses of Compound 7 caused the prostatic glands, seminal vesicles, and anal muscle weight to increase in a dose-dependent manner. Compound 7 shows lower efficacy and intrinsic activity in increasing the weight of the prostate and seminal vesicles, but shows greater efficacy and intrinsic activity in increasing the weight of the anus muscle. Detailed description, and accompanying drawings, to understand and understand more fully, wherein: Figure 1: Compounds 1 and 2 androgen and anabolic activity in rats. Rats were left untreated (control group intact), castrated (control group), treated with 1.0 mg / day of compound 1 or 1.0 mg / day of compound II, and measured androgen-responsive tissues (Prostate, seminal vesicles, and anal muscles). Figure 2: Androgen and anabolic activity of compound 7 in rats. Rats were castrated on day 0 and received daily subcutaneous doses (0.05 to 3 mg / 200307661 (69) days) of compound 7 in DMSO / PEG vehicle. Rats were sacrificed on the last day, and the wet weights of androgens (prostate and seminal vesicles) and anabolic (anal lifting) organs were measured. It should be clear to those skilled in the art that the present invention is not limited to those specifically described and described above. Instead, the scope of the invention is defined by the scope of the following patent applications:

Claims (1)

200307661 Patent application scope 1. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I Where X is a bond, 0, CH2, NH, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is an alkyl, haloalkyl, dihaloalkane Base, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, autogen, feminyl or OH; heart is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, cn, Br , I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 forms a fused ring system with the benzene ring to which it is connected, and is represented by the following structure: Z is N〇2, CN, COR, COOH or CONHR; 200307661 Y is CF3, F, Br, Cl, I, CN or SnR3; Q is H, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3 , NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring to which it is connected is a fused ring system, represented by the structure A, B or C: n is an integer of 1-4; and m is an integer of 1-3. 2. · A selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula I: Where X is a bond, 0, CH2, NH, Se, PR, NO, or NR; G is 0 or S; T is OH, OR, -NHCOCH3, or NHCOR; R is an alkyl, ialkyl, or dioxane Base, tri-functional alkyl, ch2f, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, feminyl, or OH; ~ CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; 200307661 R2 is F, α, Br, I, CH3, CF3 &lt; OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure: Z is N02, CN, COR, COOH or CONHR; Y is CF3, F, Br, Cl, I, CN or SnR3; Q is fluorene, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring connected to it is a fused ring system , Represented by structure A, B or C: η is an integer of 14; and m is an integer of 1-3; or an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N · oxide, hydrate, or any one thereof 200307661 Any combination. 3. A selective androgen receptor modulator compound according to item 1 of the scope of patent application, wherein G is 0. 4. A selective androgen receptor modulator compound according to item 1 of the application, wherein T is OH. 5. A selective androgen receptor modulator compound according to item 1 of the scope of patent application, wherein Ri is CH3. 6. A selective androgen receptor modulator compound according to item 1 of the patent application, wherein X is 0. 7. The selective androgen receptor modulator compound according to item 1 of the application, wherein z is no2. 8. A selective androgen receptor modulator compound according to item 1 of the application, wherein Z is CN. 9. A selective androgen receptor modulator compound according to item 1 of the patent application, wherein Y is CF3. 10. The selective androgen receptor modulator compound according to item 1 of the application, wherein Q is nhcoch3. 11. A selective androgen receptor modulator compound according to item 1 of the application, wherein Q is F. 12. A selective androgen receptor modulator compound according to item 1 of the patent application, wherein Q is F and heart is C1. 13. The selective androgen receptor modulator compound according to item 1 of the patent application scope, which is represented by the following structure ... 200307661 14. The selective androgen receptor modulator compound according to item 1 of the scope of patent application, which is represented by the structure of formula II: Where p is an integer from 2-5. 15. A selective androgen receptor modulator compound according to item 14 of the application, wherein P is 5. 16. The selective androgen receptor modulator compound according to item 14 of the application, which is represented by the following structure: 17. A selective androgen receptor modulator compound according to item 1 of the application, wherein the compound is an androgen receptor antagonist. 18. A selective androgen receptor modulator compound according to item 1 of the application, wherein the compound is an androgen receptor activator. 19. A selective androgen receptor modulator compound according to item 1 of the application, wherein the compound is irreversibly bound to the androgen receptor. 20. A selective androgen receptor modulator compound according to item 1 of the application, wherein the compound is reversibly bound to the androgen receptor. 21. A composition comprising a selective androgen receptor modulator compound according to item 1 of the patent application scope, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts , Pharmaceutical products, hydrates or N-oxides or any combination thereof; and a suitable carrier or dilution 200307661 22_ —a pharmaceutical composition comprising an effective amount of a selective androgen receptor modulator compound according to item 1 of the scope of patent application, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable Accepted salts, pharmaceutical products, hydrates or N-oxides or any combination thereof, and pharmaceutically acceptable carriers, diluents or salts. 23. · A method for binding a selective androgen receptor modulator compound to an androgen receptor, comprising the steps of combining an androgen receptor with a selective androgen receptor modulator according to item 1 of the scope of patent application Compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, or N-oxides, or any combination thereof, are contacted in an amount effective to bind a selective male compound Hormone receptor modulator compounds to androgen receptors. 24. —A method for inhibiting spermatogenesis in a patient, comprising combining a patient's androgen receptor with a selective androgen receptor modulator compound according to item 1 of the scope of the patent application, and / or its analogs, derivatives Contact with a substance, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to inhibit sperm production. 25 · —A method of contraception in a male patient, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 1 of the scope of patent application, and / or an analogue, derivative thereof Substances, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to inhibit sperm in the patient 200307661 26. Submanufacturing ’to achieve a method of hormonal therapy. Changes in hormone receptors and modulator compounds, and / or metabolites, pharmacological N-oxides, or any of their symptoms depending on the application. 27.-Stimulation of androgen receptors, metabolism or N- hormone dependence 28.-Seed treatment steps, androgen isomers, hydrated hormones according to 29.-Seed treatment, the hormone receptors, Xinhe Contraceptives to patients or patients. 'It includes the following steps to bring the selective androgen receptor or its analogs, derivatives, isomers, neo-Γ accepting salts, pharmaceutical products, hydrates or synthases to the patient's androgenic range item 1. The amount of which is effective to achieve a method of androgen esoxo replacement therapy, which includes the following steps: the receptor and the excipient compound according to item 1 of the scope of the patent application, and / or its analogs, derived metabolites, pharmaceutically acceptable The amount of salt, medicinal oxide, or any combination thereof may vary in sexual symptoms. A method for treating a patient with hormone-related symptoms, and administering to the patient an instant compound according to the scope of the patent application, and / or its analog, a metabolite, a pharmaceutically acceptable salt, or N-oxidation Or any combination thereof, the amount of which depends on the change in symptoms. A method for treating a patient with prostate cancer, which comprises administering a modulator compound and / or an analogue thereof, a derivative metabolite, a pharmaceutically acceptable salt, a medical agent according to item 1 of the scope of the patent application. -Oxide or any combination thereof, the amount of which can make the patient's selective androgen, isomer product, hydration effect androgenic. It includes the following items of selectivity, derivative, and medicinal product. The following steps are effective in selective androgenic organisms, isomeric drug products, and water diseases. Treatment of prostate cancer. 30 · A method for preventing prostate cancer in a patient, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 1 of the scope of patent application, and / or an analog thereof , Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent prostate cancer in the patient. 31. A method of delaying the progression of prostate cancer in a patient with prostate cancer, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 1 of the patent application scope, and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to delay prostate cancer in the patient Progress. 32 · A method for preventing the recurrence of prostate cancer in a patient with prostate cancer, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 1 of the scope of patent application And / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent the disease Recurrence of prostate cancer. 33 · A method for treating recurrence of prostate cancer in a patient with prostate cancer, comprising the steps of administering to the patient a selective androgen receptor modulator according to item 1 of the patent application park Compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof, 200307661 The amount can effectively treat the recurrence of prostate cancer in the patient. 34. A method of treating dry eye symptoms in a patient with dry eye, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 丨 of the patent application scope, And / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat dry eyes in the disease string . 35. A method for preventing dry eye symptoms in a patient, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 1 of the scope of patent application, and / or an analog thereof , Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in amounts effective to prevent dry eyes in patients. 36. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula V: Chemical 2 is F, Cl, Br, I, CH3, CF3, OH, CN, No2, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, Nh2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR 200307661 , CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure: Y ~ Y R is alkyl, fluorenyl, dialkyl, tridentyl, CH2F, CHF2, CF3, CF2 CF3; aryl, phenyl, autogen, fluorenyl, or OH; Z is N02, CN, COR, COOH or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is fluorene, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR , CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring to which it is connected is a fused ring system with structure A, B or C Means: A NH n is an integer of 1-4; and m is an integer of 1-3. 37. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula V: -10- 200307661 Where R2 is F, C, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR λ NR〗 ～ SR &gt; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure: YYR is alkyl, haloalkyl, dialkyl, tri-functional alkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halide, fluorenyl, or OH; Z is No2, CN, COR , COOH or CONHR; Y is CF3, F, Br, Cl, I, CN or SnR3 _; Q is H, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring to which it is connected is a fused ring system, represented by the structure A, B or C: -11-200307661 η is an integer from 1-4; and m is an integer from 1-3; or an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, N-oxide, hydrate, or any combination thereof 0 38. A selective androgen receptor modulator compound according to item 36 of the application, wherein Z is NO. 39. A selective androgen receptor modulator compound according to item 36 of the application, wherein Z is CN. 40. A selective androgen receptor modulator compound according to item 36 of the application, wherein Y is CF3. 41. A selective androgen receptor modulator compound according to item 36 of the application, wherein Q is nhcoch3. 42. A selective androgen receptor modulator compound according to item 36 of the application, wherein Q is F. 43. The selective androgen receptor modulator compound according to item 36 of the application, wherein Q is F and R2 is C1. 44. The selective androgen receptor modulator compound according to item 36 of the application, which is represented by the structure of Formula VI: Wherein Θ is an integer of 1-4 200307661 45. The selective androgen receptor modulator compound according to item 36 of the application, wherein Q is F and p 'is 4. 46. A selective androgen receptor modulator compound 'according to item 36 of the application, wherein the compound is an androgen receptor antagonist. 47. A selective androgen receptor modulator compound &apos; according to item 36 of the application, wherein the compound is an androgen receptor activator. 48. A selective androgen receptor modulator compound according to item 36 of the application, wherein the compound is irreversibly bound to the androgen receptor. 49. A selective androgen receptor modulator compound according to item 36 of the application, wherein the compound is reversibly bound to the androgen receptor. 50. A composition comprising a selective androgen receptor modulator compound and / or its analog, derivative, isomer, metabolism product, pharmaceutically acceptable Salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof; and appropriate carriers or diluents. 51. A pharmaceutical composition comprising an effective amount of a selective androgen receptor modulator compound according to item 36 of the scope of the patent application, and, or an analog, derivative, isomer, metabolite, pharmacologically Acceptable salts Pharmaceutical products, hydrates or N-oxides or any combination thereof; and pharmaceutically acceptable carriers, diluents or salts. 52 · / A method for binding a selective androgen receptor modulator compound to an androgen receptor, comprising the steps of combining an androgen receptor with a selective androgen receptor modulator according to item 36 of the patent application patent garden Compounds, and / or their analogs #, derivatives, isomers, metabolic products #, pharmacy 200307661 Acceptable salts, medical connotations ... A. substances, hydrates, or N-oxides, or any combination thereof, in an amount that can be # ^ λ Λ, 5 ^ ^ ~ orally selective androgen receptor modulator compounds to Androgen style. 53. An inhibitor of a hormone receptor in a patient with a mediator modulator compound, a metabolite, g or N-oxide or any of its compounds. The method of spermatogenesis, please contact item 36 of the patent scope and / or its analogues, scientifically acceptable salts, and any combination, the amount of which includes the selective androgen receptor derivatives, isomers, Pharmaceutical products and hydrates can effectively inhibit sperm production. 54. A method of contraception in male patients, which includes the following steps. The patient is administered with selective androgen receptor regulation according to item 36 of the scope of patent application Agent compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in amounts that can be in the patient Effectively inhibit sperm production to achieve contraception in this patient. 55. A method of hormonal therapy, comprising the steps of bringing a patient's androgen receptor and a selective androgen receptor modulator compound according to item 36 of the patent application scope, and / or its analogs, derivatives, Contacting an isomer, a metabolite, a pharmaceutically acceptable salt, a medicinal product, a hydrate, or an N-oxide, or any combination thereof, in an amount effective to achieve a change in androgen-dependent symptoms. 56. A method of hormonal replacement therapy, comprising the steps of combining a patient's androgen receptor with a selective androgen receptor modulator compound according to item 36 of the patent application scope, and / or an analog or derivative thereof Isomers , Metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof in an amount effective to achieve changes in androgen-dependent symptoms. 57. — A method for treating hormonal-related symptoms and symptoms of dysentery, including the following steps, and administering the disease to the patient: &amp; ▲ _ μ Very selective in the scope of patent application of item 36 Androgen receptor modulator compounds, $ / oral compounds, and / or their analogs, derivatives, isomers, metabolites, drugs, and cephalically acceptable salts, medicinal products, hydrates, or N-oxidation Or any combination of Yuan Duyi X, the amount of which can effectively achieve changes in androgen-dependent symptoms. 58. A method for treating a patient with prostate cancer, comprising the steps of administering to the patient a selective androgen receptor modulator compound and / or an analog thereof in accordance with the allowable term of the scope of patent application. , Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat prostate cancer in the patient. 59. A method for preventing prostate cancer in a patient, comprising the following steps: administering to the patient a selective androgen receptor modulator compound according to item 36 of the scope of patent application, and / or the like Substances, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent prostate cancer in the patient. 60 · —A method for delaying the progression of prostate cancer in a patient with prostate cancer ', comprising the step of administering to the patient a selective androgen receptor modulator compound according to item 36 of the patent application scope, and / Or similar to 200307661 Substances, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to delay the progression of prostate cancer in the patient. 61 · —A method for preventing the recurrence of prostate cancer in a patient with prostate cancer, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 36 of the patent application scope, And / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent prostate in the patient The recurrence of cancer. 62 · —A method for treating recurrence of prostate cancer in a patient with thistle adenocarcinoma, comprising the steps of administering to the patient a selective androgen receptor modulation according to item 36 of the patent application park Agent compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in amounts that can be in the patient Effective treatment of recurrence of prostate cancer. 63 · —A method for treating dry eye symptoms in a patient with dry eye, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to claim 36, and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat dry eye in a disease string. 64 · —A method of preventing dry eye symptoms in a patient, comprising the steps of administering to the patient a selective androgen receptor modulator compound according to item 36 of the patent application garden 'and / or the like Compounds, derivatives, isomers 200307661 , Metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in amounts effective to prevent dry eyes in patients. 65. A method for preparing a selective androgen receptor modulator (SARM) compound, the compound is represented by the structure of formula I: Where X is 0, NH, S, Se, PR or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, alkanyl, dialkyl, trialkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, or OH; 1 ^ is CH3, CH2F, CHF2, CF3 , CH2CH3 or CF2CF3; R2 is F, a, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure: 200307661 Z is N02, CN, COR, COOH or CONHR; Y is CF3, F, Bi *, Cl, I, CN or SnR3; Q is H, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, SR; or Q and the benzene ring to which it is connected is a fused ring System, represented by structure A, B or C: n is an integer of 1-4; and m is an integer of 1-3. The method comprises the following steps: νπ where 2, y, 0, chi 1, di, 113, and 111 are as defined above, and 1 ^ is a leaving group, which is coupled to a compound of formula VIII: , (R2) n 200307661 Q, X, rulers 2 and 11 are as defined above. 66. The method according to item 65 of the application, wherein G is 0. 67. The method according to item 65 of the application, wherein T is OH. 68. The method according to item 65 of the patent application, wherein R2 is CH3. 69. The method according to item 65 of the application, wherein X is 0. 70. The method according to item 65 of the patent application, wherein Z is N02. 71. The method according to item 65 of the patent application, wherein Z is CN. 72. The method according to item 65 of the patent application, wherein Y is CF3. 73. The method according to item 65 of the patent application, wherein Q is NHCOCH3. 74. The method according to item 65 of the patent application, wherein Q is F. 75. The method according to item 65 of the patent application, wherein Q is F and R2 is Cl3. 76. The method according to claim 65, wherein the selective androgen modulator compound is represented by the structure of formula II Where p is an integer from 2-5. 77. The method according to claim 65, wherein the selective androgen modulator compound is represented by the structure of formula III. ΙΠ 200307661 78. The method according to claim 65, wherein the selective androgen modulator compound is represented by the structure of formula IV -(F) P1 where p 'is an integer from 1-4. 79. The method according to claim 65, wherein the selective androgen modulator compound is represented by the structure of formula V. 80_ The method according to item 65 of the claims, wherein the selective androgen modulator compound is represented by the structure of formula VI Where pf is an integer from 1-4. 81. The method according to item 65 of the scope of patent application, wherein the coupling step is carried out in the presence of experience. 82. The method according to item 65 of the claims, wherein the leaving group L is Br. 83. The method according to item 65 of the claims, wherein the compound of formula VII is 200307661 Prepared in the following way a) By the ring-opening action of a cyclic compound of formula X, a compound of formula han X κ wherein L, Xin, G, and T are as defined above, and D 1 is 0 or nh; and b) the amine of formula XI: Wherein Z, Y, &amp; and m are as defined above, and react with a compound of formula IX in the presence of a coupling reagent to produce a compound of formula VO. 84. The method according to item 1 of the scope of patent application, further comprising converting the selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite pharmaceutical product, team oxide, derivatization Of a drug, a pharmaceutically acceptable salt hydrate, or any combination thereof.