EP1432698A2 - Substituted 3-pyridyl indoles and indazoles as c17,20 lyase inhibitors - Google Patents

Substituted 3-pyridyl indoles and indazoles as c17,20 lyase inhibitors

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Publication number
EP1432698A2
EP1432698A2 EP02778338A EP02778338A EP1432698A2 EP 1432698 A2 EP1432698 A2 EP 1432698A2 EP 02778338 A EP02778338 A EP 02778338A EP 02778338 A EP02778338 A EP 02778338A EP 1432698 A2 EP1432698 A2 EP 1432698A2
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EP
European Patent Office
Prior art keywords
pyridyl
indole
alkyl
bromo
compound
Prior art date
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EP02778338A
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German (de)
English (en)
French (fr)
Inventor
Gaetan H. Ladouceur
Michael J. Burke
Wai C. Wong
Donald Bierer
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Bayer Pharmaceuticals Corp
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Bayer Pharmaceuticals Corp
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Publication of EP1432698A2 publication Critical patent/EP1432698A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Steroid biosynthesis begins in cells of the adrenal gland where the initial product in sterol biosynthesis, cholesterol, is converted into the adrenal steroid hormones aldosterone, hydrocortisone, and corticosterone by a series of P 450 -mediated hydroxylation steps.
  • the cholesterol side-chain cleavage activity that represents the first step in steroid hormone biosynthesis is a P 450 -mediated oxidation and cleavage of a pair of adjacent methylene groups to two carbonyl fragments, pregnenolone and isocaprylaldehyde (see Walsh, Enzymatic Reaction Mechanisms, W.H. Freeman and Company: pp. 474-77, 1979).
  • CYP 17, P 450 17 Another critical set of enzymatic conversions in steroid metabolism is facilitated by 17 ⁇ - hydroxylase- 17,20-lyase (CYP 17, P 450 17).
  • CYP 17 is a bifiinctional enzyme which possesses both a CI 7,20-lyase activity and a C17-hydroxylase activity.
  • these two alternative enzymatic activities of CYP 17 result in the formation of critically different intermediates in steroid biosynthesis and each activity appear to be differentially and developmentally regulated (see e.g. l'AUemand et al. Eur. J. Clin. Invest. 2000, 30, 28-33).
  • DHEA dehydroepiandrosterone
  • DHT dihydrotestosterone
  • Estradiol and estrone are key intermediates in the synthesis of not only the androgens testosterone and dihydrotestosterone (DHT), but also the estrogens 17 ⁇ -estradiol and estrone.
  • DHT dihydrotestosterone
  • adrenal and ovarian estrogens are the main sources of estrogens in postmenopausal women (see e.g. Harris et al. Br. J.
  • the C17-hydroxylase activity of CYP 17 catalyzes the conversion of the common intermediate progesterone to 17- hydroxyprogesterone, a precursor of cortisol. Therefore the first activity of CYP 17, the C17-hydroxylase activity, promotes the formation of glucocorticoids while the second activity of CYP 17, the CI 7,20-lyase activity, promotes the formation of sex hormones - particularly androgens including testosterone as well as estrogens.
  • Prostate cancer is currently one of the most frequently diagnosed forms of cancer in men in the U.S. and Europe. Prostate cancer is typically androgen-dependent and, accordingly, the reduction in androgen production via surgical or pharmacological castration remains the major treatment option for this indication. However, complete rather than partial withdrawal of androgens may be more effective in treating prostate cancer (Labrie, F. et al, Prostate 1983, 4, 579 and Crawford, E.D. et al, N. Engl J. Med. 1989, 321, 419). Pharmacological inhibition of CYP 17 may be a promising alternative treatment to antiandrogens and LHRH agonists in that testicular, adrenal, and peripheral androgen biosynthesis would be reduced rather than only testicular androgen production (Njar, V.
  • CYP17 inhibitor the fungicide ketoconazole
  • This drug is a relatively non- selective inhibitor of cytochrome P450 (CYP) enzymes, has weak CYP 17 activity, and has a number of notable side effects associated with it including liver damage (De Coster, R. et al, J. Steroid Biochem. Mol. Biol 1996, 56, 133 and Lake-Bakaar, G. et al, Br. J. Med. 1987, 294, 419).
  • CYP 17 inhibitors In addition to the use of CYP 17 inhibitors in the treatment of prostate cancer, a second potential indication would be for estrogen-dependent breast cancer. In postmenopausal patients with advanced breast cancer, treatment with high doses of ketoconazole resulted in suppression of both testosterone and estradiol levels, implicating CYP 17 as a potential target for hormone therapy (Harris, A. L. et al, Br. J. Cancer 1988, 58, 493).
  • Chemotherapy is usually not highly effective, and is not a practical option for most patients with prostate cancer because of the adverse side effects which are particularly detrimental in older patients. However, the majority of patients initially respond to hormone ablative therapy although they eventually relapse, as is typical with all cancer treatments
  • the invention provides substituted 3-pyridyl indole and indazole compounds which inliibit the lyase activity of enzymes, e.g., 17 ⁇ -hydroxylase-Cl 7,20-lyase.
  • Indole compounds of the invention have the formula in which R 1 represents
  • R 4 represents C ⁇ alkyl; and p is 0, 1, or 2;
  • R 3 is other than a pyridyl or an N-oxide- containing group
  • R 5 represents C ⁇ , halogen, CHO, or C(0) ⁇ (R 6 ) 2 in which R 6 represents H or CM alkyl; and q is 0, 1, or 2.
  • R represents C ⁇ alkyl; and m is 0, 1, or 2.
  • R 3 represents
  • R 7 is C ⁇ alkyl or CN; and r is 0, 1, or 2;
  • R 1 is other than a pyridyl or an N-oxide- containing group
  • R 8 represents
  • s 0, or 2;
  • R 1 * is halogen; and t is 0, 1 , or 2.
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or CN provided that R 3 is other than cyano; and u is 0, 1 , or 2.
  • R 13 represents H or R 12 . Furthermore, one of R 1 and R 3 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions. Pharmaceutically acceptable salts of these compounds are also within the scope of the invention.
  • Indazole compounds of the invention have the formula
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or CN; and u is 0, 1, or 2.
  • R 13 represents H or R 12 .
  • R 15 represents
  • R . 18 represents C ⁇ alkyl; and p is 0, 1 , or 2; or
  • R 16 represents H or C ⁇ alkyl.
  • R 17 represents
  • R 19 is C ⁇ alkyl; and r is 0, 1, or 2; or
  • R 20 represents halogen; C ⁇ alkyl, C ⁇ alkoxy, ⁇ O 2 ,
  • R 21 is H or C ⁇ alkyl; and s is 0, 1, or 2.
  • R 15 and R 17 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • Pharmaceutically acceptable salts of these materials are also within the scope of the invention.
  • the invention also provides pharmaceutical compositions for inhibiting lyase activity, comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention also provides methods for inhibiting lyases, comprising contacting the lyase with a compound of the invention. More particularly, the invention provides a method of inhibiting a 17 ⁇ -hydroxylase-C 17,20 lyase, comprising contacting a 17 ⁇ -hydroxylase- C 17,20 lyase with a compound of the invention.
  • the invention further provides methods for treating diseases which can benefit from an inhibition of a lyase enzyme.
  • diseases are lyase-associated diseases, e.g., diseases resulting from an excess of androgens or estrogens.
  • the invention provides a method for treating cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of the invention, such that the cancer is treated.
  • the method of treatment may be applied where the subject is equine, canine, feline, or a primate, in particular, a human.
  • the cancer may, for example, be prostate or breast cancer.
  • a method for treating prostate cancer in a subject comprises administering to the subject a therapeutically effective amount of a compound of the invention, such that the prostate cancer in the subject is treated.
  • a method for treating breast cancer in a subject comprises administering to the subject a therapeutically effective amount of a compound of the invention, such that the breast cancer in the subject is treated.
  • indole compounds of the invention have the formula
  • R 1 represents in which R 4 represents C ⁇ alkyl
  • p is 0, 1, or 2;
  • R 3 is other than a pyridyl or an N-oxide- containing group
  • R' represents C ⁇ , halogen, CHO, or C(O) ⁇ (R°) 2 in which R represents H or C ⁇ alkyl; and q is 0, 1, or 2.
  • R 2 represents C ⁇ alkyl; and m is 0, 1, or 2.
  • R is C ⁇ alkyl or CN; and r is 0, 1, or 2;
  • R 1 is other than a pyridyl or an N-oxide- containing group
  • R 8 represents
  • R 9 is H or C ⁇ alkyl, or s is 0, l, or 2;
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or CN provided that R 3 is other than cyano; and u is 0, 1, or 2.
  • R 13 represents H or R 12 .
  • one of R 1 and R 3 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions. Pharmaceutically acceptable salts of these compounds are also within the scope of the invention.
  • indole compounds of the invention have the formula
  • R 3 is other than a pyridyl or an N-oxide- containing group; or in which R 5 represents CN, halogen, CHO, or C(O)N(R 6 ) 2 in which R 6 represents H or C ⁇ alkyl; and q is 0, 1, or 2.
  • R 2 represents C ⁇ alkyl; and m is 0, 1, or 2.
  • R 3 represents R _ AL
  • R 7 is C ⁇ alkyl or CN; and r is 0, 1, or 2;
  • R 1 is other than a pyridyl or an N-oxide- containing group
  • s is O, l, or 2;
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or CN provided that R 3 is other than cyano; and u is 0, 1, or 2.
  • R 13 represents H or R 12 .
  • R 1 and R 3 are a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • Pharmaceutically acceptable salts of these compounds are also within the scope of the invention.
  • indole compounds of the invention have the formula i
  • R 4 represents C ⁇ alkyl; and p is 0, 1 , or 2;
  • R 3 is other than a pyridyl or an N-oxide- containing group
  • R 5 represents C ⁇ , halogen, CHO, or C(O) ⁇ (R 6 ) 2 in which R 6 represents H or C ⁇ alkyl; and q is 0, 1, or 2.
  • R >2 represents C ⁇ alkyl; and m is 0, 1, or 2.
  • R 3 represents
  • R 7 is Ci- 4 alkyl or CN; and r is 0, 1, or 2;
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or CN provided that R 3 is other than cyano; and u is 0, 1, or 2.
  • R 13 represents H or R 12 .
  • R 1 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • Pharmaceutically acceptable salts of these compounds are also within the scope of the invention.
  • indazole compounds of the invention have the formula
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or CN; and u is 0, 1, or 2.
  • R 13 represents H or R 12 .
  • R 15 represents
  • R 17 is other than a pyridyl or an N-oxide- containing group.
  • R 16 represents H.
  • R 17 represents
  • R 19 is C ⁇ alkyl; and r is 0, 1, or 2; or
  • R20 s - ⁇ J ⁇ n which R 20 represents halogen; C ⁇ alkyl, C ⁇ alkoxy, ⁇ O 2 ,
  • R ⁇ .21 1 is H or C ⁇ alkyl; and s is 0, 1, or 2.
  • R 15 and R 17 is a 3-pyridyl or 3-pyridyl-N-oxide group which is unsubstituted at the 2- and 6- positions.
  • Pharmaceutically acceptable salts of these materials are also within the scope of the invention.
  • indazole compounds of the invention have the formula
  • R 12 represents C ⁇ alkyl, C ⁇ alkoxy, halogen, or C ⁇ ; and u is 0, 1, or 2.
  • R 13 represents H or R 12 .
  • R represents
  • R 16 represents H.
  • R .17 represents
  • R 19 is C ⁇ alkyl; and r is 0, 1, or 2;
  • R 15 and R 17 is a 3-pyridyl group which is unsubstituted at the 2- and 6- positions.
  • Pharmaceutically acceptable salts of these materials are also within the scope of the invention.
  • agonist of an enzyme refers to a compound that binds to the enzyme and stimulates the action of the naturally occurring enzyme, or a compound which mimics the activity of the naturally occurring enzyme.
  • an enzyme refers to a compound that binds to the enzyme and inhibits the action of the naturally occurring enzyme.
  • analog of a compound refers to a compound having a some structural similarity to a particular compound and having essentially the same type of biological activity as the compound.
  • CYP 17 substrate includes any of the various steroid hormones acted upon by a CYP 17 or a CYP17-like P 450 enzyme. Examples include pregnenolone, progesterone and their 17 ⁇ -hydroxylated forms. Pregnenolone is converted to DHEA via a CYP 17 CI 7,20-lyase reaction, but is also subject to C17 ⁇ -hydroxylation via the CI 7,20- lyase activity.
  • Progesterone is converted to delta 4- androstenedione via a CYP 17 CI 7,20- lyase reaction, but is also subject to C17 ⁇ -hydroxylation via the C17-hydroxylase activity to form 17-hydroxy-progesterone, a precursor to hydrocortisone (i.e. cortisol).
  • CYP 17 metabolite refers to any of the steroid hormones that are synthesized from a cholesterol precursor via a CYP 17-mediated reaction, such as a C17- hydroxylase reaction or a CI 7,20-lyase reaction.
  • CYP 17 metabolites include the androgens, such as testosterone, which are synthesized via a CYP 17 CI 7,20-lyase reaction from CYP 17 substrate precursors such as pregnenolone (converted to DHEA by the CYP 17 CI 7,20-lyase activity), and progesterone (converted to delta 4- androstenedione by the CYP17 C17,20-lyase activity).
  • Progestagens such as progesterone are primarily synthesized in the corpus luteum.
  • the androgens are responsible for, among other things, development of male secondary sex characteristics and are primarily synthesized in the testis.
  • Other examples include the estrogens, which are also synthesized from a cholesterol precursor via a CYP 17-mediated reaction.
  • the estrogens are responsible for, among other things, the development of female secondary sex characteristics and they also participate in the ovarian cycle and are primarily synthesized in the ovary.
  • Another group of CYP 17 metabolites are the glucocorticoids, such as hydrocortisone (i.e. cortisol), which is synthesized from progesterone via a CYP 17-mediated reaction.
  • the glucocorticoids among other functions, promote gluconeogenesis and the formation of glycogen and also enhance the degradation of fat.
  • the glucocorticoids are primarily synthesized in the adrenal cortex.
  • CYP 17 metabolite is further meant to include other steroid hormones which, although not necessarily synthesized by a CYP 17-mediated reaction, may nonetheless be understood by the skilled artisan to be readily affected by an alteration in a CYP 17-mediated activity.
  • the mineralocorticoids such as aldosterone
  • progesterone is also converted to the glucocorticoids and sex steroids via CYP 17-mediated reactions
  • an alteration of a CYP 17 activity can alter the amount of progesterone available for conversion to aldosterone.
  • inhibition of CYP 17 activity can increase the amount of progesterone available for conversion into aldosterone.
  • the mineralocorticoids function, among other things, to increase reabsorption of sodium ions, chloride ions, and bicarbonate ions by the kidney, which leads to an increase in blood volume and blood pressure.
  • the mineralocorticoids are primarily synthesized in the adrenal cortex.
  • CYP 17 metabolite-associated disease or disorder refers to a disease or disorder which may be treated by alteration of the level of one or more CYP 17 metabolites.
  • Examples include a hormone dependent cancer, such as an androgen-dependent prostate cancer, which may be treated by inhibiting CYP 17-mediated androgen synthesis, and an estrogen-dependent breast cancer or ovarian cancer, which may be treated by inhibiting
  • CYP 17-mediated estrogen synthesis Other examples of "CYP 17 metabolite-associated diseases or disorders" are Cushing's disease, hypertension, prostatic hyperplasia, and glucocorticoid deficiency. Patients with Cushing's syndrome are relatively insensitive to glucocorticoid feedback and exhibit an oversecretion of cortisol devoid of a circadian cycle
  • Another CYP 17 metabolite-associated disease or disorder is hypertension. Mineralocorticoid excess causes hypertension by facilitating the sodium retention at renal tubules.
  • derivative of a compound refers to another compound which can be derived, e.g., by chemical synthesis, from the original compound.
  • a derivative of a compound has certain structural similarities with the original compound.
  • Disease associated with an abnormal activity or level of a lyase refers to diseases in which an abnormal activity or protein level of a lyase is present in certain cells, and in which the abnormal activity or protein level of the lyase is at least partly responsible for the disease.
  • a “disease associated with a lyase” refers to a disease that can be treated with a lyase inhibitor, such as the compounds disclosed herein.
  • a “lyase” refers to an enzyme having a lyase activity.
  • Lyase activity refers to the activity of an enzyme to catalyze the cleavage of the bond C17-C20 in 17 ⁇ -hydroxy-pregnenolone and 17 ⁇ -hydroxy-progesterone to form dehydroepiandrosterone (DHEA) and delta4-androstenedione, respectively. Lyase activity also refers to the cleavage of a similar bond in related compounds.
  • a "lyase inhibitor” is a compound which inhibits at least part of the activity of a lyase in a cell. The inhibition can be at least about 20%, preferably at least about 40%, even more preferably at least about 50%, 70%, 80%, 90%, 95%, and most preferably at least about 98% of the activity of the lyase.
  • a “patient” or “subject” to be treated by the subject method can mean either a human or non-human animal. “Treating” a disease refers to preventing, curing or improving at least one symptom of a disease.
  • heteroatom as used herein means an atom of nitrogen, oxygen, or sulfur.
  • alkyl refers to the radicals of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups.
  • cycloalkyl refers to radicals of cycloalkyl compounds, examples being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • lower alkyl as used herein means an alkyl group but having from one to six carbons, preferably from one to four carbon atoms in its backbone structure. Preferred alkyl groups are lower alkyls.
  • alkoxyl or "alkoxy” as used herein refer to moiety in which an alkyl group is bonded to an oxygen atom, which is in turn bonded to the rest of the molecule. Examples are methoxy, ethoxy, propyloxy, tert-butoxy, etc.
  • nitro means -NO2; the tenn "halogen” designates -F, -CI, -
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, j?-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • the tenns triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, >-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd ed.; Wiley: New York, 1999).
  • the present invention is directed to compounds which inhibit 17 ⁇ -hydroxylase- C17,20-lyase.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and tr ⁇ /w-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivatizaton with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al., "Pharmaceutical Salts". J. Pharm. Sci. 1977, 66, 1-19).
  • compositions of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically- acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically- acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., functioning as 17 ⁇ -hydroxylase-Cl 7,20-lyase inhibitors), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to 17 ⁇ -hydroxylase-Cl 7,20-lyase receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • the present invention provides a method of inhibiting a lyase, e.g., 17 ⁇ -hydroxylase- Cl 7,20-lyase, comprising contacting a lyase with a compound of the invention.
  • the activity can be inhibited by at least 20%, preferably at least about 50%, more preferably at least about 60%, 70%, 80%, 90%, 95%, and most preferably at least about 98%.
  • the invention provides a method for inhibiting a lyase in vitro.
  • the lyase is in vivo or ex vivo.
  • the invention provides methods for inhibiting a lyase in a cell, comprising contacting the cell with a compound of the invention, such that the activity of the lyase is inhibited.
  • the cell may further be contacted with a composition stimulating the uptake of the compound into the cell, e.g., liposomes.
  • the invention provides a method for inhibiting a lyase in a cell of a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a formulation comprising a compound of the present invention, such that the lyase is inhibited in a cell of the subject.
  • the subject can be one having a disease associated with a lyase, e.g., cancer.
  • a disease associated with a lyase e.g., cancer.
  • Preferred types of cancer that can be treated according to the invention include prostate cancer and breast cancer.
  • Other diseases that can be treated include diseases in which it is desired to prevent or inhibit the formation of a hormone selected from the group consisting of the androgens testosterone and dihydrotestosterone (DHT) and the estrogens 17 ⁇ -estradiol and estrone.
  • DHT dihydrotestosterone
  • any disease that can be treated by inhibiting the activity of a lyase e.g., 17 ⁇ -hydroxylase- C 17,20-lyase, can be treated with the compounds of the invention.
  • the invention provides methods and compositions for the treatment of CYP 17 metabolite-associated diseases and disorders.
  • CYP 17 metabolite-associated diseases and disorders include particularly sex steroid hormone dependent cancers, such as androgen-dependent prostate cancer, which may be treated by inhibiting CYP 17-mediated androgen synthesis, and estrogen-dependent breast cancer or ovarian cancer, which may be treated by inhibiting CYP 17-mediated estrogen synthesis.
  • adeno carcinoma of the prostate is a common disease that causes significant morbidity and mortality in the adult male population (see Han and Nelson, Expert Opin. Pharmacother. 2000, 1, 443-9).
  • Hormonal therapy for prostate cancer is considered when a patient fails with initial curative therapy, such as radical prostatectomy or definitive radiation therapy, or if he is found with an advanced disease.
  • Hormonal agents have been developed to exploit the fact that prostate cancer growth is dependent on androgen.
  • Non- steroidal anti-androgens (NSAAs) block androgen at the cellular level. Castration is another, albeit drastic means of decreasing androgens levels in order to treat or prevent prostate cancer.
  • the methods and compositions of the invention are useful in inhibiting the CI 7,20- lyase activity of CYP 17 and thereby decreasing levels of androgen production and the associated growth of androgen-dependent cancers such as prostate cancer.
  • breast cancer in postmenopausal women, can be treated by administration of a CI 7,20-lyase inhibitor of the invention because adrenal and ovarian androgens are the main precursors of the estrogens which stimulate the growth of hormone dependent breast cancer.
  • breast cancer can be treated with inhibitors of aromatase that prevent interconversion of estrogens and adrenal and ovarian androgens (see Harris et al., Eur. J. Cancer Clin. Oncol. 1983, 19, 11). Patients failing to respond to aromatase inhibitors show elevated levels of androgens in response to aromatase inhibitor treatment (see Harris et al, Br. J. Cancer 1988, 55, 493-6).
  • inhibitors of the invention may be used alone or in combination with other drugs to treat or prevent hormone-dependent cancers such as breast and prostate cancer.
  • compositions of the invention are particularly suited to treating or preventing hormone-dependent cancers in individuals genetically predisposed to such cancers, particularly those predisposed due to an alteration in the CYP 17 gene.
  • Another group of CYP 17 metabolite-associated diseases or disorders amenable to treatment with the compositions and methods of the invention include those associated with mineralocorticoid excess such as hypertension caused by sodium retention at renal tubules. Such a mechanism operates in hypertension such as primary hyperaldosteronism and some fonns of congenital adrenal hyperplasia. Recently, deficient cortisol metabolism in the aldosterone target organ has been recognized as a novel form of hypertension known as apparent mineralocorticoid excess.
  • Disorders associated with mineralocorticoid synthesis include abnormalities of mineralocorticoid synthesis and/or metabolism which profoundly affect the regulation of electrolyte and water balance and of blood pressure (see e.g.
  • Mineralocorticoid excess may be caused by aldosterone or 11-deoxycorticosterone by inadequate conversion of cortisol to cortisone by l l ⁇ -hydroxysteroid dehydrogenase type 2 in target tissues, by glucocorticoid receptor deficiency or by constitutive activation of renal sodium channels.
  • Changes in electrolyte balance and renin as well as the abnormal pattern of corticosteroid metabolism are usually diagnostic. Where these abnormalities are inherited (e.g.
  • glucocorticoid remediable hyperaldosteronism GAA
  • receptor defects LSA
  • Liddle's syndrome the molecular basis is again usually known and, in some cases, may provide the simplest diagnostic tests.
  • Primary aldosteronism although readily identifiable, presents problems of differential diagnosis, important because optimal treatment is different for each variant.
  • a significant proportion of patients with essential hypertension show characteristics of mild mineralocorticoid excess, for example low renin levels.
  • a decrease in CYP 17 activity can result in an alteration in mineralorticoid (e.g. aldosterone) biosynthesis.
  • the "CYP 17 metabolite- associated diseases or disorders" of the invention would include those associated with altered levels of aldosterone production (e.g. hypertension, primary adrenal hyperplasia).
  • CYP 17 metabolite-associated diseases or disorders are Cushing's disease, prostatic hyperplasia, glucocorticoid deficiency, and endometrial cancer.
  • the subject that can be treated according to the invention can be a mammal, e.g., a primate, equine, canine, bovine, ovine, porcine, or feline.
  • the mammal is a human.
  • the invention provides methods for inhibiting the lyase activity of enzymes that are present in organisms other than mammals, e.g., yeast and fungus, e.g., mildew. Certain compounds of the invention may function as antifungal compounds.
  • the therapeutic methods of the invention generally comprise administering to a subject in need thereof, a pharmaceutically effective amount of a compound of the invention, or a salt, prodrug or composition thereof.
  • the compounds of the invention can be administered in an amount effective to inliibit the activity of a 17 ⁇ -hydroxylase-Cl 7,20- lyase.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • Toxicity and therapeutic efficacy of the compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD5 0 /ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such reagents to the site of affected tissue in order to minimize potential damage to normal cells and, thereby, reduce side effects.
  • Data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half- maximal inhibition of activity) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • the compounds of the invention have an IC 50 less than 10 ⁇ M as determined by the biochemical or cellular assay described herein. Some compounds of the invention are effective at concentrations of 10 nM, 100 nM, or 1 ⁇ M. Based on these numbers, it is possible to derive an appropriate dosage for administration to subjects.
  • prodrugs are well known in the art in order to enhance the properties of the parent compound. Such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” 6 ed., Ansel et al, Ed.; Williams & Wilkins: pp. 27-29, 1995). Commonly used prodrugs of the disclosed compounds can be designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include N-dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics 9 th ed., Molinoff et al, Ed.; McGraw-Hill: pp. 11-13, 1996).
  • compositions can be prepared so that they may be admimstered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
  • Dermal administration includes topical application or transdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, intraperitoneal, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
  • These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences 14 th ed., John E. Hoover, Managing Editor; Mack Publishing Co.: 1970 or Pharmaceutical Dosage Form and Drug Delivery Systems 6 th ed., Ansel et al, Ed.; Williams & Wilkins: 1995.
  • compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically acceptable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin; or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol; or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n- propyl / hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl or n- propyl / hydroxybenzoate
  • coloring agents for example ethyl or n- propyl / hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or ⁇ -tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound of the invention in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives are exemplified by those already mentioned above.
  • Additional excipients for example sweetening, flavoring and coloring agents, may also be present.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of an oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the compound of the invention is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions of the invention may also be administered in the form of a suppository for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the invention can be employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will preferably be continuous rather than intermittent throughout the dosage regimen.
  • the compounds of the invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the compounds may be administered simultaneously or sequentially.
  • the active compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the active compounds may be useful in combination with agents that are effective in the treatment and prevention of osteoporosis, inflammation, neurofibromatosis, restinosis, and viral infections.
  • the active compounds may also be useful in combination with inhibitors of other components of signaling pathways of cell surface growth factor receptors.
  • Drugs that can be co-administered to a subject being treated with a compound of the invention include antineoplastic agents selected from vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, or amsacrine.
  • antineoplastic agents selected from vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, or amsacrine.
  • Radioactive agents For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference” (PDR), 1996 edition (Medical Economics Company, Montvale, N.J., USA).
  • Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with a compound of the invention to treat a disease, e.g., cancer.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a compound of the invention, materials and/or reagents required for administering the compounds of the invention may be assembled together in a kit.
  • the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being particularly preferred.
  • the kit may further comprise one or more other drugs, e.g., a chemo- or radiotherapeutic agent.
  • drugs e.g., a chemo- or radiotherapeutic agent.
  • the container means may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the formulation may be applied to an infected area of the body, such as the lungs, or injected into an animal, or even applied to and mixed with the other components of the kit.
  • kits also may be provided in dried or lyophilized forms.
  • reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another container means.
  • the kits of the invention may also include an instruction sheet defining administration of the agent. Kits may also comprise a compound of the invention, labeled for detecting lyases.
  • kits of the present invention also will typically include a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • the kits of the invention also may comprise, or be packaged with a separate instrument for assisting with the injection/administration or placement of the ultimate complex composition within the body of an animal.
  • a separate instrument for assisting with the injection/administration or placement of the ultimate complex composition within the body of an animal.
  • Such an instrument may be an inhalant, syringe, pipette, forceps, measured spoon, eye dropper or any such medically approved delivery vehicle.
  • Other instrumentation includes devices that permit the reading or monitoring of reactions or amounts of compounds or polypeptides.
  • the eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.02% TFA. Gradient elution from 10% to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min. was used with an initial hold of 0.5 minute and a final hold at 95% B of 0.5 minute. Total run time was 6.5 minutes.
  • 3-Bromo-4-methylpyridine (1.0 g, 5.81 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled by a dry ice-acetone bath, treated with t-butyllithium in pentane (7 mL, 1.7 M, 11.9 mmol) dropwise and stirred for Vi hour before N,N,N',N'- tetramethylethylenediamine (1.8 mL, 11.93 mmol) was added. After Vz hour, triisopropyl borate (2.75 mL, 11.92 mmol) was added dropwise. After stirring for V2 hour, the mixture was allowed to warm to room temperature and stir for another 3 hours.
  • Example 2 5-Phenyl-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- lH-indole and phenylboronic acid.
  • Example 3 5-(4-Ethylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3-pyridyl)-lH- indole and 4-ethylphenylboronic acid.
  • Example 4. 5-(4-f-Butylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3-pyridyl)- lH-indole and 4-t-butylphenylboronic acid.
  • Example 5 5-(4-Chlorophenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3 -pyridyl)- lH-indole and 4-chlorohenylboronic acid.
  • Example 6 5-(4-Fluorophenyl)-l-(3-pyridyl)-lH-indol). From 5-bromo-l-(3-pyridyl)- lH-indole and 4-fluorophenylboronic acid.
  • Example 7 5-(4-Trifluoromethylphenyl)-l-(3-pyridyl)-lJ3-indole. From 5-bromo-l-(3- pyridyl)-lH-indole and 4-trifluoromethylphenylboronic acid.
  • Example 8 5-(4-Methoxyphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3 -pyridyl)- lH-indole and 4-methoxyphenylboronic acid.
  • Example 9. 5-(4-Ethoxyphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3-pyridyl)- lH-indole and 4-ethoxyphenylboronic acid.
  • Example 10 5-(4-Carbomethoxyphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3- pyridyl)-lH-indole and 4-carbomethoxyphenylboronic acid.
  • Example 11 5-(4-Carboxyphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3- pyridyl)- lH-indole and 4-carboxyphenylboronic acid.
  • Example 12 5-(3-Methylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3-pyridyl)- lH-indole and 3-methylphenylboronic acid.
  • Example 13 5-(3-Chlorophenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3 -pyridyl)- lH-indole and 3-chlorophenylboronic acid.
  • Example 14 5-(3-Fluorophenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3 -pyridyl)- lH-indole and 3-fluorophenylboronic acid.
  • Example 15 5-(3-Trifluoromethylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3- pyridyl)-lH-indole and 3-trifluoromethylphenylboronic acid.
  • Example 16 5-(3-Methoxyphenyl)-l-(3-pyridyl)-l-H-indole. From 5-bromo-l -(3- pyridyl)-lH-indole and 3-methoxyphenylboronic acid.
  • Example 17 5-(3-Ethoxyphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- lH-indole and 3-ethoxyphenylboronic acid.
  • Example 18 5-(3-Nitrophenyl)-l-(3-pyridyl)-lH ⁇ indole. From 5-bromo-l-(3-pyridyl)- lH-indole and 3-nitrophenylboronic acid.
  • Example 19 5-(3-Cyanophenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- lH-indole and 3-cyanophenylboronic acid.
  • Example 20 5-(2-Methylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- lH-indole and 2-methylphenylboronic acid.
  • Example 21 5-(2-Chlorophenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- lH-indole and 2-chlorophenylboronic acid.
  • Example 22 5-(2-Fluorophenyl)-l-(3-pyridyl)-LH-indole. From 5-bromo-l -(3-pyridyl)- lH-indole and 2-fluorophenylboronic acid.
  • Example 23 5-(2-Trifluoromethylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3- pyridyl)-lH-indole and 2-trifluoromethylphenylboronic acid.
  • Example 24 5-(2-Methoxyphenyl)-l-(3-pyridyl)-lH r -indole. From 5-bromo-l -(3- pyridyl)-lH-indole and 2-methoxyphenylboronic acid.
  • Example 25 5-(2-Acetylphenyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- IH-indole and 2-acetylphenylboronic acid.
  • Example 26 5-(3-Thienyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l -(3-pyridyl)- 1H- indole and 3-thiopheneboronic acid.
  • Example 27 5-(3-Furyl)-l-(3-pyridyl)-lH-indole. From 5-bromo-l-(3-pyridyl)-lH- indole and 3-furanboronic acid.
  • Example 28 l,5-b/s(3-Pyridyl)-lH-indole. From 5-bromo-l -(3 -pyridyl)- lH-indole and 3- pyridineboronic acid.
  • Example 32 iV-[l-(3-Pyridyl)-lH-indol-5-yl]benzenesulfonamide. From l-(3-pyridyl)- lH-indol-5-amine and benzenesulfonyl chloride.
  • Example 33 N-[l-(3-Pyridyl)-lH-indol-5-yl]benzylsulfonan ⁇ ide. From l-(3-pyridyl)- lH-indol-5-amine and benzylsulfonyl chloride.
  • Example 34 N-[l-(3-Pyridyl)-lH-indol-5-yl]-4-fluorobenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 4-fluorobenzenesulfonyl chloride.
  • Example 35 N-[l-(3-Pyridyl)-lH-indol-5-yl]-4-cyanobenzenesulfonamide. From l-(3- pyridyl)- lH-indol-5-amine and 4-cyanobenzenesulfonyl chloride.
  • Example 36 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-4-methoxybenzenesulfonamide. From 1- (3-pyridyl)-lH-indol-5-amine and 4-methoxybenzenesulfonyl chloride.
  • Example 37 N-[l-(3-Pyridyl)-lH-indol-5-yl]-4-nitrobenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 4-nitrobenzenesulfonyl chloride.
  • Example 38 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-4-trifluoromethylbenzenesulfonamide.
  • Example 39 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-4-acetylbenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 4-acetylbenzenesulfonyl chloride.
  • Example 40 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-4-methylbenzenesulfonamide. From l-(3- pyridyl)- lH-indol-5-amine and 4-methylbenzenesulfonyl chloride.
  • Example 41 iY-[l-(3-Pyridyl)-lH-indol-5-yI]-4-isopropylbenzenesulfonamide. From 1- (3-pyridyl)-lH-indol-5-amine and 4-isopropylbenzenesulfonyl chloride.
  • Example 42 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-4-f-butylbenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 4-t-butylbenzenesulfonyl chloride.
  • Example 43 N-[l-(3-Pyridyl)-lH-indol-5-yl]-3-fluorobenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 3-fluorobenzenesulfonyl chloride.
  • Example 44 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-2-fluorobenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 2-fluorobenzenesulfonyl chloride.
  • Example 45 N-[l-(3-Pyridyl)-lH-indol-5-yl]-2-trifluoromethylbenzenesulfonamide. From 1 -(3-pyridyl)- lH-indol-5-amine and 2-trifluoromethylbenzene-sulfonyl chloride.
  • Example 46 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-2-methylbenzenesulfonamide. From l-(3- pyridyl)-lH-indol-5-amine and 2-methylbenzenesulfonyl chloride.
  • Example 47 N-[l-(3-Pyridyl)-lH-indol-5-yl]-2-chloro-3-fluorobenzenesulfonamide.
  • Example 48 iV-[l-(3-Pyridyl)-lH-indol-5-yl]-3,4-difluorobenzenesulfonan ⁇ ide. From 1- (3-pyridyl)-lH " -indol-5-amine and 3,4-difluorobenzenesulfonyl chloride.
  • Example 49 N-[l-(3-Pyridyl)-lH-indol-5-yl]-2,5-difluorobenzenesulfonamide. From 1- (3-pyridyl)-lH-indol-5-amine and 2,5-difluorobenzenesulfonyl chloride.
  • Example 51 l-(3-Pyridyl)-5-(l-pyrrolidinyl)-lH-indole. From 5-amino-l-(3-pyridyl)- lH-indole dihydrochloride and 1,4-dibromobutane. White solid (70%): 1H NMR (CDC1 3 ) ⁇ 8.82 (s, 1 ⁇ ), 8.55 (d, 1 ⁇ ), 7.80 (d, 1 ⁇ ), 7.43 (m, 2 ⁇ ), 7.24 (d, IH), 6.85 (s, IH), 6.70 (d,lH), 6.60 (d,lH), 3.37 (m, 4H), 2.05 (m, 4H).
  • Example 54 l-(3-Cyanophenyl)-5-(3-pyridyl)-l£T-indole. From 5-(3-pyridyl)-lH-indole and 3-bromobenzonitrile. Pinkish oil (9%).
  • 1H NMR (CD 3 OD) ⁇ 9.20 (s, 1 ⁇ ), 8.92 (m, 1 ⁇ ), 8.77 (d, 1 ⁇ ), 8.13 (m, 2 ⁇ ), 7.96 (m, 2H), 7.76 (m, 3H), 7.66 (m, 2H), 6.86 (d, IH).
  • Example 55 l-(3-Fluorophenyl)-5-(3-pyridyl)-LH-indole. From 5-(3-pyridyl)-lH-indole and 3-bromo-l-fluorobenzene. Yellow oil (39%).
  • Example 57 l-(2-Pyridyl)-5-(3-pyridyl)-lH-indole. From 5-(3-pyridyl)- IH-indole and 2- fluoropyridine. Colorless oil (96%).
  • 1H NMR (CDC1 3 ) ⁇ 8.91 (s, 1 ⁇ ), 8.55 (m, 2 ⁇ ), 8.30 (d, IH), 7.80 (m, 4H), 7.46 (m, 2H), 7.32 (m, IH), 7.15 (m, IH), 6.75 (d, IH).
  • Example 58 l-(2-Cyanophenyl)-5-(3-pyridyl)-lJ3-indole. From 5-(3-pyridyl)- IH-indole and 2-fluorobenzonitrile. White solid (86%). Mp 138-141°C; 1H NMR (CDC1 3 ) ⁇ 8.88 (s, 1 ⁇ ), 8.55 (m, 1 ⁇ ), 7.86 (m, 3 ⁇ ), 7.71 (m, IH), 7.59 (d, IH), 7.41 (m, 5H), 6.80 (d, IH).
  • Example 59 l-(3-Bromophenyl)-5-(3-pyridyl)-lH-indole.
  • Example 60 l-(3-Chlorophenyl)-5-(3-pyridyl)-li?-indole. From 5-(3-pyridyl)- IH-indole and 3-chloro-l-fluorobenzene. Colorless oil (63%). 1H NMR (CDC1 3 ) ⁇ 8.90 (s, 1 ⁇ ), 8.58 (d, 1 ⁇ ), 7.92 (m, 1 ⁇ ), 7.87 (s, 1 ⁇ ), 7.63 (d, 1 ⁇ ), 7.44 (m, 7 ⁇ ), 6.77 (d, IH).
  • Method L Synthesis of l-(3-pyridyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-indole (Intermediate L).
  • Example 62 5-(2-Pyridyl)-l-(3-pyridyl)-lH-indole. Froml-(3-pyridyl)-5-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)- IH-indole and 2-bromopyridine. Colorless oil (31%).
  • 1H NMR (CDC1 3 ) ⁇ 8.80 (d, 1 ⁇ ), 8.63 (s, 1 ⁇ ), 8.59 (s, 1 ⁇ ), 8.28 (d, 1 ⁇ ), 7.77 (m, 4 ⁇ ), 7.55 (m, IH), 7.43 (m, IH), 7.30 (m, IH), 7.20 (m, IH), 6.78 (d, IH).
  • Example 63 l-(3-Pyridyl)-5-(4-pyridyl)-lH r -indole. Froml-(3-pyridyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole and 4-bromo ⁇ yridine. White solid (50%).
  • 1H NMR (CDC1 3 ) ⁇ 8.79 (d, 1 ⁇ ), 8.57 (m, 3 ⁇ ), 7.90 (s, IH), 7.79 (m, IH), 7.45 (m, 5H), 7.32 (d, IH), 6.74 (d, IH).
  • Example 64 l-(3-Pyridyl)-5-(4-pyridyl)-lH r -indole. Froml-(3-pyridyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)
  • Example 65 5-(5-Cyano-3-pyridyl)-l-(3-pyridyl)-117-indole. Froml-(3-pyridyl)-5- (4,4,5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)- IH-indole and 3-bromo-5-cyanopyridine. Pale yellow solid (33%).
  • 1H NMR (CDC1 3 ) ⁇ 9.10 (s, 1 ⁇ ), 8.88 (d, 1 ⁇ ), 8.82 (s, 1 ⁇ ), 8.68 (d, 1 ⁇ ), 8.20 (d, 1 ⁇ ), 7.95 (m, 2 ⁇ ), 7.60 (m, 2H), 7.45 (m, 2H), 6.83 (d, IH).
  • Example 66 5-(4-Methyl-3-pyridyl)-l-(3-pyridyI)-l J H-indole. Froml-(3- ⁇ yridyl)-5- (4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-indole and 3 -bromo-4-methylpyridine.
  • Method N Exemplified by the synthesis of 2,3-dimethyl-l,5-b s(3-pyridyl)--U ⁇ -indole (Example 67).
  • Example 68 5-(2-Chlorophenyl)-2,3-dimethyl-l-(3-pyridyl)-lH-indole . From 5-bromo- 2,3-dimethyl-l -(3-pyridyl)- IH-indole and 2-chlorophenylboronic acid. Yellow oil (13%).
  • H NMR (CD 3 OD) ⁇ 8.82 (m, 2H), 8.28 (m, IH), 7.94 (m, IH), 7.52 (s, IH), 7.47 (m, IH), 7.34 (m, 3H), 7.18 (s, 2H), 2.32 (s, 3H), 2.30 (s, 3H).
  • Example 69 l-Phenyl-5-(3-pyridyl)-lH-indole. From 5-bromo-l -phenyl- IH-indole and pyridine-3-boronic acid. Colorless oil (39%).
  • Example 70 5-(4-Methyl-3-pyridyl)-l-(2-pyridyl)-l J H-indole. From 5-bromo-l -(2- pyridy)- IH-indole and 4-methylpyridine-3 -boronic acid. Beige oil (42%).
  • 1H NMR (CDCI 3 ) ⁇ 8.59 (m, 1 ⁇ ), 8.51 (s, 1 ⁇ ), 8.43 (d, 1 ⁇ ), 8.32 (d, 1 ⁇ ), 7.83 (m, 1 ⁇ ), 7.77 (m, 1 ⁇ ), 7.59 (s, 1 ⁇ ), 7.50 (d, 1 ⁇ ), 7.20 (m, 3 ⁇ ), 6.77 (d, IH), 2.35 (s, 3H).
  • Example 71 Example 71.
  • Example 72 l-(2-Cyanophenyl)-5-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l -(2- cyanophenyl)-lH-indole and 4-methylpyridine-3 -boronic acid. Beige solid (50%).
  • 1H NMR (CDCI 3 ) ⁇ 8.52 (s, 1 ⁇ ), 8.43 (d, 1 ⁇ ), 7.88 (d, 1 ⁇ ), 7.77 (m, 1 ⁇ ), 7.62 (m, 2 ⁇ ), 7.50 (m, 2H), 7.41 (d, IH), 7.20 (m, 2H), 6.80 (d, IH), 2.33 (s, 3H).
  • Example 73 l,5-b s(3-pyridyl)-lH-indazole. From 5-bromo-l -(3-pyridyl)- lH-indazole and pyridine-3-boronic acid. White solid (60%).
  • 1H NMR (CDCI 3 ) ⁇ 9.10 (d, 1 ⁇ ), 8.90 (d, 1 ⁇ ), 8.62 (m, 2 ⁇ ), 8.30 (s, IH), 8.09 (m, IH), 8.00 (s, IH), 7.93 (m, IH), 7.83 (d, IH), 7.68 (d, IH), 7.49 (m, IH), 7.40 (m, IH).
  • Example 74 5-(4-Fluorophenyl)-l-(3-pyridyl)-lH-indazole. From 5-bromo-l -(3- pyridyl)-lH-indazole and 4-fluorophenylboronic acid. White solid (43%).
  • 1H NMR (CDCI 3 ) ⁇ 9.02 (s, 1 ⁇ ), 8.54 (m, 1 ⁇ ), 8.21 (s, 1 ⁇ ), 8.04 (m, 1 ⁇ ), 7.85 (s, 1 ⁇ ), 7.73 (d, 1 ⁇ ), 7.60 (d, 1 ⁇ ), 7.26 (m, 3 ⁇ ), 7.07 (m, 2H).
  • Example 75 5-(4-Methyl-3-pyridyl)-l-(2-pyridyl)-lJ?-indazole. From 5-bromo-l -(2- pyridyl)-lH-indazole and 4-methylpyridine-3 -boronic acid. Beige oil (43%).
  • 1H NMR (CDCI 3 ) ⁇ 8.90 (d, 1 ⁇ ), 8.53 (m, 2 ⁇ ), 8.47 (d, IH), 8.22 (s, IH), 8.05 (d, IH), 7.82 (m, IH), 7.68 (s, IH), 7.44 (d, IH), 7.19 (m, 2H), 2.31 (s, 3H).
  • Example 76 Example 76.
  • Step 1 5-Bromo-l-(3-cyanophenyl)- IH-indole (100 mg, 0.34 mmol) was stirred in cone. ⁇ 2 SO 4 at room temperature overnight. Then the mixture was carefully added to cold sodium carbonate solution until pH 4-5. Extraction with C ⁇ 2 C1 2 and also CH 2 Cl /2-propanol (4:1) gave 104 mg (98%) of 3-(5-bromo-lH-indol-l-yl)benzamide as a yellow solid.
  • Example 78 5-Bromo-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-lH-indole and 3 -bromo-4-methylpyridine.
  • Example 79. l-(4-Methyl-3-pyridyl)-lH-indole-5-carbonitrile: From lH-indole-5- carbonitrile and 3-bromo-4-methylpyridine.
  • Example 80 Benzyl l-(4-methyl-3-pyridyl)-li ⁇ -indol-5-yl ether: From Benzyl lH-indol- 5-yl ether and 3-bromo-4-methylpyridine.
  • Example 82 l-(4-Methyl-3-pyridyl)-5-(3-pyridyI)-lH-indole. From 5-bromo-l -(4- methyl-3-pyridyl)- IH-indole and pyridine-3 -boronic acid. Beige gel (27%); 1H NMR (CD 3 OD) ⁇ 9.20 (s, 1 ⁇ ), 8.85 (m, 2 ⁇ ), 8.79 (m, 2H), 8.20 (s, IH), 8.15 (m, IH), 8.02 (d, IH), 7.67 (d, IH), 7.56 (d, IH), 7.33 (d, IH), 6.97 (d, IH), 2.34 (s, 3H).
  • Example 83 l-(4-Methyl-3-pyridyl)-5-(4-pyridyl)-lH r -indole. From 5-bromo-l -(4- methyl-3-pyridyl)- IH-indole and pyridine-4-boronic acid. Yellow gel (25%); ! ⁇ NMR (CD 3 OD) ⁇ 8.79 (m, 4H), 8.43 (m, 3H), 7.94 (m, IH), 7.88 (m, IH), 7.59 (d, IH), 7.35 (d, IH), 7.00 (d, IH), 2.30 (s, 3H).
  • Example 84 l,5-b/s(4-Methyl-3-pyridyl)-lH-indole. From 5-bromo-l-(4-methyl-3- pyridyl)- IH-indole and 4-methylpyridine-3-boronic acid. Colorless gel (33%); 1H NMR (CD 3 OD) ⁇ 8.91 (broad, 1 ⁇ ), 8.80 (broad, 1 ⁇ ), 8.73 (s, 1 ⁇ ), 8.69 (d, 1 ⁇ ), 8.02 (m, 2 ⁇ ), 7.83 (s, IH), 7.58 (d, IH), 7.30 (m, 2H), 6.94 (d, IH), 2.63 (s, 3H), 2.38 (s, 3H).
  • Example 85 5-(3-Furyl)-l-(4-methyl-3-pyridyl)-lH-indole). From 5-bromo-l -(4- methyl-3 -pyridyl)- IH-indole and furan-3-boronic acid. Beige gel (19%); 1H NMR (CD 3 OD) ⁇ 8.82 (broad , 1 ⁇ ), 8.73 (broad, 1 ⁇ ), 7.94 (m, 1 ⁇ ), 7.84 (m, 2 ⁇ ), 7.53 (d, IH), 7.42 (d, IH), 7.39 (d, IH), 7.07 (d, IH), 6.80 (m, 2H), 2.32 (s, 3H).
  • Example 86 l-(4-Methyl-3-pyridyl)-5-(3-thienyl)-llf-indole. From 5-bromo-l -(4- methyl-3-pyridyl)- IH-indole and thiophene-3 -boronic acid. Yellow gel (10%); 1H NMR (CD 3 OD) ⁇ 8.78 (m, 2 ⁇ ), 7.95 (m, 2H), 7.47 (m, 5H), 7.10 (d, IH), 6.81 (d, IH), 2.30 (s, 3H).
  • Example 87 l-(4-Methyl-3-pyridyl)-5-phenyl-lH-indole.
  • Example 88 5-(2-Fluorophenyl)-l-(4-methyl-3-pyridyl)-ll ⁇ -indole. From 5-bromo-l -(4- methyl-3 -pyridyl)- IH-indole and 2-fluorophenylboronic acid. Beige gel (28%); 1H NMR (CD 3 OD) ⁇ 8.43 (m, 2 ⁇ ), 7.75 (s, IH), 7.44 (m, 2H), 7.20 (m, 5H), 6.95 (d, IH), 6.70 (d, IH), 2.08 (s, 3H).
  • Example 89 5-(2-Cyanophenyl)-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l -(4- methyl-3 -pyridyl)- IH-indole and 2-cyanophenylboronic acid. Beige gel (5%); 1H NMR (CD 3 OD) ⁇ 8.43 (m, 2 ⁇ ), 7.80 (d, IH), 7.74 (d, IH), 7.45 (m, 6H), 7.01 (d, IH), 6.75 (d, lH), 2.10 (s, 3H).
  • Example 90 5-(2-Chlorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l-(4- methyl-3 -pyridyl)- IH-indole and 2-chlorophenylboronic acid. Beige gel (7%); 1H NMR (CD 3 OD) ⁇ 8.44 (d, 2 ⁇ ), 7.60 (s, IH), 7.30 (m, 7H), 6.94 (d, IH), 6.68 (d, IH), 2.09 (s, 3H).
  • Example 91 5-(3-Fluorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole.
  • Example 92 5-(3-Chlorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l - (4-methyl-3-pyridyl)-lH-indole and 3-chloiOphenylboronic acid. Beige gel (10%); 1H NMR (CD 3 OD) ⁇ 8.65 (m, 2H), 7.82 (s, IH), 7.78 (m, IH), 7.52 (s, IH), 7.45 (d, IH), 7.37 (d, IH), 7.30 (d, 2H), 7.19 (d, IH), 7.04 (d, IH), 6.75 (d, IH), 2.20 (s, 3H).
  • Example 93 l-(4-Methyl-3-pyridyl)-5-(3-nitrophenyl)-lH-indole. From 5-bromo-l -(4- methyl-3-pyridyl)- IH-indole and 3-nitrophenylboronic acid. Yellow gel (26%); 1H NMR (CD 3 OD) ⁇ 8.82 (broad, 2 ⁇ ), 8.48 (d, IH), 8.18 (d, IH), 8.02 (m, 3H), 7.67 (m, IH), 7.57 (d, IH), 7.48 (d, IH), 7.21 (d, IH), 6.90 (d, IH), 2.36 (s, 3H).
  • Example 94 5-(4-Fluorophenyl)-l-(4-Methyl-3-pyridyl)-lH-indole. From 5-bromo-l - (4-methyl-3-pyridyl)- IH-indole and 4-fluorophenylboronic acid. Beige powder (41%); Mp 120-122°C; 1H NMR (CDC1 3 ) ⁇ 8.68 (broad, 2 ⁇ ), 7.89 (s, IH), 7.61 (m, 2H), 7.40 (d, 2H), 7.14 (m, 4H), 6.79 (d, IH), 2.18 (s, 3H).
  • Example 95 5-(4-Cyanophenyl)-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l -(4- methyl-3-pyridyl)-lH-indole and 4-cyanophenylboronic acid. Yellow gel (13%); 1H NMR (CD 3 OD) ⁇ 8.80 (m, 2 ⁇ ), 8.02 (s, IH), 7.97 (m, IH), 7.83 (d, 2H), 7.77 (d, 2H), 7.55 (d, IH), 7.46 (d, IH), 7.20 (d, IH), 6.89 (d, IH), 2.32 (s, 3H).
  • Example 96 5-(4-Cyanophenyl)-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l -(4- methyl-3-pyridyl)-lH-indole and 4-cyanophenyl
  • Example 97 l-(4-Methyl-3-pyridyl)-5-(4-trifluoromethylphenyl)-lH-indole. From 5- bromo-l-(4-methyl-3 -pyridyl)- IH-indole and 4-trifluoromethylphenyl-boronic acid. Beige gel (21%); 1H NMR (CD 3 OD) ⁇ 8.81 (m, 2 ⁇ ), 8.00 (m, 2H), 7.82 (d, 2H), 7.71 (d, 2H), 7.56 (d, IH), 7.44 (d, IH), 7.20 (d, IH), 6.88 (d, IH), 2.34 (s, 3H).
  • Example 98 5-(4-Methoxyphenyl)-l-(4-methyl-3-pyridyl)-lH-indole. From 5-bromo-l - (4-methyl-3-pyridyl)- IH-indole and 4-methoxyphenyl-boronic acid.
  • Example 99 l-(2-Methyl-3-pyridyl)-5-(3-pyridyl)-lH-indole. From 5-bromo-l -(2- methyl-3 -pyridyl)- IH-indole and pyridine-3 -boronic acid. Beige gel (96%); 1H NMR (CDC1 3 ) ⁇ 8.83 (m, 1 ⁇ ), 8.59 (m, 1 ⁇ ), 8.50 (m, 1 ⁇ ), 7.85 (m, 2 ⁇ ), 7.60 (m, IH), 7.30 (m, 3H), 7.15 (m, IH), 7.04 (d, IH), 6.72 (d, IH), 2.30 (s, 3H).
  • Example 100 5-(4-Fluorophenyl)-l-(2-methyI-3-pyridyl)-lH-indole. From 5-bromo-l - (2-methyl-3-pyridyl)- IH-indole and 4-fluorophenylboronic acid. Beige gel (41%); 1H NMR (CDCI 3 ) ⁇ 8.59 (d, 1 ⁇ ), 7.80 (s, 1 ⁇ ), 7.64 (d, 1 ⁇ ), 7.52 (m, 2 ⁇ ), 7.30 (m, 2H), 7.07 (m, 4H), 6.71 (d, lH), 2.30 (s, 3H).
  • Example 101 Example 101.
  • Example 103 3-[l-(4-Methyl-3-pyridyl)-lH-indol-5-yl]benzonitrile. From 5-bromo-l - (4-methyl-3-pyridyl)- IH-indole and 3-cyanophenylboronic acid. 1H NMR (CD 3 OD, TFA salt) ⁇ 8.80 (s, 1 ⁇ ), 8.70 (d, 1 ⁇ ), 8.00 (m, 3 ⁇ ), 7.91 (d, IH), 7.65 (m, 2H), 7.53 (d, IH), 7.45 (d, IH), 7.19 (d, IH), 6.88 (d, IH), 2.30 (s, 3H).
  • Step 1 A mixture of 5-indolylboronic acid (2 g, 12.4 mmol), 5-bromopyrimidine (1.85 g, 11.3 mmol), sodium bicarbonate (2.85 g, 33.9 mmol), tetr ⁇ f ⁇ s(triphenylphosphine) palladium (0.66 mg, 0.57 mmol), 1,2-dimethoxyethane (100 mL) and water (50 mL) were heated at reflux for 6 h. The reaction mixture was diluted with dichloromethane and washed with water (2x) a d brine. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo to give a crude product.
  • Step 2 A mixture 5-(5-pyrimidyl)-lH-indole (1.6 g, 8.196 mmol), copper(I) iodide (0.19 g, 0574 mmol), copper (0.73 g, 11.74 mmol), potassium carbonate (2.83 g, 20.5 mmol) and 3- bromo-4-methylpyridine (8 mL) was stirred at 200°C under argon for 4 h. The mixture was cooled to room temperature and diluted with dichloromethane. Filtration followed by concentration of the filtrate gave a brown oil.
  • Example 05 4-Phenyl- 1 -(3 -pyridyl)- lH-indole.
  • Example 06 6-Phenyl- 1 -(3 -pyridyl)- lH-indole.
  • Example 07 4-(4-t-Butylphenyl)- 1 -(3-pyridyl)- lH-indole.
  • Example 08 6-(4-Chlorophenyl)-l-(3-pyridyl)-lH-indole.
  • Example 09 4-(4-Fluorophenyl)-l-(3-pyridyl)-lH-indole.
  • Example 10 6-(4-Trifluoromethylphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 11 4-(4-Methoxyphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 12 6-(4-Ethoxyphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 13 4-(3-Furyl 1 -(3 -pyridyl)- lH-indole.
  • Example 14 6-(3-Methylphenyl)-l-(3-pyridyl)-lH-indole.
  • Example 15 4-(3 -Chlorophenyl)- 1 -(3-pyridyl)- lH-indole.
  • Example 16 6-(3-Fluorophenyl)-l-(3-pyridyl)-lH-indole.
  • Example 17 4-(3-Trifluoromethylphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 18 6-(3 -Methoxyphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 19 4-(3 -Ethoxyphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 20 6-(3 -Nitrophenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 21 4-(3 -Cyanophenyl)- 1 -(3-pyridyl)- lH-indole.
  • Example 22 6-(2-Methylphenyl)-l-(3-pyridyl)-lH-indole.
  • Example 23 4-(2-Chlorophenyl)- 1 -(3-pyridyl)- lH-indole.
  • Example 24 6-(2-Fluorophenyl)-l-(3-pyridyl)-lH-indole.
  • Example 25 4-(2-Trifluoromethylphenyl)-l-(3-pyridyl)-lH-indole.
  • Example 26 6-(2-Methoxyphenyl)-l-(3-pyridyl)-lH-indole.
  • Example 27 4-(2-Acetylphenyl)- 1 -(3 -pyridyl)- lH-indole.
  • Example 28 6-(3-Thienyl)- 1 -(3 -pyridyl)- IH-indole.
  • Example 130 1 ,6-bzs(3-Pyridyl)-lH-indole.
  • Example 132 6-(4-Methoxyphenyl)- 1 -(4-methyl-3 -pyridyl)- lH-indole.
  • Example 134 1 -(4-Methyl-3-pyridyl)-6-(3-pyrimidyl)- lH-indole.
  • Example 135. 1 ,6-bis(4-Metbyl-3 -pyridyl)- lH-indole.
  • Example 136 6-(4-Fluorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole.
  • Example 137 4-(4-Cyanophenyl)- 1 -(4-methyl-3 -pyridyl)- lH-indole.
  • Example 138 6-(4-Chlorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole.
  • Example 139 1 -(2-Fluorophenyl)-4-(3-pyridyl)- lH-indole.
  • Example 140 l-(3-Cyanophenyl)-6-(3-pyridyl)-lH-indole.
  • Example 141 1 -(3-Fluorophenyl)-4-(3-pyridyl)- lH-indole.
  • Example 142 1 -(2-Chlorophenyl)-6-(3-pyridyl)- lH-indole.
  • Example 143 1 -(2-Pyridyl)-4-(3-pyridyl)- lH-indole.
  • Example 145 l-(3-Bromophenyl)-4-(3-pyridyl)-lH-indole.
  • Example 146 1 -(3 -Chlorophenyl)-6-(3 -pyridyl)- lH-indole.
  • Example 1 149. 1 -Phenyl-4-(3-pyridyl)- lH-indole
  • Example ] 150 6-(4-Methyl-3-pyridyl)- 1 -(2-pyridyl)- lH-indole.
  • Example 151 l-(3-Cyanophenyl)-4-(4-methyl-3-pyridyl)-lH-indole.
  • Example 152 1 -(2-Cyanophenyl)-6-(4-methyl-3 -pyridyl)- lH-indole.
  • Example 1 154. l-(4-Methyl-3-pyridyl)-6-(4- ⁇ yridyl)-lH-indole.
  • Example 1 [55. 1 ,4-bz ' s(4-Methyl-3 -pyridyl)- lH-indole.
  • Example 1 156 4-(3-Furyl)- 1 -(4-methyl-3 -pyridyl)- IH-indole.
  • Example 157 l-(4-Methyl-3-pyridyl)-6-(3-thienyl)-lH-indole.
  • Example 158 l-(4-Methyl-3-pyridyl)-4-phenyl-lH-indole.
  • Example 159 6-(2-Fluorophenyl)-l-(4-methyl-3 -pyridyl)- lH-indole.
  • Example 160 4-(2-Cyanophenyl)-l-(4-methyl-3 -pyridyl)- lH-indole.
  • Example 161. 6-(2-Chlorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole.
  • Example 162 4-(3-Fluorophenyl)- 1 -(4-methyl-3-pyridyl)- lH-indole.
  • Example 164 l-(4-Methyl-3-pyridyl)-4-(3-nitrophenyl)-lH-indole.
  • 5-bromo-lH-indole and 5-bromo-lH-indazole intermediates can also be prepared by these or similar procedures using the appropriate starting materials.
  • Example 165 4-Fluoro-l-(3-pyridyl)-5-(3-thienyl)-lH-indole.
  • Example 166 4-Fluoro-5-phenyl-l -(3 -pyridyl)- IH-indole.
  • Example 167 4-Fluoro-l,5-b -y(3- ⁇ yridyl)-lH-indole.
  • Example 168 4-Fluoro-l,5-bz ' -s , (4-methyl-3-pyridyl)-lH-indole.
  • Example 170 4-Fluoro-5-(2-fluorophenyl)- 1 -(4-methyl-3-pyridyl)- lH-indole.
  • Example ] [71. 3 -Methyl-5-phenyl- 1 -(3 -pyridyl)- lH-indole.
  • Example 1 [76. 3-[3-Cyano- 1 -(4-methyl-3-pyridyl)- lH-indol-5-yl]benzonitrile.
  • Example . 80 7-Chloro-5-phenyl- 1 -(3 -pyridyl)- lH-indole.
  • Example 1 85 3 - [2-Methyl- 1 -(4-methyl-3 -pyridyl)- lH-indol-5 -yljbenzonitrile.
  • Example 1 6-Methoxy- 1 -(4-methyl-3-pyridyl)-5-(3 -pyridyl)- lH-indole.
  • Example 1 6-Methoxy-l-(4-methyl-3-pyridyl)-5-phenyl-lH-indole.
  • Example 1 88. 7-Methyl- 1 ,5-bM(3-pyridyl)- lH-indole.
  • Example ] 91 6-Fluoro-5-(2-fluorophenyl)-l-(4-methyl-3-pyridyl)-lH-indole.
  • Example 1 93. 5-(3-Cyanophenyl)-3-isopropyl-l-(4-methyl-3-pyridyl)-lH-indole.
  • Example 1 94. 7-Methyl- 1 -(4-methyl-3-pyridyl)-5-(3 -pyridyl)- lH-indazole.
  • Example 1 95. 5-(3-Cyanophenyl)-7-methyl- 1 -(4-methyl-3-pyridyl)- lH-indazole.
  • the structures for the compounds of the invention, and data characterizing them, are shown in Tables 1-8 below.
  • C17,20-Lyase inhibitory activity of compounds can be determined using, e.g., the biochemical or the cellular assays set forth below. A person of skill in the art will recognize that variants of these assays can also be used.
  • the compounds of the invention can also be tested in animal models, e.g., animal models of prostate or breast cancer. Each of the compounds of the invention was subjected to a biochemical assay and a cellular assay for determining its C 17,20 lyase inhibitory activity.
  • Recombinant human CI 7,20-lyase (hLyase) was expressed in baculovirus-infected Sf9 cells and hLyase enriched microsomes were prepared from cultures as described (Barnes H. J.; Jenkins, C. M.; Waterman, M. R. Archives of Biochemistry and Biophysics 1994, 315(2), 489-494).
  • Recombinant murine CI 7,20-lyase (mLyase) was prepared in a similar manner. hLyase and mLyase preparations were titrated using assay conditions to determine protein concentrations to be used for assays.
  • Test compound solutions (20 mM in DMSO) were diluted 1 :4 with DMSO and put into the top well of a 96-well mother plate. These solutions were then diluted serially in six steps (1:4 each step) with DMSO to obtain 800 ⁇ M to 51.2 nM concentrations on a mother plate (columns 3-12) for subsequent use in the assay. These compound solutions were further diluted twenty- fold in water to obtain a daughter plate containing compound concentrations ranging from 40 ⁇ M to 2.56 nM in 5% DMSO.
  • the first 2 columns (of wells) on each 96-well mother plate were used for the DHEA (dehydroepiandrosterone) standard curve.
  • DHEA standards were serially diluted (in half-logs) in DMSO to obtain 400 ⁇ M to 120 nM standards, then diluted (1:19) in water to obtain 20 ⁇ M to 6 nM solutions in 5% DMSO on the daughter plate. These 5% DMSO solutions (5 ⁇ L each) from the daughter plate were transferred to the SPA assay plate prior to adding the reaction mixture.
  • reaction mixture clear-bottomed opaque 96-well assay plates were loaded with 50 ⁇ L of assay buffer (50 mM Na 3 PO 4 , pH 7.5), 5 ⁇ L of the diluted compounds (or standards), and 30 ⁇ L of substrate solutions (7 mM NADPH, 3.35 ⁇ M 17-OH- pregnenolone, 3.35 ⁇ g/mL human cytochrome b 5 in 50 mM Na 3 PO 4 ).
  • substrate solutions 7 mM NADPH, 3.35 ⁇ M 17-OH- pregnenolone, 3.35 ⁇ g/mL human cytochrome b 5 in 50 mM Na 3 PO 4 .
  • Reactions were initiated with the addition of hLyase or mLyase in assay buffer (10 ⁇ L). Enzymatic reactions were incubated at room temperature for 2 hours with gentle agitation. Reactions were terminated with the addition of 5 ⁇ L of 1 mM (50 ⁇ M final concentration) YM116
  • the concentration of DHEA generated by hLyase (or mLyase) was determined by radioimmunoassay (RIA).
  • RIA utilized a 3 H-DHEA (0.08 ⁇ Ci) tracer in 50 ⁇ L of scintillation proximity assay (SPA) buffer (100 mM Tris-HCl, pH 7.5, 50 mM NaCl, 0.5%
  • the concentration of DHEA generated was calculated from raw data (CPM) and the standard curve.
  • the concentration of DHEA formed in the presence of test compounds was expressed as a percent inhibition compared to the DHEA concentration in the absence of test compounds: [1 - (nM DHEA formed in the presence of test compound/nM DHEA formed in the absence of test compounds)] x 100. Determination of
  • Human HEK 293-lyase stable transfectant cells were seeded in a 96-well plate at 10,000 cells/well/ 100 ⁇ L in DMEM plus 10% FBS (supplemented with 1% glutamine, 0.8 mg/mL G418) and allowed to attach overnight. On the following day, the media was removed from the cell plate and replaced with 100 ⁇ L RPMI without phenol red. Test compounds (columns 3-12), DMSO vehicle (column 2), or DHEA standards (column 1) of 5 ⁇ L each were added to the cell plate and incubated for 10 min. at room temperature. The final concentrations of DHEA standards were 750, 250, 83.3, 27.7, 9.2, 3, 1, and 0.3 nM.
  • the reaction was initiated with 10 ⁇ L of 5 ⁇ M 17-OH-pregnenolone being added to all the wells of the cell plate, then incubated for 1 hour at 37°C. Following the incubation, 90 ⁇ L of media (containing DHEA product) was removed from the cell plate and transfened to the SPA assay plate. The subsequent SPA procedure for the detection of DHEA product was performed in the same manner as described for the enzyme assay (see above). The mother plate of test compounds was also prepared in the same manner as the enzyme assay. However, the highest concentration of compounds on the daughter plate was 200 ⁇ M rather than 40 ⁇ M, such that the highest dose of compound tested was 10 ⁇ M in final concentration (cellular assay) rather than 2 ⁇ M (biochemical assay).
  • Reagents for the SPA assay were obtained from the following sources: 3 H-DHEA: NEN (NET814), Anti-DHEA: Endocrine Sciences (D7-421), Anti- Rabbit SPA Beads: Amersham (RPNQ 0016), 17-OH-pregnenolone: Steraloids (Q4710),
  • NADPH Sigma (N1630)
  • Cytochrome b5 Panvera (P2252)
  • DHEA 500 ⁇ M stock in 100%
  • test compound was considered to be active if the IC 50 in the human C 17,20 biochemical assay or the human C 17,20 cellular assay was less than 10 ⁇ M. All the compounds tested have IC 50 in the human C 17,20 biochemical assay or the human C 17,20 cellular assay of less than 10 ⁇ M.

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Families Citing this family (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE440096T1 (de) * 2000-12-08 2009-09-15 Takeda Pharmaceutical Substituierte thiazolderivate mit 3- pyridylgruppen, verfahren zu deren herstellung und deren verwendung
JP4160295B2 (ja) * 2000-12-08 2008-10-01 武田薬品工業株式会社 ３−ピリジル基を有する置換チアゾール誘導体、その製造法および用途
US20040147561A1 (en) * 2002-12-27 2004-07-29 Wenge Zhong Pyrid-2-one derivatives and methods of use
US7244739B2 (en) * 2003-05-14 2007-07-17 Torreypines Therapeutics, Inc. Compounds and uses thereof in modulating amyloid beta
ES2222827B1 (es) * 2003-07-30 2006-03-01 Laboratorios Del Dr. Esteve, S.A. Derivados de 5-indolilsulfonamidas, su preparacion y su aplicacion como medicamentos.
DE602004022319D1 (de) * 2003-11-14 2009-09-10 Vertex Pharma Thiazole udn oxazole als modulatoren von atp-bindungs-kassetten-transportern
JP2007532669A (ja) * 2004-04-13 2007-11-15 イカジェン インコーポレイテッド カリウムイオンチャネル調節剤としての多環式ピリミジン
JP4602686B2 (ja) * 2004-04-15 2010-12-22 広栄化学工業株式会社 ２，６−ジハロゲノ−４−アリールピリジン類の製造法
EP2939674A1 (en) * 2004-10-13 2015-11-04 PTC Therapeutics, Inc. Compounds for nonsense suppression, and methods for their use
PT1802579E (pt) * 2004-10-20 2014-02-17 Merck Serono Sa Derivados da 3-arilaminopiridina
WO2006051723A1 (ja) * 2004-11-09 2006-05-18 Kaneka Corporation １－ハロ－３－アリール－２－プロパノン類の製造法
GB0428514D0 (en) * 2004-12-31 2005-02-09 Prosidion Ltd Compounds
ZA200705827B (en) * 2005-01-19 2008-10-29 Biolipox Ab Indoles useful in the treatment of inflammation
BRPI0608910A2 (pt) 2005-05-09 2010-02-17 Achillion Pharmaceuticals Inc uso de um composto da fórmula ou um sal ou hidrato farmaceuticamente aceitável desse, composto ou sal ou hidrato do mesmo, composição farmacêutica e composição farmacêutica embalada
AU2006278998A1 (en) * 2005-07-29 2007-02-15 4Sc Ag Novel heterocyclic NF-kB inhibitors
FR2889526B1 (fr) 2005-08-04 2012-02-17 Aventis Pharma Sa 7-aza-indazoles substitues, compositions les contenant, procede de fabrication et utilisation
KR20080066938A (ko) * 2005-10-07 2008-07-17 깃세이 야쿠힌 고교 가부시키가이샤 질소 함유 복소환 화합물 및 그것을 함유하는 의약 조성물
TWI385169B (zh) 2005-10-31 2013-02-11 Eisai R&D Man Co Ltd 經雜環取代之吡啶衍生物及含有彼之抗真菌劑
AR056893A1 (es) * 2005-12-28 2007-10-31 Takeda Pharmaceutical Compuestos heterociclicos fusionados y no fusionados, antagonistas de receptores mineralocorticoides
KR101081293B1 (ko) * 2006-01-18 2011-11-08 에프. 호프만-라 로슈 아게 11 베타-에이치에스디1 억제제로서 티아졸
CN101374808B (zh) 2006-01-24 2011-05-25 伊莱利利公司 孕酮受体的吲哚磺酰胺调节剂
PL2001849T3 (pl) * 2006-03-29 2015-04-30 Hoffmann La Roche Pochodne pirydyny i pirymidyny jako antagoniści mGluR2
US7649007B2 (en) 2006-08-15 2010-01-19 Wyeth Llc Oxazolidine derivatives as PR modulators
US7652018B2 (en) 2006-08-15 2010-01-26 Wyeth Llc Imidazolidin-2-one derivatives useful as PR modulators
US7538107B2 (en) 2006-08-15 2009-05-26 Wyeth Oxazinan-2-one derivatives useful as PR modulators
US7618989B2 (en) 2006-08-15 2009-11-17 Wyeth Tricyclic oxazolidone derivatives useful as PR modulators
JP5284788B2 (ja) * 2006-09-21 2013-09-11 エーザイ・アール・アンド・ディー・マネジメント株式会社 ヘテロアリール環置換ピリジン誘導体およびそれらを含有する抗真菌剤
EP2065377B1 (en) 2006-09-21 2011-11-23 Eisai R&D Management Co., Ltd. Pyridine derivative substituted by heteroaryl ring, and antifungal agent comprising the same
EP2076265A4 (en) 2006-10-02 2010-09-22 Cortendo Invest Ab KETOCONAZOLE ENANTIOMER IN HUMANS
WO2008070350A2 (en) 2006-10-27 2008-06-12 The Board Of Regents Of The University Of Texas System Methods and compositions related to wrapping of dehydrons
US9187485B2 (en) 2007-02-02 2015-11-17 Baylor College Of Medicine Methods and compositions for the treatment of cancer and related hyperproliferative disorders
BRPI0811939A2 (pt) 2007-05-22 2014-11-25 Achillion Pharmaceuticals Inc Tiazóis substituídos por heteroarila
ES2542849T3 (es) 2007-08-13 2015-08-12 Monsanto Technology Llc Composiciones y procedimientos de control de nematodos
AU2008310097B2 (en) 2007-10-09 2013-05-16 Merck Patent Gmbh Pyridine derivatives useful as glucokinase activators
US8513287B2 (en) 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
CN101910153B (zh) * 2008-01-11 2014-01-22 诺华股份有限公司 作为激酶抑制剂的嘧啶类
US9029411B2 (en) 2008-01-25 2015-05-12 Millennium Pharmaceuticals, Inc. Thiophenes and uses thereof
CN101965177A (zh) 2008-02-08 2011-02-02 株式会社资生堂 美白剂和皮肤外用剂
DK2959900T3 (en) * 2008-06-16 2017-06-26 Univ Tennessee Res Found CONNECTION TO TREATMENT OF CANCER
US9029408B2 (en) 2008-06-16 2015-05-12 Gtx, Inc. Compounds for treatment of cancer
US9447049B2 (en) 2010-03-01 2016-09-20 University Of Tennessee Research Foundation Compounds for treatment of cancer
US8822513B2 (en) 2010-03-01 2014-09-02 Gtx, Inc. Compounds for treatment of cancer
US8697694B2 (en) * 2008-08-20 2014-04-15 Merck Sharp & Dohme Corp. Substituted pyridine and pyrimidine derivatives and their use in treating viral infections
MY154000A (en) 2008-09-22 2015-04-30 Cayman Chem Co Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
EP2391619A1 (en) 2009-01-30 2011-12-07 Millennium Pharmaceuticals, Inc. Heteroaryls and their use as pi3k inhibitors
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
TW201038553A (en) * 2009-03-19 2010-11-01 Sanofi Aventis Novel indazole derivatives which inhibit HSP90, compositions containing them and use thereof
JP5728487B2 (ja) * 2009-10-29 2015-06-03 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 三環式ヘテロ環化合物
WO2011051198A2 (de) * 2009-10-30 2011-05-05 Bayer Cropscience Ag Pyridin-derivate als pflanzenschutzmittel
DE102009058280A1 (de) 2009-12-14 2011-06-16 Merck Patent Gmbh Thiazolderivate
CN102883607B (zh) 2010-03-01 2015-07-22 Gtx公司 用于治疗癌的化合物
CN103140490A (zh) 2010-07-15 2013-06-05 百时美施贵宝公司 氮杂吲唑化合物
KR101594660B1 (ko) 2010-08-04 2016-02-16 펠피큐어 파마슈티걸즈 아이엔씨 전립선 암종의 치료를 위한 병용 요법
SG10201506238SA (en) 2010-08-11 2015-09-29 Millennium Pharm Inc Heteroaryls And Uses Thereof
US8859768B2 (en) 2010-08-11 2014-10-14 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
PE20141044A1 (es) 2010-10-13 2014-09-07 Millennium Pharm Inc Heteroarilos y sus usos
EP2630133A1 (de) 2010-10-22 2013-08-28 Bayer Intellectual Property GmbH Neue heterocylische verbindungen als schädlingsbekämpfungsmittel
CA2816088A1 (en) * 2010-10-28 2012-05-03 Viamet Pharmaceuticals, Inc. Metalloenzyme inhibitor compounds
EP2638041B1 (en) 2010-11-12 2015-07-22 Bristol-Myers Squibb Company Substituted azaindazole compounds
GB2485404A (en) * 2010-11-15 2012-05-16 Nat Univ Ireland Metal-complexed pyridyl-substituted tetrazole compounds and their use in treating cancer
CN102675286B (zh) * 2011-03-07 2015-08-19 中国科学院上海药物研究所 一类吲唑类化合物及其制备方法、用途和药物组合物
US9029399B2 (en) * 2011-04-28 2015-05-12 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
US20120302573A1 (en) * 2011-05-25 2012-11-29 Paul Francis Jackson Methods of inhibiting pro matrix metalloproteinase activation
WO2013049263A1 (en) 2011-09-27 2013-04-04 Bristol-Myers Squibb Company Substituted bicyclic heteroaryl compounds
US9550750B2 (en) 2012-10-05 2017-01-24 Merck Sharp & Dohme Corp. Indoline compounds as aldosterone synthase inhibitors
US9522141B2 (en) 2012-12-20 2016-12-20 Merck Sharp & Dohme Corp. Indazole compounds as aldosterone synthase inhibitors
EP2964028A4 (en) 2013-03-05 2017-06-07 University of Tennessee Research Foundation Compounds for treatment of cancer
HK1220356A1 (zh) 2013-03-14 2017-05-05 Pellficure Pharmaceuticals, Inc. 用於前列腺癌的新颖疗法
EP3191087A1 (en) 2014-09-12 2017-07-19 Pellficure Pharmaceuticals, Inc. Compositions and methods for treatment of prostate carcinoma
CA3044812A1 (en) 2016-10-24 2018-05-03 Pellficure Pharmaceuticals Inc. Pharmaceutical compositions of 5-hydroxy-2-methylnaphthalene-1,4-dione
JP7193071B2 (ja) * 2017-02-08 2022-12-20 国立大学法人東海国立大学機構 蛍光発光材料および紫外線吸収剤
WO2021126779A1 (en) * 2019-12-18 2021-06-24 The Regents Of The University Of California Inhibitors of lin28 and methods of use thereof
US20210246109A1 (en) * 2020-02-11 2021-08-12 University Of Kentucky Research Foundation Potent and selective inhibitors of cytochrome p450
WO2023049199A1 (en) * 2021-09-24 2023-03-30 Zeno Management, Inc. Azole compounds
CN117551029A (zh) * 2023-11-22 2024-02-13 河南大学 一种4-溴-3-氰基吡啶的合成方法

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK150068C (da) * 1978-06-02 1987-06-29 Pfizer Analogifremgangsmaade til fremstilling af aminothiazoler
JPS55133366A (en) * 1979-04-05 1980-10-17 Otsuka Pharmaceut Factory Inc Thiazole derivative
US4536505A (en) * 1983-05-17 1985-08-20 Ciba-Geigy Corporation Certain N-(pyridyl) indoles
DE3940476A1 (de) * 1989-12-07 1991-06-13 Bayer Ag Pyridinylpyrimidin-derivate
DE3940477A1 (de) * 1989-12-07 1991-06-13 Bayer Ag Hetaryl-substituierte pyridinylpyrimidin-derivate
JPH04154773A (ja) * 1990-10-15 1992-05-27 Green Cross Corp:The チアゾール誘導体
DE4117560A1 (de) * 1991-05-29 1992-12-03 Bayer Ag Verwendung von pyridinylpyrimidin-derivaten zum schutz technischer materialien
TW223004B (enExample) * 1991-11-25 1994-05-01 Sumitomo Chemical Co
US5599774A (en) * 1992-01-22 1997-02-04 Imperial Chemical Industries Plc N-arylindoles and their use as herbicides
US5395817A (en) * 1992-01-22 1995-03-07 Imperial Chemical Industries Plc N-arylindoles and their use as herbicides
DK0630367T3 (da) * 1992-03-09 2000-09-18 Zeneca Ltd Hidtil ukendte arylindazoler og deres anvendelse som herbicider
US5444038A (en) * 1992-03-09 1995-08-22 Zeneca Limited Arylindazoles and their use as herbicides
DE69526958T2 (de) * 1994-11-29 2003-01-16 Hisamitsu Pharmaceutical Co., Inc. Antibakterielle oder bakterizide mittel, die 2-aminothiazolderivate und deren salze enthalten
US6046136A (en) * 1997-06-24 2000-04-04 Zeneca Limited Herbicidal heterocyclic N-oxides compounds
US5840721A (en) * 1997-07-09 1998-11-24 Ontogen Corporation Imidazole derivatives as MDR modulators
WO1999018099A1 (en) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Aryl thiophene derivatives as pde iv inhibitors
CN1308618A (zh) * 1998-05-12 2001-08-15 美国家用产品公司 用于治疗胰岛素抗性和高血糖的噁唑芳基－羧酸
AU5227999A (en) * 1998-07-27 2000-02-21 Abbott Laboratories Substituted oxazolines as antiproliferative agents
ATE414079T1 (de) * 2000-03-01 2008-11-15 Janssen Pharmaceutica Nv 2,4-disubstituierte thiazolyl derivate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03027094A2 *

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EP1432706A2 (en) 2004-06-30
CA2461363A1 (en) 2003-04-03
WO2003027096A1 (en) 2003-04-03
WO2003027085A3 (en) 2003-12-04
WO2003027107A1 (en) 2003-04-03
WO2003027085A2 (en) 2003-04-03
JP2005528325A (ja) 2005-09-22
JP2005532983A (ja) 2005-11-04
AU2002362603A1 (en) 2003-04-07
WO2003027094A2 (en) 2003-04-03
WO2003027101A1 (en) 2003-04-03
CA2461360A1 (en) 2003-04-03
WO2003027100A1 (en) 2003-04-03
WO2003027095A1 (en) 2003-04-03

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