Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines

Definitions

• the present invention relates to a novel class of aldo-keto reductase inhibitors, aldo-keto reductase subfamily 1C3 (AKR1C3) inhibitors and to compositions containing AKR1C3 inhibitors, to methods for preparation of AKR1C3 inhibitors, and to methods of use thereof.
• aldo-keto reductase inhibitors aldo-keto reductase subfamily 1C3 (AKR1C3) inhibitors
• compositions containing AKR1C3 inhibitors to methods for preparation of AKR1C3 inhibitors, and to methods of use thereof.
• AKR1C3 inhibitors are useful in the treatment of, for example, prostate cancer, benign prostate hyperplasia (BPH), lung cancer, non-small cell lung cancer (NSCLC), acne, seborrhea, hirsuitism, baldness, alopecia, precocious puberty, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, endometriosis, myeloma and leiomyoma.
• AKR1C3 inhibitors may also provide a function as inhibitors of AKRlC3-mediated androgen-dependent androgen receptor-transactivation, i.e., inhibitors of an AKR1C3 co-activation function, as described herein.
• Androgens and estrogens through their intracellular receptors, promote physiological and pathological developments. Both these classes of steroid hormones are critical for the growth of secondary sexual characteristics, bone, muscle and for the function of neurological and other tissues. These hormones, their receptors and associated proteins have also been implicated in the transformation of normal reproductive tissues into cancerous tissues. A large proportion of androgens in men (40%), and the majority of estrogens in women (75% before menopause and close to 100% after menopause), are synthesized in peripheral target tissues from precursor steroids of adrenal origin. The genes encoding the enzymes responsible for the formation and metabolism of androgens and estrogens are expressed in a large series of peripheral tissues, thus providing the basis for a promising new area in hormone action, namely intracrinology.
• Testosterone and dihydrotestosterone (DHT), the active circulating androgens, and estradiol, the potent circulating estrogen, are synthesized from the weak adrenally synthesized precursors androstenedione and estrone, respectively, by steroidogenic enzymes belonging to the class of hydroxysteroid dehydrogenase (HSDs).
• HSDs hydroxysteroid dehydrogenase
• Potent endogenous androgens (testosterone and DHT) are synthesized by type 3 (testicular) and type 5 (peripheral tissues such as adrenal, prostate, etc,) 17 -HSDs.
• the human AKRIC isozymes are hydroxysteroid dehydrogenases, and are involved in the pre-receptor regulation of steroid hormone action.
• AKRIC isozymes regulate the concentration of active and inactive androgens, estrogens and progestins in target tissues by catalyzing the reduction of ketosteroids at positions C3, C17 or C20.
• AKRIC isozymes regulate the ligand occupancy and transactivation of steroid hormone receptors such as the androgen receptor, estrogen receptor, and progesterone receptor by altering the intracellular steroid hormone formation rates and thus the steroid hormone concentration in target tissues.
• Hormone dependent cancers such as breast and prostate cancer
• the AKRIC enzymes support the synthesis of these hormones locally.
• Microarray analysis of prostate cancer tissues has shown that the AKR1C3 isoform is over-expressed in advanced or metastatic prostate cancers compared to organ-confined prostate cancer.
• androgen biosynthesis continues in peripheral tissues (i.e., not in testes) and supports the post-castration proliferation of prostate cancer (e.g. castration resistant prostate cancer (CRPC)) and that the AKR1C3 is the key enzyme that mediates this peripheral androgen synthesis.
• CRPC castration resistant prostate cancer
• AKRIC aldo-keto reductase family 1 member C
• AKR1C1 20a-HSD
• AKR1C2 type 3 3a-HSD
• AKR1C3 type 5 ⁇ -HSD
• AKR1C4 type 1 3a-HSD
• the four isozymes display different substrate preferences, inhibition profiles and tissue specific expression patterns.
• AKRIC isoforms In addition to prostate cancer, alterations in the expression and function of AKRIC isoforms have been reported in other cancers, such as breast cancer, small cell lung cancer and myeloma, suggesting a role for these isozymes in the development of other cancers. Drugs that increase the function of AKR1C1 and AKR1C2 or drugs that decrease the function of AKR1C3 may be useful in treating various malignancies related to steroid hormones.
• AKR1C3 is a 37 kDa cytosolic enzyme of the NAD dependent aldo-keto reductase family. AKR1C3 is also known as 17 -hydroxysteroid dehydrogenase type 5 (17 HSD5), 3otHSD2, and prostaglandin F synthase. Isoforms AKRIC 1-4 have overlapping function depending on substrate concentration and tissue distribution.
• AKRIC enzymes catalyze multiple enzymatic reactions to include: conversion of the potent progestin progesterone to the weak progestin 20ot-hydroxyprogesterone (AKR1C1, AKR1C3); conversion of the most potent endogenous androgen 5a-dihydrotestosterone (DHT) to the weak androgen 5ot-androstane-3a,17P-diol (3a- diol) (AKR1C2); conversion of the weak adrenal androgen androstene-3,17-dione (also known as androstenedione, A'dione, or 4'dione) to the potent androgen testosterone (AKR1C3; also done by 17 HSD3 in Leydig cells); conversion of the weak androgen 5a-androstanedione (5a-dione) to the most active androgen DHT (AKR1C3) ( Figure 1); conversion of the weak estrogen estrone to 17 ⁇ - estradio
• inhibition of AKR1C3 activity may reduce the level of end products as described above.
• inhibition of AKR1C3 activity may reduce the level of the potent androgens testosterone and 5ot-dihydrotestosterone (DHT), and/or the potent estrogen 17 -estradiol and/or the proliferative prostaglandin PGF2ot.
• inhibition of AKR1C3 activity may increase the level of starting product as described above.
• inihibition of AKR1C3 activity may increase the level of the potent progestin progesterone.
• AKR1C3 is expressed in numerous tissues including liver, prostate, testes, adrenals, uterus, breast, lung, kidney, bladder, ovary, adipose, and brain.
• AKR1C3 is considered an activating enzyme for the androgen receptor (AR) through biosynthesis of testosterone, the estrogen receptor (ER) through biosynthesis of 17 -estradiol, and a deactivating enzyme of the peroxiosome proliferator-activated receptor gamma (PPARy) through the synthesis of PGF2ot.
• AR androgen receptor
• ER estrogen receptor
• PPARy peroxiosome proliferator-activated receptor gamma
• AKR1C3 inhibitors may be advantageous in the treatment of prostate cancer.
• gonadotrophin releasing hormone agonist e.g., leuprolide acetate
• CYP17A1 (17,20-lyase; 17ot-hydroxylase) inhibitors such as ketoconazole and abiraterone inhibit conversion of pregnenolone and progesterone to DHEA and androstenedione, respectively, and exhibit moderate efficacy in CRPC.
• AKR1C3 is upregulated in CRPC and represents a more specific target for preventing localized androgen biosynthesis (i.e. lyase inhibitors also prevent Cortisol synthesis leading to mineralocorticoid excess, especially abiraterone).
• lyase inhibitors also prevent Cortisol synthesis leading to mineralocorticoid excess, especially abiraterone.
• other enzymatic roles of AKR1C3 promote prostate tumor growth. These include the effects on prostaglandin metabolism which increase prostate growth and tumor vascularity by decreasing PGJ2 resulting in reduction in PPARy activity and up-regulation of COX-2. Conversion of DHT to 3ot-diol is thought to increase prostate cell proliferation through an AR-independent pathway involving epidermal growth factor-like pathway.
• inhibition of AKR1C3 may have direct anti-proliferative effects via decreases in estrogen and androgen synthesis intratumorally (as well as in adjacent tissues), which would limit the occupation of AR and ER.
• indirect anti-proliferative effects of AKR1C3 inhibition may arise from increased levels of pro-differentiative ligands, e.g., PPARy ligands and decreased levels of 3ot-diol (EGF-like pathway).
• AKR1C3 inhibitors may be advantageous for the treatment of breast cancer.
• Selective estrogen receptor modulators (SERMs) and aromatase inhibitors are widely used in treatment of ER positive breast cancer, which includes about 75% of the cases.
• AKR1C3 is consistently over expressed in breast cancer ductal carcinoma in situ and invasive breast cancer ductal carcinoma, as well as being an indicator of poor prognosis for breast cancer.
• AKR1C3 promotion of breast tumor growth exist such as: a) conversion of androstenedione to testosterone provides a substrate for CYP19 aromatase to create 17 -estradiol; b) conversion of estrone (weak estrogen) to 17 -estradiol; c) reduction of the anti-proliferative effect of PGD2; and d) decrease in progesterone by inactivation to 20ot-progesterone which further increases ER:PR ratio.
• inhibition of AKR1C3 should be therapeutic in breast cancer as inhibition of mechanisms a) and b) above should decrease intratumoral ER occupancy, and inhibition of mechanism c) should increase intratumoral occupancy of PPARy.
• AKR1C3 inhibitors may be advantageous for the treatment of AR-positive and ER-positive breast cancers.
• CRPC and refractory breast cancer are common cancers with low survival rates (less than 50% at 5 yrs).
• AKR1C3 inhibitors may be useful for androgen-dependent conditions.
• Non limiting examples of such uses include: (a) treatment of adrenal adenomas, carcinoma, or hyperplasia; (b) treatment of Leydig cell tumors in men; (c) treatment of arrhenoblastomas in women; (d) treatment of polycystic ovarian syndrome (PCOS) in women; e) treatment, prevention, decreasing the incidence of, halting and/or causing a regression of prostate cancer; f) other clinical, therapeutic, and/or diagnostic areas; or g) treatment and/or prevention of acne, seborrhea, hirsuitism, baldness and alopecia.
• PCOS polycystic ovarian syndrome
• AKR1C3 inhibitors may be useful for estrogen-dependent conditions.
• Non limiting examples of such uses include (a) treating, suppressing, inhibiting or reducing the amount of precancerous precursors of prostate adenocarcinoma, for example, those having benign prostatic hyperplasia, prostatic intraepithelial neoplasia (PIN) or an abnormally high level of circulating prostate specific antibody (PSA), or who have a family history of prostate cancer; (b) treating, preventing, suppressing, inhibiting, or reducing the incidence of osteoporosis, hot flashes, gynecomastia, and/or hair loss in male human subjects having prostate cancer; (c) treating, suppressing, inhibiting or reducing the risk of developing prostate cancer; or (d) treating, suppressing, inhibiting or reducing the risk of developing breast cancer in a subject.
• AKR1C3 inhibitors may be useful for prostaglandin-dependent diseases.
• AKR1C3 is the only known PGF2 synthase in humans.
• Diseases related to increased PGF2 levels include: endometriosis, inflammatory tachycardia, lung cancer, asthma and airway inflammation, type 2 diabetes, obesity, multiple inflammatory diseases, diseases related to oxidative stress, dysmenorrhea, and renal cell carcinoma. These diseases could result from direct increases in PGF2 levels or from decreases in PPAR- ⁇ activity (as AKR1C3 sequesters the precursor of endogenous PPAR- ⁇ ligand, which is PGJ2, to form PGF2).
• AKR1C3 also catalyzes the reduction of prostaglandin (PG) H(2) to PGF(2a) and PGD(2) to 9a,l i -PGF(2), which will limit the formation of anti-proliferative prostaglandins, including 15-deoxy-A(12,14)- PGJ(2), and contribute to proliferative signaling.
• PG prostaglandin
• AKR1C3 is overexpressed in a wide variety of cancers, including breast and prostate cancer.
• aldo-keto reductase 1C3 type 5 17 ⁇ -hydroxy steroid dehydrogenase and prostaglandin F synthase
• indomethacin which is a potent and isoform selective inhibitor of AKR1C3
• tocolysis i.e., also called anti-contraction medications or labour repressants
• medications used to suppress premature labor from the Greek tokos, childbirth, and lytic, capable of dissolving
• Non-steroidal anti-inflammatory drugs such as indomethacin and flufenamic acid are known commercial inhibitors of AKR1C3.
• NSAIDs have significant cross- reactivity with cyclooxygenase enzymes (COX-1 and COX-2), which leads to side effects such as gastric irritation, ulcers, cardiovascular problems and others.
• COX-1 and COX-2 cyclooxygenase enzymes
• there is a need in the art to develop new HSD inhibitors for example, HSD inhibitors that are specific to AKR1C3 and that lack cross-reactivity with, for example, other AKR1C isoforms and HSD isoforms, and with other enzymes, such as COX enzymes.
• AKR1C3 inhibitors of this invention do not cross-react or have significantly reduced cross-reactivity with respect to CYP17A1, COX-1, COX-2, other AKR1C enzymes, 17 ⁇ 8 ⁇ 3, and are not agonist or antagonists for steroid hormone receptors such as AR, ER, and PR. Yet, AKR1C3 inhibitors may inhibit the down-stream activities of steroid receptors, as AKR1C3 inhibitors may regulate the formation of ligands for these receptors. For example, an AKR1C3 inhibitor may decrease or inhibit the activity of the AR receptor by decreasing the amount of available testosterone and DHT.
• an AKR1C3 inhibitor may decrease or inhibit the activity of an ER receptor (ER-alpha or ER-beta) by decreasing the amount of available estradiol. Further, an AKR1C3 inhibitor may increase or augment the activity of the PR receptor by decreasing the amount of available progesterone.
• this invention provides an AKR1C3 inhibitor compound of Formula XIII:
• R 1 is H, alkyl or -alkylene-C0 2 R x , in which R x is H or alkyl;
• R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy, haloalkyl, hydroxyl, hydroxymethyl, CONH 2 , CONHR y , substituted or unsubstituted alkylene-C0 2 R y , in which R y is H or alkyl;
• R 3 is, in each case, independently selected from hydrogen, alkoxy, COOH, hydroxyl, halogen, haloalkyl, C(0)NH 2 , CF 2 OMe, CN, carboxyl, S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl;
• R 4 is, in each case, independently selected from hydrogen, alkyl, hydroxyl, halogen, haloalkyl, CN, carboxyl, CONH 2 , CONHR 2 , S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl; a is an integer 1, 2, 3, 4 or 5; b is an integer 1, 2, 3, 4 or 5; and c is an integer 1, 2 or 3; or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate, or any combination thereof.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a compound represented by the structure of formula I, or its isomer, tautomer, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof:
• A is a 5-14 membered saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof; wherein the saturated or unsaturated carbocyclic or heterocyclic rings are optionally substituted by 1 to 5 substituents independently selected from R3 or OR" ; and X is O or S; or
• A is nothing, ⁇ forms a double bond with the cyclic carbon and X is OH or OCH 2 CH 2 -heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated substituted or unsubstituted heterocyclic ring;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, heteroaryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 , or OH;
• R' is hydrogen, Alk, or COR
• R" is hydrogen, Alk, or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇ 3 ⁇ 4 ⁇ ;
• Q is SO 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• n is an integer of between 1-3;
• n is an integer between 1-2;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of
• the methods of this invention include administering a compound of formula XI, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, ester, hydrate or any combination thereof:
• OS0 2 CH 3 NHR, NHCOR, N(R) 2 , sulfonamide, S0 2 R, alkyl, cycloalkyl, haloalkyl, aryl, phenyl, benzyl, protected hydroxyl, OCH 2 CH 2 NR4R 5 , Z-Alk-Q, Z-Alk-NR ⁇ Rs, Z-Alk- heterocycle or OCH 2 CH 2 -heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
• R is alkyl, cycloalkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, C3 ⁇ 4F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH;
• R' is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇ 3 ⁇ 4 ⁇ ;
• Q is SO 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR; h is 0, 1, 2 or 3; i is 0, 1, 2, 3 or 4; n is 1, 2, 3 or 4; m is 1 or 2; p is 0, 1, 2, 3, 4 or 5; and
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cycloalkyl of
• the methods of this invention include administering a compound of formula XIII, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide,
• R 1 is H, alkyl or -alkylene-C0 2 R x , in which R x is H or alkyl;
• R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy, haloalkyl, hydroxyl, hydroxymethyl, CONH 2 , CONHR y , substituted or unsubstituted alkylene-C0 2 R y , in which R y is H or alkyl;
• R 3 is, in each case, independently selected from hydrogen, alkoxy, COOH, hydroxyl, halogen, haloalkyl, CF 2 OMe, C(0)NH 2, CN, carboxyl, S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl;
• R 4 is, in each case, independently selected from hydrogen, alkyl, hydroxyl, halogen, haloalkyl, CN, carboxyl, CONH 2 , CONHR 2 , S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl; a is an integer 1, 2, 3, 4 or 5; b is an integer 1, 2, 3, 4 or 5; and c is an integer 1, 2 or 3.
• the methods of this invention include administering a compound selected from:
• the compounds and methods of use thereof of this invention comprise administering a compound selected from:
• this invention is directed to a compound 3-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l -oxoisoquinolin-2(lH)-yl)benzamide (214) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, ester, hydrate or any combination thereof.
• this invention is directed to a compound 4-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l -oxoisoquinolin-2(lH)-yl)benzamide (215) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, ester, hydrate or any combination thereof.
• the compound of this invention is an AKR1C3 inhibitor. In one embodiment.
• the present invention relates to a method of treating, suppressing, inhibiting or reducing the incidence of, or delaying progression of a disorder or condition that responds to AKR1C3 inhibition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of this invention or its isomer, pharmaceutically acceptable salt, polymorph, metabolite, prodrug, crystal, N-oxide, hydrate or any combination thereof.
• such disorders and conditions include, but are not limited to prostate cancer, advanced prostate cancer, precancerous precursors of prostate adenocarcinoma, prostate intraepithelial neoplasia (PIN), castration resistant prostate cancer (CRPC), benign prostate hyperplasia (BPH), lung cancer, non-small cell lung cancer (NSCLC), acne, seborrhea, hirsuitism, baldness, alopecia, precocious puberty, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, metastatic breast cancer, refractory breast cancer, AR-positive breast cancer, ER-alpha positive breast cancer, ER-beta positive breast cancer, uterine cancer including endometrial and cervical cancers, uterine fibroids including myomas, endometriosis, myeloma and leiomyoma.
• PIN prostate intraepithelial neoplasia
• CRPC castration resistant prostate cancer
• BPH benign prostate hyperplasia
• this invention provides a method of lowering total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of this invention, wherein the lowering of total serum testosterone is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of lowering serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of this invention, wherein the lowering of serum free testosterone is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of lowering serum free testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of this invention, wherein the lowering of serum free testosterone is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of lowering serum PSA levels in a male subject comprising administering a therapeutically effective amount of a compound of this invention, wherein the lowering of serum PSA is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of increasing survival of a subject with advanced prostate cancer comprising administering a therapeutically effective amount of a compound of this invention.
• this invention provides a method of increasing survival of a subject with castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of this invention.
• CRPC castration-resistant prostate cancer
• this invention provides a method of prolonging progression- free survival of a subject with advanced prostate cancer comprising administering a therapeutically effective amount of a compound of this invention. In another embodiment, this invention provides a method of prolonging progression-free survival of a subject with castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of this invention.
• this invention provides a method of lowering total serum estradiol levels in a subject comprising administering a therapeutically effective amount of a compound of this invention. In another embodiment, this invention provides a method of lowering serum free estradiol in a subject comprising administering a therapeutically effective amount of a compound of this invention. In one embodiment, a subject is a male subject. In another embodiment, a subject is a female subject.
• this invention provides a method of increasing survival of a subject with advanced breast cancer comprising administering a therapeutically effective amount of a compound of this invention. In another embodiment, this invention provides a method of increasing survival of a subject with refractory breast cancer comprising administering a therapeutically effective amount of a compound of this invention. In another embodiment, this invention provides a method of increasing survival of a subject with AR-positive or ER-positive breast cancer comprising administering a therapeutically effective amount of a compound of this invention. [0031] In one embodiment, this invention provides a method of prolonging progression- free survival of a subject with advanced breast cancer comprising administering a therapeutically effective amount of a compound of this invention.
• this invention provides a method of prolonging progression-free survival of a subject with refractory breast cancer comprising administering a therapeutically effective amount of a compound of this invention. In another embodiment, this invention provides a method of prolonging progression-free survival of a subject with AR-positive or ER-positive breast cancer comprising administering a therapeutically effective amount of a compound of this invention.
• this invention provides a method of treating, increasing survival and/or prolonging progression-free survival of a subject with uterine cancer comprising administering a therapeutically effective amount of a compound of this invention.
• this invention provides a method of treating a subject with uterine fibroids comprising administering a therapeutically effective amount of a compound of this invention.
• Figure 2 depicts the effect of AKR1C3 inhibitors on Testosterone Synthesis, including activity of compound 215 compared to REF 1 and REF2
• Figure 3 depicts AKRlC3-dependent AR transactivation in cells transfected with AKR1C3.
• Figure 4 depicts that AKR1C3 augmented A'dione-dependent AR transactivation. o AKR1C3; ⁇ Vector.
• Figure 5 shows AKRlC3-dependent androgen-induced AR transactivation is not cell type dependent.
• Figure 6 shows AKRlC3-dependent increase in transactivation is specific to AR.
• Figures 6 illustrate specificity of AKRlC3-dependent transactivation with a titration of steroid receptors: A'dione-AR (6A), R1881-AR (6B), Dex-GR (6C), Prog-PR (6D), Estrogen-ERa (6E), Aldosterone-MR (6F), and Rosi-PPARy (6G), compared with vector; o AKR1C3; ⁇ Vector (pCR3.1). A'dione-androstenedione; Dex-dexamethasone; Prog-progesterone; estrogen-17 - estradiol; Rosi-rosiglitazone.
• Figure 7 shows AKR1C3 physically interacts with AR, depicting immunoprecipitation of AR and AKR1C3. Analysis of the immunoprecipitant produced by immunoprecipitation (IP) of AKR1C3 demonstrated immunoreactivity with AR on immunoblot (IB).
• IP immunoprecipitation
• Figure 8 shows that AKR1C3 is recruited to PSA enhancer.
• Figure 9A depicts crystals of purified AKR1C3.
• Figure 9B depicts crystal structure of AKR1C3 in complex with compounds 45 and 26 in Figures 9B-1 and 9B-2, respectively. The AKR1C3 crystal structures with 45 and 26 are superimposed in Figure 9B-3.
• Figure 10 depict concentration dependent increase of AR activation, individually ( Figure 10A, SRC-2; Figure 10B, AKR1C3) and together ( Figure IOC, SRC-2 and AKR1C3), demonstrating cotransfection synergistically increased AR transactivation.
• Figure 11 depicts AKR1C3 ( Figure 11 A) and cyclophilin ( Figure 11B) expression after siRNA transfection.
• Figure 12 depicts AKR1C3 translocation to nucleus requires AR.
• Figure 12A shows NIH3T3 cells stably transfected with AKR1C3, were infected with adenovirus LacZ, treated with 10 nM R1881, and the expression of AKR1C3 was detected by immunofluorescence using laser confocal microscopy.
• Figure 12B shows ⁇ 3 ⁇ 3 cells stably transfected with AKR1C3 were infected with adenovirus AR and were treated with 10 nM R1881. Cells were fixed and AR (green) and AKR1C3 (red) were detected by immunofluorescence using laser confocal microscopy.
• Figure 13 depicts AKR1C3 migrates with AR.
• LNCaP-AKRlC3 cells were treated with 0.1 nM R1881 (top panels) or 0.1 nM R1881 and 10 ⁇ SNARE-1. Cells were fixed and AR (green) and AKR1C3 (red) were detected by immunofluorescence using a laser confocal microscopy.
• Figure 14 shows AKR1C3 enhanced androgen signaling and prostate cancer xenograft growth.
• Figures 14A-14C show AKR1C3 siRNA inhibited AR function in LNCaP cells.
• Figures 14D, 14E, Figure 14F and Figure 14G show AKR1C3 transfection increased androgen induced PSA gene expression.
• Figure 14D is the PSA gene expression with a titration of 4'dione and Figure 14E is with a titration of R1881.
• solid lines are vector pCR3.1 transfected and broken lines are AKR1C3 transfected.
• Figure 14F shows AKR1C3 increased DHT-induced LNCaP tumor xenograft growth. Numbers within brackets indicate the number of animals with tumor uptake.
• Figures 14G shows AKR1C3 expression in cells tranfected with AKR1C3 (closed bars) or vector (open bars; not visible in the figure) transfected cells.
• Figure 141 shows FKBP51 protein, derived from an AR dependent gene, is increased in LNCaP- AKR1C3 xenografts.
• Figure 14J depicts over-expression of AKR1C3 increased LNCaP xenograft growth.
• Figure 14K depicts AR target FKBP51 protein expression (right panel) is increased in LNCaP-AKRlC3 xenograft tumors, despite little to no change in AR levels.
• this invention provides an AKR1C3 inhibitor of Formula XIII:
• R 1 is H, alkyl or -alkylene-C0 2 R x , in which R x is H or alkyl;
• R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy, haloalkyl, hydroxyl, hydroxymethyl, CONH 2 , CONHR y , substituted or unsubstituted alkylene-C0 2 R y , in which R y is H or alkyl;
• R 3 is, in each case, independently selected from hydrogen, alkoxy, COOH, hydroxyl, halogen, haloalkyl, CF 2 OMe, C(0)NH 2, CN, carboxyl, S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl;
• R 4 is, in each case, independently selected from hydrogen, alkyl, hydroxyl, halogen, haloalkyl, CN, carboxyl, CONH 2 , CONHR 2 , S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl; a is an integer 1, 2, 3, 4 or 5; b is an integer 1, 2, 3, 4 or 5; and c is an integer 1 , 2 or 3 ; or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate, or any combination thereof.
• R 1 of formula XIII is hydrogen. In one embodiment, R 1 of formula XIII is alkyl. [0052] In one embodiment, R 2 of formula XIII is, in each case, independently hydroxyl. In one embodiment, R 2 of formula XIII is, in each case, independently hydrogen. In another embodiment, R 2 of formula XIII is, in each case, independently CH 2 -halogen. In another embodiment, R 2 of formula XIII is, in each case, independently CH 2 -Br. In another embodiment, R 2 of formula XIII is, in each case, independently CH 2 OH. In another embodiment, R 2 of formula ⁇ is, in each case, independently C(0)NH 2 .
• R 2 of formula XIII is, in each case, independently CF 3 .
• R 2 of formula XIII is, in each case, independently halogen.
• R 2 of formula ⁇ is, in each case, independently F.
• R 2 of formula XIII is, in each case, independently CI.
• R 2 of formula XIII is, in each case, independently Br.
• R 2 of formula XIII is, in each case, independently I.
• R 3 of formula XIII is, in each case, independently hydrogen. In another embodiment, R 3 of formula XIII is, in each case, independently alkoxy. In another embodiment, R 3 of formula XIII is, in each case, independently OMe. In another embodiment, R 3 of formula XIII is, in each case, independently CF 3 . In another embodiment, R 3 of formula XIII is, in each case, independently CONH 2. In another embodiment, R 3 of formula XIII is, in each case, independently C(0)OH. In another embodiment, R 3 of formula XIII is, in each case, independently CF 3 . In another embodiment, R 3 of formula XIII is, in each case, independently halogen.
• R 3 of formula XIII is, in each case, independently F. In another embodiment, R 3 of formula XIII is, in each case, independently CI. In another embodiment, R 3 of formula XIII is, in each case, independently Br. In another embodiment, R 3 of formula XIII is, in each case, independently I. In another embodiment, R 3 of formula XIII is, in each case, independently S0 2 CH 3 .
• R 4 of formula XIII is, in each case, independently hydrogen. In another embodiment, R 4 of formula XIII is, in each case, independently hydroxyl. In another embodiment, R 4 of formula XIII is, in each case, independently CN. In another embodiment, R 4 of formula XIII is, in each case, independently halogen. In another embodiment, R 4 of formula ⁇ is, in each case, independently F. In another embodiment, R 4 of formula XIII is, in each case, independently CI. In another embodiment, R 4 of formula XIII is, in each case, independently Br. In another embodiment, R 4 of formula XIII is, in each case, independently I. In another embodiment, R 4 of formula XIII is, in each case, independently SO 2 NHCH 3 .
• an AKR1C3 inhibitor of Formula XIII of this invention is 6- hydroxy-2,4-bis(4-hydroxyphenyl)isoquinolin-l(2H)-one (6);
• an AKR1C3 inhibitor of Formula XIII of this invention is 2-(4-(hydroxymethyl)phenyl)-6-methoxy-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (10);
• an AKR1C3 inhibitor of Formula XIII of this invention is 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11);
• an AKR1C3 inhibitor of Formula XIII of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (13);
• an AKR1C3 inhibitor of Formula XIII of this invention is 2-benzyl-6-hydroxy-4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)- one (75).
• an AKR1C3 inhibitor of Formula XIII of this invention is 6- hydroxy-2-(4-hydroxyphenyl)-4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)-one (79);
• an AKR1C3 inhibitor of Formula XIII of this invention is 4-(3,4,5- trifluorophenyl)isoquinolin-l(2H)-one (90);
• an AKR1C3 inhibitor of Formula XIII of this invention is methyl 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5- trifluorophenyl)-l,2-dihydroisoquinoline-8-carbimidate (100);
• this invention provides an AKR1C3 inhibitor of Formula XIII:
• R is H, alkyl or -alkylene-C0 2 R x , in which R x is H or alkyl;
• R 2 is ⁇ , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy, haloalkyl, hydroxyl, hydroxymethyl, CONH 2 , CONHR y , substituted or unsubstituted alkylene-CC> 2 R y , in which R y is H or alkyl;
• R 3 is, in each case, independently selected from hydrogen, alkoxy, COOH, hydroxyl, halogen, haloalkyl, CF 2 OMe, C(0)NH 2, CN, carboxyl, S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl;
• R 4 is, in each case, independently selected from hydrogen, alkyl, hydroxyl, halogen, haloalkyl, CN, carboxyl, CONH 2 , CONHR 2 , S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl; a is an integer 1, 2, 3, 4 or 5; b is an integer 1, 2, 3, 4 or 5; and c is an integer 1 , 2 or 3 ; or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate, or any combination thereof; with a proviso, that said AKR1C3 inhibitor is not 2-(4-bromomethyl)phenyl-6-hydroxy- 4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinol
• the present invention relates to compounds that act as hydroxysteroid dehydrogenase inhibitors (HDIs), such as compounds that act as inhibitors of 17 ⁇ - hydroxysteroid hydrogenases (17 -HSDs), for example, and/or compounds that act as selective inhibitors of AKR1C3 (type 5 17 -HSD or 17P-HSD5).
• HDIs hydroxysteroid dehydrogenase inhibitors
• the present invention relates to compounds that act as inhibitors of AKR1C3 co-activation function, for example, inhibitors of AKR1C3 co-activation of androgen-dependent Androgen Receptor (AR)- transactivation.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) compound represented by the structure of formula I, or its isomer, tautomer, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof:
• HDI hydroxysteroid dehydrogenase inhibitor
• A is a 5-14 membered saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof; wherein the saturated or unsaturated carbocyclic or heterocyclic rings are optionally substituted by 1 to 5 substituents independently selected from R3 or OR" ; and X is O or S; or
• A is nothing, N forms a double bond with the cyclic carbon and X is OH or OCH 2 CH 2 -heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated substituted or unsubstituted heterocyclic ring;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, heteroaryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 , or OH;
• R is hydrogen, Alk, or COR
• R" is hydrogen, Alk, or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; Z is O, NH, CH 2 or ⁇
• Q is S0 3 H, C0 2 H, C0 2 R, NO2, tetrazole, S0 2 NH 2 or S0 2 NHR;
• n is an integer of between 1-3;
• n is an integer between 1-2;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) compound represented by the structure of formula I, or its isomer, tautomer, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof:
• HDI hydroxysteroid dehydrogenase inhibitor
• A is a 5-14 membered saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof; wherein the saturated or unsaturated carbocyclic or heterocyclic rings are optionally substituted by 1 to 5 substituents independently selected from R3 or OR" ; and X is O or S; or
• A is nothing, ⁇ forms a double bond with the cyclic carbon and X is OH or OCH 2 CH 2 -heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated substituted or unsubstituted heterocyclic ring;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, heteroaryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 , or OH;
• R is hydrogen, Alk, or COR
• R" is hydrogen, Alk, or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇ 3 ⁇ 4 ⁇ ;
• Q is SO 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• n is an integer of between 1-3;
• n is an integer between 1-2;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of
• said AKR1C3 inhibitor is not 2-(4-bromomethyl)phenyl-6-hydroxy- 4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-
• A is nothing, N forms a double bond with the cyclic carbon and X is OCH2CH2-heterocycle in which the heterocycle is a 3-7 membered heterocycloalkyl.
• the heterocycle is substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH2CH2-heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• heterocycle when R4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, wherein R is as defined for Formula I.
• R 2 is a halogen.
• R2 is a bromide.
• R2 is a chloride.
• R2 is a fluoride.
• R2 is an iodide.
• R2 is hydrogen.
• R 2 is a cyano.
• R 2 is a phenyl.
• Ri is a hydroxyl group.
• Ri is 0-(CO)-Ph-CF 3 .
• Ri is COOH.
• Ri is COOMe. In another embodiment Ri is hydrogen. In another embodiment Ri is a hydroxyl group and n is 1. In another embodiment Ri is in position 8 of the isoquinolinone group.
• R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is a COMe group. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is a COMe group.
• this invention provides (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a a hydroxysteroid dehydrogenase inhibitor (HDI) compound or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of Formula II:
• HDI hydroxysteroid dehydrogenase inhibitor
• A is a 5-14 membered saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof; wherein the saturated or unsaturated carbocyclic or heterocyclic ring are optionally substituted by 1 to 5 substituents independently selected from R3 or OR" ;and X is O or S; or
• A is nothing, ⁇ forms a double bond with the cyclic carbon and X is OH or OCH 2 CH 2 - heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH;
• R is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Q is S0 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• n is an integer between 1-3;
• n is an integer between 1-2;
• p is an integer between 1-4;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
• A is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe[0028] is N-(2-aminoe [0028]
• R" is hydrogen, Alk, or COR
• A is nothing, N forms a double bond with the cyclic carbon and X is OCF ⁇ CFb-heterocycle, in which the heterocycle is a 3-7 membered heterocycloalkyl.
• the heterocycle is substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• Ri, R2, R3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• heterocycle when R4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, wherein R is as defined for Formula II.
• Ri is a hydroxyl group. In another embodiment Ri is hydrogen. In another embodiment Ri is a hydroxy 1 group and n is 1. In another embodiment Ri is in position 8 of the isoquinolinone group.
• R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is a COMe group. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is a COMe group.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) ture of formula III:
• HDI hydroxysteroid dehydrogenase inhibitor
• A is a 5-14 membered saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof; wherein the saturated or unsaturated carbocyclic or heterocyclic ring are optionally substituted by 1 to 5 substituents independently selected from R 3 or OR' ' ; and X is O or S; or
• A is nothing and N forms a double bond with the cyclic carbon and X is OH or OCH 2 CH 2 - heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 , or OH;
• R' is hydrogen, Alk, or COR
• R" is hydrogen, Alk, or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 , or ⁇
• Q is SO 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 , or S0 2 NHR;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
• A is Rs ;
• A is Rs , X is an oxo group and Rio is a benzene ring, then R9 is not COOR, if R is an ester residue or CONRjRs.
• R9 is not COOR, if R is an ester residue or CONRjRs.
• A is nothing, N forms a double bond with the cyclic carbon and X is OCH2CH2-heterocycle in which the heterocycle is a 3-7 membered heterocycloalkyl.
• the heterocycle is substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH2CH2-heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, wherein R is as defined for Formula III.
• R2 is COOH. In another embodiment R2 is COOMe. In another embodiment R7 is a halogen. In another embodiment R7 is fluoride. In another embodiment R7 is chloride. In another embodiment R7 is bromide. In another embodiment R7 is iodide. In another embodiment R 3 , R 6 , R7 and Rs are hydrogens. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is a COMe. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is COMe. In another embodiment Ri, R 3 , R 6 , R7, Re, R9 and Rn are hydrogens.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI compound represented by the structure of formula IV:
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH;
• R is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇ 3 ⁇ 4 ⁇
• Q is S0 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• n is an integer between 1-3;
• n is an integer between 1-2;
• p is an integer between 1-4;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
• Ri is a hydroxyl group. In another embodiment Ri is hydrogen. In another embodiment R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is COMe. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is COMe.
• R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle
• either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• the heterocycles are optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, wherein R is as defined for Formula IV.
• substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl,
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) compound represented by the structure of formula V:
• HDI hydroxysteroid dehydrogenase inhibitor
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH;
• R is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇
• Q is S0 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• n is an integer between 1-3;
• n is an integer between 1-2;
• p is an integer between 1-4;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons or cyclic alkyl of 3-8 carbons.
• Ri is a hydroxyl group. In another embodiment Ri is hydrogen. In another embodiment R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is a COMe group In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is a COMe.
• R R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle
• either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy; and R is as defined for Formula V.
• substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alk
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI compound represented by the structure of formula VI:
• R' is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR;
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• RR i iss aallkkyyll,, hhyyddrrooggeenn,, hhaallooaallkkyyll,, ddiihhaallooaallkkyyll,, ttrriihhaallooaallkkyyll,, CCH3 ⁇ 42FF,, CCHHFF22,, CCFF 33 ,, CCFF22CCFF 33 ,, aarryyll,, pphheennyyll,, bbeennzzyyll,, --PPhh--CCFF 33 , --PPhh--CCHH 22 FF,, --PPhh--CCHHFF 22 ,, --PPhh--CCFF 22 CCFF 33 ,, hhaallooggeenn,, aallkkeennyyll,, CCNN,, NN00 22 oorr OOHH aanndd;;
• IInn aannootthheerr eemmbbooddiimmeenntt RRiioo i iss aa cchhlloorriiddee.
• IInn aannootthheerr eemmbbooddiimmeenntt RR22 i iss aa flfluuoorriiddee.
• IInn aannootthheerr eemmbbooddiimmeennttt RRiioo i iss aann iiooddiiddee..
• IInn aannootthheerr eemmbbooddiimmeenntt RR"" iiss HH.
• IInn aannootthheerr eemmbbooddiimmeenntt RR"" iiss aa mmeetthhyyll ggrroouupp.
• R' is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇ s ⁇ ;
• Q is S0 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH; n is an integer between 1-3;
• n is an integer between 1-2;
• p is an integer between 1-4;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons or cyclic alkyl of 3-8 carbons.
• Ri is a hydroxyl group. In another embodiment Ri is hydrogen. In another embodiment R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is COMe. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is a COMe.
• R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle
• either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as defined for Formula VII.
• substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alk
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) compound represented by the structure of formula VIII:
• HDI hydroxysteroid dehydrogenase inhibitor
• R is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇
• Q is S0 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH; n is an integer between 1-3;
• n is an integer between 1-2;
• p is an integer between 1-4;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons or cyclic alkyl of 3-8 carbons.
• Ri is a hydroxyl group.
• Ri is hydrogen.
• R 3 is hydrogen.
• R 3 is halogen.
• R 3 is fluoride.
• R 3 is chloride.
• R 3 is bromide.
• R 3 is iodide.
• R' is H.
• R' is a methyl group.
• R' is COMe.
• R" is H.
• R" is a methyl group.
• R" is COMe.
• R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle
• either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as defined for Formula VIII.
• substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alk
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor formula IX:
• R is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR;
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membercycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇
• Q is SO 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF 3 , CF2CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH; and
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons or cyclic alkyl of 3-8 carbons.
• R 2 is COOH. In another embodiment R 2 is COOMe. In another embodiment R 7 is a halogen. In another embodiment R7 is fluoride. In another embodiment R7 is chloride. In another embodiment R7 is bromide. In another embodiment R7 is iodide. In another embodiment R3, R 6 , R7 and Rs are hydrogens. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is a COMe. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is COMe. In another embodiment Ri, R3, R 6 , R7, Re, R9 and Rn are hydrogens.
• Ri, R2, R3, R 6 , R7, Re, R9, Rio, R11 are independently Z-Alk-heterocycle or, in another embodiment, OCH2CH2- heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as defined for Formula FX.
• substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, al
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) comp structure of formula X:
• HDI hydroxysteroid dehydrogenase inhibitor
• A is a 5-14 membered saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof; wherein the saturated or unsaturated carbocyclic or heterocyclic ring are optionally substituted by 1 to 5 substituents independently selected from R3 or OR"; and X is O or S; or
• A is nothing, N forms a double bond with the cyclic carbon and X is OH or OCH 2 CH 2 - heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
• R is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇
• Q is SO 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH; h is an integer between 0-3; o n is an integer between 1-4;
• n is an integer between 1-2;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons or cyclic alkyl of 3-8 carbons.
• A is nothing, N forms a double bond with the cyclic carbon and X is OCH 2 CH 2 -heterocycle in which the heterocycle is a 3-7 membered heterocycloalkyl.
• the heterocycle is substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• Ri, R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• heterocycle when R4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as defined for Formula X.
• Ri is a hydroxyl group. In another embodiment Ri is hydrogen. In another embodiment R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is COMe. In another embodiment R" is H. In another embodiment R" is a methyl group. In another embodiment R" is COMe.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) ture of formula XI:
• HDI hydroxysteroid dehydrogenase inhibitor
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH;
• R' is hydrogen, Alk or COR
• R" is hydrogen, Alk or COR
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; Z is O, NH, CH 2 or ⁇ ;
• Q is S0 3 H, C0 2 H, C0 2 R, NO2, tetrazole, S0 2 NH 2 or S0 2 NHR;
• h is an integer between 0-3;
• i is an integer between 0-4;
• n is an integer between 1-4;
• n is an integer between 1-2;
• p is an integer between 0-5;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HDI) compound represented by the structure of formula XIa:
• HDI hydroxysteroid dehydrogenase inhibitor
• Ri, R 2 , R3, R' and R' ' are as described above for Formula I, or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HD of formula Xlb:
• R 2 of formula XI, XIa and Xlb is a halogen.
• R 2 is a bromide.
• R 2 is a chloride.
• R 2 is a fluoride.
• R 2 is an iodide.
• R 2 is hydrogen.
• R 2 is a cyano.
• R 2 is a phenyl.
• Rj of formula XI, XIa and Xlb is 0-(CO)-Ph-CF 3 .
• Ri is COOH.
• Ri is COOMe.
• Ri is a hydroxyl group.
• Ri is a hydrogen.
• R 3 of formula XI, XIa and Xlb is a hydrogen.
• R 3 is a halogen.
• R 3 is fluoride.
• R 3 is chloride.
• R 3 is bromide.
• R 3 is iodide.
• R' of formula XI, XIa and Xlb is H.
• R' is a methyl group.
• R' is a COMe.
• R" of formula XI, XIa and Xlb is H.
• R" is a methyl group.
• R" is a COMe.
• h of formula XI, XIa and Xlb is 1.
• h is 2.
• Ri, R 2 , R 3 of formula XI, XIa and Xlb are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• R 4 and R5 of formula XI, XIa and Xlb are independently a 3 to 7 membered heterocycloalkyl
• either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R of formula XI, XIa and Xlb is as defined for Formula XI.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid dehydrogenase inhibitor (HD of formula XII:
• R 4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
• Z is O, NH, CH 2 or ⁇ * ⁇
• Q is S0 3 H, C0 2 H, C0 2 R, N0 2 , tetrazole, S0 2 NH 2 or S0 2 NHR;
• R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, -Ph-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, N0 2 or OH; n is an integer between 1-3;
• p is an integer between 1-4;
• Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
• Ri is an hydroxyl group. In another embodiment Ri is hydrogen. In another embodiment R 3 is halogen. In another embodiment R 3 is fluoride. In another embodiment R 3 is chloride. In another embodiment R 3 is bromide. In another embodiment R 3 is iodide. In another embodiment R 3 is hydrogen. In another embodiment p is 1. In another embodiment, when Ri, R 2 , R 3 are independently Z-Alk-heterocycle or, in another embodiment, OCH 2 CH 2 -heterocycle, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• heterocycle when R4 and R5 are independently a 3 to 7 membered heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine.
• any heterocycle is optionally substituted by one or more substituents comprising halogen, cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alkylamino, N,N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as defined for Formula XII.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid
• HDI dehydrogenase inhibitor
• R 1 is H, alkyl or -alkylene-C0 2 R x , in which R x is H or alkyl;
• R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy, haloalkyl, hydroxyl, hydroxymethyl, CONH 2 , CONHR y , substituted or unsubstituted alkylene-C0 2 R y , in which R y is H or alkyl;
• R 3 is, in each case, independently selected from hydrogen, alkoxy, COOH, hydroxyl, halogen, haloalkyl, CF 2 OMe, CONH 2 , CN, carboxyl, S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl;
• R 4 is, in each case, independently selected from hydrogen, alkyl, hydroxyl, halogen, haloalkyl, CN, carboxyl, CONH 2 , CONHR 2 , S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl; a is an integer 1, 2, 3, 4 or 5; b is an integer 1, 2, 3, 4 or 5; and c is an integer 1 , 2 or 3 ; or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate, or any combination thereof.
• this invention provides: (1) a method of inhibiting a hydroxysteroid dehydrogenase in a patient in need thereof; (2) a method of treating a disorder that responds to a hydroxysteroid dehydrogenase inhibitor; (3) a method of lowering serum testosterone levels in a male subject; (4) a method of lowering serum estradiol levels in a subject; (5) a method of suppressing androgen-dependent androgen receptor activation using a hydroxysteroid dehydrogenase inhibitor; comprising administering to the patient a hydroxysteroid
• R 1 is H, alkyl or -alkylene-C0 2 R x , in which R x is H or alkyl;
• R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, alkoxy, haloalkyl, hydroxyl, hydroxymethyl, CONH 2 , CONHR y , substituted or unsubstituted alkylene-C0 2 R y , in which R y is H or alkyl;
• R 3 is, in each case, independently selected from hydrogen, alkoxy, COOH, hydroxyl, halogen, haloalkyl, CF 2 OMe, CONH 2 , CN, carboxyl, S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl;
• R 4 is, in each case, independently selected from hydrogen, alkyl, hydroxyl, halogen, haloalkyl, CN, carboxyl, CONH 2 , CONHR 2 , S0 2 R z or S0 2 NHR z in which R z is, in each case, independently, H or alkyl; a is an integer 1, 2, 3, 4 or 5; b is an integer 1, 2, 3, 4 or 5; and c is an integer 1 , 2 or 3 ; or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate, or any combination thereof;
• said AKR1C3 inhibitor is not 2-(4-bromomethyl)phenyl-6-hydroxy- 4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4- (4-hydroxyphenyl)isoquinolin-l(2H)-one (14), 2-(4-(bromomethyl)-3-hydroxyphenyl)-6- hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), and 6-hydroxy-2-(4- hydroxyphenyl)- 1 -oxo-4-(3 ,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8-carbonitrile (85).
• R 2 of formula XIII is, in each case, independently hydroxyl. In one embodiment, R 2 of formula XIII is, in each case, independently hydrogen. In another embodiment, R 2 of formula XIII is, in each case, independently CH 2 -halogen. In another embodiment, R 2 of formula XIII is, in each case, independently CH 2 -Br. In another embodiment, R 2 of formula XIII is, in each case, independently CH 2 OH. In another embodiment, R 2 of formula ⁇ is, in each case, independently C(0)NH 2 . In another embodiment, R 2 of formula XIII is, in each case, independently CF 3 . In another embodiment, R 2 of formula XIII is, in each case, independently halogen.
• R 2 of formula ⁇ is, in each case, independently F.
• R 2 of formula XIII is, in each case, independently CI.
• R 2 of formula XIII is, in each case, independently Br.
• R 2 of formula XIII is, in each case, independently I.
• R 3 of formula XIII is, in each case, independently hydrogen. In another embodiment, R 3 of formula XIII is, in each case, independently alkoxy. In another embodiment, R 3 of formula XIII is, in each case, independently OMe. In another embodiment, R 3 of formula XIII is, in each case, independently CONH 2 . In another embodiment, R 3 of formula ⁇ is, in each case, independently CF 3 . In another embodiment, R 3 of formula XIII is, in each case, independently C(0)OH. In another embodiment, R 3 of formula XIII is, in each case, independently CF 3 . In another embodiment, R 3 of formula XIII is, in each case, independently halogen.
• R 3 of formula XIII is, in each case, independently F. In another embodiment, R 3 of formula XIII is, in each case, independently CI. In another embodiment, R 3 of formula XIII is, in each case, independently Br. In another embodiment, R 3 of formula XIII is, in each case, independently I. In another embodiment, R 3 of formula XIII is, in each case, independently S0 2 CH 3 . [0063] In one embodiment, R 4 of formula XIII is, in each case, independently hydrogen. In another embodiment, R 4 of formula XIII is, in each case, independently hydroxyl. In another embodiment, R 4 of formula XIII is, in each case, independently CN.
• R 4 of formula XIII is, in each case, independently halogen.
• R 4 of formula ⁇ is, in each case, independently F.
• R 4 of formula XIII is, in each case, independently CI.
• R 4 of formula XIII is, in each case, independently Br.
• R 4 of formula XIII is, in each case, independently I.
• R 4 of formula XIII is, in each case, independently SO 2 NHCH 3 .
• each case in this invention refers to the substituents of the compounds of this invention wherein each substituent, if there is more than one, can be the same or different.
• each substituent if there is more than one, can be the same or different.
• R 3 b - wherein b is 3, each of R 3 can be "in each case” the same or different.
• an AKR1C3 inhibitor of Formula XIII of this invention is 6- hydroxy-2,4-bis(4-hydroxyphenyl)isoquinolin-l(2H)-one (6);
• an AKR1C3 inhibitor of Formula XIII of this invention is 2-(4-(hydroxymethyl)phenyl)-6-methoxy-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (10);
• an AKR1C3 inhibitor of Formula XIII of this invention is 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11);
• an AKR1C3 inhibitor of Formula XIII of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (13);
• an AKR1C3 inhibitor of Formula XIII of this invention is 2-benzyl-6-hydroxy-4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)- one (75); In another embodiment an AKR1C3 inhibitor of Formula XIII of this invention is 6- hydroxy-2-(4-hydroxyphenyl)-4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)-one (79); In another embodiment an AKR1C3 inhibitor of Formula XIII of this invention is 4-(3,4,5- trifluorophenyl)isoquinolin-l(2H)-one (90); In another embodiment an AKR1C3 inhibitor of Formula XIII of this invention is methyl 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5- trifluorophenyl)-l,2-dihydroisoquinoline-8-carbimidate (100); In another embodiment an AKR1C3 inhibitor
• an HDI compound of this invention is 4-cyano-6,8-dihydroxy-2-(4- hydroxyphenyl)isoquinolin-l(2H)-one.
• an HDI compound of this invention is 4-bromo-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin-l(2H)-one.
• an HDI compound of this invention is l-(2-(piperidin-l-yl)ethoxy)isoquinolin-6-ol.
• an HDI compound of this invention is 6-hydroxy-2-(4- hydroxyphenyl)isoquinolin-l(2H)-one.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)isoquinolin-l(2H)-one. In another embodiment an HDI compound of this invention is 4-bromo-2-(4-hydroxyphenyl)-6- methoxyisoquinolin-l(2H)-one. In another embodiment an HDI compound of this invention is 4- bromo-2-(3-fluoro-4-hydroxyphenyl)-6-hydroxyisoquinolin-l (2H)-one. In another embodiment an HDI compound of this invention is 4-bromo-2-(4-fluorophenyl)-6-hydroxyisoquinolin- l(2H)- one.
• an HDI compound of this invention is 4-chloro-6-hydroxy-2-(4- hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 4-chloro-2-(3-fluoro-4-hydroxyphenyl)-6-hydroxyisoquinolin- l(2H)-one.
• an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4- iodoisoquinolin- l(2H)-one.
• an HDI compound of this invention is 4- bromo-6-hydroxy-2-(3-hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 8-hydroxy-2-(4-hydroxyphenyl)-6-methoxy-isoquinolin- l(2H)- one.
• an HDI compound of this invention is 5-bromo-8-hydroxy-2-(4- hydroxyphenyl)-6-methoxy-isoquinolin-l (2H)-one.
• an HDI compound of this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)-isoquinolin- l(2H)-one.
• an HDI compound of this invention is 5-bromo-6,8-dihydroxy-2-(4- hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 2-(3-fluoro-4-hydroxyphenyl)-6-hydroxy-4-iodoisoquinolin- l(2H)-one.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4-hydroxy-3- methylphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 2-(4-hydroxyphenyl)-6,8-dihydroxy-isoquinoline-l (2H)-thione.
• an HDI compound of this invention is 8-hydroxy-2-(4-hydroxyphenyl)-6-methoxy- l-oxo- l ,2-dihydroisoquinoline-5-carbonitrile.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)isoquinoline-l (2H)-thione.
• an HDI compound of this invention is 2-(3-fluoro-4-hydroxyphenyl)-6,8- dihydroxyisoquinolin- l(2H)-one.
• an HDI compound of this invention is 2-(3-fluoro-4-hydroxyphenyl)-8-hydroxy-6-methoxyisoquinolin-l (2H)-one.
• an HDI compound of this invention is 4-bromo-8-hydroxy-2-(4-hydroxyphenyl)-6- methoxyisoquinolin- l(2H)-one.
• an HDI compound of this invention is 4- chloro-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 4-bromo-6,8-dihydroxy-2-(3-fluoro-4- hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 4,5-dibromo-2-(3,5-dibromo-4-hydroxyphenyl)-6-hydroxyisoquinolin-l (2H)-one.
• an HDI compound of this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)- 5-(trifluoromethylsulfonyl)isoquinolin-l (2H)-one.
• an HDI compound of this invention is 4-(l ,2-dibromoethyl)-6-hydroxy-2-(4-hydroxyphenyl)isoquinolin-l (2H)-one.
• an HDI compound of this invention is 6-methoxy-2-(4-methoxyphenyl)-l - oxo- l ,2-dihydroisoquinolin-8-yltrifluoromethanesulfonate.
• an HDI compound of this invention is 4,5-dibromo-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 6-hydroxy-2-(4- hydroxyphenyl)-4-vinylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 6-methoxy-2-(4-methoxyphenyl)- l -oxo- l ,2-dihydroisoquinoline-4-carbonitrile.
• an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-l - oxo- 1 ,2-dihydroisoquinoline-4-carbonitrile.
• an HDI compound of this invention is 6-methoxy-2-(4-methoxyphenyl)- l -oxo- l ,2-dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is 4-bromo-6-methoxy-2-(4- methoxyphenyl)- 1 -oxo- l ,2-dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)- l -oxo- 1 ,2- dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-vinylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)-l -oxo- l ,2- dihydroisoquinoline-4-carbonitrile or 4-cyano-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 6-hydroxy-2-(4- hydroxyphenyl)- 1 -oxo- l ,2-dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-l -oxo-4- vinyl- 1 ,2- dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is 4-chloro-6-hydroxy-2-(4-hydroxyphenyl)-l -oxo- l ,2-dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is 4-bromo-6-methoxy-2-(4- methoxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 8-hydroxy-6-methoxy-2-(4-methoxyphenyl)isoquinolin-l (2H)-one.
• an HDI compound of this invention is 4-chloro-6-methoxy-2-(4-methoxyphenyl)-l - oxo- l ,2-dihydroisoquinolin-8-yl trifluoromethanesulfonate.
• an HDI compound of this invention is 4-chloro-6-methoxy-2-(4-methoxyphenyl)- l -oxo- 1 ,2- dihydroisoquinoline-8-carbonitrile.
• an HDI compound of this invention is isoquinoline-l ,6-diol.
• an HDI compound of this invention is 4-bromo- 6-hydroxy-2-(4-methoxyphenyl)isoquinolin-l (2H)-one.
• an HDI compound of this invention is 4-(6-acetoxy-4-bromo- l-oxoisoquinolin-2(lH)-yl)phenyl acetate.
• an HDI compound of this invention is 4-(4-bromo-6-methoxy- l - oxoisoquinolin-2(lH)-yl)phenyl acetate.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)- 1 -oxo- 1 ,2-dihydroisoquinoline-8- carbimidic acid.
• an HDI compound of this invention is methyl 4-bromo- 6-hydroxy-2-(4-hydroxyphenyl)- 1 -oxo- 1 ,2-dihydroisoquinoline-8-carboxylate.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)- l- oxo- l ,2-dihydroisoquinoline-8-carboxylic acid.
• an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 2-(3-fluoro-4-hydroxyphenyl)-6,8-dihydroxy-4-vinylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 2-(3-fluoro-4-hydroxyphenyl)-6,8- dihydroxy- 1 -oxo- l ,2-dihydroisoquinoline-4-carbonitrile.
• an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-8-vinylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 4-bromo-6-hydroxy-2-(4- hydroxyphenyl)-8-vinylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)- 4-phenylisoquinolin- l(2H)-one.
• an HDI compound of this invention is (£ ' )-6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(prop-l -enyl)isoquinolin- l(2H)-one.
• an HDI compound of this invention is (E)-ethy ⁇ 3-(8-hydroxy-6-methoxy-2-(4- methoxyphenyl)- 1 -oxo- l ,2-dihydroisoquinolin-4-yl)acrylate.
• an HDI compound of this invention is (£)-3-(6-hydroxy-2-(4-hydroxyphenyl)-l -oxo-l ,2- dihydroisoquinolin-4-yl)acrylic acid.
• an HDI compound of this invention is (£ ' )-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- l-oxo-l ,2-dihydroisoquinolin-4-yl)acrylic acid.
• an HDI compound of this inventions is 2-(4-bromomethyl)phenyl-6- hydroxy-4-(4-hydroxyphenyl)isoquinolin-l (2H)-one.
• HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin- l(2H)-one.
• an HDI compound of this invention is 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin- 1 (2H)- one.
• an HDI compound of this invention is 2-(4- (bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l (2H)- one.
• an HDI compound of this invention is 4-chloro-6-methoxy-2-(4- methoxyphenyl)- 1 -oxo- l ,2-dihydroisoquinolin-8-yl 4-(trifluoromethyl)benzoate.
• an HDI compound of this invention is 6-hydroxy-2,4-bis(4- hydroxyphenyl)isoquinolin- l(2H)-one (6); In another embodiment an HDI compound of this invention is 2-(4-(hydroxymethyl)phenyl)-6-methoxy-4-(4-methoxyphenyl)isoquinolin- 1 (2H)- one (10); In another embodiment an HDI compound of this invention is 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11); In another embodiment an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (13); In another embodiment an HDI compound of this invention is 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin- l(2H)-one (6)
• an HDI compound of this invention is 2-benzyl-6- hydroxy-4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)-one (75); In another embodiment an HDI compound of this invention is 6-hydroxy-2-(4-hydroxyphenyl)-4-(3,4,5- trifluorophenyl)isoquinolin-l(2H)-one (79); In another embodiment an HDI compound of this invention is 4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)-one (90); In another embodiment an HDI compound of this invention is 2-benzyl-6-hydroxy-4-(3,4,5-trifluorophenyl)isoquinolin-l(2H)- one (75); In another embodiment an HDI compound of this invention is methyl 6-hydroxy-2-(4- hydroxyphenyl)- 1 -oxo-4-(3 ,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8-car
• an HDI compound of this invention is 4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methoxy)isoquinolin- 1 (2H)-one (214), or its prodrug, analog, isomer, metabolite, dermivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• an HDI compound of this invention is 4-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, analog, isomer, metabolite, dermivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4- (3,4,5-trifluorophenyl)-l ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 6-hydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin-l(2H)-one, (15a) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one, (15g) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 6,8-dihydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin-l(2H)-one, (15h) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l- oxo- 1 ,2-dihydroisoquinolin-4-yl)acrylic acid, (151) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one, (11) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one, (13) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one, (14) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• the HDI compound is 2-(4-(bromomethyl)-3-hydroxyphenyl)-6- hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one, (26) or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate, or any combination thereof.
• an HDI compound of this invention may comprise any combinations of such HDI compound as described herein.
• the compound of Formula I is selected from:
• this invention provides a compound of Formula I-XIII,, or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof. In one embodiment, this invention provides a compound of Formula I-XII, or an isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, N-oxide, hydrate or any combination thereof. In one embodiment, this invention provides a compound of Formula I-XIII, or an isomer, tautomer, pharmaceutically acceptable salt, polymorph, N-oxide, hydrate or any combination thereof.
• this invention provides a compound of Formula I-XIII, or an isomer, tautomer, pharmaceutically acceptable salt, N-oxide, hydrate or any combination thereof. In one embodiment, this invention provides a compound of Formula I-XIII, or an isomer, pharmaceutically acceptable salt, or any combination thereof.
• this invention provides an isomer of a compound of
• this invention provides a metabolite of a compound of Formula I-XIII.
• this invention provides a pharmaceutically acceptable salt of a compound of Formula I-XIII.
• this invention provides a hydrate of a compound of Formula I-XIII.
• this invention provides a tautomer of a compound of Formula I-XIII.
• this invention provides an N-oxide of a compound of Formula I-XIII.
• this invention provides a prodrug of a compound of Formula I-XIII.
• this invention provides a polymorph of a compound of Formula I-XIII.
• this invention provides a crystal of a compound of Formula I-XIII.
• a compound of this invention is a hydroxysteroid dehydrogenase inhibitor (HSDi).
• HSDi is an aldo-keto reductase inhibitor.
• an HSDi is a AKR1C3 inhibitor.
• the compounds of the present invention are active as selective hydroxysteroid dehydrogenase inhibitors (HSDi). In one embodiment, the compounds of the present invention are active as selective inhibitors of AKRIC. In another embodiment, the compounds of the present invention are active as selective inhibitors of AKR1C3.
• a selective inhibitor of AKR1C3 is 6-hydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a),or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one e (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is (£)-3-(6,8- dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 6-hydroxy-2-(4- hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 2-(4-(bromomethyl)-3- hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 6-hydroxy-2-(4-
• a selective inhibitor of AKR1C3 is 6-hydroxy-2-(4- hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• a selective inhibitor of AKR1C3 is 3-(4-(3-fluoro-4-
• a selective inhibitor of AKR1C3 is 4-(4-(3-fluoro-4-
• a selective inhibitor of AKR1C3 of this invention (Formula I-
• XIII) and methods of use thereof is not 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11).
• a selective inhibitor of AKR1C3 of this invention and methods of use thereof is not 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13).
• a selective inhibitor of AKR1C3 of this invention and methods of use thereof is not 2-(4-(bromomethyl)-3- hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26). In one embodiment, a selective inhibitor of AKR1C3 of this invention and methods of use thereof is not 6- hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14).
• a selective inhibitor of AKR1C3 of this invention and methods of use thereof is not 6- hydroxy-2-(4-hydroxyphenyl)- 1 -oxo-4-(3,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8- carbonitrile (85).
• alkyl refers, in one embodiment, to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups.
• the alkyl group has 1-12 carbons.
• the alkyl group has 1-7 carbons.
• the alkyl group has 1-6 carbons.
• the alkyl group has 1-4 carbons.
• the cyclic alkyl group has 3-8 carbons.
• the cyclic alkyl group has 3-12 carbons.
• the branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons.
• the branched alkyl is an alkyl substituted by haloalkyl side chains of 1 to 5 carbons.
• the alkyl group may be unsubstituted or substituted by a halogen, haloalkyl, hydroxyl, cyano, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
• alkenyl group refers, in another embodiment, to an unsaturated hydrocarbon, including straight chain, branched chain and cyclic groups having one or more double bonds.
• the alkenyl group may have one double bond, two double bonds, three double bonds, etc.
• the alkenyl group has 2-12 carbons.
• the alkenyl group has 2-6 carbons.
• the alkenyl group has 2-4 carbons.
• the alkenyl group may be unsubstituted or substituted by a halogen, hydroxy, cyano, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
• cycloalkyl refers to a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, for example, 3 to 6 carbon atoms.
• Non limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant- 1-yl, and adamant-2-yl.
• Suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl.
• haloalkyl group refers, in another embodiment, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, CI, Br or I.
• aryl group refers, in another embodiment, to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl.
• Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
• a "hydroxyl” group refers, in another embodiment, to an OH group.
• R R 2 or R 3 of the compounds of the present invention is OR, then R is not OH.
• halo refers to a halogen, such as F, CI, Br or I.
• the phrase "phenol” refers to an alcohol (OH) derivative of benzene.
• a “heterocycle” group refers, in one embodiment, to a ring structure comprising in addition to carbon atoms, sulfur, oxygen, nitrogen or any combination thereof, as part of the ring.
• the heterocycle is a 3-12 membered ring.
• the heterocycle is a 6 membered ring.
• the heterocycle is a 5-7 membered ring.
• the heterocycle is a 4-8 membered ring.
• the heterocycle group may be unsubstituted or substituted by a halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO 2 H, amino, alkylamino, dialkylamino, carboxyl, thio and/or thioalkyl.
• the heterocycle ring may be fused to another saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered ring.
• the heterocyclic ring is a saturated ring.
• the heterocyclic ring is an unsaturated ring.
• Examples of a heterocycle group comprise pyridine, piperidine, morpholine, piperazine, thiophene, pyrrole or indole.
• the 5-14 member saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic ring comprises a phenyl, naphthalene, anthracene, pyridine, piperidine, thiophene, morpholine, piperazine, pyrimidine, cyclohexyl, cycloheptyl, pyrrole, pyrazole, furan, oxazole. quinoline, pyrazine or indole groups.
• unsaturated cycloalkyl or heterocyeloalkyl groups refer to cycloalkyl or heterocyeloalkyl comprising at list one double bond, in another embodiment unsaturated cycloalkyl or heterocyeloalkyl refer to an aryi or heieroaryi group.
• protected hydroxyl includes the incorporation of a substituent bonded to an oxygen atom bound to a benzene ring, wherein the substituent may be readily removed.
• phenolic protecting groups may comprise a: methyl ether, methoxymethyl (MOM) ether, benzoyloxymethyl (BOM) ether, methoxyethoxymethyl (MEM) ether, 2-(trimethylsilyl)ethoxymethyl(SEM) ether, methylthiomethyl (MTM) ether, phenylthiomethyl (PTM) ether, azidomethyl ether, cyanomethyl ether, 2,2-dichloro-l,l- difluoroethyl ether, 2-chloroethyl ether, 2-bromoethyl ether, tetrahydropyranyl (THP) ether, 1- ethoxyethyl (EE) ether, phenacyl ether, 4-bromophenacy
• XIII can exist in different tautomeric and/or conformational and/or geometrical isomeric and/or optical isomeric forms. All of these forms, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, e.g., no more than 2%, such as no more than 1%.
• the term “isomer” is meant to encompass optical isomers of the compound. In one embodiment, the term “isomer” is meant to encompass stereoisomers of the compound. In one embodiment, the term “isomer” is meant to encompass conformational isomers. one embodiment, the term “isomer” is meant to encompass tautomers. It is to be understood that the present invention encompasses any optically-active, or stereroisomeric form, or mixtures thereof, and use of these for any application is to be considered within the scope of this invention.
• the compounds of Formula I-XIII are substantially pure (£)- isomers. In another embodiment, the compounds of Formula I-XIII are substantially pure (Z)- isomers. In another embodiment, the compounds of Formula I-XIII are a mixture of (E) and the (Z) isomers. In one embodiment, the compounds of Formula I-XIII are pure (£)-isomers. In another embodiment, the compounds of Formula I-XIII are pure (Z)-isomers. In one embodiment, the compounds of Formula I-XIII are substantially pure ( ?)-isomers. In another embodiment, the compounds of Formula I-XIII are substantially pure ( ⁇ -isomers.
• the compounds of Formula I-XIII are a mixture of (R) and the (5) isomers. In one embodiment, the compounds of Formula I-XIII are pure ( ?)-isomers. In another embodiment, the compounds of Formula I-XIII are pure ( ⁇ -isomers.
• optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
• appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
• Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
• optically active bases or acids are then liberated from the separated diastereomeric salts.
• a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful.
• the optically active compounds of Formula I- Xlllcan likewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization.
• the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
• the compounds are deuterated.
• Such deuterated forms can be made via the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
• deuteration can improve the efficacy and increase the duration of action of drugs.
• Deuterium substituted compounds can be synthesized using various methods such as described in, for example, Dean, Dennis C; Editor. Recent Advances in the Synthesis and Applications of Radio labeled Compounds for Drug Discovery and Development. [In: Curr. Pharm. Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of radio labeled compounds via organometallic intermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony. Synthesis of radio labeled compounds, J. Radioanal. Chem. (1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.
• the present invention also relates to useful forms of the compounds as disclosed herein, such as base free forms, and pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared.
• Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid.
• Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
• an appropriate base e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
• acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
• alkali and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
• acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, prop
• the pharmaceutically acceptable salt can be a hydrochloride, a hydrobromide, a hydroformate, a maleate or a sodium salt.
• the salts formed are pharmaceutically acceptable for administration to mammals.
• pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent.
• the free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
• Formula I-XIII can exist in different polymorphic forms.
• polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
• a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
• Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in crystal structure as crystalline structures of two different chemical compounds.
• the compounds of Formula I-XIII can exist in different solvate forms.
• Solvates of the compounds of the invention may form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process.
• a compound of Formula I-XIII may exist in the form of a hydrate, such as, for example, a monohydrate, hemihydrate, sesquihydrate, dihydrate, trihydrate, or any combination thereof.
• prodrug means a compound that is a drug precursor which upon administration to a subject undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention includes prodrugs of the disclosed compounds and methods of delivering the same. Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
• prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively.
• Examples include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, feri-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.
• Such prodrugs are considered to be within the scope of this invention.
• This invention provides, in other embodiments, metabolites of a compound of
• the term "metabolite” refers to any substance produced from another substance by metabolism or a metabolic process.
• the present invention relates to methods for preparing the compounds of Formula I-XIII.
• the compounds of the present invention may be prepared by conventional methods, known to one or ordinary skill in the art. For example, some of the processes that can be used are given in the general reaction schemes outlined below. Modifications to these exemplary reaction schemes will be readily apparent to those skilled in the art upon reading the present disclosure and examples which follow. All starting materials are commercially available or can be conventionally prepared from known starting materials, unless otherwise indicated.
• HSDi HSDi
• HDI high-di
• this invention provides general and specific synthetic routes for embodiments of isoquinolinones and isoquinolin-6-ols.
• Intermediate compound 4 can be prepared by three different paths starting from 2-(2- carboxy-vinyl) benzoic acid (compound 1) via step a; or starting with 3 -phenyl- acrylic acid, (compound 2) together with sodium azide (step b) to obtain an acyl derivative of compound 3, followed by Curtius rearrangement and a cyclization step (step c) in the presence of diphenyl ether and tributylamine at 230 °C to obtain compound 4; or starting with 2-iodo benzonitrile (compound 10) via the Sonogashira reaction (step i) followed by methanolysis (step j) to obtain compound 4.
• 2-(2- carboxy-vinyl) benzoic acid compound 1
• step a or starting with 3 -phenyl- acrylic acid, (compound 2) together with sodium azide (step b) to obtain an acyl derivative of compound 3, followed by Curtius rearrangement and a cyclization step (step c) in the presence of diphen
• Compound 4 is further coupled with an iodo substituted formula A (step d), yielding compound 5, which may be further brominated, chlorinated, or iodinated (using NBS, NCS, or NIS, respectively) followed by further substitutions to obtain the desired R 2 group (step f) compound 8 or compound 8', or obtain the sulfone compound 9 using P2S5 reagent (step h).
• step d an iodo substituted formula A
• step d yielding compound 5, which may be further brominated, chlorinated, or iodinated (using NBS, NCS, or NIS, respectively) followed by further substitutions to obtain the desired R 2 group (step f) compound 8 or compound 8', or obtain the sulfone compound 9 using P2S5 reagent (step h).
• Compounds 8 or 9 can be optionally demethylated with BBr 3 to yield the phenolic products, however if step h is executed, then the phenol must be protected.
• compound 4 may be brominated, chlorinated, or iodinated (using NBS, NCS, or NIS, respectively) and further substituted (step e) to obtain the desired R 2 of compound 6 or 6' .
• Compound 6 or 6' may be coupled together with an iodo substituted formula A (step d), yielding compound 8 or 8' , or the OH group of compound 6 or 6' is further substituted (step g) to obtain the desired X group of compound 7 or compound 7' .
• this invention provides synthetic route for embodiments of 4- halogenated isoquinolinones.
• a synthetic procedure for a compound of this invention 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)isoquinolin- l(2H)-one, is
• this invention provides synthetic route for embodiments of 6,8- dihydroxy-isoquinolinones.
• An example of these embodiments of this invention provides a synthetic route for 4-bromo-6, 8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin- l(2H)-one_(12u].
• this invention provides synthetic route for embodiments of 4- alkenyl isoquinolinones.
• An example of these embodiments of this invention provides a synthetic route for 6-hydroxy-2-(4-hydroxyphenyl)-4-vinylisoquinolin-l(2H)-one (14f) compound.
• this invention provides synthetic route for embodiments of 4- carbonitrile derivatives of l-oxo-l,2-dihydroisoquinolines.
• this invention provides synthetic routes for 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinoline-4- carbonitrile (14h).
• this invention provides synthetic route for embodiments of 8- carbonitrile derivatives of l-oxo-l,2-dihydroisoquinolines.
• this invention provides synthetic routes for 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinoline-8- carbonitrile (14k):
• this invention provides synthetic route for 14o compound
• this invention provides synthetic route for 14p compound
• this invention provides synthetic routes for 14xME, 14xME_AC and 14xAC compounds.
• this invention provides synthetic routes for 4-bromo-6-hydroxy-2- (4-hydroxyphenyl)-l-oxo-l ,2-dihydroisoquinoline-8-carbimidic acid (14 AM), methyl 4-bromo- 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-l ,2-dihydroisoquinoline-8-carboxylate (14yME), and 4- bromo-6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-l ,2-dihydroisoquinoline-8-carboxylic acid (14z) com ounds.
• this invention provides synthetic routes for 6-hydroxy-2-(4- h droxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a).
• the compounds of the invention can be administered alone or as an active ingredient of a formulation.
• the present invention also includes pharmaceutical compositions of compounds of formula I-XIII, containing, for example, one or more pharmaceutically acceptable carriers.
• the mode of administration and dosage forms is closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application.
• Suitable dosage forms include but are not limited to oral, rectal, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra- articular, intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterile administration, and other dosage forms for systemic delivery of active ingredients. Formulations suitable for oral administration are preferred.
• the active ingredient may be mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• any of the usual pharmaceutical media may be employed.
• suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, tablets may be sugar coated or enteric coated by standard techniques.
• the carrier will usually comprise sterile water, though other ingredients, for example, ingredients that aid solubility or for preservation, may be included. Injectable solutions may also be prepared in which case appropriate stabilizing agents may be employed.
• the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
• a suitable biomolecule such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
• Treatment methods of the present invention using formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as, for example, a powder or granules.
• a suspension in an aqueous liquor or a non-aqueous liquid may be employed, such as a syrup, an elixir, an emulsion, or a draught.
• a tablet may be made by compression or molding, or wet granulation, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with, for example, a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent.
• Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
• a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s).
• a sugar for example sucrose
• Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
• Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution).
• Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
• the formulations may be presented in unit-dose or multi-dose form.
• Parenteral administration may comprise any suitable form of systemic delivery.
• Administration may for example be intravenous, intra-arterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal), etc., and may be effected by infusion pumps (external or implantable) or any other suitable means appropriate to the desired administration modality.
• Nasal and other mucosal spray formulations can comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucous membranes. Alternatively, they can be in the form of finely divided solid powders suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, e.g., by nebulizer, atomizer, metered dose inhaler, or the like.
• Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
• Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
• a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose
• formulations of this invention may further include one or more accessory ingredient(s) selected from, for example, diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
• accessory ingredient(s) selected from, for example, diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
• formulations of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to one skilled in the art.
• the compounds of the present invention may be useful as hydroxysteroid dehydrogenase inhibitors.
• the compounds of the present invention may be useful as AKR1C inhibitors, for example AKR1C3 inhibitors.
• the compounds of this invention may be useful as selective inhibitors of AKR1C3.
• some embodiments provide methods of treating a condition that responds to a hydroxysteroid dehydrogenase inhibitor comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
• the present invention provides methods of treatment of conditions related to cancer.
• the present invention in certain embodiments, provides methods of treatment of hormone dependent or hormone independent cancers.
• hormone dependent cancers include prostate cancer, breast cancer uterine fibroids including myomas and uterine cancer including cervical and endometrial cancers.
• hormone independent cancers include lung cancer including non-small cell lung cancer, bladder cancer, colon cancer, leukemias including acute myelogenous leukemia, and/or lymphoma.
• a method of treating a condition is the method of treating prostate cancer.
• prostate cancer refers to prostate cancer, primary prostate cancer, advanced prostate cancer, metastatic prostate cancer, hormone naive prostate cancer, refractory prostate cancer and/or castration resistant prostate cancer (CRPC) or any combination thereof.
• a method of treating a condition is the method of treating breast cancer.
• breast cancer refers to breast cancer; metastatic breast cancer; advanced breast cancer; refractory breast cancer; AR-positive breast cancer; ER-positive breast cancer, wherein ER-positive breast cancer may refer to ER-alpha- positive breast cancer and/or ER-beta-positive breast cancer; AR-positive refractory breast cancer; ER-positive refractory breast cancer; AR-positive metastatic breast cancer; ER-positive metastatic breast cancer; triple negative breast cancer; and/or breast cancer that has failed SERM (tamoxifen, toremifene), aromatase inhibitor, trastuzumab (Herceptin ® ), exemestane (Aromasin ® ), bevacizumab (Avastin ® ), and/or fulvestrant treatment, or any combination thereof.
• SERM tamoxifen, toremifene
• aromatase inhibitor trastuzumab (Her
• Metastasis refers to the transfer of a disease from one organ or part thereof to another not directly connected with it. Metastasis can occur for example as a result of transfer of malignant cells from one organ (for example breast) to other organs.
• this invention provides a method of treating a subject suffering from prostate cancer, comprising the step of administering to said subject a compound of this invention, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, prodrug, metabolite or any combination thereof, or a composition comprising the same in an amount effective to treat prostate cancer in the subject.
• treating refers to treating, preventing, suppressing, inhibiting or delaying the progression of.
• the methods of this invention are directed to treating prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of prostate cancer. In another embodiment, this invention is directed to suppressing prostate cancer. In another embodiment, this invention is directed to reducing the incidence of prostate cancer. In another embodiment, this invention is directed to reducing the severity of prostate cancer. In another embodiment, this invention is directed to inhibiting prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with prostate cancer.
• the methods of this invention are directed to treating primary prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting primary prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of primary prostate cancer. In another embodiment, this invention is directed to suppressing primary prostate cancer. In another embodiment, this invention is directed to reducing the incidence of primary prostate cancer. In another embodiment, this invention is directed to reducing the severity of primary prostate cancer. In another embodiment, this invention is directed to inhibiting primary prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with primary prostate cancer.
• the methods of this invention are directed to treating naive hormone prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting hormone naive prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of hormone naive prostate cancer. In another embodiment, this invention is directed to suppressing hormone naive prostate cancer. In another embodiment, this invention is directed to reducing the incidence of hormone naive prostate cancer. In another embodiment, this invention is directed to reducing the severity of hormone naive prostate cancer. In another embodiment, this invention is directed to inhibiting hormone naive prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with hormone naive prostate cancer.
• the methods of this invention are directed to treating advanced prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting advanced prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of advanced prostate cancer. In another embodiment, this invention is directed to suppressing advanced prostate cancer. In another embodiment, this invention is directed to reducing the incidence of advanced prostate cancer. In another embodiment, this invention is directed to reducing the severity of advanced prostate cancer. In another embodiment, this invention is directed to inhibiting advanced prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with advanced prostate cancer.
• the methods of this invention are directed to treating refractory prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting refractory prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of refractory prostate cancer. In another embodiment, this invention is directed to suppressing refractory prostate cancer. In another embodiment, this invention is directed to reducing the incidence of refractory prostate cancer. In another embodiment, this invention is directed to reducing the severity of refractory prostate cancer. In another embodiment, this invention is directed to inhibiting refractory prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with refractory prostate cancer.
• the methods of this invention are directed to treating metastatic prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting metastatic prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of metastatic prostate cancer. In another embodiment, this invention is directed to suppressing metastatic prostate cancer. In another embodiment, this invention is directed to reducing the incidence of metastatic prostate cancer. In another embodiment, this invention is directed to reducing the severity of metastatic prostate cancer. In another embodiment, this invention is directed to inhibiting metastatic prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with metastatic prostate cancer.
• the methods of this invention are directed to treating castration resistant prostate cancer. In one embodiment, the methods of this invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting castration resistant prostate cancer. In one embodiment, the methods of this invention are directed to palliative treatment of castration resistant prostate cancer. In another embodiment, this invention is directed to suppressing castration resistant prostate cancer. In another embodiment, this invention is directed to reducing the incidence of castration resistant prostate cancer. In another embodiment, this invention is directed to reducing the severity of castration resistant prostate cancer. In another embodiment, this invention is directed to inhibiting castration resistant prostate cancer. In another embodiment, this invention is directed to increasing the survival of a subject with castration resistant prostate cancer.
• this invention provides a method of delaying the progression of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of prostate cancer in the subject.
• this invention provides a method of delaying the progression of primary prostate cancer in a subject suffering from primary prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of primary prostate cancer in the subject.
• this invention provides a method of delaying the progression of hormone naive prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of prostate cancer in the subject.
• this invention provides a method of delaying the progression of advanced prostate cancer in a subject suffering from advanced prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of advanced prostate cancer in the subject.
• this invention provides a method of delaying the progression of metastatic prostate cancer in a subject suffering from metastatic prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of metastatic prostate cancer in the subject.
• this invention provides a method of delaying the progression of refractory prostate cancer in a subject suffering from refractory prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of refractory prostate cancer in the subject.
• this invention provides a method of delaying the progression of castration resistant prostate cancer in a subject suffering from castration resistant prostate cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of castration resistant prostate cancer in the subject.
• the methods of this invention make use of compounds of Formula I. In another embodiment, the methods of this invention make use of compounds of Formula II. In yet another embodiment, the methods of this invention make use of compounds of Formula III. In still another embodiment, the methods of this invention make use of compounds of Formula IV. In a further embodiment, the methods of this invention make use of compounds of Formula V. In another embodiment, the methods of this invention make use of compounds of Formula VI. In yet another another embodiment, the methods of this invention make use of compounds of Formula VII. In still another embodiment, the methods of this invention make use of compounds of Formula VIII. In a further embodiment, the methods of this invention make use of compounds of Formula FX. In another embodiment, the methods of this invention make use of compounds of Formula X.
• the methods of this invention make use of compounds of Formula XI. In still another embodiment, the methods of this invention make use of compounds of Formula XII. In still another embodiment, the methods of this invention make use of compounds of Formula XIII. In a further embodiment, the methods of this invention make use of compounds of Formula I-XIII in combination with LH-RH agonist. In still another embodiment, the methods of this invention make use of compounds of Formula I-XIII in combination with an anti-androgen.
• the methods of this invention make use of compounds of Formula I-XIII in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec ® ) or gefitinib (Iressa ® )) or other prostate cancer therapies (e.g., vaccines (sipuleucel-T (Provenge ® ), GVAX, etc.), herbal (PC-SPES) or a lyase inhibitor (abira
• the methods of this invention make use of compounds of
• the methods of treating prostate cancer make use of a compound of Formula I. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula II. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula III. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula IV. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula V. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula VI. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula VII. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula EX.
• the methods of treating prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating prostate cancer make use of a compound of Formula XIII.
• the methods of treating prostate cancer make use of 6-hydroxy-
• 2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 2-(4- (bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5- trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 3- (4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating prostate cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin- 2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of a compound of Formula I. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula II. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula III. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula IV. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula V. In another embodiment the methods of treating primary prostate cancer make use of a compound of Formula VI. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula VII. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula VIII.
• the methods of treating primary prostate cancer make use of a compound of Formula FX. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating primary prostate cancer make use of a compound of Formula ⁇ .
• the methods of treating primary prostate cancer make use of 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 6-hydroxy- 2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 6-hydroxy-2- (4-hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin- 2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating primary prostate cancer make use of 4-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of a compound of Formula I. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula II. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula III. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula IV. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula V. In another embodiment the methods of treating hormone naive prostate cancer make use of a compound of Formula VI. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula VII.
• the methods of treating hormone naive prostate cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula FX. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating hormone naive prostate cancer make use of a compound of Formula XIII.
• the methods of treating hormone naive prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l (2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l -oxo-l ,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 6- hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 2- (4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)- one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4- (3,4,5-trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)- yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating hormone naive prostate cancer make use of 4-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of a compound of Formula I. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula II. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula III. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula IV. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula V. In another embodiment the methods of treating advanced prostate cancer make use of a compound of Formula VI. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula VII. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula VIII.
• the methods of treating advanced prostate cancer make use of a compound of Formula FX. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating advanced prostate cancer make use of a compound of Formula XIII.
• the methods of treating advanced prostate cancer make use of 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 6- hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 6-hydroxy- 2-(4-hydroxyphenyl)- 1 -oxo-4-(3,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced prostate cancer make use of 4-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of a compound of Formula I.
• the methods of treating metastatic prostate cancer make use of a compound of Formula II.
• the methods of treating metastatic prostate cancer make use of a compound of Formula III.
• the methods of treating metastatic prostate cancer make use of a compound of Formula IV. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula V. In another embodiment the methods of treating metastatic prostate cancer make use of a compound of Formula VI. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula VII. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula FX. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating metastatic prostate cancer make use of a compound of Formula XIII.
• the methods of treating metastatic prostate cancer make use of
• 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 6- hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 6-hydroxy- 2-(4-hydroxyphenyl)- 1 -oxo-4-(3,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy- l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic prostate cancer make use of 4-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of a compound of Formula I. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula II. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula III. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula IV. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula V. In another embodiment the methods of treating refractory prostate cancer make use of a compound of Formula VI. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula VII.
• the methods of treating refractory prostate cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula FX. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating refractory prostate cancer make use of a compound of Formula XIII.
• the methods of treating refractory prostate cancer make use of
• 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 6- hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 6-hydroxy- 2-(4-hydroxyphenyl)- 1 -oxo-4-(3,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory prostate cancer make use of 4-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula I.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula II.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula III.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula IV.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula V.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula VI.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula VII.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula VIII.
• the methods of treating castration resistant prostate cancer make use of a compound of Formula FX. In another embodiment, the methods of treating castration resistant prostate cancer make use of a compound of Formula X. In another embodiment, the methods of treating castration resistant prostate cancer make use of a compound of Formula XI. In another embodiment, the methods of treating castration resistant prostate cancer make use of a compound of Formula XII. In another embodiment, the methods of treating castration resistant prostate cancer make use of a compound of Formula XIII.
• the methods of treating castration resistant prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 2- (4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy- 4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l,2- dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 3- (4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating castration resistant prostate cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6- hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of this invention make use of 6-hydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or a prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron®).
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec ® ) or gefit
• the methods of this invention make use of 6,8-dihydroxy-2- (4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an LH-RH agonist.
• the methods of this invention make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti- androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (G)
• the methods of this invention make use of 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec ® )
• the methods of this invention make use of (E)-3-(6,8- dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4- yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti- androgen.
• the methods of this invention make use of (£)-3-(6,8- dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imat
• the methods of this invention make use of (£)-3-(6,8- dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (
• the methods of this invention make use of 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer,metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin- l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti- androgen.
• the methods of this invention make use of 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-4- (4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-4- (4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleeve
• the methods of this invention make use of 6-hydroxy-2-(4-)
• the methods of this invention make use 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin- l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 6- hydroxy-2-(4-(hydroxymemyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4- (4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec
• the methods of this invention make use of 2-(4-(bromomethyl)-
• the methods of this invention make use 2-(4-(bromomethyl)-3-hydroxyphenyl)-6- hydroxy-4-(4-(trifluoromethyl)phenyl) isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin- l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors
• the methods of this invention make use of 6-hydroxy-2-(4- hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4- (3,4,5-trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5- trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l,2- dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (i)
• the methods of this invention make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin- 2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use 3-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 3-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (
• the methods of this invention make use of 4-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with LH-RH agonist.
• the methods of this invention make use 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with leuprolide acetate (Lupron ® ).
• the methods of this invention make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin- 2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in combination with an anti-androgen.
• the methods of this invention make use of 4-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, in combination with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (degarelix), anti-androgens (e.g., bicalutamide, nilutamide, flutamide, MDV3100, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imat
• primary prostate cancer refers to prostate cancer that develops in the prostate.
• hormone naive prostate cancer refers to prostate cancer that has not been treated with hormones such as estrogens or androgens, agents that block hormones such antiandrogens and antiestrogens, or agents that manipulate hormone levels such as LH-RH agonists or antagonists like leuprolide acetate (Lupron ® ) and degarelix, respectively.
• refractory prostate cancer refers to a prostate cancer that has not responded to treatment.
• a "refractory prostate cancer” is a prostate cancer resistant to treatment.
• refractory prostate cancer is refractory metastatic prostate cancer.
• refractory prostate cancer has not responded to chemical/surgical castration, i.e., the reduction of available androgen/testosterone/DHT by chemical or surgical means.
• refractory prostate cancer may in some embodiments be referred to as "androgen-independent prostate cancer”.
• refractory prostate cancer may in some embodiment be referred to as castration resistant prostate cancer.
• the term "castration resistant prostate cancer” refers to advanced prostate cancer which was developed despite ongoing androgen deprivation therapy (ADT) and/or surgical castration. In another embodiment, ADT refers to treatment consisting leuprolide acetate (Lupron ® ).
• ADT refers to treatment consisting leuprolide acetate (Lupron ® ).
• the term "advanced prostate cancer” refers to metastatic cancer having originated in the prostate, and having widely metastasized to beyond the prostate such as the surrounding tissues to include the seminal vesicles the pelvic lymph nodes or bone, or to other parts of the body. Prostate cancer pathologies are graded with a Gleason grading from 1 to 5 in order of increasing malignancy. In another embodiment, patients with significant risk of progressive disease and/or death from prostate cancer should be included in the definition and that any patient with cancer outside the prostate capsule with disease stages as low as IIB clearly has "advanced" disease.
• metastatic prostate cancer refers to prostate cancer that has spread from the place where it first started to another place in the body. Other places in the body include but are not limited to, the lungs, liver and bone.
• the present invention provides methods of treatment of conditions related to the prostate.
• the present invention provides methods of treatment of treatment of prostatic dysplasia, prostatic hyperplasia, benign prostate hyperplasia (BPH), and prostatitis.
• the present invention also provides methods of treatment of precancerous precursors of prostate adenocarcinoma.
• the precancerous precursor of prostate adenocarcinoma is prostate intraepithelial neoplasia (PIN).
• the PIN is high-grade PIN (HGPIN).
• the present invention provides methods of treatment conditions such as, but not limited to, prostate cancer, benign prostate hyperplasia (BPH), lung cancer, acne, seborrhea, hirsuitism, baldness, alopecia, precocious puberty, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, endometriosis, myeloma and leiomyoma.
• BPH benign prostate hyperplasia
• lung cancer acne, seborrhea, hirsuitism, baldness, alopecia, precocious puberty, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, endometriosis, myeloma and leiomyoma.
• this invention provides a method of treating a subject suffering from breast cancer, comprising the step of administering to said subject a compound of this invention, or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, prodrug, metabolite or any combination thereof, or a composition comprising the same in an amount effective to treat breast cancer in the subject.
• the compounds of this invention are useful for a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from triple negative breast cancer; h) treating a subject suffering from advanced breast cancer; i) treating a subject suffering breast cancer that have failed SERM (tamoxifen, toremifene), aromatase inhibitor, trastuzumab (Herceptin ® ), exemestane (Aromasin ® ), bevacizumab (Avastin ® ), and/or fulvestrant treatment; j) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; k) prolong
• a "refractory breast cancer” is a breast cancer that has not responded to treatment.
• a "refractory breast cancer” is a breast cancer resistant to treatment.
• refractory breast cancer is refractory metastatic breast cancer.
• refractory breast cancer has not responded to treatment with anthracyclines, taxanes, capecitabine, ixabepilone, SERM (tamoxifen, toremifene), aromatase inhibitor, trastuzumab (Herceptin ® ), exemestane (Aromasin ® ), bevacizumab (Avastin ® ), fulvestrant or a combination thereof.
• a "triple negative breast cancer” is defined by lack of expression of estrogen, progesterone, and ErbB2 (also known as human epidermal growth factor receptor 2 (HER2)) receptors. This subgroup accounts for 15% of all types of breast cancer. This subtype of breast cancer is clinically characterized as more aggressive and less responsive to standard treatment and associated with poorer overall patient prognosis.
• the methods of this invention are directed to treating a subject suffering from AR-positive breast cancer, regardless of grade, stage or prior treatments. [00184] In one embodiment, the methods of this invention are directed to treating a subject suffering from ER-positive breast cancer, regardless of grade, stage or prior treatments.
• the methods of this invention are first, second, third, or fourth line therapies for breast cancer.
• a first line therapy refers to a medical therapy recommended for the initial treatment of a disease, sign or symptom.
• a second line therapy therapy is given when initial treatment (first-line therapy) does not work, or stops working.
• Third line therapy is given when both initial treatment (first-line therapy) and subsequent treatment (second-line therapy) does not work, or stop working, etc.
• this invention provides a method of delaying the progression of breast cancer in a subject suffering from breast cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of breast cancer in the subject.
• this invention provides a method of delaying the progression of advanced breast cancer in a subject suffering from advanced breast cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of advanced breast cancer in the subject.
• this invention provides a method of delaying the progression of metastatic breast cancer in a subject suffering from metastatic breast cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of metastatic breast cancer in the subject.
• this invention provides a method of delaying the progression of hormone-resistant breast cancer in a subject suffering from hormone-resistant breast cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of hormone-resistant breast cancer in the subject.
• the methods of treating breast cancer make use of a compound of Formula I. In another embodiment, the methods of treating breast cancer make use of a compound of Formula II. In another embodiment, the methods of treating breast cancer make use of a compound of Formula III. In another embodiment, the methods of treating breast cancer make use of a compound of Formula IV. In another embodiment, the methods of treating breast cancer make use of a compound of Formula V. In another embodiment the methods of treating breast cancer make use of a compound of Formula VI. In another embodiment, the methods of treating breast cancer make use of a compound of Formula VII. In another embodiment, the methods of treating breast cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating breast cancer make use of a compound of Formula FX.
• the methods of treating breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating breast cancer make use of a compound of Formula XIII.
• the methods of treating breast cancer make use of 6-hydroxy-2-
• (4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 6,8- dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 2-(4-(bromomethyl)- 3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l,2- dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 3-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)- yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of a compound of Formula I.
• the methods of treating advanced breast cancer make use of a compound of Formula II.
• the methods of treating advanced breast cancer make use of a compound of Formula III.
• the methods of treating advanced breast cancer make use of a compound of Formula IV. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula V. In another embodiment the methods of treating advanced breast cancer make use of a compound of Formula VI. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula VII. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula ⁇ . In another embodiment, the methods of treating advanced breast cancer make use of a compound of Formula XIII.
• the methods of treating advanced breast cancer make use of 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin- l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4- (4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 2-(4- (bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5- trifluorophenyl)- l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating advanced breast cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy- l- oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of a compound of Formula I.
• the methods of treating metastatic breast cancer make use of a compound of Formula II.
• the methods of treating metastatic breast cancer make use of a compound of Formula III.
• the methods of treating metastatic breast cancer make use of a compound of Formula IV. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula V. In another embodiment the methods of treating metastatic breast cancer make use of a compound of Formula VI. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula VII. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating metastatic breast cancer make use of a compound of Formula XIII.
• the methods of treating metastatic breast cancer make use of 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 6-hydroxy- 2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 6-hydroxy-2- (4-hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy- l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating metastatic breast cancer make use of 4-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of a compound of Formula I.
• the methods of treating refractory breast cancer make use of a compound of Formula II.
• the methods of treating refractory breast cancer make use of a compound of Formula III.
• the methods of treating refractory breast cancer make use of a compound of Formula IV.
• the methods of treating refractory breast cancer make use of a compound of Formula V.
• the methods of treating refractory breast cancer make use of a compound of Formula VI.
• the methods of treating refractory breast cancer make use of a compound of Formula VII.
• the methods of treating refractory breast cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating refractory breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating refractory breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating refractory breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating refractory breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating refractory breast cancer make use of a compound of Formula XIII.
• the methods of treating refractory breast cancer make use of 6-hydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l (2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 6,8-dihydroxy- 2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l ,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin- l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)- 4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 2-(4- (bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5- trifluorophenyl)- l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating refractory breast cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy- l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of a compound of Formula I.
• the methods of treating AR-positive breast cancer make use of a compound of Formula II.
• the methods of treating AR-positive breast cancer make use of a compound of Formula III.
• the methods of treating AR-positive breast cancer make use of a compound of Formula IV.
• the methods of treating AR-positive breast cancer make use of a compound of Formula V.
• the methods of treating AR-positive breast cancer make use of a compound of Formula VI.
• the methods of treating AR-positive breast cancer make use of a compound of Formula VII.
• the methods of treating AR-positive breast cancer make use of a compound of Formula VIII.
• the methods of treating AR-positive breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating AR-positive breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating AR-positive breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating AR-positive breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating AR-positive breast cancer make use of a compound of Formula XIII.
• the methods of treating AR-positive breast cancer make use of
• 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR- positive breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of 6- hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating AR- positive breast cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of 6-hydroxy- 2-(4-hydroxyphenyl)- 1 -oxo-4-(3,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR- positive breast cancer make use of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive breast cancer make use of 4-(4-(3- fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of a compound of Formula I. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula II. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula III. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula IV. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula V. In another embodiment the methods of treating AR-positive refractory breast cancer make use of a compound of Formula VI. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula VII.
• the methods of treating AR-positive refractory breast cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating AR- positive refractory breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating AR-positive refractory breast cancer make use of a compound of Formula XIII.
• the methods of treating AR-positive refractory breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR- positive refractory breast cancer make use of (£ , )-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating AR- positive refractory breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating AR- positive refractory breast cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4- (4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)- 1 -oxo-4-(3 ,4,5 -trifluorophenyl)- 1 ,2-dihydroisoquinoline-8- carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive refractory breast cancer make use of 3-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR- positive refractory breast cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy- l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula I. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula II. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula III. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula IV. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula V. In another embodiment the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula VI. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula VII.
• the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula VIII. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating AR- positive metastatic breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating AR-positive metastatic breast cancer make use of a compound of Formula XIII.
• the methods of treating AR-positive metastatic breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR- positive metastatic breast cancer make use of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating AR- positive metastatic breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating AR- positive metastatic breast cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4- (4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)- 1 -oxo-4-(3 ,4,5 -trifluorophenyl)- 1 ,2-dihydroisoquinoline-8- carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR-positive metastatic breast cancer make use of 3-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating AR- positive metastatic breast cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy- l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of a compound of Formula I. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula II. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula III. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula IV. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula V. In another embodiment the methods of treating triple negative breast cancer make use of a compound of Formula VI. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula VII. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula VIII.
• the methods of treating triple negative breast cancer make use of a compound of Formula FX. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula X. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula XI. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula XII. In another embodiment, the methods of treating triple negative breast cancer make use of a compound of Formula XIII.
• the methods of treating triple negative breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 6- hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 6- hydroxy-2-(4-hydroxyphenyl)- 1 -oxo-4-(3,4,5-trifluorophenyl)- 1 ,2-dihydroisoquinoline-8- carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 3-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating triple negative breast cancer make use of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula I.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula II.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula III.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula IV.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula V.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula VI.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula VII.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula VIII.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula FX.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula X.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula XI.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula ⁇ .
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of Formula ⁇ .
• SERM tamoxifen, toremifene
• aromatase inhibitor trastuzumab (Herceptin ® )
• trastuzumab Herceptin ®
• exemestane Aromasin ®
• bevacizumab Avastin ®
• fulvestrant treatment make use of a compound of 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- 1 (2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 6-hydroxy-2-(4- (hydroxymethyl)phenyl)-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4-
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 6-hydroxy-2-(4- hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)-l,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin- 2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• the methods of treating breast cancer that failed to respond to SERM make use of a compound of 4-(4-(3-fluoro-4- (trifluoromethyl)phenyl)-6-hydroxy-l-oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof.
• this invention provides a method of treating a subject suffering from uterine cancer, comprising the step of administering to said subject a compound of this invention, or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, prodrug, metabolite or any combination thereof, or a composition comprising the same in an amount effective to treat uterine cancer in the subject.
• uterine cancer refers to an endometrial cancer. In another embodiment, uterine cancer refers to a cervical cancer.
• the compounds of this invention are useful for a) treating a subject suffering from uterine cancer; b) treating a subject suffering from metastatic uterine cancer; c) treating a subject suffering from refractory uterine cancer; d) treating a subject suffering from advanced uterine cancer; e) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from uterine cancer; f) prolonging survival of a subject with uterine cancer, and/or 1) prolonging the progression-free survival of a subject with uterine cancer.
• a "refractory uterine cancer” is a uterine cancer that has not responded to treatment.
• a "refractory uterine cancer” is a uterine cancer resistant to treatment.
• refractory uterine cancer is refractory metastatic uterine cancer.
• this invention provides a method of delaying the progression of uterine cancer or uterine fibroids in a subject suffering from uterine cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of uterine cancer in the subject.
• this invention provides a method of delaying the progression of advanced uterine cancer in a subject suffering from advanced uterine cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of advanced uterine cancer in the subject.
• this invention provides a method of delaying the progression of metastatic uterine cancer in a subject suffering from metastatic uterine cancer, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N- oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of metastatic uterine cancer in the subject.
• this invention provides a method of treating a subject suffering from uterine fibroids, comprising the step of administering to said subject a compound of this invention, or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, prodrug, metabolite or any combination thereof, or a composition comprising the same in an amount effective to treat uterine fibroids in the subject.
• uterine fibroids refer to myomas.
• the compounds of this invention are useful for treating a subject suffering from uterine fibroids.
• this invention provides a method of delaying the progression of uterine cancer or uterine fibroids in a subject suffering from uterine cancer or uterine fibroids, comprising the step of administering to said subject a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, or a composition comprising the same in an amount effective to delay the progression of uterine cancer or uterine fibroids in the subject.
• the methods of this invention make use of compounds of Formula I or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula II or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula III or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula IV or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula V or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula VI or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula VII or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula VIII or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula FX or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula X or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula XI or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula XII or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula XIII or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula I-XI and/or formula XII and/or formula XIII or their isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in combination with LH-RH agonist, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of this invention make use of compounds of Formula I-XI and/or formula XII and/or formula XIII or their isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in combination with leuprolide acetate (Lupron ® ), in an amount effective to treat uterine cancer or uterine fibroids.
• leuprolide acetate Liupron ®
• the methods of treating uterine cancer or uterine fibroids makes use of a compound of Formula I or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids make use of a compound of Formula II or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of Formula XIII or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate, prodrug or metabolite or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- l(2H)-one (15h), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l,2- dihydroisoquinolin-4-yl)acrylic acid (151), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-l(2H)-one (13), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 6-hydroxy-2-(4-(hydroxymethyl)phenyl)-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (14), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 2-(4-(bromomethyl)-3-hydroxyphenyl)-6-hydroxy-4-(4- (trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 6-hydroxy-2-(4-hydroxyphenyl)-l-oxo-4-(3,4,5-trifluorophenyl)- l ,2-dihydroisoquinoline-8-carbonitrile (85), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 3-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (214), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• the methods of treating uterine cancer or uterine fibroids and make use of a compound of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (215), or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• a compound of 4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-6-hydroxy-l- oxoisoquinolin-2(lH)-yl)benzamide (215) or its prodrug, isomer, tautomer, metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, in an amount effective to treat uterine cancer or uterine fibroids.
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to inhibit AKR1C3.
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to decrease androgen levels in said subject.
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N- oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to suppress the transcriptional activity of the androgen receptor in said subject.
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to effect a change in an androgen-dependent condition
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to inhibit AKR1C3.
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to decrease estrogen levels in said subject.
• this invention provides a method of hormone therapy comprising the step of contacting an AKR1C3 enzyme of a subject with a compound of this invention or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N- oxide, metabolite, prodrug or any combination thereof, or a composition comprising the same, in an amount effective to effect a change in an estrogen-dependent condition.
• this invention provides for the use of a compound as herein described, or its prodrug, analog, isomer, tautomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, hydrate or any combination thereof, for treating, reducing the severity of, reducing the incidence of, or delaying the onset of lung cancer.
• this invention provides for the use of a compound as herein described, or its prodrug, analog, isomer, tautomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, hydrate or any combination thereof, for treating, reducing the severity of, reducing the incidence of, and delaying the onset of non small cell lung cancer.
• the present invention provides a method for treating, reducing the incidence, delaying the onset or progression, or reducing and/or abrogating the symptoms associated with a metabolic disease in a subject, comprising the step of administering to said subject a compound of this invention, or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N- oxide, prodrug, metabolite or any combination thereof, or a composition comprising the same in an amount effective to treat symptoms associated with a metabolic disease in the subject.
• this invention provides a method of treating a subject suffering from obesity-associated metabolic disorder, comprising the step of administering to said subject a compound of this invention, or its isomer, tautomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, hydrate, N-oxide, prodrug, metabolite or any combination thereof, or a composition comprising the same in an amount effective to treat obesity-associated metabolic disorder in the subject.
• the compounds of this invention are useful for a) treating a subject suffering from obesity; b) preventing obesity in a subject; c) treating a subject suffering from obesity-associated metabolic disorder; d) preventing obesity-associated metabolic disorder in a subject; e) inducing anti-proliferative effects in a subject; f) treating a subject suffering from a prostaglandin-associated metabolic disorders; and g) preventing prostaglandin-associated metabolic disorders.
• the methods of treating obesity make use of a compound of
• the methods of treating obesity make use of a compound of Formula II. In another embodiment, the methods of treating obesity make use of a compound of Formula III. In another embodiment, the methods of treating obesity make use of a compound of Formula IV. In another embodiment, the methods of treating obesity make use of a compound of Formula V. In another embodiment the methods of treating obesity make use of a compound of Formula VI. In another embodiment, the methods of treating obesity make use of a compound of Formula VII. In another embodiment, the methods of treating obesity make use of a compound of Formula VIII. In another embodiment, the methods of treating obesity make use of a compound of Formula FX. In another embodiment, the methods of treating obesity make use of a compound of Formula X.
• the methods of treating obesity make use of a compound of Formula XI. In another embodiment, the methods of treating obesity make use of a compound of Formula XII. In another embodiment, the methods of treating obesity make use of a compound of Formula XIII.
• the methods of preventing obesity make use of a compound of
• the methods of preventing obesity make use of a compound of Formula II. In another embodiment, the methods of preventing obesity make use of a compound of Formula III. In another embodiment, the methods of preventing obesity make use of a compound of Formula IV. In another embodiment, the methods of preventing obesity make use of a compound of Formula V. In another embodiment the methods of preventing obesity make use of a compound of Formula VI. In another embodiment, the methods of preventing obesity make use of a compound of Formula VII. In another embodiment, the methods of preventing obesity make use of a compound of Formula VIII. In another embodiment, the methods of preventing obesity make use of a compound of Formula EX. In another embodiment, the methods of preventing obesity make use of a compound of Formula X.
• the methods of preventing obesity make use of a compound of Formula XI. In another embodiment, the methods of preventing obesity make use of a compound of Formula XII. In another embodiment, the methods of preventing obesity make use of a compound of Formula XIII.
• the methods of treating obesity-associated metabolic disorder make use of a compound of Formula I. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula II. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula III. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula IV. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula V. In another embodiment the methods of treating obesity-associated metabolic disorder make use of a compound of Formula VI. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula VII. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula VIII.
• the methods of treating obesity-associated metabolic disorder make use of a compound of Formula LX. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula X. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula XI. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula XII. In another embodiment, the methods of treating obesity-associated metabolic disorder make use of a compound of Formula ⁇ . [00235] In one embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula I. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula II.
• the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula III. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula IV. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula V. In another embodiment the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula VI. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula VII. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula VIII. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula LX.
• the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula X. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula XL In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula XII. In another embodiment, the methods of preventing obesity-associated metabolic disorder make use of a compound of Formula XIII.
• the methods of inducing an anti-proliferative effect make use of a compound of Formula I. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula II. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula III. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula IV. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula V. In another embodiment the methods of inducing an anti-proliferative effect make use of a compound of Formula VI.
• the methods of inducing an anti-proliferative effect make use of a compound of Formula VII. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula VIII. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula FX. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula X. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula XI. In another embodiment, the methods of inducing an antiproliferative effect make use of a compound of Formula XII. In another embodiment, the methods of inducing an anti-proliferative effect make use of a compound of Formula XIII.
• the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula I. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula II. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula III. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula IV. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula V. In another embodiment the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula VI. In another embodiment, the methods of treating prostaglandin- associated metabolic disorders make use of a compound of Formula VII.
• the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula VIII. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula EX. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula X. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula XI. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula XII. In another embodiment, the methods of treating prostaglandin-associated metabolic disorders make use of a compound of Formula XIII.
• the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula I. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula II. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula ⁇ . In another embodiment, the methods of preventing prostaglandin- associated metabolic disorders make use of a compound of Formula IV. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula V. In another embodiment the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula VI.
• the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula VII. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula VIII. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula FX. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula X. In another embodiment, the methods of preventing prostaglandin- associated metabolic disorders make use of a compound of Formula XI. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula XII. In another embodiment, the methods of preventing prostaglandin-associated metabolic disorders make use of a compound of Formula XIII.
• the term "obesity-associated metabolic disorder” refers, in one embodiment, to a disorder which results from, is a consequence of, is exacerbated by or is secondary to obesity.
• a disorder which results from, is a consequence of, is exacerbated by or is secondary to obesity.
• Non-limiting examples of such a disorder are osteoarthritis, Type II diabetes mellitus, increased blood pressure, stroke, and heart disease.
• prostaglandin-associated metabolic disorder refers, in one embodiment, to a disorder which results from, is a consequence of, is exacerbated by changes in prostaglandin levels.
• VLDL very low density lipoproteins
• IDL intermediate density lipoproteins
• LDL low density lipoproteins
• HDL high density lipoproteins
• LDL- Cholesterol in the blood correlates with atherosclerosis which is a progressive disease characterized in part by sedimentation of lipids in inner walls of arteries, particularly of coronary arteries. It has also been shown that a high blood level of LDL- Cholesterol correlates with coronary heart disease. Also, a negative correlation exists between blood levels of FiDL cholesterol and coronary heart disease.
• the level of total cholesterol in blood which is the sum of HDL- Cholesterol, LDL- Cholesterol, VLDL-Cholesterol and chylomicron- Cholesterol, is not necessarily predictive of the risk of coronary heart disease and atherosclerosis.
• this invention provides methods of use of the compounds as herein described for improving the lipid profile and/or reducing the circulating lipid levels in a subject.
• the subject suffers from one or more conditions selected from the group consisting of: atherosclerosis and its associated diseases, premature aging, Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis, peripheral vascular insufficiency, renal disease, and hyperglycemia, and the invention provides for the administration of a compound or composition comprising the same, as herein described, which in some embodiments positively affects a lipid profile in the subject, which is one means by which the method is useful in treating the indicated diseases, disorders and conditions.
• the invention provides for the treatment of atherosclerosis and its associated diseases, such as for example, cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, intestinal vascular disorders, or combinations thereof.
• cardiovascular disorders comprise of hypertention (HTN), coronary artery disease (CAD) or myocardial perfusion.
• this invention provides methods of use of the SARM compounds as herein described for promoting aortic smooth muscle cell proliferation.
• this invention provides methods of use of the compounds as herein described for treating arteriosclerosis.
• this invention provides methods of use of the compounds as herein described for lowering blood pressure.
• this invention provides methods of use of the compounds as herein described for treating cardiac diseases and disorders comprising cardiomyopathy, cardiac dysfunctions such as, myocardial infarction, cardiac hypertrophy and cognitive heart failure.
• this invention provides methods of use of the compounds as herein described for cardioprotection comprising cardioprotection in insulin resistance; treating diabetes type I ans II, metabolic syndrome, syndrome X and/or high blood pressure.
• the invention provides a method of treating, preventing, reducing the risk of mortality from cardiovascular and/or cerebrovascular disease in a subject, comprising administering a compound of this invention or its prodrug, analog, isomer, tautomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, hydrate or any combination thereof, or a pharmaceutical composition comprising the same.
• the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula I.
• the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula II.
• the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula III.
• the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula IV. In a further embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula V. In another embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of FormulaVI. In yet another embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula VII. In still another embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula VIII. In a further embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula FX. In another embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula X.
• the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula XI. In still another embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula XII. In still another embodiment, the method of treating cardiovascular and/or cerebrovascular disease makes use of a compound of Formula XIII.
• compounds of Formulae I- XII are co-administered with HDL- elevating agents.
• a compound of this invention is co-administered with an HDL-elevating agent.
• HDL-elevating agents include niacin.
• the HDL-elevating agents include fibrates including gemfibrozil (Lopid), thiourea based gemfibrozil analogues, and fenofibrate (TriCor ® ).
• HDL-elevating agents include statins.
• HDL-elevating agents include l-hydroxyalkyl-3- phenylthiourea, and analogs thereof.
• this invention provides a method of reducing circulating lipid levels in a subject, said method comprising administering a compound of this invention or its isomer, tautomer, prodrug, metabolite, pharmaceutically acceptable salt, hydrate, N-oxide, or any combination thereof, or a composition comprising the same.
• the subject suffers from atherosclerosis and its associated diseases, premature aging, Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis, peripheral vascular insufficiency, renal disease, hyperglycemia, or any combination thereof.
• this invention provides a method of treating atherosclerosis and its associated diseases, such as, for example, cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, or intestinal vascular disorders in a subject, the method comprising the step of administering to the subject compound of this invention or its pharmaceutically acceptable salt, isomer, tautomer, hydrate, N-oxide, or any combination thereof, or a composition comprising the same.
• the present invention provides methods of treating a condition.
• the present invention provides methods of preventing a condition.
• the present invention provides methods of delaying the onset of a condition.
• the present invention provides methods of reducing the recurrence of a condition.
• the present invention provides methods of reducing the severity of a condition.
• the methods of the present invention are useful for treating prostate cancer. In one embodiment the methods of the present invention are useful for treating PIN. In one embodiment, the methods of the present invention are useful for treating breast cancer. In one embodiment, the methods of the present invention are useful for treating acne. In one embodiment, the methods of the present invention are useful for treating alopecia.
• cyclooxygenase (COX) enzymes e.g., COX-1 and/or COX-2
• COX-1 and/or COX-2 cyclooxygenase enzymes
• compounds of the present invention are much more potent inhibitors of AKR1C3 than they are inhibitors of cyclooxygenase.
• the compounds of the present invention lack cross-reactivity with cyclooxygenase (COX) enzymes. In one embodiment, the compounds of the present invention lack cross-reactivity with COX-1 enzyme. In one embodiment, the compounds of the present invention lack cross-reactivity with COX-2 enzyme. In one embodiment, the compounds of the present invention lack cross-reactivity with COX-1 and COX-2 enzymes.
• cross- reactivity means that the ratio of inhibition of AKR1C3 to inhibition of cyclooxygenase for a compound of the present invention is greater than about 10-fold. In another embodiment, the ratio of inhibition is for example greater than about 100. In a further embodiment, the ratio of inhibition is greater than about 1000.
• the methods described herein prevent or lessen typical side-effects associated with inhibition of AKR1C3 from occurring. In certain embodiments, the methods described herein prevent or lessen gastric irritation, ulcers, and/or cardiovascular problems.
• a compound of this invention may be an estrogen receptor (ER) agonists. In other embodiment, a compound of this invention may be an ER antagonist. In still another embodiment, a compound of this invention may be an ER partial agonist/antagonist. In yet another embodiment, a compound of this invention is not an ER agonist. In a further embodiment, a compound of this invention is not an ER antagonist. In one embodiment, a compound of this invention is not an ER partial agonist/antagonist. In another embodiment, a compound of this invention does not bind to an ER.
• ER estrogen receptor
• an AKR1C3 inhibitor of this invention may modulate the activity of androgen receptor (AR) agonists. In other embodiments, an AKR1C3 inhibitor of this invention may modulate the activity of an AR antagonist. In still another embodiment, an AKR1C3 inhibitor of this invention may modulate the activity of a selective androgen receptor modulator (SARM). In yet another embodiment, a compound of this invention is not an AR agonist. In a further embodiment, a compound of this invention is not an AR antagonist. In one embodiment, a compound of this invention is not a SARM. In another embodiment, a compound of this invention does not bind to an AR.
• AR androgen receptor
• this invention provides a method of lowering total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In another embodiment, this invention provides a method of lowering serum testosterone in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In yet another embodiment, this invention provides a method of lowering serum free testosterone in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In still another embodiment, this invention provides a method of lowering serum levels of prostate- specific antigen (PSA) in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• PSA prostate- specific antigen
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin-l(2H)-one (15h), (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l ,2- dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(4-
• this invention provides a method of lowering total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention, wherein the lowering of total serum testosterone is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of lowering serum testosterone levels in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention, wherein the lowering of serum free testosterone is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of lowering serum free testosterone levels in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention, wherein the lowering of serum free testosterone is independent of a reduction of serum luteinizing hormone levels.
• this invention provides a method of lowering serum PSA levels in a male subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention, wherein the lowering of serum PSA is independent of a reduction of serum luteinizing hormone levels.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin-l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin-l(2H)-one (15h), (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l ,2- dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)pheny
• this invention provides a method of increasing survival of a subject with advanced prostate cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• this invention provides a method of increasing survival of a subject with castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• the AKR1C3 inhibitor is a compound of formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15h), (E)-3-(6,8- dihydroxy-2-(4-hydroxyphenyl)-l-oxo-l ,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4- bromomethyl)phenyl-6-hydroxy-4-(4-hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2- (4-hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinoquinolin
• this invention provides a method of prolonging progression-free survival of a subject with advanced prostate cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• this invention provides a method of prolonging progression-free survival of a subject with castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• CRPC castration-resistant prostate cancer
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula ⁇ or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8- dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l (2H)-one (15h), (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6- hydroxy-4-(4-hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin-
• this invention provides a method of lowering total serum estradiol levels in a subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In another embodiment, this invention provides a method of lowering serum free estradiol in a subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In one embodiment, a subject is a male subject. In another embodiment, a subject is a female subject.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin- 1 (2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin- 1 (2H)-one (15g), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin- 1 (2H)-one (15h), (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- 1 -oxo- 1 ,2- dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin-l(2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(4-
• this invention provides a method of lowering intratumor levels of testosterone in a subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• a subject is a male subject.
• a subject is a female subject.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), 6,8- dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin- 1 (2H)-one (15g), 6,8-dihydroxy- 2-(4-hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15h), (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6- hydroxy-4-(4-hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquinolin- 1 (2H)
• this invention provides a method of lowering intratumor levels of DHT in a subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• a subject is a male subject.
• a subject is a female subject.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15a), 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15h), (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-
• this invention provides a method of lowering intratumor levels of estrogen in a subject comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• a subject is a male subject.
• a subject is a female subject.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is 6- hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15a), 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8-dihydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin-l (2H)-one (15h), (£)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-
• this invention provides a method of increasing survival of a subject with advanced breast cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In another embodiment, this invention provides a method of increasing survival of a subject with refractory breast cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In another embodiment, this invention provides a method of increasing survival of a subject with AR-positive or ER-positive breast cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8- dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15h), (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l-oxo-l,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6- hydroxy-4-(4-hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylisoquino
• this invention provides a method of prolonging progression-free survival of a subject with advanced breast cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In another embodiment, this invention provides a method of prolonging progression-free survival of a subject with refractory breast cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention. In another embodiment, this invention provides a method of prolonging progression-free survival of a subject with AR-positive or ER-positive breast cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N- oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4- hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin- 1 (2H)-one (15g), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin- 1 (2H)-one (15h), (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- 1 -oxo- 1 ,2- dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-(4-
• this invention provides a method of increasing survival of a subject with advanced uterine cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula ⁇ or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)isoquinolin-l(2H)-one (15g), 6,8- dihydroxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin- 1 (2H)-one (15h), (£)-3-(6,8-dihydroxy-2-(4- hydroxyphenyl)-l -oxo- l,2-dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6- hydroxy-4-(4-hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenylis
• this invention provides a method of prolonging progression-free survival of a subject with advanced uterine cancer comprising administering a therapeutically effective amount of an AKR1C3 inhibitor of this invention.
• the AKR1C3 inhibitor is a compound of Formula I-XI and/or formula XII and/or formula XIII or their prodrug, isomer, tautomer metabolite, pharmaceutically acceptable salt, polymorph, crystal, N-oxide, hydrate or any combination thereof, or any embodiment thereof, as herein described.
• the AKR1C3 inhibitor is characterized by the structure of 6-hydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin- l(2H)-one (15a), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-(4- methoxyphenyl)isoquinolin- 1 (2H)-one (15g), 6,8-dihydroxy-2-(4-hydroxyphenyl)-4- phenylisoquinolin- 1 (2H)-one (15h), (E)-3-(6,8-dihydroxy-2-(4-hydroxyphenyl)- 1 -oxo- 1 ,2- dihydroisoquinolin-4-yl)acrylic acid (151), 2-(4-bromomethyl)phenyl-6-hydroxy-4-(4- hydroxyphenyl)isoquinolin- 1 (2H)-one (11), 6-hydroxy-2-(4-hydroxyphenyl)-4-(4- (trifluoromethyl)phenyl
• a compound of this invention is not a nuclear receptor binding agent.
• the methods of this invention do not comprise administering 2-
• the methods of this invention do not comprise administering 6-hydroxy-2-(4- hydroxyphenyl)-4-(4-(trifluoromethyl)phenylisoquinolin-l(2H)-one (13). In one embodiment, the methods of this invention do not comprise administering 2-(4-(bromomethyl)-3-hydroxyphenyl)-6- hydroxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-l(2H)-one (26).

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