US2021069154A1PendingUtilityA1
Treatment of Breast Cancer
Assignee: MEDIVATION PROSTATE THERAPEUTICS LLCPriority: Jul 29, 2011Filed: Jan 22, 2020Published: Mar 11, 2021
Est. expiryJul 29, 2031(~5 yrs left)· nominal 20-yr term from priority
A61P 35/00A61K 31/4184A61K 31/4166
62
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Claims
Abstract
The disclosure describes compounds useful for treating breast cancers.
Claims
exact text as granted — not AI-modified1 . A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (I):
wherein:
X is selected from the group consisting of trifluoromethyl and iodo;
W is selected from the group consisting of O and NR5, wherein R 5 is selected from the group consisting of H, methyl, and
wherein D is S or O and E is N or O and G is alkyl, aryl,
substituted alkyl or substituted aryl; or D is S or O and E-G together are C1-C4 lower alkyl;
R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group;
R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl, with the proviso that R3 is not methylaminomethyl or dimethylaminomethyl; and
R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl.
2 . The method of claim 1 , wherein the compound is selected from the group consisting of:
3 . The method of claim 1 , wherein the compound is enzalutamide:
4 . A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (II):
wherein:
Het represents a heterocyclic unit of 5 or 6 atoms;
A and B are independently selected from oxygen, sulfur, and N—R 9 ;
R 1 is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO 2 R 11 , NR 11 R 12 , NR 12 (CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , or NR 12 (CS)OR 11 ;
R 2 and R 3 are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or, together with the carbon to which they are linked, form a cycle which can be cycloalkyl, substituted cycloalkyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic; or R 2 and R 3 can be connected to form a cycle which can be heterocyclic aromatic or non aromatic, substituted heterocyclic aromatic or non aromatic;
R 9 is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO 2 R 11 , NR 11 R 12 , NR 12 (CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , or NR 12 (CS)OR 11 ; and
R 11 and R 12 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic or non-aromatic; or R 11 and R 12 can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, or substituted cycloalkyl.
5 . The method of claim 3 wherein the compound is selected from the group consisting of:
6 . A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (III)
wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z 1 is S or O
Z 2 is S, O or NR 4 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R 1 is —C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d or —C(O)NR e R f , where:
R a is a C 2 -C 12 alkyl and R b is H or a C 1 -C 2 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R e is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is a C 2 -C 12 alkyl and R f is H or a C 1 -C 2 alkyl, or
R e is a C 1 -C 12 alkyl and R f is C 1 -C 2 alkyl, or
R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halogen, nitro, alkyl and substituted alkyl; and
R 4 is independently H, alkyl, or aryl.
7 . A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (IV):
wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, O or NR 5 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R 1 is —C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d or —C(O)NR e R f ,
R a is a C 1 -C 12 alkyl and R b is H or a C 1 -C 12 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R d is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is a C 1 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl, or R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R 4 is H, alkyl, substituted alkyl, aryl or substituted aryl; and
R 5 is H, alkyl, substituted alkyl, aryl or substituted aryl.
8 . A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (V):
wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, O or NR 5 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
Y 3 is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkylhydroxymethyl, substituted alkoxymethyl, thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl; heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;
T is carbon or nitrogen and can be at any position in the ring;
R 1 is hydrogen, —C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d , —C(O)NR e R f or —NR g R h ,
R a is a C 1 -C 12 alkyl and R b is H or a C 1 -C 12 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R d is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is H or a C 1 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl, or R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R g is H or a C 1 -C 12 alkyl and R h is H or a C 1 -C 12 alkyl, or R g and R h are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R 4 is H, alkyl, substituted alkyl, aryl or substituted aryl; and
R 5 is H, alkyl, substituted alkyl, aryl or substituted aryl.
9 . A method of treating triple negative breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of structural formula (VI): and
wherein:
X is S or O, and
when X is S, then R 1 is OH or NH 2 ; and
when X is O then R 1 is OH, NH 2 or NHMe.
10 . The method of any of claims 1 - 9 , wherein the triple negative breast cancer is a subtype selected from the group consisting of basal-like type 1 (BL1), basal-like type 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR) subtypes.
11 . The method of any of claims 1 - 10 , wherein cells of the triple negative breast cancer comprise a BRCA1 mutation.
12 . A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (I):
wherein:
X is selected from the group consisting of trifluoromethyl and iodo;
W is selected from the group consisting of O and NR5, wherein R5 is selected from the group consisting of H, methyl, and
wherein D is S or O and E is N or O and G is alkyl, aryl,
substituted alkyl or substituted aryl; or D is S or O and E-G together are C1-C4 lower alkyl;
R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group;
R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl, with the proviso that R3 is not methylaminomethyl or dimethylaminomethyl; and
R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl.
13 . The method of claim 12 , wherein the compound is selected from the group consisting of:
14 . The method of claim 12 , wherein the compound is enzalutamide:
15 . A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (II):
wherein:
Het represents a heterocyclic unit of 5 or 6 atoms;
A and B are independently selected from oxygen, sulfur, and N—R 9 ;
R 1 is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO 2 R 11 , NR 11 R 12 , NR 12 (CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , or NR 12 (CS)OR 11 ;
R 2 and R 3 are independently selected from hydrogen, aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or, together with the carbon to which they are linked, form a cycle which can be cycloalkyl, substituted cycloalkyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic; or R 2 and R 3 can be connected to form a cycle which can be heterocyclic aromatic or non aromatic, substituted heterocyclic aromatic or non aromatic;
R 9 is selected from hydrogen, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO 2 R 11 , NR 11 R 12 , NR 12 (CO)OR 11 , NH(CO)NR 11 R 12 , NR 12 (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , or NR 12 (CS)OR 11 ; and
R 11 and R 12 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, aryl, substituted aryl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, or substituted heterocyclic aromatic or non-aromatic; or R 11 and R 12 can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, or substituted cycloalkyl.
16 . The method of claim 15 wherein the compound is selected from the group consisting of:
17 . A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (II):
wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z 1 is S or O
Z 2 is S, O or NR 4 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R is —C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d or —C(O)NR e R f , where:
R a is a C 2 -C 12 alkyl and R b is H or a C 1 -C 2 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R e is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is a C 2 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl, or
R e is a C 1 -C 12 alkyl and R f is C 1 -C 12 alkyl, or
R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halogen, nitro, alkyl and substituted alkyl; and
R 4 is independently H, alkyl, or aryl.
18 . A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (IV):
wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, O or NR 5 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
T is carbon or nitrogen and can be at any position in the ring;
R 1 is —C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d or —C(O)NR e R f ,
R a is a C 1 -C 12 alkyl and R b is H or a C 1 -C 12 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R d is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is a C 1 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl, or R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R 4 is H, alkyl, substituted alkyl, aryl or substituted aryl; and
R 5 is H, alkyl, substituted alkyl, aryl or substituted aryl.
19 . A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (V):
wherein:
W 1 is CN, NO 2 or SO 2 R 4 ;
W 2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or halogen;
Z is S, O or NR 5 ;
Y 1 and Y 2 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaralkyl, heterocyclyl, substituted heterocyclyl or Y 1 and Y 2 are taken together with the carbon to which they are attached to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl;
Y 3 is carboxyl, formyl, alkyl carbonyl, substituted alkyl carbonyl, alkenyl carbonyl, substituted alkenyl carbonyl, alkynyl carbonyl, substituted alkynyl carbonyl, aryl carbonyl, substituted aryl carbonyl, heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkylhydroxymethyl, substituted alkoxymethyl, thiocarboxyl, thioformyl, alkyl thiocarbonyl, substituted alkyl thiocarbonyl, alkenyl thiocarbonyl, substituted alkenyl thiocarbonyl, alkynyl thiocarbonyl, substituted alkynyl thiocarbonyl, aryl thiocarbonyl, substituted aryl thiocarbonyl, heteroaryl thiocarbonyl, substituted heteroaryl thiocarbonyl, arylalkyl thiocarbonyl, arylalkenyl thiocarbonyl, arylalkynyl thiocarbonyl, heteroaralkyl thiocarbonyl, heterocyclyl thiocarbonyl, substituted heterocyclyl thiocarbonyl, thiocarbamyl, N-alkyl thiocarbamyl, N,N-dialkyl thiocarbamyl, N-substituted alkyl thiocarbamyl, N,N-bis-substituted alkyl thiocarbamyl, alkoxy thiocarbonyl, substituted alkoxy thiocarbonyl, halothiocarbonyl, mercaptomethyl, substituted alkylthiomethyl; heteroaryl carbonyl, substituted heteroaryl carbonyl, arylalkyl carbonyl, arylalkenyl carbonyl, arylalkynyl carbonyl, heteroaralkyl carbonyl, heterocyclyl carbonyl, substituted heterocyclyl carbonyl, cyano, aminocarbonyl, N-alkyl aminocarbonyl, N,N-dialkyl aminocarbonyl, N-substituted alkyl aminocarbonyl, N,N-bis-substituted alkyl aminocarbonyl, alkoxy carbonyl, substituted alkoxy carbonyl, halocarbonyl, hydroxymethyl, alkoxymethyl, substituted alkoxymethyl;
T is carbon or nitrogen and can be at any position in the ring;
R 1 is hydrogen, —C 1 -C 8 alkyl-NR a R b , —O—C 1 -C 8 alkyl-NR c R d , —C(O)NR e R f or —NR g R h , R a is a C 1 -C 12 alkyl and R b is H or a C 1 -C 12 alkyl or R a and R b are taken together with the N to which they are attached to form a heterocyclic ring;
R c is a C 1 -C 12 alkyl and R d is H or a C 1 -C 12 alkyl or R c and R d are taken together with the N to which they are attached to form a heterocyclic ring;
R e is H or a C 1 -C 12 alkyl and R f is H or a C 1 -C 12 alkyl, or R e and R f are taken together with the N to which they are attached to form a heterocyclic ring;
R g is H or a C 1 -C 12 alkyl and R h is H or a C 1 -C 12 alkyl, or R g and R h are taken together with the N to which they are attached to form a heterocyclic ring;
R 2 is hydrogen, halogen, nitro, alkyl or substituted alkyl;
R 4 is H, alkyl, substituted alkyl, aryl or substituted aryl; and
R 5 is H, alkyl, substituted alkyl, aryl or substituted aryl.
20 . A method of treating breast cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein cells of the breast cancer express detectable estrogen receptor but the breast cancer is resistant to endocrine therapy, and wherein the compound is a compound of structural formula (VI):
wherein:
X is S or O, and
when X is S, then R 1 is OH or NH 2 ; and
when X is O then R 1 is OH, NH or NHMe
21 . The method of any of claims 12 - 20 , wherein the patient is post-menopausal.
22 . The method of any of claims 12 - 21 , wherein the endocrine therapy is administration of an aromatase inhibitor.
23 . The method of any of claims 12 - 21 , wherein the endocrine therapy is administration of an estrogen receptor modulator.
24 . The method of any of claims 1 - 23 wherein the breast cancer comprises cells that do not express detectable androgen receptor.
25 . The method of any of claims 1 - 23 wherein the breast cancer comprises cells that express an androgen receptor.
26 . The method of any of claims 1 - 25 further comprising administering to the patient a second therapeutic treatment.Cited by (0)
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