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WO2020190792A1 - Compositions et procédés pour traiter des formes positives de récepteurs des androgènes du cancer - Google Patents

Compositions et procédés pour traiter des formes positives de récepteurs des androgènes du cancer Download PDF

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Publication number
WO2020190792A1
WO2020190792A1 PCT/US2020/022823 US2020022823W WO2020190792A1 WO 2020190792 A1 WO2020190792 A1 WO 2020190792A1 US 2020022823 W US2020022823 W US 2020022823W WO 2020190792 A1 WO2020190792 A1 WO 2020190792A1
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WIPO (PCT)
Prior art keywords
methyl
compound
cancer
breast cancer
methoxycarbonyl
Prior art date
Application number
PCT/US2020/022823
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English (en)
Inventor
Maureen Caligiuri
Anna Ericsson
Sylvie GUICHARD
Qunli Xu
Original Assignee
Forma Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2019/039936 external-priority patent/WO2020006483A1/fr
Application filed by Forma Therapeutics, Inc. filed Critical Forma Therapeutics, Inc.
Priority to CA3132995A priority Critical patent/CA3132995A1/fr
Priority to BR112021018266A priority patent/BR112021018266A2/pt
Priority to EP20774663.7A priority patent/EP3938365A4/fr
Priority to CN202080021617.5A priority patent/CN113784967B/zh
Priority to MX2021011154A priority patent/MX2021011154A/es
Priority to AU2020241709A priority patent/AU2020241709A1/en
Publication of WO2020190792A1 publication Critical patent/WO2020190792A1/fr

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    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • compositions and methods for inhibiting CREB-binding protein are useful, for example, in pharmaceutical compositions for the treatment of certain Androgen Receptor dependent forms of cancer.
  • the androgen receptor a key driver in prostate cancer and subsets of breast cancers, controls the expression of about 100 androgen-responsive target genes. Expression of these AR target genes is important for normal tissue development and cellular activities but can have pathological effects that underlie tumor initiation and progression. Direct targeting of androgen biosynthesis and androgen interaction with the AR can provide clinical utility. However, acquired resistance to these therapies can circumvent ligand-driven AR function while retaining continued dependence on AR-driven transcriptional programs.
  • Nuclear receptors are part of multiprotein complexes involving co-activators and co-repressors which control the impact of the nuclear receptor on its downstream target genes.
  • CBP/P300 are critical co-activators of AR, modifying the chromatin environment surrounding the nuclear receptor to increase its intrinsic transcriptional activity and recruiting additional co-factors. Given the co-regulatory relationship between the AR and CBP/P300, inhibition of CBP/P300 activity offers a rational approach to suppress AR-dependent oncogenic programs in AR-dependent tumors such as breast and prostate cancers.
  • the present invention provides methods of and compositions for treating AR+ cancers, including patients diagnosed with certain forms of AR+ cancer that are resistant to other treatments, such as patients resistant or refractory to apalutamide, darolutamide or enzalutamide (e.g., patients with disease progression or with disease refractory to treatment with enzalutamide), by the administration of a CBP Inhibitor compound (e.g., compounds of formula (I)) to a patient in need thereof.
  • a CBP Inhibitor compound e.g., compounds of formula (I)
  • the CBP Inhibitor compositions are preferably used in a therapeutically effective amount to inhibit CBP and antagonize androgen receptor signaling, leading to clinical benefit in AR+ Triple Negative Breast Cancer (TNBC), and mCRPC expressing the AR-v7 splice form.
  • AR is an oncogenic driver in prostate cancer and progression of the disease towards castration- and drug-resistance is associated with aberrations of AR such as amplification of AR, mutations in the LBD and increase in a splice variant of AR lacking the LBD (AR-v7).
  • AR is also expressed in a subset of TNBC in which it substitutes for ER and drives ER signaling via binding to ER response elements.
  • ER is the main oncogenic driver in ER+ breast cancer.
  • the CBP Inhibitor is useful to treat hormone-receptor positive subjects with relapsed or refractory-to-hormone-therapy cancers (e.g., by antagonizing ER activity in these subjects).
  • R 1 is H or -OH
  • each R 2 is independently selected from C 1 -C 6 alkyl (e.g., methyl), halogen, -CN, and -OR 3 , (e.g., methoxy) wherein the alkyl is optionally substituted with one or more halogen; each R 3 is independently H or C 1 -C 6 alkyl (e.g., methyl), wherein the alkyl is optionally substituted with one or more halogen; and
  • n is an integer selected from 0, 1, 2, 3, 4 or 5, wherein n is preferably 0, 1, 2, or 3, provide an active moiety useful for the treatment of AR-positive cancer, such as certain AR-positive forms of breast cancer (e.g., TNBC) and prostate cancer (e.g., CRPC).
  • AR-positive cancer such as certain AR-positive forms of breast cancer (e.g., TNBC) and prostate cancer (e.g., CRPC).
  • the disclosure includes the use of compounds of formula (I), and pharmaceutically acceptable salts thereof, for the treatment of diseases or disorders associated with the inhibition of CBP, including certain AR-positive forms of cancer, including the AR-v7 splice form of AR.
  • CBP/P300 is an attractive target for development of novel therapy to meet these patients’ needs.
  • the compound of formula (I) is Compound 1:
  • Compound 1 is the first eluting isomer when eluted by preparative HPLC under the conditions defined in Example 1.2.
  • the compound of formula (I) is Compound 2:
  • Compound 2 is the first eluting isomer when eluted by preparative HPLC under the conditions defined in Example 1.3.
  • the compound of formula (I) is Compound 3:
  • Compound 3 is the second eluting isomer when eluted by preparative HPLC under the conditions defined in Example 1.4.
  • the compound of formula (I) is Compound 4:
  • Figure 1 is a table of compounds in accordance with various embodiments of the disclosure.
  • Figure 2 is a series of reaction schemes for chemical syntheses of compounds of Formula (I) and useful intermediates in the preparation of compounds of Formula (I).
  • Figure 3 is an immunoblot showing H3K27Ac, total H3, and b-actin protein expression levels from a breast cancer cell line exposed to increasing concentrations of compound 1 for 24h.
  • Figure 4 is a graph showing the in vivo activity of Compound 1 in a cell line derived xenograft model of AR+ triple negative breast cancer.
  • Figure 5 is an immunoblot showing AR and AR-v7 expression levels in an AR-v7+ prostate cancer cell line after 24h exposure to increasing concentrations of Compound 3.
  • Figure 6 is a graph showing the in vivo activity of Compound 4 in a patient-derived xenograft model of prostate cancer resistant to enzalutamide.
  • CBP Inhibitor Compounds defined herein as compounds having one or more of the following characteristics when tested according to the HTRF biochemical Assay Protocol below in Example 2: (1) a CBP IC50 value of less than 1 mM; and (2) a CBP IC50 value of between 0.001 and 1 pM.
  • CBP Inhibitor Compounds can be of formula (I):
  • the compounds of formula (I) and Group A may contain one or more stereocenters, and, therefore, exist in different stereoisomeric forms. It is intended that unless otherwise indicated all stereoisomeric forms of the compounds of formula (I) and Group A, as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.
  • the present disclosure embraces all geometric and positional isomers. For example, if a compound of formula (I) or Group A incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure.
  • Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
  • the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
  • the assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
  • Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of formula (I) or Group A may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure.
  • the compounds of formula (I) or Group A may form acid addition salts, which may be pharmaceutically acceptable salts.
  • the disclosure also includes pharmaceutical compositions comprising one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutical compositions reported herein can be provided in a unit dosage form (e.g., capsule, tablet or the like).
  • pharmaceutical compositions reported herein can be provided in an oral dosage form.
  • an oral dosage form of a compound of formula (I) or Group A can be a capsule.
  • an oral dosage form of a compound of formula (I) or Group A is a tablet.
  • an oral dosage form comprises one or more fillers, disintigrants, lubricants, glidants, anti- adherents and/or anti-statics.
  • an oral dosage form is prepared via dry blending.
  • an oral dosage form is a tablet and is prepared via dry granulation.
  • a CBP Inhibitor compound of the present disclosure can be dosed at a therapeutically effective level.
  • a Selective CBP Inhibitor compound of the present disclosure can be dosed at a therapeutically effective level.
  • the disclosure relates to compounds of formula (I):
  • R 1 is H or -OH
  • each R 2 is independently selected from C1-C6 alkyl, halogen, -CN, and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen;
  • each R 3 is independently H or C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen;
  • n is an integer selected from 0-5, wherein n is preferably 0, 1, 2, or, 3.
  • R 2 is -Cl, -CH 3 , -CHF 2 , -CN, -OCH 3 , -OCHF 2 , -0CH(CH 3 ) 2 .
  • R 2 is -F, -CH 3 , -CHF 2 , -CN, or -OR 3 .
  • R 2 is -F, -Cl, -CHF 2 , -CN, or -OR 3 .
  • R 2 is -F, -Cl, -CH 3 , -CN, or -OR 3 .
  • R 2 is -F, -Cl, -CH 3 , -CHF 2 , or -OR 3 . In some embodiments, R 2 is -F, -Cl, -CH 3 , -CHF 2 , or -CN.
  • the disclosure provides compounds of formula (lb):
  • R 1 is H or -OH
  • R 2a is selected from H, C1-C6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF2);
  • R 2b is selected from H, C1-C6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF2);
  • R 2C is selected from H, C1-C6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen;
  • R 2d is selected from H or halogen (e.g., F or Cl);
  • R 2e is selected from H, C1-C6 alkyl (e.g., methyl), halogen (e.g., F or Cl), -CN, and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., methyl); and
  • R 3 is H or C1-C6 alkyl (e.g., methyl), wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF2).
  • halogen e.g., CHF2
  • the disclosure provides compounds of formula (lb): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is -OH
  • R 2a is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 );
  • R 2b is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 );
  • R 2C is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen;
  • R 2d is selected from H or halogen (e.g., F or Cl);
  • R 2e is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), -CN, and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., methyl); and
  • R 3 is H or C 1 -C 6 alkyl (e.g., methyl), wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 ).
  • the disclosure provides compounds of formula (lb):
  • R 1 is H
  • R 2a is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 );
  • R 2b is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 );
  • R 2C is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen;
  • R 2d is selected from H or halogen (e.g., F or Cl);
  • R 2e is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), -CN, and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., methyl); and
  • R 3 is H or C 1 -C 6 alkyl (e.g., methyl), wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 ).
  • the disclosure provides compounds of formula (lb):
  • R 1 is H or -OH
  • R 2a is selected from H, C 1 -C 6 alkyl (e.g., methyl), halogen (e.g., F or Cl), and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 );
  • R 2b is H
  • R 2C is H
  • R 2d is independently selected from H or halogen (e.g., F or Cl);
  • R 2e is H
  • R 3 is independently H or C 1 -C 6 alkyl (e.g., methyl), wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF 2 ).
  • the disclosure provides compounds of formula (lb): R,c Rob
  • R 1 is H or -OH
  • R 2a is selected from H, and -OR 3 ;
  • R 2b is H
  • R 2C is H
  • R 2d is independently selected from H or halogen (e.g., F or Cl);
  • R 2e is H
  • R 3 is independently H or C1-C6 alkyl (e.g., methyl), wherein the alkyl is optionally substituted with one or more halogen (e.g., CHF2).
  • halogen e.g., CHF2
  • Selective CBP Inhibitor Compounds of formula (I) are provided.
  • Selective CBP Inhibitor Compounds of Formula (lb) are provided.
  • the present disclosure encompasses the recognition that compounds of formula (I) are CBP Inhibitor Compounds, defined herein as compounds having one or more of the following characteristics when tested according to the HTRF biochemical Assay Protocol below in Example 2: (1) a CBP IC50 value of less than 1 mM; and (2) a CBP IC50 value of between 0.001 and 1 pM.
  • the disclosure relates to compounds of formula (I) that are of a formula selected from Group A:
  • the disclosure relates to a compound of formula (I) selected from Figure 1.
  • Figure 1 “Eluted Isomer” refers to the order in which the compound eluted by preparative HPLC.
  • R 1 is H or -OH. In some embodiments, R 1 is H. In some embodiments, R 1 is -OH.
  • each R 2 is independently selected from C1-C6 alkyl, halogen, -CN, and -OR 3 , wherein the alkyl is optionally substituted with one or more halogen.
  • R 2 is C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen.
  • R 2 is C1-C6 alkyl, wherein the alkyl is substituted with one halogen.
  • R 2 is C1-C6 alkyl, wherein the alkyl is substituted with two halogens.
  • R 2 is selected from -C3 ⁇ 4 and -CHF2.
  • R 2 is -CH3. In some embodiments, R 2 is -CHF2. In some embodiments R 2 is halogen. In some embodiments, R 2 is selected from -F and -Cl. In some embodiments, R 2 is -F. In some embodiments, R 2 is -Cl. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -OR 3 , wherein R 3 is as described herein.
  • each R 3 is independently C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen. In some embodiments, R 3 is C1-C6 alkyl, wherein the alkyl is substituted with one halogen. In some embodiments, R 3 is C1-C6 alkyl, wherein the alkyl is substituted with two halogens. In some embodiments, R 3 is selected from -CH3, -CHF2, and propyl. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CHF2. In some embodiments, R 3 is propyl.
  • n is selected from 0, 1, 2, and 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • n is 2 and R 2 is CH3 in one instance and F in the second instance. In some embodiments, n is 2 and R 2 is -OCH3 in one instance and Cl in the second instance. In some embodiments, n is 2 and R 2 is -OCH3 in one instance and -OCH3 in the second instance. In some embodiments, n is 2 and R 2 is -CH3 in one instance and F in the second instance. In some embodiments, n is 2 and R 2 is F in one instance and F in the second instance. In some embodiments, n is 2 and R 2 is -CHF2 in one instance and F in the second instance.
  • n is 2 and R 2 is -OCH(CH3)2 in one instance and F in the second instance. In some embodiments, n is 2 and R 2 is -OCHF2 in one instance and F in the second instance. In some embodiments, n is 3 and R 2 is -OCH3 in one instance, F in the second instance, and F in the third instance. In some embodiments, n is 3 and R 2 is -OCH3 in one instance, -OCH3 in the second instance, and F in the third instance.
  • R 1 is H and n is 0.
  • R 1 is -OH and n is 0.
  • R 1 is -OH, n is 2, and R 2 is -F in one instance and -OR 3 in the second instance, wherein R 3 is -CH3.
  • R 1 is -OH, n is 2, and R 2 is -F in one instance and -OR 3 in the second instance, wherein R 3 is -CHF2.
  • the compound of formula (I) is Compound 1:
  • the compound of formula (I) is (lR,3R)-3-[(7S)-2-[(R)-(5-fluoro- 2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H- imidazo[4,5-f]quinolin-3-yl]cyclohexane-l -carboxylic acid.
  • the compound of formula (I) is (lR,3R)-3-((S)-2-((R)-(5-fluoro-2- methoxyphenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H- imidazo[4,5-f]quinolin-3-yl)cyclohexane-l -carboxylic acid.
  • the compound of formula (I) is Compound 2:
  • the compound of formula (I) is 3-((7S)-2-(hydroxy(phenyl)methyl)- 6-(methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-
  • the compound of formula (I) is the first eluting isomer of 3-((7S)-
  • the compound of formula (I) is (lR,3R)-3-((S)-2-((R)- hydroxy(phenyl)methyl)-6-(methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5- f]quinolin-3-yl)cyclohexane- 1-carboxylic acid.
  • the compound of formula (I) is Compound 3:
  • the compound of formula (I) is 3-((7S)-2-((2-(difluoromethoxy)-5- fluorophenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H- imidazo[4,5-f]quinolin-3-yl)cyclohexane- 1-carboxylic acid.
  • the compound of formula (I) is the first eluting isomer of 3-((7S)- 2-((2-(difluoromethoxy)-5-fluorophenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl- 6, 7, 8, 9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane- 1-carboxylic acid when eluted from a preparative HPLC using the conditions defined in Example 1.5.
  • the compound of formula (I) is (lR,3R)-3-((S)-2-((R)-(2- (difluoromethoxy)-5-fluorophenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl-6, 7,8,9- tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane- 1-carboxylic acid.
  • the compound of formula (I) is Compound 4:
  • the compound of formula (I) is 3-((S)-2-benzyl-6- (methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-l- carboxylic acid.
  • the compound of formula (I) is (lR,3R)-3-((S)-2-benzyl-6- (methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-l- carboxylic acid.
  • compounds of formula (I) are Selective CBP Inhibitor Compounds, defined herein as CBP Inhibitors having a BRD4 IC50 value greater than that of their CBP IC50 value, preferably wherein its BRD4 IC50 value is greater than 1 mM (e.g., 1 micromolar to 10 micomolar, or greater), wherein the IC50 values are determined as in the procedures set forth in the assay described in Example 2.
  • CBP Inhibitors having a BRD4 IC50 value greater than that of their CBP IC50 value, preferably wherein its BRD4 IC50 value is greater than 1 mM (e.g., 1 micromolar to 10 micomolar, or greater), wherein the IC50 values are determined as in the procedures set forth in the assay described in Example 2.
  • compounds of formula (I) can be Selective CBP Inhibitor Compounds, wherein the BRD4 IC50 value is greater than 500 nM (e.g., 500 nanomolar to 10 micomolar, or greater), wherein the IC50 values are determined as in the procedures set forth in the assay described in Example 2.
  • 500 nM e.g., 500 nanomolar to 10 micomolar, or greater
  • Compound 1 is a Selective CBP Inhibitor Compound, defined herein as a CBP Inhibitor having a BRD4 IC50 value greater than that of its CBP IC50 value, preferably wherein its BRD4 IC50 value greater than 1 mM (e.g., 1 micromolar to 10 micomolar, or greater), wherein the IC50 values are determined as in the procedures set forth in the assay described in Example 2.
  • mM e.g., 1 micromolar to 10 micomolar, or greater
  • the discovery includes the use of one or more compounds of formula (I), and pharmaceutically acceptable salts thereof, in pharmaceutical preparations for the treatment of patients diagnosed with a disease or disorder associated with the inhibition of CBP (e.g., certain forms of cancer).
  • the compositions comprising one or more compounds of formula (I), and pharmaceutically acceptable salts thereof, can be obtained by certain processes also provided herein.
  • a Selective CBP Inhibitor Compound of formula (I) is used to treat breast cancer (e.g., TNBC) or prostate cancer.
  • a Selective CBP Inhibitor Compound of Formula (lb) is used to treat an AR+ form of cancer, including AR+ breast cancer or prostate cancer.
  • a Selective CBP Inhibitor Compound of formula (I) is provided for treatment of a patient diagnosed with a AR+ form of cancer, such as AR+ breast cancer (e.g., AR+ TNBC) or AR+ prostate cancer (e.g., a AR-v7+ form of prostate cancer).
  • a AR+ form of cancer such as AR+ breast cancer (e.g., AR+ TNBC) or AR+ prostate cancer (e.g., a AR-v7+ form of prostate cancer).
  • the discovery includes the use of (lR,3R)-3-[(7S)-2-[(R)-(5-fluoro- 2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)7-methyl-3H,6H,7H,8H,9H- imidazo[4,5-f]quinolin-3-yl]cyclohexane-l -carboxylic acid (Compound 1), and pharmaceutically acceptable salts thereof, in pharmaceutical preparations for the treatment of patients diagnosed with a disease or disorder associated with the inhibition of CBP (e.g., certain forms of cancer).
  • the compositions comprising Compound 1 and pharmaceutically acceptable salts thereof can be obtained by certain processes also provided herein.
  • the discovery includes the use of Compound 2, and pharmaceutically acceptable salts thereof, in pharmaceutical preparations for the treatment of patients diagnosed with a disease or disorder associated with the inhibition of CBP (e.g., certain forms of cancer).
  • compositions comprising Compound 2 and pharmaceutically acceptable salts thereof can be obtained by certain processes also provided herein.
  • the discovery includes the use of Compound 3, and pharmaceutically acceptable salts thereof, in pharmaceutical preparations for the treatment of patients diagnosed with a disease or disorder associated with the inhibition of CBP (e.g., certain forms of cancer).
  • compositions comprising Compound 3 and pharmaceutically acceptable salts thereof can be obtained by certain processes also provided herein.
  • the discovery includes the use of Compound 4, and pharmaceutically acceptable salts thereof, in pharmaceutical preparations for the treatment of patients diagnosed with a disease or disorder associated with the inhibition of CBP (e.g., certain forms of cancer).
  • compositions comprising Compound 4 and pharmaceutically acceptable salts thereof can be obtained by certain processes also provided herein.
  • the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the examples given below.
  • the compounds of the present disclosure i.e., compounds of Formula (I), (II), or Group A or a pharmaceutically acceptable salt thereof, may be prepared by methods known in the art of organic synthesis as set forth in part by the synthetic schemes depicted in the examples. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I), (II), or Group A.
  • stereocenters exist in the compounds of Formula (I), (II), or Group A. Accordingly, the present disclosure includes both possible stereoisomers (unless otherwise indicated and/or specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. Unless otherwise indicated, when a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereo specific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • compounds of formula (I) are tool compounds useful for studying the effects of CBP/p300 inhibition in vitro or in an in vivo model.
  • the tool compounds of formula (I) may be useful for studying the effects of CBP/p300 inhibition on purified proteins, cellular extracts, in intact cells and cell line models, and the like.
  • the tool compounds of formula (I) may be useful for studying the effects of CBP/p300 inhibition in cell line derived xenografts, in patient derived xenografts, in knock-in mouse model, in knock-out mouse models, and the like.
  • the disclosure provides pharmaceutical preparations for the treatment of patients diagnosed with AR+ cancer.
  • compounds provided herein can be formulated as an active pharmaceutical composition comprising one or more compounds of formula (I) (or a pharmaceutically acceptable salt and/or enantiomer thereof) useful for treatment of prostate cancer, including metastatic castrate resistant prostate cancer (CRPC), and/or AR+ breast cancers including locally advanced or metastatic AR+ breast cancer.
  • the inhibition of CBP/P300 can target AR transcriptional activity through H3K27Ac, reduction of AR target gene expression, or reduction of AR expression with, ultimately, a reduction in proliferation.
  • CBP/P300 BRD inhibitors present the possibility of suppressing ER-driven signaling in hormone-receptor positive breast cancers.
  • the pharmaceutical composition comprises Compound 1.
  • the pharmaceutical composition comprises Compound 2.
  • the pharmaceutical composition comprises Compound 3.
  • the pharmaceutical composition comprises Compound 4.
  • Compounds and compositions described herein are inhibitors of CBP having a lower inhibition concentration compared to its inhibition concentration with respect to BRD4.
  • Methods of treatment can comprise administering to a subject in need thereof a therapeutically effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Methods of treatment can comprise administering to a subject in need thereof a therapeutically effective amount of (1) Compound 1 or a pharmaceutically acceptable salt thereof; (2) a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Methods of treatment can comprise administering to a subject in need thereof a therapeutically effective amount of (1) Compound 2 or a pharmaceutically acceptable salt thereof; (2) a pharmaceutical composition comprising Compound 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Methods of treatment can comprise administering to a subject in need thereof a therapeutically effective amount of (1) Compound 3 or a pharmaceutically acceptable salt thereof; (2) a pharmaceutical composition comprising Compound 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • Methods of treatment can comprise administering to a subject in need thereof a therapeutically effective amount of (1) Compound 4 or a pharmaceutically acceptable salt thereof; (2) a pharmaceutical composition comprising Compound 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions may be orally administered in any orally acceptable dosage form. Accordingly, a patient and/or subject can be selected for treatment using a compound described herein by first evaluating the patient and/or subject to determine whether the subject is in need of inhibition of CBP, and if the subject is determined to be in need of inhibition of CBP, then administering to the subject a composition described herein.
  • the CBP Inhibitor compounds and compositions are useful, for example, in suppressing AR-driven transcriptional programs through inhibition of the CBP/P300 BRD, including AR-v7 variants.
  • the growth inhibitory effect of Compounds 1, 2 and 4 and enzalutamide was determined across a panel of prostate cancer cell lines including androgen-dependent and independent models as well as AR-negative cell lines.
  • Compound 1 induced a concentration-dependent reduction of H3K27Ac, a mark specific to CBP/P300, in an AR positive breast cancer cell line ( Figure 3).
  • Compounds 1, 2, and 4 reduced the mRNA expression of TMPRSS2 and XBP1 in an AR positive breast cancer cell line.
  • Compound 1, 2 and 4 inhibit proliferation of breast cancer cell lines after 10 days continuous exposure to the drug, and the cell lines with high expression of AR mRNA are more sensitive than those with low expression.
  • Compound 1 treatment produced a tumor growth inhibition in an AR positive breast cancer cell line derived xenograft model ( Figure 4).
  • an AR positive breast cancer cell line can be MDA-MB-453.
  • Treatment of prostate cancer cells with Compound 2 led to the reduction of both full length and variant forms of the AR including AR-v7 ( Figure 5).
  • Compounds 1, 2, and 4 reduced AR target genes TMPRSS2 and KLK3, as well as MYC in a concentration-dependent manner in an AR-v7+ prostate cancer cell line.
  • an AR-v7+ prostate cancer cell line can be 22Rvl.
  • Compounds 1, 2, and 4 had a potent and concentration-dependent growth inhibitory effect in all AR+ cell lines, including AR-v7 harboring cell lines.
  • Treatment with Compound 4 at 40 mg/kg/dose daily Monday - Thursday repeated weekly or 80 mg/kg/dose Monday and Thursday (twice weekly) repeated weekly resulted in a strong antitumor response in a patient-derived xenograft model resistant to enzalutamide (Figure 6).
  • Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with castration resistant prostate cancer or metastatic castration-sensitive prostate cancer. Patients receiving enzalutamide can also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or can have had bilateral orchiectomy.
  • GnRH gonadotropin-releasing hormone
  • Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA.
  • a major metabolite, N-desmethyl enzalutamide exhibited similar in vitro activity to enzalutamide.
  • Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.
  • compounds of formula (I), or pharmaceutically acceptable salts thereof are indicated for the treatment of patients with castration resistant prostate cancer or metastatic castration-sensitive prostate cancer.
  • Patients receiving a compound of formula (I), or a pharmaceutically acceptable salt thereof can also receive gonadotropin-releasing hormone (GnRH) analog concurrently or can have had a bilateral orchiectomy.
  • GnRH gonadotropin-releasing hormone
  • CBP/P300 can interact with AR directly via the NRID domain in CBP/P300. However, contrary to other nuclear receptors, this interaction is not believed to be dependent on ligand binding. Also, CBP/P300 can interact with both the LBD of AR and its N-terminal domain. Both these factors are of relevance in castrate resistant prostate cancer and it is expected that CBP/P300 interacts with AR-v7 very similarly as with AR. CBP/P300 also interact with AR indirectly via the co-factor TIP60/SRC-1 which itself interacts with AR. This approach can differ from direct receptor antagonists and can have the advantage of being unaffected by structural variations in the AR ligand binding domain (LBD).
  • LBD AR ligand binding domain
  • Such CBP/P300 BRD inhibitors can have activity in a number of cancers dependent upon nuclear hormone-receptor transcriptional programs, such as metastatic CRPC and locally advanced or metastatic AR+ breast cancers.
  • the therapeutic benefits of AR inhibition have been demonstrated clinically in these cancers, but with limitations that highlight the need for alternative approaches with long term benefit and mechanisms of resistance that are non-overlapping with anti-androgen therapy.
  • the inhibition of CBP/P300 can target AR transcriptional activity through reduction of H3K27 acetylation, reduction of AR target gene expression, and/or reduction of AR expression, ultimately leading to a reduction in proliferation.
  • CBP/P300 inhibitor-mediated inhibition of AR activities is expected to be insensitive to AR LBD structural variations, and thus insensitive to LBD-related mechanisms of resistance to androgen antagonists.
  • CBP/P300 BRD inhibitors can be useful for suppressing ER-driven signaling in hormone-receptor positive breast cancers.
  • AR aberrations in the LBD can render the receptor ligand-independent and insensitive to AR antagonists.
  • Approximately twenty AR mRNA splice variants have been identified, with a subset that are constitutively active. Notably, all biologically active forms of the AR retain the NTD; drugs that target the NTD have the potential to impact all AR forms, including those that may drive resistance to AR-LBD-targeting therapies.
  • all AR-v7 and ARv567es have been detected at the protein level and AR-v7 has been the most studied.
  • Various methods for measuring and defining AR positivity can be employed to select patients to receive a pharmaceutical composition comprising one or more compounds of formula (I).
  • AR expression is largely maintained in the target population of relapse patients.
  • AR and AR-v7 protein or mRNA can be detected in CTC while AR mutations and AR amplification can be detected from circulating tumor DNA (ctDNA).
  • Current IHC methods for measuring AR in breast cancer vary on multiple factors including the antibody used, the IHC methodology, and the cut-off criterion for positivity (Safarpour el al, Am. J. Cancer Res., 2014, 4:353-368). Most of the studies use the AR441 antibody clone from Dako (Agilent) and 1% or 10% positive nuclei as the threshold for positivity. Overall, the frequency of AR+ TNBC has been reported to be 20% to 30%.
  • compositions comprising one or more compounds of formula (I) can be used to treat certain forms of prostate cancer.
  • compositions comprising one or more compounds of formula (I) are useful for the inhibition of CBP/P300 BRD, with a differentiated mechanism of antagonizing the AR-driven transcriptional program (e.g., as an early line of therapy).
  • Pharmaceutical compositions comprising one or more compounds of formula (I) can be used to treat mCRPC, or other cancers dependent on AR-driven transcription.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist-based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • Compounds of formula (I) are useful for treatment of patients diagnosed with an AR-v-7 variant form of AR.
  • patients diagnosed with mCRPC with AR- v7 positive circulating tumor cells can be treated with the pharmaceutical composition comprising one or more compounds of formula (I).
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising one or more compounds of formula (I).
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 1 to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist-based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • Compound 1 is also useful for treatment of patients diagnosed with an AR-v-7 variant form of AR.
  • patients diagnosed with mCRPC with AR-v7 positive circulating tumor cells (CTC) can be treated with the pharmaceutical composition comprising Compound 1.
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising Compound 1.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising (lR,3R)-3-((S)-2-((R)-(5-fluoro-2- methoxyphenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H- imidazo[4,5-f]quinolin-3-yl)cyclohexane-l -carboxylic acid to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist-based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • patients diagnosed with mCRPC with AR-v7 positive circulating tumor cells can be treated with the pharmaceutical composition comprising (lR,3R)-3-((S)-2-((R)-(5-fluoro-2- methoxyphenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H- imidazo[4,5-f]quinolin-3-yl)cyclohexane-l -carboxylic acid.
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising (lR,3R)-3-((S)-2-((R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl)-6- (methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-l- carboxylic acid.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 2 to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist-based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • Compound 2 is also useful for treatment of patients diagnosed with an AR-v-7 variant form of AR.
  • patients diagnosed with mCRPC with AR-v7 positive circulating tumor cells (CTC) can be treated with the pharmaceutical composition comprising Compound 2.
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising Compound 2.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 3 to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist-based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • Compound 3 is also useful for treatment of patients diagnosed with an AR-v-7 variant form of AR.
  • patients diagnosed with mCRPC with AR-v7 positive circulating tumor cells can be treated with the pharmaceutical composition comprising Compound 3.
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising Compound 3.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 4 to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist-based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • Compound 4 is also useful for treatment of patients diagnosed with an AR-v-7 variant form of AR.
  • patients diagnosed with mCRPC with AR-v7 positive circulating tumor cells (CTC) can be treated with the pharmaceutical composition comprising Compound 4.
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising Compound 4.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising (lR,3R)-3-((S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane- 1-carboxylic acid to patients diagnosed with mCRPC with progressive castration-resistant disease who have failed or been intolerant to at least two prior systemic therapies, including at least one androgen antagonist- based therapy with evaluable disease (anti-androgen+LHRH analog, enzalutamide, or abiraterone) and either a rising PSA with or without detectable metastatic disease per standard definitions or neuroendocrine features.
  • a pharmaceutical composition comprising (lR,3R)-3-((S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-6,7,8,9-tetrahydro-3H-imidazo
  • patients diagnosed with mCRPC with AR-v7 positive circulating tumor cells can be treated with the pharmaceutical composition comprising (lR,3R)-3-((S)-2-benzyl-6-(methoxycarbonyl)-7- methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane- 1-carboxylic acid.
  • patients diagnosed with disease progression after treatment with enzalutamide can be treated with the pharmaceutical composition comprising (lR,3R)-3-((S)-2-benzyl-6- (methoxycarbonyl)-7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-l- carboxylic acid.
  • compositions comprising one or more compounds of formula (I) are useful for the treatment of certain forms of AR+ breast cancer.
  • the suppression of AR and/or ER transcriptional activity with a compound of formula (I) (or a pharmaceutical composition comprising one or more compounds of formula (I)) can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and metastatic ER+ tumors, via its inhibition of CBP/P300 BRD.
  • the suppression of AR and/or ER transcriptional activity with a compound of formula (I) can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and ER+ tumors, via its inhibition of CBP/P300 BRD.
  • the suppression of AR and/or ER transcriptional activity with Compound 1 (or a pharmaceutical composition comprising Compound 1) can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and metastatic ER+ tumors, via its inhibition of CBP/P300 BRD.
  • the suppression of AR and/or ER transcriptional activity with Compound 1 can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and ER+ tumors, via its inhibition of CBP/P300 BRD.
  • the suppression of AR and/or ER transcriptional activity with Compound 2 can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and ER+ tumors, via its inhibition of CBP/P300 BRD.
  • the suppression of AR and/or ER transcriptional activity with Compound 3 can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and ER+ tumors, via its inhibition of CBP/P300 BRD.
  • the suppression of AR and/or ER transcriptional activity with Compound 4 can be useful in treating antitumor effects in AR+ breast cancers, including TNBC and ER+ tumors, via its inhibition of CBP/P300 BRD.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) to patients diagnosed with invasive breast carcinoma with triple negative status (per College of American Pathologists [CAP] guidelines) and detectable AR expression in > 1% of tumor cells, with progressive disease who has failed at least two prior systemic therapies with evaluable disease or invasive breast carcinoma AR positive > 1% and ER, PR, or HER positive (per CAP guidelines) with progressive disease who has failed at least three prior systemic therapies.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) to patients diagnosed with Her2- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of formula (I) to patients diagnosed with ER-, PR-, or ER-/PR- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 1 to patients diagnosed with invasive breast carcinoma with triple negative status (per College of American Pathologists [CAP] guidelines) and detectable AR expression in > 1% of tumor cells, with progressive disease who has failed at least two prior systemic therapies with evaluable disease or invasive breast carcinoma AR positive > 1% and ER, PR, or HER positive (per CAP guidelines) with progressive disease who has failed at least three prior systemic therapies.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 1 to patients diagnosed with Her2- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 1 to patients diagnosed with ER-, PR-, or ER- /PR- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 2 to patients diagnosed with invasive breast carcinoma with triple negative status (per College of American Pathologists [CAP] guidelines) and detectable AR expression in > 1% of tumor cells, with progressive disease who has failed at least two prior systemic therapies with evaluable disease or invasive breast carcinoma AR positive > 1% and ER, PR, or HER positive (per CAP guidelines) with progressive disease who has failed at least three prior systemic therapies.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 2 to patients diagnosed with Her2- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 2 to patients diagnosed with ER-, PR-, or ER- /PR- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 3 to patients diagnosed with invasive breast carcinoma with triple negative status (per College of American Pathologists [CAP] guidelines) and detectable AR expression in > 1% of tumor cells, with progressive disease who has failed at least two prior systemic therapies with evaluable disease or invasive breast carcinoma AR positive > 1% and ER, PR, or HER positive (per CAP guidelines) with progressive disease who has failed at least three prior systemic therapies.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 3 to patients diagnosed with Her2- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 3 to patients diagnosed with ER-, PR-, or ER- /PR- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 4 to patients diagnosed with invasive breast carcinoma with triple negative status (per College of American Pathologists [CAP] guidelines) and detectable AR expression in > 1% of tumor cells, with progressive disease who has failed at least two prior systemic therapies with evaluable disease or invasive breast carcinoma AR positive > 1% and ER, PR, or HER positive (per CAP guidelines) with progressive disease who has failed at least three prior systemic therapies.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 4 to patients diagnosed with Her2- breast cancer.
  • Some methods include administering a therapeutically effective amount of a pharmaceutical composition comprising Compound 4 to patients diagnosed with ER-, PR-, or ER- /PR- breast cancer.
  • Scheme 1 provides methods useful for synthesizing compounds of Formula I.
  • Scheme 2 provides methods useful for synthesizing compounds of Formula I.
  • Scheme 3 provides methods useful for synthesizing certain compounds of Formula I.
  • Scheme 4 provides methods useful for synthesizing certain compounds of Formula I.
  • Figure 2(A) provides a synthetic scheme for the preparation of Intermediate 1, as described below.
  • Step 6 methyl (S)-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroquinoline-l(2H)- carboxylate
  • Step 7 methyl (S)-5-((diphenylmethylene)amino)-2-methyl-3,4-dihydroquinoline-l(2H)- carboxylate
  • Example 1.2 Synthesis of (lR,3R)-3-[(7S)-2-[(R)-(5-fluoro-2- methoxyphenyl)(hydroxy)methyl]-6(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H- imidazo[4,5-f]quinolin-3-yl]cyclohexane-lcarboxylic acid (1); (lR,3R)-3-[(7S)-2-[(S)-(5- fluoro-2-methoxyphenyl)(hydroxy)methyl]-6(methoxycarbonyl)-7-methyl- 3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-lcarboxylic acid (1’)
  • Figure 2(B) provides a synthetic scheme for the preparation of Compound 1 and Compound 1 ', as described below.
  • the resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1: 1 ethyl acetate/petroleum ether) to afford the crude product (35.0 g).
  • the crude product was dissolved in ethyl acetate (230 mL), followed by the addition of D- Camphor sulfonic acid (36.9 g, 0.158 mol).
  • the resulting solution was stirred for 1 h at 60 °C and then cooled to room temperature.
  • the solids were collected by filtration, and rinsed with ethyl acetate (120 mL).
  • the solids were dissolved in water (50 mL).
  • the pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution).
  • Step 7 methyl (2S)-5-amino-6-[[(lR,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl- 1,2,3,4-tetrahydroquinoline-l-carboxylate
  • Step 8 methyl (2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(lR,3R)- 3(methoxycarbonyl)cyclohexyl]amino]-2-methyl-l,2,3,4-tetrahydroquinoline-l-carboxylate
  • the crude product was purified by Prep-HPLC (Column, XBridge Prep C18 OBD Column, 19x150 mm, 5um; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: ACN (15.0% to 29.0% over 14 min); Detector, UV 220/254nm).
  • the product was separated by Chiral-Prep-HPLC (Column, CHIRALPAK IE, 2x25cm, 5 um; Mobile phase, A: Hex (containing 0.1 %LA) and B: ethanol (hold 50.0% ethanol over 12 min); Detector, UV 220/254 nm).
  • Second eluting isomer (1’): ⁇ -NMR (CD 3 OD, 400 MHz) d (ppm): 7.69-7.44 (m, 2H), 7.44- 7.29 (m, 1H), 7.12-6.99 (m, 1H), 6.98-6.82 (m, 1H), 6.37(s, 1H), 5.03-4.91(m, 1H), 4.81-4.69(m, 1H), 3.78(s, 3H), 3.61(s, 3H), 3.22-3.04(m, 1H), 3.02-2.87 (m, 2H), 2.54-2.41 (m, 1H), 2.41-2.27 (m, 1H), 2.27-2.08 (m, 3H), 1.82-1.58 (m, 3H), 1.58-1.41 (m, 2H), 1.14 (d, / 6.4 Hz, 3H).
  • a composition of Formula (I) can comprise a compound of one or more of Formula (Il-a), (Il-b), (II-c), (Il-d), (Il-e), (Il-f), (Il-g), (Il-h), (Il-i), (Il-j), (Il-k), (II-l), (Il-m), (Il-n), and/or (II-o).
  • the disclosure provides a composition comprising compound 1 of the foregoing structure or a pharmaceutically acceptable salt thereof at a purity of at least 90% wherein the composition comprises less than 10%, e.g.
  • the disclosure provides a pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof at a purity of at least 95% as determined by the above HPLC method of Example 1.7.
  • the disclosure also provides a pharmaceutical composition comprising compound 1 at a purity of at least 95% as determined by the above HPLC method.
  • each of the stereoisomers of the compound of Formula (II) can be obtained by varying the stereochemistry of the appropriate reagents utilized in the method of Example 1.2 above. For instance, by adjusting the reagent used in Step 4 of Example 1.2, compounds such as those of Formulae (II-m) and (Il-n) can be synthesized.
  • Step 6 of Example 1.2 the reagent methyl (lS,3R)-3-aminocyclohexane-l-carboxylate can be used in place of methyl (lR,3R)-3-aminocyclohexane-l-carboxylate to obtain compounds of Formulae (Il-b) and (Il-e). It will be apparent to the skilled reader that by making a combination of these types of modifications to the process set out in Example 1.2, each of compounds (Il-a) to (II-o) depicted above can be synthesized.
  • Figure 2(C) provides a synthetic scheme for the preparation of Compound 2, as described below.
  • the resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1: 1 ethyl acetate/petroleum ether) to afford the crude product (35.0 g).
  • the crude product was dissolved in ethyl acetate (230 mL), followed by the addition of D- Camphor sulfonic acid (36.9 g, 0.158 mol).
  • the resulting solution was stirred for 1 h at 60 °C and then cooled to room temperature.
  • the solids were collected by filtration, and rinsed with ethyl acetate (120 mL).
  • the solids were dissolved in water (50 mL).
  • the pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution).
  • Step 6 methyl (2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(lR,3R)-3- (methoxycarbonyl)cyclohexyl]amino]-2-methyl-l,2,3,4-tetrahydroquinoline-l-carboxylate
  • the resulting solution was diluted with water (30 mL), and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with brine (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5um, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: ACN (3% to 30% over 21 min); Detector: UV 254 nm).
  • a composition of Formula (I) can comprise a compound of one or more of Formula (III- a), (Ill-b), (III-c), (Ill-d), (Ill-e), (Ill-f), (Ill-g), (Ill-h), (III-l), (Ill-j), (Ill-k), (III-l), (Ill-m), (Ill-n), and/or (III-o).
  • the disclosure provides a composition comprising compound 2 of the foregoing structure or a pharmaceutically acceptable salt thereof at a purity of at least 90% wherein the composition comprises less than 10%, e.g.
  • the disclosure provides a pharmaceutical composition comprising compound 2 or a pharmaceutically acceptable salt thereof at a purity of at least 95% as determined by the above HPLC method of Example 1.7.
  • the disclosure also provides a pharmaceutical composition comprising compound 2 at a purity of at least 95% as determined by the above HPLC method.
  • Example 1.4 (lR,3R)-3-[(7S)-2-[(S)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy) methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3- yl]cyclohexane-l-carboxylic acid (452), (lR,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5- fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo
  • Figure 2(D) provides a synthetic scheme for the preparation of Compound 3 and Compound 452, as described below.
  • the resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1: 1 ethyl acetate/petroleum ether) to afford the crude product (35.0 g).
  • the crude product was dissolved in ethyl acetate (230 mL), followed by the addition of D- Camphor sulfonic acid (36.9 g, 0.158 mol).
  • the resulting solution was stirred for 1 h at 60 °C and then cooled to room temperature.
  • the solids were collected by filtration, and rinsed with ethyl acetate (120 mL).
  • the solids were dissolved in water (50 mL).
  • the pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution).
  • Step 8 methyl (2S)-5-amino-6-[[(lR,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-
  • Step 9 methyl (2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6- [ [( 1R,3R) -3- (methoxycarbonyl)cyclohexyl] amino] -2-methyl- 1 ,2,3,4- tetrahydroquinoline- 1 - carboxylate
  • the crude product was purified by Prep-HPLC (Column, XBridge Shield RP18 OBD Column, 30x150 mm, 5 um; Mobile phase, A: water (containing 10 mmol/L NH4HCO3) and B: ACN (25.0% to 35.0% over 8 min); Detector, UV 254/220 nm).
  • a composition of Formula (I) can comprise a compound of one or more of Formula (IV- a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-f), (IV-g), (IV-h), (IV-i), (IV-j), (IV-k), (IV-1), (IV-m), (IV- n), and/or (IV-o).
  • the disclosure provides a composition comprising compound 3 of the foregoing structure or a pharmaceutically acceptable salt thereof at a purity of at least 90% wherein the composition comprises less than 10%, e.g. less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2% or less than 1%, collectively of one or more of the following stereoisomers of compound 3, represented as Formulae (IV-a) - (IV-o) below:
  • the disclosure provides a pharmaceutical composition comprising compound 3 or a pharmaceutically acceptable salt thereof at a purity of at least 95% as determined by the above HPLC method of Example 1.7.
  • the disclosure also provides a pharmaceutical composition comprising compound 3 at a purity of at least 95% as determined by the above HPLC method.
  • Figure 2(E) provides a synthetic scheme for the preparation of Compound 4, as described below.
  • Step 1 methyl (S)-5-amino-6-(((lR,3R)-3-(methoxycarbonyl)cyclohexyl)amino)-2-methyl- 3,4-dihydroquinoline- 1 - (2H) -carboxylate
  • Example 1.6 3-((7S)-2-((4-chlorophenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl- 6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-l-carboxylic acid (413); and (lR,3R)-3-((S)-2-((S)-(4-chlorophenyl)(hydroxy)methyl)-6-(methoxycarbonyl)-7-methyl- 6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolin-3-yl)cyclohexane-l-carboxylic acid (501)
  • Figure 2(F) provides a synthetic scheme for the preparation of Compound 413 and Compound 501, as described below.
  • the resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1: 1 ethyl acetate/petroleum ether) to afford the crude product (35.0 g).
  • the crude product was dissolved in ethyl acetate (230 mL), followed by the addition of D- Camphorsulfonic acid (36.9 g, 0.158 mol).
  • the resulting solution was stirred for 1 h at 60 °C and then cooled to room temperature.
  • the solids were collected by filtration, and rinsed with ethyl acetate (120 mL).
  • the solids were dissolved in water (50 mL).
  • the pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution).
  • the resulting solution was diluted with water (30 mL), and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with brine (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 5um, 19 x 150 mm; Mobile Phase, A: water (containing 10 mmol/L NH 4 HCO 3 ) and B: ACN (10% to 37% over 12 min); Detector: UV 254 nm).
  • Second eluting isomer (501): ⁇ -NMR (CD 3 OD, 400 MHz) d (ppm): 7.52-7.33 (m, 6H), 6.22 (s, 1H), 4.84-4.73 (m, 2H), 3.78 (s, 3H), 3.27-3.16 (m, 1H), 3.04-2.92 (m, 1H), 2.90-2.88 (m, 1H), 2.46-2.35 (m, 2H), 2.30-2.22 (m, 1H), 2.15-2.02 (m, 2H), 1.82-1.71 (m, 1H), 1.63-1.55 (m, 2H), 1.40-1.28 (m, 1H), 1.15 (d, J 6.6 Hz, 4H).
  • the percentage purity recited may be determined by HPLC.
  • the percentage purity is determined using the following HPLC method:
  • Example 2 HTRF biochemical assay for CBP and BRD4 activity
  • IC50 values are shown in Figure 1. As set forth in Figure 1, an IC50 value of greater than or equal to 0.001 pM and less than or equal to 0.01 pM is marked“++++”; a value greater than 0.01 pM and less than or equal to 0.1 pM is marked“+++”; a value greater than 0.1 pM and less than or equal to 1 pM is marked“++”; and a value greater than 1 pM and less than 1000 pM is marked“+”.
  • Example 3 Compounds 1 and Compound Y demonstrated in vitro activity against CBP
  • Compound 1 was evaluated in screening assays for kinase inhibition and BRD binding. Compound 1 showed no to low binding affinity for the human kinases and disease relevant mutant variants evaluated in a KINOMEscanTM screen. A panel of 10 BRD representing the various branches or the bromodomain tree were tested using an AlphaScreen. Of the 10 bromodomains surveyed, Compound 1 was inactive against 8. Compound 1 IC 50 values for bromodomains of CREBBP and BRD4 (tandem BD1/BD2) were 0.1 and > 10 mM, respectively, confirming the high selectivity of Compound 1 for CBP.
  • AR-positive breast cancer cells were exposed to increasing concentrations of Compound 1 for 24 hours. Lysates were prepared in E-PAGE loading buffer (Invitrogen) and analyzed by western blot with antibodies diluted 1:1000 for anti-H3K27Ac, 1:2000 for anti-total H3 and 1: 10,000 for anti-b actin. The blots were scanned and analyzed on a LI-COR Odyssey image analyzer. H3K27Ac levels were normalized to b-Actin.
  • Compound 1 induced a concentration-dependent reduction of H3K27Ac, a mark specific to CBP/P300, in an AR positive breast cancer cell line. (Figure 3). Fifty percent reduction was seen between 0.03 and 0.1 mM with maximal reduction of approximately 60% seen at 0.3 mM.
  • Example 5 Compound 1, 2 and 4 reduce AR target gene TMPRSS2 and ER target gene XBP1 in AR-positive breast cancer cells
  • AR-positive breast cancer cells were exposed to increasing concentrations of compounds for 24 hours.
  • RNA was extracted and gene expression measured using Taqman® assays for TMPRSS2 and XBP1.
  • Example 6 Compounds 1, 2 and 4 have antiproliferative activity against AR+ breast cancer cell lines in vitro
  • Compound 1, 2 and 4 inhibit proliferation of breast cancer cell lines after 10 days continuous exposure to the drug.
  • the cell lines with high expression of AR mRNA are more sensitive than those with low expression.
  • an IC50 value of less than 0.2 mM is marked“++++”; a value greater than 0.2 pM and less than 0.5 pM is marked“+++”; a value greater than 0.5 pM and less than 1 pM is marked“++”; and a value greater than 1 pM is marked“+”.
  • Example 7 Compound 1 demonstrated in vivo efficacy in AR-positive human derived breast cancer xenografts (TNBC)
  • TGI tumor growth inhibition
  • “TVfinal” and“TVinitial” are the mean tumor volumes on the final day and initial day of dosing). The average body weight loss was 3.7%.
  • Example 8 Compound 2 modulates the level of AR and variants at the protein level.
  • AR-v7+ Prostate cancer cells were exposed to Compound 2 for 24 hours at which time lysates were prepared and the impact of the compound on the protein level of AR was assessed by western blot. The results are shown in Figure 5. Treatment of prostate cancer cells with Compound 2 led to the reduction of both full length and variant forms of the AR including AR-v7.
  • Example 9 Compounds 1, 2 and 4 demonstrate modulation of AR target genes TMPRSS2 and KLK3 as well as MYC in an AR-v7+ prostate cancer cell line
  • AR-v7+ prostate cancer cells were exposed to compounds 1, 2, and
  • an IC50 value of less than 10 nM is marked“++++”; a value greater than 10 nM and less than 50 nM is marked“+++”; a value greater than 50 nM and less than 100 nM is marked“++”; and a value greater than 100 nM is marked“+”.
  • Table 4 an IC50 value of less than 10 nM is marked“++++”; a value greater than 10 nM and less than 50 nM is marked“+++”; a value greater than 50 nM and less than 100 nM is marked“++”; and a value greater than 100 nM is marked“+”.
  • Example 10 Compounds 1, 2 and 4 demonstrate antiproliferative activity in prostate cancer cell lines
  • Prostate cancer cells Prostate cancer cells, androgen-dependent (LnCaP and VCaP) and androgen- independent (22Rvl), were plated and incubated overnight. The following day, cells were exposed to Compounds 1, 2, 4, and enzalutamide (final top concentration 10 mM, half-log dilutions) continuously. Cell viability was assessed using a CellTiter-Glo ® assay (Promega) after 10 days drug exposure. The growth inhibitory effect was assessed by the concentration inhibiting growth by 50% using a nonlinear regression equation and a variable slope (Graphpad Prism).
  • Enzalutamide was active against androgen-dependent cell lines LnCaP and VCaP but was inactive in AR negative (PC3 and DU145) and the AR-v7 expressing 22Rvl cell line. Conversely, all compounds had a potent and concentration-dependent growth inhibitory effect in all AR+ cell lines including 22Rvl cells. All compounds were inactive in AR- cell lines.
  • an IC50 value of less than 0.5 mM is marked“+++”; a value greater than 0.5 mM and less than 1 pM is marked“++”; and a value greater than 1 pM is marked
  • Example 11 Compound 4 demonstrates antitumor activity in a patient-derived xenograft model of prostate cancer resistant to enzalutamide
  • mice Male NOG mice (6-8 weeks of age) were implanted with prostate PDX tumor fragments. When tumors reached an average tumor volume of 100-300 mm 3 animals were randomized into different cohort groups and dosing initiated on the same day (Day 0). Compound 4 was formulated in (0.5 CMC/0.5% Tween 80) pH8 and administered as a solution. Animals were weighed twice weekly. Tumors were measured twice weekly. The maximum tumor volume of control animals was 1500 mm 3 .
  • Compound 4 was administered by oral gavage at a dose and schedule of 40 mg/kg/dose daily Mon-Thu repeated weekly or 80 mg/kg/dose Mo and Thu (twice weekly) repeated weekly.
  • Example 12 Pharmaceutical Composition comprising Compound 1 and Compound Y
  • a pharmaceutical composition can comprise one or more compounds of formula (I), as provided herein, including Compound 1 and/or Compound 12
  • an active pharmaceutical ingredient can comprise about 90% or more of Compound 1 and up to about 10% (preferably up to about 5%, most preferably up to about 2.5% including about 1.5%) of Compound 12
  • Oral dosage forms comprising Compound 1 can be prepared as a dmg-in-capsule (DiC), encapsulated simple dry-blend granulation, and lipid-based solution in hard shell capsule.
  • the capsules can contain pharmaceutically acceptable excipients, and encapsulated capsules can be packaged in high-density polyethylene induction sealed bottles.
  • a method of treating a patient diagnosed with an enzalutamide-resistant form of AR+ cancer comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof:
  • a method of treating a patient diagnosed with an enzalutamide-resistant form of AR+ cancer comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (lR,3R)-3-[(7S)-2-[(R)-(5-fluoro-2- methoxyphenyl)(hydroxy)methyl] -6-(methoxycarbonyl)-7 -methyl-

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Abstract

Des compositions pharmaceutiques comprenant un composé inhibiteur de CBP peuvent être utilisées pour traiter des patients chez lesquels on a diagnostiqué des formes positives de récepteurs des androgènes du cancer, tels que mCRPC et TNBC, y compris des patients diagnostiqués avec la forme d'épissage AR-v7.
PCT/US2020/022823 2019-03-15 2020-03-13 Compositions et procédés pour traiter des formes positives de récepteurs des androgènes du cancer WO2020190792A1 (fr)

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CA3132995A CA3132995A1 (fr) 2019-03-15 2020-03-13 Compositions et procedes pour traiter des formes positives de recepteurs des androgenes du cancer
BR112021018266A BR112021018266A2 (pt) 2019-03-15 2020-03-13 Composições e métodos para tratar formas positivas de receptor andrógeno de câncer
EP20774663.7A EP3938365A4 (fr) 2019-03-15 2020-03-13 Compositions et procédés pour traiter des formes positives de récepteurs des androgènes du cancer
CN202080021617.5A CN113784967B (zh) 2019-03-15 2020-03-13 用于治疗雄激素受体阳性形式的癌症的组合物和方法
MX2021011154A MX2021011154A (es) 2019-03-15 2020-03-13 Composiciones y metodos para tratar formas de cancer con receptores de androgenos positivos.
AU2020241709A AU2020241709A1 (en) 2019-03-15 2020-03-13 Compositions and methods for treating androgen receptor positive forms of cancer

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US201962819487P 2019-03-15 2019-03-15
US62/819,487 2019-03-15
US62/819,472 2019-03-15
US62/819,490 2019-03-15
US62/819,476 2019-03-15
US62/819,482 2019-03-15
US201962821660P 2019-03-21 2019-03-21
US62/821,660 2019-03-21
PCT/US2019/039936 WO2020006483A1 (fr) 2018-06-29 2019-06-28 Inhibition de la protéine de liaison à creb (cbp)
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CN113784967A (zh) 2021-12-10
AU2020241709A1 (en) 2021-09-23
CN113784967B (zh) 2024-07-26
MX2021011154A (es) 2021-10-22
CA3132995A1 (fr) 2020-09-24

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