WO2024229221A1 - Modulateurs du récepteur des androgènes et leurs méthodes d'utilisation - Google Patents

Modulateurs du récepteur des androgènes et leurs méthodes d'utilisation Download PDF

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WO2024229221A1
WO2024229221A1 PCT/US2024/027412 US2024027412W WO2024229221A1 WO 2024229221 A1 WO2024229221 A1 WO 2024229221A1 US 2024027412 W US2024027412 W US 2024027412W WO 2024229221 A1 WO2024229221 A1 WO 2024229221A1
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fluorine
optionally substituted
alkyl group
compound
group optionally
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Inventor
Michael John Green
Ravikumar MUTTINENI
Sumana GHOSH
Naveen NAGANABOINA
Barry Hart
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Capulus Therapeutics LLC
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Capulus Therapeutics LLC
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Embodiments of the present invention generally relate to androgen receptor modulators, and more particularly to N-terminal domain androgen receptor inhibitors.
  • Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation.
  • the androgen receptor (AR) is encoded by the NR3C4 gene and is within the nuclear receptor family. The binding of AR to its endogenous ligand 5 a- dihydrotestosterone (DHT) and testosterone is responsible for starting male sexual development and differentiation. Testosterone is synthesized by the Leydig cells in the testes and circulates mostly bound to the serum sex hormone -binding globulin (SHBG) and albumin.
  • SHBG serum sex hormone -binding globulin
  • the free form enters prostate cells, where testosterone is converted to the more potent form of DHT, which promotes growth and survival of prostate cells.
  • High affinity binding of DHT to AR displaces other AR-bound proteins and drives the AR complex to the nucleus where it dimerizes and binds to androgen response elements (AREs) in the promoter region of target genes.
  • the full-length AR protein has three major domains, the N-terminal domain (NTD), the DNA-binding domain (DBD), and the ligand-binding domain (LBD). All three are required for the proper regulation and function of AR.
  • the AR can be activated in the absence of testicular androgens by alternative signal transduction pathways in castration-resistant disease, which is consistent with the finding that nuclear AR protein is present in secondary prostate cancer tumors.
  • Prostate cancer is one of the most common male malignancies and is the second leading cause of cancer deaths among males in the United States.
  • the current standard of care is androgen deprivation therapy, which is initially effective for the treatment of metastatic prostate cancer, but most patients develop castration-resistant prostate cancer (CRPC) that can further develop into metastatic CRPC (mCRPC).
  • CRPC castration-resistant prostate cancer
  • mCRPC metastatic CRPC
  • AR targeting agents available for treatment primarily target the LBD of AR.
  • point mutations, gene rearrangements resulting in overexpression of AR, development of constitutively active AR structural variants, and several other mechanisms may render AR-LBD targeting inhibitors ineffective.
  • Multiple mechanisms may lead to resistance in prostate cancer cells, one of them being increased production of short AR splice variants.
  • the most prominent variants in prostate and breast cancer are ARV7 and ARV567es.
  • AR-V7 AR splice variant-7
  • CRPC castration-resistant prostate cancer
  • AR-V7 is expressed in over 80% of CRPC patient samples in Stand Up to Cancer (SU2C) prostate cancer cohort.
  • AR-V7 can dimerize without the presence of the receptor-ligand and drive AR response genes transcription in the nucleus, this provides them with the ability to drive prostate cancer even in the absence of LBD.
  • ARV7 displays noncanonical nuclear import kinetics and short chromatin residence time as compared to ARFL. Further, in-vitro and in-vivo studies have shown that AR-V7 can drive prostate cancer and its inhibition leads to tumor growth control and induces tumor regression.
  • the AR pathway has also been implicated in breast cancer and may be a suitable target for triple-negative breast cancer (TNBC) where AR plays a role in the proliferation of breast cancer cells by either promoting proliferation or inhibiting proliferation depending on the expression of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), as well as ovarian cancers.
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • HER2 human epidermal growth factor receptor 2
  • up to 90% of breast cancer have AR expression and AR-V7 has been detected in primary breast cancer samples and cell lines.
  • n is an integer from 0 to 5; “p” is an integer from 0 to 4;
  • A is a C3-C9 cycloalkyl group, a C 3 -C 12 heterocycloalkyl group, a C6-C12 aryl group, or a C3-C12 heteroaryl group;
  • X 1 , X 3 , X 4 and X 5 are independently at each occurrence nitrogen, NH, CH or CH2;
  • X 2 is independently at each occurrence carbon or nitrogen; wherein in formula (I) at least one of X 1 , X 2 , X 3 , X 4 and X 5 is carbon, CH or CH2 and at least two of X 1 , X 2 , X 3 , X 4 and X 5 are nitrogen or NH, and in formula (II) at least two of X 1 , X 2 , X 3 , X 4 and X 5 are nitrogen or NH;
  • Y is O, S, or NR 6 ;
  • R 1 is a C 1 -C 6 alkyl group optionally substituted with one or more fluorine or deuterium or a C 3 -C 7 cycloalkyl group optionally substituted with one or more fluorine or deuterium;
  • R 2 is a C 1 -C 6 alkyl group optionally substituted with one or more fluorine, a C 3 -C 7 cycloalkyl group optionally substituted with one or more fluorine, — OR 7 , or SF5;
  • R 5 is a C 1 -C 12 heterocycloalkyl group or a C 1 -C 12 heteroaryl group optionally substituted with one or more R 9 ;
  • R 6 is hydrogen, a C 1 -C 6 alkyl group, or a C 3 -C 7 cycloalkyl group
  • R 7 and R 8 are independently at each occurrence hydrogen, a C 1 -C 6 alkyl group optionally substituted with one or more fluorine or an aminoalkyl group, a Ce-Cio aryl group optionally substituted with one or more fluorine, or R 7 and R 8 together with the carbon or nitrogen to which each is attached form a C 3 -C 7 cycloalkyl group optionally substituted with one or more fluorine or a C3-C15 heterocycloalkyl group optionally substituted with one or more fluorine; and
  • a pharmaceutical composition in some aspects of the present invention, includes a compound having a formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or co-crystal thereof, and a pharmaceutically carrier, diluent, or excipient.
  • a method for modulation of androgen receptor activity for treatment of prostate cancer, breast cancer, ovarian cancer, or melanoma includes administering to a patient a therapeutically effective amount of a pharmaceutical composition including a compound of formula (I).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • a particular enantiomer may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.”
  • “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments, the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high-pressure liquid chromatography
  • alkyl group refers to a saturated monovalent group consisting of a linear or branched array of atoms that is not cyclic. Alkyl groups are defined to include at least one carbon atom and are represented by formula C n H 2n +1. The array of atoms included in the alkyl group may be composed exclusively of carbon and hydrogen.
  • C 1 -C 10 alkyl group contains at least one but no more than 10 carbon atoms.
  • a methyl group i.e. CH3 —
  • a decyl group (i.e., CH 3 (CH 2 )9 — ) is an example of a monovalent C 10 alkyl group.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • cycloalkyl group refers to a group having a valence of at least three, and consisting of a saturated or a partially unsaturated array of atoms which is cyclic but which is not aromatic.
  • a “cycloalkyl” may include one or more noncyclic components.
  • a cyclohexylmethyl group (C 6 H 11 CH 2 ) is a cycloalkyl group which includes a cyclohexyl ring (the array of atoms which is cyclic but which is not aromatic) and a methylene group (the noncyclic component).
  • a cycloalkyl group may be monocyclic or may include one or more ring systems.
  • a C 3 -C 10 cycloalkyl group includes cycloalkyl groups containing at least three but no more than 10 carbon atoms.
  • the cycloalkyl group 2 -tetrahydrofuranyl (C 4 H 7 O — ) represents a C 4 cycloalkyl group.
  • the cyclohexylmethyl group (C 6 H 1 1 CH 2 — ) represents a C7 cycloalkyl group.
  • aryl group refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Aryl group encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryl group also encompasses multiple ring systems having at least one carbocyclic aromatic ring fused to at least one carbocyclic aromatic ring, cycloalkyl ring, or heterocycloalkyl ring.
  • aryl group includes 5- and 6- membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing one or more heteroatoms chosen from N, O, and S.
  • bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring.
  • aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.
  • an aryl group include, but are
  • heteroaryl group refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Heteroaryl group encompasses multiple ring systems having at least one aromatic ring fused to at least one other ring, which can be aromatic or non-aromatic in which at least one ring atom is a heteroatom.
  • Heteroaryl group encompasses 5- to 12-membered aromatic, monocyclic rings (such as 5- to 7-membered rings) containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon; and bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3 , heteroatoms chosen fromN, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the cycloalkyl ring.
  • the heteroatoms when the total number of N, S, and O atoms in the heteroaryl group exceeds one, the heteroatoms are not adjacent to one another. In certain embodiments, the total number of N, S, and O atoms in the heteroaryl group is not more than two.
  • the total number of N, S, and O atoms in the aromatic heterocycle is not more than one.
  • the term “C5-C10 heteroaryl group” contains at least 5 but no more than 10 carbon atoms.
  • the heteroaryl group benzoimidazolyl (C7H5N2 — ) represents a C7 heteroaryl group.
  • the pyridyl group (C5H4N — ) represents a C5 heteroaryl group.
  • heterocycloalkyl group refers to non-aromatic group having a valence of one which consists of at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocycloalkyl group can be partially or fully saturated.
  • C4-C7 heterocycloalkyl group contains at least 4 but no more than 7 carbon atoms.
  • the heterocycloalkyl group dioxyl (C4H7O2 — ) represents a C4 heterocycloalkyl group.
  • the piperidyl group (C5H9N — ) represents a C5 heterocycloalkyl group.
  • heteroaryl and heterocycloalkyl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, beta-carboline, chromane, chromene, cinnoline, furan, furazan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,
  • the term “therapeutically effective amount” refers to an amount (of a compound) that is sufficient to provide a therapeutic benefit to a patient in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • salts refers to any salt suitable for administration to a patient.
  • salts include, but are not limited to, acid-derived, base-derived, organic, inorganic, amine, and alkali or alkaline earth metal salts, including but not limited to calcium salts, magnesium salts, potassium salts, sodium salts, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • dotted line “ - ” is a single bond or a double bond
  • n is an integer from 0 to 5; “p” is an integer from 0 to 4;
  • A is a C3-C9 cycloalkyl group, a C3-C12 heterocycloalkyl group, a C6-C12 aryl group, or a C3-C12 heteroaryl group;
  • X 1 , X 3 , X 4 and X 5 are independently at each occurrence nitrogen, NH, CH or CH2;
  • X 2 is independently at each occurrence carbon or nitrogen; wherein in formula (I) at least one of X 1 , X 2 , X 3 , X 4 and X 5 is carbon, CH or CH2 and at least two of X 1 , X 2 , X 3 , X 4 and X 5 are nitrogen or NH, and in formula (II) at least two of X 1 , X 2 , X 3 , X 4 and X 5 are nitrogen or NH;
  • Y is O, S, or NR 6 ;
  • R 1 is a C 1 -C 6 alkyl group optionally substituted with one or more fluorine or deuterium or a C 3 -C 7 cycloalkyl group optionally substituted with one or more fluorine or deuterium;
  • R 2 is a C 1 -C 6 alkyl group optionally substituted with one or more fluorine, a C 3 -C 7 cycloalkyl group optionally substituted with one or more fluorine, — OR 7 , or SF5;
  • R 5 is a C 1 -C 12 heterocycloalkyl group or a C 1 -C 12 heteroaryl group optionally substituted with one or more R 9 ;
  • R 6 is hydrogen, a C 1 -C 6 alkyl group, or a C 3 -C 7 cycloalkyl group;
  • R 7 and R 8 are independently at each occurrence hydrogen, a C 1 -C 6 alkyl group optionally substituted with one or more fluorine or an aminoalkyl group, a Ce-Cio aryl group optionally substituted with one or more fluorine, or R 7 and R 8 together with the carbon or nitrogen to which each is attached form a C 3 -C 7 cycloalkyl group optionally substituted with one or more fluorine or a C3-C15 heterocycloalkyl group optionally substituted with one or more fluorine; and
  • the compound has formula (I) and is selected from the group consisting of:
  • the compound has formula (III) to (XX), wherein Y is O, S, or NR 6 , R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 2 is a C1-C3 alkyl group substituted with one or more fluorine, and R 6 is hydrogen, a Ci- Ce alkyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound has formula (III) to (XX), wherein Y is O, S, or NR 6 , R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 2 is a C1-C3 alkyl group substituted with one or more fluorine, R 3 is independently at each occurrence halogen, — CN, — OR 7 , or a C1-C3 alkyl group substituted with one or more fluorine, and R 6 is hydrogen, a C 1 -C 6 alkyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound has formula (III) to (XX), wherein Y is O, S, or NR 6 , R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 2 is a C1-C3 alkyl group substituted with one or more fluorine, R 3 is independently at each occurrence a C1-C3 alkyl group substituted with one or more fluorine, and R 6 is hydrogen, a C 1 -C 6 alkyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound has formula (III) to (XX), wherein Y is NR 6 , R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 2 is a C1-C3 alkyl group substituted with one or more fluorine, R 3 is independently at each occurrence a C1-C3 alkyl group substituted with one or more fluorine, and R 6 is a C1-C3 alkyl group.
  • Non-limiting examples of compounds having a formula (I) include:
  • the compound has a formula (XXI) or any pharmaceutically acceptable salt thereof:
  • n is an integer from 1 to 5, and at least one R 3 is a C 1 -C 12 heterocycloalkyl group optionally substituted with one or more R 9 or a C 1 -C 12 heteroaryl group optionally substituted with one or more R 9 .
  • the compound has a formula (XXI) and is selected from the group consisting of:
  • the compound has formula (XXII) to (XXIV), and R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 2 is a C1-C3 alkyl group substituted with one or more fluorine, and R 6 is hydrogen.
  • Non-limiting examples of compounds having a formula (XXI) include:
  • the compound has formula (II) and is selected from the group consisting of: S3
  • the compound has formula (XXV) to (XXXIX), and R 5 is selected from the group consisting of:
  • R 9 is halogen or a C1-C3 alkyl group optionally substituted with one or more fluorine.
  • the compound has formula (XXV) to (XXXIX), Y is O, S, or NR 6 , R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 4 is independently at each occurrence halogen, and R 6 is hydrogen, a C 1 -C 6 alkyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound has formula (XXV) to (XXXIX), Y is NR 6 , R 1 is a C1-C3 alkyl group optionally substituted with one or more fluorine, R 4 is independently at each occurrence halogen, and R 6 is a C1-C3 alkyl group.
  • Non-limiting examples of compounds having a formula (II) include:
  • the compound of the present invention is an optically enriched R-isomer. In some embodiments, the compound of the present invention is an optically enriched S -isomer. In some embodiments, the compound of the present invention is a mixture of R and S-isomers.
  • compounds of the present invention may be capable of targeting NTD of AR.
  • targeting NTD of AR may facilitate inhibition of AR function and also mitigate the current drug resistance mechanisms that may develop post androgendeprivation or LBD inhibitor treatment. Further, targeting NTD may mitigate variant and LBD point mutation driven resistance thereby providing effective treatment against all stages of AR driven prostate cancer.
  • the compounds of the present description may be capable of targeting NTD of ARV7.
  • ARV7 may include NTD, DBD and a cryptic exon.
  • NTD of ARV7 may include Taul, Tau5 and a FXXLF motif.
  • the compounds of the present description may be capable of targeting FXXLF motif of ARV7.
  • a pharmaceutical composition includes a compound as described herein above or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or co-crystal thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutical composition includes a compound having a formula (I) to (XXXIX).
  • the pharmaceutical composition may further one or more other additional anticancer therapeutic agents in some embodiments.
  • compositions of the present invention may be in any form that allows for the composition to be administered to a subject.
  • the composition may be in the form of a solid, liquid, or gas (aerosol).
  • Pharmaceutical compositions may be formulated to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a subject.
  • the compounds may be administered in conjunction with a suitable delivery vehicle (e.g., microcapsules, microspheres, biodegradable polymer films, lipid-based delivery systems such as liposomes and lipid foams, viscous instillates and absorbable mechanical barriers) useful for maintaining the necessary concentrations of the prodrugs or the therapeutic agent at the site of the disease.
  • a suitable delivery vehicle e.g., microcapsules, microspheres, biodegradable polymer films, lipid-based delivery systems such as liposomes and lipid foams, viscous instillates and absorbable mechanical barriers
  • a process for preparing a pharmaceutical composition includes mixing a compound as described herein above or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or co-crystal thereof with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the process includes mixing a compound having a formula (I) to (XXXIX) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or co-crystal thereof with a pharmaceutically acceptable carrier, diluent, or excipient.
  • methods of treating or reducing symptoms of a certain disease by administering a compound of the present invention are also presented.
  • the compounds or derivatives thereof can be administered to any host, including a human, a non-human animal, and mammals, in an amount effective to treat a disorder.
  • methods of treating or reducing symptoms of a certain disease by administering a compound having a formula (I) to (XXXIX) is presented.
  • the compounds of the present description may be used as single agents or in combination with other additional anticancer therapeutic agents for treating metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, non-metastatic castration-sensitive prostate cancer, localized prostate cancer or metastatic/non-metastatic castration-resistant prostate cancer that exhibits intrinsic or acquired resistance to enzalutamide, abiraterone acetate or any other androgen signaling axis/receptor inhibitors.
  • the compounds of the present description may be used as single agents or in combination with other additional anticancer therapeutic agents for treating AR-positive HER2 positive metastatic, advanced breast cancer, AR-positive advanced TNBC, ER-negative HER2 positive (ER-HER2+) breast cancer, or ER-positive HER2 negative (ER+HER2-) breast cancer that exhibit poor therapeutic efficacy against known ER antagonists.
  • the compounds of the present description may be used as single agents or in combination with other additional anticancer therapeutic agents for treating ovarian cancer. In some embodiments, the compounds of the present description may be used as single agents or in combination with other additional anticancer therapeutic agents for treating BRAF/MEK targeted therapy resistant melanoma.
  • the compounds of the present description may be used as single agents or in combination with other additional AR antagonists or AR LBD inhibitors.
  • additional AR antagonists or AR LBD inhibitors include bicalutamide, enzalutamide, flutamide, nilutamide, apalutamide, darolutmide, proxalutamide, or combinations thereof.
  • the compounds of the present invention may be used in combination with docetaxel, olaparib, talazoparib (PARP inhibitors), selumetinib, capivasertib (AKT inhibitors), ribociclib (CDK inhibitor), BET inhibitors, or combinations thereof.
  • the compounds of the present description may be used as single agents or in combination with other antibody -radioligand conjugate, immune check point therapy like pembrolizumab, cell therapy like prostate targeting CART-T cell, prostate targeting bi-specific antibodies and combinations thereof.
  • a method of treating prostate cancer, breast cancer ovarian cancer, or melanoma is presented.
  • a method of treating prostate cancer is presented.
  • prostate cancer include metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, non- metastatic castration-resistant prostate cancer, non-metastatic castration-sensitive prostate cancer, localized prostate cancer or metastatic/non-metastatic castration resistant prostate cancer that exhibits intrinsic or acquired resistance to enzalutamide, abiraterone acetate or any other androgen signalling axis/receptor inhibitors.
  • Non-limiting examples of breast cancer include AR positive HER2 positive metastatic, advanced breast cancer, AR positive advanced TNBC, ER negative HER2 positive (ER-HER2+) breast cancer, and ER positive HER2 negative (ER+HER2-) breast cancer that exhibit poor therapeutic efficacy against known ER antagonists.
  • Non-limiting example of melanoma includes BRAF/MEK targeted therapy resistant melanoma.
  • the method includes administering to a patient an effective amount of a pharmaceutical composition including a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or co-crystal thereof.
  • the pharmaceutical composition may further one or more other additional anticancer therapeutic agents in some embodiments.
  • the pharmaceutical composition may be administered by any suitable method known to a person skilled in the art.
  • Typical routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal.
  • parenteral as used herein includes intravenous, intraperitoneal, intramuscular, intradermal, and epidermal including subcutaneous and intradermal, oral, or application to mucosal surfaces, e.g, by intranasal administration using inhalation of aerosol suspensions, and by implanting to muscle or other tissue in the subject.
  • Example 1 Synthesis of (S)-N-(l-(4-fhiorophenyl)ethyl)-7-
  • Step 1 Synthesis of 2,2, 2-trifluoro-N-((6-oxo- 1,4,5, 6-tetrahydropyridazin- 3-yl)methyl)acetamide
  • Step 2 Synthesis of 2,2,2-trifhioro-N-((6-oxo-l,6-dihydropyridazin-3- yl)methyl)acetamide
  • Step 3 Synthesis of 2-chloro-7-(trifluoromethyl)imidazo[l,5-b]pyridazine
  • Step 4 Synthesis of(S)-N-(l-(4-fhiorophenyl)ethyl)-7-
  • step 3 A mixture of the product of step 3 (150mg, 0.67mM) in DMA (5 mL), potassium carbonate (280 mg, 0.67 mmol) and (S)- 1 -(4-fluorophenyl)ethan- 1 -amine (94.2 mg, 0.67 mmol) was heated at 80°C for 16 h. The reaction mixture was diluted with ice water and the product was extracted into ethyl acetate.
  • Step 1 To the solution of l-(pyridin-4-yl)ethanone (2.0 g, 0.016 mol) and (R )-2-methylpropane-2-sulfinamide (3.9 g, 0.033 mol) in anhydrous THF (20 ml) at 0 °C, was added Ti(O i Pr)4 (10.4 ml, 0.033). The reaction was heated at 60 °C for 24 h. The reaction mixture was poured into crushed ice and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 2 To the solution of (R)-2-methyl-N-(l-(pyridin-4- yl)ethylidene)propane-2-sulfinamide (1.4 g, 0.0625 mol) was added DIBAL-H (12.5 ml, 0.0125 mol) at -78 °C and stirred for 6 h. The reaction mixture was quenched with ammonium chloride, poured over crushed ice and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated.
  • Step 3 To the solution of (R)-2-methyl-N-((R)-l-(pyridin-4- yl)ethyl)propane-2-sulfinamide (0.6 g, 0.0013 mol) in DCM (20 ml) was added 4M HC1 in dioxane (10 ml) at 0 °C and stirred at RT for overnight. The reaction mixture was concentrated and co-precipitated with MeOH:Ether as co-solvent to provide (R )- 1 - (pyridin-4-yl)ethanamine hydrochloride as a white solid (0.5 g, 93%).
  • Step 4 To the solution of (R)-1-(pyridin-4-yl)ethanamine hydrochloride (0.200 g, 0.90 mol) in DMF (10 ml) was added DIPEA (0.313 ml, 0.90 mol) followed by 6-chloro-3-(trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazine (0.100 g, 0.81 mol). The reaction was sealed and heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 1 To the solution of l-(pyri din-3 -yl)ethanone (3.0 g, 0.024 mol) and (R)-2-methylpropane-2-sulfinamide (6.0 g, 0.048 mol) in anhydrous THF (60 ml) at 0 °C, was added Ti(O‘Pr)4 (10.2 ml, 0.036 mol). The reaction was heated at 60 °C for 24 h. The reaction mixture was poured into crushed ice and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated.
  • Step 2 To the solution of (E)-2-methyl-N-( l-(pyri din-3 - yl)ethylidene)propane-2-sulfinamide (0.9 g, 0.004 mol) was added DIBAL-H (8 ml , 0.008 mol) at - 78 °C and stirred for 6 h. The reaction mixture was quenched with ammonium chloride and poured over crushed ice followed by extraction with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 3 To the solution of (R)-2-methyl-N-((R)-l-(pyri din-3 - yl)ethyl)propane-2-sulfinamide (0.9 g, 0.002 mol) in DCM (5 ml) was added 4M HC1 in dioxane (15 ml) at 0 °C and stirred at RT for 16 h. The reaction mixture was concentrated and co-precipitated with MeOH: ether as co-solvent to provide (R)-l-(pyridin-3- yl)ethanamine hydrochloride as a white solid (0.51 g, 99.4%).
  • Step 4 To the solution of (R)-l-(pyri din-3 -yl)ethanamine hydrochloride (0.5 g, 0.0032 mol) in DMF (10 ml) in a reaction vessel was added DIPEA (1.67 ml, 0.0096 mol) followed by 6-chloro-3-(trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazine (0.780 g, 0.0035 mol). The reaction mixture was then placed in a seal tube and heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 1 - S-(l-(4-fluorophenyl)ethyl) ethanethioate: To a stirred solution of 1 -(4-fluorophenyl)ethan- 1 -ol (1g, 7.13mmol) and thioacetic acid (1.08g, 14.3mmol) in THF (3 mL) was added triphenylphosphine (3.74g, 14.3mmol) and diisopropyl azodicarboxylate (2.88g, 2.85mmol) at 0°C under argon.
  • Step 2 - (R,S)-6-((l-(4-fhiorophenyl)ethyl)thio)-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine:
  • the product of step 1 (0.2g, 0.5mmol) was added to a stirred solution of LiAlH4 (0.14g, Immol) in THF at 0 °C.
  • the reaction was allowed to warm up to RT and stirring was continued for a further 2h when 6-chloro-3- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazine (0.14g, 0.64mmol) was added.
  • Step 1 To the solution of 1 -(4-phenoxyphenyl)ethanone (2.0 g, 0.009 mol) and (R)-2-methylpropane-2-sulfinamide (1.36 g, 0.0113 mol) in anhydrous THF (80 ml) at 0 °C was added Ti(O‘Pr)4 (4.1 ml, 0.0141 mol). The reaction was heated at 60 °C for 48 h. The reaction mixture was poured over crushed ice and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 2 To the solution of ((R)-2-methyl-N-(l-(4- phenoxyphenyl)ethylidene)propane-2-sulfinamide (0.9g, 0.004 mol) in THF (10 ml) was added DIBAL-H (8 ml, 0.008 mol) at -78 °C and stirred for 6 h. The reaction mixture was quenched with ammonium chloride, poured over crushed ice and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 3 To the solution of (R)-2-methyl-N-((R)-l-(4- phenoxyphenyl)ethyl)propane-2-sulfinamide (0.9 g, 0.002 mol) in DCM (20 ml) was added 4M HC1 in dioxane (15 ml) at 0 °C and stirred at RT for overnight. The reaction mixture was concentrated and co-precipitated with MeOH:ether as co-solvent to provide (R)-l-(4-phenoxyphenyl)ethanamine hydrochloride as a white solid (0.630 g, 54%).
  • Step 4 To the solution of (R )-1 -(4-phenoxyphenyl)ethanamine hydrochloride (0.600 g, 0.0024 mol) in DMF (10 ml) was added DIPEA (0.936 ml, 0.007 mol) followed by addition of 6-chloro-3-(trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazine (0.590 g, 0.003 mol). The reaction was heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated.
  • Example 8 Synthesis of (R)-N-(l-(4-fhiorophenyl)ethyl)-3- (trifluoromethyl)-7,8-dihydro-[l ,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 8)
  • Step 1 To the solution of (6-chloro-3-trifluoromethyl-[l,2,4]triazolo[4,3- b]pyridazine) (11.00 g, 0.049 mol) in DMF (220 ml) was added DIPEA (19 ml, 0.1486 mol) followed (R)-l-(4-fhiorophenyl)ethanamine (7.23 g, 0.052 mol). The reaction mixture was placed in a seal tube and heated at 90 °C for 16 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated.
  • Step 2 To the solution of (R)-N-(l-(4-fhiorophenyl)ethyl)-3- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-amine (0.250 g, 0.76 mol) in MeOH (5 ml) in a reaction vial was added Pd/C (0.25 g) and reaction was stirred in hydrogen atmosphere for 16 h. Reaction mixture was filtered through celite to get the crude compound.
  • Step 1 N-(l-(3-bromophenyl)ethyl)-3-(trifluoromethyl)-
  • reaction mixture was evaporated to dryness and, after an aqueous/ethyl acetate extraction work up, the crude product was purified by column chromatography to give N-(l-(3- bromophenyl)ethyl)-3-(trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-amine an off- white solid (0.35g, 67%).
  • Step 2 N-(l-(3-(pyrrolidin-l-yl)phenyl)ethyl)-3-(trifluoromethyl)- [ 1 ,2,4]triazolo[4,3 -b]pyridazin-6-amine
  • reaction mass was diluted with water (7 mL) and after an aqueous/ethyl acetate extraction work up, the crude product was purified by column chromatography (Davisil ) using 5% methanol in DCM to give N-(l-(3-(pyrrolidin-l-yl)phenyl)ethyl)-3- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-amine (50mg, 47%).
  • Example 10 Synthesis of N-(l-(4-(lH-benzo[d]imidazol-l- yl)phenyl)ethyl)-3-(trifluoromethyl)-[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-amine ⁇ Compound 10)
  • Example 12 Synthesis of N-(l-(3-fhioro-4-(2-methyl-lH-imidazol-l- yl)phenyl)ethyl)-lH-imidazo[4,5-b]pyridin-5-amine (Compound 12) [0118] Step 1: N2-(l-(3-fluoro-4-(2-methyl-lH-imidazol-l-yl)phenyl)ethyl)-5- nitropyridine-2,6-diamine
  • Step 2 N6-(l-(3-fhioro-4-(2-methyl-lH-imidazol-l- yl)phenyl)ethyl)pyridine-2,3,6-triamine
  • Step 3 N-(l-(3-fhioro-4-(2-methyl-lH-imidazol-l-yl)phenyl)ethyl)-lH- imidazo[4,5-b]pyridin-5-amine
  • Triethyl orthoformate (132 mL) was added to a stirred solution of the product of Step 2 (6.53g, 26.3mmol) in formic acid (28mL) at 0°C. Reaction mixture was heated to 80°C for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure and the crude product was purified by flash column chromatography (Davisil), eluted with 8% methanol in DCM to give N-(l-(3-fhioro-4-(2-methyl-lH-imidazol-l- yl)phenyl)ethyl)-lH-imidazo[4,5-b]pyridin-5-amine as white solid (0.042g).
  • Step 1 6-bromo-l -(triisopropylsilyl)- lH-pyrrolo[2,3-b]pyridine
  • Step 2 N-(l-(3-fhioro-4-(2-methyl-lH-imidazol-l-yl)phenyl)ethyl)-l-
  • Step 3 N-(l-(3-fluoro-4-(2-methyl-lH-imidazol-l-yl)phenyl)ethyl)-lH- pyrrolo[2,3-b]pyridin-6-amine
  • Step- 1 1 -(3 -fluoro-4-(2 -methyl- 1 H-imidazol- 1 -yl)phenyl)ethan- 1 -one
  • Step-2 N-((R)- 1 -(3-fluoro-4-(2 -methyl- 1 H-imidazol- 1 -yl)phenyl)ethyl)-2- methylpropane-2-sulfinamide [0138] To the solution of l-(3-fluoro-4-(2 -methyl- IH-imidazol-l -yl)phenyl)ethan-
  • Step-3 (R)- 1 -(3 -fluoro-4-(2 -methyl- 1 H-imidazol- 1 -yl)phenyl)ethan- 1 - amine hydrochloride
  • Step-4 (R)-N-( 1 -(3 -fluoro-4-(2 -methyl- 1 H-imidazol- 1- yl)phenyl)ethyl)tetrazolo[l,5-b]pyridazin-6-amine
  • Example 15 Synthesis of (S)-N-(l-(3-fhioro-4-(2-methyl-lH-imidazol-l- yl)phenyl)ethyl)tetrazolo[l,5-b]pyridazin-6-amine( Compound 15)
  • Compound 15 was prepared in a similar fashion as Example 14 to provide (S)-N-(l -(3-fluoro-4-(2 -methyl- 1 H-imidazol- 1 -yl)phenyl)ethyl)tetrazolo[ 1 ,5-b]pyridazin- 6-amine (0.1g, 32% yield).
  • Step 1 2-(Trifluoromethyl)-lH-imidazole (1.0 g, 0.0073 mol) in DMSO (20 mL) was taken in a sealed tube followed by 1 -(3,4-difluorophenyl)ethanone (1.26 g, 0.0080 mol) and K2CO3 (2.01 g, 0.0146 mol) was added. The reaction mixture was heated at 80°C for 16 h. The reaction mass was dissolved in EtOAc and washed with brine solution. The organic layer was separated, and the aqueous layer was extracted two times with EtOAc.
  • Step 2 To the solution of l-(3-fhioro-4-(2-(trifluoromethyl)-lH-imidazol- 1 -yl)phenyl)ethanone (1.3 g, 0.0047 mol) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 0.0086 mol) in anhydrous THF (30 ml) at 0 °C was added Ti(O‘Pr)4 (5.9 ml, 0.0188). The reaction mixture was heated at 60 °C for 16 h. The reaction was cooled to -78 °C and NaBH4 (0.715 g, 0.0188 mol) was added and allowed to stir for overnight at room temp.
  • Step 3 To the solution of (R)-N-((R)-l-(3-fhioro-4-(2-(trifhioromethyl)- lH-imidazol-l-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8 g, 0.0021 mol) in DCM (20 ml) was added 4M HC1 in dioxane (5 ml) at 0 °C and stirred at RT for 16 h.
  • reaction mixture was concentrated and co-precipitated with a mixture of solvents MeOH and ether to provide (R)-1-(3-fluoro-4-(2-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)ethanamine hydrochloride as a white solid (0.670 g, 99%). .
  • Step 4 To the solution of (R)-1-(3-fhioro-4-(2-(trifluoromethyl)-lH- imidazol-l-yl)phenyl)ethanamine hydrochloride (0.670 g, 0.0025 mol) in DMF (10 ml) was added DIPEA (1.3 ml, 0.0073 mol) followed by 6-chlorotetrazolo[l,5-b]pyridazine (0.418 g, 0.00269 mol). The reaction was heated in a seal tube at 90 °C for 16 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated.
  • the aim of this study was to evaluate compounds of the present invention for antagonist activities against human AR.
  • Reporter Cells used in these assays expressed a native receptor (AR).
  • the reporter gene firefly luciferase, is functionally linked to an upstream receptor-specific genetic response element (GRE).
  • GRE upstream receptor-specific genetic response element
  • Step 1 A suspension of reporter cells was prepared in Cell Recovery Medium (CRM). Reporter cells were first supplemented with 2x-EC80 concentration of the reference agonist, 5oc-dihydro-l 1-keto testosterone, then 100 ul of the Reporter Cell suspension was dispensed into wells of a white 96-well assay plate
  • Step 2 Test compound master stocks were diluted in DMSO to generate solutions at '500x-concentration' relative to the final treatment concentration and diluted directly into ENDlGO’s Compound Screening Medium (CSM; containing charcoalstripped FBS) to generate ‘2x-concentration’ treatment media. This was diluted into the wells to the final concentration. Assay plates were incubated at 37°C, 5% CO2 and -70% humidity for 24 hr.
  • CSM Compound Screening Medium
  • Step 3 Following the incubation period, wells were rinsed once with Live Cell Multiplex (LCM) Buffer, then LCM substrate was added. Following incubation at room temperature for 15 min, LCM substrate was discarded and 100 pL/wcll of luciferase detection reagent was added. Subsequently, fluorescence was measured to determine the relative number of live cells per assay well. RLU values were quantified after a 10 min incubation period at room temperature to determine nuclear receptor activities
  • Preincubation mixture 2.5 pL Test Cpd. + 75 pL Liver microsomes (human or mouse source) @ 3.33 mg/mL + 85 pL of 100 mM potassium phosphate buffer (preincubate for 10 min @ 37°C). Incubation mixture 62 pL of cofactor (2.85 mM) + Remaining incubation mixture (Incubated for 60 min @ 37 °C). Sample preparation 25 pL incubation mixture + 200 pL of acetonitrile containing internal standard + Vortex 5 min @ 1200 rpm + Centrifuge 10 min @ 4000 rpm. Supernatant diluted 2-fold with water and injected on LC-MS/MS.
  • Table 1 shows the AR antagonist indigo cell based average IC50 (nM) values for example compounds of the present invention.
  • T able 2 shows the in vitro microsome stability data for example compounds of the present description

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Abstract

L'invention concerne des modulateurs du récepteur des androgènes, et plus particulièrement des inhibiteurs du récepteur des androgènes à domaine N-terminal. L'invention concerne également des compositions pharmaceutiques et des méthodes associées.
PCT/US2024/027412 2023-05-03 2024-05-02 Modulateurs du récepteur des androgènes et leurs méthodes d'utilisation Ceased WO2024229221A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100022550A1 (en) * 2005-06-24 2010-01-28 Cellectis Tetrahydrocarbazole derivatives useful as androgen receptor modulators
US20200325123A1 (en) * 2017-11-06 2020-10-15 Oncostellae, S.L. New analogs as androgen receptor and glucocorticoid receptor modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100022550A1 (en) * 2005-06-24 2010-01-28 Cellectis Tetrahydrocarbazole derivatives useful as androgen receptor modulators
US20200325123A1 (en) * 2017-11-06 2020-10-15 Oncostellae, S.L. New analogs as androgen receptor and glucocorticoid receptor modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 2 August 2011 (2011-08-02), "CCG-137461 (Substance)", XP093233870, Database accession no. 124688335 *
DATABASE PubChem 25 April 2023 (2023-04-25), "Z219191338 (Substance)", XP093233868, Database accession no. 335426188 *

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