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WO2025090847A1 - Agents de dégradation du récepteur des oestrogènes et leur utilisation dans le traitement du cancer - Google Patents

Agents de dégradation du récepteur des oestrogènes et leur utilisation dans le traitement du cancer Download PDF

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WO2025090847A1
WO2025090847A1 PCT/US2024/052928 US2024052928W WO2025090847A1 WO 2025090847 A1 WO2025090847 A1 WO 2025090847A1 US 2024052928 W US2024052928 W US 2024052928W WO 2025090847 A1 WO2025090847 A1 WO 2025090847A1
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compound
alkyl
pharmaceutically acceptable
halo
acceptable salt
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Dinesh U. Chimmanamada
Vivek K. VISHNUDAS
Ramesh Subbiah
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BPGbio Inc
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BPGbio Inc
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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the estrogen receptor is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor involved with the up and down regulation of gene expression.
  • the natural hormone for the estrogen receptor is 17-beta-estradiol (E2) and closely related metabolites. Binding of estradiol to the estrogen receptor causes a dimerization of the receptor and the dimer in turn binds to estrogen response elements (ERE's) on DNA.
  • ERE estrogen response elements
  • the ER-DNA complex recruits other transcription factors responsible for the transcription of DNA downstream from the ERE into mRNA, which is eventually translated into protein.
  • the interaction of ER with DNA may be indirect through the intermediacy of other transcription factors, most notably fos and jun.
  • ERs are widely expressed in different tissue types, but there are some notable differences in their expression patterns.
  • the ERa is found in endometrium, breast cancer cells, ovarian stroma cells, and the hypothalamus.
  • ERa protein is found in the epithelium of the efferent ducts.
  • the expression of the ERP protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells. Development therefore of selective ligands may therefore preserve the beneficial aspects of estrogen.
  • FIG. 4 shows dose dependent degradation of ERa in T47D cells upon treatment with Example 20.
  • an effective amount refers to an amount of a compound described herein that will elicit a biological or medical response of a subject e.g., a dosage of between 0.01 - 100 mg/kg body weight/day.
  • subject and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • companion animals e.g., dogs, cats, and the like
  • farm animals e.g., cows, pigs, horses, sheep, goats and the like
  • laboratory animals e.g., rats, mice, guinea pigs and the like.
  • the subject is a human in need of treatment.
  • Z 1 and Z 2 are each independently N or CH;
  • R 1 is (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, or -NR c R d , wherein two available hydrogen atoms on said halo(Ci-C6)alkyl and halo(Ci-C6)alkoxy may be taken together to which the carbon atoms they are attached to form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, and halo(Ci-C6)alkoxy;
  • R 2 is CN, halo, OH, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, or halo(Ci-C6)alkoxy; or
  • R 1 and R 2 when on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered oxygen-containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, and halo(Ci-C 6 )alkyl;
  • R 3 is hydrogen, (Ci-Ce)alkyl, or halo(Ci-C6)alkyl;
  • Y is CH 2 , -CHR a , -CR a R b , S, or SO; p is 0 or 1 ;
  • R a and R b are each independently halo, (Ci-Ce)alkyl, or halo(Ci-C6)alkyl; or R a and R b together with the carbon atom they are bound form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which is optionally substituted with 1 to 3 groups selected from halo, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-Cejalkoxy, halo(Ci-C6)alkoxy, (Ci-C 6 )alkylOH, (Ci-C 6 )alkylO(Ci-C 6 )alkyl, and OH;
  • R c and R d are each independently hydrogen (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C 6 )alkylO(Ci-C 6 )alkyl, halo(Ci-C 6 )alkylO(Ci-C 6 )alkyl, (Ci-C 6 )alkyl-O-halo(Ci-C 6 )alkyl, halo(Ci-C6)alkyl-O-halo(Ci-C6)alkyl, or (Ci-CejalkylOH; or R c and R d together with the nitrogen atom they are bound form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, and oxo; ring
  • X, X 1 , and X 2 are each, as valency permits, independently selected from -CR 7 , N, O, and S;
  • R 7 is hydrogen or (Ci-Ce)alkyl; the dotted line in ring B represents a single or double bond; when the dotted line in ring B is a single bond,
  • R 5 is selected from hydrogen, (Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, -S(Ci-C6)alkyl, -SH, OH, (C3-C6)cycloalkyl, 4- to 7-membered heterocyclyl, and -NR e R f , wherein said (C3-C6)cycloalkyl and 4- to 7-membered heterocyclyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy, halo(Ci-C6)alkoxy, and oxo;
  • R e and R f are each independently hydrogen, (Ci-C4)alkyl, (Ci-C 4 )alkylNH(Ci-C 4 )alkyl, (Ci-C 4 )alkylN[(Ci-C 4 )alkyl] 2 , (Ci-C 4 )alkylO(Ci-C 4 )alkyl;
  • R 6 is hydrogen or (Ci-C6)alkyl; when the dotted line in ring B is a double bond,
  • R 5 is absent and R 6 is absent;
  • d, d 1 , d 2 and d 3 are each independently selected from CR 8 and N;
  • R 8 is halogen, hydrogen, (Ci-C6)alkyl, halo(Ci-C6)alkyl, CN, or OH;
  • W is absent, NH, -N(Ci-C6)alkyl, O, or S;
  • L is a linker
  • Tar is a target protein binding moiety which binds estrogen receptor.
  • a fourth embodiment provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 are each CH and the remaining variables are as defined in the first or third embodiment.
  • a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein Y is CH2 and the remaining variables are as defined in the first, third, or fourth embodiment.
  • a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein p is 0 and the remaining variables are as defined in the first, third, fourth, or fifth embodiment.
  • a seventh embodiment provided is a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein R 1 is (Ci-Ce)alkyl, halo(Ci-C6)alkyl, halo(Ci-C6)alkoxy, (Ci-C6)alkoxy, or -NR c R d ; and R c and R d together with the nitrogen atom they are bound form a 5- to 6-membered heterocyclyl optionally substituted with 1 to 3 halo and the remaining variables are as defined in the first, third, fourth, fifth, or sixth embodiment.
  • a compound of structural formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is N and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof wherein W is NH or -NCH3, preferably NH, and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment.
  • W is NH.
  • a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein linker L is a straight or branched alkyl group substituted with one to two oxo groups ( 0), and the remaining variables are as defined in the nineteenth, twentieth, or twenty-first embodiment.
  • A2 is absent, -C(O)-4- to 10-membered nitrogen containing heterocyclyl, or 4- to 6- membered nitrogen containing monocyclic heterocyclyl; provided when Ai, A2 and j are absent, e is not 0, and the remaining variables are as defined in the nineteenth or twentieth embodiment.
  • a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof wherein e is 1 or 2; Ai is absent; j is 0; A2 is -C(O)-4- to 6-membered nitrogen containing monocyclic heterocyclyl or -C(O)-7- to 9- membered nitrogen containing spiro heterocyclyl and the remaining variables are as defined in the twenty-fourth embodiment.
  • a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof wherein e is 1 or 2; Ai is 4- to 6- membered nitrogen containing monocyclic heterocyclyl; j is 1; A2 is
  • Li is absent, -CH2-, or O and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, or seventeenth embodiment.
  • a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof wherein L is X1-A1-X2-A2-X3, wherein XI is absent, (CEh , or (CH2) V C(O); Al is phenyl, 4- to 10-membered nitrogen containing heterocyclyl, or 5- to 6-membered heteroaryl; X2 is absent, (CtDg, C(O), or (CH2) g C(O); A2 is absent or is a 4- to 10-membered nitrogen containing heterocyclyl or 5- to 6-membered heteroaryl; X2 is absent, (CHTJI. C(O), or (CH2)fC(O
  • a thirty-first embodiment provided is a compound of structural formula (I)-(XII), or a pharmaceutically acceptable salt thereof, wherein ring N1 is piperidinyl or piperazinyl and the remaining variables are as defined in the twenty-eighth, twenty-ninth, or thirtieth embodiment.
  • ring N1 is piperidinyl or piperazinyl and the remaining variables are as defined in the twenty-eighth, twenty-ninth, or thirtieth embodiment.
  • a compound of structural formula (I)-(XII) or a pharmaceutically acceptable salt thereof, wherein L is selected from
  • a thirty-second embodiment provided is a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof, wherein Tar is a target protein binding moiety which binds estrogen receptor alpha (ERa) and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, seventeenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eight, twenty-ninth, thirtieth, or thirty-first embodiment.
  • Tar is a target protein binding moiety which binds estrogen receptor alpha (ERa) and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, seventeenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-f
  • a compound of structural formula (I)- (XII), or a pharmaceutically acceptable salt thereof wherein Tar is of the structure: wherein the wavy bond denotes the point of attachment to linker L and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, seventeenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eight, twenty-ninth, thirtieth, thirty-first or thirty-second embodiments.
  • Tar is of the structure: wherein the wavy bond denotes the point of attachment to linker L and the remaining variables are as defined in the first, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, sixteenth, seventeenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth
  • Tar is of the structure .
  • the compound of formula (I) is not selected from any one of Examples 10, 11, 18, 35, 37, 39, 40, 58, 62, 63, and 68.
  • compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • compositions described herein are formulated for administration to a patient in need of such composition.
  • Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension.
  • the compounds and compositions described herein are generally useful for modulating the activity of the target protein (e.g., ER or ERa). In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade the target protein (e.g., ER or ERa).
  • a disease responsive to the degradation of a target protein e.g., ER or ERa
  • methods of treating a disease responsive to the degradation of a target protein comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof for treating a disease responsive to the degradation of a target protein (e.g., ER or ERa).
  • a target protein e.g., ER or ERa
  • a target protein e.g., ER or ERa
  • a linker which covalently attaches the E2 binding moiety to the target protein binding moiety
  • a disease responsive to the degradation of a target protein e.g., ER or ERa
  • a target protein e.g., ER or ERa
  • administering to a subject in need thereof, a therapeutically effective amount of an effective amount of a compound comprising an E2 binding moiety, a target protein binding moiety (z.e., binding moiety that binds to the target protein which, when degraded, treats the disease), and a linker which covalently attaches the E2 binding moiety to the target protein binding moiety, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof, thereby treating the disease.
  • a target protein e.g., ER or ERa
  • a target protein binding moiety z.e., binding moiety that binds to the target protein which, when degraded, treats the disease
  • linker which covalently attaches the E2 binding moiety to the target protein binding moiety, or a pharmaceutically acceptable
  • a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease responsive to the degradation of a target protein (e.g., ER or ERa).
  • a target protein e.g., ER or ERa
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound described herein in the composition will also depend upon the particular compound in the composition.
  • the disease to be treated by the present methods is a cancer.
  • cancers treated using the compounds and methods described herein include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, actue promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyo
  • the disease is at least one of breast cancer, uterine cancer, ovarian cancer, prostate cancer, endometrial cancer, endometriosis, or a combination thereof. In another embodiment, the disease is breast cancer. EXEMPLIFICATION
  • Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintuplet) or bs (broad singlet).
  • Microwave reactions were conducted with a Monowave 300 by Anton Paar GmbH using standard protocols.
  • Step 1 Synthesis of 6-(tert-butoxy)-3,4-dihydronaphthalen-l(2H)-one (15):
  • Step 3 Synthesis of 4-(6-(tert-butoxy)-3,4-dihydronaphthalen-l-yl)phenol (19):
  • Step 4 Synthesis of 4-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-l- yl)phenol (20):
  • Step 5 Synthesis of 4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-l- yl)phenol (22): [00111] To a stirred solution of 4-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-l- yl)phenol, 20 (0.500 g, 1.339 mmol) in 1,4-Dioxane (6 mL) and water (1.2 mL) at 25 °C, K2CO3 (0.370 g, 2.68 mmol) and phenylboronic acid, 21 (0.163 g, 1.339 mmol) were added and purged with N2 for 10 minutes.
  • Linkers (L) The following linkers are either commercially available or synthesized as per the literature and used for synthesizing the disclosed examples.
  • Linker Lil was prepared as reported in PCT Publication No. WO 2020/201080.
  • Step 1 Synthesis of N-((lH-pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Step 3 Synthesis of N-((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)-2-(trifluoromethoxy)benzamide (35) :
  • Step 4 Synthesis of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (37):
  • Step 5 Synthesis of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-(trifluoromethoxy)benzamide (38):
  • Step 6 Synthesis of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (El):
  • Step 1 Synthesis of N-((lH-pyrazol-3-yl) methyl)-2-methoxybenzamide (40):
  • Step 2 Synthesis of 2-methoxy-N-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)benzamide (41):
  • Step 3 Synthesis of N-((5-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-3- yl)methyl)-2-methoxybenzamide (42):
  • Step 4 Synthesis of N-((5-(2-aminophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazol-3-yl)methyl)-2-methoxybenzamide (43):
  • Step 5 Synthesis of N-((5-(2-aminophenyl)-lH-pyrazol-3-yl)methyl)-2- methoxybenzamide (44):
  • Step 6 Synthesis of N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- methoxybenzamide (E2):
  • Step 1 Synthesis of rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidine-l -carboxylate (53):
  • Step 2 rel-(5R,6S)-6-phenyl-5-(4-(piperidin-4-yloxy)phenyl)-5,6,7,8- tetrahydronaphthalen-2-ol, 54 was synthesized using general procedure (GP2) and the crude product was purified by preparative HPLC to afford the title product.
  • Step 3 Synthesis of Example 6: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl- l,2,3,4-tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)-2-oxoethyl)thio)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:
  • Step 1 Synthesis of rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (55):
  • Method B Deprotection using ZnBr : General procedure (GP5): For spirocycles.
  • Step 4 Syntheses of Examples 7 to 10:
  • Example 8 rel-N-((5-((2-(2-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:
  • Step 1 rel-4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4-tetrahydronaphthalen-l- yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate, 56 was synthesized from rel-4- (( lR,2S)-6-(tert-butoxy)-2-phenyl- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl)phenol [POI_5] using the procedure described for intermediate 55.
  • Step 2 rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazine-l -carboxylate, 57 was synthesized using general procedure [GP4].
  • Step 3 rel-(5R,6S)-6-phenyl-5-(4-(piperazin- l-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, 58 was synthesized using general procedure, GP2
  • Step 4 Synthesis of Example 11: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenyl)piperazin- 1 -yl)-2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:
  • Step 1 rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenyl)-3,6-dihydropyridine- l(2H)-carboxylate (59):
  • Step 2 rel-tert-butyl 4-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenyl)-3,6-dihydropyridine- l(2H)-carboxylate (60):
  • Step 3 rel-(5R,6S)-6-phenyl-5-(4-(piperidin-4-yl)phenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol, 61 was synthesized using general procedure, GP2.
  • Step 4 Synthesis of Example 12: rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenyl)piperidin- 1 - yl ) - 2- oxoethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide:
  • Step 1 Synthesis of tert-butyl 4-(((2-((2-)
  • Step 3 Synthesis of tert-butyl 2-(4-(((2-((2-)
  • Step 4 Synthesis of 2-(4-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[l,5- c]quinazolin-5-yl)thio)methyl)piperidin-l-yl)acetic acid (65):
  • Step 5 Synthesis of rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Example 14 rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide: [00214] The title compound was prepared employing general procedure (GP3), starting from 2-(4-(((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-5- yl)thio)methyl)piperidin-l-yl)acetic acid, 65 (70 mg, 0.122 mmol) and rel-(5R,6S)-6-phenyl- 5-
  • Example 17 rel-N-((5-((((l-(2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)azetidin-3- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide: [00218] Scheme VIII
  • Step 1 Synthesis of tert-butyl 3-(((2-((2-)
  • Step 2 Synthesis of N-((5-((azetidin-3-ylmethyl)thio)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (67):
  • Step 3 Synthesis of tert-butyl 2-(3-(((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo[l,5-c]quinazolin-5-yl)thio)methyl)azetidin-l- yl)acetate (68):
  • Step 5 Synthesis of Example 17: rel-N-((5-(((l-(2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1,2,3, 4-tetr ahydronaphthalen- l-yl)phenoxy)piperidin- l-yl)-2-oxoethyl)azetidin-3- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Step 1 Synthesis of tert-butyl 4-((2-((2-)
  • tert-butyl 4-(tosyloxy)piperidine-l -carboxylate, L10 (85 mg, 0.239 mmol) and K2CO3 (49.5 mg, 0.359 mmol) were added and stirred at 80 °C for 16 h .
  • the reaction mixture was filtered through celite, washed with EtOAc (5 mL) and the filtrate was concentrated under reduced pressure to give the crude product, It was purified by Silica gel (60-120 mesh) column chromatography using 20% EtOAc in Petroleum ether to afford tert-butyl 4-((2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5-c]quinazolin-
  • Step 2 Synthesis of N-((5-(piperidin-4-ylthio)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide (71):
  • Step 3 Synthesis of tert-butyl 2-(4-((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidin- 1 - yl)acetate (72):
  • Step 4 Synthesis of 2-(4-((2-((2- (trifluoromethoxy)benzamido)methyl)pyrazolo [ 1 ,5-c] quinazolin-5-yl)thio)piperidin- 1 - yl)acetic acid (73):
  • Step 5 Synthesis of Example 18: rel-N-((5-((l-(2-(4-(4-((lR,2S)-6-hydroxy-2- phenyl- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)phenoxy)piperidin- 1 -yl)-2-oxoethyl)piperidin-4- yl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Step 1 Synthesis of rel-l-(4-((lR,2S)-6-(tert-butoxy)-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)-4-(dimethoxymethyl)piperidine (74):
  • Step 2 Synthesis of rel-l-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen- l-yl)phenyl)piperidine-4-carbaldehyde (75):
  • Step 3 Synthesis of Example 19: General procedure for Reductive Amination (GP6):
  • Example 20 rel-N-((5-(((l-((l-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)azetidin-3- yl)methyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Example 21 rel-N-((5-((l-((l-(4-((lR,2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)thio)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Example 22 rel-N-((5-((2-(l-((l-(4-((lR, 2S)-6-hydroxy-2-phenyl-l, 2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)ethyl)thio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Example 23 rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide
  • Step 1 Synthesis of N-((5-(methylthio)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (76): [00259] The title compound was prepared by following a similar procedure described for intermediate-51, starting from N-((5-mercaptopyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide, El (250 mg, 0.598 mmol) and lodomethane (85 mg, 0.598 mmol), and was isolated as an off-white solid (220 mg, 85.3% yield). LCMS: 433.0 [M+H].
  • Step 2 Synthesis of N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (77):
  • Step 3 Synthesis of rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (Example 23):
  • Example 27 rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide
  • Step 1 tert-butyl 4-(2-((2-(trifluoromethoxy)benzamido)methyl)pyrazolo[ 1 ,5- c]quinazolin-5-yl)piperazine-l-carboxylate (78) was synthesized using the procedure described for Step 3 of Example 23, starting from N-((5-(methylsulfonyl)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide, 77 (18 mg, 0.039 mmol) and tertbutyl piperazine- 1 -carboxylate, L12 (7.22 mg, 0.039 mmol), was obtained as an off-white sold (5.8 mg, 26.2% yield).
  • LCMS 571.0 [M+H]
  • Step 2 N-((5-(piperazin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (79) was synthesized using the general procedure, GP2.
  • Step 3 Synthesis of rel-N-((5-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide (Example 27):
  • Example 35 rel-N-((5-((4-(2-(4-(4-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)-2-oxoethyl)benzyl)thio)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Step 1 Synthesis of 2-(4-(((2-((2-)
  • Example 36 rel-N-((5-((S)-3-((2-(4-((lR*,2S*)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)pyrrolidin-l- yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Step 1 N-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide was synthesized using the procedure described for Step 3 of Example 23, starting from N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide, 77 (100 mg, 0.140 mmol) and (S)-pyrrolidin-3- ylmethanol (14.16 mg, 0.140 mmol), was obtained as an off-white sold (34 mg, 50% yield).
  • Step 2 Synthesis of (S)-N-((5-(3-formylpyrrolidin-l-yl)pyrazolo[l,5-c]quinazolin- 2-yl)methyl)-2-(trifluoromethoxy)benzamide:
  • Example 37 rel-N-((5-((S)-3-((4-(4-((lR*,2S*)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperidin-l-yl)methyl)pyrrolidin-l-yl)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Example 38 rel-N-((5-(4-((4-(4-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenoxy)piperidin-l-yl)methyl)piperidin-l-yl)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • Step 1 N-((5-(4-(dimethoxymethyl)piperidin-l-yl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide was synthesized using the procedure described for Step 3 of Example 23, starting from N-((5-(methylsulfonyl)pyrazolo[l,5-c]quinazolin-2- yl)methyl)-2-(trifluoromethoxy)benzamide, 77 (27 mg, 0.058 mmol) and 4- (dimethoxymethyl)piperidine, Lil (9.26 mg, 0.058 mmol), was obtained as an off-white sold (22 mg, 70% yield).
  • Step 2 N-((5-(4-formylpiperidin-l-yl)pyrazolo[l,5-c]quinazolin-2-yl)methyl)-2- (trifluoromethoxy)benzamide was synthesized using the procedure described for intermediate 75.
  • Example 39 rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazin-l-yl)-2-oxoethyl)thio)pyrazolo[l,5-c]quinazolin- 2-yl)methyl)-2-methoxybenzamide
  • Step 1 Synthesis of 2-((2-((2-methoxybenzamido)methyl)pyrazolo[l,5- c]quinazolin-5-yl)thio)acetic acid:
  • Step 2 Synthesis of 2-((2-((2-methoxybenzamido)methyl)pyrazolo[l,5- c]quinazolin-5-yl)thio)acetic acid:
  • Step 3 Synthesis of Example 39: [00295] The title compound was synthesized using the procedure described for Step 3 of Example 1, starting from 2-((2-((2-methoxybenzamido)methyl)pyrazolo[l,5-c]quinazolin-5- yl)thio)acetic acid (26.4 mg, 0.062 mmol) and rel-(5R,6S)-6-phenyl-5-(4-(piperazin-l- yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (20 mg, 0.052 mmol), was obtained as an off- white sold (5 mg, 12.2% yield). LCMS: 789.3 [M+H],
  • Example 40 rel-N-((5-((2-(4-(4-((lR,2S)-6-hydroxy-2-phenyl-l,2,3,4- tetrahydronaphthalen-l-yl)phenyl)piperazin-l-yl)-2-oxoethyl)(methyl)amino)pyrazolo[l,5- c]quinazolin-2-yl)methyl)-2-(trifluoromethoxy)benzamide
  • MCF-7 cells (0.8 million cells/well in 2 mL of Phenol red-free DMEM containing 5% charcoal stripped FBS) were seeded in 6 well plates and placed back in the cell culture incubator overnight. The next day, 3-fold serial dilutions of compounds were prepared in DMSO and added to the cells (final DMSO in each well is 0.5%). The cells were incubated with compound dilutions for 24 h and were harvested. Cell lysates were prepared in lx cell lysis buffer and 20 pg each of the lysates were used to estimate the levels of ERa by Western blot. Antibody used: ERa primary antibody, Thermofisher Scientific #MA5- 14501, 1:1000 dilution.
  • Nonfat dry milk powder in TBST was used for blocking. Representative data when treated with Examples 7 and 13 is shown in Tables 1 and 2, respectively. The data shows that significant degradation of ERa observed upon treatment with Examples 7 and 13. In addition, a dose dependent effect was observed. See FIG. 1.
  • T47D cells (20k cells/well in 25
  • the cells were fixed using 25 pL of 8% paraformaldehyde in PBS (Electron Microscopy Science #15710) for 30 mins at RT. Paraformaldehyde was removed, and the cells were permeabilized with 0.1% Triton in PBS for 30 mins at RT. Permeabilization solution was removed and the 50 pL of blocking buffer (Licor #927-60001) was added to the plate and placed on a rocker for 1 h at RT. Blocking buffer was removed and 25 pL diluted primary antibodies (1:500 dilution each of Thermofisher Scientific #MA5- 14501 and CST #13258 in blocking buffer) was added to the wells and the plate was incubated overnight at 4° C.
  • blocking buffer Lior #927-60001
  • T47D cells (0.5million cells/well in 2 mL of Phenol red-free RPMI containing 5% charcoal stripped FBS) were seeded in 6 well plates and placed back in the cell culture incubator overnight. The following day, cells were treated with 2 pM of MG 132 (final DMSO 0.1%) for 1 h. The cells were then treated with serial dilutions of test compounds prepared in DMSO (final DMSO in each well is 0.5%). Cells were harvested 6 h and 12 h post compound treatment. Cell lysates were prepared in lx cell lysis buffer and 0.5 pg/mL (pL) each of the lysates were used to estimate the levels of ERa using Protein Simple.
  • Antibody used ERa primary antibody, Thermofisher Scientific #MA5- 14501, 1:30 dilution. Results are shown in Table 5 below.
  • ESRI HiBiT MCF7 cells (3k cells/well in 25p L of Phenolred-free DMEM containing 10% charcoal stripped FBS) were seeded in 384well plates and placed back in the cell culture incubator overnight. Next day, 3-fold serial dilutions of test compounds were prepared in DMSO in a 384well polypropylene plate. lOpL of each dilution was transferred to ECHO source plate (Labcyte #LP-0200). 125nL of each compound dilution was stamped on the cells in 384well plates using ECHO acoustic liquid dispenser. The plate was transferred to the cell culture incubator and incubated for 24hrs.

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Abstract

L'invention concerne des agents de dégradation à petites molécules du récepteur des oestrogènes et leurs utilisations dans le traitement du cancer. (Formule (I)
PCT/US2024/052928 2023-10-25 2024-10-25 Agents de dégradation du récepteur des oestrogènes et leur utilisation dans le traitement du cancer Pending WO2025090847A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180155322A1 (en) * 2016-12-01 2018-06-07 Arvinas, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
WO2020201080A1 (fr) 2019-03-29 2020-10-08 Astrazeneca Ab Protac dégradant le récepteur des œstrogènes
WO2021138540A1 (fr) * 2020-01-03 2021-07-08 Berg Llc Amides polycycliques utilisés en tant que modulateurs d'ube2k pour le traitement du cancer
WO2022020550A1 (fr) * 2020-07-24 2022-01-27 Merck Sharp & Dohme Corp. Antagonistes doubles du récepteur a2a et du récepteur a2b de l'adénosine pour l'immuno-oncologie
WO2023023531A1 (fr) * 2021-08-20 2023-02-23 Biotheryx, Inc. Agents de dégradation du récepteur des œstrogènes, compositions pharmaceutiques et applications thérapeutiques
WO2023205219A1 (fr) * 2022-04-19 2023-10-26 Berg Llc Compositions de chimères ciblant la protéolyse (protac) à l'aide de ligands enzymatiques de conjugaison de l'ubiquitine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180155322A1 (en) * 2016-12-01 2018-06-07 Arvinas, Inc. Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
WO2020201080A1 (fr) 2019-03-29 2020-10-08 Astrazeneca Ab Protac dégradant le récepteur des œstrogènes
WO2021138540A1 (fr) * 2020-01-03 2021-07-08 Berg Llc Amides polycycliques utilisés en tant que modulateurs d'ube2k pour le traitement du cancer
WO2022020550A1 (fr) * 2020-07-24 2022-01-27 Merck Sharp & Dohme Corp. Antagonistes doubles du récepteur a2a et du récepteur a2b de l'adénosine pour l'immuno-oncologie
WO2023023531A1 (fr) * 2021-08-20 2023-02-23 Biotheryx, Inc. Agents de dégradation du récepteur des œstrogènes, compositions pharmaceutiques et applications thérapeutiques
WO2023205219A1 (fr) * 2022-04-19 2023-10-26 Berg Llc Compositions de chimères ciblant la protéolyse (protac) à l'aide de ligands enzymatiques de conjugaison de l'ubiquitine

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* Cited by examiner, † Cited by third party
Title
J. ORG. CHEM., vol. 62, no. 21, 1997, pages 7512 - 7515

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