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WO2024256988A1 - Agents de dégradation de smarca2 et leurs utilisations - Google Patents

Agents de dégradation de smarca2 et leurs utilisations Download PDF

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Publication number
WO2024256988A1
WO2024256988A1 PCT/IB2024/055751 IB2024055751W WO2024256988A1 WO 2024256988 A1 WO2024256988 A1 WO 2024256988A1 IB 2024055751 W IB2024055751 W IB 2024055751W WO 2024256988 A1 WO2024256988 A1 WO 2024256988A1
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Prior art keywords
methyl
piperidin
hydroxyphenyl
amino
pyridazin
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English (en)
Inventor
Esther Cheng Yin LEE
Ariamala Gopalsamy
Michael Schneider
Kyle David REICHL
Paul Tomas MARCYK
Christopher Elias REIMANN
Alisha Danielle CALIMAN
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AstraZeneca AB
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AstraZeneca AB
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Publication of WO2024256988A1 publication Critical patent/WO2024256988A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure provides Proteolysis Targeting Chimera (PROTAC) compounds and the use of such PROTAC compounds for the treatment of diseases or disorders dependent on SMARCA2 in mammals.
  • Degradation of SMARCA2 may provide, for example, an anti-tumor effect.
  • the present disclosure thus provides the use of SMARCA2 degraders and pharmaceutical compositions comprising SMARCA2 degraders for the treatment of cancer. It also provides intermediate compounds that may be useful in the preparation of such PROTACs.
  • PROTAC molecules are described as having three parts - (1) a part that is capable of binding to the protein to be degraded, (2) a second part that is capable of binding to an E3 ubiquitin ligase, and (3) a linker that connects parts (1) and (2) together.
  • the PROTAC binds to both the target protein and E3 ubiquitin ligase simultaneously to form a ternary complex.
  • the E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, which ubiquitinates the target protein. This has the effect of labelling the target protein for degradation by the cell's proteasome machinery.
  • a PROTAC can then dissociate from the target protein and initiate another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target proteins are recognized by the cell's proteasome machinery and are then degraded by it.
  • This PROTAC-mediated approach may be valuable as a method of treating certain diseases, including cancer.
  • SMARCA4 is a frequently mutated in several tumor types - including lung, liver, colon, skin, bladder, esophageal, gastric, brain, endometrial, cervical and ovarian cancers. Furthermore, it has been established that SMARCA2 is essential for growth of tumors harboring such SMARCA4 mutations. Accordingly, selective suppression of SMARCA2 has been proposed as a therapeutic strategy against cancers that may include SMARCA4 mutations. Accordingly, selective suppression of SMARCA2 may be useful against a number of cancer types, including lung, liver, colon, skin, bladder, esophageal, gastric, brain, endometrial, cervical and ovarian cancers.
  • WO2019/207538 discloses certain PROTAC compounds described as "SMARCA 2/4 degraders" and W02020251969 discloses PROTAC compounds which target one or more of SMARCA2, SMARCA4 and PB1.
  • W02019/195201 also discloses 'bifunctional' compounds described as modulators of SMARCA2.
  • WO2019/213005 relates to compounds that are said to degrade PBRM1.
  • WO2018/ 144649 and WO2021/053495 also disclose certain PROTAC molecules.
  • WO2021/053555 discloses glue degrader compounds which bind to the E3 ubiquitin ligase, cereblon.
  • PROTAC As part of developing a PROTAC against cancer, there is a need to develop further PROTAC compounds with a combination of beneficial/improved properties that make them more suitable for use as a therapeutic drug for human use.
  • Properties of interest during pharmaceutical discovery and development may relate to selectivity profile, absorption/bioavailability, distribution, metabolism, elimination, toxicity and side-effect profile, stability, manufacturability and so on.
  • the present disclosure provides PROTAC compounds represented by any one of Formulae (A), (IA), or (I)-(XVI), below, and the pharmaceutically acceptable salts thereof, or stereoisomers thereof.
  • the present disclosure provides any one or more of the PROTAC compounds of Compound List 1, below, and the pharmaceutically acceptable salts thereof or stereoisomers thereof.
  • the present disclosure provides any one or more of the PROTAC compounds of Compound List 2, below, and the pharmaceutically acceptable salts thereof.
  • the present disclosure provides any one or more of the PROTAC compounds of Compound List 3, below, and the pharmaceutically acceptable salts thereof.
  • the present disclosure provides any one or more of the PROTAC compounds of Compound List 4, below, and the pharmaceutically acceptable salts thereof. In another aspect, the present disclosure provides any one or more of the PROTAC compounds of Compound List 5, below, and the pharmaceutically acceptable salts thereof.
  • Compounds having any one of Formulae (A), (IA), or (I)-(XVI), and the pharmaceutically acceptable salts thereof, or stereoisomers thereof, and the PROTAC compounds of Compound List 1, Compound List 2, Compound List 3, Compound List 4 and/or Compound List 5, and the pharmaceutically acceptable salts thereof, or stereoisomers thereof, are collectively referred to as "Compounds of the Disclosure” or individually as a “Compound of the Disclosure.”
  • Compounds of the Disclosure exhibit protein degradation activity against SMARCA2.
  • Compounds of the Disclosure also may have a beneficial degree of selectivity to minimize certain undesirable off-target degradation activities. As such, Compounds of the Disclosure may be useful in the treatment of cancer.
  • Compounds of the Disclosure also may have a surprisingly beneficial combination of properties of relevance in the context of pharmaceutical discovery and development.
  • Structural features found in all three regions of a PROTAC have the potential to operate (collectively or in some cases separately) towards delivering a beneficial combination and/or balance of such additional beneficial properties. Avoidance of off-target activity in pharmaceutical development is often important to avoid or reduce unwanted toxicities, side-effects or other problems with tolerability when used in patients
  • Compounds of the Disclosure may show a beneficial selectivity profile by achieving a potent degree of degradation against SMARCA2 while having a margin of selectivity, i.e., relatively lower degradation, against SMARCA4.
  • a SMARCA2 PROTAC for use in cancer
  • Compounds of the Disclosure may show a beneficial selectivity profile between SMARCA2 and PBRM1.
  • Compounds of the Disclosure may show high potency against SMARCA2 while simultaneously achieving a beneficial selectivity profile with respect to SALL4 and/or Ikaros (IKZF1), and in some cases a surprisingly beneficial margin of selectivity against SMARCA4 and/or PBRM1.
  • compositions comprising a Compound of the Disclosure and one or more pharmaceutically acceptable excipients.
  • the present disclosure provides methods of degrading SMARCA2 protein in a human, comprising administering to a human in need thereof an effective amount of a Compound of the Disclosure.
  • the present disclosure provides methods of reducing SMARCA2 protein in a human, comprising administering to a human in need thereof an effective amount of a Compound of the Disclosure.
  • the present disclosure provides methods of treating cancer in a human, comprising administering to a human in need thereof an effective amount of a Compound of the Disclosure.
  • the present disclosure provides a Compound of the Disclosure, or pharmaceutical composition thereof, for use in degrading SMARCA2 protein in a human.
  • the present disclosure provides a Compound of the Disclosure, or pharmaceutical composition thereof, for use in reducing SMARCA2 protein in a human.
  • the present disclosure provides a Compound of the Disclosure, or pharmaceutical composition thereof, for use in treating cancer in a human.
  • the present disclosure provides use of a Compound of the Disclosure, or pharmaceutical composition thereof in the manufacture of a medicament for degrading SMARCA2 protein in a human.
  • the present disclosure provides use of a Compound of the Disclosure, or pharmaceutical composition thereof in the manufacture of a medicament for reducing SMARCA2 protein in a human.
  • the present disclosure provides use of a Compound of the Disclosure, or pharmaceutical composition thereof in the manufacture of a medicament for treating cancer in a human.
  • the present disclosure provides methods of preparing Compounds of the Disclosure.
  • the present disclosure provides intermediates used to prepare Compounds of the Disclosure.
  • Compounds of the Disclosure are compounds having Formula (A), or pharmaceutically acceptable salt and/or stereoisomer thereof: wherein:
  • R 2 is hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or
  • X 1 is CR 3 orN
  • R 3 is hydrogen, halogen, or (Ci-Ce)alkyl
  • X 2 is CR 4 or N;
  • R 4 is hydrogen, halogen, or (Ci-Ce)alkyl
  • R 5a is hydrogen, halogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three substituents independently selected from halogen or cyano; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, or (Ci-Ce)alkyl;
  • R 5b is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cycloalkyl;
  • R 6 is hydrogen, (Ci-Ce)alkyl, or cyano;
  • X 3 is -(CR 13a R 13b ) n - or -O-;
  • n 0 or 1
  • each R 13a and R 13b is independently hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy;
  • G 1 is 4- to 6-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano; 7- to 11- membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano; or (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci- Ce)alkoxy, or cyano;
  • G 3 is 4- to 7-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano; 7- to 11- membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano; or (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci- Ce)alkoxy, or cyano;
  • G 4 is (Ci-C6)alkylenyl or a direct bond
  • R 7 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • R 8 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • R 9 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • R 10 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • m is 0, 1, 2, 3, or 4;
  • R 12a and R 12b are each independently hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen; or
  • R 12a and R 12b taken together with the carbon atoms to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl or an optionally substituted (C5-C7)cycloalkyl;
  • R 12c is hydrogen or halogen
  • R a is hydrogen or halogen
  • R b is hydrogen or halogen.
  • Compounds of the Disclosure are compounds having Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof:
  • R 1 is hydrogen, halogen, (Ci-C6)alkyl, (Ci-Ce)alkoxy, or
  • R 2 is hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or with the provisos:
  • R 1 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R 2 is:
  • R 1 when R 2 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R 1 is:
  • X 1 is CR 3 or N;
  • R 3 is hydrogen, halogen, or (Ci-C6)alkyl;
  • X 2 is CR 4 or N;
  • R 4 is hydrogen, halogen, or (Ci-Ce)alkyl
  • R 5a is hydrogen, halogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three substituents independently selected from halogen or cyano; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, or (Ci-Ce)alkyl;
  • R 5b is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cycloalkyl;
  • R 6 is hydrogen, (Ci-Ce)alkyl, or cyano
  • X 3 is -(CR 13a R 13b ) n - or -O-;
  • n 0 or 1
  • each R 13a and R 13b is independently H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy;
  • L is -G ⁇ GF-G -G 4 -, wherein G 1 is attached to W;
  • G 1 is 4- to 6-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; 7- to 11- membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; or (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci- Ce)alkoxy, or cyano;
  • G 2 is (Ci-Ce)alkylenyl or a direct bond
  • G 3 is 4- to 6-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; 7- to 11- membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; or (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci- Ce)alkoxy, or cyano;
  • G 4 is (Ci-C6)alkylenyl or a direct bond
  • R 7 is hydrogen, halogen, (Ci-C6)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-C6)alkyl is optionally substituted with one, two, or three halogen;
  • R 8 is hydrogen, halogen, (Ci-C6)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-C6)alkyl is optionally substituted with one, two, or three halogen;
  • R 9 is hydrogen, halogen, (Ci-C6)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-C6)alkyl is optionally substituted with one, two, or three halogen;
  • R 10 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • each R 12 is independently halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy;
  • m is 0, 1, 2, 3, or 4.
  • Compounds of the Disclosure are compounds having Formula (IA), or pharmaceutically acceptable salt and/or stereoisomer thereof: wherein:
  • R 1 is hydrogen, halogen, (Ci-C6)alkyl, (Ci-Ce)alkoxy, or
  • R 2 is hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or with the provisos:
  • R 1 is hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R 2 is:
  • X 1 is CR 3 orN
  • R 3 is hydrogen, halogen, or (Ci-Ce)alkyl
  • X 2 is CR 4 or N;
  • R 4 is hydrogen, halogen, or (Ci-Ce)alkyl
  • R 5a is hydrogen, halogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, cyano, aryl, or 5- or 6-membered heteroaryl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three substituents independently selected from halogen or cyano; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, or (Ci-Ce)alkyl;
  • R 5b is hydrogen, (Ci-Ce)alkyl, or (C3-C6)cycloalkyl;
  • R 6 is hydrogen, (Ci-Ce)alkyl, or cyano
  • X 3 is -(CR 13a R 13b ) n - or -O-;
  • n 0 or 1
  • each R 13a and R 13b is independently hydrogen, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy;
  • L is -G ⁇ GF-G -G 4 -, wherein G 1 is attached to W;
  • G 1 is 4- to 6-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; 7- to 11- membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; or (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-
  • G 3 is 4- to 7-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; 7- to 11- membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or cyano; or (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-C6)alkyl, (Ci- Ce)alkoxy, or cyano;
  • G 4 is (Ci-C6)alkylenyl or a direct bond
  • R 7 is hydrogen, halogen, (Ci-C6)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-C6)alkyl is optionally substituted with one, two, or three halogen;
  • R 8 is hydrogen, halogen, (Ci-C6)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • R 9 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • R 10 is hydrogen, halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen;
  • R 12a and R 12b are each independently hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen; or
  • R 12a and R 12b taken together with the carbon atoms to which they are attached form an optionally substituted 5- to 7-membered heterocycloalkyl or an optionally substituted (C5-C7)cycloalkyl ; and [0118] R 12c is hydrogen or halogen.
  • Compounds of the Disclosure are compounds having Formula (II):
  • R 7 , R 8 , R 9 , R 12 , m, E, L, and X 3 are as defined in connection with Formula (I).
  • Compounds of the Disclosure are compounds having Formula (III):
  • R 7 , R 8 , R 9 , R 12 , m, E, L, and X 3 are as defined in connection with Formula (I).
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein X 3 is -(CR 13a R 13b )-.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R13a and R13b are hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R13a and R13b are fluoro.
  • Compounds of the Disclosure are compounds having any one Formulae (A), (IA), or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein R13a is methyl or methoxy; and R13b is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein X3 is -O-.
  • Compounds of the Disclosure are compounds having any one Formulae (A) or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein m is 0.
  • Compounds of the Disclosure are compounds having any one of Formulae (A) or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein m is 2.
  • Compounds of the Disclosure are compounds having any one Formulae (A) or (I)-(III), or a pharmaceutically acceptable salt thereof, wherein m is 1.
  • Compounds of the Disclosure are compounds having Formula (IV): (IV),
  • R 7 , R 8 , R 9 , R 12 , E, L, and X 3 are as defined in connection with Formula (I).
  • Compounds of the Disclosure are compounds having Formula (V):
  • R 7 , R 8 , R 9 , R 12 , E, L, and X 3 are as defined in connection with Formula (I).
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having Formula (VIII): [0137] wherein R 7 , R 8 , R 9 , R 10 , R 12a , R 12b , R 12c , X 3 , W, L, and E are as defined in connection with Formula (IA).
  • Compounds of the Disclosure are compounds having Formula (IX):
  • R 7 , R 8 , R 9 , R 10 , R 12a , R 12b , R 12c , X 3 , W, L, and E are as defined in connection with Formula (IA).
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, wherein R 12a is hydrogen and R 12b is hydrogen, fluoro, methyl, ethyl, or methoxy.
  • Compounds of the Disclosure are compounds having Formula (X): wherein:
  • X 4 is O
  • d and e are independently 1 or 2;
  • R 7 , R 8 , R 9 , R 10 , X 3 , W, L, and E are as defined in connection with Formula (IA).
  • Compounds of the Disclosure are compounds having Formula (XI): wherein:
  • X 4 is O
  • d and e are independently 1 or 2;
  • R 7 , R 8 , R 9 , R 10 , X 3 , W, L, and E are as defined in connection with Formula (IA).
  • Compounds of the Disclosure are compounds having Formula (XII):
  • X 4 is O
  • d and e are independently 1 or 2;
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is (Ci-Ce)alkyl optionally substituted with one, two, or three substituents independently selected from halogen or cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is (C3-C6)cycloalkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is cyclopropyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is 4- to 6-membered heterocycloalkyl optionally substituted with one, two, or three substituents independently selected from halogen, cyano, or (Ci-C6)alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is aryl optionally substituted with one, two, or three substituents independently selected from halogen, cyano, or (Ci-C 6 )alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5a is 5- or 6-membered heteroaryl optionally substituted with one, two, or three substituents independently selected from halogen, cyano, or (Ci-C6)alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein E is E-2.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5b is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5b is (Ci-C 6 )alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5b is methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof wherein R 5b is (C3-C6)cycloalkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 5b is cyclopropyl or cyclobutyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 6 is (Ci-C 6 )alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 6 is cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein: [0173] R 1 is:
  • R 2 is hydrogen, halogen, (Ci-C6)alkyl, or (Ci-C6)alkoxy.
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, fluoro, or methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 is:
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, fluoro, or methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 3 .
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 3 is (Ci-C 6 )alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein X 1 is N.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein X 2 is CR 4 .
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 4 is (Ci-C 6 )alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein X 2 is N.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein E-l is:
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein E-l is:
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 1 is 4- to 6-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein:
  • G 1 is:
  • each R 14 is independently halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano;
  • n 0, 1, 2, or 3;
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein n is 0.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 14 is fluoro, methyl, or methoxy; and n is 1, or 2.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 1 is:
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 1 is a 7- to 11 -membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 1 is:
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 2 is (Ci-C6)alkylenyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 2 is - CH 2 - or -CH(CH 3 )-.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V) or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is 4- to 6-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano.
  • Compounds of the Disclosure are compounds having any one of F
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V) or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is:
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is 4- to 7-membered heterocycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is:
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is:
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein:
  • G 3 is:
  • each R 15 is independently selected from halogen, (Ci-C6)alkyl, (Ci-Ce)alkoxy, or cyano;
  • u is 0, 1, 2, or 3;
  • v, w, x, and t are independently 1, 2, or 3;
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein v, w, x, and y are independently 1 or 2.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is:
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V) or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is:
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V) or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 3 is (C3-C6)cycloalkylenyl optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or cyano.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 4 is (Ci-C6)alkylenyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein G 4 is a direct bond.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein L is:
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 7 is halogen or (Ci-C6)alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 7 is fluoro or methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 8 , R 9 , and R 10 are hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 8 is halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 8 is halogen or (Ci-C6)alkyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 8 is fluoro or methyl.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 7 , R 9 , and R 10 are hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 9 is halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 9 is halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 9 is fluoro.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 , and R 10 are hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 10 is halogen, (Ci-Ce)alkyl, cyano, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 10 is halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 10 is fluoro.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 , and R 9 are hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (I)-(V), or (VIII)-(XII), or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 , R 9 , and R 10 are hydrogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b are each independently hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, wherein (Ci-Ce)alkyl is optionally substituted with one, two, or three halogen.
  • Compounds of the Disclosure are compounds having any one of Formulae (A), (IA), (VIII), or (IX), or a pharmaceutically acceptable salt thereof, wherein R 12a and R 12b taken together with the carbon atoms to which they are attached form an optionally substituted 5- to 7- membered heterocycloalkyl or an optionally substituted (C5-C7)cycloalkyl.
  • Compounds of the Disclosure are compounds having Formulae (A), wherein R a is fluoro and R b is hydrogen.
  • Compounds of the Disclosure are compounds having Formulae (A), wherein R a is hydrogen and R b is fluoro.
  • Compounds of the Disclosure are compounds having Formula (VI): wherein:
  • R 15a is fluoro
  • p is 0, 1, or 2;
  • Z 1 is CR 15b orN
  • R 15b is hydrogen, fluoro, methyl, or methoxy
  • R 16 is hydrogen or methyl
  • Z 2 is CH or N
  • R 17 is fluoro or methyl
  • q is 0, 1, or 2;
  • R 12 is fluoro, methyl, ethyl, or methoxy; and m is 1; or R 12 is hydrogen; and m is 0;
  • R 7 , R 8 , R 9 , and R 10 are independently hydrogen, fluoro, chloro, methyl, -CF3, cyclopropyl, methoxy, or cyano;
  • X 3 and E are as defined in connection with Formula (I).
  • Compounds of the Disclosure are compounds having Formula (VII): wherein:
  • R 15a is fluoro; [0283] p is 0, 1, or 2;
  • Z 1 is CR 15b orN
  • R 15b is hydrogen, fluoro, methyl, or methoxy
  • R 16 is hydrogen or methyl
  • Z 2 is CH or N
  • R 17 is fluoro or methyl
  • q is 0, 1, or 2;
  • R 12 is fluoro, methyl, ethyl, or methoxy; and m is 1; or R 12 is hydrogen; and m is 0;
  • R 7 , R 8 , R 9 , and R 10 are independently hydrogen, fluoro, chloro, methyl, -CF3, cyclopropyl, methoxy, or cyano;
  • X 3 and E are as defined in connection with Formula (I).
  • Compounds of the Disclosure are compounds having Formula (XIII): (XIII), wherein:
  • R 7 , R 8 , R 9 , and R 10 are independently hydrogen or methyl
  • R 12a and R 12b are independently hydrogen or methyl
  • R 15a is fluoro
  • p is 0, 1, or 2;
  • Z 1 is CR 15b or N
  • R 15b is hydrogen or fluoro
  • Z 2 is CH or N
  • R 17 is fluoro
  • q is 0, 1, or 2;
  • Compounds of the Disclosure are compounds having Formula (XIV): (XIV), wherein:
  • R 7 , R 8 , R 9 , and R 10 are independently hydrogen or methyl;
  • R 12a and R 12b are independently hydrogen or methyl;
  • R 15a is fluoro
  • p is 0, 1, or 2;
  • Z 1 is CR 15b or N
  • R 15b is hydrogen or fluoro
  • Z 2 is CH or N
  • R 17 is fluoro
  • q is 0, 1, or 2;
  • E is as defined in connection with Formula (IA).
  • Compounds of the Disclosure are compounds having Formula (XV): wherein:
  • R a and R b are independently hydrogen or fluoro
  • R 7 , R 8 , R 9 , and R 10 are independently hydrogen or methyl
  • R 12a and R 12b are independently hydrogen or methyl
  • R 12a and R 12b taken together with the carbon atoms to which they are attached form a
  • Z 3 is CH orN.
  • Z 4 is CR 15b or N
  • R 15b is hydrogen or fluoro
  • Z 5 is CH orN
  • E is as defined in connection with Formula (A).
  • Compounds of the Disclosure are compounds having Formula (XV), wherein R 12a and R 12b are independently hydrogen or methyl.
  • Compounds of the Disclosure are compounds having Formula (XVI): (XVI), [0327] wherein R a , R b , R 7 , R 8 , R 9 , R 10 , Z 3 , Z 4 , Z 5 , and E are as definied in connection with Formula (XV).
  • Compounds of the Disclosure are any one or more of the compounds of Compound Lists 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  • a compound having an "*" in its chemical name indicates that the absolute configuration and/or relative configuration at that position of the molecule has not yet been confirmed.
  • "ethyl (R*)-4-(pyrrolidin-3-yl)benzoate” indicates that the compound may be ethyl (/?)-4-(pyrrolidin-3- yl)benzoate or ethyl (.S')-4-(pyrrolidin-3-yl)bcnzoatc. See Intermediates 18d and 18de of EXAMPLE 18.
  • Compounds of the Disclosure are any one or more of the compounds of Compound List 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  • Compounds of the Disclosure are any one or more of the compounds of Compound List 2, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof.
  • Compounds of the Disclosure are any one or more of the compounds of Compound List 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  • Compounds of the Disclosure are any one or more of the compounds of Compound List 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  • Compounds of the Disclosure are any one or more of the compounds of Compound List 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
  • a Compound of the Disclosure is: [0986] or a pharmaceutically acceptable salt thereof.
  • a Compound of the Disclosure is: [1006] or a pharmaceutically acceptable salt thereof.
  • compositions comprising a Compound of the Disclosure and one or more pharmaceutically acceptable excipients.
  • Compounds of the Disclosure may have one or more chiral centres and it will be recognised that such compounds may be prepared, isolated and/or supplied with or without the presence of one or more of the other possible enantiomeric and/or diastereomeric isomers of the compounds, or that such isomers may be provided in any relative proportions.
  • enantioenriched or enantiopure and/or diastereoenriched or diastereopure compounds may be carried out by standard techniques of organic chemistry that are well known in the art, for example by synthesis from enantioenriched or enantiopure starting materials, and/or by use of an appropriately enantioenriched or enantiopure catalyst during synthesis, and/or by resolution of a racemic or partially enriched mixture of stereoisomers, for example via chiral chromatography.
  • the scope of the present disclosure includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the present disclosure includes all combinations and subsets of the particular groups defined hereinabove.
  • the present disclosure provides a composition
  • a composition comprising a Compound of the Disclosure optionally together with one or more of the other stereoisomeric forms of the compound, wherein the Compound of the Disclosure is present within the composition with a diastereomeric excess (%de) of > 55%.
  • the %de in the above-mentioned composition is > 90%.
  • the %de in the above-mentioned composition is > 95%.
  • the %de in the above-mentioned composition is > 98%.
  • the %de in the above-mentioned composition is > 99%.

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Abstract

La présente invention concerne des composés représentés par la formule (A), ou un sel et/ou un stéréoisomère pharmaceutiquement acceptable de ceux-ci : (A), Ra, Rb, R7, R8, R9, R10, R12, R12a, R12b, R12c, m, X3, W, L et E étant tels que définis dans la description. Les composés représentés par la formule (A) sont des agents de dégradation de protéine SMARCA2 et sont ainsi utiles pour le traitement du cancer et d'autres maladies.
PCT/IB2024/055751 2023-06-14 2024-06-12 Agents de dégradation de smarca2 et leurs utilisations Pending WO2024256988A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016138114A1 (fr) * 2015-02-25 2016-09-01 Genentech, Inc. Composés thérapeutiques de pyridazine et leurs utilisations
WO2018144649A1 (fr) 2017-01-31 2018-08-09 Arvinas, Inc. Ligands de céréblon et composés bifonctionnels les contenant
WO2019195201A1 (fr) 2018-04-01 2019-10-10 Arvinas Operations, Inc. Composés ciblant brm et procédés d'utilisation associés
WO2019207538A1 (fr) 2018-04-26 2019-10-31 Aurigene Discovery Technologies Limited Dérivés de pyridazine en tant qu'agents de dégradation de smarca2/4
WO2019213005A1 (fr) 2018-04-30 2019-11-07 Dana-Farber Cancer Institute, Inc. Agents de dégradation à petites molécules de polybromo-1 (pbrm1)
WO2021053555A1 (fr) 2019-09-16 2021-03-25 Novartis Ag Agents de dégradation de colle et leurs procédés d'utilisation
WO2021053495A1 (fr) 2019-09-16 2021-03-25 Novartis Ag Agents de dégradation bifonctionnels et leurs méthodes d'utilisation
WO2022069520A1 (fr) * 2020-09-30 2022-04-07 Astrazeneca Ab Composés et leur utilisation dans le traitement du cancer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016138114A1 (fr) * 2015-02-25 2016-09-01 Genentech, Inc. Composés thérapeutiques de pyridazine et leurs utilisations
WO2018144649A1 (fr) 2017-01-31 2018-08-09 Arvinas, Inc. Ligands de céréblon et composés bifonctionnels les contenant
WO2019195201A1 (fr) 2018-04-01 2019-10-10 Arvinas Operations, Inc. Composés ciblant brm et procédés d'utilisation associés
WO2019207538A1 (fr) 2018-04-26 2019-10-31 Aurigene Discovery Technologies Limited Dérivés de pyridazine en tant qu'agents de dégradation de smarca2/4
WO2019213005A1 (fr) 2018-04-30 2019-11-07 Dana-Farber Cancer Institute, Inc. Agents de dégradation à petites molécules de polybromo-1 (pbrm1)
WO2021053555A1 (fr) 2019-09-16 2021-03-25 Novartis Ag Agents de dégradation de colle et leurs procédés d'utilisation
WO2021053495A1 (fr) 2019-09-16 2021-03-25 Novartis Ag Agents de dégradation bifonctionnels et leurs méthodes d'utilisation
WO2022069520A1 (fr) * 2020-09-30 2022-04-07 Astrazeneca Ab Composés et leur utilisation dans le traitement du cancer

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Title
CORWIN HANSCH: "Comprehensive Medicinal Chemistry", 1990, PERGAMON PRESS

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