WO2023056423A1 - Modulateurs de récepteurs des androgènes et procédés d'utilisation en tant qu'agents de dégradation bifonctionnels - Google Patents

Modulateurs de récepteurs des androgènes et procédés d'utilisation en tant qu'agents de dégradation bifonctionnels Download PDF

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WO2023056423A1
WO2023056423A1 PCT/US2022/077353 US2022077353W WO2023056423A1 WO 2023056423 A1 WO2023056423 A1 WO 2023056423A1 US 2022077353 W US2022077353 W US 2022077353W WO 2023056423 A1 WO2023056423 A1 WO 2023056423A1
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alkyl
compound
independently
optionally substituted
heterocycle
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Peter Virsik
Zhou HAN-JIE
Berenger BIANNIC
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Essa Pharma, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K47/545—Heterocyclic compounds
    • 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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • 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
    • C07D471/10—Spiro-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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present disclosure generally relates to bifunctional chemical protein degraders comprising a ligase modulator/binder and a molecule that binds to a protein target of interest, and methods of treating various diseases and conditions with the degraders.
  • the molecule that binds to a protein target is an androgen receptor modulator.
  • 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 (R. K. Ross, G. A. Coetzee, C. L.
  • Androgens also play a role in female diseases such as polycystic ovary syndrome as well as cancers.
  • ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)).
  • the AR has been detected in a majority of ovarian cancers (H. A.
  • prostate cancer can eventually grow again in the absence of testicular androgens (castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol. 104, 33-39). Castration-resistant prostate cancer that is still driven by AR is biochemically characterized before the onset of symptoms by a rising titre of serum PSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomes castration-resistant most patients succumb to their disease within two years.
  • the AR has distinct functional domains that include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zinc finger motifs, and an N- terminus domain (NTD) that contains two transcriptional activation units (tau1 and tau5) within activation function-1 (AF-1). Binding of androgen (ligand) to the LBD of the AR results in its activation such that the receptor can effectively bind to its specific DNA consensus site, termed the androgen response element (ARE), on the promoter and enhancer regions of “normally” androgen regulated genes, such as PSA, to initiate transcription.
  • LBD carboxy-terminal ligand-binding domain
  • DBD DNA-binding domain
  • NTD N- terminus domain
  • AF-1 activation function-1
  • the AR can be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res.54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem.277, 38087-38094).
  • PKA cAMP-dependent protein kinase pathway
  • IL-6 interleukin-6
  • the mechanism of ligand-independent transformation of the AR has been shown to involve: 1) increased nuclear AR protein suggesting nuclear translocation; 2) increased AR/ARE complex formation; and 3) the AR-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
  • 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 (Kim et al 2002 Am. J.
  • Ubiquitin-Proteasome Pathway System is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins.
  • UPS is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases.
  • Posttranslational modification of proteins by ubiquitin is a fundamental cellular mechanism that regulates protein stability and activity and underlies a multitude of functions, from almost every aspect of biology.
  • the covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
  • E3 ubiquitin ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity.
  • Deubiquitinating proteins and ubiquitin-specific proteases (DUBs and USPs) and E3 ligases play a vital role in the UPS.
  • the present invention relates to bifunctional chemical protein degraders (“degrader compounds”), also known as proteolysis targeting chimeric molecules, that induce ubiquitination and degrade a protein of interest.
  • Degrader compounds are typically designed with three parts: 1) a ligand/molecule that binds to and/or modulates ubiquitin ligases; 2) a small molecule that binds to the target protein of interest for proteolysis; and 3) a linker that links the two molecules together.
  • Degrader compounds thus function by allowing the ligand/molecule to bind to the ubiquitin ligases, thereby recruiting the target of protein of interest to the ligase for ubiquitination and ultimately proteolysis and degradation.
  • the present invention discloses degrader compounds intended to degrade and/or inhibit AR proteins associated with cancer, especially prostate cancer.
  • SUMMARY OF THE INVENTION The compound of the present disclosure can be useful for modifying the ubiquitination and subsequent degradation of androgen receptor proteins.
  • the compound is a bifunctional compound wherein a E3 ligase binding group (e.g., cereblon or a derivative thereof) is covalently attached to one end of a Linker (“LI”), and the androgen receptor modulator (“PTC”) is covalently attached to the other end of the linker (LI).
  • a E3 ligase binding group e.g., cereblon or a derivative thereof
  • PTC androgen receptor modulator
  • the compound of the present disclosure is represented by formula (Q ⁇ -I): [0014] or a pharmaceutically acceptable salt thereof, wherein: [0015] E a , E b , E c , and E d are each independently CR a or N; [0016] E e and E f are each C; [0017] wherein up to two of E a , E b , E c , and E d can be N; [0018] K 1 is NR b , -C(O)- or -C(R b ) 2 -; [0019] K 2 is absent, NR b , or -C(R b ) 2 -, wherein when K 2 is present, the bond between K 1 and K 2 is a single bond or a double bond; [0020] each R a is independently hydrogen, halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0021] R b is H
  • A is a 5- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl
  • B is a 5- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl
  • C is a 3- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl
  • at least one of A, B, and C is a fused or bridged bicyclic ring
  • Y is a bond, -(CR 8 R 9 ) m -, -O-, -S-, -
  • the compound of the present disclosure is represented by formula (Q-I) as described herein.
  • the compound has the structure of formula (Q-Ia) as described herein.
  • the compound of formula (Q ⁇ -I) has the structure of formula (Q-Ib) as described herein.
  • the compound is a compound of formula (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), or (ix) as described herein.
  • the compound is a compound of formula (x) (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), or (xviii) as described herein.
  • PTC is selected from Compounds B7, B8, B9, B10, B17, B18, B19, B20, B21, B22 B23, B24, B28, B29, B30, B31, B32, B33, B34, B35, B35(R), B35(S), B36, B40, B44, B45, B46, B52, B53, B55, B56, B57, B58, B59, B60, B61, B62, B63, B64, B65, B69, B70, B71, B73, B74, B77, B81, B82, B83, B84, B85, B115, B122, B123, B124, B125, B126, B131, B133, B134, B135, B136, B137, B138, B139, B140, B143
  • PTC is selected from Compounds B200-B285. [0060] In one embodiment of the compounds of the present disclosure, PTC is selected from Table C. In one embodiment of the compounds of the present disclosure, PTC is selected from B1-B285. [0061] In one embodiment of the compound of formula (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), or (i)- (xviii), PTC is selected from:
  • the PTC is [0062] In one embodiment of the compound of formula (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), or (i)- (xviii), PTC is selected form Compounds B51, B57, B59, and/or B135. In one embodiment, PTC is selected from Compounds B51, B57, B59, B132, and/or B135.
  • the compound of formula (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), or (i)- (xviii) is the compound is selected from Compounds 53-62, 72, 78, 79, 85, 86, 89, 90, 104, 106, 123-125, and/or 127. In some embodiments, the compound is selected from Compounds 53-62, 72, 78, 79, 85, 86, 89, 90, 104, 106, 123-125, 127, and/or 342.
  • the compound of the present disclosure is represented by formula (Q ⁇ -II): [0065] or a pharmaceutically acceptable salt thereof, wherein: [0066] E a , E b , E c , and E d , are each independently CR a or N; [0067] E e and E f are each C; [0068] wherein up to two of E a , E b , E c , and E d can be N; [0069] K 1 is NR b , -C(O)- or -C(R b ) 2 -; [0070] K 2 is absent, NR b , or -C(R b ) 2 -, wherein when K 2 is present, the bond between K 1 and [0071] K 2 is a single bond or a double bond; [0072] each R a is independently hydrogen, halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [00
  • the compound of the present disclosure is represented by formula (Q-II), or a pharmaceutically acceptable salt thereof, as described herein.
  • the compound has the structure of formula (Q-IIa), or a pharmaceutically acceptable salt thereof, as described herein.
  • the compound has the structure of formula (Q-IIb), or a pharmaceutically acceptable salt thereof, as described herein.
  • the compound is a compound of formula (a), (b), (c), (d), or (e), or a pharmaceutically acceptable salt thereof, as described herein.
  • the compound in one embodiment of the compound of formula (Q ⁇ -II), is a compound of formula (f), (g), (h), (j), or (k), or a pharmaceutically acceptable salt thereof, as described herein. [0099] In one embodiment of the compound of formula (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (a)-(h), (j), or (k), the PTC is A109 or A204.
  • the PTC is A74, A109, A165, A181, A204, A205, A206, A212, A213, B48, B66, B90, B150, B267, and/or B283.
  • the compound is selected from Compounds 1-52, 63-69, 73-77, 80-84, 87, 88, 91-103, 105, 107-122, 126, and/or 128-149.
  • the compound is selected from Compounds 1-52, 63-69, 73-77, 80-84, 87, 88, 91-103, 105, 107-122, 126, 128- 175, 176-196, 200. 201, 203, 204, and/or 206-223.
  • the compound is selected from Compounds 1-52, 63-69, 73-77, 80- 84, 87, 88, 91-103, 105, 107-122, 126, 128-175, 176-196, 200, 201, 203, 204, 206-227, 229-250, 252-275, 277-280, 284-311, 313-316, 318-320, 323-334, 337-354, 356-367, 369-372, and/or 374-379.
  • the compound is selected from Compounds 197-199.
  • the compound is selected from Compounds 197-199, 228, 251, 276, 281-283, 312, 317, 322, 335, 336, 368, 373, 380, and/or 381. [0101] In one embodiment of the present disclosure, the compound is Compound 70 or 71, or a pharmaceutically acceptable salt thereof.
  • the compound of the present disclosure is represented by formula (Q-III): [0103] or a pharmaceutically acceptable salt thereof, wherein: [0104] K is -C(O)- or -C(R b ) 2 -; [0105] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0106] each R b is H or C 1-3 alkyl; [0107] R c is H, deuterium, C 1-3 alkyl, or halogen; [0108] R d is H or C 1-3 alkyl; [0109] s is 0, 1, 2 or 3; [0110] LI is a linker, and [0111] PTC is selected from Table C; [0112] LI is a linker having the formula —LX A —Y—LX B — [0113] wherein: [0114] Y is –(CH 2 ) m1 –, –(CH
  • the compound of the present disclosure is represented by formula (Q-IV): [0124] or a pharmaceutically acceptable salt thereof, wherein: [0125] K is -C(O)- or -C(R b ) 2 -; [0126] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0127] each R b is H or C 1-3 alkyl; [0128] R c is H, deuterium, C 1-3 alkyl, or halogen; [0129] R d is H or C 1-3 alkyl; [0130] s is 0, 1, 2 or 3; [0131] LI is a linker, and [0132] PTC is selected from Table D; [0133] LI is a linker having the formula —LX A —Y—LX B — [0134] wherein: [0135] Y is –(CH 2 ) m1 –, –(CH
  • a pharmaceutical composition comprising a compound of formula (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q- IV), (i)-(xviii), (a)-(h), (j), or (k), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is provided.
  • the composition further comprising one or more additional therapeutic agents.
  • the present disclosure relates to methods for modulating androgen receptor activity, comprising administering a compound of formula (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a compound of formula Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the modulating androgen receptor activity is for treating a condition or disease selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
  • a condition or disease selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
  • the present disclosure relates to methods for treating cancer, comprising administering a compound of formula (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, or salivary gland carcinoma.
  • the cancer is prostate cancer.
  • prostate cancer is metastatic castration-resistant prostate cancer.
  • the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.
  • Fig. 1A shows a Western blot demonstrating dose dependent activity in degrading AR and AR-V7 in 22Rv1 cell line.
  • Fig.1B shows a Western blot demonstrating dose dependent activity in degrading AR in LNCaP cell line.
  • Fig. 1C shows a Western blot demonstrating dose dependent activity in degrading AR and AR-V7 in VCaP cell line.
  • Fig.1D shows a Western blot demonstrating dose dependent activity in degrading AR- V567es in CWR-R1-D567 cell line.
  • Fig.2A shows a Western blot analysis of glucocorticoid receptor expression in DU145 cell line.
  • Fig.2B shows a Western blot analysis of glucocorticoid receptor expression in PC-3 cell line.
  • a or “an” refers to one or more of that entity; for example, “a androgen receptor modulator” refers to one or more androgen receptor modulators or at least one androgen receptor modulator. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.
  • an inhibitor by the indefinite article “a” or “an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.
  • the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
  • the present invention may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and/or reagents described in the claims.
  • the claims may be drafted to exclude any optional element.
  • Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • the term “treating” means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • the compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • a “prodrug” refers to a derivative of a compound of the present disclosure that will be converted to the compound in vivo.
  • a prodrug includes a PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), having a free hydroxyl group (-OH) that is acetylated (-OCOMe) at one or more positions.
  • An "effective amount” means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment.
  • the “effective amount” will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated. [0169]
  • the term "therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
  • a “subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like.
  • the subject can be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
  • a cancer such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer
  • acne hirsutism
  • alopecia benign prostatic hyperplasia
  • ovarian cysts ovarian cysts
  • polycystic ovary disease precocious puberty
  • spinal and bulbar muscular atrophy or age-related macular degeneration.
  • Diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, salivary gland carcinoma, or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of ordinary skill in the art.
  • “Mammal” includes humans and both domestic animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • All weight percentages i.e., "% by weight” and “wt. %” and w/w referenced herein, unless otherwise indicated, are measured relative to the total weight of the pharmaceutical composition.
  • “substantially” or “substantial” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is "substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of "substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • a composition that is "substantially free of" other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents.
  • Ubiquitin Proteasome Pathway System relates to the ubiquitin proteasome pathway, conserved from yeast to mammals, and is required for the targeted degradation of most short-lived proteins in the eukaryotic cell. Targets include cell cycle regulatory proteins, whose timely destruction is vital for controlled cell division, as well as proteins unable to fold properly within the endoplasmic reticulum. Ubiquitin modification is an ATP-dependent process carried out by three classes of enzymes.
  • E1 An “ubiquitin activating enzyme” (E1) forms a thio-ester bond with ubiquitin, a highly conserved 76-amino acid protein. This reaction allows subsequent binding of ubiquitin to a “ubiquitin conjugating enzyme” (E2), followed by the formation of an isopeptide bond between the carboxy-terminus of ubiquitin and a lysine residue on the substrate protein. The latter reaction requires a “ubiquitin ligase” (E3). E3 ligases can be single- or multi-subunit enzymes. In some cases, the ubiquitin-binding and substrate binding domains reside on separate polypeptides brought together by adaptor proteins or culling.
  • E3 ligases provide specificity in that each can modify only a subset of substrate proteins. Further specificity is achieved by post-translational modification of substrate proteins, including, but not limited to, phosphorylation. Effects of monoubiquitination include changes in subcellular localization. However, multiple ubiquitination cycles resulting in a polyubiquitin chain are required for targeting a protein to the proteasome for degradation.
  • the multisubunit 26S proteasome recognizes, unfolds, and degrades polyubiquitinated substrates into small peptides. The reaction occurs within the cylindrical core of the proteasome complex, and peptide bond hydrolysis employs a core threonine residue as the catalytic nucleophile.
  • the central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases (Wang et al. Cell Mol Immunol. 2006 Aug; 3(4):255-61).
  • “Ligase” as used herein, is an enzyme that can catalyze the joining of two or more compounds or biomolecules by bonding them together with a new chemical bond.
  • the “ligation” of the two usually with accompanying hydrolysis of a small chemical group dependent to one of the larger compounds or biomolecules, or the enzyme catalyzing the linking together of two compounds, e.g., enzymes that catalyze joining of groups C-O, C-S, C-N, etc.
  • Ubiquitin-protein (E3) ligases are a large family of highly diverse enzymes selecting proteins for ubiquitination.
  • “Ub Ligases” are involved in disease pathogenesis for oncology, inflammation & infectious disease.
  • Ligands as used herein bind to metal via one or more atoms in the ligand, and are often termed as chelating ligands. A ligand that binds through two sites is classified as bidentate, and three sites as tridentate.
  • the "bite angle” refers to the angle between the two bonds of a bidentate chelate.
  • Chelating ligands are commonly formed by linking donor groups via organic linkers.
  • a classic bidentate ligand is ethylenediamine, which is derived by the linking of two ammonia groups with an ethylene (-CH 2 CH 2 -) linker.
  • a classic example of a polydentate ligand is the hexadentate chelating agent EDTA, which is able to bond through six sites, completely surrounding some metals.
  • the binding affinity of a chelating system depends on the chelating angle or bite angle. Many ligands are capable of binding metal ions through multiple sites, usually because the ligands have lone pairs on more than one atom.
  • Some ligands can bond to a metal center through the same atom but with a different number of lone pairs.
  • the bond order of the metal ligand bond can be in part distinguished through the metal ligand bond angle (M-X- R).
  • This bond angle is often referred to as being linear or bent with further discussion concerning the degree to which the angle is bent.
  • an imido ligand in the ionic form has three lone pairs. One lone pair is used as a sigma X donor, the other two lone pairs are available as L type pi donors. If both lone pairs are used in pi bonds then the M-N-R geometry is linear.
  • halides and pseudohalides are important anionic ligands whereas ammonia, carbon monoxide, and water are particularly common charge-neutral ligands.
  • Simple organic species are also very common, be they anionic (RO ⁇ and RCO 2 ⁇ ) or neutral (R 2 O, R 2 S, R 3 ⁇ x NH x , and R 3 P).
  • Complexes of polydentate ligands are called chelate complexes. They tend to be more stable than complexes derived from monodentate ligands. This enhanced stability, the chelate effect, is usually attributed to effects of entropy, which favors the displacement of many ligands by one polydentate ligand.
  • “Chelator” as used herein relates to a binding agent that suppresses chemical activity by forming a chelate (a coordination compound in which a metal atom or ion is bound to a ligand at two or more points on the ligand, so as to form, for example, a heterocyclic ring containing a metal atom).
  • “Chelation” as used herein relates to a particular way that ions and molecules bind metal ions.
  • chelation involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central atom.
  • ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.
  • electrophile as used herein relates to species that is attracted to an electron rich center.
  • an electrophile is a reagent attracted to electrons. It participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids.
  • the I moiety at this position is enriched for 123 I.
  • the compounds contain more than the natural abundance of 123 I at the indicated position(s). It is not required that the compounds comprise 100% 123 I at the indicated positions, provided 123 I is present in more than the natural abundance.
  • the 123 I isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 80% or greater than 90%, relative to 127 I.
  • 18 F refers to the radioactive isotope of fluorine having atomic mass 18.
  • F or “ 19 F” refers to the abundant, non-radioactive fluorine isotope having atomic mass 19.
  • Alkyl or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included.
  • An alkyl comprising up to 12 carbon atoms is a C 1 -C 12 alkyl
  • an alkyl comprising up to 10 carbon atoms is a C 1 -C 10 alkyl
  • an alkyl comprising up to 6 carbon atoms is a C 1 -C 6 alkyl
  • an alkyl comprising up to 5 carbon atoms is a C 1 -C 5 alkyl.
  • a C 1 -C 5 alkyl includes C 5 alkyls, C 4 alkyls, C 3 alkyls, C 2 alkyls and C 1 alkyl (i.e., methyl).
  • a C 1 -C 6 alkyl includes all moieties described above for C 1 -C 5 alkyls but also includes C 6 alkyls.
  • a C 1 -C 10 alkyl includes all moieties described above for C 1 -C 5 alkyls and C 1 -C 6 alkyls, but also includes C 7 , C 8 , C 9 and C 10 alkyls.
  • a C 1 -C 12 alkyl includes all the foregoing moieties, but also includes C 11 and C 12 alkyls.
  • Non-limiting examples of C 1 -C 12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n- butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • an alkyl group can be optionally substituted.
  • Alkylene or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • C 1 -C 12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • alkylene chain can be optionally substituted.
  • alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkenyl group comprising up to 12 carbon atoms is a C 2 -C 12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C 2 - C 10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C 2 -C 5 alkenyl.
  • a C 2 -C 5 alkenyl includes C 5 alkenyls, C 4 alkenyls, C 3 alkenyls, and C 2 alkenyls.
  • a C 2 -C 6 alkenyl includes all moieties described above for C 2 -C 5 alkenyls but also includes C 6 alkenyls.
  • a C 2 -C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
  • a C 2 -C 12 alkenyl includes all the foregoing moieties, but also includes C 11 and C 12 alkenyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethenyl (vinyl), 1-propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-non
  • alkyl group can be optionally substituted.
  • alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds.
  • C 2 -C 12 alkenylene include ethene, propene, butene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • alkenylene chain can be optionally substituted.
  • alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkynyl group comprising up to 12 carbon atoms is a C 2 -C 12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C 2 - C 10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C 2 -C 5 alkynyl.
  • a C 2 -C 5 alkynyl includes C 5 alkynyls, C 4 alkynyls, C 3 alkynyls, and C 2 alkynyls.
  • a C 2 -C 6 alkynyl includes all moieties described above for C 2 -C 5 alkynyls but also includes C 6 alkynyls.
  • a C 2 -C 10 alkynyl includes all moieties described above for C 2 -C 5 alkynyls and C 2 -C 6 alkynyls, but also includes C 7 , C 8 , C 9 and C 10 alkynyls.
  • a C 2 -C 12 alkynyl includes all the foregoing moieties, but also includes C 11 and C 12 alkynyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds.
  • Non-limiting examples of C 2 -C 12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • alkynylene chain can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Alkylamino refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.
  • Alkylcarbonyl groups can also be referred to as “Cw-Cz acyl” where w and z depicts the range of the number of carbon in R a , as defined above.
  • C1- C 10 acyl refers to alkylcarbonyl group as defined above, where R a is C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl radical as defined above.
  • R a is C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl radical as defined above.
  • an alkyl carbonyl group can be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl is meant to include aryl radicals that are optionally substituted.
  • “Aralkyl” or “arylalkyl” refers to a radical of the formula -R b -R c where R b is an alkylene group as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • “Aralkenyl” or “arylalkenyl” refers to a radical of the formula -R b -R c where R b is an alkenylene o group as defined above and R c is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.
  • “Aralkynyl” or “arylalkynyl” refers to a radical of the formula -R b -R c where R b is an alkynylene group as defined above and R c is one or more aryl radicals as defined above.
  • Carbocyclyl refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
  • Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
  • Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
  • Cycloalkylalkyl refers to a radical of the formula -R b -R d where R b is an alkylene, alkenylene, or alkynylene group as defined above and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.
  • Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like.
  • Heterocyclyl refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
  • the heterocyclyl radical 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 heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • Heterocyclylalkyl refers to a radical of the formula -R b -R e where R b is an alkylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkylalkyl group can be optionally substituted.
  • Heterocyclylalkenyl refers to a radical of the formula -R b -R e where R b is an alkenylene group as defined above and R e is a heterocyclyl radical as defined above.
  • Heterocyclylalkynyl refers to a radical of the formula -R b -R e where R b is an alkynylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkylalkynyl group can be optionally substituted.
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group can be optionally substituted.
  • Heteroaryl refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical 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 heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl,
  • heteroaryl group can be optionally substituted.
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula -R b -R f where R b is an alkylene chain as defined above and R f is a heteroaryl radical as defined above.
  • heteroarylalkyl group can be optionally substituted.
  • “Heteroarylalkenyl” refers to a radical of the formula -R b -R f where R b is an alkenylene, chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkenyl group can be optionally substituted.
  • “Heteroarylalkynyl” refers to a radical of the formula -R b -R f where R b is an alkynylene chain as defined above and R f is a heteroaryl radical as defined above.
  • a heteroarylalkynyl group can be optionally substituted.
  • Ring refers to a cyclic group which can be fully saturated, partially saturated, or fully unsaturated. A ring can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless stated otherwise specifically in the specification, a ring can be optionally substituted.
  • Thioalkyl refers to a radical of the formula -SR a where R a is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
  • substituted means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups;
  • a non-hydrogen atoms such as
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple-bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • a point of attachment bond indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond.
  • the specific point of attachment to the non-depicted chemical entity can be specified by inference.
  • the compound CH 3 -R 3 wherein R 3 is H or “ ” infers that when R 3 is “XY”, the point of attachment bond is the same bond as the bond by which R 3 is depicted as being bonded to CH 3 .
  • “Fused” refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring can be replaced with a nitrogen atom.
  • Ubiquitination is crucial for a plethora of physiological processes, including cell survival and differentiation and innate and adaptive immunity. Proteins are built-up to cater for the structural and biochemical requirements of the cell and they are also broken-down in a highly- regulated process serving more purposes than just destruction and space management. Proteins have different half-lives, determined by the nature of the amino acids present at their N-termini. Some will be long-lived, while other will rapidly be degraded. Proteolysis not only enables the cell to dispose of misfolded or damaged proteins, but also to fine-tune the concentration of essential proteins within the cell, such as the proteins involved in the cell cycle.
  • Ub ligases These ubiquitin ligases, called “Ub ligases” are known to have a role in various diseases and conditions, including but not limited to, cancer, inflammation and infectious diseases. [0231] Further, there are various known methods for regulating ligases known in the art. Many ligases, particularly ligases involved in the Ubiquitin-Proteasome Pathway System (UPS), are known to have Zinc Finger (ZnF) domains that stabilize critical protein binding regions in that ligase. ZnF domains coordinate zinc ions and this coordination stabilizes functional activity of the protein.
  • UPS Ubiquitin-Proteasome Pathway System
  • the functional activity provided by proteins with ZnF domains can include the regulation of important cellular signaling pathways, such as recognizing ubiquitins, regulation of DNA, such as transcription and repair, and acting as cellular redox sensors.
  • the binding of zinc to ZnF domains, or simply just regulating how zinc interacts with the ZnF domains, are essential to ligases involved in the UPS.
  • the present invention relates to bifunctional chemical protein degraders (“degrader compounds”) that induce ubiquitination by the use of a ligase, such as E3 ligase and degrade a protein of interest.
  • Degrader compounds are typically designed with three parts: 1) a ligand/molecule that binds to and/or modulates ubiquitin ligases; 2) a small molecule that binds to the target protein of interest for proteolysis; and 3) a linker that links the two molecules together.
  • Degrader compounds thus function by allowing the ligand/molecule to bind to the ubiquitin ligases, thereby recruiting the target of protein of interest to the ligase for ubiquitination and ultimately proteolysis and degradation.
  • the present invention thus exhibits a broad array of applications in the pharmaceutical arts for degradation and/or inhibition of target proteins associated with disease, such as prostate cancer.
  • the compounds of the present invention can be used to treat diseases associated with overexpression and/or uncrontrolled activation of a protein/enzyme.
  • the compounds are bifunctional by binding to both a ligase and a target protein of interest for inhibitition or degredation, thereby reducing and/or inhibiting the undesirable overexpression and/or uncontrolled activation of said protein target.
  • the compounds of the present invention include molecules that are selective in binding to a ligase, such as an E3 ligase.
  • the present invention also also provides various options of linking the ligand/molecule that binds to and/or modulates ubiquitin ligases to the small molecule that binds to the target protein of interest.
  • the compounds of the present invention are linked in such a way so that the target protein is close enough in proximity to the ligase and thus effect degradation of the target protein, such as androgen receptor proteins.
  • the target protein such as androgen receptor proteins.
  • the following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
  • Degrader Compounds of the Present Disclosure [0235] The degrader compounds of the present disclosure can be useful for modifying the ubiquitination and subsequent degradation of androgen receptor proteins.
  • the compound is a bifunctional compound having an E3 ligase binding group that is covalently attached to one end of a Linker (“LI”), and an androgen receptor modulator (“PTC”) that is covalently attached to the other end of the linker (LI).
  • androgen receptor modulator is androgen receptor N-terminal domain inhibitor.
  • the compound of the present disclosure can be useful for treating various diseases and conditions including, but not limited to, cancer.
  • the linker is independently covalently bonded to the E3 ligase binding group and the PTC for example, through an amide, ester, thioester, keto, carbamate, carbon or ether, wherein the linking position can be anywhere on the E3 ligase binding group and/or PTC.
  • suitable linking positions provide maximum binding of the E3 ligase binding group to the E3 ligase and the PTC to the androgen receptor protein to be degraded, as well as maximum target ubiquitination.
  • the linker (LI) is of a length appropriate to bring together the androgen receptor protein and E3 ligase and thereby elicit the ubiquitination of the protein of interest and its subsequent degradation in the proteasome. It is therefore understood that the LI of the present disclosure serves as a spacer, physically separating the E3 ligase group and the PTC to a degree sufficient to ensure that binding with their respective targets occurs.
  • the length of the linker is optimized to maximize binding affinity between the PTC and androgen receptor protein, and the E3 ligase binding group and E3 ligase, as well as maximize target ubiquitination.
  • a compound of the invention comprises a E3 ligase binding group, a linker moiety, and a protein target compound moiety.
  • a compound of the invention has the structure of formula (Q ⁇ ): PTC—LI—CRB (Q ⁇ ); [0240] or a pharmaceutically acceptable salt thereof, wherein: [0241] CRB is an E3 ligase substrate receptor cereblon or a derivative thereof; [0242] LI is a linker, and [0243] PTC is an androgen receptor modulator; [0244] wherein one atom or one chemical group in the PTC is replaced to form a covalent bond to the LI; and [0245] wherein one atom or one chemical group in the CRB is replaced to form a covalent bond to the LI.
  • the degrader compounds of the present disclosure comprise an E3 ligase substrate receptor cereblon or a derivative thereof (collectively “CRB”) as the E3 ligase binding group.
  • CRB E3 ligase substrate receptor cereblon or a derivative thereof
  • Any one of CRB as disclosed herein can be used in formula (Q ⁇ ), including but not limited to, the structure depicted below and as presented in formula (Q), (Q-I), (Q-II), (Q-III), and (Q-IV).
  • Any one of CRB as disclosed herein can be used in formula (Q ⁇ ), including but not limited to, the structure depicted below and as presented in formula (Q ⁇ -I) and (Q ⁇ -II).
  • the dash “-” indicated between CRB and LI or LI and PTC in formula (Q ⁇ ), (Q), (Q ⁇ -I) (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), and (Q- IV) represents each component’s spacial orientation and not strictly as a C-C bond.
  • the CRB can be discussed as its own component having a chemical group necessary to covalently attach to LI.
  • the PTC can be discussed as its own component having a chemical group necessary to covalently attach to LI.
  • a compound of the invention has the structure of formula (Q): [0251] or a pharmaceutically acceptable salt thereof, wherein: [0252] K is -C(O)- or -C(R b ) 2 -; [0253] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0254] each R b is H or C 1-3 alkyl; [0255] R c is H, deuterium, C 1-3 alkyl, or halogen; [0256] R d is H or C 1-3 alkyl; [0257] s is 0, 1, 2 or 3; [0258] LI is a linker, and [0259] PTC is an androgen receptor modulator.
  • the compound of the present disclosure is represented by formula (Q): [0261] or a pharmaceutically acceptable salt thereof, wherein: [0262] K is -C(O)- or -C(R b ) 2 -; [0263] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0264] each R b is H or C 1-3 alkyl; [0265] R c is H, deuterium, C 1-3 alkyl, or halogen; [0266] R d is H or C 1-3 alkyl; [0267] s is 0, 1, 2 or 3; [0268] LI is a linker, and [0269] PTC is an androgen receptor modulator represented by formula (A), or any compounds of Tables C and D; [0270] wherein one atom or one chemical group in the PTC is replaced to form a covalent bond to the LI.
  • K is -C(O)- or -C(R b
  • the compound of the present disclosure is represented by formula (Q ⁇ -I): [0272] or a pharmaceutically acceptable salt thereof, wherein: [0273] E a , E b , E c , and E d are each independently CR a or N; [0274] E e and E f are each C; [0275] wherein up to two of E a , E b , E c , and E d can be N; [0276] K 1 is NR b , -C(O)- or -C(R b ) 2 -; [0277] K 2 is absent, NR b , or -C(R b ) 2 -, wherein when K 2 is present, the bond between K 1 and K 2 is a single bond or a double bond; [0278] each R a is independently hydrogen, halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0279] R b is H
  • the compound of the present disclosure is represented by formula (Q-I): [0316] or a pharmaceutically acceptable salt thereof, wherein: [0317] K is -C(O)- or -C(R b ) 2 -; [0318] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0319] each R b is H or C 1-3 alkyl; [0320] R c is H, deuterium, C 1-3 alkyl, or halogen; [0321] R d is H or C 1-3 alkyl; [0322] s is 0, 1, 2 or 3; [0323] LI is a linker, and [0324] PTC is an androgen receptor modulator represented by formula (I): [0325] or a pharmaceutically acceptable salt,
  • the compound has the structure of formula (Q-Ia): [0353] or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: [0354] K is -C(O)- or -C(R b ) 2 -; [0355] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0356] each R b is H or C 1-3 alkyl; [0357] R c is H, deuterium, C 1-3 alkyl, or halogen; [0358] R d is H or C 1-3 alkyl; [0359] s is 0, 1, 2 or 3; [0360] LI is a linker having the formula —LX A —Y—LX B — [0361] wherein: [0362] Y is –(CH 2 ) m1 –, –(CH 2 )
  • the compound has the structure of formula (Q-Ib): [0372] wherein: [0373] K 1 is N or -CR b ; [0374] K 2 is N or -CR b -, [0375] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0376] each R b is H or C 1-3 alkyl; [0377] R c is H, deuterium, C 1-3 alkyl, or halogen; [0378] R d is H or C 1-3 alkyl; [0379] s is 0, 1, 2 or 3; [0380] LI is a linker having the formula —LX A —Y—LX B — [0381] wherein: [0382] Y is –(CH 2 ) m1 –, –(CH 2 ) m2 -O–, –(CH 2 )
  • the compound is a compound of formula (x) (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), or (xviii): wherein p is 1 or 2;
  • the compound is Compounds 53- 62, 72, 78, 79, 85, 86, 89, 90, 104, 106, 123-125, and/or 127.
  • the compound of the present disclosure is represented by formula (Q ⁇ -II): [0395] or a pharmaceutically acceptable salt thereof, wherein: [0396] E a , E b , E c , and E d are each independently CR a or N; [0397] E e and E f are each C; [0398] wherein up to two of E a , E b , E c , and E d can be N; [0399] K 1 is NR b , -C(O)- or -C(R b ) 2 -; [0400] K 2 is absent, NR b , or -C(R b ) 2 -, wherein when K 2 is present, the bond between K 1 and K 2 is a single bond or a double bond; [0401] each R a is independently hydrogen, halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0402] R b is
  • the compound of the present disclosure is represented by formula (Q-II): [0429] or a pharmaceutically acceptable salt thereof, wherein: [0430] K is -C(O)- or -C(R b ) 2 -; [0431] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0432] each R b is H or C 1-3 alkyl; [0433] R c is H, deuterium, C 1-3 alkyl, or halogen; [0434] R d is H or C 1-3 alkyl; [0435] s is 0, 1, 2 or 3; [0436] LI is a linker, and [0437] PTC is an androgen receptor modulator represented by formula (II), or a pharmaceutically acceptable salt, tauto
  • the compound has the structure of formula (Q-IIa): [0441] or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: [0442] K is -C(O)- or -C(R b ) 2 -; [0443] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0444] each R b is H or C 1-3 alkyl; [0445] R c is H, deuterium, C 1-3 alkyl, or halogen; [0446] R d is H or C 1-3 alkyl; [0447] s is 0, 1, 2 or 3; [0448] LI is a linker having the formula —LX A —Y—LX B — [0449] wherein: [0450] Y is –(CH 2 ) m1 –, –(CH 2
  • the compound has the structure of formula (Q-IIb): [0460] wherein: [0461] K 1 is N or -CR b -; [0462] K 2 is N or -CR b -, [0463] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0464] each R b is H or C 1-3 alkyl; [0465] R c is H, deuterium, C 1-3 alkyl, or halogen; [0466] R d is H or C 1-3 alkyl; [0467] s is 0, 1, 2 or 3; [0468] LI is a linker having the formula —LX A —Y—LX B — [0469] wherein: [0470] Y is –(CH 2 ) m1 –, –(CH 2 ) m2 -O–, –(CH 2 ).
  • the compound in one embodiment of the compound of formula (Q-II), is a compound of formula (a), (b), (c), (d), or (e): or a pharmaceutically acceptable salt thereof.
  • the compound in one embodiment of the compound of formula (Q ⁇ -II), is a compound of formula (f), (g), (h), (j), or (k): (k); or a pharmaceutically acceptable salt thereof.
  • the compound is selected from Compounds 1-52, 63-69, 73-77, 80-84, 87, 88, 91-103, 105, 107-122, 126, and/or 176-196, 200.201, 203, 204, and/or 206-223.
  • the compound is selected from Compounds 1-52, 63-69, 73-77, 80-84, 87, 88, 91-103, 105, 107-122, 126, and/or 176-196, 200.
  • the compound is selected from Compounds 197-199. In one embodiment of the compound of formula (Q ⁇ -II), the compound is selected from Compounds 197-199, 228, 251, 276, 281-283, 312, 317, 322, 335, 336, 368, 373, 380, and/or 381.
  • the compound of the present disclosure is represented by formula (Q-III): [0483] or a pharmaceutically acceptable salt thereof, wherein: [0484] K is -C(O)- or -C(R b ) 2 -; [0485] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0486] each R b is H or C 1-3 alkyl; [0487] R c is H, deuterium, C 1-3 alkyl, or halogen; [0488] R d is H or C 1-3 alkyl; [0489] s is 0, 1, 2 or 3; [0490] LI is a linker, and [0491] PTC is selected from Table C; [0492] LI is a linker having the formula —LX A —Y—LX B — [0493] wherein: [0494] Y is –(CH 2 ) m1 –, –(CH
  • the compound of the present disclosure is represented by formula (Q-IV): [0504] or a pharmaceutically acceptable salt thereof, wherein: [0505] K is -C(O)- or -C(R b ) 2 -; [0506] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0507] each R b is H or C 1-3 alkyl; [0508] R c is H, deuterium, C 1-3 alkyl, or halogen; [0509] R d is H or C 1-3 alkyl; [0510] s is 0, 1, 2 or 3; [0511] LI is a linker, and [0512] PTC is selected from Table D; [0513] LI is a linker having the formula —LX A —Y—LX B — [0514] wherein: [0515] Y is –(CH 2 ) m1 –, –(CH
  • the PTC in formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-III), and/or (Q-IV) is a compound of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II) minus any functional group that would be involved in making the PTC-LI bond.
  • the compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-III), and/or (Q-IV), LI can be bound directly to the aryl ring of the CRB or to substituent R a of the CRB.
  • the compound of the present disclosure relates to the degrader compounds of Table A.
  • the compound is selected from Compounds 1-102.
  • the compound is selected from Compounds 1-149.
  • the compound is selected from Compounds 1-174, 176-201, 203, 204, or 206-223.
  • the compound is selected from Compounds 1-174, 176-201, 203, 204, 206-320, 322-354, or 356-381. [0527] Table A. Degrader Compounds [0528] In some embodiments the compound is not a compound disclosed in Table B: [0529] Table B
  • the degrader compounds of the present disclosure comprise an E3 ligase substrate receptor cereblon or a derivative thereof (collectively “CRB”). Any one of CRB as disclosed herein can be used in formula (Q ⁇ ), including but not limited to, the structure depicted below and as presented in formula which has the below structure as presented in formula (Q), (Q ⁇ -I), (Q-I), [0532] Examples of celeblon ligands are disclosed in US9,750,816 and Wustrow, D.; Zhou, H.- J.; Rolfe, M., Annu. Rep. Med.
  • CRB has the following structure: [0534] wherein: [0535] K is -C(O)- or -C(R b ) 2 -; [0536] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0537] R b is H or C 1-3 alkyl; [0538] R c is H, deuterium, C 1-3 alkyl, F, or Cl; [0539] R d is H or C 1-3 alkyl; [0540] R e is each independently H or C 1-3 alkyl; or two R e , together with the carbon atom to which they are attached, form a C(O), a C 3 -C 6 carbocycle, or a 4- to 6-membered heterocycle comprising 1 or 2 heteroatom
  • CRB has the following structure: [0546] wherein: [0547] K is -C(O)- or -C(R b )2-; [0548] each R a is independently C 1-6 alkoxy; [0549] R b is H or C 1-3 alkyl; [0550] R c is H, deuterium, C 1-3 alkyl, F, or Cl; [0551] R d is H or C 1-3 alkyl; [0552] R e is each independently H or C 1-3 alkyl; or two R e , together with the carbon atom to which they are attached, form a C(O) or a C 3 -C 6 carbocycle; [0553] R f is each independently C 1-3 alkyl; [0554] s is 0, 1, 2 or 3; [0555] r is 0, 1 or 2; and [0556] wherein one atom or one chemical group in the CRB is replaced to form
  • K is -C(O)- or -CH 2 -.
  • s is 0, 1, or 2. In some embodiments, s is 0 or 1.
  • R a is a hydrogen or halogen. In some embodiments, R a is a hydrogen.
  • R a is a hydrogen.
  • R a is a halogen. In some embodiments, R a is a fluorine.
  • R d is H.
  • the CRB is selected from: wherein any one of the hydrogen atoms in the CRB can be replaced to form a covalent bond to the LI.
  • the CRB is selected from: , wherein any one of the hydrogen atoms in the CRB can be replaced to form a covalent bond to the LI.
  • CRB is selected from: ,
  • any one of the hydrogen atoms in the CRB can be replaced to form a covalent bond to the LI.
  • the CRB is .
  • the CRB is [0566] In some embodiments of the compound of formula (Q ⁇ ), (Q), (Q-I), (Q-Ia), (Q-II), (Q- IIa), (Q-III), and/or (Q-IV), the CRB is [0566] In some embodiments of the compound of formula (Q ⁇ ), (Q), (Q-I), (Q-Ia), (Q-II), (Q- IIa), (Q-III), and/or (Q-IV), the CRB is [0566] In some embodiments of the compound of formula (Q ⁇ ), (Q), (Q-I), (Q-Ia), (Q-II), (Q- IIa), (Q-III), and/or (Q-IV), the CRB is [0566] In some embodiments of the compound of formula (Q ⁇ ), (Q), (Q-I), (Q-Ia), (Q-II), (Q- IIa), (Q-III), and/or (Q-IV), the CRB is [0566] In some embodiments of the
  • CRB has the following structure: [0568] wherein: [0569] E a , E b , E c , and E d are each independently CR a or N; [0570] E e and E f are each C; [0571] wherein up to two of E a , E b , E c , and E d can be N; [0572] K 1 is NR b , -C(O)- or -C(R b ) 2 -; [0573] K 2 is absent, NR b , or -C(R b ) 2 -; [0574] each R a is independently hydrogen, halogen, OH, C 1-6 alkyl, or C 1-6
  • CRB has the following structure: [0585] wherein: [0586] K 3 is absent, -NR b -, alkylene, or -O-; [0587] each R a is independently halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy; [0588] R b is H or C 1-3 alkyl; [0589] R c is H, deuterium, C 1-3 alkyl, F, or Cl; [0590] R d is H or C 1-3 alkyl; [0591] R e is each independently H or C 1-3 alkyl; or two R e , together with the carbon atom to which they are attached, form a C(O), a C 3 -C 6 carbocycle, or a 4- to 6-membered heterocycle comprising 1 or
  • any of the LI disclosed herein can be the linker as covalently attached to the CRB and/or to the PTC. In certain embodiments, any of the LI disclosed herein can describe the linker moiety before covalently attaching it to the CRB and/or to the PTC.
  • LI can comprise a chemical group (e.g., alcohol, amine, azides, -C ⁇ CH, etc) which can be reacted with another chemical group on or attached to the CRB or the PTC in order to form a covalent bond, e.g., amine bond, ether bond, amide bond, ester bond, triazole (Click chemistry).
  • a chemical group already present in the LI as described herein can be used to covalently attach the LI to the CRB and/or to the PTC.
  • the chemistry used to covalently attach the CRB to the LI and LI to the PTC can be readily understood by one skilled in the art.
  • any of the LI disclosed herein can further comprise a chemical group useful in covalently attaching LI to the CRB and/or to the PTC.
  • the linker LI has the formula: —LX A —Y—LX B — [0601] wherein: [0602] Y is –(CH 2 ) m1 –, –(CH 2 ) m2 -O–, –(CH 2 ) m2 -NR 20 –, –(CH 2 ) m2 -NR 20 C(O)NR 20 - (CH 2 ) m2 –, –(CH 2 ) m2 C(O)NR 20 (CH 2 ) m2 –, –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 ) m2 – , –(CH 2 ) m2 - W 2 -(CH 2 CH 2 –W 1 )
  • the linker LI has the formula: —LX A —Y—LX B — [0612] wherein: [0613] Y is –(CH 2 ) m1 –, –(CH 2 ) m2 -O–, –(CH 2 ) m2 -NR 20 –, –(CH 2 ) m2 -NR 20 C(O)NR 20 - (CH 2 ) m2 –, –(CH 2 ) m2 C(O)NR 20 (CH 2 ) m2 –, –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 ) m2 – , –(CH 2 ) m2 - W 2 -(CH 2 CH 2 –W 1 )
  • Y can be bound to LX A and LX B in either direction. For example, if Y is –(CH 2 ) m2 -O–, then it can have the connectivity —LX A —(CH 2 ) m2 -O—LX B — or —LX A —O- (CH 2 ) m2 —LX B —.
  • each –CH 2 – in the linker is optionally substituted with halogen, methyl, cycloalkyl, or heterocycloalkyl. In some embodiments, each –CH 2 – in the linker is optionally substituted with halogen or methyl.
  • one or more –CH 2 – in the O linker is optionally substituted cyclopropyl or oxetane to form .
  • Y is –(CH 2 ) m2 -(triazole)-(CH 2 ) m2 –.
  • Y is —(CH 2 ) m2 -(CO) m3 -(heterocycle)- (CH 2 ) m2 –, –(CH 2 ) m2 -(W 1 –CH 2 CH 2 ) m1 -(CH 2 ) m2 -(heterocycle)-(CH 2 ) m2 –, –(CH 2 ) m2 - (heterocycle)-(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 CH 2 –W 2 )-(CH 2 ) m2 – , –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 CH 2 –W 2 )-(CH 2 ) m2 – , –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 CH 2 –W
  • Y is —(CH 2 ) m2 -(CO) m3 -(heterocycle)- (CH 2 ) m2 –, –(CH 2 ) m2 -(W 1 –CH 2 CH 2 ) m1 -(CH 2 ) m2 -(heterocycle)-(CH 2 ) m2 –, –(CH 2 ) m2 - (heterocycle)-(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 CH 2 –W 2 )-(CH 2 ) m2 – , –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 CH 2 –W 2 )-(CH 2 ) m2 – , –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 CH 2 –W
  • Y is —(CH 2 ) m2 -O– or –(CH 2 ) m2 -NR 20 – .
  • Y is –(CH 2 ) m2 -O– or –(CH 2 ) m2 -NR 20 –, wherein m2 is each independently, 0, 1, 2, 3, 4, or 5.
  • Y is –(CH 2 ) m2 -O– or –(CH 2 ) m2 -NR 20 –; m2 is each independently, 0, 1, 2, 3, 4, or 5; and LX B is –C(O)NR 20 –.
  • Y is –(CH 2 ) m2 -O– or –(CH 2 ) m2 -NR 20 –; m2 is each independently, 0, 1, 2, 3, 4, or 5; LX A is absent; and LX B is –C(O)NR 20 –.
  • the heterocycle, the heteroaryl, and/or the carbocycle in Y is optionally substituted.
  • the heterocycle, the heteroaryl, and/or the carbocycle in Y is optionally substituted with one or more selected from halogen, methyl, hydroxyl, oxo, or -NH 2 .
  • the heterocycle, the heteroaryl, and/or the carbocycle in Y is monocyclic or bicyclic.
  • the heterocycle, and/or the carbocycle in Y is a spiral bicycle or bridged bicycle.
  • Y is —(CH 2 ) m1 –, –(CH 2 ) m2 -O—, –(CH 2 ) m2 -NR 20 –, –(CH 2 ) m2 -NR 20 C(O)NR 20 - (CH 2 ) m2 –, –(CH 2 ) m2 C(O)NR 20 (CH 2 ) m2 –, –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 ) m2 – , –(CH 2 ) m2 - W 2 -(CH 2
  • Y is —(CH 2 ) m1 –, –(CH 2 ) m2 -O—, –(CH 2 ) m2 -NR 20 –, –(CH 2 ) m2 -NR 20 C(O)NR 20 - (CH 2 ) m2 –, –(CH 2 ) m2 C(O)NR 20 (CH 2 ) m2 –, –(CH 2 ) m2 -(CH 2 CH 2 –W 1 ) m1 -(CH 2 ) m2 – , –(CH 2 ) m2 - W 2 -(CH 2
  • the heterocycle is a monocyclic or bicyclic 3- to 8-membered saturated or partially saturated ring containing one, two, or three heteroatoms selected from N, O, or S; [0651] wherein the carbocycle is a mono monocyclic or bicyclic 3- to 8-membered saturated or partially saturated ring; [0652] each m1 is independently 1, 2, 3, 4, 5, 6, 7, or 8; [0653] each m2 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8; [0654] each –CH 2 – in Y is optionally substituted with halogen or methyl; and [0655] each -NH- in Y is optionally
  • the heterocycle in Y is morpholine, piperidine, piperazine, azetidine, hexahydropyrimidine, tetrahydropyrimidin-2(1H)-one, piperazin-2-one, azaspiro[3.3]heptane, 1-oxa-4,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, 1-oxa- 3,8-diazaspiro[4.5]decan-2-one, 5-oxa-2,8-diazaspiro[3.5]nonane, 3,9-diazaspiro[5.5]undecane, or 3,9-diazaspiro[5.5]undecan-2-one.
  • the heterocycle in Y is morpholine, piperidine, piperazine, azetidine, or azaspiro[3.3]heptane; and the carbocycle is bicyclo[1.1.1]pentane.
  • the compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q- Y is optionally methylated.
  • Y is , , each -NH- in Y is optionally methylated.
  • LI is wherein NH is optionally methylated.
  • LI is , wherein NH is optionally methylated.
  • LI is , wherein NH is optionally methylated.
  • LI is or ; wherein NH is optionally methylated.
  • LI is or ; wherein NH is optionally methylated.
  • LI is O wherein NH is optionally methylated.
  • LI is , , , , ; wherein NH is optionally methylated.
  • LI is , , , , ; wherein NH is optionally methylated.
  • LI is -O-, , wherein NH is optionally methylated.
  • NH is optionally methylated.
  • LI is w herein NH is optionally methylated.
  • LI is H , H , O O O O wherein NH is optionally methylated.
  • LI is , , O O wherein NH is optionally methylated.
  • each m1 is independently 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each m1 is independently 1, 2, 3, 4, 5, or 6. In some embodiments, each m1 is independently 1, 2, 3, or 4.
  • each m2 is independently 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, each m2 is independently 1, 2, 3, 4, 5, or 6. In some embodiments, each m2 is independently 1, 2, 3, or 4. [0673] In some embodiments, W 1 and W 2 are each independently, –O– or –N(R 20 )–.
  • linker LI corresponds to formula: —LX A —(CH 2 ) m1 —(CH 2 —CH 2 —LX B ) m2 —(CH 2 ) m3 —LX C —, wherein: [0677] —LX A is covalently bound to the PTC or CRB, and LX C — is covalently bound to the CRB or PTC; [0678] each m1 and m2 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; [0679] m3 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; [0680] LX A is absent (a bond), —CH 2 C(O)
  • LX A is absent (a bond), —CH 2 C(O)NR 20 —, or —NR 20 C(O)CH 2 —; wherein R 20 is hydrogen or C 1 -C 3 alkyl.
  • LX A is absent (a bond), —CH 2 C(O)NR 20 —, or —NR 20 C(O)CH 2 —; wherein R 20 is hydrogen, deuterium, halogen, or C 1 -C 3 alkyl.
  • LX A is absent (a bond), —CH 2 C(O)NH—, —NHC(O)CH 2 —.
  • LX B is absent (a bond), –CH 2 –, –O–, or –N(R 20 )–; wherein R 20 is hydrogen, deuterium, halogen, or C 1 -C 3 alkyl.
  • LX B is absent (a bond), –CH 2 –, –O– or –N(R 20 )–; wherein R 20 is hydrogen or C 1 -C 3 alkyl.
  • LX C is absent (a bond), –CH 2 –, –O–, or –NH–.
  • m1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • m2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • m3 is 1, 2, 3, 4, 5, or 6.
  • the sum of m1, m2, and m3 is less than or equal to 24.
  • the sum of m1, m2, and m3 is less than or equal to 24, less than or equal to 23, less than or equal to 22, less than or equal to 21, less than or equal to 20, less than or equal to 19, less than or equal to 18, less than or equal to 17, less than or equal to 16, less than or equal to 15, less than or equal to 14, less than or equal to 13, or less than or equal to 12.
  • the sum of m1, m2, and m3 is less than or equal to 12. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 13.
  • the sum of m1, m2, and m3 is less than or equal to 12. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 11. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 10. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 9. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 8. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 7. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 6. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 5.
  • the total number of atoms in a straight chain between PTC and CRB is 20 or less.
  • the linker LI corresponds to formula: —(CH 2 —CH 2 —O) m2 —CH 2 CH 2 —LX C —; —CH 2 C(O)NH—(CH 2 —CH 2 ) m2 —CH 2 CH 2 —LX C —; —CH 2 C(O)NH—(CH 2 —CH 2 —O) m2 —CH 2 —LX C —; —CH 2 C(O)NH—(CH 2 —CH 2 —O) m2 —CH 2 CH 2 —LX C —; or —CH 2 C(O)NH—CH 2 —(CH 2 —CH 2 —O) m2 —CH 2 CH 2 CH 2 —LX C —; [0695] wherein —(CH 2 —CH 2 —CH 2 —O) m2 —CH 2 CH 2 CH 2 —LX C —; [0695] wherein —(CH 2 —CH 2 —CH
  • the linker LI corresponds to formula —(CH 2 ) m1 —LX 1 —(CH 2 —CH 2 —LX 2 ) m2 —(CH 2 ) m3 —C(LX 3 )—, wherein: [0701] —(CH 2 ) m1 is covalently bound to the PTC or PLM, and C(LX 3 )— is covalently bound to the CRB or PTC; [0702] each m1, m2, and m3 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and [0703] each LX 1 , LX 2 , and LX 3 is independently absent (a bond), –O–, –S–, –S(O)–, – S(O) 2 –, or –N(R 20 ).
  • the sum of m1, m2, and m3 is less than or equal to 24. In one embodiment, the sum of m1, m2, and m3 is less than or equal to 24, less than or equal to 23, less than or equal to 22, less than or equal to 21, less than or equal to 20, less than or equal to 19, less than or equal to 18, less than or equal to 17, less than or equal to 16, less than or equal to 15, less than or equal to 14, less than or equal to 13, or less than or equal to 12.
  • LX 1 , LX 2 , and LX 3 are –O–.
  • the linker LI corresponds to formula —(CH 2 ) m1 —LX B —(CH 2 ) m2 —LX C —(CH 2 ) m3 —LX D —(CH 2 ) m4 —C(O)—, [0708] wherein: (CH 2 ) m1 is covalently bound to the PTC or CRB, and C(O) is covalently bound to the PLM or PTC; [0709] each m1, and m2 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; [0710] m3 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; [0711] m4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; [0712] LX B , LX C , and L
  • the sum of m1, m2, m3 and m4 is less than or equal to 24. In one embodiment, the sum of m1, m2, m3, and m4 is less than or equal to 23, less than or equal to 22, less than or equal to 21, less than or equal to 20, less than or equal to 19, less than or equal to 18, less than or equal to 17, less than or equal to 16, less than or equal to 15, less than or equal to 14, less than or equal to 13, or less than or equal to 12.
  • the Linker corresponds to formula —(CH 2 ) m1 —LX B —(CH 2 ) m2 — LX C —(CH 2 ) m3 —O—(CH 2 ) m4 —C(O)—, wherein: [0716] (CH 2 ) m1 is covalently bound to the PTC, and C(O) is covalently bound to the PLM; [0717] m1 is 0, 1, 2, or 3; [0718] m2 is independently 0, 1, 2, 3, 4, or 5; [0719] m3 is independently 1, 2, 3, 4, or 5; [0720] m4 is 1, 2 or 3; [0721] LX B and LX C are each independently absent (a bond), –O– or –N(R 20 )–; [0722] wherein each R 20 is independently selected from the group consisting of hydrogen, deuterium, C 1 -C 6 alkyl
  • the linker LI is a polyethylene glycol chain ranging in size from about 1 to about 12 ethylene glycol units, wherein each –CH 2 – in the polyethylene glycol is optionally substituted. In some embodiments, the linker LI is a polyethylene glycol chain ranging in size from about 2 to about 10 ethylene glycol units, wherein each –CH 2 – in the polyethylene glycol is optionally substituted.
  • the linker LI is a polyethylene glycol chain ranging in size from about 3 to about 5 ethylene glycol units, wherein each –CH 2 – in the polyethylene glycol is optionally substituted.
  • the linker LI corresponds to the formula: –L I —L II (q)–, [0725] wherein: [0726] L I is a bond or a chemical group coupled to at least one of a CRB, a PTC or a combination thereof, [0727] L II is a bond or a chemical group coupled to at least one of a CRB, a PTC, [0728] and q is an integer greater than or equal to 0; [0729] wherein each L I and L II is independently selected from a bond, CR L1 R L2 , — (CH 2 ) i
  • q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.
  • L I and L II are independently selected from a bond, —(CH 2 ) i —O—, —(CH 2 ) i —O—, —O—(CH 2 ) i —, —(CH 2 ) i —S—, — (CH 2 ) i —N—(CH 2 ) i —, —S—, —S(O)—, —S(O) 2 —, —OP(O)O—(CH 2 ) i —, —Si—(CH 2 ) i —, wherein i is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and at least one of L I and L II is not a bond.
  • the linker LI is selected from Table L1, wherein LI is covalently bound to CRB by replacing a hydrogen from LI with a covalent bond to the CRB; and wherein LI is covalently bound to PTC by replacing a hydrogen from LI with a covalent bond the PTC.
  • Linkers [0735] In some embodiments of the compound of formula (Q ⁇ ), (Q), (Q-I), and/or (Q-II), the linker LI is selected from Table L2: [0736] Table L2. Linkers
  • the linker LI is selected from Table L3: [0738] Table L3.
  • PTCs Protein Target Compounds
  • the PTCs of the present disclosure can be useful for modulating androgen receptor (AR). Further, the PTCs of the present disclosure can be useful for treating various diseases and conditions including, but not limited to, cancer.
  • the cancer is prostate cancer or breast cancer.
  • any of the PTCs disclosed herein can be a compound depicted as the compound before covalently attaching it to the LI.
  • one atom or one chemical group in the PTC is replaced to form a covalent bond to the LI.
  • one atom in the PTC is replaced to form a covalent bond to the LI.
  • one chemical group in the PTC is replaced to form a covalent bond to the LI.
  • the present disclosure provides PTCs comprising the structure of formula (I):
  • A is a 5- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl
  • B is a 5- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl
  • C is a 3- to 15-membered ring selected from aryl, carbocyclyl, heteroaryl, or heterocyclyl
  • Y is a bond, -(CR 8 R 9 ) m -, -O-, -S-, -
  • C is not [0896]
  • A is phenyl and B is a fused bicyclic 8-10 membered heteroaryl or aryl.
  • B is phenyl and A is a fused bicyclic 8-10 membered heteroaryl or aryl.
  • A is a 6,6-fused heteroaryl or heterocyclyl, 5,6-fused heteroaryl or heterocyclyl, 6,5-fused heteroaryl or heterocyclyl, or 5,5-fused heteroaryl or heterocyclyl.
  • A is , , , [0899] ring A3 is aromatic; [0900] E 1 , E 2 , E 3 , E 4 , and E 5 are each independently, C, CR 1 or N; [0901] G 1 , G 2 , G 3 , and G 4 , are each independently, C, CR 1 , C(R 1 ) 2 , O, S, N, or NR 1 ; [0902] wherein at least two of E 1 , E 2 , E 3 , E 4 , and E 5 is C or CR 1 (i.e., maximum 3 of E 1 , E 2 , E 3 , E 4 , and E 5 can be N); and [0903] wherein at least three of E 1 , E 2 , G 1 , G 2 , G 3 , and G 4 , is C,
  • ring A3 is phenyl. In one embodiment, ring A3 is a heteroaryl ring. In one embodiment, ring A3 is a pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-trizaine, or 1,3,5-triazine ring. [0905] In one embodiment, E 1 , E 2 , E 3 , E 4 , and E 5 is N, C, CH or CR 1 . In one embodiment, E 1 and E 2 are C, and E 3 , E 4 , and E 5 are each independently N, CH or CR 1 . [0906] In one embodiment, ring A5 is aromatic.
  • ring A5 is a heteroaryl ring. [0907] In one embodiment, ring A5 is partially aromatic. In one embodiment, ring A5 is a heterocyclyl or a carbocyclyl ring. In one embodiment, the bond between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , G 3 -G 4 and G 3 -E 2 are each a single bond. In one embodiment, one of the bond between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , G 3 -G 4 and G 3 -E 2 is a double bond.
  • E 1 and E 2 are each independently N or C, and G 1 , G 2 , G 3 , and G 4 , are each independently N, NR 1 , C, CH, CR 1 , O, or S.
  • A is a ring selected from bicyclo[1.1.1]pentane, 4,5,6,7-tetrahydroindole, indoline, indole, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, indazole, benzo[d]imidazole, benzo[d]isoxazole, benzo[b]thiophene, 1,3-dihydroisobenzofuran, quinazoline, 3,4- dihydrobenzo[b][1,4]oxazine, benzo[d]
  • A is a 5- to 10-membered fused or a bridged bicyclic ring.
  • A is ring selected from bicyclo[1.1.1]pentane, indoline, indole, indazole, quinazoline, 3,4- dihydro-2H-benzo[b][1,4]oxazine, 1H-benzo[d][1,2,3]triazole, naphthalene, 1,2- dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 2,3- dihydrobenzo[b][1,4]dioxine, isoindoline, or isoindolin-1-one, each ring is optionally substituted with one or two R 1 .
  • A is wherein each 1 ring is optionally substituted with one or two R . In one embodiment, A is
  • each ring is optionally substituted with one or two R 1 .
  • B is 5- or 6-membered aryl or heteroaryl.
  • B is a fused or a bridged bicyclic ring, optionally substituted with one or two R 2 .
  • B is a 6,6-fused ring, 6,5-fused ring, or 5,6-fused ring, each optionally substituted with one or two R 2 .
  • B is , optionally substituted with one or two R 2 , wherein B2 is a 5- or a 6-membered aryl, carbocyclyl, heteroaryl, or heterocyclyl ring.
  • B2 is a 6-membered aryl, carbocyclyl, heteroaryl or heterocyclyl ring.
  • B2 is a 6-membered aryl or heteroaryl ring. In one embodiment, B2 is a 5-membered carbocyclyl, heteroaryl or heterocyclyl ring. In one embodiment, B2 is a 5-membered heterocyclyl or heteroaryl ring. In one embodiment, heterocyclyl ring contains one, two, or three heteroatoms selected from N, S, or O. In one embodiment, heteroaryl contains one, two, or three heteroatoms selected from N, S, or O. In one embodiment, heteroaryl contains one or two nitrogen atoms as ring atoms.
  • B is wherein: [0915] ring B3 is aromatic; [0916] E 1 , E 2 , E 3 , E 4 , and E 5 are each independently, C, CR 2 or N; [0917] G 1 , G 2 , and G 3 , are each independently, C, CR 2 , C(R 2 ) 2 , O, S, N, or NR 2 ; [0918] wherein at least two of E 1 , E 2 , E 3 , E 4 , and E 5 is C or CR 2 (i.e., maximum 3 of E 1 , E 2 , E 3 , E 4 , and E 5 can be N); and [0919] wherein at least two of E 1 , E 2 , G 1 , G 2 , and G 3 , is C, CR 2 or C(R 2 ) 2 (
  • ring B3 is phenyl. In one embodiment, ring B3 is a heteroaryl ring. In one embodiment, ring B3 is a pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-trizaine, or 1,3,5-triazine ring. [0921] In one embodiment, ring B4 is aromatic. In one embodiment, ring B4 is a heteroaryl ring. [0922] In one embodiment, ring B4 is partially aromatic. In one embodiment, ring B4 is a heterocyclyl or a carbocyclyl ring.
  • the bond between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , and G 3 -E 2 are each a single bond.
  • B is , , , ,
  • ring B3 is aromatic; [0925] E 1 , E 2 , E 3 , E 4 , and E 5 are each independently, C, CR 2 or N; [0926] G 1 , G 2 , G 3 , and G 4 , are each independently, C, CR 2 , C(R 2 ) 2 , O, S, N, or NR 2 ; [0927] wherein at least two of E 1 , E 2 , E 3 , E 4 , and E 5 is C or CR 2 (i.e., maximum 3 of E 1 , E 2 , E 3 , E 4 , and E 5 can be N); and [0928] wherein at least three of E 1 , E 2 , G 1 , G 2 , G 3 , and G 4 , is C, CR 2 or C(R 2 ) 2 (i.e., maximum 3 of E 1 , E 2 , G 1 , G 2 , G 3 , and G 4 can be heteroatoms).
  • ring B3 is phenyl. In one embodiment, ring B3 is a heteroaryl ring. In one embodiment, ring B3 is a pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-trizaine, or 1,3,5-triazine ring. [0930] In one embodiment, ring B5 is aromatic. In one embodiment, ring B5 is a heteroaryl ring. [0931] In one embodiment, E 1 , E 2 , E 3 , E 4 , and E 5 are each independently N, C, CH or CR 2 .
  • E 1 and E 2 are C, and E 3 , E 4 , and E 5 are each independently N, CH or CR 2 .
  • ring B5 is partially aromatic.
  • ring B5 is a heterocyclyl or a carbocyclyl ring.
  • the bond between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , G 3 -G 4 and G 3 -E 2 are each a single bond.
  • one of the bonds between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , G 3 -G 4 and G 3 -E 2 is a double bond.
  • E 1 and E 2 are each independently N or C, and G 1 , G 2 , G 3 , and G 4 , are each independently N, NR 1 , C, CH, CR 1 , O, or S.
  • B is a 5- to 10-membered fused or a bridged bicyclic ring, optionally substituted with one or two R 2 .
  • B is an 8- to 10-membered fused or a bridged bicyclic ring, optionally substituted with one or two R 2 .
  • B is ring selected from bicyclo[1.1.1]pentane, indoline, indole, indazole, quinazoline, 3,4- dihydrobenzo[b][1,4]oxazine, benzo[d][1,2,3]triazole, naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, 2,3-dihydrobenzo[b][1,4]dioxine, isoindoline, or isoindolin-1-one, each ring is optionally substituted with one or two R 2 .
  • B is ring selected from bicyclo[1.1.1]pentane, indoline, indole, indazole, quinazoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 1H-benzo[d][1,2,3]triazole, naphthalene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 2,3- dihydrobenzo[b][1,4]dioxine, isoindoline, or isoindolin-1-one, each ring is optionally substituted with one or two R 2 .
  • B is: wherein each ring is optionally substituted with one or two R 2 .
  • a and B are each phenyl.
  • C is aryl or heteroaryl. In some embodiments, C is 5- to 10-membered aryl or heteroaryl. In other embodiments, C is aryl. In some embodiments, C is phenyl or naphthyl.
  • C is aryl. In some embodiments, C is phenyl. [0937] In one embodiment of the PTC of formula (A), (A-I), (A-II), (A-III), (B-I), (G), or (I), C is heteroaryl. In one embodiment, C monocyclic or bicyclic heteroaryl. In another embodiment, C is monocyclic heteroaryl. In some embodiments, C is 5- or 10-membered heteroaryl. In some embodiments, C is 5- or 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from O, S, or N, wherein the heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is 3- to 6-membered heterocyclyl; 5- or 6-membered heteroaryl or aryl; fused bicyclic 8-10 membered heteroaryl or aryl; or 3- to 7-membered carbocyclyl.
  • C is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, or pyrimidyl, which are each optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C which is substituted with (R 3 )n3, is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl.
  • C is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl, which are each substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is a bridged bicyclic carbocycle, 6,6-fused heteroaryl or heterocycle, 5,6-fused heteroaryl or heterocycle, 6,5-fused heteroaryl or heterocycle, or 5,5-fused heteroaryl or heterocycle.
  • C is a 6,6-fused heteroaryl or heterocycle, 5,6-fused heteroaryl or heterocycle, 6,5- fused heteroaryl or heterocycle, or 5,5-fused heteroaryl or heterocycle.
  • C is 3- to 6-membered heterocyclyl; 5- or 6-membered heteroaryl or aryl; fused bicyclic 8-10 membered heteroaryl or aryl; or 3- to 7-membered carbocyclyl.
  • C is pyrimidine, quinazoline, azetidine, or bicyclo[1.1.1]pentane. In one embodiment, C is a 6,6- fused heteroaryl or heterocycle, 5,6-fused heteroaryl or heterocycle, 6,5-fused heteroaryl or heterocycle, or 5,5-fused heteroaryl or heterocycle.
  • R 3 substituent(s) can be on the phenyl portion of the fused ring, on the pyrimidine portion of the fused ring, and/or on both the phenyl portion and the pyrimidine portion of the fused ring. This type of depiction of substituents on a multi-cyclic ring applies throughout this disclosure.
  • ring C3 and C5 is aromatic; [0946] E 1 , E 2 , E 3 , E 4 , E 5 , and E 6 are each independently, C, CH, CR 3 or N; [0947] G 1 , G 2 , and G 3 , are each independently, CH, CH 2 , CR 3 , C(R 3 ) 2 , O, S, N, NH, or NR 3 ; [0948] wherein at least two of E 1 , E 2 , E 3 , E 4 , and E 5 in ring C3 is C, CH, or CR 3 (i.e., maximum 3 of E 1 , E 2 , E 3 , E 4 , and E 5 is N); [0949] wherein at least three of E 1 , E 2 , E 3 , E 4 ,
  • ring C3 and C5 is aromatic;
  • E 1 , E 2 , E 3 , E 4 , E 5 and E 6 are each independently, C, CH, CR 3 or N;
  • G 1 , G 2 , G 3 , and G 4 are each independently, CH, CH 2 , CR 3 , C(R 3 ) 2 , O, S, N, NH, or NR 3 ;
  • E 1 , E 2 , E 3 , E 4 , and E 5 in ring C3 is C, CH, or CR 3 ;
  • at least three of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 in ring C7 is C, CH, or CR 3 ;
  • ring C3 or C5 is phenyl. In one embodiment, ring C3 or C5 is a heteroaryl ring. In one embodiment, ring C3 or C5 is a pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-trizaine, or 1,3,5-triazine ring. [0959] In one embodiment, ring C4 is aromatic. In one embodiment, ring C4 is a heteroaryl ring. [0960] In one embodiment, ring C4 is partially aromatic. In one embodiment, ring C4 is a heterocyclyl or a carbocyclyl ring.
  • the bond between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , and G 3 -E 2 are each a single bond.
  • E 1 , E 2 , E 3 , E 4 , E 5 and E 6 are each independently N, C, CH or CR 2 .
  • E 1 and E 2 are C
  • E 3 , E 4 , and E 5 are each independently N, CH or CR 3 .
  • ring C6 is partially aromatic.
  • ring C6 is a heterocyclyl or a carbocyclyl ring.
  • the bond between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , G 3 -G 4 and G 3 -E 2 are each a single bond. In one embodiment, one of the bonds between E 1 -G 1 , G 1 -G 2 , G 2 -G 3 , G 3 -G 4 and G 3 -E 2 is a double bond. [0963] In one embodiment, E 1 and E 2 are each independently N or C and G 1 , G 2 , G 3 , and G 4 , are each independently N, NH, NR 3 , C, CH, CR 3 , O, or S.
  • X is a bond or -(CR 5 R 6 )-.
  • Y is a bond, -CH 2 -, -C(CH 3 )H-, -NH-, or -O-; and
  • W is -CH 2 -, -CH 2 CH 2 -, -C(CH 3 )H-, -NR 7 -, -N(R 7 )CO-, or -CONR 7 -.
  • Y is -O- and W is -CH 2 -; or [0970] Y and W are each a bond.
  • Z is a bond or -O-;
  • L is hydrogen, halogen, -CF 2 R 10 , -CF 3 , -CN, -OR 10 , -NR 11 R 12 , -SO 2 R 17 , or - CONR 11 R 12 .
  • Z is a bond or -O-;
  • V is a bond, -CH 2 - or -CH 2 CH 2 -;
  • L is halogen or -NR 11 R 12 ; and
  • R 11 and R 12 are each independently hydrogen or C 1 -C 3 alkyl; or R 11 and R 12 taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl which optionally contains one or two additional heteroatoms selected from N, S, or O.
  • R 1 and R 2 are each independently Cl, -CN, -CF 3 , -NR 13 R 14 , -NR 14 COR 16 , or - CONR 13 R 14 , [0986] R 13 and R 14 are each independently hydrogen or C 1 -C 3 alkyl; [0987] R 16 is hydrogen or C 1 -C 3 alkyl. [0988] In one embodiment of the PTC of formula (A) or (I), [0989] n2 is 1 or 2; and [0990] at least one R 2 is Cl or -CN.
  • the PTC is selected from Compounds B7, B8, B9, B10, B17, B18, B19, B20, B21, B22 B23, B24, B28, B29, B30, B31, B32, B33, B34, B35, B35(R), B35(S), B36, B40, B44, B45, B46, B52, B53, B55, B56, B57, B58, B59, B60, B61,B62, B63, B64, B65, B69, B70, B71, B73, B74, B77, B81, B82, B83, B84, B85, B115, B122, B123, B124, B125, B126, B131, B133, B134, B135, B136, B137, B138, B139, B140, B143
  • the PTC is selected from: ; ; In one embodiment, the PTC is selected from: [0992] In one embodiment of the PTC of formula (A), (A-I), (A-II), (A-III), (B-I), (G), or (I), is selected from:
  • the present disclosure provides PTCs comprising the structure of formula (II): [0994] or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: [0995] C is a 5- to 7-membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member; [0996] X is a bond, -(CR 5 R 6 ) t -, or -NR 7 ; [0997] Y is a bond, -CH 2 -, -C(CH 3 )H-, -O-, -S-, -NH-, -NCH 3 -, or –N(COCH 3 )-; [0998] Z is a bond, -CH 2 -, -O-, or -NH-; [0999] W is a bond, -CH 2 -, -C(CH 3 )H
  • At least one R 3 is optionally substituted 4- or 6-membered heterocyclyl or heteroaryl, provided that 5- or 6-membered heterocyclyl is not when R 3 is pyrimidyl.
  • Z is a bond; V is a bond; L is -NR 11 R 12 ; and R 11 and R 12 , taken together with the nitrogen atom to which it is attached, form an optionally substituted heterocyclic ring.
  • the present disclosure provides PTCs comprising the structure of formula (J): [1034] or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein: [1035] C is pyrimidyl; [1036] X is a bond, -CH 2 - or -C(CH 3 ) 2 -; [1037] Z is -O- and -V-L is -CH 2 CH(OH)CH 3 , -CH 2 CH(OH)CH 2 Cl, or -CH 2 CH 2 CH 2 Cl; or [1038] Z is -NH-, V is -(CR 8a R 9a ) m -, and L is hydrogen or halogen; [1039] at least one R 3 is -CH 2 NHSO 2 CH 3 , -CH 2 N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 3 , - NHSO 2 CH 2 CH 3 , -SO 2 NH 2 ,
  • C is substituted with (R 3 )n3, and C is a pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl.
  • C is substituted with (R 3 )n3, and C is selected from C 1 -C 3 alkyl.
  • R 5 and R 6 are each independently hydrogen, or C 1 -C 3 alkyl; [1053] W is -CH 2 - or -C(CH 3 )H-; [1054] V is -CH 2 CH 2 -; and [1055] R 1 and R 2 are each independently hydrogen, halogen, or –CN.
  • the PTC is selected from Table C or Table D. In one embodiment, the PTC is selected from Table C. In one embodiment, the PTC is selected from Table D. [1067] In some embodiments of any one of the PTCs as disclosed herein, one atom in the PTC is replaced to form a covalent bond to the LI. In some embodiments, one chemical group in the PTC is replaced to form a covalent bond to the LI.
  • –V-L is –CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 Cl, –CH 2 CH 2 NH 2 , or -CH 2 CH 2 CH 2 NH 2 .
  • X is a bond, -CH 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • a and B are each independently 5- or 6-membered aryl or heteroaryl. In one embodiment, A and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene.
  • a and B are each phenyl. In another embodiment, A has a meta or para connectivity with X and Y. In some embodiments, B has a meta or para connectivity with X and Z. [1072] In one embodiment of the PTC of formula (A), (G), (H), (J), A and B are phenyl and has one of the connectivity as shown: . [1073] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), C is aryl or heteroaryl. In some embodiments, C is 5- to 10-membered aryl or heteroaryl. In other embodiments, C is aryl.
  • C is phenyl or naphthyl. In other embodiments, C is aryl. In some embodiments, C is phenyl. [1074] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), C is heteroaryl. In one embodiment, C monocyclic or bicyclic heteroaryl. In another embodiment, C is monocyclic heteroaryl. In some embodiments, C is 5- or 10-membered heteroaryl. In some embodiments, C is 5- or 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from O, S, or N, wherein the heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, or pyrimidyl, which are each optionally substituted with 1, 2, 3, 4, or 5 R 3 .
  • C which is substituted with (R 3 )n3, is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl.
  • C is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl, which are each substituted with 1, 2, 3, 4, or 5 R 3 .
  • C is selected from ,
  • R 3a is C 1 -C 3 alkyl.
  • C is selected from wherein R 3a is C 1 -C 3 alkyl. [1077] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), C is [1078] In one embodiment, C is or in its tautomeric form . In one embodiment, C is or in its tautomeric form .
  • C is heterocyclyl.
  • C is saturated or partially saturated heterocycle.
  • C is monocyclic or bicyclic.
  • C is 5- to 7-membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member.
  • C is aryl.
  • C is phenyl or naphthyl.
  • PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), or (I) C is phenyl.
  • C is bicyclic heteroaryl or heterocyclyl.
  • C is [1082] [1083]
  • Z is a bond, -CH 2 -, -C(CH 3 )H-, -O-, -S-, -NH-, -NCH 3 -, or –N(COCH 3 )-.
  • Z is -CH 2 -, -C(CH 3 )H-, -O-, -S-, -NH-, -NCH 3 -, or –N(COCH 3 )-.
  • Y is -CH2-, -C(CH3)H-, -O-, -S-, -NH-, -NCH3-, or –N(COCH3)-.
  • Y is a bond, -CH 2 -, -O-, or -NCH 3 -.
  • Y is a bond, -CH 2 -, - O-, or -NH-.
  • Y is -O-.
  • V is -(CR 8a R 9a ) m -, wherein m is 1, 2, or 3.
  • V is -(CR 8a R 9a ) m -, wherein R 8a and R 9a are each independently hydrogen, -OH, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl, optionally substituted C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, - NR 13 R 14 , optionally substituted –(C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted - (C 1 -C 3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , or optionally substituted -(C 1 -C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 9a taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl.
  • V is -(CR 8a R 9a ) m -, wherein R 8a and R 9a are each independently hydrogen, -OH, halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -NR 13 R 14 , – (C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , -(C 1 -C 3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , or -(C 1 -C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 9a , on the same carbon atom or on a different carbon atom, taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl.
  • V is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • V is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -, each optionally substituted with one or more of – OH, halogen, or C 1 -C 3 alkyl.
  • V is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(OH)CH 2 - or -CH 2 CH 2 CH 2 -.
  • V is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • V is -CH 2 - or -CH 2 CH 2 -.
  • V is -CH 2 - or -CH 2 CH 2 -.
  • V is -CH 2 - and L is halogen, -NH 2 , or -CF 3 ; or V is -CH 2 CH 2 - and L is halogen or -NH 2 .
  • L is hydrogen, halogen, -CF 2 H, -CF 3 , -CN, -O(C 1 -C 3 alkyl), -NR 11 R 12 , or -CONR 11 R 12 .
  • L is hydrogen, halogen, -CF 2 H, -CF 3 , -CN, -O(C 1 -C 3 alkyl), -NH 2 , -NH(C 1 - C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -CONH 2 , -CONH(C 1 -C 3 alkyl), or -CON(C 1 -C 3 alkyl) 2 .
  • L is hydrogen, halogen, -CF 3 , or –NH 2 .
  • L is halogen, -CCl 3 , -CCl 2 , -CF 3 , or –NH 2 .
  • L is halogen, -CF 3 , or –NH 2 .
  • L is hydrogen or halogen.
  • L is halogen.
  • L is Cl, or Br.
  • L is Cl.
  • W is a bond.
  • W is - (CR 8a R 9a ) m -, wherein m is 1, 2, or 3.
  • W is a bond, -CH 2 -, or -C(CH 3 )H-.
  • W is a -CH 2 - or -C(CH 3 )H-.
  • –Y-W- is –OCH 2 -, –OCH 2 CH 2 -, or –OCH(CH 3 )-.
  • Z is a bond, -CH 2 -, -C(CH 3 )H-, -O-, -S-, -NH-, -NCH 3 -, or –N(COCH 3 )-; and [1100] V is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • Z is a bond, -CH 2 -, -C(CH 3 )H-, -O-, -S-, -NH-, -NCH 3 -, or –N(COCH 3 )-;
  • V is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -; and
  • L is halogen, -NH 2 , or -CF 3 .
  • –Z-V-L is –Z-CH 2 CH 2 Cl, -Z-CH 2 CH 2 CH 2 Cl, –Z-CH 2 CH 2 NH 2 , or -Z-CH 2 CH 2 CH 2 NH 2 , wherein Z is a bond, -O-, –NH-, or –N(COCH 3 )-.
  • –Z-V-L is –OCH 3 .
  • -V-L is -CH 3 .
  • X is a bond, -CH 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -NH-, or –N(C 1 -C 6 alkyl)- .
  • X is a bond, -CH 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -NH-, –N(CH 3 )- , –N(CH 2 CH 3 )-, –N(iPr)-, or –N(tBu)-.
  • X is a bond, -CH 2 -, -C(CH 3 )H-, - C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • X is -CH 2 -, -C(CH 3 )H-, - C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • X is -CH 2 -, -C(CH 3 )H-, or -C(CH 3 ) 2 -.
  • X is -C(CH 3 ) 2 -.
  • R 1 and R 2 are each independently halogen, -CN, -CF 3 , -OH, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, – (C 1 -C 3 alkyl)-(C 1 -C 3 alkoxy), –(C 1 -C 3 alkyl)-OH, -NR 13 R 14 , –(C 1 -C 3 alkyl)-NR 13 R 14 , - NR 14 SO 2 R 16 , -(C 1 -C 3 alkyl)NR 14 SO 2 R 16 , -NR 14 COR 16 , -(C 1 -C 3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , -(C 1 -C 3 alkyl)-CONR 14 R 15 ,
  • R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted –(C 1 -C 6 alkyl)-(C 1 -C 6 alkoxy), optionally substituted –(C 1 -C 6 alkyl)-OH, -NR 13 R 14 , optionally substituted –(C 1 -C 6 alkyl)-NR 13 R 14 , -NR 14 SO 2 R 16 , optionally substituted -(C 1 -C 6 alkyl)NR 14 SO 2 R 16 , -NR 14 COR 16 , optionally substituted -(C 1 -C 6 alkyl)-NR 14 COR 16 , optionally substituted -(C 1 -C 6 alkyl)-NR 14 COR 16 , optionally substituted -(C 1 -C 6 alkyl)-NR 14 COR 16
  • R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy, optionally substituted –(C 1 -C 3 alkyl)-(C 1 -C 3 alkoxy), optionally substituted –(C 1 -C 3 alkyl)-OH, -NR 13 R 14 , –(C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 SO 2 R 16 , optionally substituted - (C 1 -C 3 alkyl)NR 14 SO 2 R 16 , -NR 14 COR 16 , optionally substituted -(C 1 -C 3 alkyl)-NR 14 COR 16 , - CONR 14 R 15 , optionally substituted -(C 1 -C 3 alkyl)-CONR 14 R 15 , -SO 2 NR 14 R 15 , optionally substituted -(C
  • R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , - OH, C 1 -C 3 alkyl, C 1 -C 3 alkoxy,–(C 1 -C 3 alkyl)-(C 1 -C 3 alkoxy), –(C 1 -C 3 alkyl)-OH, -NR 13 R 14 , – (C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 SO 2 R 16 , -(C 1 -C 3 alkyl)NR 14 SO 2 R 16 , -NR 14 COR 16 , -(C 1 -C 3 alkyl)- NR 14 COR 16 , -CONR 14 R 15 , -(C 1 -C 3 alkyl)-CONR 14 R 15 , -SO 2 NR 14 R 15 , -(C 1 -C 3 alkyl)-CONR 14 R 15 , -SO 2 NR 14 R 15 , -
  • R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, C 1 -C 3 alkyl, or - CONR 14 R 15 .
  • R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, methyl, methoxy, or –CONH 2 .
  • R 1 and R 2 are each independently hydrogen, Cl, -CN, -CF 3 , -OH, methyl, methoxy, or –CONH 2 .
  • R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, or methyl. In one embodiment, R 1 and R 2 are each independently Cl, -CN, -CF 3 , -OH, methyl, methoxy, or –CONH 2 . In one embodiment, R 1 and R 2 are each independently halogen, -CN, -CF 3 , -OH, or methyl. [1113] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), R 1 and R 2 are each halogen, methyl, -CF 3 , or -CN.
  • R 1 and R 2 are each halogen or -CN. In one embodiment, at least one of R 1 and R 2 is Cl or -CN. In one embodiment, at least two of R 1 and R 2 are each independently Cl or -CN. In one embodiment, R 1 and R 2 are each Cl or -CN. [1114] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), R 1 and R 2 are each independently optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 1 and R 2 are each independently 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl.
  • R 1 have one of the connectivity as shown below with respect to X and Y:
  • R 2 have one of the connectivity as shown below with respect to X and Z: .
  • n1 is 0, 1, or 2. In some embodiments, n1 is 0 or 1. In other embodiments, n1 is 0. In some embodiments, n1 is 1. In one embodiment, the sum of n1 and n2 is 0, 1, 2, 3, or 4. In some embodiments, the sum of n1 and n2 is 1, 2, 3, or 4. In one embodiment, the sum of n1 and n2 is 2.
  • n2 is 0, 1, or 2. In some embodiments, n2 is 1 or 2. In other embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. [1119] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), n3 is 1, 2, 3, 4, or 5. In some embodiments, n3 is 1, 2, 3, or 4. In one embodiment, n3 is 1, 2, or 3.
  • n3 is 1 or 2.
  • R 3 is selected from -NR 14 SO 2 R 16 , optionally substituted -(C 1 -C 6 alkyl)NR 14 SO 2 R 16 , or optionally substituted -SO 2 R 16 ; wherein R 16 is hydrogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl, optionally substituted C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl, or phenyl.
  • R 3 is selected from -NR 14 SO 2 R 16 , -(C 1 -C 6 alkyl)NR 14 SO 2 R 16 , or - SO 2 R 16 ; wherein R 16 is hydrogen, C 1 -C 3 alkyl, -(C 1 -C 3 alkyl)-NH 2 , C 3 -C 6 cycloalkyl, or phenyl.
  • R 3 is -SO 2 CH 3 , - NHSO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -SO 2 NH 2 , -CONH 2 , or -NHCOCH 3 .
  • R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF 3 , -OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -S(C 1 -C 3 alkyl), -SO 2 (C 1 -C 3 alkyl), -NH 2 , -NHSO 2 CH 3 , - NHSO 2 CF 3 , -N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -N(CH 3 )SO 2 CH 2 CH 3 , -CH 2 NHSO 2 CH 3 , - CH 2 N(CH 3 )SO 2 CH 3 , -SO 2 NH 2
  • R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF 3 , -OH, C 1 - C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -S(C 1 -C 3 alkyl), -SO 2 (C 1 -C 3 alkyl), -NH 2 , -NHSO 2 CH 3 , -NHSO 2 CF 3 , -N(CH 3 )SO 2 CH 3 , -CH 2 NHSO 2 CH 3 , -CH 2 N(CH 3 )SO 2 CH 3 , - SO 2 NH 2 , -CONH 2 , -CON(C 1 -C 3 alkyl) 2 , -CONH(C 1 -C 3 alkyl), -NHCO(C 1 -C 3 alkyl), - N(CH 3 )COO(C 1 -C 1 -
  • R 3 on a sp 2 carbon is each selected from hydrogen, halogen, -CN, -CF 3 , -OH, -S(C 1 -C 3 alkyl), C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, –(C 1 -C 3 alkyl)-(C 1 -C 3 alkoxy), –(C 1 -C 3 alkyl)-OH, -NR 13 R 14 , –(C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 SO 2 R 16 ,
  • R 3 on a nitrogen atom is each selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 - C 3 alkoxy, -(C 1 -C 3 alkyl)-(C 1 -C 3 alkoxy), -(C 1 -C 3 alkyl)-OH, -(C 1 -C 3 alkyl)-NR 13 R 14 , -(C 1 -C 3 alkyl)NR 14 SO 2 R 16 , -(C 1 -C 6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , -(C 1 -C 3 alkyl)-CONR 14 R 15 , -(C 1 - C 3 alkyl)-SO 2 NR
  • At least one R 3 is selected from -CN, C 1 -C 3 alkoxy, -CONH 2 , -NHSO 2 CH 3 , - N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -N(CH 3 )SO 2 CH 2 CH 3 , or -SO 2 CH 3 and the other R 3 , if present, is selected from -CN, -CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, - S(C 1 -C 3 alkyl), -SO 2 (C 1 -C 3 alkyl), -NH 2 , -(C 1 -C 3 alkyl)NH 2 ,
  • At least one R 3 is selected from -NHSO 2 CH 3 , -NHSO 2 CH 2 CH 3 , or - SO 2 CH 3 and the other R 3 , if present, is selected from -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -SO 2 (C 1 - C 3 alkyl), -NH 2 , -(C 1 -C 3 alkyl)NH 2 , -NHSO 2 CH 3 , -N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , - N(CH 3 )SO 2 CH 2 CH 3 , -SO 2 NH 2 , -CONH 2 , -CON(C 1 -C 3 alkyl) 2 , -CONH(C 1 -C 3 alkyl), - NHCO(C 1 -C 3 alkyl), -N(CH 3 )COO(C 1 -C 3 alkyl), -NHCO(C 1
  • R 3 is not hydrogen. [1129] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), at least one R 3 is -SO 2 CH 3 , -NHSO 2 CH 3 , -NCH 3 SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , or - N(CH 3 )SO 2 CH 2 CH 3 . In one embodiment, at least one R 3 is -SO 2 CH 3 , -NHSO 2 CH 3 , or - NCH 3 SO 2 CH 3 .
  • R 3 is heterocyclyl. In one embodiment, R 3 is heterocyclyl selected from . [1131] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), R 3 is -NR 14 SO 2 R 16 , wherein R 14 and R 16 together form a 5 or 6 membered ring including the nitrogen and sulfur atoms.
  • R 3 is -NR 14 SO 2 R 16 , wherein R 16 is optionally substituted C 1 -C 6 alkyl.
  • R 3 is -NR 14 SO 2 R 16 , wherein R 16 is C 1 -C 6 alkyl optionally substituted with one or more groups selected from halogen, -CN, -CF 3 , -OH, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NH 2 , -NH(C 1 -C 3 alkyl), - N(C 1 -C 3 alkyl) 2 , -SCH 3 .
  • R 3 is -NR 14 SO 2 R 16 , wherein R 16 is C 1 -C 3 alkyl substituted with -NH 2 .
  • R 3 is each independently, -CN, -CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, oxo, -S(C 1 -C 3 alkyl), -SO 2 (C 1 -C 3 alkyl), -NH 2 , -NH(C 1 -C 3 alkyl), -(C 1 -C 3 alkyl)NH 2 , - NHSO 2 CH 3 , -NHSO 2 CF 3 , -N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -N(CH 3 )SO 2 CH 2 CH 3 , - CH 2 NHSO 2 CH 3 , -CH 2 N
  • At least one R 3 is -CH 2 NHSO 2 CH 3 , -CH 2 N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 3 , -NHSO 2 CH 2 CH 3 , - SO 2 NH 2 , -SO 2 CH 3 , -NH 2 , or -NH(C 1 -C 3 alkyl).
  • At least one R 3 is -NHSO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -SO 2 NH 2 , or -SO 2 CH 3 .
  • the other R 3 is -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, - SO 2 (C 1 -C 3 alkyl), -NH 2 , -(C 1 -C 3 alkyl)NH 2 , -NHSO 2 CH 3 , -N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , - N(CH 3 )SO 2 CH 2 CH 3 , -SO 2 NH 2 , -CONH 2 , -CON(C 1 -C 3 alkyl) 2 , -CONH(C 1 -C 3 alkyl), - NHCO(C 1 -C 3 alkyl), -NHCOO(C 1 -C 3 alkyl), -N(CH 3 )CO(C 1 -C 3 alkyl), or -N(CH 3 )COO(C 1 -C 3 alkyl).
  • At least one R 3 is -CH 2 NHSO 2 CH 3 , -CH 2 N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 3 , -NHSO 2 CH 2 CH 3 , - SO 2 NH 2 , or -SO 2 CH 3 .
  • the other R 3 is -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -SO 2 (C 1 -C 3 alkyl), -NH 2 , -(C 1 -C 3 alkyl)NH 2 , -NHSO 2 CH 3 , - N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -N(CH 3 )SO 2 CH 2 CH 3 , -SO 2 NH 2 , -CONH 2 , -CON(C 1 -C 3 alkyl) 2 , -CONH(C 1 -C 3 alkyl), -NHCO(C 1 -C 3 alkyl), -NHCOO(C 1 -C 3 alkyl), -N(CH 3 )CO(C 1 -C 3 alkyl), or -N(CH 3 )COO(C 1 -C 3 alkyl).
  • At least one R 3 is -CH 2 NHSO 2 CH 3 , -CH 2 N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 3 , -NHSO 2 CH 2 CH 3 , - SO 2 NH 2 , or -SO 2 CH 3 ; and the other R 3 is, if present, -CN, -CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 - C 3 alkynyl, C 1 -C 3 alkoxy, oxo, -S(C 1 -C 3 alkyl), -SO 2 (C 1 -C 3 alkyl), -NH 2 , -NH(C 1 -C 3 alkyl), - (C 1 -C 3 alkyl)NH 2 ,
  • At least one R 3 is selected from -CN, C 1 -C 3 alkoxy, -CONH 2 , -NHSO 2 CH 3 , - N(CH 3 )SO 2 CH 3 , -NHSO 2 CH 2 CH 3 , -N(CH 3 )SO 2 CH 2 CH 3 , or -SO 2 CH 3 and the other R 3 , if present, is selected from -CN, -CF 3 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, - S(C 1 -C 3 alkyl), -SO 2 (C 1 -C 3 alkyl), -NH 2 , -(C 1 -C 3 alkyl)NH 2 ,
  • R 5 and R 6 are each independently hydrogen, halogen, -OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 - C 3 alkynyl, or C 1 -C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6- membered carbocyclyl or heterocyclyl.
  • R 5 and R 6 are each independently hydrogen, halogen, -OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl. In one embodiment, R 5 and R 6 are hydrogen, halogen, -OH, or C 1 -C 3 alkyl. In one embodiment, R 5 and R 6 are each independently hydrogen, F, -OH, or C 1 -C 3 alkyl. In one embodiment, R 5 and R 6 are each independently, hydrogen, F, - OH, or methyl. In one embodiment, R 5 and R 6 are each H. In one embodiment, R 5 and R 6 are each methyl.
  • R 5 and R 6 are each H or methyl.
  • R 7 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 7 is hydrogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl, optionally substituted C 2 -C 3 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 7 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 7 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 7 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl. In some embodiments, R 7 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl. In some embodiments, R 7 is hydrogen or C 1 -C 6 alkyl.
  • R 7 is hydrogen or C 1 -C 4 alkyl. In some embodiments, R 7 is hydrogen or C 1 -C 3 alkyl.
  • R 8a and R 9a are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, -NR 13 R 14 , optionally substituted –(C 1 -C 6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C 1 -C 6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C 1 -C 6 alkyl)- CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted
  • R 8a and R 9a are each independently hydrogen, -OH, halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -NR 13 R 14 , –(C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , -(C 1 -C 3 alkyl)- NR 14 COR 16 , -CONR 14 R 15 , or -(C 1 -C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 9a taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl.
  • R 8a and R 9a are each independently hydrogen, halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, -NR 13 R 14 , –(C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , -(C 1 -C 3 alkyl)-NR 14 COR 16 , - CONR 14 R 15 , or -(C 1 -C 3 alkyl)-CONR 14 R 15 .
  • R 8a and R 9a are not –OH. In one embodiment, R 8a and R 9a are not –OH.
  • R 7 and R 8a taken together form an optionally substituted heterocyclyl. In one embodiment, R 7 and R 8a taken together form an optionally substituted 3- to 7-membered heterocycle.
  • R 8 and R 9 are each independently hydrogen, halogen, or C 1 -C 3 alkyl.
  • R 10 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 10 is hydrogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl, optionally substituted C 2 -C 3 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 10 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 10 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl. In some embodiments, R 10 is hydrogen or C 1 -C 3 alkyl.
  • R 11 and R 12 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 11 and R 12 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl. In some embodiments. R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl. In some embodiments. R 11 and R 12 are each independently hydrogen or C 1 -C 3 alkyl.
  • R 11 and R 12 taken together form an optionally substituted heterocyclyl. In one embodiment, R 11 and R 12 taken together form an optionally substituted 3- to 7-membered heterocyclyl. In other embodiments, R 11 and R 12 taken together form 3- to 7-membered heterocyclyl.
  • R 13 and R 14 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 13 and R 14 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl. In some embodiments R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl. In some embodiments R 13 and R 14 are each independently hydrogen or C 1 -C 3 alkyl.
  • R 15 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, R 15 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl.
  • R 15 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl. In some embodiments, R 15 is hydrogen or C 1 -C 3 alkyl. [1153] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), or (I), R 14 and R 15 taken together form an optionally substituted heterocyclyl. In one embodiment, R 14 and R 15 taken together form an optionally substituted 3- to 7-membered heterocyclyl. In other embodiments, R 14 and R 15 taken together form 3- to 7-membered heterocyclyl.
  • R 16 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R 16 is hydrogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 3 alkenyl, optionally substituted C 2 -C 3 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R 16 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 16 is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl. In some embodiments, R 16 is hydrogen or C 1 -C 3 alkyl. [1155] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), or (I), m is 1 or 2. [1156] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), t is 1 or 2. In one embodiment, t is 1.
  • optional substituent is selected from halogen, -CN, -CF 3 , -OH, -S(C 1 -C 3 alkyl), C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, –(C 1 -C 3 alkyl)-(C 1 -C 3 alkoxy), –(C 1 -C 3 alkyl)-OH, -NR 13 R 14 , –(C 1 -C 3 alkyl)-NR 13 R 14 , -NR 14 SO 2 R 16 , -(C 1 -C 3 alkyl)NR 14 SO 2 R 16 , -NR 14 COR 16 , - NR 14 COOR 16 , -(C 1 -C 3 alkyl),
  • the optional substituent is selected from halogen, -CN, -CF 3 , -OH, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, -NH 2 , -SCH 3 , -SO 2 CH 3 , -NHSO 2 CH 3 , - CH 2 NHSO 2 CH 3 , -SO 2 NH 2 , -CONH 2 , or -NHCOCH 3 .
  • a and B are each monocyclic ring.
  • C is a 4- to 10-membered ring.
  • X is a bond, -CH 2 -, -C(CH 3 )H-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • X is -CH 2 -, - C(CH 3 )H-, or -C(CH 3 ) 2 -. In some embodiments, X is -C(CH 3 ) 2 -. [1164] In one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), or (I), X is –NR 7 -. In one embodiment, X is -NH-, –N(CH 3 )-, –N(CH 2 CH 3 )-, –N(iPr)-, or –N(tBu)-.
  • Y is –O-.
  • Z is –O-.
  • Y and Z are both –O-.
  • -V-L is CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 Cl, or –CH 3 . In some embodiments, -V-L is CH 2 CH 2 Cl or -CH 2 CH 2 CH 2 Cl.
  • n1 is 0.
  • n2 is 0, 1, or 2.
  • n2 is 2.
  • n2 is 2 and R 2 are each ortho to Z.
  • n2 is 2 and R 2 are each ortho to Z, wherein R 2 is halogen or –CN.
  • the compound in one embodiment of the PTC of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), the compound can be a stereoisomer.
  • the carbon attached to R 5 and R 6 can be in an S configuration or an R configuration.
  • X is a bond or -(CR 5 R 6 ) t ;
  • W is a bond, -CH 2 -, or -C(CH 3 )H-;
  • Y is -O-;
  • Z is -O-;
  • V is -CH 2 - or -CH 2 CH 2 -; and [1176] L is halogen.
  • a hydrogen atom can be replaced with a deuterium atom.
  • the PTC is selected from Table C below, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the PTC is selected from PTC A1-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the PTC is selected from Table D below, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the PTC is selected from PTC B1-B199, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the PTC is selected from PTC B1- B285, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • PTC in formula (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q ⁇ -II), (Q-II), (Q-IIa), (Q- III), and/or (Q-IV) is a compound of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), or any compounds of Table C and Table D, minus any functional group that was involved in making the PTC-LI bond. [1181] Table C. PTCs
  • any of the PTCs disclosed herein can further comprise a chemical group useful in covalently attaching the PTC to the LI.
  • any of the PTCs disclosed herein can be derivatized with a chemical group useful in covalently attaching the PTC to the LI.
  • any of the PTCs disclosed herein can be derivatized with a chemical group useful in covalently attaching the PTC to the LI.
  • the derivatization may include small linking group that can be covalently attach to LI (e.g., -NH-; - OC(O)NH-; -OC(O)-, etc).
  • the PTCs as disclosed herein is an androgen receptor modulator. In one embodiment, the PTCs as disclosed herein binds to androgen receptor. In another embodiment, the PTCs as disclosed herein binds to androgen receptor N-terminal domain. Therapeutic Use [1185] The present compounds find use in any number of methods. For example, in some embodiments the compounds are useful in methods for modulating androgen receptor (AR).
  • AR androgen receptor
  • the present disclosure provides the use of compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, for modulating androgen receptor (AR) activity.
  • modulating androgen receptor (AR) activity is in a mammalian cell.
  • Modulating androgen receptor can be in a subject in need thereof (e.g., a mammalian subject) and for treatment of any of the described conditions or diseases.
  • the modulating AR is binding to AR.
  • the modulating AR is inhibiting AR.
  • the modulating AR is modulating AR N-terminal domain (NTD).
  • the modulating AR is binding to AR NTD.
  • the modulating AR is inhibiting AR NTD.
  • the modulating AR is modulating AR N-terminal domain (NTD).
  • modulating the AR is inhibiting transactivation of androgen receptor N-terminal domain (NTD).
  • the present disclosure provides the use of compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, for degrading AR.
  • the present disclosure provides a means for degrading AR.
  • the present disclosure provides a means for inhibiting AR.
  • AR is full length AR (AR-FL) or AR splice variant.
  • AR splice variant is AR-V7 or AR-V567es.
  • AR is AR NTD.
  • modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age related macular degeneration, and combinations thereof.
  • the indication is prostate cancer.
  • the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, metastatic castration-resistant prostate cancer (CRPC), non-metastatic castration-resistant prostate cancer, or hormone-sensitive prostate cancer.
  • the prostate cancer is androgen dependent prostate cancer.
  • the spinal and bulbar muscular atrophy is Kennedy’s disease.
  • the present disclosure provides a method for treating cancer in a subject, comprising administering to the subject in need thereof, means for inhibiting AR.
  • cancer is prostate cancer.
  • the present disclosure provides a means for inhibiting AR.
  • AR is full length AR (AR-FL) or AR splice variant.
  • AR splice variant is AR-V7 or AR-V567es.
  • AR is AR NTD.
  • the degrader compounds of the present disclosure form a complex with an E3 ligase and an AR. In some embodiments, the complex is formed in vivo.
  • the CRB portion of the degrader compound binds to the E3 ligase and the PTC portion of the degrader compound binds to the AR to form the complex.
  • the degrader compounds can dissociate from the complex at the E3 ligase end and/or the AR end. In some embodiments, the complex formation is reversible. [1194] In one embodiment, the degrader compounds of the present disclosure facilitate or increase the rate of ubiquitination of the AR protein. [1195] In one embodiment, the degrader compounds of the present disclosure facilitate or increase the rate of degradation of the AR protein. In one embodiment, the degrader compounds of the present disclosure cause degradation of the AR protein.
  • the degrader compounds of the present disclosure have a half- maximal degradation concentration (DC 50 ) of about 0.001 ⁇ M to about 100 ⁇ M in an androgen receptor (AR) HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is about 0.001 ⁇ M to about 10 ⁇ M in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, or less than about 1 ⁇ M in an AR HiBiT 22Rv1 degradation assay at 24 hours. In some embodiments, the DC 50 of the degrader compound is about 0.01 ⁇ M to about 1 ⁇ M in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is less than about 1 ⁇ M in an AR HiBiT 22Rv1 degradation assay at 24 hours. In some embodiments, the DC 50 of the degrader compound is about 0.01 ⁇ M, about 0.02 ⁇ M, about 0.03 ⁇ M, about 0.04 ⁇ M, about 0.05 ⁇ M, about 0.06 ⁇ M, about 0.07 ⁇ M, about 0.08 ⁇ M, about 0.09 ⁇ M, about 0.1 ⁇ M, about 0.12 ⁇ M, about 0.14 ⁇ M, about 0.16 ⁇ M, about 0.18 ⁇ M, about 0.2 ⁇ M, about 0.22 ⁇ M, about 0.24 ⁇ M, about 0.26 ⁇ M, about 0.28 ⁇ M, about 0.3 ⁇ M, about 0.32 ⁇ M, about 0.34 ⁇ M, about 0.36 ⁇ M, about 0.38 ⁇ M, about 0.4 ⁇ M, about 0.42 ⁇ M, about 0.44 ⁇ M, about 0.46 ⁇ M, about 0.48 ⁇ M, about
  • the degrader compounds of the present disclosure have a half- maximal degradation concentration (DC 50 ) of about 0.5 nM to about 500 nM in an androgen receptor (AR) HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is about 1 nM to about 400 nM in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is about 1 nM to about 300 nM in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is about 1 nM to about 200 nM in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween. In some embodiments, the DC 50 of the degrader compound is about 1 nM to about 100 nM in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween. In some embodiments, the DC 50 of the degrader compound is about 1 nM to about 50 nM in an AR HiBiT 22Rv1 degradation assay at 24 hours, including all ranges and values therebetween.
  • the DC 50 of the degrader compound is less than about 100 nM, or less than about 50 nM in an AR HiBiT 22Rv1 degradation assay at 24 hours. In some embodiments, the DC 50 of the degrader compound is about 500 nM, about 475 nM, about 450 nM, about 425 nM, about 400 nM, about 375 nM, about 350 nM, about 325 nM, about 300 nM, about 275 nM, about 250 nM, about 225 nM, about 200 nM, about 175 nM, about 150 nM, about 125 nM, about 100 nM, about 95 nM, about 90 nM, about 85 nM, about 80 nM, about 75 nM, about 70 nM, about 65 nM, about 60 nM, about 55 nM, about 50 nM, about 45 nM, about 40 nM, about 35 nM, about 30
  • the degrader compounds of the present disclosure have a maximal degradation (D max ) of about 60% to about 95 % in an androgen receptor (AR) HiBiT 22Rv1 degradation assay, including all ranges and values therebetween. In some embodiments, the degrader compounds of the present disclosure have D max of about 70% to about 95 % in an androgen receptor (AR) HiBiT 22Rv1 degradation assay, including all ranges and values therebetween. In some embodiments, the degrader compounds of the present disclosure have D max of about 75% to about 90 % in an androgen receptor (AR) HiBiT 22Rv1 degradation assay, including all ranges and values therebetween.
  • the degrader compounds of the present disclosure have D max of about 70%, about 71%, about to 72%, about to 73%, about to 74%, about to 75%, about to 76%, about to 77%, about to 78%, about to 79%, about to 80%, about to 81%, about to 82%, about to 83%, about to 84%, about to 85%, about to 86%, about to 87%, about to 88%, about to 89%, about to 90%, about to 91%, about to 92%, about to 93%, about to 94%, or about 95 % in an androgen receptor (AR) HiBiT 22Rv1 degradation assay.
  • AR androgen receptor
  • the degrader compounds of the present disclosure have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.01 ⁇ M to about 300 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.01 ⁇ M to about 30 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.01 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.01 ⁇ M to about 6 ⁇ M, about 0.01 ⁇ M to about 5 ⁇ M, about 0.01 ⁇ M to about 4 ⁇ M, about 0.01 ⁇ M to about 3 ⁇ M, or about 0.01 ⁇ M to about 2 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.05 ⁇ M to about 1 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of less than about 300 ⁇ M, less than about 250 ⁇ M, less than about 200 ⁇ M, less than about 150 ⁇ M, less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, or less than about 1 ⁇ M.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.01 ⁇ M, about 0.02 ⁇ M, about 0.03 ⁇ M, about 0.04 ⁇ M, about 0.05 ⁇ M, about 0.06 ⁇ M, about 0.07 ⁇ M, about 0.08 ⁇ M, about 0.09 ⁇ M, about 0.1 ⁇ M, about 0.2 ⁇ M, about 0.3 ⁇ M, about 0.4 ⁇ M, about 0.5 ⁇ M, about 0.6 ⁇ M, about 0.7 ⁇ M, about 0.8 ⁇ M, about 0.9 ⁇ M, about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 9 ⁇ M, or about 10 ⁇ M.
  • the degrader compounds of the present disclosure have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 0.5 nM to about 500 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 1 nM to about 400 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 1 nM to about 300 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 1 nM to about 200 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 1 nM to about 100 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 1 nM to about 50 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP cells of about 500 nM, about 475 nM, about 450 nM, about 425 nM, about 400 nM, about 375 nM, about 350 nM, about 325 nM, about 300 nM, about 275 nM, about 250 nM, about 225 nM, about 200 nM, about 175 nM, about 150 nM, about 125 nM, about 100 nM, about 95 nM, about 90 nM, about 85 nM, about 80 nM, about 75 nM, about 70 nM, about 65 nM, about 60 nM, about 55 nM, about 50 nM, about 45 nM, about 40 nM, about 35 nM, about 30 nM, about 25 nM, about 20 nM, about 15 nM, about 10 nM, about 9 nM
  • the degrader compounds of the present disclosure have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.01 ⁇ M to about 300 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.01 ⁇ M to about 30 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.01 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.01 ⁇ M to about 6 ⁇ M, about 0.01 ⁇ M to about 5 ⁇ M, about 0.01 ⁇ M to about 4 ⁇ M, about 0.01 ⁇ M to about 3 ⁇ M, or about 0.01 ⁇ M to about 2 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.05 ⁇ M to about 1 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of less than about 300 ⁇ M, less than about 250 ⁇ M, less than about 200 ⁇ M, less than about 150 ⁇ M, less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, or less than about 1 ⁇ M.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.01 ⁇ M, about 0.02 ⁇ M, about 0.03 ⁇ M, about 0.04 ⁇ M, about 0.05 ⁇ M, about 0.06 ⁇ M, about 0.07 ⁇ M, about 0.08 ⁇ M, about 0.09 ⁇ M, about 0.1 ⁇ M, about 0.2 ⁇ M, about 0.3 ⁇ M, about 0.4 ⁇ M, about 0.5 ⁇ M, about 0.6 ⁇ M, about 0.7 ⁇ M, about 0.8 ⁇ M, about 0.9 ⁇ M, about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 9 ⁇ M, or about 10 ⁇ M.
  • the degrader compounds of the present disclosure have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 0.5 nM to about 500 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 1 nM to about 400 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 1 nM to about 300 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 1 nM to about 200 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 1 nM to about 100 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 1 nM to about 50 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in LNCaP95 cells of about 500 nM, about 475 nM, about 450 nM, about 425 nM, about 400 nM, about 375 nM, about 350 nM, about 325 nM, about 300 nM, about 275 nM, about 250 nM, about 225 nM, about 200 nM, about 175 nM, about 150 nM, about 125 nM, about 100 nM, about 95 nM, about 90 nM, about 85 nM, about 80 nM, about 75 nM, about 70 nM, about 65 nM, about 60 nM, about 55 nM, about 50 nM, about 45 nM, about 40 nM, about 35 nM, about 30 nM, about 25 nM, about 20 nM, about 15 nM, about 10 nM, about 9 nM, about 300
  • the degrader compounds of the present disclosure have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 0.01 ⁇ M to about 300 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 0.01 ⁇ M to about 30 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 0.01 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 0.01 ⁇ M to about 6 ⁇ M, about 0.01 ⁇ M to about 5 ⁇ M, about 0.01 ⁇ M to about 4 ⁇ M, about 0.01 ⁇ M to about 3 ⁇ M, or about 0.01 ⁇ M to about 2 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 0.05 ⁇ M to about 1 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of less than about 300 ⁇ M, less than about 250 ⁇ M, less than about 200 ⁇ M, less than about 150 ⁇ M, less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, or less than about 1 ⁇ M.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR- R1-D567 cells of about 0.01 ⁇ M, about 0.02 ⁇ M, about 0.03 ⁇ M, about 0.04 ⁇ M, about 0.05 ⁇ M, about 0.06 ⁇ M, about 0.07 ⁇ M, about 0.08 ⁇ M, about 0.09 ⁇ M, about 0.1 ⁇ M, about 0.2 ⁇ M, about 0.3 ⁇ M, about 0.4 ⁇ M, about 0.5 ⁇ M, about 0.6 ⁇ M, about 0.7 ⁇ M, about 0.8 ⁇ M, about 0.9 ⁇ M, about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 9 ⁇ M, or about 10 ⁇ M.
  • the degrader compounds of the present disclosure have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 0.5 nM to about 500 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 1 nM to about 400 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 1 nM to about 300 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 1 nM to about 200 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 1 nM to about 100 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR- R1-D567 cells of about 1 nM to about 50 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in an AR reporter assay in CWR-R1-D567 cells of about 500 nM, about 475 nM, about 450 nM, about 425 nM, about 400 nM, about 375 nM, about 350 nM, about 325 nM, about 300 nM, about 275 nM, about 250 nM, about 225 nM, about 200 nM, about 175 nM, about 150 nM, about 125 nM, about 100 nM, about 95 nM, about 90 nM, about 85 nM, about 80 nM, about 75 nM, about 70 nM, about 65 nM, about 60 nM, about 55 nM, about 50 nM, about 45 nM, about 40 nM, about 35 nM, about 30 nM, about 25 nM, about 20 nM, about 15 nM, about 10 nM,
  • the degrader compounds of the present disclosure have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 0.01 ⁇ M to about 300 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 0.01 ⁇ M to about 30 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 0.01 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 0.01 ⁇ M to about 6 ⁇ M, about 0.01 ⁇ M to about 5 ⁇ M, about 0.01 ⁇ M to about 4 ⁇ M, about 0.01 ⁇ M to about 3 ⁇ M, or about 0.01 ⁇ M to about 2 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 0.05 ⁇ M to about 1 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of less than about 300 ⁇ M, less than about 250 ⁇ M, less than about 200 ⁇ M, less than about 150 ⁇ M, less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, or less than about 1 ⁇ M.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 0.01 ⁇ M, about 0.02 ⁇ M, about 0.03 ⁇ M, about 0.04 ⁇ M, about 0.05 ⁇ M, about 0.06 ⁇ M, about 0.07 ⁇ M, about 0.08 ⁇ M, about 0.09 ⁇ M, about 0.1 ⁇ M, about 0.2 ⁇ M, about 0.3 ⁇ M, about 0.4 ⁇ M, about 0.5 ⁇ M, about 0.6 ⁇ M, about 0.7 ⁇ M, about 0.8 ⁇ M, about 0.9 ⁇ M, about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 9 ⁇ M, or about 10 ⁇ M.
  • the degrader compounds of the present disclosure have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 1 nM to about 500 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 10 nM to about 450 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 20 nM to about 400 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 25 nM to about 350 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP cells of about 500 nM, about 475 nM, about 450 nM, about 425 nM, about 400 nM, about 375 nM, about 350 nM, about 325 nM, about 300 nM, about 275 nM, about 250 nM, about 225 nM, about 200 nM, about 175 nM, about 150 nM, about 125 nM, about 100 nM, about 95 nM, about 90 nM, about 85 nM, about 80 nM, about 75 nM, about 70 nM, about 65 nM, about 60 nM, about 55 nM, about 50
  • the degrader compounds of the present disclosure have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 0.01 ⁇ M to about 300 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 0.01 ⁇ M to about 30 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 0.01 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 0.01 ⁇ M to about 6 ⁇ M, about 0.01 ⁇ M to about 5 ⁇ M, about 0.01 ⁇ M to about 4 ⁇ M, about 0.01 ⁇ M to about 3 ⁇ M, or about 0.01 ⁇ M to about 2 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 0.05 ⁇ M to about 1 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of less than about 300 ⁇ M, less than about 250 ⁇ M, less than about 200 ⁇ M, less than about 150 ⁇ M, less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, or less than about 1 ⁇ M.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 0.01 ⁇ M, about 0.02 ⁇ M, about 0.03 ⁇ M, about 0.04 ⁇ M, about 0.05 ⁇ M, about 0.06 ⁇ M, about 0.07 ⁇ M, about 0.08 ⁇ M, about 0.09 ⁇ M, about 0.1 ⁇ M, about 0.2 ⁇ M, about 0.3 ⁇ M, about 0.4 ⁇ M, about 0.5 ⁇ M, about 0.6 ⁇ M, about 0.7 ⁇ M, about 0.8 ⁇ M, about 0.9 ⁇ M, about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 9 ⁇ M, or about 10 ⁇ M.
  • the degrader compounds of the present disclosure have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 1 nM to about 2000 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 50 nM to about 1900 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 75 nM to about 1800 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 100 nM to about 1700 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 150 nM to about 1600 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 200 nM to about 1500 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in LNCaP95 cells of about 2000 nM, about 1975 nM, about 1950 nM, about 1925 nM, about 1900 nM, about 1875 nM, about 1850 nM, about 1825 nM, about 1800 nM, about 1775 nM, about 1750 nM, about 1725 nM, about 1700 nM, about 1675 nM, about 1650 nM, about 1625 nM, about 1600 nM, about 1575 nM, about 1550 nM, about 1525 nM, about 1500 nM, about 1475 nM, about 1450 nM, about 1425 nM, about 1400 nM, about 1375 nM, about 1350 nM, about 1325 nM, about 1300 nM, about 1275 nM, about 1250 nM, about 1225 nM, about 1200 n
  • the degrader compounds of the present disclosure have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 0.01 ⁇ M to about 300 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 0.01 ⁇ M to about 30 ⁇ M, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 0.01 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 0.01 ⁇ M to about 10 ⁇ M, about 0.1 ⁇ M to about 10 ⁇ M, or about 1 ⁇ M to about 10 ⁇ M, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of less than about 300 ⁇ M, less than about 250 ⁇ M, less than about 200 ⁇ M, less than about 150 ⁇ M, less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, or less than about 5 ⁇ M.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 9 ⁇ M, about 10 ⁇ M, about 11 ⁇ M, about 12 ⁇ M, about 13 ⁇ M, about 14 ⁇ M, or about 15 ⁇ M. [1210] In some embodiments, the degrader compounds of the present disclosure have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 100 nM to about 9000 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 250 nM to about 9000 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 500 nM to about 9000 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 750 nM to about 8500 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 1000 nM to about 8500 nM, including all ranges and values therebetween. In some embodiments, the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 2000 nM to about 8000 nM, including all ranges and values therebetween.
  • the degrader compounds have an in vitro IC 50 in a cell viability assay in PC-3 cells of about 9000 nM, about 8500 nM, about 8000 nM, about 7500 nM, about 7000 nM, about 6500 nM, about 6000 nM, about 5500 nM, about 5000 nM, about 4500 nM, about 4000 nM, about 3500 nM, about 3000 nM, about 2500 nM, about 2000 nM, about 1500 nM, or about 1000 nM.
  • the AR transcriptional activity of the degrader compounds of the present disclosure is suppressed in the presence of an E3 ligase inhibitor.
  • the AR transcriptional activity of the degrader compounds of the present disclosure is suppressed in the presence of an E3 ligase inhibitor in LNCaP cells.
  • the degrader compounds of the present disclosure do not affect glucocorticoid receptor expression. In some embodiments, the degrader compounds of the present disclosure do not affect glucocorticoid receptor expression in DU145 cells. In some embodiments, the degrader compounds of the present disclosure do not affect glucocorticoid receptor expression in PC-3 cells.
  • a method of treating a condition associated with cell proliferation in a patient in need thereof comprising administering a compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q- III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, to a subject in need thereof.
  • the present invention provides a method of treating cancer or tumors.
  • the present invention provides a method of treating prostate cancer or breast cancer.
  • the present invention provides a method of treating prostate cancer.
  • prostate cancer is metastatic castration-resistant prostate cancer.
  • prostate cancer is non-metastatic castration-resistant prostate cancer.
  • the present invention provides a method of treating breast cancer.
  • breast cancer is triple negative breast cancer.
  • a method of reducing, inhibiting, or ameliorating proliferation comprising administering a therapeutically effective amount of a compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q- III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof is provided.
  • the reducing, inhibiting, or ameliorating in the method disclosed herein is in vivo.
  • the cells in the method disclosed herein are a cancer cells.
  • the cancer cells are a prostate cancer cells.
  • the prostate cancer cells are cells of primary/localized prostate cancer (newly diagnosed or early stage), locally advanced prostate cancer, recurrent prostate cancer (e.g., prostate cancer which was not responsive to primary therapy), metastatic prostate cancer, advanced prostate cancer (e.g., after castration for recurrent prostate cancer), metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
  • the prostate cancer cells are cells of a metastatic castration-resistant prostate cancer.
  • the prostate cancer cells are an androgen-dependent prostate cancer cells or an androgen-independent prostate cancer cells.
  • the cancer cells are breast cancer cells.
  • the condition or disease associated with cell proliferation is cancer.
  • the cancer is selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.
  • the condition or disease is prostate cancer.
  • prostate cancer is selected from primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, metastatic castration- resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
  • the prostate cancer is a metastatic castration-resistant prostate cancer.
  • prostate cancer is non-metastatic castration-resistant prostate cancer.
  • the prostate cancer is an androgen-dependent prostate cancer cells or an androgen-independent prostate cancer.
  • the condition or disease is breast cancer.
  • a method for reducing or preventing tumor growth comprising contacting tumor cells with a therapeutically effective amount of a compound of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q- III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof is provided.
  • reducing or preventing tumor growth includes reduction in tumor volume.
  • reducing or preventing tumor growth includes complete elimination of tumors. In one embodiment, reducing or preventing tumor growth includes stopping or halting the existing tumor to grow. In one embodiment, reducing or preventing tumor growth includes reduction in the rate of tumor growth. In one embodiment, reducing or preventing tumor growth includes reduction in the rate of tumor growth such that the rate of tumor growth before treating a patient with the methods disclosed herein (r1) is faster than the rate of tumor growth after said treatment (r2) such that r1 > r2. [1221] In one embodiment, the reducing or preventing in the method disclosed herein is in vivo. In another embodiment, the treating is in vitro.
  • the tumor cell in the method disclosed herein is selected from prostate cancer, breast cancer, ovarian cancer, endometrial cancer, or salivary gland carcinoma.
  • the tumor cells are prostate cancer tumor cells.
  • the prostate cancer tumor cells are tumor cells of primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
  • the prostate cancer is a metastatic castration-resistant prostate cancer.
  • prostate cancer is non-metastatic castration-resistant prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer or androgen- independent prostate cancer.
  • the tumor cells are is breast cancer tumor cells.
  • the degrader compounds of the present disclosure provide metabolic stability.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in human liver microsomes (HLMs) of less than about 1000 ⁇ L/min/mg protein, less than about 900 ⁇ L/min/mg protein, less than about 800 ⁇ L/min/mg protein, less than about 700 ⁇ L/min/mg protein, less than about 600 ⁇ L/min/mg protein, less than about 500 ⁇ L/min/mg protein, less than about 450 ⁇ L/min/mg protein, less than about 400 ⁇ L/min/mg protein, less than about 350 ⁇ L/min/mg protein, less than about 300 ⁇ L/min/mg protein, less than about 250 ⁇ L/min/mg protein, less than about 225 ⁇ L/min/mg protein, or less than about 200 ⁇ L/min/mg protein.
  • HLMs human liver microsomes
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs of less than about 200 ⁇ L/min/mg protein, less than about 190 ⁇ L/min/mg protein, less than about 180 ⁇ L/min/mg protein, less than about 170 ⁇ L/min/mg protein, less than about 160 ⁇ L/min/mg protein, less than about 150 ⁇ L/min/mg protein, less than about 140 ⁇ L/min/mg protein, less than about 130 ⁇ L/min/mg protein, less than about 120 ⁇ L/min/mg protein, less than about 110 ⁇ L/min/mg protein, less than about 100 ⁇ L/min/mg protein, less than about 90 ⁇ L/min/mg protein, less than about 80 ⁇ L/min/mg protein, less than about 70 ⁇ L/min/mg protein, less than about 60 ⁇ L/min/mg protein, or less than about 50 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs of less than about 50 ⁇ L/min/mg protein, less than about 48 ⁇ L/min/mg protein, less than about 45 ⁇ L/min/mg protein, less than about 40 ⁇ L/min/mg protein, less than about 35 ⁇ L/min/mg protein, less than about 30 ⁇ L/min/mg protein, less than about 25 ⁇ L/min/mg protein, less than about 20 ⁇ L/min/mg protein, or less than about 15 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs of less than about 15 ⁇ L/min/mg protein, less than about 14 ⁇ L/min/mg protein, less than about 13 ⁇ L/min/mg protein, less than about 12 ⁇ L/min/mg protein, less than about 11 ⁇ L/min/mg protein, or less than about 10 ⁇ L/min/mg protein. [1224] In some embodiments, the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs of less than 12 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs in the range of about 0.1 ⁇ L/min/mg protein to about 12 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs of less than 48 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs in the range of about 12 ⁇ L/min/mg protein to about 48 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in HLMs in the range of about 0.1 ⁇ L/min/mg protein to about 48 ⁇ L/min/mg protein. [1225] In some embodiments, the degrader compounds of the present disclosure have an HLM in vitro metabolic clearance of less than about 20 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an HLM in vitro metabolic clearance of less than about 15 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an HLM in vitro metabolic clearance of less than about 12 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an HLM in vitro metabolic clearance of less than about 11.55 ⁇ L/min/mg protein.
  • the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof have an HLM in vitro metabolic clearance of less than about 20 ⁇ L/min/mg protein.
  • the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof have an HLM in vitro metabolic clearance of less than about 15 ⁇ L/min/mg protein.
  • the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof have an HLM in vitro metabolic clearance of less than about 12 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof. have an HLM in vitro metabolic clearance of less than about 11.55 ⁇ L/min/mg protein. [1227] In some embodiments, the degrader compounds of the present disclosure provide metabolic stability.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in mouse liver microsomes (MLMs) of less than about 1000 ⁇ L/min/mg protein, less than about 900 ⁇ L/min/mg protein, less than about 800 ⁇ L/min/mg protein, less than about 700 ⁇ L/min/mg protein, less than about 600 ⁇ L/min/mg protein, less than about 500 ⁇ L/min/mg protein, less than about 450 ⁇ L/min/mg protein, less than about 400 ⁇ L/min/mg protein, less than about 350 ⁇ L/min/mg protein, less than about 300 ⁇ L/min/mg protein, less than about 250 ⁇ L/min/mg protein, less than about 225 ⁇ L/min/mg protein, or less than about 200 ⁇ L/min/mg protein.
  • MLMs mouse liver microsomes
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs of less than about 200 ⁇ L/min/mg protein, less than about 190 ⁇ L/min/mg protein, less than about 180 ⁇ L/min/mg protein, less than about 170 ⁇ L/min/mg protein, less than about 160 ⁇ L/min/mg protein, less than about 150 ⁇ L/min/mg protein, less than about 140 ⁇ L/min/mg protein, less than about 130 ⁇ L/min/mg protein, less than about 120 ⁇ L/min/mg protein, less than about 110 ⁇ L/min/mg protein, less than about 100 ⁇ L/min/mg protein, less than about 90 ⁇ L/min/mg protein, less than about 80 ⁇ L/min/mg protein, less than about 70 ⁇ L/min/mg protein, less than about 60 ⁇ L/min/mg protein, or less than about 50 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs of less than about 50 ⁇ L/min/mg protein, less than about 48 ⁇ L/min/mg protein, less than about 45 ⁇ L/min/mg protein, less than about 40 ⁇ L/min/mg protein, less than about 35 ⁇ L/min/mg protein, less than about 30 ⁇ L/min/mg protein, less than about 25 ⁇ L/min/mg protein, less than about 20 ⁇ L/min/mg protein, or less than about 15 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs of less than about 15 ⁇ L/min/mg protein, less than about 14 ⁇ L/min/mg protein, less than about 13 ⁇ L/min/mg protein, less than about 12 ⁇ L/min/mg protein, less than about 11 ⁇ L/min/mg protein, or less than about 10 ⁇ L/min/mg protein. [1228] In some embodiments, the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs of less than 12 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs in the range of about 0.1 ⁇ L/min/mg protein to about 12 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs of less than 48 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs in the range of about 12 ⁇ L/min/mg protein to about 48 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an in vitro metabolic clearance in MLMs in the range of about 0.1 ⁇ L/min/mg protein to about 48 ⁇ L/min/mg protein. [1229] In some embodiments, the degrader compounds of the present disclosure have an MLM in vitro metabolic clearance of less than about 20 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an HMLM in vitro metabolic clearance of less than about 15 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of the present disclosure have an MLM in vitro metabolic clearance of less than about 12 ⁇ L/min/mg protein.
  • the degrader compounds of the present disclosure have an MLM in vitro metabolic clearance of less than about 11.55 ⁇ L/min/mg protein.
  • the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof have an MLM in vitro metabolic clearance of less than about 20 ⁇ L/min/mg protein.
  • the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof have an MLM in vitro metabolic clearance of less than about 15 ⁇ L/min/mg protein.
  • the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof have an MLM in vitro metabolic clearance of less than about 12 ⁇ L/min/mg protein. In some embodiments, the degrader compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof. have an MLM in vitro metabolic clearance of less than about 11.55 ⁇ L/min/mg protein. [1231] In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 15 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 30 minutes.
  • the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 45 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 50 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 60 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 120 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 180 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 200 minutes.
  • the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 240 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 300 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 360 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 420 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse plasma greater than about 480 minutes.
  • the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 1 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 2 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 5 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 10 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 15 minutes.
  • the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 30 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 45 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 60 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 100 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse microsomes greater than about 120 minutes.
  • the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 15 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 30 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 45 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 60 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 80 minutes.
  • the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 120 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 180 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 240 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 300 minutes. In some embodiments, the degrader compounds of the present disclosure have an in vitro half-life in mouse hepatocytes greater than about 360 minutes.
  • a pharmaceutical composition comprises one or more compounds of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q- II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k) wherein the PTC has the structure of formula (A), (A-II), (A-III), (B-I), (G), (H), (J), (I), or (II), or structure disclosed in Tables C and D, or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound wherein the compound is selected from compounds of Table A, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound wherein the compound is selected from Compounds 1-149, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound wherein the compound is selected from Compounds 150-223, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound wherein the compound is selected from Compounds 1-223, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound wherein the compound is selected from Compounds 1-174, 176-202, 203, 204, 206-320, 322-354, and/or 356-381, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
  • the present disclosure also provides pharmaceutical compositions comprising (a) means for degrading AR and (b) a pharmaceutically acceptable carrier or excipient.
  • the present disclosure also provides pharmaceutical compositions comprising (a) means for inhibiting AR and (b) a pharmaceutically acceptable carrier or excipient.
  • AR is full length AR (AR-FL) or AR splice variant.
  • AR splice variant is AR-V7 or AR-V567es.
  • AR is AR N-terminal domain.
  • a pharmaceutical composition, as described herein further comprises one or more additional therapeutically active agents.
  • one or more additional therapeutically active agents are selected from therapeutics useful for treating cancer, neurological disease, a disorder characterized by abnormal accumulation of ⁇ -synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
  • the pharmaceutical composition of the present disclosure comprises a pharmaceutically acceptable excipient or adjuvant is provided.
  • the pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes.
  • a pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels.
  • the pharmaceutical compositions may contain additional, compatible, pharmaceutically active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters.
  • the compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compounds disclosed herein can also be formulated as a preparation for implantation or injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05M phosphate buffer or 0.8% saline.
  • Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • Liquid carriers suitable for use in the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
  • the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active compound.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross- linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.
  • Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Carriers suitable for use in the present application can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
  • Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle.
  • Diluents for solid compositions and/or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL
  • microfine cellulose e.g., lactose, starch, pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • dextrin dextrin
  • dextrose dibasic calcium phosphate dihydrate
  • a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates).
  • a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient’s stomach may be increased by the addition of a disintegrant to the composition and/or combination.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.
  • a disintegrant include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.
  • Glidants can be added to improve the flowability of a non-compacted solid composition and/or combination and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • Liquid pharmaceutical compositions can be prepared using compounds of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k) or a pharmaceutically acceptable salt or solvate thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers can be useful excipients to control the release of active compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate.
  • a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations.
  • a pharmaceutical composition of the present invention comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds.
  • certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical composition of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300.
  • a pharmaceutical composition of the present invention comprises a sustained-release system.
  • a non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
  • Appropriate pharmaceutical compositions of the present disclosure can be determined according to any clinically-acceptable route of administration of the composition to the subject. The manner in which the composition is administered is dependent, in part, upon the cause and/or location. One skilled in the art will recognize the advantages of certain routes of administration.
  • the method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders.
  • the route of administration is systemic, e.g., oral or by injection.
  • the agents or compounds, or pharmaceutically acceptable salts or derivatives thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportally, and parenterally.
  • the route of administration is local, e.g., topical, intra-tumor and peri-tumor.
  • the compound is administered orally.
  • a pharmaceutical composition of the present disclosure is prepared for oral administration.
  • a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers.
  • Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical compositions are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • pharmaceutical compositions for oral administration are push- fit capsules made of gelatin.
  • Such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • pharmaceutical compositions are prepared for buccal administration.
  • compositions are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical composition is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical composition is prepared for administration by inhalation. Certain of such pharmaceutical compositions for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
  • the compounds of the present disclosure are administered by the intravenous route.
  • a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema. Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical composition is prepared for topical administration. Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions.
  • Suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • one or more compounds of formula (Q ⁇ ), (Q), (Q ⁇ -I), (Q-I), (Q- Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt or solvate thereof are formulated as a prodrug.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically more active form.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • a prodrug is an ester.
  • the ester is metabolically hydrolyzed to carboxylic acid upon administration.
  • the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is cleaved upon administration to form the corresponding active form.
  • a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • the amount of the PTCs in the compounds of formula (Q ⁇ ), (Q), (Q ⁇ - I), (Q-I), (Q-Ia), (Q-Ib), (Q ⁇ -II), (Q-II), (Q-IIa), (Q-IIb), (Q-III), (Q-IV), (i)-(xviii), or (a)-(h), (j), or (k), or a pharmaceutically acceptable salt or solvate thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.01 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
  • the concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration.
  • the agent may be administered in a single dose or in repeat doses.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s).
  • novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th.
  • Example 1 Synthesis of N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5- cyanophenyl)propan-2-yl)phenoxy) methyl)pyrimidin-2-yl)methanesulfonamideN-(4-((4-(2-(3- chloro-4-(2-chloroethoxy)-5-cyanophenyl) propan-2-yl) phenoxy) methyl)pyrimidin-2- yl)methanesulfonamide (A109) [1302] 2-chloro-4-(chloromethyl)pyrimidine (2): To a mixture of 2-chloro-4-methyl-pyrimidine (50.0 g, 398 mmol) and NCS (77.9 g, 583 mmol) in MeCN (250 mL) was added benzoyl benzenecarboperoxoate (28.3 g, 117 mmol) in portions at 20 °
  • N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl) pyrimidin-2-yl)methanesulfonamide (A109): To a mixture of 3-chloro-2-(2-chloroethoxy)-5-(2- (4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (15.5 g, 32.5 mmol), methane sulfonamide (9.3 g, 97.5 mmol), Cs2CO3 (21.2 g, 65.0 mmol) and Xantphos (1.88 g, 3.25 mmol) in 1,4-dioxane (450 mL) was added Pd2(dba)3 (3.0 g, 3.3 mmol) at 20 °C and the mixture was stirred at 90 °C for
  • a degrader compound of formula (Q), (Q-I), (Q-Ia), (Q-II), (Q-IIa), (Q-III), (Q-IV), (i)- (ix), or (a)-(e), or their pharmaceutically acceptable salts can be prepared by the general approaches described herein, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to one skilled in the art.
  • the PTC can have a chemical group suitable as a leaving group and the linker LI has a chemical group suitable as a nucleophile (Scheme 1).
  • Scheme 1 Scheme 1
  • LG can be any leaving group commonly known to person skilled in the art, including but not limited to halogen and sulfonates (e.g., tosylate, mesylate).
  • Nu- H can be any nucleophile commonly known to person skilled in the art including but not limited to –OH and –NH 2 .
  • R 3 can be a chemical group that would be useful in forming a covalent bond with the CRB. In one embodiment, R 3 is protected by a commonly known protecting group such that it does not interfere with the reaction of forming a covalent bond between PTC and LI.
  • LG can be any leaving group commonly known to person skilled in the art, including but not limited to halogen and sulfonates (e.g., tosylate, mesylate).
  • electrophile can be any group commonly known to person skilled in the art, including but not limited to carboxylic acid.
  • Nu-H can be any nucleophile commonly known to person skilled in the art including but not limited to –OH and –NH 2 .
  • W is an electrophile
  • an amide or an ester bond formation, or the like can be performed.
  • R 3 can be a chemical group that would be useful in forming a covalent bond with the CRB.
  • R 3 is protected by a commonly known protecting group such that it does not interfere with the reaction of forming a covalent bond between PTC and LI.
  • Schemes 1 and 2 represents examples of means and positions of the covalent bond formation between PTC and LI but is not meant to be limiting examples. Further, in preparation of the degrader compounds of the present disclosure, the covalent bond between CRB and LI can be formed first followed by bond formation between LI and PTC.
  • reaction mixture was stirred at 50°C for 3 hours. LCMS showed the reaction was completed.
  • the reaction was added EtOAc (20 mL), washed with H 2 O (10 mL x 2), brine (20 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the impure product was purified by p-HPLC(TFA) to give 3-chloro-2-(2-chloroethoxy)-N-(5-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-5-(2-(4-((2- (methylsulfonamido)pyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzamide (0.0110 g, yield: 13.6 %) as a white solid.
  • the reaction mixture was stirred at 20°C for 15 hours. LCMS showed the reaction was completed.
  • the mixture was quenched with sat. aq. Na 2 SO 3 (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the reaction mixture was stirred at 25°C for 15 hours.
  • the residue was poured into sat. aq. Na 2 SO 3 (20 mL).
  • the aqueous phase was extracted with ethyl acetate (20 mL x 3).
  • the combined organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • reaction mixture was quenched with water (10 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give tert-butyl 4,4- difluoro-5-(trifluoromethylsulfonyloxy)pentanoate (90.0 %, 0.188 g) as a brown oil.
  • [1509] [3-[tert-butyl(dimethyl)silyl]oxy-2,2-difluoro-propyl] trifluoromethanesulfonate (2): To a solution of 3-[tert-butyl(dimethyl)silyl]oxy-2,2-difluoro-propan-1-ol (400 mg, 1.77 mmol) in DCM (6.00 mL) was added pyridine (0.699 g, 8.84 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (0.997 g, 3.53 mmol) at 0°C. Then the mixture was stirred at 20°C for 3 hours.
  • reaction mixture was stirred for 16 hours at 110 o C. LCMS showed the reaction was completed. Then the reaction was stopped by addition of aq.NaHCO 3 (100 mL). The reaction product was extracted with EA (100 mL x 3) and the combined organic phases were washed with water (50 mL x 3). The organic phase was dried with Na 2 SO 4 .

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Abstract

La présente invention concerne des agents de dégradation de protéines chimiques, bifonctionnels, comprenant un modulateur/liant de ligase et une molécule qui se lie à une cible protéique d'intérêt, et des procédés de traitement de maladies et états divers avec les composés de dégradation, y compris des maladies associées à des récepteurs des androgènes.
PCT/US2022/077353 2021-09-30 2022-09-30 Modulateurs de récepteurs des androgènes et procédés d'utilisation en tant qu'agents de dégradation bifonctionnels WO2023056423A1 (fr)

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CN114829352A (zh) * 2019-12-16 2022-07-29 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
WO2024012570A1 (fr) * 2022-07-15 2024-01-18 西藏海思科制药有限公司 Dérivé hétérocyclique contenant de l'azote, composition et utilisation pharmaceutique de celui-ci
CN114829352B (zh) * 2019-12-16 2024-05-31 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物

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US20200123117A1 (en) * 2018-10-18 2020-04-23 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
WO2021121261A1 (fr) * 2019-12-16 2021-06-24 北京泰德制药股份有限公司 Composé pour inhiber et induire la dégradation de la kinase egfr

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WO2021121261A1 (fr) * 2019-12-16 2021-06-24 北京泰德制药股份有限公司 Composé pour inhiber et induire la dégradation de la kinase egfr

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CHAN KWOK-HO, ZENGERLE MICHAEL, TESTA ANDREA, CIULLI ALESSIO: "Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 2, 25 January 2018 (2018-01-25), US , pages 504 - 513, XP055930443, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01912 *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114829352A (zh) * 2019-12-16 2022-07-29 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
CN114829352B (zh) * 2019-12-16 2024-05-31 昂科比克斯有限公司 新型氘代嘧啶衍生物及包含其的药物组合物
WO2024012570A1 (fr) * 2022-07-15 2024-01-18 西藏海思科制药有限公司 Dérivé hétérocyclique contenant de l'azote, composition et utilisation pharmaceutique de celui-ci

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