Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/46—Sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
• • C—CHEMISTRY; METALLURGY
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  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
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  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
  • C07D231/40—Acylated on said nitrogen atom
• • C—CHEMISTRY; METALLURGY
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
• • C—CHEMISTRY; METALLURGY
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
• • C—CHEMISTRY; METALLURGY
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/84—Sulfur atoms
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  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/88—Nitrogen atoms, e.g. allantoin
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  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
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  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • 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
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
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Definitions

• the present disclosure generally relates to tricyclic compounds and their use for treatment of various indications.
• the disclosure relates to tricyclic compounds and their use for treatment of various cancers, for example prostate cancer, including but not limited to, primary/localized prostate cancer (newly diagnosed), locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
• This invention also relates to tricyclic compounds and their use for modulating androgen receptor (AR) activity, including truncated AR.
• AR androgen receptor
• 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. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)).
• prostate cancer does not develop if humans or dogs are castrated before puberty (J. D. Wilson & C. Roehrbom, J Clin Endocrinol Metah 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of prostatic epithelium while eliciting no effect on other male external genitalia (E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgens provides the underlying rationale for treating prostate cancer with chemical or surgical castration (androgen ablation), also known as androgen ablation therapy (ABT) or androgen depravation therapy (ADT).
• ABT androgen ablation therapy
• ADT androgen depravation therapy
• 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.
• 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 (taul and tau5) within activation fimction-l (AF-l). 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
• ARE activation fimction-l
• 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. Pathol. 160, 219-226; and van der Kwast e/ o/ 1991 Inter. J. Cancer 48, 189-193).
• Clinically available inhibitors of the AR include nonsteroidal antiandrogens such as apalutamide, darolutamide, bicalutamide (CasodexTM), nilutamide, flutamide, and enzalutamide.
• nonsteroidal antiandrogens such as apalutamide, darolutamide, bicalutamide (CasodexTM), nilutamide, flutamide, and enzalutamide.
• steroidal antiandrogens such as cyproterone acetate and spironolactone.
• Both steroidal and non-steroidal antiandrogens target the UBD of the AR and predominantly fail presumably due to poor affinity and mutations that lead to activation of the AR by these same antiandrogens (Taplin, M.E., Bubley, G.J., Kom Y.J., Small E.J., Uptonm M., Rajeshkumarm B., Balkm S.P., Cancer Res., 59, 2511-2515 (1999)), and constitutively active AR splice variants.
• Antiandrogens have no effect on the constitutively active AR splice variants that lack the ligand-binding domain (LBD) and are associated with castration-recurrent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DT, Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest.
• LBD ligand-binding domain
• AR degraders such as niclosamide (Liu C et al 2014), galeterone (Njar et al 2015; Yu Z at al 2014), and ARV- 330/Androgen receptor PROTAC (Neklesa et al 2016 J Clin Oncol 34 suppl 2S; abstr 267); AR DBD inhibitor VPC-14449 (Dalal K et al 2014 JBiol Chem.
• the AR-NTD is also a target for drug development (e g. WO 2000/001813; Myung et al. J. Clin. Invest 2013, 123, 2948), since the NTD contains Activation-Function- 1 (AF-l) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404).
• AF-l Activation-Function- 1
• the AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M.D. 1999 J. Biol. Chem. 274, 7777-7783; Sadar MD et al 1999 Endocr Relat Cancer . 6, 487-502; Ueda et al 2002 J. Biol.
• the AR-NTD is important in hormonal progression of prostate cancer as shown by application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).
• Compounds that modulate AR, potentially through interaction with NTD domain include the bisphenol compounds disclosed in published PCT Nos: WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2012/139039; WO 2012/145328; WO 2013/028572; WO 2013/028791; WO 2014/179867; WO 2015/031984; WO 2016/058080; WO 2016/058082; WO 2016/112455; WO 2016/141458; WO 2017/177307; WO 2017/210771; and WO 2018/045450, and which are hereby incorporated by reference in their entireties.
• AR-Vs AR splice variants
• LBD ligand-binding domain
• Anti-androgens such as bicalutamide and enzalutamide target AR LBD, but have no effect on truncated constitutively active AR-Vs such as AR-V7 (Li Y. etal Cancer Research 2013, 73, 483-489). Expression of AR-V7 is associated with resistance to current hormone therapies (Li Y. et al Cancer Research 2013, 73, 483-489; Antonarakis E. S. et al The New England Journal of Medicine 2014, 371, 1028-1038).
• the compounds of the present disclosure are androgen receptor modulators which may be useful in treating various diseases and conditions as disclosed herein.
• the present disclosure provides compounds comprising the structure of formula (HI A):
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 ;
• Z is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• V is -CH2- and L is halogen, -NH2, -CHCh, -CCl 3 , or -CF 3 ; or
• V is -CH2CH2- and L is halogen or -NH2;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C1C1
• R 5 and R 6 are each independently hydrogen, halogen, -OH, Ci-C 3 alkyl, C2- alkenyl, C2-C 3 alkynyl, or Ci-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• R 8 and R 9 are each independently hydrogen, halogen, or Ci-C 3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, Ci-C 3 alkyl, C2-C 3 alkenyl, C2- alkynyl, Ci-C 3 alkoxy, -NR 13 R 14 , -(Ci-C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , - (Ci-C 3 alkyl) -NR 14 COR 16 , -CONR 14 R 15 , or -(Ci-C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, optionally substituted Ci-C 3 alkyl, optionally substituted C2- C 3 alkenyl, optionally substituted C2-C 3 alkynyl, C 3 -C6 cycloalky, or phenyl;
• each m is independently 0, 1, or 2;
• nl and n2 are each independently 0, 1, or 2;
• R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, optionally substituted Ci-C 3 alkyl, optionally substituted C2- C 3 alkenyl, optionally substituted C2-C 3 alkynyl, C 3 -C6 cycloalky, or phenyl;
• each m is independently 0, 1, or 2;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1, 2, 3, 4 or 5;
• t 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y and Z are each independently a bond, -CH2-, -C(CH3)H-, -0-, -S-, -NH-, - NCH3-, or -N(COCH 3 )-;
• V is -CH2- and L is halogen, -NH2, or -CF 3 ; or
• V is -CH2CH2- and L is halogen or -NH2;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - SC NR 14 R 15 , optionally substituted -(C1-C1-
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C1-C3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 7 is H or C1-C6 alkyl
• R 13 , R 14 and R 15 are each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C2-C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1, 2, 3, 4 or 5;
• t 0, 1 or 2.
• C is 5- to lO-membered heteroaryl or aryl.
• C is 5- to 7-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member.
• C, which is substituted with (R 3 )n3, is pyrazole, imidazole, oxazole, oxadiazole, oxazolone, isoxazole, thiazole, pyridyl, pyrazine, furan or pyrimidyl.
• R 1 and R 2 are each independently Cl, -CN, -CF3, -OH, methyl, methoxy, or -CONH2.
• a and B are phenyl
• X is -(CR 5 R 6 ) t -;
• Y and Z are each -0-;
• V is -CH2- or -CH2CH2-;
• L is halogen
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3 , -OH, or optionally substituted C1-C6 alkyl;
• R 5 and R 6 are each independently hydrogen, halogen, -OH, or C1-C3 alkyl
• R 16 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl.
• a and B are phenyl
• X is -(CR 5 R 6 ) t -;
• W is -CHi- or -C(CH 3 )H-;
• Y and Z are each -0-;
• V is -CH2CH2-
• R 1 and R 2 are each independently hydrogen, halogen, or -CN;
• R 5 and R 6 are each independently hydrogen, or Ci-C 3 alkyl;
• R 16 is hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C2-C 3 alkynyl.
• C is a phenyl or a 5- to 7-membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member;
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• Z is a bond, -CH 2 -, -O-, or -NH-;
• V is -CH2- and L is halogen, -NH2, or -CF 3 ; or
• V is -CH2CH2- and L is halogen or -NH2;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , methyl, or - CONH2;
• R 3 is selected from from -CN, Ci-C 3 alkoxy, -CF 3 , Ci-C 3 alkyl, C2-C 3 alkenyl, C 2 -C 3 alkynyl, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , -(Ci-C 3 alkyl)NH 2 , -NHSC Cft, -NHS0 2 CF , -N(CH )S0 2 CH , -NHS0 2 CH 2 CH , -N(CH )S0 2 CH 2 CH , -CH 2 NHS0 2 CH , -CH 2 N(CH )S0 2 CH , -SO2NH2, -CONH2, -CON(CI-C 3 alkyl) 2 , -CONH(CI-C 3 alkyl), - NHCO(CI-C 3 alkyl), -N(CH )COO(CI-C 3
• R 5 and R 6 are each independently hydrogen, halogen, -OH, or Ci-C 3 alkyl;
• R 7 is H or C1-C6 alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1, 2, 3, 4 or 5;
• At least one R 3 is selected from -CN, C1-C3 alkoxy, -CONHi, -NHSO2CH3, -N(CH 3 )S02CH 3 , -NHSO2CH2CH3, - N(CH3)SC>2CH2CH3, or -SO2CH3 and the other R 3 , if present, is selected from -CN, -CF3, Ci- C 3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), - NH2, -(C1-C3 alkyl)NH 2 , -NHSO2CH3, -NHSO2CF3, -N(CH 3 )S02CH3, -NHSO2CH2CH3, - N(CH3)S02CH 2 CH3, -CH2NHSO2CH3,
• X is a bond or -(CR 5 R 6 ) t ;
• W is a bond, -CH2-, or -C(CH 3 )H-;
• V is -CH2- or -CH2CH2-
• the present disclosure provides compounds comprising the structure of formula (G-II):
• X is -(CR 5 R 6 ) t -;
• Y is -0-
• W is -CHi- or -C(CH 3 )H-;
• V is -CH2CH2-
• L is halogen
• R 1 and R 2 are each independently Cl or -CN;
• At least one R 3 is selected from -CN, C1-C3 alkoxy, -CONH2, -NHSO2CH3, - N(CH3)S0 2 CH3, -NHSO2CH2CH3, -N(CH3)S02CH 2 CH3, or -SO2CH3 and the other R 3 , if present, is selected from -CN, -CF3, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , -(C1-C3 alkyl)NH 2 , -NHSO2CH3, - NHSO2CF3, -N(CH 3 )S02CH 3 , -NHSO2CH2CH3, -N(CH 3 )S02CH 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S0 2
• R 5 and R 6 are each independently hydrogen or methyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1 or 2;
• At least one R 3 is selected from -NHSO2CH3, -NHSO2CH2CH3, or -SO2CH3 and the other R 3 , if present, is selected from -CN, C1-C3 alkyl, C1-C3 alkoxy, -S02(Ci-C3 alkyl), -NFk, -(C1-C3 alkyl)NFh, -NHSO2CH3, - N(CH 3 )S0 2 CH3, -NHSO2CH2CH3, -N(CH3)S0 2 CH 2 CH3, -SO2NH2, -CONH2, -CON(CI-C3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), -N(CH 3 )COO(CI-C3 alkyl), -NHCO(Ci- C3 alkyl), or -N(CH 3 )C
• the present disclosure provides Compounds A1-A96, A98-A116, A118-A159, A161-A175, and A177-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides Compounds A13, A57, A74, A93, A109, Al 12, A122, A126, A131, A134, A136, A137, A164, A168, A169, A170, A171, A172, A184, A185, A195, and/or A204, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides a pharmaceutical composition comprising any one of the compound of formula (IIIA), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a pharmaceutical composition comprising any one of the compound of formula (IVA), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a pharmaceutical composition comprising any one of the compound of formula (A-I), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a pharmaceutical composition comprising any one of the compound of formula (G-II), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising any one of Compounds A1-A96, A98-A116, A118-A159, A161-A175, and A177- A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising any one of Compounds A13, A57, A74, A93, A109, Al 12, A122, A126, A131, A134, A136, A137, A164, A168, A169, A170, A171, A172, A184, A185, A195, and A204, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a method for treating cancer, comprising administering any one of the compound of formula (IIIA), (IVA), (A-I), or (G-II), and Compounds A1-A96, A98-A116, A118-A159, A161-A175, or A177-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, to a subject in need thereof.
• the cancer is prostate cancer.
• the prostate cancer is metastatic castration-resistant prostate cancer.
• the prostate cancer expresses full-length androgen receptor or truncated androgen receptor splice variant.
• the present disclosure provides a method for treating cancer, comprising administering any one of Compounds A13, A57, A74, A93, A109, A112, A122, A126, A131, A134, A136, A137, A164, A168, A169, A170, A171, A172, A184, A185, A195, and A204, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• Fig. 1 shows a dose-dependent curve of PSA-luciferase activities in response to representative compounds in transiently transfected LNCaP cells treated with synthetic androgen (R1881).
• Fig. 2A shows the percent PSA-luciferase activities of representative compounds in LNCaP cells transiently transfected with the PSA(6. lkb)-luciferase reporter and treated without or with R1881.
• Fig. 2B shows the percent PSA-luciferase activities of representative compounds in LNCaP cells co-transfected with an expression vector for AR-V7 and the PSA- luciferase reporter and treated without or with Rl 881.
• FIG. 3 shows concentration of representative compounds in plasma of male CD-l mice after a single dose PO (oral) dose.
• Fig. 4 shows change in tumor volume in male NCG mice bearing LNCaP tumors after oral administration of representative compounds.
• Fig. 5 shows change in % body weight in male NCG mice bearing LNCaP tumors after oral administration of representative compounds.
• Fig. 6 shows individual tumor volume change from baseline measured at the end of experiment for oral administration of representative compounds to male NCG mice bearing LNCaP tumors.
• Fig. 7 shows concentration dependent effects on cell proliferation of LNCaP, PC3, and LNCaP95 cells treated with Compound A13.
• ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range“from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
• the term“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.
• “a” (or“an”),“one or more” and“at least one” are used interchangeably herein.
• reference to“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.
• compositions include both acid and base addition salts.
• 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.
• 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 (5)- or, as (D)- or (L)- for amino acids.
• the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein.
• Optically active (+) and (-), ( R )- and (5)-, 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).
• HPLC high pressure liquid chromatography
• 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.
• the present disclosure includes tautomers of any said compounds.
• 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 compound of formula (I), (IA), (IB), (IC), (II), (IIA), (IIIA), (IIB), (III), (IV), (V), (VA), (VI), (A), (A-I), (B)-(D), (E), (E-I)-(E-VII), (F), (G), (G-I), (G-II), (H), and (H-I), 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.
• 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.
• 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.
• laboratory animals e.g., mice, rats, monkeys, dogs, etc.
• household pets e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits
• non-domestic animals such as wildlife and the like.
• substantially 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.
• compositions 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.
• a composition that is "substantially free of' an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof
• Halo or“halogen” refers to bromo, chloro, fluoro or iodo radical, including their radioisotopes.
• “ 123 I” refers to the radioactive isotope of iodine having atomic mass 123.
• the compounds of Formula I can comprise at least one 123 I moiety. Throughout the present application, where structures depict a 123 I moiety at a certain position it is meant that the I moiety at this position is enriched for 123 I. In other words, 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%, greaterthan, 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.
• the compounds of Formula I can comprise at least one 18 F moiety. Throughout the present application, where structures depict a 18 F moiety at a certain position it is meant that the F moiety at this position is enriched for 18 F. In other words, the compounds contain more than the natural abundance of 18 F at the indicated position(s).
• the compounds comprise 100% 18 F at the indicated positions, provided 18 F is present in more than the natural abundance.
• 18 F isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90%, relative to 19 F.
• 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 C1-C1 0 alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C 6 alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl.
• a C1-C5 alkyl includes C5 alkyls, C4 alkyls, C 3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl).
• a C1-C 6 alkyl includes all moieties described above for C1-C5 alkyls but also includes G alkyls.
• a C1-C1 0 alkyl includes all moieties described above for C1-C5 alkyls and C1-C 6 alkyls, but also includes C7, G. C 9 and C10 alkyls.
• a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls.
• Non-limiting examples of C1-C12 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.
• C1-C12 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. Unless stated otherwise specifically in the specification, an 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 C2-C12 alkenyl
• an alkenyl comprising up to 10 carbon atoms is a C2-C1 0 alkenyl
• an alkenyl group comprising up to 6 carbon atoms is a C2-C 6 alkenyl
• an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
• a C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls.
• a C2-C 6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes G, alkenyls.
• a C2-C1 0 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C 6 alkenyls, but also includes C7, G. C 9 and C10 alkenyls.
• a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls.
• Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), l-propenyl, 2-propenyl (allyl), iso-propenyl, 2 -methyl- l-propenyl, l-butenyl, 2-butenyl, 3- butenyl, l-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, l-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, l-nonenyl, 2-non
• 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.
• C2-C12 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. Unless stated otherwise specifically in the specification, an 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 C2-C1 0 alkynyl
• an alkynyl group comprising up to 6 carbon atoms is a C2-C 6 alkynyl
• an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl.
• a C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls.
• a C2-C 6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes G alkynyls.
• a C2-C1 0 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C 6 alkynyls, but also includes C7, G. C 9 and C10 alkynyls.
• a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls.
• Non-limiting examples of C2-C12 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.
• C2-C12 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.
• the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group 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 -ORa where Ra 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 -NHRa or -NRaRa where each Ra 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.
• a non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.
• Alkylcarbonyl groups can also be referred to as“Cw-Cz acyl” where w and z depicts the range of the number of carbon in Ra, as defined above.
• Cl-Cio acyl refers to alkylcarbonyl group as defined above, where Ra is Ci-Cio alkyl, Ci-Cio alkenyl, or Ci-Cio alkynyl radical as defined above. Unless stated otherwise specifically in the specification, 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.
• the term“aryl” is meant to include aryl radicals that are optionally substituted.
• Aralkyl or“arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rc 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.
• alkenyl or“arylalkenyl” refers to a radical of the formula -Rb-Rc where Rb is an alkenylene o group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.
• Alkynyl or“arylalkynyl” refers to a radical of the formula -Rb-Rc where Rb is an alkynylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.
• Carbocyclyl “carbocyclic ring” or“carbocycle” 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, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]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. l]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.
• Cycloalky lalkyl refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd 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, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,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., l-fluoropropenyl, l,l-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., l-fluoropropynyl, l-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
• 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 quatemized; and the heterocyclyl radical can be partially or fully saturated.
• heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,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, l-oxoxo
• Heterocyclylalkyl refers to a radical of the formula -Rb-Re where Rb is an alkylene group as defined above and Re 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 -Rb-Re where Rb is an alkenylene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkylalkenyl group can be optionally substituted.
• Heterocyclylalkynyl refers to a radical of the formula -Rb-Re where Rb is an alkynylene group as defined above and Re 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 quatemized.
• Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene,
• 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 -Rb-Rf where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.
• Heteroarylalkenyl refers to a radical of the formula -Rb-Rf where Rb is an alkenylene, chain as defined above and Rf 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 -Rb-Rf where Rb is an alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, 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 -SRa where Ra 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.
• Rg and Rh 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
• 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
• T 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 CFF.
• ‘‘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.
• the compound of the present disclosure can be useful for modulating androgen receptor (AR). Further, the compound 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.
• a and B are each independently aryl or heteroaryl
• C is a 3-to lO-membered ring
• L is hydrogen, halogen, -CF2R 10 , -CF3, -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 SOiR 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 ,
• R 5 and R 6 are each independently hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , - CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 taken together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
• R 8 and R 9 are each independently hydrogen, halogen, or C 1 -C3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted -OCO(Ci-C6 alkyl), - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)- CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 8a and R 8b taken together form an optionally substituted carbocyclyl or optionally substituted heteroaryl
• R 7 , R 10 and R 16 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 7 and R 8a taken together form an optionally substituted heterocyclyl;
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or (R 11 and R 12 ) or (R 14 and R 15 ) taken together form an optionally substituted heterocyclyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, 2, 3, or 4;
• n3 is 0, 1, 2, 3, 4 or 5;
• each t is independently 0, 1 or 2.
• a and B are each independently aryl or heteroaryl
• C is a 3- to lO-membered ring
• L is hydrogen, halogen, -CF 2 R 10 , -CFs, -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C 6 alkyl, optionally substituted C1-C 6 alkoxy, optionally substituted -(C1-C 6 alkyl)-(Ci-C 6 alkoxy), optionally substituted -(C1-C 6 alkyl) -OH, - NR 13 R 14 , optionally substituted -(C1-C 6 alkyl)-NR 13 R 14 , -NR 14 SC R 16 , optionally substituted -(C1-C 6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C 6 alkyl)- NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C 6 alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C1-C
• R 5 and R 6 are each independently hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , - CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 taken together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
• R 8 and R 9 are each independently hydrogen, halogen, or C1-C 3 alkyl; [229] R 8a and R 9a are each independently hydrogen, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted -OCO(Ci-C 6 alkyl), - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)- CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroary
• R 7 , R 10 and R 16 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, optionally substituted carbocyclyl, optionally substituted -CO(Ci-C 6 alkyl), -CO(optionally substituted heterocyclyl), optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 7 and R 8a taken together form an optionally substituted heterocyclyl;
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted -COO(Ci-C 6 alkyl), optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or (R 11 and R 12 ) or (R 14 and R 15 ) taken together form an optionally substituted heterocyclyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, 2, 3, or 4;
• n3 is 0, 1, 2, 3, 4 or 5;
• each t is independently 0, 1 or 2.
• C is a 3- to lO-membered ring
• W is a bond, -(CR 8a R 9a )m-, -N(R 7 )CO-, -CONR 7 -, or -NSO2R 7 -;
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH2CH2CH2-;
• L is hydrogen, halogen, -CF2R 10 , -CF 3 , -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, deuterium, halogen, -CN, -CF 3 , - OH, optionally substituted C1-C 6 alkyl, optionally substituted C1-C 6 alkoxy, optionally substituted -(C1-C 6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C 6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C 6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C 6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C 6 alkyl)- NR 14 COR 16 , optionally substituted -(C1-C 6 alkyl)- NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(Ci-Ce alkyl
• R 5 and R 6 are each independently hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , - CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 5 and R 6 taken together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
• R 8 and R 9 are each independently hydrogen, halogen, or C1-C3 alkyl
• R 8a and R 9a are each independently hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)- NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(Ci-Ce alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 8a and R 8b taken together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
• R 7 , R 10 and R 16 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkyl-Nhk, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, optionally substituted carbocyclyl, optionally substituted -CO(Ci-C 6 alkyl), - CO(optionally substituted heterocyclyl), optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 7 and R 8a taken together form an optionally substituted heterocyclyl;
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted -COO(Ci-C 6 alkyl), optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or (R 11 and R 12 ) or (R 14 and R 15 ) or (R 14 and R 16 ) taken together form an optionally substituted heterocyclyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, 2, 3, or 4;
• n3 is 0, 1, 2, 3, 4 or 5;
• each t is independently 0, 1 or 2.
• a and B are each independently aryl or heteroaryl
• [260] C is a 3- to lO-membered ring
• V is -CH2-, -CH2CH2-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH2CH2CH2-;
• L is hydrogen, halogen, -CF2R 10 , -CF , -CCI2R 10 , -CCl 3 , -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, deuterium, halogen, -CN, -CF 3 , - OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alkyl
• R 5 and R 6 are each independently hydrogen, halogen, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -
• R 8 and R 9 are each independently hydrogen, halogen, or C 1 -C3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -
• CONR 14 R 15 optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 8a and R 8b taken together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
• R 7 , R 10 and R 16 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkyl-NH2, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, optionally substituted carbocyclyl, optionally substituted -CO(Ci-C6 alkyl), - CO(optionally substituted heterocyclyl), optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 7 and R 8a taken together form an optionally substituted heterocyclyl;
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted -COO(Ci-C6 alkyl), optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or (R 11 and R 12 ) or (R 14 and R 15 ) or (R 14 and R 16 ) taken together form an optionally substituted heterocyclyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, 2, 3, or 4;
• n3 is 0, 1, 2, 3, 4 or 5;
• each t is independently 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• L is hydrogen, halogen, -CF2R 10 , -CF 3 , -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C1-C3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 8 and R 9 are each independently hydrogen, halogen, or C1-C3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, C 1 -C3 alkyl, C 2 -C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , -(C1-C3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , - (C1-C3 alkyl) -NR 14 COR 16 , -CONR 14 R 15 , or -(C1-C3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 7 , R 10 and R 16 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• the present disclosure provides compounds comprising the structure of formula (PA):
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CHi-, -C(CH 3 )H-, -0-, -S-, -NH-, -NOB-, or -N(COCH 3 )-;
• W is a bond, -CH2-, -C(CH 3 )H-, -NHCO-, -N(CI-C 3 alkyl)CO-, or -CONH-, or -CON(CI-C 3 alkyl)-;
• V is -CH2-, -CH2CH2-, -CH(CH )CH 2 -, -CH 2 CH(CH )-, or -CH2CH2CH2-;
• L is hydrogen, halogen, -CF2R 10 , -CF , -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, deuterium, halogen, -CN, -CF 3 , -
• R 5 and R 6 are each independently hydrogen, halogen, -OH, Ci-C 3 alkyl, C2- alkenyl, C2-C 3 alkynyl, or Ci-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 8 and R 9 are each independently hydrogen, halogen, or Ci-C 3 alkyl
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C2-C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 7 , R 10 and R 16 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkyl-NFb; or R 14 and R 16 taken together form a 3- to 6-membered heterocyclyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• W is a bond, -CH2-, or -C(CH 3 )H-;
• L is hydrogen, halogen, -CF2R 10 , -CF 3 , -CN, -OR 10 ; -NR n R 12 , or -CONR n R 12 ;
• R 1 and R 2 are each independently hydrogen, deuterium, halogen, -CN, -CF 3 , -
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C1-C3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 8 and R 9 are each independently hydrogen, halogen, or C1-C3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, C 1 -C3 alkyl, C 2 -C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , -(C1-C3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , - (C1-C3 alkyl) -NR 14 COR 16 , -CONR 14 R 15 , or -(C1-C3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 7 , R 10 and R 16 are each independently hydrogen, C 1 -C6 alkyl, C 2 -C6 alkenyl, C2-C6 alkynyl or C1-C6 alkyl-MH; or R 14 and R 16 taken together form a 3- to 6-membered heterocyclyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF 3 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl) -OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C(C
• R 5 and R 6 are each independently hydrogen, halogen, -OH, Ci-C 3 alkyl, C2-C 3 alkenyl, C2-C 3 alkynyl, or Ci-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; [353] R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• R 8 and R 9 are each independently hydrogen, halogen, or Ci-C 3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, Ci-C 3 alkyl, C2-C 3 alkenyl, C 2 -C 3 alkynyl, Ci-C 3 alkoxy, -NR 13 R 14 , -(Ci-C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , - (Ci-C 3 alkyl) -NR 14 COR 16 , -CONR 14 R 15 , or -(Ci-C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C2-C 3 alkynyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 ;
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH -, or -N(COCH )-;
• V is -CH2- and L is halogen, -NH2, -CHCh, -CCl 3 , or -CF 3 ; or
• V is -CH2CH2- and L is halogen or -NH2;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C 6 alkyl, optionally substituted C1-C 6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 SOiR 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CON
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C2-C 3 alkynyl, or C1-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• R 8 and R 9 are each independently hydrogen, halogen, or C1-C3 alkyl
• R 8a and R 9a are each independently hydrogen, -OH, halogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C2-C 3 alkynyl, C1-C 3 alkoxy, -NR 13 R 14 , -(C1-C 3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , - (C1-C 3 alkyl) -NR 14 COR 16 , -CONR 14 R 15 , or -(C1-C 3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 13 , R 14 and R 15 are each independently hydrogen, C1-C 3 alkyl, C2-C 3 alkenyl, or C2-C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, optionally substituted C1-C 3 alkyl, optionally substituted C2- C 3 alkenyl, optionally substituted C2-C 3 alkynyl, C 3 -C 6 cycloalkyl, or phenyl;
• each m is independently 0, 1 or 2;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 3- to lO-membered ring
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y and Z are each independently a bond, -CH2-, -C(CH3)H-, -0-, -S-, -NH-, - NCH3-, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF3;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C1-
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C 1 -C3 alkyl, C 2 -C3 alkenyl, C2-C3 alkynyl, or C1-C3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; [396] R 7 is H or Ci-Ce alkyl;
• R 13 , R 14 and R 15 are each independently hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 5- to lO-membered heteroaryl or aryl
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF3;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C 6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - SC NR 14 R 15 , optionally substituted -(C1-
• R 5 and R 6 are each independently hydrogen, halogen, -OH, Ci-C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, Ci-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 7 is H or C1-C6 alkyl
• R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, Ci-C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 5- to lO-membered heteroaryl or aryl
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 ;
• Y is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• Z is a bond, -CHi-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH 3 )-;
• V is -CH 2 -, -CH2CH2-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH )-, or -CH2CH2CH2-;
• L is hydrogen, halogen, -OH, -NH2, or -CF 3 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C
• R 5 and R 6 are each independently hydrogen, halogen, -OH, -NH2, Ci-C 3 alkyl, C2-CN alkenyl, C2-C3 alkynyl, or Ci-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 7 is H, Ci-Ce alkyl, -CO(Ci-Ce alkyl);
• R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C2-C3 alkenyl, C 2 -C 3 alkynyl, or -COO(Ci-C6 alkyl); or R 14 and R 15 taken together form a 3- to 6- membered heterocyclyl;
• R 16 is hydrogen, Ci-C 3 alkyl, Ci-C 3 haloalkyl, C 2 -C 3 alkenyl, or C2- alkynyl;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• C is a 5 - to lO-membered heterocyclyl
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• Z is a bond, -CH 2 -, -C(CH )H-, -0-, -S-, -NH-, -NCH -, or -N(COCH )-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF 3 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(C1C1
• R 5 and R 6 are each independently hydrogen, halogen, -OH, Ci-C 3 alkyl, C2-C 3 alkenyl, C2-C 3 alkynyl, or Ci-C 3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl; [453] R 7 is H or C1-C6 alkyl;
• R 13 , R 14 and R 15 are each independently hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, Ci-C 3 alkyl, C2-C 3 alkenyl, or C2-C 3 alkynyl;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t 0, 1 or 2.
• C is a phenyl or a 5- to 7-membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member;
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• Z is a bond, -CH 2 -, -0-, or -NH-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF 3 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , methyl, or - CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF 3 , -OH, Ci-C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NHSC Cft, - N(CH )S0 2 CH , -CH 2 NHS0 2 CH , -CH 2 N(CH )S0 2 CH , -SO2NH2, -CONH2, -CON(Ci- C 3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH )CO(CI-C 3 alkyl);
• R 5 and R 6 are each independently hydrogen, halogen, -OH, or Ci-C 3 alkyl;
• R 7 is H or Ci-Ce alkyl; [472] nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• C is a 5- to 7-membered saturated or partially saturated monocyclic heterocycle comprising 1, 2, or 3 heteroatoms selected from O, S, or N as a ring member;
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH 2 -, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH )-;
• Z is a bond, -CH 2 -, -O-, or -NH-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF 3 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , methyl, or - CONH2;
• R 5 and R 6 are each independently hydrogen, halogen, -OH, or Ci-C 3 alkyl;
• R 7 is H or Ci-Ce alkyl
• R 16 is hydrogen or Ci-C 3 alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• t is 0, 1 or 2.
• -V-L is -CH2CH2CI, -CH2CH2CH2CI, -CH2CH2NH2, or -CH2CH2CH2NH2.
• X is a bond, -CH2-, -C(CH 3 )H-, -C(CH 3 ) 2 -, or -CH2CH2-.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene;
• X is a bond, (CR 5 R 6 )t-, or -NR 7 -;
• Y is a bond, -CH2-, -C(CH )H-, -0-, -S-, -NH-, -NCH -, or -N(COCH )-;
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH 3 -, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF 3 ;
• D is -NH or -NR 3 ;
• U is each independently O, S, or NR 16 ;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, - NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)- NR 14 COR 16 , -CONR 13 R 14 , optionally substituted -(Ci-Ce alkyl)-CONR 14 R 15 , - SC NR 14 R 15 , optionally substituted -(C
• R 3 is selected from hydrogen, halogen, -CN, -CF3, -OH, -S(Ci-C3 alkyl), C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , -(C1-C3 alkyl)-NR 13 R 14 , - NR 14 S0 2 R 16 , -(C1-C3 alkyl)NR 14 S0 2 R 16 , -NR 14 COR 16 , -(Ci-Ce alkyl)-NR 14 COR 16 , - CONR 14 R 15 , -(C1-C3 alkyl)-CONR 14 R 15 , -S0 2 NR 14 R 15 , -(C1-C3 alkyl)-S0 2 NR 14 R 15 , - S0 2 (Ci-C3 alkyl), or -(Ci-Ce alkyl),
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C1-C3 alkoxy; or R 5 and R 6 taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl;
• R 7 is H or Ci-Ce alkyl
• R 13 , R 14 and R 15 are each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C2-C 3 alkynyl; or R 14 and R 15 taken together form a 3- to 6-membered heterocyclyl;
• R 16 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl;
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, or 3;
• t is 0, 1 or 2.
• C is a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from O, S, or N as a ring member;
• X is -(CR 5 R 6 )t- or -NR 7 -;
• Y is a bond, -CH 2 -, -0-, or -NH-;
• Z is a bond, -CH 2 -, -O-, or -NH-;
• W is a bond, -CHi-, or -C(CH 3 )H-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is hydrogen, halogen, -NH2, or -CF3;
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, methyl, or - CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -S(Ci-C 3 alkyl), -S0 2 (Ci-C3 alkyl), -NHSO2CH3, - N(CH3)S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S02CH3, -SO2NH2, -CONH2, -CON(Ci- C3 alkyl)2, -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH 3 )CO(CI-C3 alkyl);
• R 5 and R 6 are each independently hydrogen, halogen, -OH, or C1-C3 alkyl;
• R 7 is H or Ci-Ce alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, 2, 3, 4 or 5;
• t is 0, 1 or 2.
• L is hydrogen or halogen
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , methyl, or - CONHi;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NHSO2CH3, - N(CH3)S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S02CH3, -SO2NH2, -CONH2, -CON(Ci- C3 alkyl)2, -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH 3 )CO(CI-C3 alkyl);
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• R 7 is H or Ci-Ce alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, or 2;
• t is 1 or 2.
• W is a bond, -CH 2 -, or -C(CH 3 )H-;
• V is -CHi-, -CH2CH2-, -CH2CH2CH2-, or -CH2CHCICH2-;
• L is hydrogen, -OH, or halogen
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, methyl, or - CONHi;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C3 alkyl), -NHi, - NHSO2CH3, -NHSO2CF3, -N(CH3)S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S02CH3, - SO2NH2, -CONHi, -CON(CI-C3 alkyl)2, -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), - N(CH 3 )COO(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH 3 )COO(CI-C 3 alkyl);
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• R 7 is H or Ci-Ce alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, or 2;
• t is 1 or 2.
• R 3 is selected from hydrogen, F, Cl, Br, I, -CN, -CF3, -OH, methyl, methoxy, -S(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NHi, -NHSO2CH3, -NHSO2CF3, -N(CH3)S0 2 CH3, -SO2NH2, -CONHi, -CON(CI-C 3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or -NHCO(CI-C 3 alkyl).
• X is -(CR 5 R 6 )t- or -NR 7 -;
• Y is -0-
• W is -CHi- or -C(CH 3 )H-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• L is hydrogen or halogen
• R 1 and R 2 are each independently halogen or -CN;
• R 3 is selected from -NHSO2CH3, -N(CH 3 )S02CH 3 , or -SC Cft;
• R 5 and R 6 are each independently hydrogen or Ci-C 3 alkyl
• R 7 is H or Ci-Ce alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 0, 1, or 2;
• W is -CH 2 - or -C(CH 3 )H-;
• V is -CH2- and L is hydrogen
• V is -CH2CH2- or -CH2CH2CH2-, and L is halogen;
• R 1 and R 2 are each independently Cl or -CN;
• R 3 is selected from -NHSO2CH3, -N(CH 3 )SC>2CH 3 , or -SC CHy
• R 5 and R 6 are each independently hydrogen or methyl
• R 7 is H or Ci-Ce alkyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1, or 2;
• X is -(CR 5 R 6 )t-;
• Y is -0-
• W is -CHi- or -C(CH 3 )H-;
• V is -CH2CH2- or -CH2CH2CH2-;
• L is halogen
• R 1 and R 2 are each independently Cl or -CN;
• R 3 is selected from -NHSO2CH3, -N(CH 3 )S02CH 3 , or -SOiCft;
• R 5 and R 6 are each independently hydrogen or methyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1 or 2;
• the present disclosure provides compounds comprising the structure of formula (G-II)
• X is -(CR 5 R 6 ) t -;
• Y is -0-
• W is -CH 2 - or -C(CH 3 )H-;
• V is -CH2CH2-
• L is halogen
• R 1 and R 2 are each independently Cl or -CN; [621] at least one R 3 is selected from -CN, Ci-C 3 alkoxy, -CONH 2 , -NHS0 2 CH 3 , - N(CH 3 )S0 2 CH 3 , -NHS0 2 CH 2 CH 3 , -N(CH 3 )S0 2 CH 2 CH 3 , or -S0 2 CH 3 and the other R 3 , if present, is selected from -CN, -CF 3 , Ci-C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, Ci-C 3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , -(C1-C 3 alkyl)NH 2 , -NHS0 2 CH 3 , -
• NHS0 2 CF 3 , -N(CH 3 )S0 2 CH 3 , -NHS0 2 CH 2 CH 3 , -N(CH 3 )S0 2 CH 2 CH 3 , -CH 2 NHSO 2 CH 3 , -CH 2 N(CH 3 )S0 2 CH 3 , -S0 2 NH 2 , -CONH 2 , -CON(CI-C 3 alkyl) 2 , -CONH(CI-C 3 alkyl), - NHCO(CI-C 3 alkyl), -N(CH 3 )COO(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or - N(CH 3 )COO(CI-C 3 alkyl);
• R 5 and R 6 are each independently hydrogen or methyl
• nl and n2 are each independently 0, 1, or 2;
• n3 is 1 or 2;
• X is -(CR 5 R 6 )t- or -NR 7 -;
• Y is -O-
• W is -CH 2 - or -C(CH 3 )H-;
• V is -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -;
• L is halogen; [635] R 1 and R 2 are each independently Cl or -CN;
• R 5 and R 6 are each independently hydrogen or methyl
• R 7 is H or Ci-Ce alkyl
• nl and n2 are each independently 0, 1, or 2;
• V is -CH2-, -CH2CH2- or -CH2CH2CH2-;
• L is halogen
• R 1 and R 2 are each independently Cl or -CN;
• R 5 and R 6 are each independently hydrogen or methyl
• R 7 is H or C1-C6 alkyl
• nl and n2 are each independently 0, 1, or 2;
• X is -(CR 5 R 6 )-;
• Y is a bond, -CH 2 -, -0-, or -NH-;
• Z is a bond, -CHi-, -0-, or -NH-;
• W is a bond, -CH 2 -, or -C(CH 3 )H-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• R 1 , R 2A and R 2B are each independently hydrogen, halogen, -CN, -CF3, methyl, or -CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , - NHSO2CH3, -NHSO2CF3, -N(CH3)S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S02CH3, - SO2NH2, -CONH2, -CON(CI-C 3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), -
• R 5 and R 6 are each independently hydrogen or Ci-C 3 alkyl
• nl is 0, 1, or 2;
• n3 is 1 or 2;
• X is -(CR 5 R 6 )-;
• Y is a bond, -CH 2 -, -O-, or -NH-;
• Z is a bond, -CH 2 -, -O-, or -NH-;
• W is a bond, -CH 2 -, or -C(CH 3 )H-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen
• R 1 , R 2A and R 2B are each independently hydrogen, halogen, -CN, -CF 3 , methyl, or -CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH2, - NHSO2CH3, -NHSO2CF3, -N(CH 3 )S02CH 3 , -CH2NHSO2CH3, -CH 2 N(CH 3 )S02CH3, - SO2NH2, -CONH2, -CON(CI-C3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), - N
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• nl is 0, 1, or 2;
• n3 is 1 or 2;
• X is -(CR 5 R 6 )-;
• Y is a bond, -CH2-, -O-, or -NH-;
• Z is a bond, -CH2-, -O-, or -NH-;
• W is a bond, -CH2-, or -C(CH 3 )H-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen;
• R 1 , R 2A and R 2B are each independently hydrogen, halogen, -CN, -CF3, methyl, or -CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , - NHSO2CH3, -NHSO2CF3, -N(CH3)S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S02CH3, - SO2NH2, -CONHi, -CON(CI-C3 alkyl)2, -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), - N(CH 3 )COO(CI-C3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH 3 )COO(CI-C3 alkyl);
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• nl is 0, 1, or 2;
• n3 is l or 2.
• X is -(CR 5 R 6 )-;
• Y is a bond, -CH 2 -, -0-, or -NH-;
• Z is a bond, -CH 2 -, -0-, or -NH-;
• W is a bond, -CH 2 -, or -C(CH 3 )H-;
• V is -CHi-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen
• R 1 , R 2A and R 2B are each independently hydrogen, halogen, -CN, -CF3, methyl, or -CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , - NHSO2CH3, -NHSO2CF3, -N(CH 3 )S02CH 3 , -CH2NHSO2CH3, -CH 2 N(CH 3 )S02CH3, - SO2NH2, -CONH2, -CON(CI-C3 alkyl)2, -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), - N(CH 3 )COO(CI-C3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH 3 )COO(CI-C 3 alky
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• nl is 0, 1, or 2;
• n3 is l or 2; ⁇
• R 2A and R 2B are not both Cl.
• L is halogen
• R 1 , R 2A and R 2B are each independently hydrogen, halogen, -CN, -CF3, methyl, or -CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C 3 alkyl), -NH 2 , -
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• nl is 0, 1, or 2;
• n3 is 1 or 2;
• W is a bond, -CH 2 -, or -C(CH 3 )H-;
• V is -CH 2 -, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen
• R 1 , R 2A and R 2B are each independently hydrogen, halogen, -CN, -CF3, methyl, or -CONH2;
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C 3 alkyl), -S0 2 (Ci-C3 alkyl), -NHi, - NHSO2CH3, -NHSO2CF3, -N(CH3)S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S02CH3, - SO2NH2, -CONHi, -CON(CI-C3 alkyl)2, -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), - N(CH 3 )COO(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), or -N(CH 3 )COO(CI-C 3 alkyl);
• R 5 and R 6 are each independently hydrogen or C1-C3 alkyl
• nl is 0, 1, or 2;
• n3 is l or 2.
• a and B are each independently 5- or 6-membered aryl or heteroaryl.
• a and B are each independently selected from phenyl, pyridyl, pyrimidyl, or thiophene.
• a and B are each phenyl.
• A has a meta or para connectivity with X and Y.
• B has a meta or para connectivity with X and Z.
• a and B are phenyl and has one of the connectivity as shown:
• C is aryl or heteroaryl.
• C is 5- to lO-membered aryl or heteroaryl.
• C is aryl.
• C is phenyl or naphthyl.
• C is aryl.
• C is phenyl.
• 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 lO-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 . In some embodiments, 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 . In some embodiments, 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 C1-C3 alkyl.
• C is selected from
• C is in its tautomeric form
• C is N ' ⁇ or in its tautomeric form H
• 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 imidazolidine, imidazolidine-dione, or dihydrooxazole. In one embodiment, C is selected from
• C is each independently O, S, or NR 16 .
• D is -NH- or -NR 3 -.
• at least one U is O.
• each U is O.
• at least one R 3 is -SO2CH3, -NHSO2CH3, - CH2NHSO2CH3, -SO2NH2, -CONH2, or -NHCOCH3.
• C is aryl. In some embodiments, C is phenyl or naphthyl. In one embodiment of the compounds of formula (I)- (VA) or (A), C is phenyl.
• C is bicyclic heteroaryl
• heterocyclyl In one embodiment,
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-.
• Z is -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-.
• Z is a bond, - CH2-, -0-, or -NCH3-.
• Z is a bond, -CH2-, -0-, or -NH-. In some embodiments of the compounds of formula (I)-(VI) and (A)-(H-I), Z is -0-.
• “compounds of formula (I)-(IV) and (A)-(H-I)” refers to compounds of formula (I), (IA), (IB), (IC), (II), (IIA), (IIIA), (IIB), (III), (IV), (IVA), (V), (VA), (VI), (A), (A-I), (B)-(D), (E), (E- I)-(E-VII), (F), (G), (G-I), (G-II), (H), and (H-I).
• Y is a bond, -CH2-, -C(CH3)H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH3)-.
• Y is -CH2-, -C(CH3)H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH3)-.
• Y is a bond, -CH2-, -0-, or -NCH3-.
• Y is a bond, -CH2-, -0-, or -NH-.
• Y is -0-.
• 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 8b are each independently hydrogen, -OH, halogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , optionally substituted - (C1-C3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C3 alkyl)-NR 14 COR 16 , - CONR 14 R 15 , or optionally substituted -(C1-
• V is -(CR 8a R 9a )m-, wherein R 8a and R 8b are each independently hydrogen, -OH, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , -(C1-C3 alkyl)- NR 13 R 14 , -NR 14 COR 16 , -(C1-C3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , or -(C1-C3 alkyl)- CONR 14 R 15 ; or R 8a and R 8b , 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 -CH2-, - CH2CH2-, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH2CH2CH2-.
• V is -CH2- , -CH2CH2-, or -CH2CH2CH2-, each optionally substituted with one or more of -OH, halogen, or C1-C3 alkyl.
• V is -CH2-, -CH2CH2-, -CH2CH(OH)CH2- or - CH2CH2CH2-.
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-.
• V is -CH 2 - or -CH2CH2-.
• V is -CH2- and L is halogen, -NH2, or -CF3; or V is -CH2CH2- and L is halogen or -NH2.
• L is hydrogen, halogen, -CF 2 H, -CF3, -CN, -0(Ci-C3 alkyl), -NR n R 12 , or -CONR n R 12 .
• L is hydrogen, halogen, -CF2H, -CF3, -CN, -0(Ci-C3 alkyl), -NH2, -NH(CI-C3 alkyl), -N(CI-C3 alkyl)2, -CONH2, -CONH(CI-C3 alkyl), or -CON(CI-C3 alkyl)2.
• L is hydrogen, halogen, -CF3, or -NFh.
• L is halogen, - CCb, -CCI2, -CF3, or -NFk.
• L is halogen, -CF3, or -NFh.
• 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, -CH2-, or -C(CH3)H-.
• W is a -CH2- or -C(CH3)H-.
• -Y-W- is -OCH2-, - OCH2CH2-, or -OCH(CH 3 )-.
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-.
• Z is a bond, -CH2-, -C(CH 3 )H-, -0-, -S-, -NH-, -NCH3-, or -N(COCH 3 )-;
• V is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
• L is halogen, -NH2, or -CF3.
• -Z-V-L is -Z-CH2CH2CI, -Z-CH2CH2CH2CI, -Z-CH2CH2NH2, or -Z-CH2CH2CH2NH2, wherein Z is a bond, -0-, -NH-, or -N(COCH3)-.
• -Z-V-L is -OCH3.
• -Z-V-L is - O-CH2CH2CI or -O-CH2CH2CH2CI.
• -V-L is - CH2CH2CI, -CH2CH2CH2CI, -CH2CH2NH2, or -CH2CH2CH2NH2. In one embodiment, -V-L is -CH 3 .
• X is a bond, -(CR 5 R 6 )t-, or -NR 7 -.
• X is a bond or - (CR 5 R 6 )t-.
• X is a bond, -CH2-, -C(CH3)H-, -C(CH3)2-, -CH2CH2-, -NH- , or -N(CI-C6 alkyl)-. In some embodiments, X is a bond, -CH2-, -C(CH3)H-, -C(CH3)2-, - CH2CH2-, -NH-, -N(CH3)-, -N(CH2CH3)-, -N(zPr)-, or -N(/Bu)-. In some embodiments, X is a bond, -CH2-, -C(CH 3 )H-, -C(CH 3 ) 2 -, or -CH2CH2-.
• X is -CH2-, - C(CH 3 )H-, or -C(CH 3 )2-. In one embodiment, X is -C(CH 3 )2-.
• R 1 and R 2 are each independently halogen, -CN, -CF 3 , -OH, Ci-C 3 alkyl, Ci-C 3 alkoxy, -(Ci-C 3 alkyl)- (Ci-C 3 alkoxy), -(Ci-C 3 alkyl)-OH, -NR 13 R 14 , -(Ci-C 3 alkyl)-NR 13 R 14 , -NR 14 S0 2 R 16 , -(Ci-C 3 alkyl)NR 14 S0 2 R 16 , -NR 14 COR 16 , -(Ci-C 3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , -(Ci-C 3 alkyl)- CONR 14 R 15 , -S0 2 NR 14 R 15 , -(CI-C 3 alkyl)-S0 2 NR
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted Ci- Ce alkyl, optionally substituted C1-C6 alkoxy, optionally substituted -(C1-C6 alkyl)-(Ci-C6 alkoxy), optionally substituted -(C1-C6 alkyl)-OH, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 S0 2 R 16 , optionally substituted -(Ci-Ce alkyl)NR 14 S0 2 R 16 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alky
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, optionally substituted Ci-C 3 alkyl, Ci-C 3 alkoxy, optionally substituted -(Ci-C 3 alkyl)-(Ci-C 3 alkoxy), optionally substituted -(Ci-C 3 alkyl)-OH, -NR 13 R 14 , -(Ci-C 3 alkyl)-NR 13 R 14 , -NR 14 S0 2 R 16 , optionally substituted -(Ci-C 3 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , optionally substituted -(Ci-C 3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(Ci-C 3 alkyl)-CONR 14 R 15 , - S02NR 14 R 15 , optionally substituted -(Ci-C 3 alkyl)-S02
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF 3 , -OH, Ci-C 3 alkyl, Ci-C 3 alkoxy, -(Ci-C 3 alkyl)-(Ci-C 3 alkoxy), -(Ci-C 3 alkyl)-OH, -NR 13 R 14 , -(Ci-C 3 alkyl)-NR 13 R 14 , -NR 14 S0 2 R 16 , -(Ci-C 3 alkyl)NR 14 S0 2 R 16 , -NR 14 COR 16 , -(C1-C3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , -(C1-C3 alkyl)- CONR 14 R 15 , -S0 2 NR 14 R 15 , -(C1-C3 alkyl)-CONR 14 R 15 , -S0 2 NR 14 R 15 , -(C1-C3 alkyl
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, -OH, C 1 -C3 alkyl, or - CONR 14 R 15 .
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, -OH, methyl, methoxy, or -CONH 2 .
• R 1 and R 2 are each independently hydrogen, Cl, -CN, -CF3, -OH, methyl, methoxy, or -CONH 2 .
• R 1 and R 2 are each independently hydrogen, halogen, -CN, -CF3, -OH, or methyl. In one embodiment, R 1 and R 2 are each independently Cl, -CN, -CF3, -OH, methyl, methoxy, or -CONH 2 . In one embodiment of the compounds of formula (I)-(VI), R 1 and R 2 are each independently halogen, -CN, -CF3, -OH, or methyl.
• R 1 and R 2 are each halogen, methyl, -CF3, or -CN. In one embodiment of the compounds of formula (I)-(VI) and (A)-(F), R 1 and R 2 are each halogen or -CN. In one embodiment of the compounds of formula (I)-(VI) and (A)-(H-I), at least one of R 1 and R 2 is Cl or -CN. In one embodiment of the compounds of formula (I)-(VI) and (A)-(H-I), at least two of R 1 and R 2 are each independently Cl or -CN. In one embodiment of the compounds of formula (I)-(VI) and (A)- (H-I), R 1 and R 2 are each Cl or -CN.
• R 1 and R 2 are each independently optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, 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:
• nl is 0, 1, or 2. In some embodiments, nl is 0 or 1. In other embodiments, nl is 0. In some embodiments, nl is 1. In one embodiment, the sum of nl and n2 is 0, 1, 2, 3, or 4. In some embodiments, the sum of nl and n2 is 1, 2, 3, or 4. In one embodiment, the sum of nl 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.
• n3 is 1, 2, 3, 4, or 5. In som emebodiments, n3 is 1, 2, 3, or 4. In one embodiment, n3 is 1, 2, or 3. In one embodiment, n3 is 1 or 2.
• R 3 is selected from -NR 14 SOiR 16 , optionally substituted -(C1-C 6 alkyl)NR 14 S02R 16 , or optionally substituted -SO2R 16 ; wherein R 16 is hydrogen, optionally substituted C1-C 3 alkyl, optionally substituted C2-C 3 alkenyl, optionally substituted C2-C 3 alkynyl, C 3 -C 6 cycloalkyl, or phenyl.
• R 3 is selected from -NR 14 SC R 16 , -(C1-C 6 alkyl)NR 14 S02R 16 , or -SO2R 16 ; wherein R 16 is hydrogen, C1-C 3 alkyl, -(C1-C 3 alkyl)-NH2, C 3 -C 6 cycloalkyl, or phenyl.
• R 3 is -SO2CH3, -NHSO2CH3, -CH2NHSO2CH3, -SO2NH2, -CONH2, or -NHCOCH3.
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NH2, -NHSO2CH3, -NHSO2CF3, - N(CH 3 )S02CH 3 , -NHSO2CH2CH3, -N(CH 3 )S02CH 2 CH3, -CH2NHSO2CH3, CH 2 N(CH3)S0 2 CH3, -SO2NH2, -CONH2, -CON(CI-C3 alkyl) 2 , -CONH(CI-C 3 alkyl), - NHCO(CI-C 3 alkyl),
• R 3 is selected from hydrogen, F, Cl, Br, I, oxo, -CN, -CF3, -OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -S(Ci-C3 alkyl), -S02(Ci-C3 alkyl), -NH2, -NHSO2CH3, -NHSO2CF3, - N(CH 3 )S0 2 CH3, -CH2NHSO2CH3, -CH 2 N(CH3)S0 2 CH3, -SO2NH2, -CONH2, -CON(CI-C3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), -N(CH 3 )COO(CI-C 3 alkyl), -NHCO(Ci- C
• R 3 on a sp 2 carbon is each selected from hydrogen, halogen, -CN, -CF 3 , -OH, -S(Ci-C 3 alkyl), Ci- C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, Ci-C 3 alkoxy, -(Ci-C 3 alkyl)-(Ci-C 3 alkoxy), -(Ci-C 3 alkyl) -OH, -NR 13 R 14 , -(Ci-C 3 alkyl)-NR 13 R 14 , -NR 14 S0 2 R 16 , -(Ci-C 3 alkyl)NR 14 S0 2 R 16 , - NR 14 COR 16 , -(Ci-Ce alkyl)-NR 14 COR 16 , -CONR 14 R
• R 3 on a nitrogen atom is each selected from Ci-C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, Ci-C 3 alkoxy, -(Ci-C 3 alkyl)-(Ci-C 3 alkoxy), -(Ci-C 3 alkyl)-OH, -(Ci-C 3 alkyl)-NR 13 R 14 , -(Ci-C 3 alkyl)NR 14 S0 2 R 16 , -(Ci-Ce alkyl)-NR 14 COR 16 , -CONR 14 R 15 , -(Ci-C 3 alkyl)-CONR 14 R 15 , -(Ci- C 3 alkyl)-S0 2 NR 14 R 15 , or -(Ci-Ce alkyl)-S0 2 (C
• At least one R 3 is selected from -CN, Ci-C 3 alkoxy, -CONH 2 , -NHS0 2 CH 3 , -N(CH 3 )S0 2 CH 3 , - NHS0 2 CH 2 CH 3 , -N(CH 3 )S0 2 CH 2 CH 3 , or -S0 2 CH 3 and the other R 3 , if present, is selected from -CN, -CF 3 , Ci-C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, Ci-C 3 alkoxy, -S(Ci-C 3 alkyl), - S0 2 (Ci-C 3 alkyl), -NH 2 , -(Ci-C 3 alkyl)NH 2 , -NHS0 2 CH 3 , -NHS0 2 CF 3 , -N
• At least one R 3 is selected from -NHSChCft, -NHS0 2 CH 2 CH 3 , or -SChCft and the other R 3 , if present, is selected from -CN, Ci-C 3 alkyl, Ci-C 3 alkoxy, -S0 2 (Ci-C 3 alkyl), -NH 2 , -(Ci-C 3 alkyl)NH 2 , - NHSChCft, -N(CH 3 )S0 2 CH 3 , -NHS0 2 CH 2 CH 3 , -N(CH 3 )S0 2 CH 2 CH 3 , -S0 2 NH 2 , -CONH 2 , - CON(CI-C 3 alkyl) 2 , -CONH(CI-C 3 alkyl), -NHCO(CI-C 3 alkyl), -N(CH 3 )COO(CI-C 3 alkyl), - NHCO(CI-C 3 alkyl),
• R 3 is not hydrogen
• At least one R 3 is -S0 2 CH 3 , -NHSC Cft, -NCH 3 S0 2 CH 3 , -NHS0 2 CH 2 CH 3 , or -N(CH 3 )S0 2 CH 2 CH 3 .
• at least one R 3 is - S0 2 CH 3 , -NHSChCft, or -NCftSChCft.
• R 3 is heterocyclyl.
• R 3 is heterocyclyl selected from
• R 3 is - NR 14 SC 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 SC R 16 , wherein R 16 is optionally substituted C1-C6 alkyl.
• R 3 is - NR 14 SC R 16 , wherein R 16 is C1-C6 alkyl optionally substituted with one or more groups selected from halogen, -CN, -CF3, -OH, C1-C3 alkyl, C1-C3 alkoxy, -NH2, -NH(CI-C3 alkyl), - N(CI-C3 alkyl)2, -SCH3.
• R 3 is -NR 14 S02R 16 , wherein R 16 is C1-C3 alkyl substituted with -NH2.
• R 5 and R 6 are each independently hydrogen, halogen, -OH, C 1 -C3 alkyl, C 2 -C3 alkenyl, C 2 -C3 alkynyl, or C1-C3 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 C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl.
• R 5 and R 6 are hydrogen, halogen, -OH, or C 1 -C3 alkyl. In one embodiment, R 5 and R 6 are each independently hydrogen, F, -OH, or C 1 -C3 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. In one embodiment of the compounds of formula (I)-(VI) and (A)-(H-I), R 5 and R 6 are each H or methyl.
• R 7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 7 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R 7 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl. In some embodiments, R 7 is hydrogen or C1-C6 alkyl. In some embodiments, R 7 is hydrogen or C1-C4 alkyl. In some embodiments of the compounds of formula (I)-(VI) and (A)-(H-I), R 7 is hydrogen or C1-C3 alkyl.
• R 8a and R 9a are each independently hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 , -NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , optionally substituted -(C1-C6 alkyl)- CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R 8a and R 9a taken together form an optionally substituted carbocyclyl or optionally
• R 8a and R 8b are each independently hydrogen, -OH, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , -(C1-C3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , -(Ci- C3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , or -(C1-C3 alkyl)-CONR 14 R 15 ; or R 8a and R 8b taken together form an optionally substituted 3- to 6-membered carbocyclyl or heterocyclyl.
• R 8a and R 9a are each independently hydrogen, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 , -(C1-C3 alkyl)-NR 13 R 14 , -NR 14 COR 16 , -(Ci- C3 alkyl)-NR 14 COR 16 , -CONR 14 R 15 , or -(C1-C3 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 C1-C3 alkyl.
• R 10 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 10 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 10 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl. In some embodiments, R 10 is hydrogen or C1-C3 alkyl.
• R 11 and R 12 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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 C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl.
• R 11 and R 12 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2- Ce alkynyl.
• R 11 and R 12 are each independently hydrogen or C1-C3 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 C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In one embodiment, R 13 and R 14 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl.
• R 13 and R 14 are each independently hydrogen, C1-C6 alkyl, C2- Ce alkenyl, or C2-C6 alkynyl. In some embodiments R 13 and R 14 are each independently hydrogen or C1-C3 alkyl.
• R 15 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 15 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl.
• R 15 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
• R 15 is hydrogen or C1-C3 alkyl.
• 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 C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 16 is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
• R 16 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• R 16 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl.
• R 16 is hydrogen or C1-C3 alkyl.
• m is 1 or 2.
• t is 1 or 2. In one embodiment of the compounds of formula (I)-(VI) and (A)-(H-I), t is 1.
• optional substituent is selected from halogen, -CN, -CF3, -OH, -S(Ci-C3 alkyl), C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -(C1-C3 alkyl)-(Ci-C3 alkoxy), -(C1-C3 alkyl)-OH, - NR 13 R 14 , -(C1-C3 alkyl)-NR 13 R 14 , -NR 14 S0 2 R 16 , -(C1-C3 alkyl)NR 14 S02R 16 , -NR 14 COR 16 , - (Ci-Ce alkyl)-NR 14 COR 16 , -CONR 14 R 15 , -(C1-C3 alkyl)-CONR 14 R 15 , -(C1-C3 alkyl)-CONR 14 R 15 , -(C1-C
• the optional substituent is selected from halogen, -CN, -CF3, -OH, Ci- C 3 alkyl, C1-C3 alkoxy, -NH 2 , -SCH3, -SO2CH3, -NHSO2CH3, -CH2NHSO2CH3, -SO2NH2, - CONH2, or -NHCOCH3.
• a and B are each monocyclic ring.
• B is phenyl, pyridyl, or pyrimidyl.
• Z and V are not both a bond.
• C is a 4- to lO-membered ring.
• X is a bond, -CH2-, - C(CH3)H-, -C(CH3)2-, or -CH2CH2-. In one embodiment, X is -CH2-, -C(CH3)H-, or -C(CH3)2- . In some embodiments, X is -C(CH3)2-.
• X is -NR 7 -.
• X is -NH-, -N(CH3)-, -N(CH2CH3)-, -N(zPr)-, or -N(7Bu)-.
• Y is -0-. In one embodiment of the compounds of formula (D)-(H-I), Z is -0-. In one embodiment of the compounds of formula (D)-(H-I), Y and Z are both -0-.
• -V-L is CH2CH2CI, - CH2CH2CH2CI, or -CH3. In some embodiments, -V-L is CH2CH2CI or -CH2CH2CH2CI.
• nl is 0.
• n2 is 0, 1, or 2. In some embodiments, n2 is 2. In some embodiments, n2 is 2 and R 2 are each ortho to Z. In other embodiments, 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 compound of formula (I)-(VI) and (A)-(H-I), can be a stereoisomer.
• the carbon attached to R 5 and R 6 can be in an S configuration or an R configuration.
• a hydrogen atom can be replaced with a deuterium atom.
• the compound of formula (I)-(VA), (A), (A-I), or (D)-(H-I) is selected from Table A below, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A3, A5, A7, A13, A17, A18, A22, A23, A24, A25, A28, A30, A31, A32, A34, A35, A38, A40, A41, A42, A45, A49, A52, A53, A54, A56, A57, A58, A62, A63, A64, A65, A68, A73, A74, A75, or A76, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds Al, A2, A4, A6, A8, A9, A10, Al l, A12, A14, A15, A16, A19, A20, A21, A26, A27, A29, A33, A36, A37, A39, A43, A44, A46, A47, A48, A50, A51, A55, A59, A60, A61, A66, A67, A69, A70, A71, A72, A77, A78, A79, A80, A81, A82, A83, A84, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, or A97, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A98-A186, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A187-A211, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A1-A211, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A212-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A1-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds A1-A96, A98-A116, A118-A159, A161-A175, and A177-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound of formula (I)-(VA), (A), (A-I), or (D)-(H-I) is selected from A13, A57, A74, A93, A109, A112, A122, A126, A131, A134, A136, A137, A164, A168, A169, A170, A171, A172, A184, A185, A195, and/or A204, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Table B below, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds Bl, B2, B3, or B6 or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds B4, B5, B7, B8, B9, B10, or B l l or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the compound is selected from Compounds B l-Bl l or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (I), (IA), (IB), (IC), (II), (IIA), (IIIA), (IIB), (III), (IV), (IV A), (V), (VA), (VI), (A), (A-I), (B)-(D), (E), (E-I)-(E-VII), (F), (G), (G-I), (G-II), (H), and (H-I) (“formula (I)-(VI) and (A)-(H-I)”) or compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound selected from Compounds A3, A5, A7, A13, A17, A18, A22, A23, A24, A25, A28, A30, A31, A32, A34, A35, A38, A40, A41, A42, A45, A49, A52, A53, A54, A56, A57, A58, A62, A63, A64, A65, A68, A73, A74, A75, A76, Bl, B2, B3, or B6 or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound selected from Compounds Al, A2, A4, A6, A8, A9, A10, Al l, A12, A14, A15, A16, A19, A20, A21, A26, A27, A29, A33, A36, A37, A39, A43, A44, A46, A47, A48, A50, A51, A55, A59, A60, A61, A66, A67, A69, A70, A71, A72, A77, A78, A79, A80, A81, A82, A83, A84, A85, A86, A87, A88, A89, A90, A91, A92, A93, A94, A95, A96, A97, B4, B5, B7, B8, B9, B10, or B l l, or a pharmaceutically acceptable salt, tautomer, stereoisome
• the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound selected from Compounds A98-A186, 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 selected from Compounds A 187-A211, 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 selected from Compounds A212-A234, 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 selected from Compounds A1-A96, A98-A116, Al 18-A159, A161-A175, and A177-A234, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound selected from Compounds A 13, A57, A74, A93, A109, A112, A122, A126, A131, A134, A136, A137, A164, A168, A169, A170, A171, A172, A184, A185, A195, and/or A204, 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 selected from Compounds A1-A211 or Bl-B l l, 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 selected from Compounds A1-A234 or Bl-B l l, or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (D)-(H-I), or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.
• the present compounds find use in any number of methods.
• the compounds are useful in methods for modulating androgen receptor (AR).
• the present disclosure provides the use of any one of the foregoing compounds of formula (I)-(VI) and (A)-(H-I), 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 (AR) 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. In other embodiments, the modulating AR is inhibiting AR.
• the modulating AR is modulating AR N-terminal domain (NTD). In one embodiment, the modulating AR is binding to AR NTD. In other embodiments, the modulating AR is inhibiting AR NTD. In one embodiment, the modulating AR is modulating AR N-terminal domain (NTD). In some embodiments, modulating the AR is inhibiting transactivation of androgen receptor N-terminal domain (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, non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer. While in other embodiments, the prostate cancer is androgen dependent prostate cancer. In other embodiments, the spinal and bulbar muscular atrophy is Kennedy’s disease. In other embodiments, the prostate cancer is primary /localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer. While in other embodiments, the prostate cancer is androgen dependent prostate cancer. In other embodiments, the spinal and bulbar muscular atrophy is Kennedy’s disease.
• a method of treating a condition associated with cell proliferation in a patient in need thereof comprising administering a compounds of formula (I)-(VI) and (A)-(H-I), 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.
• a method of reducing, inhibiting, or ameliorating proliferation comprising administering a therapeutically effective amount of a compound of formula (I)-(VI) and (A)-(H-I), 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 reducing, inhibiting, or ameliorating is in vitro.
• 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, non-metastatic castration-resistant 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 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, non-metastatic castration-resistant prostate cancer, advanced prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone- sensitive 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.
• 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 (I)-(VI) and (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof is provided.
• reducing or preventing tumor growth includes reduction in tumor volume. In one embodiment, 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 (rl) is faster than the rate of tumor growth after said treatment (r2) such that rl > r2.
• the reducing or preventing in the method disclosed herein is in vivo.
• 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, non-metastatic castration-resistant prostate cancer, advanced prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
• 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.
• the prostate cancer is androgen-dependent prostate cancer or androgen- independent prostate cancer.
• the tumor cells are is breast cancer tumor cells.
• the compounds of the present disclosure are compounds having the structure of formula(I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds provide metabolic stability.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in human liver microsomes (HLMs) of less than about 500 pL/min/mg protein, less than about 450 pL/min/mg protein, less than about 400 pL/min/mg protein, less than about 350 pL/min/mg protein, less than about 300 pL/min/mg protein, less than about 250 pL/min/mg protein, less than about 225 pL/min/mg protein, or less than about 200 pL/min/mg protein.
• HLMs human liver microsomes
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs of less than about 200 pL/min/mg protein, less than about 190 pL/min/mg protein, less than about 180 pL/min/mg protein, less than about 170 pL/min/mg protein, less than about 160 pL/min/mg protein, less than about 150 pL/min/mg protein, less than about 140 pL/min/mg protein, less than about 130 pL/min/mg protein, less than about 120 pL/min/mg protein, less than about 110 pL/min/mg protein, less than about 100 pL/min/mg
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs of less than about 50 pL/min/mg protein, less than about 48 pL/min/mg protein, less than about 45 pL/min/mg protein, less than about 40 pL/min/mg protein, less than about 35 pL/min/mg protein, less than about 30 pL/min/mg protein, less than about 25 pL/min/mg protein, less than about 20 pL/min/mg protein, or less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs of less than about 15 pL/min/mg protein, less than about 14 pL/min/mg protein, less than about 13 pL/min/mg protein, less than about 12 pL/min/mg protein, less than about 11 pL/min/mg protein, or less than about 10 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs of less than 12 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)- (VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs in the range of about 0.1 pL/min/mg protein to about 12 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs of less than 48 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs in the range of about 12 pL/min/mg protein to about 48 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HLMs in the range of about 0.1 pL/min/mg protein to about 48 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 20 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 12 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 20 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 12 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in mouse liver microsomes (MLMs) of less than about 500 pL/min/mg protein, less than about 450 pL/min/mg protein, less than about 400 pL/min/mg protein, less than about 350 pL/min/mg protein, less than about 300 pL/min/mg protein, less than about 250 pL/min/mg protein, less than about 225 pL/min/mg protein, or less than about 200 pL/min/mg protein.
• MLMs mouse liver microsomes
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MLMs of less than about 200 pL/min/mg protein, less than about 190 pL/min/mg protein, less than about 180 pL/min/mg protein, less than about 170 pL/min/mg protein, less than about 160 pL/min/mg protein, less than about 150 pL/min/mg protein, less than about 140 pL/min/mg protein, less than about 130 pL/min/mg protein, less than about 120 pL/min/mg protein, less than about 110 pL/min/mg protein, less than about 100 pL/min/mg
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MLMs of less than about 50 pL/min/mg protein, less than about 48 pL/min/mg protein, less than about 45 pL/min/mg protein, less than about 40 pL/min/mg protein, less than about 35 pL/min/mg protein, less than about 30 pL/min/mg protein, less than about 25 pL/min/mg protein, less than about 20 pL/min/mg protein, or less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MLMs of less than about 15 pL/min/mg protein, less than about 14 pL/min/mg protein, less than about 13 pL/min/mg protein, less than about 12 pL/min/mg protein, less than about 11 pL/min/mg protein, or less than about 10 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MLMs of less than 12 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MLMs in the range of about 0.1 pL/min/mg protein to about 12 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MLMs of less than 48 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MLMs in the range of about 12 pL/min/mg protein to about 48 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MLMs in the range of about 0.1 pL/min/mg protein to about 48 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 20 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 20 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an MLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in human hepatocytes (HHs) of less than about 500 pL/min/million cells, less than about 450 pL/min/million cells, less than about 400 pL/min/million cells, less than about 350 pL/min/million cells, less than about 300 pL/min/million cells, less than about 250 pL/min/million cells, less than about 225 pL/min/million cells, or less than about 200 pL/min/million cells.
• HHs human hepatocytes
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 200 pL/min/million cells, less than about 190 pL/min/million cells, less than about 180 pL/min/million cells, less than about 170 pL/min/million cells, less than about 160 pL/min/million cells, less than about 150 pL/min/million cells, less than about 140 pL/min/million cells, less than about 130 pL/min/million cells, less than about 120 pL/min/million cells, less than about 110 pL/min/million cells, less than about 100 pL/min/million cells, less than about 90 pL/min
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 50 pL/min/million cells, less than about 48 pL/min/million cells, less than about 45 pL/min/million cells, less than about 40 pL/min/million cells, less than about 35 pL/min/million cells, less than about 30 pL/min/million cells, less than about 25 pL/min/million cells, less than about 20 pL/min/million cells, or less than about 15 pL/min/million cells.
• the compounds of the present disclosure have an in vitro metabolic clearance in HHs of less than about 15 pL/min/million cells, less than about 14 pL/min/million cells, less than about 13 pL/min/million cells, less than about 12 pL/min/million cells, less than about 11 pL/min/million cells, less than about 10 pL/min/million cells, less than about 9 pL/min/million cells, less than about 8 pL/min/million cells, less than about 8 pL/min/million cells, less than about 6 pL/min/million cells, or less than about 5 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in HHs of less than 4 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in HHs in the range of about 0.1 pL/min/million cells to about 4 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in HHs of less than 18 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in HHs in the range of about 4 pL/min/million cells to about 18 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in HHs in the range of about 0.1 pL/min/million cells to about 18 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)- (VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 10 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 5 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 10 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in HHs of less than about 5 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in human hepatocytes of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in mouse hepatocytes (MHs) of less than about 500 pL/min/million cells, less than about 450 pL/min/million cells, less than about 400 pL/min/million cells, less than about 350 pL/min/million cells, less than about 300 pL/min/million cells, less than about 250 pL/min/million cells, less than about 225 pL/min/million cells, or less than about 200 pL/min/million cells.
• MHs mouse hepatocytes
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 200 pL/min/million cells, less than about 190 pL/min/million cells, less than about 180 pL/min/million cells, less than about 170 pL/min/million cells, less than about 160 pL/min/million cells, less than about 150 pL/min/million cells, less than about 140 pL/min/million cells, less than about 130 pL/min/million cells, less than about 120 pL/min/million cells, less than about 110 pL/min/million cells, less than about 100 pL/m in/m ill ion cells, less than about
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 50 pL/min/million cells, less than about 48 pL/min/million cells, less than about 45 pL/min/million cells, less than about 40 pL/min/million cells, less than about 35 pL/min/million cells, less than about 30 pL/min/million cells, less than about 25 pL/min/million cells, less than about 20 pL/min/million cells, or less than about 15 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 15 pL/min/million cells, less than about 14 pL/min/million cells, less than about 13 pL/min/million cells, less than about 12 pL/min/million cells, less than about 11 pL/min/million cells, less than about 10 pL/min/million cells, less than about 9 pL/min/million cells, less than about 8 pL/min/million cells, less than about 8 pL/min/million cells, less than about 6 pL/min/million cells, or less than about 5 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MHs of less than 4 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MHs in the range of about 0.1 pL/min/million cells to about 4 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MHs of less than 18 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MHs in the range of about 4 pL/min/million cells to about 18 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in MHs in the range of about 0.1 pL/min/million cells to about 18 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)- (VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 17 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 7 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 17 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 7 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A or B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in MHs of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are any compounds with a combination of in vitro metabolic clearance in HLM, MLM, HHs, and MHs as described herein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 20 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H- I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 20 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 15 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein.
• the compounds of the present disclosure are any compound of Tables A and B or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in human and mouse hepatocytes of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in mouse hepatocytes of less than about 17 pL/min/million cells and a an in vitro metabolic clearance in human hepatocytes of less than about 10 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in mouse hepatocytes of less than about 7 pL/min/million cells, and an in vitro metabolic clearance in human hepatocytes of less than about 5 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an in vitro metabolic clearance in human and mouse hepatocytes of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in human and mouse hepatocytes of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in mouse hepatocytes of less than about 17 pL/min/million cells and a an in vitro metabolic clearance in human hepatocytes of less than about 10 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in mouse hepatocytes of less than about 7 pL/min/million cells, and an in vitro metabolic clearance in human hepatocytes of less than about 5 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an in vitro metabolic clearance in human and mouse hepatocytes of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 20 pL/min/mg protein and an in vitro metabolic clearance in human and mouse hepatocytes of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 15 pL/min/mg protein, an in vitro metabolic clearance in human and mouse hepatocytes of less than about 17 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein, an in vitro metabolic clearance in human and mouse hepatocytes of less than about 7 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds s have an HLM and MLM in vitro metabolic clearance of less than about 11.55 pL/min/mg protein, an in vitro metabolic clearance in human and mouse hepatocytes of less than about 3.85 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM or MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein and b) an in vitro metabolic clearance in human or mouse hepatocytes of less than about 4 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM or MLM in vitro metabolic clearance of less than 12 pL/min/mg protein and b) an in vitro metabolic clearance in human or mouse hepatocytes of less than 4 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM and MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein and b) an in vitro metabolic clearance in human or mouse hepatocytes of less than about 4 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM or MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein and b) an in vitro metabolic clearance in human and mouse hepatocytes of less than about 4 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM and MLM in vitro metabolic clearance of less than about 12 pL/min/mg protein and b) an in vitro metabolic clearance in human and mouse hepatocytes of less than about 4 pL/min/million cells.
• the compounds of the present disclosure are compounds having the structure of formula (I)-(VI) and/or (A)-(H-I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or the compounds of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM and MLM in vitro metabolic clearance of less than 12 pL/min/mg protein and b) an in vitro metabolic clearance in human and mouse hepatocytes of less than 4 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein the compounds have an a) HLM and MLM in vitro metabolic clearance of less than 12 pL/min/mg protein and b) an in vitro metabolic clearance in human and mouse hepatocytes of less than 4pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 20 pL/min/mg protein and an in vitro metabolic clearance in human and mouse hepatocytes of less than about 20 pL/min/million cells.
• the compounds of the present disclosure are any compound of Tables A and B, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and wherein the compounds have an HLM and MLM in vitro metabolic clearance of less than about 15 pL/min/mg protein, an in vitro metabolic clearance in human and mouse hepatocytes of less than about 17 pL/min/million cells.

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