WO2022182845A1 - Macrocycles and their use - Google Patents

Macrocycles and their use Download PDF

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Publication number
WO2022182845A1
WO2022182845A1 PCT/US2022/017660 US2022017660W WO2022182845A1 WO 2022182845 A1 WO2022182845 A1 WO 2022182845A1 US 2022017660 W US2022017660 W US 2022017660W WO 2022182845 A1 WO2022182845 A1 WO 2022182845A1
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alkyl
chloro
compound
pharmaceutically acceptable
acceptable salt
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PCT/US2022/017660
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French (fr)
Inventor
Jingrong J. Cui
Evan W. ROGERS
Eugene Yuanjin Rui
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Blossomhill Therapeutics, Inc.
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Publication of WO2022182845A1 publication Critical patent/WO2022182845A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/18—Bridged systems

Definitions

  • Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli.
  • the human genome encodes approximately 518 protein kinases (Manning G, et al The protein kinase complement of the human genome. Science.2002, 298:1912–34).
  • Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462–469).
  • the molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res.2018, 78:15-29).
  • the critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 52 small molecule kinase inhibitors have been approved and 46 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609).
  • kinase inhibitors have achieved dramatical success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier C, et al Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, and also overcome most frequent resistance mutations for better efficacy and longer disease control.
  • Non-small-cell lung cancer is the leading cause of cancer mortality worldwide (World Health Organisation. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10% to 15% of cases of adenocarcinoma in white patients and 50% of cases in Asian patients (Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015; 4:36-54).
  • the two most frequent EGFR alterations found in NSCLC tumors are short in-frame deletions in exon 19 (del19) of the EGFR gene and L858R, a single missense mutation in exon 21 (Konduri K. et al.
  • EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery 2016, 6:601-11).
  • the first-generation reversible EGFR inhibitors, erlotinib and gefitinib are superior to chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and have been used as first-line standard of care in this setting.
  • advanced EGFR mutation-positive (Del19 or L858R) NSCLC have been used as first-line standard of care in this setting.
  • most patients will develop resistance to gefitinib or erlotinib with 50% to 70% of tumors developing EGFR T790M gatekeeper mutation with time of treatment (Sequist LV, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3:75ra26).
  • EGFR inhibitors afatinib and dacomitinib are covalent, irreversible EGFR inhibitors that also inhibit HER2 and ERB4 of the ERB family (Li D, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015; 9:5641-53).
  • afatinib and dacomitinib are more potent EGFR inhibitors approved as first-line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC with longer progression free survival time (PFS) in comparison with gefitinib and erlotinib
  • PFS progression free survival time
  • EGFR T790M has been developed with time of treatment with afatinib (Tanaka K, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30).
  • Egfr T790M confers resistance to dacomitinib
  • the third-generation EGFR inhibitor Osimertinib is also an irreversible inhibitor targeting both EGFR activating mutations (Del19 and L858R) and T790M resistant double mutations, with selectivity over the wild-type EGFR (Finlay MR, et al.
  • Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and later approved in the first-line setting for patients with EGFR mutation-positive NSCLC following the phase III FLAURA trial with head-to-head trials comparing with erlotinib or gefitinib (Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
  • HER2 HER2 (ERBB2) amplification has been established as an oncogenic driver in breast cancer, which led to the approval of the monoclonal antibodies trastuzumab and pertuzumab, the antibody–drug conjugates trastuzumab emantasine and trastuzumab deruxtecan for advanced breast cancer.
  • HER2-targeted tyrosine kinase inhibtors have also been approved for the treatment of HER2+ breast cancer after progression following HER2-targeted therapy (Conlon NT, et al Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors, British Journal of Cancer 2021, 124:1249–1259).
  • Activating mutations in the HER2 gene have been reported in multiple solid cancers and can serve as actionable targets for therapeutic invention (Cocco E, et al Prevalence and role of HER2 mutations in cancer. Pharmacol Ther.
  • HER2 and HER3 heterodimer can act as an oncogenic driver and is also responsible for the development of resistance in HER2-targeted therapies. Inhibition of HER2 kinase stimulates the HER2/HER3 heterodimeric complex, either via growth factors, such as Neuregulin-1 (NRG1) or by increasing the concentrations of HER2 and HER3 at the membrane.
  • growth factors such as Neuregulin-1 (NRG1)
  • the approved HER2 small molecule kinase inhibitors lapatinib, neratinib, and tucatinib are Type II kinase inhibitors targeting HER2 inactive conformation.
  • HER2/HER3 heterodimer stabilizes HER2 in an active conformation leading to diminished activity of approved HER2 TKIs (Novotny CJ, et al Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nat Chem Biol. 2016, 12:923-930).
  • NRG1-related gene fusions have been reported as oncogene drivers in solid tumors.
  • NRG1 fusions result in ErbB-mediated pathway activation and present a rational candidate for targeted treatment (Laskin J, et al NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol.2020, 31:1693-1703). [006] Overall, it is urgent to develop next generation kinase inhibitors that can target both primary mutations and clinical emerging secondary mutations for achieving better efficacy and longer treatment duration as first-line therapy or overcoming resistance mutations for refractory patients.
  • a new generation reversible EGFR inhibitors that are potent against oncogenic driver EGFR mutations , such as L858R, Del19, exon 20 insertion, L858R/T790M, Del19/T790M, L858R/T790M/C979S, Del19/T790M/C979S, L858R/C979S, and Del19/C979S, as well as other emrging and established resistance mutations, while maintaining good selectivity over wild-type EGFR.
  • oncogenic driver EGFR mutations such as L858R, Del19, exon 20 insertion, L858R/T790M, Del19/T790M, L858R/T790M/C979S, Del19/T790M/C979S, L858R/C979S, and Del19/C979S, as well as other emrging and established resistance mutations, while maintaining good selectivity over wild-type
  • the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [008] wherein [009] X is a -X 1 - or -X 1 -(ring A)-; [010] X 1 is -O-, -S-, -NR 1 -; [011] each Y is independently a ring B or -C(O)NR 2 -; [012] ring A is C 6 -C 10 arylene or 5- to 10-membered heteroarylene, and wherein each hydrogen atom in C 6 -C 10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C
  • the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [029] wherein [030] X is a -X 1 - or -X 1 -(ring A)-; [031] X 1 is -O-, -S-, -NR 1 -; [032] each Y is independently a ring B or -C(O)NR 2 -; [033] ring A is C 6 -C 10 arylene or 5- to 10-membered heteroarylene, and wherein each hydrogen atom in C 6 -C 10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl,
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [050] wherein R 2 , A, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [051] In some embodiments of the above aspects, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [052] wherein A, B, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [053] In some embodiments of the above aspects, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [055] wherein R 2 , L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, [057] wherein B, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [058] In some embodiments of the above aspects, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof, [060] wherein R 1 , R 2 , L, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [062] wherein R 1 , B, L, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [063] In some embodiments of the above aspects, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, [065] wherein R 2 , L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof, [067] wherein B, L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [068] In some embodiments of the above aspects, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof, [071] wherein L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [072] In certain embodiments of the above aspects and embodiments, the compound of Formula (I)-(XIV) is a compound selected from those species described or exemplified in the detailed description below.
  • the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XIV) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.
  • the disclosure relates to a compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.
  • the disclosure relates to a method of inhibiting a tyrosine kinase, such as EGFR, comprising contacting a cell comprising one or more of kinase with an effective amount of at least one compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • R 1 when present, is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -SR e , -S(O)R e , -S(O) 2
  • each L is independently selected from the group consisting of -C(R 3 )(R 4 )-, -C(O)-, -O-, or -N(R 5 )-, provided that (L) n does not comprise a –O-O- or a –O- N(R 5 )- bond.
  • each R 3 and R 4 is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, -NR c C(O)R d , and -CN, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR
  • [0215] 48 A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • 49 A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 48.
  • 50 A compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 48, for use in a method of treating cancer in a subject.
  • 51 A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • DETAILED DESCRIPTION [0220]
  • the portion of A-B defined by the group or chemical structure A can be represented by , here “ presents a bond to A and the point of covalent bond attachment to B.
  • the portion of A-B defined by the group or chemical structure B can be represented by , where represents a bond to B and the point of covalent bond attachment to A.
  • alkyl refers to a straight- or branched-chain mono-valent hydrocarbon group.
  • alkylene refers to a straight- or branched-chain di-valent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C 1 -C 20 alkyl or C 1 -C 20 alkylene, C 1 -C 12 alkyl or C 1 -C 12 alkylene, or C 1 -C 6 alkyl or C 1 -C 6 alkylene.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkylene groups examples include methylene (-CH 2 -), ethylene ((-CH 2 -) 2 ), n- propylene ((-CH 2 -) 3 ), iso-propylene ((-C(H)(CH 3 )CH 2 -)), n-butylene ((-CH 2 -) 4 ), and the like. It will be appreciated that an alkyl or alkylene group can be combined with another group as described herein or an atom, such as a N, O, or S.
  • an O can be combined with an alkyl to provide a mono-valent -O-alkyl group, such as -O-C 1 -C 6 alkyl, having an open valence on only one end for connection with another structure.
  • an O can be combined with an alkylene to provide a di-valent -O-alkylene- group, such as -O-C 1 -C 6 alkylene-, -O- (C 1 -C 6 alkylene)-, or –O(C 1 -C 6 alkylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • alkyl or alkylene group can be unsubstituted or substituted as described herein.
  • An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkenyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds.
  • alkenylene refers to a straight- or branched-chain di-valent hydrocarbon group having one or more double bonds.
  • alkenyl or “alkenylene”
  • alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl.
  • an alkenyl or alkenylene group can be combined with another group as described herein or an atom, such as a N, O, or S.
  • an O can be combined with an alkyl to provide a mono-valent -O-alkenyl group, such as -O-C 1 -C 6 alkenyl, having an open valence on only one end for connection with another structure.
  • an O can be combined with an alkenylene to provide a di-valent -O-alkenylene- group, such as -O-C 1 -C 6 alkenylene-, -O-(C 1 -C 6 alkenylene)-, or –O(C 1 -C 6 alkenylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • a di-valent -O-alkenylene- group such as -O-C 1 -C 6 alkenylene-, -O-(C 1 -C 6 alkenylene)-, or –O(C 1 -C 6 alkenylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • an alkenyl or alkenylene group can be unsubstituted or substituted as described herein.
  • An alkenyl or alkenylene group can be substituted with any of the substituents in the various embodiments
  • alkynyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more triple bonds.
  • alkynylene refers to a straight- or branched- chain di-valent hydrocarbon group having one or more triple bonds.
  • alkynyl or “alkynylene”
  • alkynyl groups include acetylenyl (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH), but-3-yn-1,4-diyl (-C ⁇ C-CH 2 CH 2 -), and the like.
  • an alkynyl or alkynylene group can be combined with another group as described herein or an atom, such as a N, O, or S.
  • an O can be combined with an alkyl to provide a mono-valent -O-alkynyl group, such as -O-C 1 -C 6 alkynyl, having an open valence on only one end for connection with another structure.
  • an O can be combined with an alkynylene to provide a di-valent -O-alkynylene- group, such as -O-C 1 - C 6 alkynylene-, -O-(C 1 -C 6 alkynylene)-, or –O(C 1 -C 6 alkynylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • a di-valent -O-alkynylene- group such as -O-C 1 - C 6 alkynylene-, -O-(C 1 -C 6 alkynylene)-, or –O(C 1 -C 6 alkynylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • an alkynyl or alkynylene group can be unsubstituted or substituted as described herein.
  • An alkynyl or alkynylene group can be substitute
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle.
  • cycloalkylene refers to a saturated or partially saturated, monocyclic or polycyclic di-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms.
  • Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems.
  • cycloalkyl groups include mono-valent radicals of the following entities, while cycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties:
  • a cyclopropyl moiety can be depicted by the structural formula .
  • a cyclopropylene moiety can be depicted by the structural formula .
  • a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein.
  • a cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF 3 , -(CH 2 )F, -CHF 2 , -CH 2 Br, -CH 2 CF 3 , and -CH 2 CH 2 F.
  • haloalkylene refers to an alkyl group with one or more halo substituents.
  • haloalkyl groups include -CF 2 -, -C(H)(F)-, -C(H)(Br)-, -CH 2 CF 2 -, and -CH 2 C(H)(F)-.
  • aryl refers to a mono-valent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • arylene refers to a mono- valent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • an “aryl” or “arylene” can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C 6 -C 14 aryl), mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms ( C 6 -C 10 aryl), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C 6 - C 14 arylene), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6 -C 10 arylene).
  • aryl groups are phenyl, naphthalenyl and anthracenyl.
  • aryl groups are phenylene, naphthalenylene and anthracenylene.
  • an aryl or arylene group can be combined with another group as described herein or an atom, such as a N, O, or S.
  • an O can be combined with an alkyl to provide a mono-valent -O-aryl group, such as -O-C 6 -C 10 aryl, having an open valence on only one end for connection with another structure.
  • an O can be combined with an arylene to provide a di-valent -O-arylene- group, such as -O-C 6 -C 10 arylene-, -O-(C 6 -C 10 arylene)-, or –O(C 6 -C 10 arylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • a di-valent -O-arylene- group such as -O-C 6 -C 10 arylene-, -O-(C 6 -C 10 arylene)-, or –O(C 6 -C 10 arylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • an aryl or arylene group can be unsubstituted or substituted as described herein.
  • An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heterocycloalkyl refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • heterocycloalkylene refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • a “heterocycloalkyl” or “heterocycloalkylene” can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membereed), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6- membered), or 4 to 6 ring atoms (4- to 6-membered), or 5 to 7 ring atoms (5- to 7-membered).
  • heterocycloalkyl or “heterocycloalkylene”
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • the ring structure may optionally contain an oxo group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • heterocycloalkyl groups include mono-valent radicals of the following entities, while heterocycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties: [0238] It will be appreciated that a nitrogen containing heterocycloalkyl can be represented by the formula -N(alkylene), where the alkylene group is described by a parenthetical with no indicated open valence, in which case the alkylene group is understood to occupy two valence positions on the nitrogen atom to provide a heterocycloalkyl structure.
  • the group -N(C 2 -C 6 alkylene) is within the scope of the term 3- to 7-membered heterocycloalkyl, where the 3- to 7-heterocycloalkyl has one nitrogen atom in the ring that represents the point of attachment.
  • -N(C 2 -C 6 alkylene) includes each of the following heterocycloalkyl structures.
  • an heterocycloalkyl or heterocycloalkylene group can be combined with another group as described herein or an atom, such as a N, O, or S.
  • an O can be combined with an alkyl to provide a mono-valent -O- heterocycloalkyl group, such as -O-(3- to 7-membered heterocycloalkyl), having an open valence on only one end for connection with another structure.
  • a mono-valent -O- heterocycloalkyl group such as -O-(3- to 7-membered heterocycloalkyl) having an open valence on only one end for connection with another structure.
  • an O can be combined with an heterocycloalkylene to provide a di-valent -O-heterocycloalkylene- group, such as -O-3- to 7- membered heterocycloalkylene-, -O-(3- to 7-membered heterocycloalkylene)-, or -O(3- to 7- membered heterocycloalkylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein.
  • heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heteroaryl refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle.
  • heteroarylene refers to a di-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • a “monocyclic” heteroaryl can be an aromatic five- or six-membered heterocycle.
  • a five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-liniting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • Non-liniting examples of five- membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heteroaryl groups include mono-valent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • Non-limiting examples of six-membered heteroarylene groups include di-valent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • a “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring.
  • a pyrazolyl moiety can be depicted by the structural formula .
  • an example of a pyrazolylene moiety can be depicted by the structural formula .
  • an O can be combined with an alkyl to provide a mono-valent -O-heteroaryl group, such as -O-5- to 10- membered heteroaryl, having an open valence on only one end for connection with another structure.
  • an O can be combined with a heteroarylene to provide a di-valent -O-heteroarylene- group, such as -O-5- to 10-membered heteroarylene-, -O-(5- to 10- membered heteroarylene)-, or –O(5- to 10-membered heteroarylene)-, having open valences on both ends of the group for covalent attachment to two different structures.
  • a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein.
  • a heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substituted means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent. [0244] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. [0245] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • disubstituent –A-B- where A ⁇ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
  • a compound portion –(L)n- having the formula -CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -, connecting two groups, A and B, will be understood that -CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -, can include both of the embodiments A-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -B and B-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -A.
  • compounds of the formula (I)-(XIV) having a compound portion –(L)n- of the formula -CH(CH 3 )-CH 2 NH-(CH 2 ) 2 - connecting groups -Z- and -NR 2 - will be understood to include both embodiments -Z-CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -NR 2 - and -NR 2 -CH(CH 3 )-CH 2 NH-(CH 2 ) 2 -A.
  • the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XIV), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyr
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like
  • an organic acid such as acetic
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XIV), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XIV)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XIV), and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XIV) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med.
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [0257] wherein R 2 , A, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0259] wherein A, B, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [0260] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, [0261] wherein R 2 , A, B, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [0263] wherein R 2 , L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [0264] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, [0265] wherein B, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [0266] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
  • R 2 , B, L, X 1 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof, [0268] wherein R 1 , R 2 , L, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [0270] wherein R 1 , B, L, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [0271] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , B, L, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, [0274] wherein R 2 , L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof, [0276] wherein B, L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein. [0277] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
  • R 2 , B, L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and n are as described herein.
  • X is -X 1 -. In some embodiments, X is -X 1 -(ring A)-.
  • Ring A is a 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -S(O)
  • Ring A is a 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -S(O)
  • Ring A is a 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a 5- to 10-membered heteroarylene, wherein one hydrogen atom in 5- to 10-membered heteroarylene is substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a 5- to 10-membered heteroarylene, wherein two hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a 5- to 10- membered heteroarylene, wherein three hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a 5- to 10-membered heteroarylene.
  • Ring A is a C 6 -C 10 arylene, wherein each hydrogen atom in C 6 -C 10 arylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -S(O)
  • Ring A is a C 6 -C 10 arylene, wherein each hydrogen atom in C 6 -C 10 arylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -S(O)
  • Ring A is a C 6 -C 10 arylene, wherein each hydrogen atom in C 6 -C 10 arylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a C 6 -C 10 arylene, wherein one hydrogen atom in C 6 -C 10 arylene is substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a C 6 -C 10 arylene, wherein two hydrogen atoms in C 6 -C 10 arylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a C 6 -C 10 arylene, wherein three hydrogen atoms in C 6 -C 10 arylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a C 6 -C 10 arylene.
  • Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is
  • Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein one hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is
  • Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein two hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene
  • Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein three hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene
  • Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom
  • Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein one hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein one hydrogen atom
  • Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein two hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein two hydrogen
  • Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein three hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein three hydrogen
  • Ring A is a phenylene or pyridinylene, wherein each hydrogen atom in phenylene or pyridinylene is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a phenylene or pyridinylene, wherein one hydrogen atom in phenylene or pyridinylene is substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a phenylene or pyridinylene, wherein two hydrogen atoms in phenylene or pyridinylene are each independently substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl. In some embodiments, Ring A is a phenylene or pyridinylene, wherein three hydrogen atoms in phenylene or pyridinylene are each independently substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a phenylene or a pyridinylene of the formula , , , , , [0294] wherein each hydrogen atom is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a phenylene or a pyridinylene of the formula , , , , , [0296] wherein one hydrogen atom is independently substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a phenylene or a pyridinylene of the formula [0298] wherein two hydrogen atoms are each independently substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is a phenylene or a pyridinylene of the formula [0300] wherein three hydrogen atoms are each independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C 1 -C 6 alkyl.
  • Ring A is [0302]
  • -X 1 - is -O-.
  • -X 1 - is -S-. In some embodiments, -X 1 - is –NR 1 -.
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R
  • R 1 is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e C(O)R f , -NR e C(O)OR
  • R 1 is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C 1 - C6 alkyl.
  • R 1 is of the formula [0305] In some embodiments, R 1 is H.
  • ring B is C 6 -C 10 arylene or 5- to 10-membered heteroarylene, wherein each hydrogen atom in C 6 -C 10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -OR a , -OC
  • ring B is C 6 -C 10 arylene, wherein each hydrogen atom in C 6 -C 10 arylene is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)
  • ring B is C 6 -C 10 arylene, wherein one hydrogen atom in C 6 -C 10 arylene is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a
  • ring B is C 6 -C 10 arylene, wherein one hydrogen atom in C 6 -C 10 arylene is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS
  • ring B is C 6 -C 10 arylene, wherein two hydrogen atoms in C 6 -C 10 arylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)
  • ring B is C 6 -C 10 arylene, wherein two hydrogen atoms in C 6 -C 10 arylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R
  • ring B is C 6 -C 10 arylene, wherein three hydrogen atoms in C 6 -C 10 arylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)
  • ring B is C 6 -C 10 arylene, wherein three hydrogen atoms in C 6 -C 10 arylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R
  • ring B is 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)
  • ring B is 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R
  • ring B is 5- to 10-membered heteroarylene, wherein one hydrogen atom in 5- to 10-membered heteroarylene is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a
  • ring B is 5- to 10-membered heteroarylene, wherein one hydrogen atom in 5- to 10-membered heteroarylene is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R b , -OS
  • ring B is 5- to 10-membered heteroarylene, wherein two hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)
  • ring B is 5- to 10-membered heteroarylene, wherein two hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R
  • ring B is 5- to 10-membered heteroarylene, wherein three hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)
  • ring B is 5- to 10-membered heteroarylene, wherein three hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O)NR a R
  • ring B is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene,
  • ring B is [0317] In some embodiments, Z 1 is N. In some embodiments, Z 2 is N. In some embodiments, Z 3 is N. In some embodiments, Z 4 is N. In some embodiments, Z 5 is N. In some embodiments, Z 6 is N. In some embodiments, Z 1 is C(R 6 ). In some embodiments, Z 2 is C(R 7 ). In some embodiments, Z 3 is C(R 8 ). In some embodiments, Z 4 is C(R 9 ). In some embodiments, Z 5 is C(R 10 ). In some embodiments, Z 6 is C(R 11 ). In some embodiments, any of the possible combinations of Z 1 -Z 7 as provided above can be combined.
  • Z 1 is N
  • Z 2 is C(R 7 )
  • Z 3 is C(R 8 )
  • Z 4 is N
  • Z 5 is C(R 10 )
  • Z 6 is C(R 11 ).
  • Z 1 is N
  • Z 2 is C(R 7 )
  • Z 3 is C(R 8 )
  • Z 4 is C(R 9 )
  • Z 5 is C(R 10 )
  • Z 6 is C(R 11 ).
  • Z 1 is N
  • Z 2 is C(R 7 )
  • Z 3 is N
  • Z 4 is N
  • Z 5 is C(R 10 )
  • Z 6 is C(R 11 ).
  • Z 1 is N
  • Z 2 is C(R 7 ), Z 3 is N
  • Z 4 is C(R 9 ), Z 5 is C(R 10 ), and Z 6 is C(R 11 ).
  • Z 1 is N
  • Z 2 is C(R 7 ), Z 3 is C(R 8 ), Z 4 is C(R 9 ), Z 5 is N
  • Z 6 is C(R 11 ).
  • Z 1 is N
  • R 6 is H.
  • R 7 is H.
  • R 8 is H.
  • R 9 is H.
  • R 10 is H or –OCH 3 .
  • R 11 is H.
  • each L is independently selected from the group consisting of -C(R 3 )(R 4 )-, -C(O)-, -O-, or -N(R 5 )-, provided that (L)n does not comprise a –O-O- or a –O- N(R 5 )- bond.
  • -(L)n- comprises one or more of -(CR 3 R 4 ) 3 -, -(CR 3 R 4 ) 4 -, -(CR 3 R 4 ) 5 -, -(CR 3 R 4 ) 6 -, -(CR 3 R 4 ) 7 -, -(CR 3 R 4 ) 8 -, -C(O)N(R 5 )-(CR 3 R 4 ) 2 O(CR 3 R 4 ) 2 -, -CR 3 R 4 - C(O)N(R 5 )-(CR 3 R 4 ) 2 O-, -CR 3 R 4 -C(O)N(R 5 )-(CR 3 R 4 ) 3 O-, -N(R 5 )-C(O)CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 -N(R 5 )-C(O)CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4
  • -(L)n- is -(CR 3 R 4 ) 3 -, -(CR 3 R 4 ) 4 -, -(CR 3 R 4 ) 5 -, -(CR 3 R 4 ) 6 -, -(CR 3 R 4 ) 7 -, -(CR 3 R 4 ) 8 -, -C(O)N(R 5 )-(CR 3 R 4 ) 2 O(CR 3 R 4 ) 2 -, -CR 3 R 4 -C(O)N(R 5 )-(CR 3 R 4 ) 2 O-, -CR 3 R 4 -C(O)N(R 5 )-(CR 3 R 4 ) 3 O-, -N(R 5 )-C(O)CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 -N(R 5 )-C(O)CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 -N(R
  • -(L) n - comprises one or more of -(CR 3 R 4 ) 3 -, -(CR 3 R 4 ) 4 -, -(CR 3 R 4 ) 5 -, -(CR 3 R 4 ) 6 -, -(CR 3 R 4 ) 7 -, -(CR 3 R 4 ) 8 -, -C(O)N(R 5 )-(CR 3 R 4 ) 2 O(CR 3 R 4 ) 2 -, -N(R 5 )-C(O)CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 -O(CR 3 R 4 ) 3 -, -(CR 3 R 4 ) 2 O- CR 3 R 4 -, -(CR 3 R 4 ) 3 O-CR 3 R 4 -, -(CR 3
  • -(L)n- is -(CR 3 R 4 ) 3 -, -(CR 3 R 4 ) 4 -, -(CR 3 R 4 ) 5 -, -(CR 3 R 4 ) 6 -, -(CR 3 R 4 ) 7 -, -(CR 3 R 4 ) 8 -, -C(O)N(R 5 )-(CR 3 R 4 ) 2 O(CR 3 R 4 ) 2 -, -N(R 5 )-C(O)CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 O(CR 3 R 4 ) 2 -, -CR 3 R 4 -O(CR 3 R 4 ) 3 -, -(CR 3 R 4 ) 2 O-CR 3 R 4 -, -(CR 3 R 4 ) 3 O-CR 3 R 4 -, -(CR 3 R 4 ) 3 O-
  • each R 3 and R 4 is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, -NR c C(O)R d , and -CN, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -S(O
  • -(L) n - comprises one or more of -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -, -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -, -NHC(O)CH 2 O(CH 2 ) 2 -, -N(CH 3 )-C(O)CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 3 -, -CH 2 O(CH 2 ) 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-,
  • -(L) n - is -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -, -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -, -NHC(O)CH 2 O(CH 2 ) 2 -, -N(CH 3 )-C(O)CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 3 -, -CH 2 O(CH 2 ) 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-CH 2 -, -CH 2 OCH(CH 2 ) OCH(CH
  • –(L)n- comprises one or more of -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -, -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -, -NHC(O)CH 2 O(CH 2 ) 2 -, -N(CH 3 )-C(O)CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 3 -, -CH 2 O(CH 2 ) 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-CH 2
  • –(L) n - is -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, -C(O)NH-(CH 2 ) 2 O(CH 2 ) 2 -, -C(O)N(CH 3 )-(CH 2 ) 2 O(CH 2 ) 2 -, -NHC(O)CH 2 O(CH 2 ) 2 - , -N(CH 3 )-C(O)CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 3 -, -CH 2 O(CH 2 ) 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-, -CH 2 OCH 2 CH(CH 3 )-CH 2 -
  • n is 0, 1 or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0329] In some embodiments, n is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is 3, 4, 5, 6, 7, or 8. In some embodiments, n is 4, 5, 6, or 7. In some embodiments, n is 4, 5, or 6. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9.
  • the compound is selected from the group consisting of 1-(3- chloro-4-fluorophenyl)-17-methoxy-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0331] 1-(3-chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0332] (3R)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0332
  • the compound is selected from the group consisting of 7- chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-f]pyrido[4,3- b][8,11,1,4]benzodioxadiazacyclotetradecine; [0342] 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; [0343] 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; [0343] 7-chloro
  • the compound is selected from the group consisting of 1-(3- chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0365] 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,10]oxadiazacyclotridecin-9(1H)-one; [0366] 15-(3-chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-ethenopyrimido[4,5- e][1,4,10]oxadiazacyclotridecin-7(13H)-one; [0367] 1-(3-chloro-4-fluoropheny
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient.
  • compositions according to the disclosure are sterile compositions.
  • Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • the term “subject” refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • cancer includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congen
  • cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.
  • Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources.
  • Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.
  • Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
  • Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
  • the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR.
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases.
  • methods of treatment target cancer In preferred embodiments, methods are for treating lung cancer or non-small cell lung cancer.
  • an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the disclosure, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g.
  • crizotinib Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids.
  • suitable combination agents include anti-inflammatories such as NSAIDs.
  • the pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • A-1 can be prepared under palladium catalyzed condition: [0422] To a mixture of A1-1 (1.0 eq.) and A1-2 (1.1 eq) in anhydrous dioxane (0.1 M) are added Pd(dba) 2 (0.04 eq.), 2,2'-bis (diphenyl phosphino)-1,1-binaphthalene (0.045 eq.) and sodium tert-butoxide (1.5 eq.) under nitrogen. The mixture is refluxed for 7 hours or until the reaction is completed. The mixture is cooled down, diluted with EtOAc, filtered via a celite pad, and concentrated.
  • A-1—A-13 are prepared with General Method A: [0424] General Method B [0425] To a solution of A2-1 ( 1 eq.) and B1-2 (1.1 eq.) in DMF (0.5M) is added Cs 2 CO 3 (2 eq.). The mixture is heated at 100 oC until the reaction is complete. The mixture is cooled, diluted with EtOAc, washed with water and brine, and dried over Na 2 SO 4 . After filtration and condensation, the residue is purified on a silica gel column to provide B-1. [0426] B-1—B-4 are prepared with General Method B:
  • C-1—C-6 are prepared with General Method C: [0430] General Method D [0431] The alcohol starting material (1.0 eq.) is added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in anhydrous THF (0.5 M) at ambient temperature. After 30 min, to above suspension is added the halide compound (1.0 eq). After the reaction is complete, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc for three times. The combined extracts are washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and purified on a silica gel column to provide the product. [0432] D-1—D-12 are prepared with General Method D:
  • E-1—E-9 are prepared with General Method E: [0436] General Method F [0437] To a solution of C-1 (1.0 eq.) and F1-2 (1.2 eq.) and Cs 2 CO 3 (3 eq.) in DME/H 2 O (5:1, 0.2 M) under N 2 , is added Pd(dppf)Cl 2 (0.05 eq.). The mixture is stirred at 85 oC overnight, cooled to ambient temperature, and quenched with H 2 O. The resulting mixture is extracted with EtOAc for three times. The combined extracts are washed with brine and dried over anhydrous Na 2 SO 4 . After filtration and condensation, the resulting residue is purified by silica gel chromatography to afford the desired product F-1. [0438] F-1—F-16 are prepared with General Method F:
  • E-1 (1.0 eq.) is added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in anhydrous DMF (0.5 M) at ambient temperature. After 30 min, to above suspension is added alkyl halide Gl-2 (1.0 eq). After the reaction is complete, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc for three times. The combined extracts are washed with brine, dreid over Na 2 SO 4 , filtered, concentrated, and purified on a silica, gel column to provide G-1.
  • G-1 — G-20 are prepared with General Method G: [0442] [0443] General Method H [0444] Step 1. To a solution of F-1 (1.0 eq.) in MeOH (0.2 M) is added LiOH (3 eq) in H 2 O (1 M). The mixture is stirred at 60 oC until the hydrolysis reaction is completed. The solution is cooled to ambient temperature, concentrated to remove methanol, acidified by aqueous HCl (1 N) until pH ⁇ 4-5, and then extracted with CH 2 Cl 2 . The combined extracts are dried over Na 2 SO 4 , concentrated, and dried under vacuum to provide the crude product. [0445] Step 2.
  • Step 3 To a solution of the crude solid (1 eq. assume 100% from step 1 and step 2) in DMF (0.2 M) are added DIPEA (3 eq.) and pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq). The solution is stirred at ambient temperature until the amide formation is completed.
  • DIPEA 3 eq.
  • FDPP pentafluorophenyl diphenylphosphinate
  • Step 2 To a solution of F9-2 (1.0 eq.) and triphenylphosphine (1.1 eq.) in anhydrous THF (0.1 M) is added dropwise a solution of diisopropyl azodicarboxylate (1.1 eq.) in anhydrous THF (2 M). The resulting mixture is stirred at ambient temperature under nitrogen until the reaction is completed.
  • Step 1 To a solution of tert-butyl N-(3-hydroxypropyl)-carbamate (9.25 g, 52.84 mmol, 1 eq) and diacetoxyrhodium (1.17 g, 2.64 mmol, 0.05 eq) in DCM (100 mL) was added a solution of ethyl 2-diazoacetate (30.15 g, 264.20 mmol, 5 eq) in DCM (15 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 To a mixture of ethyl 2-[3-(tert-butoxycarbonylamino)propoxy]acetate (4.00 g, 15.3 mmol, 1.00 eq) in MeOH (30.0 mL) and H 2 O (3.00 mL) was added LiOH•H 2 O (1.28 g, 30.6 mmol, 2.00 eq) in one portion. The mixture was stirred at 20 °C for 2 hours.
  • Step 3 To a mixture of [2-[3-(tert-butoxycarbonylamino)propoxy]acetyl]oxylithium (4.00 g, crude, 1 eq) and 3-chloro-4-fluoro-aniline (2.43 g, 16.7 mmol, 1.00 eq) in DMF (40.0 mL) was added DIEA (6.48 g, 50.2 mmol, 8.74 mL, 3.00 eq), followed by HATU (9.54 g, 25.1 mmol, 1.50 eq).
  • J2 Preparation of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]-N-methyl- carbamate (J2) C [0459] J2 was prepared using similar methods as J1 using tert-butyl N-(3-hydroxypropyl)-N- methyl-carbamate as starting material to replace tert-butyl N-(3-hydroxypropyl)-carbamate. LCMS: m/z 361.1 (M+H) + .
  • Step 1 To a solution of 3-chloro-4-fluoro-aniline (13 g, 89.3 mmol, 1 eq) in DMSO (100 mL) was added DIEA (23.1 g, 178.62 mmol, 2 eq) and ethyl 2-bromoacetate (16.4 g, 98.2 mmol, 1.1 eq). The mixture was stirred at 90 °C for 2 hours.
  • Step 3 To a solution of 2-(3-chloro-4-fluoro-anilino)acetic acid (15.5 g, 76.1 mmol, 1 eq) in THF (200 mL) was added DIEA (29.5 g, 228 mmol, 39.8 mL, 3 eq). Then tert-butyl N- (3-aminopropyl)carbamate (15.9 g, 91.4 mmol, 16 mL, 1.2 eq), T 3 P (29.1 g, 91.4 mmol, 27.2 mL, 1.2 eq) was added into mixture at 0°C.
  • the mixture was stirred at 25 °C for 2 hours.
  • the reaction mixture was partitioned between ethyl acetate (50 mL ⁇ 3) and water (200 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 To a mixture of tert-butyl N-[3-[[2-(3-chloro-4-fluoro-anilino)acetyl]- amino]propyl]carbamate (5 g, 13.9 mmol, 1 eq) in THF (50 mL) was added BH 3 .THF (1 M, 34.7 mL, 2.5 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 12 hours, and then quenched by addition of MeOH (20 mL) at 0° C followed by stirring for 30 minutes.
  • J4 Preparation of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]ethyl]-N-methyl- carbamate (J4) [0467] J4 was prepared using similar methods as J1 using tert-butyl N-(3-hydroxyethyl)-N- methyl-carbamate as starting material to replace tert-butyl N-(3-hydroxypropyl)-carbamate.
  • J7 was prepared from J7-3 following similar methods as J3-2 to J3.
  • J8 was prepared following similar methods as J3 using 3,4-dichloro-2-fluoro-aniline as a starting material.
  • J12 was prepared using similar methods as J3-4 in J3 as a as a colorless oil.
  • J13 Preparation of benzyl (3-((tert-butoxycarbonyl)amino)propyl)(2-((4-chloro-3-fluoroph enyl)amino)ethyl)carbamate (J13) [0492] J13 was prepared as a colorless oil with similar methods as J3 using 4-chloro-3-fluoro -aniline to replace 3-chloro-4-fluoro-aniline.
  • J14 was prepared as a brown gum with similar methods as J3 using 3,4-dichloroaniline to replace 3-chloro-4-fluoro-aniline.
  • J15 was prepared as a colorless oil with similar methods as J3 using tert-butyl N-(3- aminopropyl)-N-methyl-carbamate to tert-butyl N-(3-aminopropyl)-carbamate.
  • J16 was prepared as a colorless oil with similar methods as J3 using 3,4-dichloro-2- fluoro-aniline to replace 3-chloro-4-fluoro-aniline.
  • Step 3 To a solution of 6-chloro-1,5-naphthyridin-4-ol (1.6 g, 8.86 mmol, 1 eq) in ACN (15 mL) was added dropwise TMSBr (10.9 g, 70.9 mmol, 8 eq). The mixture was stirred at 85 °C for 16 hours. The mixture was cooled and filtered. The filtrate was concentrated to give 6-bromo-1, 5-naphthyridin-4-ol (2.8 g, crude) as brown solid. LCMS: 226.7 (M+H) + . [0510] Step 4.
  • Step 1 A mixture of 8-bromo-2-methoxy-1,5-naphthyridine (120 mg, 0.502 mmol, 1.00 eq), tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]carbamate (192 mg, 0.552 mmol, 1.10 eq), RuPhos Pd G3 (42.0 mg, 0.0502 mmol, 0.10 eq) and Cs 2 CO 3 (491 mg, 1.51 mmol, 3.00 eq) in toluene (3.00 mL) was stirred at 110 °C for 20 hours under N2. On completion, the mixture was concentrated in vacuum.
  • Ex.2 was prepared from 2-2 after hydrolysis of ester, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex.1.
  • Step 1 To a mixture of methyl 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3- carboxylate (2.00 g, 6.63 mmol, 1 eq) and CaCl2 (2.21 g, 19.89 mmol, 3 eq) in EtOH (40 mL) was added NaBH 4 (501 mg, 13.3 mmol, 2 eq) at 0 °C slowly. The mixture was stirred at 25 °C for 12 hours.
  • NaBH 4 501 mg, 13.3 mmol, 2 eq
  • Ex.40 was obtained from 40-5 after hydrolysis of ester, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex. 1.
  • Ex.41 was obtained from 41-5 after hydrolysis of ester, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex.1.
  • Step 1 To a solution of 6-chloroquinolin-4-ol (1 g, 5.57 mmol, 1 eq) in DMF (15 mL) was added PBr 3 (1.96 g, 7.24 mmol, 1.3 eq) at 0 °C. The reaction was stirred at 20 °C for 2 hours. The reaction mixture was poured into 50 mL of water and solid was filtered to give 4- bromo-6-chloro-quinoline (0.85 g, 3.15 mmol, 56% yield) as a white solid.
  • Step 8 To a solution of 42-8 (27 mg, 0.0419 mmol, 1 eq) in DCM (3 mL) was added HBr/HOAc (0.5 mL). The reaction was stirred at 20 °C for 0.5 hour. The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 4 To a solution of 5-[4-[N-[2-[benzyloxycarbonyl-[3-[[2-(methylamino)-2-oxo- ethyl]amino]propyl]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolyl]-2-methyl-pyrazole- 3-carboxylic acid (68.6 mg, 0.0977 mmol, 1 eq) in THF (40 mL) was added T 3 P (46.6 mg, 0.146 mmol, 1.5 eq) and DIEA (37.9 mg, 0.293 mmol, 3 eq).
  • Step 1 A solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-chloro-4-fluoro- aniline (1.7 g, 5.59 mmol, 1 eq) , 4-chloro-6-methoxy-quinoline (1.1 g, 5.68 mmol, 1.02 eq), RuPhos Pd G 3 (200 mg, 0.239 mmol, 0.043 eq) and Cs 2 CO 3 (5.47 g, 16.7 mmol, 3 eq) in Tol. (20 mL) was stirred at 120 °C for 12 hours.
  • Step 3 To a solution of 2-(3-chloro-4-fluoro-N-(6-methoxy-4-quinolyl)anilino)ethanol (800 mg, 2.31 mmol, 1 eq) in DCM (20 mL) was added BBr 3 (1 M, 6.92 mL, 3 eq) at 0 °C. The reaction was stirred at 20 °C for 12 hours under N2. The reaction mixture was quenched by added aq NaHCO 3 (10 mL). The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (20 mL x 3).
  • Step 4 A solution of 4-[3-chloro-4-fluoro-N-(2-hydroxyethyl)anilino]quinolin-6-ol (600 mg, 1.80 mmol, 1 eq), 3-chloro-2-(chloromethyl)prop-1-ene (600 mg, 4.80 mmol, 2.66 eq) and K 2 CO 3 (747 mg, 5.41 mmol, 3 eq) in DMF (10 mL) was stirred at 40 °C for 12 hours. The reaction mixture was diluted with H 2 O (100 mL) and extracted with EtOAc (20 mL x 3).
  • Step 5 To a solution of 2-(3-chloro-N-[6-[2-(chloromethyl)allyloxy]-4-quinolyl]-4- fluoro-anilino)ethanol (300 mg, 0.712 mmol, 1 eq) in THF (60 mL) was added NaH (60.0 mg, 1.50 mmol, 60% purity, 2.11 eq) at 0 °C. The reaction was stirred at 20 °C for 6 hours. The reaction was quenched by aq NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 8 To a solution of 49-7 (35 mg, 0.0905 mmol, 1 eq) and ammonium acetate (13.9 mg, 0,180 mmol, 2 eq) in THF (1 mL) and MeOH (1 mL) was added NaBH 3 CN (8.53 mg, 0.135 mmol, 1.5 eq). The reaction was stirred at 20 °C for 12 hours. The reaction mixture was concentrated to provide a crude product 49-8 (30 mg, crude) as a yellow solid which was used without further purification. [0580] Step 9.
  • Step 1 51-1 was prepared with a similar method as 49-1 in Ex. 49 using J11 to replace J10.
  • Step 2. To a solution of tert-butyl N-[2-(3-chloro-4-fluoro-N-(6-methoxy-4- quinolyl)anilino)ethyl]carbamate (1.6 g, 3.59 mmol, 1 eq) in DMF (20 mL) was added NaH (260 mg, 6.50 mmol, 60% purity, 1.81 eq) and CH 3 I (611 mg, 4.31 mmol, 1.2 eq) at 0 °C.
  • the reaction was stirred at 20 °C for 2 hours.
  • the reaction was quenched by water (50 ml), diluted with H 2 O (100 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 5 To a solution of N'-(3-chloro-4-fluoro-phenyl)-N-[2-(chloromethyl)allyl]-N'- (6-methoxy-4-quinolyl)-N-methyl-ethane-1,2-diamine (0.9 g, 2.01 mmol, 1 eq) in DCM (20 mL) was added BBr3 (1 M, 6.02 mL, 3 eq). The reaction was stirred at 40 °C for 2 hours. The reaction mixture was diluted with aq NaHCO 3 (100 mL) and extracted with EtOAc (20 mL x 3).
  • Step 6 To a solution of 4-[3-chloro-N-[2-[2-(chloromethyl)allyl-methyl-amino]ethyl]- 4-fluoro-anilino]quinolin-6-ol (0.3 g, 0.690 mmol, 1 eq) in DMF (60 mL) was added K 2 CO 3 (114 mg, 0.828 mmol, 1.2 eq). The reaction was stirred at 80 °C for 1 hour, diluted with H 2 O (300 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 1 A mixture of ethyl 2-(3-chloro-4-fluoro-anilino)acetate (2 g, 8.63 mmol, 1 eq), 8-chloro-2-methoxy-1,5-naphthyridine (1.85 g, 9.50 mmol, 1.1 eq), Cs 2 CO 3 (8.44 g, 25.9 mmol, 3 eq), XPhos (412 mg, 0.863 mmol, 0.1 eq) and Pd(dba) 2 (496 mg, 0.863 mmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with N2 for 3 times.
  • Step 4 To a solution of 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin-4- yl)anilino)acetic acid (400 mg, 1.15 mmol, 1 eq) and 3-aminopropan-1-ol (86.4 mg, 1.15 mmol, 1 eq) in DMF (5 mL) was added T3P (439 mg, 1.38 mmol, 1.2 eq) and DIEA (446 mg, 3.45 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours.
  • Step 5 A mixture of 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin-4- yl)anilino)-N-(3-hydroxypropyl)acetamide (100 mg, 0.247 mmol, 1 eq), DIAD (150 mg, 0.741 mmol, 3 eq), PPh 3 (194 mg, 0.741 mmol, 3 eq) in THF (1 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 25 °C for 16 hours under N2 atmosphere.
  • Kinase binding assays are performed at Eurofins/DiscoveRx using the general KINOMEscan Protocol (Fabian, M. A. et al., “A small molecule-kinase interaction map for clinical kinase inhibitors,” Nat. Biotechnol. 2005, 23(3):329-36).
  • kinase- tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis.
  • the lysates are centrifuged and filtered to remove cell debris.
  • the remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection.
  • Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding.
  • Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions are performed in polystyrene 96-well plates in a final volume of 0.135 mL. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 ⁇ M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • 1x binding buffer 20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT. All reactions are performed in polystyrene 96-well plates in a final volume of 0.135 mL. The assay plates are incubated
  • %Ctrl Biochemical Assay
  • the inhibition activities against enzymatic kinases will be evaluated at Reaction Biology Corporation (www.reactionbiology.com) using HotSpot assay platfrom, a radiometric assay based on conventional filter-binding assays, that directly measures kinase catalytic activity toward a specific substrate (Anastassiadis T, et al. Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selectivity.
  • reaction buffer 20 mM Hepes pH 7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.
  • Compounds are delivered into the reaction, followed ⁇ 20 minutes later by addition of a mixture of ATP (Sigma, St. Louis MO) and 33 P ATP (Perkin Elmer, Waltham MA) to a final concentration of 10 ⁇ M.
  • kinase activity data is expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC 50 values and curve fits are obtained using Prism (GraphPad Software).
  • the cellular kinase assays include EGFR wild-type, EGFR L858R mutant, EGFR T790M mutant, EGFR G719S mutant, EGFR L861Q mutant, EGFR ⁇ 752-759 mutant, EGFR L858R/T790M mutant, EGFR ⁇ 746-750/T790M mutant, EGFR ⁇ 746- 750/C797S mutant, EGFR T790M/C797S/L858R mutant, EGFR ⁇ 746-750/T790M/C797S mutant, and EGFR ⁇ 747-749/A750P mutant.
  • Table 1 The inhibition activities against WT and Mutant EGFR kinases

Abstract

The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer.

Description

MACROCYCLES AND THEIR USE CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application claims priority under 35 U.S.C. § 119(e) to U. S. Provisional Application Serial No. 63/153,686 filed on February 25, 2021 and U. S. Provisional Application Serial No.63/309,910 filed on February 14, 2022, the entire disclosures of which are incorporated herein by reference. TECHNICAL FIELD [002] The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer. BACKGROUND [003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al The protein kinase complement of the human genome. Science.2002, 298:1912–34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462–469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res.2018, 78:15-29). The critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 52 small molecule kinase inhibitors have been approved and 46 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609). Although kinase inhibitors have achieved dramatical success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier C, et al Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, and also overcome most frequent resistance mutations for better efficacy and longer disease control. [004] Non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide (World Health Organisation. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10% to 15% of cases of adenocarcinoma in white patients and 50% of cases in Asian patients (Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res 2015; 4:36-54). The two most frequent EGFR alterations found in NSCLC tumors are short in-frame deletions in exon 19 (del19) of the EGFR gene and L858R, a single missense mutation in exon 21 (Konduri K. et al. EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery 2016, 6:601-11). In addition to exon 19 deletions and L858R mutation, 4-10% of EGFR mutations in NSCLC are heterogeneous in-frame insertions of between 10=-7 amino acids across a span of ~15 amino acids (D761-C775) in exon 20 (Vyse S and Huang P.H, Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4, 5 (2019)). The first-generation reversible EGFR inhibitors, erlotinib and gefitinib are superior to chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and have been used as first-line standard of care in this setting. However, most patients will develop resistance to gefitinib or erlotinib with 50% to 70% of tumors developing EGFR T790M gatekeeper mutation with time of treatment (Sequist LV, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3:75ra26). The second generation of EGFR inhibitors afatinib and dacomitinib are covalent, irreversible EGFR inhibitors that also inhibit HER2 and ERB4 of the ERB family (Li D, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015; 9:5641-53). Although afatinib and dacomitinib are more potent EGFR inhibitors approved as first-line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC with longer progression free survival time (PFS) in comparison with gefitinib and erlotinib, EGFR T790M has been developed with time of treatment with afatinib (Tanaka K, et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30). Egfr T790M confers resistance to dacomitinib In vitro studies (Kobayashi Y, et al. EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol 2018; 13: 727-31). The third-generation EGFR inhibitor Osimertinib is also an irreversible inhibitor targeting both EGFR activating mutations (Del19 and L858R) and T790M resistant double mutations, with selectivity over the wild-type EGFR (Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014; 57:8249-67). Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and later approved in the first-line setting for patients with EGFR mutation-positive NSCLC following the phase III FLAURA trial with head-to-head trials comparing with erlotinib or gefitinib (Soria JC, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378:113-25). The mutation C797S at the EGFR covalent binding residue with irreversible EGFR inhibitor Osimertinib has been detected in Osimertinib-resistant patients (Ramalingam SS, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at the ESMO 2018). Therefore, it is necessary to develop a new generation reversible EGFR inhibitor that are potent against oncogenic driver EGFR mutations L858R and del 19, the L858R/T790M and Del19/T790M resistance mutations, L858R/T790M/C979S, Del19/T790M/C979S, L858R/C979S, and Del19/C979S, as well as other resistant compound mutations, while with good selectivity over wild-type EGFR. To date, clinically approved EGFR inhibitors have failed to effectively treat NSCLC driven by EGFR exon 20 insertion mutations. It is urgent to develop new generation of EGFR inhibitors that are potent against EGFR exon 20 insertion mutations. [005] HER2 (ERBB2) amplification has been established as an oncogenic driver in breast cancer, which led to the approval of the monoclonal antibodies trastuzumab and pertuzumab, the antibody–drug conjugates trastuzumab emantasine and trastuzumab deruxtecan for advanced breast cancer. Three small molecule HER2-targeted tyrosine kinase inhibtors, lapatinib, neratinib, and tucatinib, have also been approved for the treatment of HER2+ breast cancer after progression following HER2-targeted therapy (Conlon NT, et al Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors, British Journal of Cancer 2021, 124:1249–1259). Activating mutations in the HER2 gene have been reported in multiple solid cancers and can serve as actionable targets for therapeutic invention (Cocco E, et al Prevalence and role of HER2 mutations in cancer. Pharmacol Ther. 2019, 199:188-196). However, efforts to target HER2 mutations has not been successful in clinical studies. In addition, the success of HER2-targeting agents in HER2+ breast cancer is overshadowed with the development of treatment resistance. The HER2 and HER3 heterodimer can act as an oncogenic driver and is also responsible for the development of resistance in HER2-targeted therapies. Inhibition of HER2 kinase stimulates the HER2/HER3 heterodimeric complex, either via growth factors, such as Neuregulin-1 (NRG1) or by increasing the concentrations of HER2 and HER3 at the membrane. The approved HER2 small molecule kinase inhibitors lapatinib, neratinib, and tucatinib are Type II kinase inhibitors targeting HER2 inactive conformation. HER2/HER3 heterodimer stabilizes HER2 in an active conformation leading to diminished activity of approved HER2 TKIs (Novotny CJ, et al Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nat Chem Biol. 2016, 12:923-930). In addition, NRG1-related gene fusions have been reported as oncogene drivers in solid tumors. NRG1 fusions result in ErbB-mediated pathway activation and present a rational candidate for targeted treatment (Laskin J, et al NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol.2020, 31:1693-1703). [006] Overall, it is urgent to develop next generation kinase inhibitors that can target both primary mutations and clinical emerging secondary mutations for achieving better efficacy and longer treatment duration as first-line therapy or overcoming resistance mutations for refractory patients. For example, it is necessary to develop a new generation reversible EGFR inhibitors that are potent against oncogenic driver EGFR mutations , such as L858R, Del19, exon 20 insertion, L858R/T790M, Del19/T790M, L858R/T790M/C979S, Del19/T790M/C979S, L858R/C979S, and Del19/C979S, as well as other emrging and established resistance mutations, while maintaining good selectivity over wild-type EGFR. Furthermore, it is urgent to develop next generation HER2 inhibitors targeting HER2 active conformation for the effective treatment of patients with HER2-targeted therapy resistance, or cancers with HER2 or NRG1 mutations. SUMMARY [007] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000005_0001
[008] wherein [009] X is a -X1- or -X1-(ring A)-; [010] X1 is -O-, -S-, -NR1-; [011] each Y is independently a ring B or -C(O)NR2-; [012] ring A is C6-C10 arylene or 5- to 10-membered heteroarylene, and wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, - ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, - P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [013] each ring B is C6-C10 arylene or 5- to 10-membered heteroarylene, wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, - ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [014] each L is independently -C(R3)(R4)-, -C(O)-, -O-, -N(R5)-, -S-, -S(O)- or -S(O)2-, provided that (L)n does not comprise a –O-O-, a –O-S-, a -S-S-, or a –O-N(R5)- bond; [015] Z1 is N or C(R6); [016] Z2 is N or C(R7); [017] Z3 is N or C(R8); [018] Z4 is N or C(R9); [019] Z5 is N or C(R10); [020] Z6 is N or C(R11); [021] provided that at least one of Z1-Z6 is N; [022] each of R1, R2, and R5 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, - NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; [023] each R3 and R4 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, -NO2, or two of R3 and R4 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, - P(O)ORe, -P(O)2ORe, -CN, or -NO2; [024] each of R6, R7, R8, R9, R10, and R11 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, - SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or R6 and R7, R7 and R8, or R10 and R11 taken together with the carbons to which they are attached form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or a C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [025] each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, and 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, or 5- to 10- membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O) (H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, - P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2; [026] m is 0, 1, or 2; and [027] n is 3, 4, 5, 6, 7, 8, or 9. [028] In another aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000009_0001
[029] wherein [030] X is a -X1- or -X1-(ring A)-; [031] X1 is -O-, -S-, -NR1-; [032] each Y is independently a ring B or -C(O)NR2-; [033] ring A is C6-C10 arylene or 5- to 10-membered heteroarylene, and wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, - ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, - P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [034] each ring B is C6-C10 arylene or 5- to 10-membered heteroarylene, wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, - ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [035] each L is independently -C(R3)(R4)-, -C(O)-, -O-, -N(R5)-, -S-, -S(O)- or -S(O)2-, provided that (L)n does not comprise a –O-O-, a –O-S-, a -S-S-, or a –O-N(R5)- bond; [036] Z1 is N or C(R6); [037] Z2 is N or C(R7); [038] Z3 is N or C(R8); [039] Z4 is N or C(R9); [040] Z5 is N or C(R10); [041] Z6 is N or C(R11); [042] provided that at least one of Z1-Z6 is N; [043] each of R1, R2, and R5 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, - NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; [044] each R3 and R4 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, -NO2, or two of R3 and R4 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, - P(O)ORe, -P(O)2ORe, -CN, or -NO2; [045] each of R6, R7, R8, R9, R10, and R11 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, - SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or R6 and R7, R7 and R8, or R10 and R11 taken together with the carbons to which they are attached form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or a C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [046] each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; [047] m is 1 or 2; and [048] n is 3, 4, 5, 6, 7, or 8. [049] In some embodiments of the above aspects, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000012_0001
[050] wherein R2, A, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [051] In some embodiments of the above aspects, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000012_0002
[052] wherein A, B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [053] In some embodiments of the above aspects, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
Figure imgf000013_0002
V wherein R2, A, B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [054] In some embodiments of the above aspects, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000013_0003
[055] wherein R2, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [056] In some embodiments of the above aspects, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000013_0001
[057] wherein B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [058] In some embodiments of the above aspects, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
Figure imgf000014_0003
wherein R2, A, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [059] In some embodiments of the above aspects, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000014_0001
[060] wherein R1, R2, L, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [061] In some embodiments of the above aspects, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000014_0002
[062] wherein R1, B, L, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [063] In some embodiments of the above aspects, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
Figure imgf000015_0001
wherein R1, R2, B, L, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [064] In some embodiments of the above aspects, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000015_0002
[065] wherein R2, L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [066] In some embodiments of the above aspects, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000015_0003
[067] wherein B, L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [068] In some embodiments of the above aspects, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000016_0001
[069] wherein R2, B, L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [070] In some embodiments of the above aspects, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000016_0002
[071] wherein L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [072] In certain embodiments of the above aspects and embodiments, the compound of Formula (I)-(XIV) is a compound selected from those species described or exemplified in the detailed description below. [073] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XIV) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient. [074] In further aspects, the disclosure relates to a compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof, for use as a medicament. [075] In further aspects, the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof. [076] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases. [077] In further aspects, the disclosure relates to a method of inhibiting a tyrosine kinase, such as EGFR, comprising contacting a cell comprising one or more of kinase with an effective amount of at least one compound of Formula (I)-(XIV), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo. [078] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another. [079] 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000017_0001
[080] wherein [081] X is a -X1- or -X1-(ring A)-; [082] X1 is -O-, -S-, -NR1-; [083] each Y is independently a ring B or -C(O)NR2-; [084] ring A is C6-C10 arylene or 5- to 10-membered heteroarylene, and wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [085] each ring B is C6-C10 arylene or 5- to 10-membered heteroarylene, wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [086] each L is independently -C(R3)(R4)-, -C(O)-, -O-, -N(R5)-, -S-, -S(O)- or -S(O)2-, provided that (L)n does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R5)- bond; [087] Z1 is N or C(R6); [088] Z2 is N or C(R7); [089] Z3 is N or C(R8); [090] Z4 is N or C(R9); [091] Z5 is N or C(R10); [092] Z6 is N or C(R11); [093] provided that at least one of Z1-Z6 is N; [094] each of R1, R2, and R5 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; [095] each R3 and R4 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, -NO2, or two of R3 and R4 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [096] each of R6, R7, R8, R9, R10, and R11 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or R6 and R7, R7 and R8, or R10 and R11 taken together with the carbons to which they are attached form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or a C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; [097] each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, or 5- to 10- membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O) (H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2; [098] m is 0, 1, or 2; and [099] n is 3, 4, 5, 6, 7, 8, or 9. [0100] 2. The compound of clause 1 having the formula II
Figure imgf000021_0001
[0101] or a pharmaceutically acceptable salt thereof. [0102] 3. The compound of clause 1 having the formula III
Figure imgf000021_0002
[0103] or a pharmaceutically acceptable salt thereof. [0104] 4. The compound of clause 1 having the formula IV
Figure imgf000021_0003
[0105] or a pharmaceutically acceptable salt thereof. [0106] 5. The compound of clause 1 having the formula V
Figure imgf000022_0003
[0107] or a pharmaceutically acceptable salt thereof. [0108] 6. The compound of clause 1 having the formula VI
Figure imgf000022_0001
[0109] or a pharmaceutically acceptable salt thereof. [0110] 7. The compound of clause 1 having the formula VII
Figure imgf000022_0002
[0111] or a pharmaceutically acceptable salt thereof. [0112] 8. The compound of clause 1 having the formula VIII
Figure imgf000023_0003
[0113] or a pharmaceutically acceptable salt thereof. [0114] 9. The compound of clause 1 having the formula IX
Figure imgf000023_0001
[0115] or a pharmaceutically acceptable salt thereof. [0116] 10. The compound of clause 1 having the formula X
Figure imgf000023_0002
[0117] or a pharmaceutically acceptable salt thereof. [0118] 11. The compound of clause 1 having the formula XI
Figure imgf000024_0001
[0119] or a pharmaceutically acceptable salt thereof. [0120] 12. The compound of clause 1 having the formula XII
Figure imgf000024_0002
[0121] or a pharmaceutically acceptable salt thereof. [0122] 13. The compound of clause 1 having the formula XIII
Figure imgf000024_0003
[0123] or a pharmaceutically acceptable salt thereof. [0124] 14. The compound of clause 1 having the formula XIV
Figure imgf000024_0004
[0125] or a pharmaceutically acceptable salt thereof,. [0126] 15. The compound of any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0127] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is phenylene or pyridinylene, wherein each hydrogen atom in phenylene or pyridinylene is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0128] 17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is a phenylene or a pyridinylene of the formula
Figure imgf000025_0001
[0129] wherein each hydrogen atom is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0130] 18. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is
Figure imgf000026_0002
, ,
Figure imgf000026_0001
, , [0131] 19. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein X1 is –NR1-. [0132] 20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is hydrogen, C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. [0133] 21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is hydrogen. [0134] 22. The compound of any one of clauses 1-20, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. [0135] 23. The compound of any one of clauses 1-20 or 22, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0136] 24. The compound of any one of clauses 1-20, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is of the formula
Figure imgf000027_0001
, , , , [0137] 25. The compound of any one of clauses 1-18, or a pharmaceutically acceptable salt thereof, wherein X1 is -O-. [0138] 26. The compound of any one of clauses 1-18, or a pharmaceutically acceptable salt thereof, wherein X1 is -S-. [0139] 27. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B, when present, is 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0140] 28. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B, when present, is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0141] 29. The compound of any one the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B, when present, is
Figure imgf000028_0001
, , ,
Figure imgf000028_0002
, , , , , , [0142] 30. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z1 is N. [0143] 31. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is C(R8), Z4 is N, Z5 is C(R10), and Z6 is C(R11). [0144] 32. The compound of any one of clauses 1-30, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is C(R8), Z4 is C(R9), Z5 is C(R10), and Z6 is C(R11). [0145] 33. The compound of any one of clauses 1-30, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is N, Z4 is N, Z5 is C(R10), and Z6 is C(R11). [0146] 34. The compound of any one of clauses 1-30, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is N, Z4 is C(R9), Z5 is C(R10), and Z6 is C(R11). [0147] 35. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6, when present is H. [0148] 36. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7, when present is H. [0149] 37. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8, when present is H. [0150] 38. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9, when present is H. [0151] 39. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R10, when present is H or –OCH3. [0152] 40. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R11, when present is H. [0153] 41. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from the group consisting of -C(R3)(R4)-, -C(O)-, -O-, or -N(R5)-, provided that (L)n does not comprise a –O-O- or a –O- N(R5)- bond. [0154] 42. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein -(L)n- is -(CR3R4)3-, -(CR3R4)4-, -(CR3R4)5-, -(CR3R4)6-, -(CR3R4)7-, -(CR3R4)8-, -C(O)N(R5)-(CR3R4)2O(CR3R4)2-, -CR3R4-C(O)N(R5)-(CR3R4)2O-, -CR3R4-C(O)N(R5)-(CR3R4)3O-, -N(R5)-C(O)CR3R4O(CR3R4)2-, -CR3R4-N(R5)-C(O)(CR3R4)2O-, -CR3R4-N(R5)-C(O)(CR3R4)3O-, -CR3R4O(CR3R4)2-, -CR3R4-O(CR3R4)3-, -(CR3R4)2O-CR3R4-, -(CR3R4)3O-CR3R4-, -(CR3R4)2O(CR3R4)2-, -(CR3R4)3O(CR3R4)2-, -(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)5O(CR3R4)3-, -O-CR3R4- O(CR3R4)3-, -CR3R4-O(CR3R4)2O-, -CR3R4-O(CR3R4)3O-, -O(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)3O-, -O-(CR3R4)2-, -(CR3R4)2O-, –O-(CR3R4)3-, -(CR3R4)3O-, -O-(CR3R4)2O(CR3R4)2-, -(CR3R4)2O(CR3R4)2O-, -CR3R4-N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)3-, -(CR3R4)3O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)2C(O)N(R5)-(CR3R4)-, -(CR3R4)2N(R5)-(CR3R4)3-, -O-(CR3R4)2N(R5)-(CR3R4)2-, -CR3R4N(R5)-(CR3R4)2O-, -(CR3R4)2N(R5)-(CR3R4)2O-, or -(CR3R4)2N(R5)-(CR3R4)3O-. [0155] 43. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, -NRcC(O)Rd, and -CN, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0156] 44. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein -(L)n- comprises -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)2CH(CH3)-, -CH2OCH2CH(CH3)-CH2-, -CH2OCH(CH3)-(CH2)2-, -CH(CN)-O-(CH2)3-, -CH(CH3)-O-(CH2)3-, -CH2O(CH2)2-O-, -(CH2)2O(CH2)2-, -CH2- C(CH3)2-O(CH2)2-, -CH2-C(CH3)2-O(CH2)3-, -(CH2)2OCH2-, -(CH2)2O(CH2)2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -(CH2)2OCH(CH3)-(CH2)2-, -(CH2)2OC(CH3)2-(CH2)2-, -(CH2)2O(CH2)2-CH(CH3)-, -(CH2)2O-(CH2)2-C(CH3)2-CH2-CH(CH3)-O-(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O-(CH2)2-, –O-(CH2)3-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -(CH2)2OCH2CH(NH-C(O)-CH=CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2OCH2CH(NH-C(O)- CH2CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)2NH-CH2CH(NH- C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)3O(CH2)C(O)N(CH3)CH2-, -(CH2)3O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)C(O)N(CH3)CH2-, -(CH2)2O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)2C(O)N(CH3)CH2-, -(CH2)2O(CH2)2C(O)N(H)CH2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -(CH2)2NH-(CH2)3-, -(CH2)2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)3-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2C(O)N(H)-(CH2)3O-, -CH2C(O)N(CH3)-(CH2)3O-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)-(CH2)2-. [0157] 45. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 1-(3-chloro-4-fluorophenyl)-17-methoxy-2,3,5,6,7,8-hexahydro- 10,12-ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0158] 1-(3-chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0159] (3R)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0160] (3S)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0161] 1-(3-chloro-4-fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0162] (5S)-1-(3-chloro-4-fluorophenyl)-5-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0163] (7R)-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0164] 12-(3-chloro-4-fluorophenyl)-1-methyl-4,13,14,16-tetrahydro-1H-6,8- ethenopyrazolo[4,3-k]pyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-5(12H)-one; [0165] 14-(3-chloro-4-fluorophenyl)-5-methyl-5,9,10,12,13,14-hexahydro-2,18-etheno-3,6- (metheno)pyrido[3,4-l][1,4,7,8,11,14]oxapentaazacyclohexadecin-7(8H)-one; and [0166] 1-(3-chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7,10-hexahydro-12,9-(azeno)-13,15- ethenopyrido[3,4-l][1,4,7,14]oxatriazacyclohexadecin-8(5H)-one. [0167] 46. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18- ethenopyrazolo[4,3-f]pyrido[4,3-b][8,11,1,4]benzodioxadiazacyclotetradecine; [0168] 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; [0169] 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; [0170] 15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-f]pyrimido[4,5- b][8,11,1,4]benzodioxadiazacyclotetradecine; [0171] 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrimido[4,5-b][8,11,1]benzodioxazacyclotetradecine; [0172] 7,15-dimethyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-m]pyrido[3,4- f]pyrimido[4,5-i][1,4,8]dioxazacyclotetradecine; [0173] 7-chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-ethenodipyrido[4,3-b:2',3'- f][8,11,1]benzodioxazacyclotetradecine; [0174] 7-chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-ethenodibenzo[e,l]pyrido[3,4- i][1,4,8,11]dioxadiazacyclotetradecine; [0175] 7-chloro-6-fluoro-14-methyl-5,13,14,17-tetrahydro-10H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][14,1,8,11]benzoxatriazacycloheptadecin-15(12H)-one; [0176] 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][14,1,8,11]benzoxatriazacycloheptadecin-15(12H)-one; [0177] 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-1,20-etheno-19,16- (metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one; [0178] 7-chloro-6-fluoro-14-methyl-13,14-dihydro-10H,17H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0179] 7-chloro-8-fluoro-13,14-dihydro-10H,17H-19,16-(azeno)-1,20-ethenopyrido[4,3- b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0180] 7-chloro-6-fluoro-13,14-dihydro-10H,17H-19,16-(azeno)-1,20-ethenopyrido[4,3- b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0181] 7-chloro-6-fluoro-14,17-dimethyl-13,14-dihydro-10H,17H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0182] 16-chloro-17-fluoro-8-methyl-8,9,10,11,13,18-hexahydro-7H-4,6-ethenopyrido[4,3- b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0183] 16-chloro-17-fluoro-8,9,10,11,13,18-hexahydro-7H-4,6-ethenopyrido[4,3- b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0184] (13R)-16-chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0185] (13S)-16-chloro-17-fluoro-7-oxo-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecine-13-carbonitrile; [0186] (9R)-16-chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0187] 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7H,13H-4,6-ethenopyrido[4,3- b][1,11,7]benzodioxazacyclotetradecin-7-one; and [0188] 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7H,13H-4,6-ethenopyrido[4,3- b][11,1,7]benzoxathiazacyclotetradecin-7-one. [0189] 47. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0190] 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,10]oxadiazacyclotridecin-9(1H)-one; [0191] 15-(3-chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-ethenopyrimido[4,5- e][1,4,10]oxadiazacyclotridecin-7(13H)-one; [0192] 1-(3-chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-etheno- 13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one; [0193] 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16- etheno-13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one; [0194] 1-(3-chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; [0195] 1-(3-chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-etheno- 12,9-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecin-8(5H)-one; [0196] 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-etheno- 13,10-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacycloheptadecin-7(6H)-one; [0197] N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide; [0198] 3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]-N-(propan-2- yl)benzamide; [0199] N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide; [0200] 1-(3,4-dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; [0201] 1-(3-chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; [0202] 2-[1-(3-chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16- etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-8(9H)-yl]-N- methylacetamide; [0203] 15-(3-chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno- 3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0204] N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-ethenopyrido[4,3- e][1,9,4]dioxazacyclododecin-6-yl]prop-2-enamide; [0205] N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-ethenopyrido[4,3- e][1,9,4]dioxazacyclododecin-6-yl]propanamide; [0206] N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11- ethenopyrido[4,3-i][1,5,8]oxadiazacyclododecin-6-yl]prop-2-enamide; [0207] 15-(3-chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0208] 15-(4-chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno- 3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0209] 15-(3,4-dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno-3,6- (metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0210] 15-(3-chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0211] 10-(3-chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-ethenopyrido[3,4- d][1,3,6,9]oxatriazacyclododecin-8-one; [0212] 1-(3-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-ethenopyrido[4,3- i][1,5,8]oxadiazacyclododecin-3-one; [0213] 15-(3,4-dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; and [0214] 7-chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-etheno-19,16- (metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one. [0215] 48. A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [0216] 49. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 48. [0217] 50. A compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 48, for use in a method of treating cancer in a subject. [0218] 51. A compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 48, for treating cancer in a subject. [0219] 52. Use of a compound of any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of clause 48, in the manufacture of a medicament for treating cancer in a subject. DETAILED DESCRIPTION [0220] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. [0221] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference. [0222] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. [0223] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. [0224] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. [0225] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. [0226] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp.360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001. [0227] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer). [0228] As used herein and in connection with chemical structures depicting the vaious embodiments described herein,
Figure imgf000036_0001
represents a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion of A-B defined by the group or chemical structure A can be represented by
Figure imgf000036_0004
, here “
Figure imgf000036_0005
presents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by
Figure imgf000036_0002
, where
Figure imgf000036_0003
represents a bond to B and the point of covalent bond attachment to A. [0229] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. CHEMICAL DEFINITIONS [0230] The term “alkyl” refers to a straight- or branched-chain mono-valent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain di-valent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or C1-C12 alkylene, or C1-C6 alkyl or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n- propylene ((-CH2-)3), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be combined with another group as described herein or an atom, such as a N, O, or S. For example, an O can be combined with an alkyl to provide a mono-valent -O-alkyl group, such as -O-C1-C6 alkyl, having an open valence on only one end for connection with another structure. Alternatively, an O can be combined with an alkylene to provide a di-valent -O-alkylene- group, such as -O-C1-C6 alkylene-, -O- (C1-C6 alkylene)-, or –O(C1-C6 alkylene)-, having open valences on both ends of the group for covalent attachment to two different structures. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0231] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. The term “alkenylene” refers to a straight- or branched-chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6 alkenyl or C2-C6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Examples of alkenylene groups include ethenylene (or vinylene) (-CH=CH-), n-propenylene (-CH=CHCH2-), iso-propenylene (-CH=CH(CH3)-), and and the like. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl or alkenylene group can be combined with another group as described herein or an atom, such as a N, O, or S. For example, an O can be combined with an alkyl to provide a mono-valent -O-alkenyl group, such as -O-C1-C6 alkenyl, having an open valence on only one end for connection with another structure. Alternatively, an O can be combined with an alkenylene to provide a di-valent -O-alkenylene- group, such as -O-C1-C6 alkenylene-, -O-(C1-C6 alkenylene)-, or –O(C1-C6 alkenylene)-, having open valences on both ends of the group for covalent attachment to two different structures. It will be appreciated that an alkenyl or alkenylene group can be unsubstituted or substituted as described herein. An alkenyl or alkenylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0232] The term “alkynyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched- chain di-valent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” or “alkynylene” to a specific range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6 alkynyl or C2-C6 alkynylene. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be combined with another group as described herein or an atom, such as a N, O, or S. For example, an O can be combined with an alkyl to provide a mono-valent -O-alkynyl group, such as -O-C1-C6 alkynyl, having an open valence on only one end for connection with another structure. Alternatively, an O can be combined with an alkynylene to provide a di-valent -O-alkynylene- group, such as -O-C1- C6 alkynylene-, -O-(C1-C6 alkynylene)-, or –O(C1-C6 alkynylene)-, having open valences on both ends of the group for covalent attachment to two different structures. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0233] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. The term “cycloalkylene” refers to a saturated or partially saturated, monocyclic or polycyclic di-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include mono-valent radicals of the following entities, while cycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties:
Figure imgf000038_0001
In particular, a cyclopropyl moiety can be depicted by the structural formula
Figure imgf000039_0001
. n particular, a cyclopropylene moiety can be depicted by the structural formula
Figure imgf000039_0002
. It will be appreciated that a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0234] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine. [0235] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F. The term “haloalkylene” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-. [0236] The term “aryl” refers to a mono-valent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term “arylene” refers to a mono- valent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms ( C6-C10 aryl), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6- C14 arylene), di-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10 arylene). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. Examples, without limitation, of aryl groups are phenylene, naphthalenylene and anthracenylene. It will be appreciated that an aryl or arylene group can be combined with another group as described herein or an atom, such as a N, O, or S. For example, an O can be combined with an alkyl to provide a mono-valent -O-aryl group, such as -O-C6-C10 aryl, having an open valence on only one end for connection with another structure. Alternatively, an O can be combined with an arylene to provide a di-valent -O-arylene- group, such as -O-C6-C10 arylene-, -O-(C6-C10 arylene)-, or –O(C6-C10 arylene)-, having open valences on both ends of the group for covalent attachment to two different structures. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0237] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. The term “heterocycloalkylene” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membereed), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6- membered), or 4 to 6 ring atoms (4- to 6-membered), or 5 to 7 ring atoms (5- to 7-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or “heterocycloalkylene” to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include mono-valent radicals of the following entities, while heterocycloalkylene groups include di-valent radicals of the following entities, in the form of properly bonded moieties:
Figure imgf000040_0001
[0238] It will be appreciated that a nitrogen containing heterocycloalkyl can be represented by the formula -N(alkylene), where the alkylene group is described by a parenthetical with no indicated open valence, in which case the alkylene group is understood to occupy two valence positions on the nitrogen atom to provide a heterocycloalkyl structure. For example, the group -N(C2-C6 alkylene) is within the scope of the term 3- to 7-membered heterocycloalkyl, where the 3- to 7-heterocycloalkyl has one nitrogen atom in the ring that represents the point of attachment. In particular, -N(C2-C6 alkylene) includes each of the following heterocycloalkyl structures.
Figure imgf000041_0001
[0239] It will be appreciated that an heterocycloalkyl or heterocycloalkylene group can be combined with another group as described herein or an atom, such as a N, O, or S. For example, an O can be combined with an alkyl to provide a mono-valent -O- heterocycloalkyl group, such as -O-(3- to 7-membered heterocycloalkyl), having an open valence on only one end for connection with another structure. Alternatively, an O can be combined with an heterocycloalkylene to provide a di-valent -O-heterocycloalkylene- group, such as -O-3- to 7- membered heterocycloalkylene-, -O-(3- to 7-membered heterocycloalkylene)-, or -O(3- to 7- membered heterocycloalkylene)-, having open valences on both ends of the group for covalent attachment to two different structures. It will be appreciated that a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein. A heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0240] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a di-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In some instances, a 5- to 10- membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. In some instances, a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. Illustrative examples of 5- to 10-membered heteroaryl groups include mono-valent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include di- valent radicals of the following entities, in the form of properly bonded moieties:
Figure imgf000042_0001
In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or six-membered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-liniting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-liniting examples of five- membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include mono-valent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include di-valent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. In particular, a pyrazolyl moiety can be depicted by the structural formula
Figure imgf000043_0002
. In particular, an example of a pyrazolylene moiety can be depicted by the structural formula
Figure imgf000043_0001
. [0241] It will be appreciated that a heteroaryl or heteroarylene group can be combined with another group as described herein or an atom, such as a N, O, or S. For example, an O can be combined with an alkyl to provide a mono-valent -O-heteroaryl group, such as -O-5- to 10- membered heteroaryl, having an open valence on only one end for connection with another structure. Alternatively, an O can be combined with a heteroarylene to provide a di-valent -O-heteroarylene- group, such as -O-5- to 10-membered heteroarylene-, -O-(5- to 10- membered heteroarylene)-, or –O(5- to 10-membered heteroarylene)-, having open valences on both ends of the group for covalent attachment to two different structures. It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0242] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone. [0243] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent. [0244] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. [0245] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 36Cl, and 125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. [0246] The nomenclature “(ATOM)i-j” with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-3 refers independently to embodiments that have one carbon member (C1), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3). [0247] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent –A-B-, where A ≠ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member. For example, in certsain embodiments, where applicable, a compound portion –(L)n- having the formula -CH(CH3)-CH2NH-(CH2)2-, connecting two groups, A and B, will be understood that -CH(CH3)-CH2NH-(CH2)2-, can include both of the embodiments A-CH(CH3)-CH2NH-(CH2)2-B and B-CH(CH3)-CH2NH-(CH2)2-A. More particularly in the present case, compounds of the formula (I)-(XIV) having a compound portion –(L)n- of the formula -CH(CH3)-CH2NH-(CH2)2- connecting groups -Z- and -NR2- will be understood to include both embodiments -Z-CH(CH3)-CH2NH-(CH2)2-NR2- and -NR2-CH(CH3)-CH2NH-(CH2)2-A. [0248] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XIV), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts. [0249] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. [0250] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2- sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985. [0251] For a compound of Formula (I)-(XIV) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology. [0252] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XIV), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XIV)). A "pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. [0253] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XIV), and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XIV) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem.1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res.1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard- Larsen et al., eds., Harwood Academic Publishers, 1991). REPRESENTATIVE EMBODIMENTS [0254] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000047_0002
[0255] wherein L, X, Y, Z1, Z2, Z3, Z4, Z5, Z6, m and n are as described herein. [0256] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000047_0001
[0257] wherein R2, A, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0258] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000047_0003
[0259] wherein A, B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0260] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
Figure imgf000048_0002
[0261] wherein R2, A, B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0262] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000048_0003
[0263] wherein R2, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0264] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000048_0001
[0265] wherein B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0266] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
Figure imgf000049_0001
wherein R2, B, L, X1, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0267] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000049_0003
[0268] wherein R1, R2, L, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0269] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000049_0002
[0270] wherein R1, B, L, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0271] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
Figure imgf000050_0001
[0272] wherein R1, R2, B, L, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0273] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000050_0002
[0274] wherein R2, L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0275] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000050_0003
[0276] wherein B, L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0277] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000051_0001
[0278] wherein R2, B, L, X, Z1, Z2, Z3, Z4, Z5, Z6, and n are as described herein. [0279] In some embodiments, X is -X1-. In some embodiments, X is -X1-(ring A)-. [0280] In some embodiments, Ring A is a 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; and wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0281] In some embodiments, Ring A is a 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. In some embodiments, Ring A is a 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a 5- to 10-membered heteroarylene, wherein one hydrogen atom in 5- to 10-membered heteroarylene is substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a 5- to 10-membered heteroarylene, wherein two hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a 5- to 10- membered heteroarylene, wherein three hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a 5- to 10-membered heteroarylene. [0282] In some embodiments, Ring A is a C6-C10 arylene, wherein each hydrogen atom in C6-C10 arylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; and wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0283] In some embodiments, Ring A is a C6-C10 arylene, wherein each hydrogen atom in C6-C10 arylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. In some embodiments, Ring A is a C6-C10 arylene, wherein each hydrogen atom in C6-C10 arylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a C6-C10 arylene, wherein one hydrogen atom in C6-C10 arylene is substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a C6-C10 arylene, wherein two hydrogen atoms in C6-C10 arylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a C6-C10 arylene, wherein three hydrogen atoms in C6-C10 arylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a C6-C10 arylene. [0284] In some embodiments, Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0285] In some embodiments, Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein one hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is substituted by a deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0286] In some embodiments, Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein two hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene are each independently substituted by a deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0287] In some embodiments, Ring A is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein three hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene are each independently substituted by a deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0288] In some embodiments, Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0289] In some embodiments, Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein one hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0290] In some embodiments, Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein two hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0291] In some embodiments, Ring A is a phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein three hydrogen atoms in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene are each independently substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0292] In some embodiments, Ring A is a phenylene or pyridinylene, wherein each hydrogen atom in phenylene or pyridinylene is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a phenylene or pyridinylene, wherein one hydrogen atom in phenylene or pyridinylene is substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a phenylene or pyridinylene, wherein two hydrogen atoms in phenylene or pyridinylene are each independently substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. In some embodiments, Ring A is a phenylene or pyridinylene, wherein three hydrogen atoms in phenylene or pyridinylene are each independently substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0293] In some embodiments, Ring A is a phenylene or a pyridinylene of the formula
Figure imgf000057_0001
, , , , , [0294] wherein each hydrogen atom is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0295] In some embodiments, Ring A is a phenylene or a pyridinylene of the formula
Figure imgf000057_0002
, , , , , [0296] wherein one hydrogen atom is independently substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0297] In some embodiments, Ring A is a phenylene or a pyridinylene of the formula
Figure imgf000057_0003
[0298] wherein two hydrogen atoms are each independently substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0299] In some embodiments, Ring A is a phenylene or a pyridinylene of the formula
Figure imgf000057_0004
[0300] wherein three hydrogen atoms are each independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl. [0301] In some embodiments, Ring A is
Figure imgf000057_0005
Figure imgf000057_0006
[0302] In some embodiments, -X1- is -O-. In some embodiments, -X1- is -S-. In some embodiments, -X1- is –NR1-. [0303] In some embodiments, R1 is hydrogen, C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. In some embodiments, R1 is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. [0304] In some embodiments, R1 is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C1- C6 alkyl. In some embodiments, R1 is of the formula
Figure imgf000058_0001
[0305] In some embodiments, R1 is H. [0306] In some embodiments, ring B is C6-C10 arylene or 5- to 10-membered heteroarylene, wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0307] In some embodiments, ring B is C6-C10 arylene, wherein each hydrogen atom in C6-C10 arylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; and wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0308] In some embodiments, ring B is C6-C10 arylene, wherein one hydrogen atom in C6-C10 arylene is substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; and wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is C6-C10 arylene, wherein one hydrogen atom in C6-C10 arylene is substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0309] In some embodiments, ring B is C6-C10 arylene, wherein two hydrogen atoms in C6-C10 arylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; and wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is C6-C10 arylene, wherein two hydrogen atoms in C6-C10 arylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0310] In some embodiments, ring B is C6-C10 arylene, wherein three hydrogen atoms in C6-C10 arylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; and wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is C6-C10 arylene, wherein three hydrogen atoms in C6-C10 arylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0311] In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0312] In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein one hydrogen atom in 5- to 10-membered heteroarylene is substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein one hydrogen atom in 5- to 10-membered heteroarylene is substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0313] In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein two hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein two hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0314] In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein three hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, ring B is 5- to 10-membered heteroarylene, wherein three hydrogen atoms in 5- to 10-membered heteroarylene are each independently substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2. [0315] In some embodiments, ring B is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0316] In some embodiments, ring B is
Figure imgf000064_0001
[0317] In some embodiments, Z1 is N. In some embodiments, Z2 is N. In some embodiments, Z3 is N. In some embodiments, Z4 is N. In some embodiments, Z5 is N. In some embodiments, Z6 is N. In some embodiments, Z1 is C(R6). In some embodiments, Z2 is C(R7). In some embodiments, Z3 is C(R8). In some embodiments, Z4 is C(R9). In some embodiments, Z5 is C(R10). In some embodiments, Z6 is C(R11). In some embodiments, any of the possible combinations of Z1-Z7 as provided above can be combined. In some embodiments, Z1 is N, Z2 is C(R7), Z3 is C(R8), Z4 is N, Z5 is C(R10), and Z6 is C(R11). In some embodiments, Z1 is N, Z2 is C(R7), Z3 is C(R8), Z4 is C(R9), Z5 is C(R10), and Z6 is C(R11). In some embodiments, Z1 is N, Z2 is C(R7), Z3 is N, Z4 is N, Z5 is C(R10), and Z6 is C(R11). In some embodiments, Z1 is N, Z2 is C(R7), Z3 is N, Z4 is C(R9), Z5 is C(R10), and Z6 is C(R11). In some embodiments, Z1 is N, Z2 is C(R7), Z3 is C(R8), Z4 is C(R9), Z5 is N, and Z6 is C(R11). In some embodiments, Z1 is N, Z2 is C(R7), Z3 is C(R8), Z4 is C(R9), Z5 is C(R10), and Z6 is N. In some embodiments, R6 is H. In some embodiments, R7 is H. In some embodiments, R8 is H. In some embodiments, R9 is H. In some embodiments, R10 is H or –OCH3. In some embodiments, R11 is H. [0318] In some embodiments, each L is independently selected from the group consisting of -C(R3)(R4)-, -C(O)-, -O-, or -N(R5)-, provided that (L)n does not comprise a –O-O- or a –O- N(R5)- bond. [0319] In some embodiments, -(L)n- comprises one or more of -(CR3R4)3-, -(CR3R4)4-, -(CR3R4)5-, -(CR3R4)6-, -(CR3R4)7-, -(CR3R4)8-, -C(O)N(R5)-(CR3R4)2O(CR3R4)2-, -CR3R4- C(O)N(R5)-(CR3R4)2O-, -CR3R4-C(O)N(R5)-(CR3R4)3O-, -N(R5)-C(O)CR3R4O(CR3R4)2-, -CR3R4-N(R5)-C(O)(CR3R4)2O-, -CR3R4-N(R5)-C(O)(CR3R4)3O-, -CR3R4O(CR3R4)2-, -CR3R4-O(CR3R4)3-, -(CR3R4)2O-CR3R4-, -(CR3R4)3O-CR3R4-, -(CR3R4)2O(CR3R4)2-, -(CR3R4)3O(CR3R4)2-, -(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)5O(CR3R4)3-, -O-CR3R4-O(CR3R4)3-, -CR3R4-O(CR3R4)2O-, -CR3R4-O(CR3R4)3O-, -O(CR3R4)2O(CR3R4)3- , -(CR3R4)2O(CR3R4)3O-, -O-(CR3R4)2-, -(CR3R4)2O-, –O-(CR3R4)3-, -(CR3R4)3O-, -O-(CR3R4)2O(CR3R4)2-, -(CR3R4)2O(CR3R4)2O-, -CR3R4-N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)3-, -(CR3R4)3O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)2C(O)N(R5)-(CR3R4)-, -(CR3R4)2N(R5)-(CR3R4)3-, -O-(CR3R4)2N(R5)-(CR3R4)2-, -CR3R4N(R5)-(CR3R4)2O-, -(CR3R4)2N(R5)-(CR3R4)2O-, or -(CR3R4)2N(R5)-(CR3R4)3O-. [0320] In some embodiments, -(L)n- is -(CR3R4)3-, -(CR3R4)4-, -(CR3R4)5-, -(CR3R4)6-, -(CR3R4)7-, -(CR3R4)8-, -C(O)N(R5)-(CR3R4)2O(CR3R4)2-, -CR3R4-C(O)N(R5)-(CR3R4)2O-, -CR3R4-C(O)N(R5)-(CR3R4)3O-, -N(R5)-C(O)CR3R4O(CR3R4)2-, -CR3R4-N(R5)-C(O)(CR3R4)2O-, -CR3R4-N(R5)-C(O)(CR3R4)3O-, -CR3R4O(CR3R4)2-, -CR3R4-O(CR3R4)3-, -(CR3R4)2O-CR3R4-, -(CR3R4)3O-CR3R4-, -(CR3R4)2O(CR3R4)2-, -(CR3R4)3O(CR3R4)2-, -(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)5O(CR3R4)3-, -O-CR3R4-O(CR3R4)3-, -CR3R4-O(CR3R4)2O-, -CR3R4-O(CR3R4)3O-, -O(CR3R4)2O(CR3R4)3- , -(CR3R4)2O(CR3R4)3O-, -O-(CR3R4)2-, -(CR3R4)2O-, –O-(CR3R4)3-, -(CR3R4)3O-, -O-(CR3R4)2O(CR3R4)2-, -(CR3R4)2O(CR3R4)2O-, -CR3R4-N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)3-, -(CR3R4)3O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)2C(O)N(R5)-(CR3R4)-, -(CR3R4)2N(R5)-(CR3R4)3-, -O-(CR3R4)2N(R5)-(CR3R4)2-, -CR3R4N(R5)-(CR3R4)2O-, -(CR3R4)2N(R5)-(CR3R4)2O-, or -(CR3R4)2N(R5)-(CR3R4)3O-. [0321] In some embodiments, -(L)n- comprises one or more of -(CR3R4)3-, -(CR3R4)4-, -(CR3R4)5-, -(CR3R4)6-, -(CR3R4)7-, -(CR3R4)8-, -C(O)N(R5)-(CR3R4)2O(CR3R4)2-, -N(R5)-C(O)CR3R4O(CR3R4)2-, -CR3R4O(CR3R4)2-, -CR3R4-O(CR3R4)3-, -(CR3R4)2O- CR3R4-, -(CR3R4)3O-CR3R4-, -(CR3R4)2O(CR3R4)2-, -(CR3R4)3O(CR3R4)2-, -(CR3R4)2O(CR3R4)3-, -O-CR3R4-O(CR3R4)3-, -CR3R4-O(CR3R4)2O-, -CR3R4-O(CR3R4)3O-, -O(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)3O-, -O-(CR3R4)2-, -(CR3R4)2O-, –O-(CR3R4)3-, -(CR3R4)3O-, -O-(CR3R4)2O(CR3R4)2-, -(CR3R4)2O(CR3R4)2O-, -CR3R4-N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)2-, -O-(CR3R4)2N(R5)-(CR3R4)2-, -CR3R4N(R5)-(CR3R4)2O-, -(CR3R4)2N(R5)-(CR3R4)2O-, or -(CR3R4)2N(R5)-(CR3R4)2O-. [0322] In some embodiments, -(L)n- is -(CR3R4)3-, -(CR3R4)4-, -(CR3R4)5-, -(CR3R4)6-, -(CR3R4)7-, -(CR3R4)8-, -C(O)N(R5)-(CR3R4)2O(CR3R4)2-, -N(R5)-C(O)CR3R4O(CR3R4)2-, -CR3R4O(CR3R4)2-, -CR3R4-O(CR3R4)3-, -(CR3R4)2O-CR3R4-, -(CR3R4)3O-CR3R4-, -(CR3R4)2O(CR3R4)2-, -(CR3R4)3O(CR3R4)2-, -(CR3R4)2O(CR3R4)3-, -O-CR3R4-O(CR3R4)3-, -CR3R4-O(CR3R4)2O-, -CR3R4-O(CR3R4)3O-, -O(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)3O-, -O-(CR3R4)2-, -(CR3R4)2O-, –O-(CR3R4)3-, -(CR3R4)3O-, -O-(CR3R4)2O(CR3R4)2-, -(CR3R4)2O(CR3R4)2O-, -CR3R4-N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)2-, -O-(CR3R4)2N(R5)-(CR3R4)2-, -CR3R4N(R5)-(CR3R4)2O-, -(CR3R4)2N(R5)-(CR3R4)2O-, or -(CR3R4)2N(R5)-(CR3R4)2O-. [0323] In some embodiments, each R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, -NRcC(O)Rd, and -CN, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. [0324] In some embodiments, -(L)n- comprises one or more of -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)2CH(CH3)-, -CH2OCH2CH(CH3)-CH2-, -CH2OCH(CH3)-(CH2)2-, -CH(CN)-O-(CH2)3-, -CH(CH3)-O-(CH2)3-, -CH2O(CH2)2-O-, -(CH2)2O(CH2)2-, -CH2- C(CH3)2-O(CH2)2-, -CH2-C(CH3)2-O(CH2)3-, -(CH2)2OCH2-, -(CH2)2O(CH2)2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -(CH2)2OCH(CH3)-(CH2)2-, -(CH2)2OC(CH3)2-(CH2)2-, -(CH2)2O(CH2)2-CH(CH3)-, -(CH2)2O-(CH2)2-C(CH3)2-CH2-CH(CH3)-O-(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O-(CH2)2-, –O-(CH2)3-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -(CH2)2OCH2CH(NH-C(O)-CH=CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2OCH2CH(NH-C(O)- CH2CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)2NH-CH2CH(NH- C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)3O(CH2)C(O)N(CH3)CH2-, -(CH2)3O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)C(O)N(CH3)CH2-, -(CH2)2O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)2C(O)N(CH3)CH2-, -(CH2)2O(CH2)2C(O)N(H)CH2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -(CH2)2NH-(CH2)3-, -(CH2)2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)3-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2C(O)N(H)-(CH2)3O-, -CH2C(O)N(CH3)-(CH2)3O-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)-(CH2)2-. [0325] In some embodiments, -(L)n- is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)2CH(CH3)-, -CH2OCH2CH(CH3)-CH2-, -CH2OCH(CH3)-(CH2)2-, -CH(CN)-O-(CH2)3-, -CH(CH3)-O-(CH2)3-, -CH2O(CH2)2-O-, -(CH2)2O(CH2)2-, -CH2-C(CH3)2-O(CH2)2-, -CH2-C(CH3)2-O(CH2)3-, -(CH2)2OCH2-, -(CH2)2O(CH2)2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -(CH2)2OCH(CH3)-(CH2)2-, -(CH2)2OC(CH3)2-(CH2)2-, -(CH2)2O(CH2)2- CH(CH3)-, -(CH2)2O-(CH2)2-C(CH3)2-CH2-CH(CH3)-O-(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O-(CH2)2-, –O-(CH2)3-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2- , -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -(CH2)2OCH2CH(NH-C(O)-CH=CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)-C(O)- CH=CH2)CH2O-, -(CH2)2OCH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)- C(O)-CH2CH2)CH2O-, -(CH2)2NH-CH2CH(NH-C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)3O(CH2)C(O)N(CH3)CH2-, -(CH2)3O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)C(O)N(CH3)CH2-, -(CH2)2O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)2C(O)N(CH3)CH2-, -(CH2)2O(CH2)2C(O)N(H)CH2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -(CH2)2NH-(CH2)3-, -(CH2)2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)3-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2C(O)N(H)-(CH2)3O-, -CH2C(O)N(CH3)-(CH2)3O-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)-(CH2)2-. [0326] In some embodiments, –(L)n- comprises one or more of -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)2CH(CH3)-, -CH2OCH2CH(CH3)-CH2-, -CH2OCH(CH3)-(CH2)2-, -CH(CN)-O-(CH2)3-, -CH(CH3)-O-(CH2)3-, -CH2O(CH2)2-O-, -(CH2)2O(CH2)2-, -CH2- C(CH3)2-O(CH2)2-, -(CH2)2OCH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2-CH(CH3)-O- (CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, –O-(CH2)2-, –O-(CH2)3-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)- (CH2)2-. [0327] In some embodiments, –(L)n- is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2- , -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)2CH(CH3)-, -CH2OCH2CH(CH3)-CH2-, -CH2OCH(CH3)-(CH2)2-, -CH(CN)-O-(CH2)3-, -CH(CH3)-O-(CH2)3-, -CH2O(CH2)2-O-, -(CH2)2O(CH2)2-, -CH2-C(CH3)2-O(CH2)2-, -(CH2)2OCH2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -CH2-CH(CH3)-O-(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, –O-(CH2)2-, –O-(CH2)3-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)- (CH2)2-. [0328] In some embodiments, m is 0, 1 or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0329] In some embodiments, n is 3, 4, 5, 6, 7, 8, or 9. In some embodiments, n is 3, 4, 5, 6, 7, or 8. In some embodiments, n is 4, 5, 6, or 7. In some embodiments, n is 4, 5, or 6. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. [0330] In some embodiments, the compound is selected from the group consisting of 1-(3- chloro-4-fluorophenyl)-17-methoxy-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0331] 1-(3-chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0332] (3R)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0333] (3S)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0334] 1-(3-chloro-4-fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0335] (5S)-1-(3-chloro-4-fluorophenyl)-5-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0336] (7R)-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0337] 12-(3-chloro-4-fluorophenyl)-1-methyl-4,13,14,16-tetrahydro-1H-6,8- ethenopyrazolo[4,3-k]pyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-5(12H)-one; [0338] 14-(3-chloro-4-fluorophenyl)-5-methyl-5,9,10,12,13,14-hexahydro-2,18-etheno-3,6- (metheno)pyrido[3,4-l][1,4,7,8,11,14]oxapentaazacyclohexadecin-7(8H)-one; and [0339] 1-(3-chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7,10-hexahydro-12,9-(azeno)-13,15- ethenopyrido[3,4-l][1,4,7,14]oxatriazacyclohexadecin-8(5H)-one; [0340] or a pharmaceutically acceptable salt thereof. [0341] In some embodiments, the compound is selected from the group consisting of 7- chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-f]pyrido[4,3- b][8,11,1,4]benzodioxadiazacyclotetradecine; [0342] 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; [0343] 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; [0344] 15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-f]pyrimido[4,5- b][8,11,1,4]benzodioxadiazacyclotetradecine; [0345] 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrimido[4,5-b][8,11,1]benzodioxazacyclotetradecine; [0346] 7,15-dimethyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-m]pyrido[3,4- f]pyrimido[4,5-i][1,4,8]dioxazacyclotetradecine; [0347] 7-chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-ethenodipyrido[4,3-b:2',3'- f][8,11,1]benzodioxazacyclotetradecine; [0348] 7-chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-ethenodibenzo[e,l]pyrido[3,4- i][1,4,8,11]dioxadiazacyclotetradecine; [0349] 7-chloro-6-fluoro-14-methyl-5,13,14,17-tetrahydro-10H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][14,1,8,11]benzoxatriazacycloheptadecin-15(12H)-one; [0350] 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][14,1,8,11]benzoxatriazacycloheptadecin-15(12H)-one; [0351] 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-1,20-etheno-19,16- (metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one; [0352] 7-chloro-6-fluoro-14-methyl-13,14-dihydro-10H,17H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0353] 7-chloro-8-fluoro-13,14-dihydro-10H,17H-19,16-(azeno)-1,20-ethenopyrido[4,3- b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0354] 7-chloro-6-fluoro-13,14-dihydro-10H,17H-19,16-(azeno)-1,20-ethenopyrido[4,3- b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0355] 7-chloro-6-fluoro-14,17-dimethyl-13,14-dihydro-10H,17H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; [0356] 16-chloro-17-fluoro-8-methyl-8,9,10,11,13,18-hexahydro-7H-4,6-ethenopyrido[4,3- b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0357] 16-chloro-17-fluoro-8,9,10,11,13,18-hexahydro-7H-4,6-ethenopyrido[4,3- b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0358] (13R)-16-chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0359] (13S)-16-chloro-17-fluoro-7-oxo-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecine-13-carbonitrile; [0360] (9R)-16-chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; [0361] 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7H,13H-4,6-ethenopyrido[4,3- b][1,11,7]benzodioxazacyclotetradecin-7-one; and [0362] 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7H,13H-4,6-ethenopyrido[4,3- b][11,1,7]benzoxathiazacyclotetradecin-7-one; [0363] or a pharmaceutically acceptable salt thereof. [0364] In some embodiments, the compound is selected from the group consisting of 1-(3- chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; [0365] 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,10]oxadiazacyclotridecin-9(1H)-one; [0366] 15-(3-chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-ethenopyrimido[4,5- e][1,4,10]oxadiazacyclotridecin-7(13H)-one; [0367] 1-(3-chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-etheno- 13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one; [0368] 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16- etheno-13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one; [0369] 1-(3-chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; [0370] 1-(3-chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-etheno- 12,9-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecin-8(5H)-one; [0371] 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-etheno- 13,10-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacycloheptadecin-7(6H)-one; [0372] N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide; [0373] 3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]-N-(propan-2- yl)benzamide; [0374] N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide; [0375] 1-(3,4-dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; [0376] 1-(3-chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; [0377] 2-[1-(3-chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16- etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-8(9H)-yl]-N- methylacetamide; [0378] 15-(3-chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno- 3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0379] N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-ethenopyrido[4,3- e][1,9,4]dioxazacyclododecin-6-yl]prop-2-enamide; [0380] N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-ethenopyrido[4,3- e][1,9,4]dioxazacyclododecin-6-yl]propanamide; [0381] N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11- ethenopyrido[4,3-i][1,5,8]oxadiazacyclododecin-6-yl]prop-2-enamide; [0382] 15-(3-chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0383] 15-(4-chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno- 3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0384] 15-(3,4-dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno-3,6- (metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0385] 15-(3-chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; [0386] 10-(3-chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-ethenopyrido[3,4- d][1,3,6,9]oxatriazacyclododecin-8-one; [0387] 1-(3-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-ethenopyrido[4,3- i][1,5,8]oxadiazacyclododecin-3-one; [0388] 15-(3,4-dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; and [0389] 7-chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-etheno-19,16- (metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one. [0390] or a pharmaceutically acceptable salt thereof. [0391] The following represent illustrative embodiments of compounds of Formula (I-XIV):
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
and pharmaceutically acceptable salts thereof. [0392] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected. PHARMACEUTICAL COMPOSITIONS [0393] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. [0394] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions. [0395] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration. [0396] For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. [0397] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. [0398] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents. [0399] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. [0400] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository. [0401] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery. [0402] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. [0403] The term “subject” refers to a mammalian patient in need of such treatment, such as a human. [0404] Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term “cancer” includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+ breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease. Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury. [0405] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases. In preferred embodiments, methods of treatment target cancer. In other embodiments, methods are for treating lung cancer or non-small cell lung cancer. [0406] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of EGFR. [0407] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID). [0408] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. DRUG COMBINATIONS [0409] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure. [0410] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g. crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents. CHEMICAL SYNTHESIS METHODS [0411] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(XIV). [0412] The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below which use a selected example for illustration: [0413] Scheme I
Figure imgf000086_0001
[0414] Scheme II
Figure imgf000086_0002
[0415] Scheme III
Figure imgf000087_0001
[0416] Scheme IV
Figure imgf000087_0002
[0417] Scheme V
Figure imgf000088_0001
[0418] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
Figure imgf000088_0002
Figure imgf000089_0001
Figure imgf000090_0002
[0419] General Method A
Figure imgf000090_0001
[0420] To a solution of A1-1 (1 eq.) and A1-2 (1.1 eq.) in ethanol (0.5M) are added a catalytic amount of KI and HCl aqueous solution (2N, 0.5% volume of ethanol). The solution is refluxed for 12 hours and the product A-1 is precipitated out, filtered, and washed by ethanol. [0421] Alternatively, A-1 can be prepared under palladium catalyzed condition:
Figure imgf000091_0001
[0422] To a mixture of A1-1 (1.0 eq.) and A1-2 (1.1 eq) in anhydrous dioxane (0.1 M) are added Pd(dba)2 (0.04 eq.), 2,2'-bis (diphenyl phosphino)-1,1-binaphthalene (0.045 eq.) and sodium tert-butoxide (1.5 eq.) under nitrogen. The mixture is refluxed for 7 hours or until the reaction is completed. The mixture is cooled down, diluted with EtOAc, filtered via a celite pad, and concentrated. The residue is purified on a silica gel column to provide A-1. [0423] A-1—A-13 are prepared with General Method A:
Figure imgf000091_0002
Figure imgf000092_0001
Figure imgf000093_0002
[0424] General Method B
Figure imgf000093_0001
[0425] To a solution of A2-1 ( 1 eq.) and B1-2 (1.1 eq.) in DMF (0.5M) is added Cs2CO3 (2 eq.). The mixture is heated at 100 ºC until the reaction is complete. The mixture is cooled, diluted with EtOAc, washed with water and brine, and dried over Na2SO4. After filtration and condensation, the residue is purified on a silica gel column to provide B-1. [0426] B-1—B-4 are prepared with General Method B:
Figure imgf000094_0002
[0427] General Method C
Figure imgf000094_0001
[0428] To a solution of A-1 (1.0 eq.) in DMF (1 M) at 0ºC is added dropwise phosphoryl chloride (2.0 eq.). The solution is heated at 80 ºC until the reaction is completed. After cooling, the reaction is quenched with methanol, diluted with EtOAc, and washed with water, sat. Na2CO3 aqueous solution and brine. The organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified on a silica gel column to provide C-1. [0429] C-1—C-6 are prepared with General Method C:
Figure imgf000095_0001
Figure imgf000096_0003
[0430] General Method D
Figure imgf000096_0001
[0431] The alcohol starting material (1.0 eq.) is added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in anhydrous THF (0.5 M) at ambient temperature. After 30 min, to above suspension is added the halide compound (1.0 eq). After the reaction is complete, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc for three times. The combined extracts are washed with brine, dried over Na2SO4, filtered, concentrated, and purified on a silica gel column to provide the product. [0432] D-1—D-12 are prepared with General Method D:
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0002
[0433] General Method E
Figure imgf000098_0001
[0434] A solution of C-1 (1.0 eq.), Pd(OAc)2 (0.025 eq.), 1,3-bis(diphenylphosphino)propane (0.0325 eq.) and Et3N (2 eq.) in MeOH/MeCN 1:1 (0.1 M) is pumped at a flow rate of 2.4 mL/min and CO at a flow rate of 12 mLn/min into the reactor at 170 °C and 23 bar pressure. The reaction solution is concentrated and purified on a silica gel column to provide E-1. [0435] E-1—E-9 are prepared with General Method E:
Figure imgf000099_0001
Figure imgf000100_0002
[0436] General Method F
Figure imgf000100_0001
[0437] To a solution of C-1 (1.0 eq.) and F1-2 (1.2 eq.) and Cs2CO3 (3 eq.) in DME/H2O (5:1, 0.2 M) under N2, is added Pd(dppf)Cl2 (0.05 eq.). The mixture is stirred at 85 ºC overnight, cooled to ambient temperature, and quenched with H2O. The resulting mixture is extracted with EtOAc for three times. The combined extracts are washed with brine and dried over anhydrous Na2SO4. After filtration and condensation, the resulting residue is purified by silica gel chromatography to afford the desired product F-1. [0438] F-1—F-16 are prepared with General Method F:
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0002
[0439] General Method G
Figure imgf000104_0001
[0440] E-1 (1.0 eq.) is added to a suspension of NaH (60% in mineral oil, 1.1 eq.) in anhydrous DMF (0.5 M) at ambient temperature. After 30 min, to above suspension is added alkyl halide Gl-2 (1.0 eq). After the reaction is complete, the reaction is quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc for three times. The combined extracts are washed with brine, dreid over Na2SO4, filtered, concentrated, and purified on a silica, gel column to provide G-1.
[0441] G-1 — G-20 are prepared with General Method G: [0442]
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
[0443] General Method H
Figure imgf000109_0001
[0444] Step 1. To a solution of F-1 (1.0 eq.) in MeOH (0.2 M) is added LiOH (3 eq) in H2O (1 M). The mixture is stirred at 60 ºC until the hydrolysis reaction is completed. The solution is cooled to ambient temperature, concentrated to remove methanol, acidified by aqueous HCl (1 N) until pH ~4-5, and then extracted with CH2Cl2. The combined extracts are dried over Na2SO4, concentrated, and dried under vacuum to provide the crude product. [0445] Step 2. The crude solid is dissolved in CH2Cl2 (0.2 M) and to the solution is added a solution of HCl in dioxane (4 eq HCl). The solution is stirred at 40ºC until the de-Boc is completed. The solvents are removed under rotavap and the residue is dried under vacuum to provide a crude solid which is used for the next step without purification. [0446] Step 3. To a solution of the crude solid (1 eq. assume 100% from step 1 and step 2) in DMF (0.2 M) are added DIPEA (3 eq.) and pentafluorophenyl diphenylphosphinate (FDPP) (1.1 eq). The solution is stirred at ambient temperature until the amide formation is completed. The mixture is diluted with water and extracted with EtOAc for three times. The combined extracts are washed with water for three times, aqueous HCl (1N), saturated aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated. The resulting residue is purified by a silica gel column to afford Ex.1. [0447] Ex.1—Ex.26 are prepared with General Method H: [0448]
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0002
[0449] General Method I
Figure imgf000115_0001
[0450] Step 1. To a solution of F-9 (1.0 eq.) in methanol (1.0 M) is added sodium borohydride 0.5 eq.) at ambient temperature and the mixture is stirred until the reaction is completed. The reaction solution is quenched with HCl aqueous solution (1 M) followed by extraction with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. After filtration and condensation, the residue is purified on a silica gel column to provide F9-2. [0451] Step 2. To a solution of F9-2 (1.0 eq.) and triphenylphosphine (1.1 eq.) in anhydrous THF (0.1 M) is added dropwise a solution of diisopropyl azodicarboxylate (1.1 eq.) in anhydrous THF (2 M). The resulting mixture is stirred at ambient temperature under nitrogen until the reaction is completed. The mixtures is concentrated under reduced pressure, diluted with in EtOAc, washed with aq.2M NaOH (100 mL), and dried over Na2SO4. After filtration and condensation, the residue is purified with a silica gel column to provide the product Ex. 27. [0452] Ex.27 —Ex.34 are prepared with General Method I:
Figure imgf000116_0001
Figure imgf000117_0001
[0453] Preparation of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]carbamate (J1)
Figure imgf000118_0001
[0454] Step 1. To a solution of tert-butyl N-(3-hydroxypropyl)-carbamate (9.25 g, 52.84 mmol, 1 eq) and diacetoxyrhodium (1.17 g, 2.64 mmol, 0.05 eq) in DCM (100 mL) was added a solution of ethyl 2-diazoacetate (30.15 g, 264.20 mmol, 5 eq) in DCM (15 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column on silica gel (PE to PE/EtOAc =40:1) to give ethyl 2-[3-[tert- butoxycarbonylamino]propoxy]acetate (5.8 g, crude) as yellow oil. [0455] Step 2. To a mixture of ethyl 2-[3-(tert-butoxycarbonylamino)propoxy]acetate (4.00 g, 15.3 mmol, 1.00 eq) in MeOH (30.0 mL) and H2O (3.00 mL) was added LiOH•H2O (1.28 g, 30.6 mmol, 2.00 eq) in one portion. The mixture was stirred at 20 °C for 2 hours. On completion, the mixture was concentrated in vacuum to give [2-[3-(tert- butoxycarbonylamino)-propoxy]acetyl]oxylithium (4.00 g, crude) as a yellow solid. [0456] Step 3. To a mixture of [2-[3-(tert-butoxycarbonylamino)propoxy]acetyl]oxylithium (4.00 g, crude, 1 eq) and 3-chloro-4-fluoro-aniline (2.43 g, 16.7 mmol, 1.00 eq) in DMF (40.0 mL) was added DIEA (6.48 g, 50.2 mmol, 8.74 mL, 3.00 eq), followed by HATU (9.54 g, 25.1 mmol, 1.50 eq). The mixture was stirred at 20 °C for 1 hour. On completion, the residue was poured into ice-water (50.0 mL). The aqueous phase was extracted with ethyl acetate (60.0 mL * 3). The combined organic phase was washed with brine (30.0 mL * 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=30/1 to 15/1) to give tert-butyl N-[3-[2-(3- chloro-4-fluoro-anilino)-2-oxo-ethoxy]propyl]carbamate (4.20 g, 11.6 mmol, 69.3% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 9.18 - 8.92 (m, 1H), 7.99 - 7.86 (m, 1H), 7.73 - 7.59 (m, 1H), 7.10 (t, J = 8.8 Hz, 1H), 4.66 (br s, 1H), 4.07 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.40 (br d, J = 5.6 Hz, 2H), 1.82 (quin, J = 5.6 Hz, 2H), 1.44 (s, 9H). LC-MS: m/z 383.1 (M+Na)+. [0457] Step 4. To a mixture of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)-2-oxo- ethoxy]propyl]carbamate (1.70 g, 4.71 mmol, 1.00 eq) in THF (15.0 mL) was added LiAlH4 (268 mg, 7.07 mmol, 1.50 eq) in three portions at 0 °C under N2. The mixture was stirred at 20 °C for 6 hours. On completion, to the mixture was added water (0.26 mL) dropwise at 0 °C. Then to the mixture was added aq. NaOH (15%, 0.78 mL) slowly, followed by water (0.26 mL). The mixture was dried with anhydrous Na2SO4 (5.00 g), filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=30/1 to 15/1) to give tert-butyl N-[3-[2-(3-chloro-4-fluoro- anilino)ethoxy]propyl]carbamate (865 mg, 2.49 mmol, 52.9% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 6.97 (t, J = 8.8 Hz, 1H), 6.76 (br d, J = 3.2 Hz, 1H), 6.64 - 6.53 (m, 1H), 4.72 (br s, 1H), 3.66 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.33 - 3.19 (m, 4H), 1.79 - 1.73 (m, 2H), 1.45 (s, 9H). LC-MS: m/z 347.1 (M+H)+. [0458] Preparation of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]-N-methyl- carbamate (J2) C
Figure imgf000119_0001
[0459] J2 was prepared using similar methods as J1 using tert-butyl N-(3-hydroxypropyl)-N- methyl-carbamate as starting material to replace tert-butyl N-(3-hydroxypropyl)-carbamate. LCMS: m/z 361.1 (M+H)+. [0460] Preparation of benzyl (3-((tert-butoxycarbonyl)amino)propyl)(2-((3-chloro-4- fluorophenyl)amino)ethyl)carbamate (J3)
Figure imgf000119_0002
[0461] Step 1. To a solution of 3-chloro-4-fluoro-aniline (13 g, 89.3 mmol, 1 eq) in DMSO (100 mL) was added DIEA (23.1 g, 178.62 mmol, 2 eq) and ethyl 2-bromoacetate (16.4 g, 98.2 mmol, 1.1 eq). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate (100 mL × 3) and water (300 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 2-(3- chloro-4-fluoro-anilino) acetate (21 g, crude) as yellow solid. LCMS: m/z 231.8 (M+H)+. [0462] Step 2. To a solution of ethyl 2-(3-chloro-4-fluoro-anilino)acetate (21 g, 90.7 mmol, 1 eq) in MeOH (150 mL) was added LiOH.H2O (11.4 g, 272 mmol, 3 eq) and H2O (50 mL). The mixture was stirred at 40 °C for 1 hour. The mixture was concentrated in vacuum to remove MeOH, acidified with 2M HCl to pH = 4, the solid was filtered and the filter cake was concentrated to give 2-(3-chloro-4-fluoro-anilino) acetic acid (15.5 g, 74.6 mmol, 82% yield) as yellow solid. LCMS: m/z 204.2 (M+H)+. [0463] Step 3. To a solution of 2-(3-chloro-4-fluoro-anilino)acetic acid (15.5 g, 76.1 mmol, 1 eq) in THF (200 mL) was added DIEA (29.5 g, 228 mmol, 39.8 mL, 3 eq). Then tert-butyl N- (3-aminopropyl)carbamate (15.9 g, 91.4 mmol, 16 mL, 1.2 eq), T3P (29.1 g, 91.4 mmol, 27.2 mL, 1.2 eq) was added into mixture at 0°C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL × 3) and water (200 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 0:1) to give tert-butyl N-[3-[[2-(3-chloro-4-fluoro-anilino) acetyl] amino] propyl] carbamate (20 g, 55.6 mmol, 73% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.91 (t, J = 4.8 Hz, 1H), 7.11 (t, J = 9.2 Hz, 1H), 6.74 (s, 1H), 6.62 (dd, J = 2.4, 6.0 Hz, 1H), 6.48 (td, J = 3.2, 8.8 Hz, 1H), 6.17 (br t, J = 6.0 Hz, 1H), 3.60 (d, J = 6.0 Hz, 2H), 3.06 (q, J = 6.0 Hz, 2H), 2.88 (q, J = 6.0 Hz, 2H), 1.47 (m, 2H), 1.36 (s, 9H); LCMS: m/z 360.0 (M+H)+. [0464] Step 4. To a mixture of tert-butyl N-[3-[[2-(3-chloro-4-fluoro-anilino)acetyl]- amino]propyl]carbamate (5 g, 13.9 mmol, 1 eq) in THF (50 mL) was added BH3.THF (1 M, 34.7 mL, 2.5 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 12 hours, and then quenched by addition of MeOH (20 mL) at 0° C followed by stirring for 30 minutes. The mixture was concentrated and the residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to Ethyl acetate /Methanol=5:1) to provide tert-butyl N-[3- [2-(3-chloro-4-fluoro-anilino) ethyl amino] propyl] carbamate (3 g, 8.24 mmol, 59% yield) as light yellow oil. LCMS: m/z 346.2 (M+H)+. [0465] Step 5. To a solution of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino) ethylamino] propyl] carbamate (3 g, 8.67 mmol, 1 eq) in EtOAc (20 mL) and H2O (10 mL) were added NaHCO3 (1.09 g, 13.0 mmol, 1.5 eq) and CbzCl (888 mg, 5.20 mmol, 0.6 eq). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5:1 to 1:1) to give benzyl N-[3- (tert-butoxycarbonylamino) propyl]-N-[2-(3-chloro-4-fluoro-anilino) ethyl] carbamate (2.7 g, 5.57 mmol, 64.2% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.41 - 7.28 (m, 5H), 7.13 - 6.93 (m, 1H), 6.83 - 6.61 (m, 2H), 6.58 - 6.40 (m, 1H), 5.88 (t, J = 5.6 Hz, 1H), 5.07 (s, 2H), 3.30 (s, 2H), 3.24 (t, J = 6.8 Hz, 2H), 3.16 (s, 2H), 2.90 (d, J = 5.2 Hz, 2H), 1.61 (t, J = 6.8 Hz, 2H), 1.37 (s, 9H); LCMS: m/z 480.0 (M+H)+. [0466] Preparation of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]ethyl]-N-methyl- carbamate (J4)
Figure imgf000121_0002
[0467] J4 was prepared using similar methods as J1 using tert-butyl N-(3-hydroxyethyl)-N- methyl-carbamate as starting material to replace tert-butyl N-(3-hydroxypropyl)-carbamate.1H NMR (400 MHz, DMSO-d6) δ = 7.09 - 7.06 (m, 1H), 6.71 - 6.68 (m, 1H), 6.57 - 6.54 (m, 1H), 5.78 - 5.76 (m, 1H), 3.55 - 3.49 (m, 4H), 3.32 - 3.31 (m, 2H), 3.16 - 3.15 (m, 2H), 2.79 (s, 3H), 1.38 (s, 9H). LCMS: m/z 347.2 (M+H)+. [0468] Preparation of ethyl 2-[3-(3-chloro-4-fluoro-anilino)propoxy]acetate (J5)
Figure imgf000121_0001
[0469] Step 1. To a mixture of 3-bromopropan-1-ol (10.0 g, 71.9 mmol, 6.49 mL, 1 eq) and diacetoxyrhodium (318 mg, 1.44 mmol, 0.02 eq) in DCM (50 mL) was dropwise slowly added solution of ethyl 2-diazoacetate (20.0 g, 175 mmol, 2.44 eq) in DCM (50 mL) at 0 °C, the resulting mixture was stirred at 25 °C for 12 hours. The residue was diluted with H2O (20 mL) and extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-(3-bromopropoxy)acetate (30.0 g, crude) as a yellow oil.1H NMR (400 MHz, CDCl3-d) δ = 4.23 - 4.20 (m, 2H), 4.07 (s, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 2.15 (quin, J = 6.4 Hz, 2H), 1.30 - 1.28 (m, 3H). [0470] Step 2. To a mixture of 3-chloro-4-fluoro-aniline (3.00 g, 20.6 mmol, 1 eq) and KI (342 mg, 2.06 mmol, 0.1 eq) and DIEA (7.99 g, 61.8 mmol, 10.7 mL, 3 eq) in DMSO (40 mL) was added ethyl 2-(3-bromopropoxy)acetate (11.6 g, 51.5 mmol, 2.5 eq), the resulting mixture was stirred at 110 °C for 12 hours. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-[3-(3- chloro-4-fluoro-anilino)propoxy]acetate (J5, 2.76 g, 8.97 mmol, 43.5% yield, 94.2% purity) as a brown oil.1H NMR (400 MHz, CDCl3-d) δ = 6.93 (t, J = 8.8 Hz, 1H), 6.62 (dd, J = 2.8, 6.0 Hz, 1H), 6.46 (td, J = 3.2, 8.8 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 4.08 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 6.4 Hz, 2H), 1.90 (quin, J = 6.0 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). LCMS: m/z 290.0 (M+1). [0471] Preparation of tert-butyl N-[2-[(2-amino-4-chloro-5-fluoro- phenyl)methoxy]ethyl]carbamate (J6)
Figure imgf000122_0001
[0472] Step 1. To a mixture of 1-chloro-2-fluoro-4-methyl-5-nitro-benzene (25.0 g, 131 mmol, 1 eq) in ACN (200 mL) was added AIBN (2.17 g, 13.1 mmol, 0.1 eq) and NBS (37.5 g, 211 mmol, 1.6 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0) to give crude compound. The crude compound was further purified by reversed-phase HPLC (0.1% FA condition) to afford 1-(bromomethyl)-4- chloro-5-fluoro-2-nitro-benzene (17.0 g, 62.6 mmol, 47.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.22 (d, J = 6.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 4.80 (s, 2H). [0473] Step 2. To a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (10.1 g, 62.9 mmol, 9.76 mL, 1.3 eq) in DCM (200 mL) was added TBAI (8.94 g, 24.2 mmol, 0.5 eq) and KOH (1.36 g, 24.2 mmol, 0.5 eq) and Na2CO3 (2.57 g, 24.2 mmol, 0.5 eq), the mixture was stirred at 25 °C for 1 hour. Then 1-(bromomethyl)-4-chloro-5-fluoro-2-nitro-benzene (13.0 g, 48.4 mmol, 1 eq) was added, the mixture was stirred at 50 °C for 12 hours. The reaction was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 15/1). The product was further purified by reversed-phase HPLC to afford tert-butyl N-[2-[(4-chloro-5-fluoro-2-nitro- phenyl)-methoxy]ethyl]-carbamate (1.50 g, 3.89 mmol, 8.04% yield) as a yellow solid. LCMS: m/z 249 (M-100)+. [0474] Step 3. To a mixture of tert-butyl N-[2-[(4-chloro-5-fluoro-2-nitro-phenyl)-methoxy]- ethyl]carbamate (1.50 g, 4.30 mmol, 1 eq) in H2O (4.00 mL) and EtOH (20.0 mL) was added Fe (720 mg, 12.9 mmol, 3 eq) and NH4Cl (1.15 g, 21.5 mmol, 5 eq). The mixture was stirred at 85 °C for 2 h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum to removed EtOH. The reaction mixture was partitioned between H2O (2 mL) and EtOAc (5 mL). The organic phase was separated, washed with brine (3 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide tert-butyl N-[2-[(2-amino-4-chloro-5-fluoro- phenyl)-methoxy]ethyl]carbamate (J6, 1.00 g, 2.17 mmol, 50.4% yield) as a yellow oil. LCMS: m/z 341.0 (M+Na)+. [0475] Preparation of methyl 3-[2-[benzyloxycarbonyl-[3-(tert-butoxycarbonylamino)- propyl]-amino]ethylamino]benzoate (J7)
Figure imgf000123_0001
[0476] Step 1. A solution of methyl 3-aminobenzoate (10 g, 66.1 mmol, 1 eq), tert-butyl 2- bromoacetate (14.2 g, 72.8 mmol, 1.1 eq) and DIEA (17.1 g, 132 mmol, 2 eq) in DMSO (100 mL) was stirred at 80 °C for 2 hours. The reaction mixture was diluted with H2O (1000 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 3-((2-(tert-butoxy)-2-oxoethyl)amino)benzoate (19 g, crude) as a yellow oil and used for next step directly. 1H NMR (400 MHz, DMSO-d6) δ = 7.24 - 7.11 (m, 3H), 6.83 - 6.78 (m, 1H), 6.32 (t, J = 6.4 Hz, 1H), 3.84 - 3.77 (m, 5H), 1.41 (s, 9H) [0477] Step 2. A solution of methyl 3-((2-(tert-butoxy)-2-oxoethyl)amino)benzoate (19 g, 71. 6 mmol, 1 eq) in TFA (100 mL) and DCM (100 mL) was stirred at 20 °C for 2 hours. The rea ction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL x 3). The co mbined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and conc entrated under reduced pressure to give a residue. The residue was purified by column chrom atography to give 2-(3-methoxycarbonylanilino)acetic acid (J7-3, 11 g, 49.9 mmol, 69.7% yie ld, 95% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.25 - 7.10 (m, 3H), 6. 82 (d, J = 7.6 Hz, 1H), 3.84 (s, 2H), 3.81 (s, 3H); LCMS: m/z 210.3 (M+H)+. [0478] J7 was prepared from J7-3 following similar methods as J3-2 to J3.1H NMR (400 MH z, DMSO-d6) δ = 7.37 - 7.26 (m, 6H), 7.18 (s, 1H), 7.11 (s, 1H), 6.89 - 6.69 (m, 2H), 6.02 (s, 1H), 5.08 (s, 2H), 3.37 - 3.31 (m, 5H), 3.28 - 3.17 (m, 4H), 2.90 (d, J = 5.2 Hz, 2H), 1.62 (d, J = 6.4 Hz, 2H), 1.36 (s, 9H); LCMS: m/z 486.8 (M+H)+. [0479] Preparation of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[2-(3,4-dichloro-2- fluoro-anilino)ethyl] carbamate (J8)
Figure imgf000124_0001
[0480] J8 was prepared following similar methods as J3 using 3,4-dichloro-2-fluoro-aniline as a starting material.1H NMR (400 MHz, DMSO-d6) δ = 7.39 - 7.29 (m, 6H), 7.21 - 6.91 (m, 1H), 6.78 (s, 1H), 6.07 (s, 1H), 5.05 (d, J = 17.2 Hz, 2H), 3.39 - 3.32 (m, 2H), 3.30 - 3.17 (m, 4H), 2.89 (s, 2H), 1.66 - 1.53 (m, 2H), 1.36 (s, 9H). [0481] Preparation of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[2-(3-chloro-2- fluoro-anilino)ethyl]carbamate (J9)
Figure imgf000124_0002
[0482] J8 was prepared following similar methods as J3 using 3-chloro-2-fluoro-aniline as a s tarting material.1H NMR (400 MHz, DMSO-d6) δ = 7.41 - 7.28 (m, 5H), 6.83 - 6.69 (m, 2H), 6.68 - 6.57 (m, 1H), 5.88 (s, 1H), 5.06 (d, J =12.0 Hz, 2H), 3.38 - 3.34 (m, 1H), 3.32 - 3.28 (m , 1H), 3.24 (s, 4H), 2.89 (s, 2H), 1.65 - 1.55 (m, 2H), 1.36 (s, 9H); LCMS: m/z 480.2 (M+H)+ . [0483] Preparation of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-chloro-4-fluoro-aniline (J1 0)
Figure imgf000125_0001
[0484] Step 1. To a solution of 3-chloro-4-fluoroaniline (2 g, 13.7 mmol, 1 eq) in THF (20 mL) was added NaH (0.6 g, 15.0 mmol, 60% purity, 1.09 eq) at 0 °C. Then to the reaction was added 1,3,2-dioxathiolane 2,2-dioxide (2 g, 16.1 mmol, 1.17 eq). The reaction mixture was stirred at 20 °C for 12 hours and then quenched with aq NH4Cl (100 mL) at 0 °C. The reaction mixture was diluted with 400 mL of H2O and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide crude 2-(3-chloro-4-fluoro-anilino)ethyl hydrogen sulfate (3.71 g, crude) as a yellow oil. [0485] Step 2. To a solution of 2-(3-chloro-4-fluoro-anilino)ethyl hydrogen sulfate (3.71 g, 13.7 mmol, 1 eq) in MeOH (40 mL) was added concentrated H2SO4 (674 mg, 6.88 mmol, 0.5 eq). The reaction was stirred at 60 °C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to provide 2-(3-chloro-4-fluoro-anilino)ethanol (2 g, 10.44 mmol, 76% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.31 (t, J = 9.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.01 - 6.92 (m, 1H), 3.60 - 3.54 (m, 2H), 3.21 (t, J = 5.6 Hz, 2H); LCMS: m/z 190.0 (M+H)+. [0486] Step 3. To a solution of 2-(3-chloro-4-fluoro-anilino)ethanol (1.5 g, 7.91 mmol, 1 eq) in DCM (20 mL) was added TBSCl (1.40 g, 9.29 mmol, 1.17 eq) and TEA (2.40 g, 23.73 mmol, 3 eq). The reaction was stirred at 20 °C for 2 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 4/1) to provide N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-chloro-4-fluoro- aniline (1.9 g, 6.19 mmol, 78.2% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.07 (t, J = 9.2 Hz, 1H), 6.69 (dd, J = 2.8, 6.4 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 5.75 (t, J = 6.0 Hz, 1H), 3.68 (t, J = 6.0 Hz, 2H), 3.11 (q, J = 6.0 Hz, 2H), 0.85 (s, 9H), 0.02 (s, 6H); LCMS: m/z 304.2 (M+H)+. [0487] Preparation of tert-butyl N-[2-(3-chloro-4-fluoro-anilino)ethyl]carbamate (J11)
Figure imgf000126_0001
[0488] To a solution of 3-chloro-4-fluoroaniline (5 g, 34.35 mmol, 1 eq) in THF (50 mL) was added NaH (1.50 g, 37.50 mmol, 60% purity, 1.09 eq) at 0 °C. Then to the reaction was added tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (8.00 g, 35.8 mmol, 1.04 eq) . The reaction was stirred at 20 °C for 12 hours. The reaction was quenched by added to aq NH4Cl (100 mL) at 0 °C. The crude product was purified by reversed-phase HPLC( 0.1% TFA condition).The compound of tert-butyl N-[2-(3-chloro-4-fluoro-anilino)ethyl]carbamate (6.7 g, 22.04 mmol, 64% yield, 95% purity) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.09 (t, J = 9.2 Hz, 1H), 6.84 (s, 1H), 6.65 (d, J = 3.6 Hz, 1H), 6.57 - 6.48 (m, 1H), 3.04 (s, 4H), 1.37 (s, 9H); LCMS: m/z 288.8 (M+H)+. [0489] Preparation of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino) ethyl-methyl-amino] propyl] carbamate (J12)
Figure imgf000126_0002
[0490] J12 was prepared using similar methods as J3-4 in J3 as a as a colorless oil.1H NMR ( 400 MHz, DMSO-d6) δ = 7.08 (t, J = 9.2 Hz, 1H), 6.77 (t, J = 5.2 Hz, 1H), 6.69 (d, J = 6.0 H z, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.56 (t, J = 5.2 Hz, 1H), 3.03 (q, J = 6.4 Hz, 2H), 2.95 (q, J = 6.4 Hz, 2H), 2.46 (t, J = 6.4 Hz, 2H), 2.31 (t, J = 6.8 Hz, 2H), 2.15 (s, 3H), 1.56 - 1.46 (m, 2H ), 1.36 (s, 9H); LCMS: m/z 359.9 (M+H)+. [0491] Preparation of benzyl (3-((tert-butoxycarbonyl)amino)propyl)(2-((4-chloro-3-fluoroph enyl)amino)ethyl)carbamate (J13)
Figure imgf000127_0003
[0492] J13 was prepared as a colorless oil with similar methods as J3 using 4-chloro-3-fluoro -aniline to replace 3-chloro-4-fluoro-aniline.1H NMR (400 MHz, DMSO-d6) δ = 7.40 - 7.27 ( m, 5H), 6.77 (s, 1H), 6.50 - 6.39 (m, 1H), 6.19 (t, J = 5.6 Hz, 1H), 5.06 (d, J = 11.2 Hz, 2H), 3.29 (s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 3.17 (d, J = 5.2 Hz, 2H), 2.89 (d, J = 4.8 Hz, 2H), 2.52 ( d, J = 2.0 Hz, 2H), 1.65 - 1.55 (m, 2H), 1.36 (s, 9H); LCMS: m/z (M+H)+. [0493] Preparation of benzyl N-[3-(tert-butoxycarbonylamino)propyl]-N-[2-(3,4-dichloroanil ino)ethyl]carbamate (J14)
Figure imgf000127_0001
[0494] J14 was prepared as a brown gum with similar methods as J3 using 3,4-dichloroaniline to replace 3-chloro-4-fluoro-aniline.1H NMR (400 MHz, DMSO-d6) δ = 7.34 (d, J = 7.2 Hz, 5H), 7.25 - 7.07 (m, 1H), 6.84 - 6.69 (m, 2H), 6.63 - 6.44 (m, 1H), 6.16 (s, 1H), 5.06 (s, 2H), 3.32 - 3.15 (m, 6H), 2.89 (br s, 2H), 1.65 - 1.56 (m, 2H), 1.36 (s, 9H); LCMS: m/z 496.0 (M+H)+. [0495] Preparation of tert-butyl N-[3-[benzyloxycarbonyl-[2-(3-chloro-4-fluoro- anilino)ethyl]amino]propyl]-N-methyl-carbamate (J15)
Figure imgf000127_0002
[0496] J15 was prepared as a colorless oil with similar methods as J3 using tert-butyl N-(3- aminopropyl)-N-methyl-carbamate to tert-butyl N-(3-aminopropyl)-carbamate.1H NMR (400 MHz, DMSO- d6) δ = 7.44 - 7.26 (m, 5H), 7.13 - 6.91 (m, 1H), 6.76 - 6.60 (m, 1H), 6.60 - 6.39 (m, 1H), 5.89 (s, 1H), 5.07 (s, 2H), 3.35 - 3.10 (m, 8H), 2.78 - 2.61 (m, 3H), 1.74 - 1.62 (m, 2H), 1.36 (s, 9H); LCMS: m/z 494.0 (M+H)+.
Figure imgf000128_0001
[0497] J16 was prepared as a colorless oil with similar methods as J3 using 3,4-dichloro-2- fluoro-aniline to replace 3-chloro-4-fluoro-aniline.1H NMR (400 MHz, DMSO-d6) δ = 7.37 - 7.30 (m, 5H), 6.76 (s, 1H), 6.09 - 5.98 (m, 1H), 5.04 (d, J = 16.4 Hz, 2H), 3.31 (s, 3H), 2.88 (d, J = 2.8 Hz, 2H), 1.67 - 1.53 (m, 2H), 1.35 (s, 9H); LCMS: m/z 513.9 (M+H)+. [0498] Preparation of methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole-3-carboxylate (K1)
Figure imgf000128_0002
[0499] Step 1. To a solution of TEA (48.0 g, 475 mmol, 66.1 mL, 2.25 eq) in MeOH (300 mL) and H2O (150 mL) was added methylhydrazine sulfuric acid (30.4 g, 211 mmol, 1 eq). The mixture was stirred at 25 °C for 1 hour. Then dimethyl but-2-ynedioate (30.0 g, 211 mmol, 1 eq) was added and the mixture was stirred at 70 °C for 13 hours. The reaction mixture was concentrated in vacuum to remove MeOH. The crude product was triturated with H2O (200 mL) at 25 °C for 1 hour. Then the filter cake was triturated with MeOH (100 mL) at 25 °C for 1 hour. The filter cake was dried in vacuum to afford methyl 5-hydroxy-2-methyl-pyrazole-3- carboxylate (18.0 g, 115 mmol, 54.6% yield, 100% purity) as a white solid. [0500] Step 2. To a mixture of methyl 5-hydroxy-2-methyl-pyrazole-3-carboxylate (8.00 g, 51.2 mmol, 1 eq) in DCM (100 mL) was added pyridine (4.86 g, 61.4 mmol, 4.96 mL, 1.2 eq) at 0 °C, followed by Tf2O (15.9 g, 56.3 mmol, 9.30 mL, 1.1 eq) dropwise at 0 °C, the mixture was stirred at 25 °C for 2 hours. The reaction mixture was partitioned between H2O (30 mL) and DCM (60 mL * 2). The organic phase was separated, washed with brine (50 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford compound methyl 2- methyl-5-(trifluoromethylsulfonyloxy)pyrazole-3-carboxylate (13.4 g, 45.0 mmol, 87.8% yield, 96.8% purity) as a white solid. LCMS: m/z 289.0 (M+H)+. [0501] Step 3. A mixture of methyl 2-methyl-5-(trifluoromethylsulfonyloxy)pyrazole-3- carboxylate (13.4 g, 46.5 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (13.0 g, 51.1 mmol, 1.1 eq), KOAc (13.6 g, 139 mmol, 3 eq), Pd(dppf)Cl2 (3.40 g, 4.65 mmol, 0.1 eq) in dioxane (150 mL) was degassed and purged with N2 for 3 hours, and then the mixture was stirred at 100 °C for 16 hours under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography to afford methyl 2-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate (14.0 g, crude) as a white solid.1H NMR (400 MHz, CDCl3-d) δ = 7.22 - 7.22 (m, 1H), 7.23 (s, 1H), 4.22 (s, 3H), 3.85 (s, 3H), 1.34 (s, 12H). [0502] Preparation of 5-borono-2-methyl-pyrazole-3-carboxylic acid (K2)
Figure imgf000129_0001
[0503] To a solution of methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole-3-carboxylate (2 g, 7.52 mmol, 1 eq) in THF (40 mL) was added LiOH (360 mg, 15.0 mmol, 2 eq) and H2O (10 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give 5-borono-2-methyl-pyrazole-3-carboxylic acid (3 g, crude) as white solid and used for next step directly. LCMS: m/z 619.2 (M+H)+. [0504] Preparation of methyl 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3-carboxylate (M1)
Figure imgf000129_0002
[0505] A mixture of 6-bromo-4-chloro-quinoline (5.00 g, 20.6 mmol, 1 eq), methyl 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate (6.04 g, 22.6 mmol, 1.1 eq), Pd(dppf)Cl2·CH2Cl2 (1.68 g, 2.06 mmol, 0.1 eq) and K2CO3 (7.12 g, 51.5 mmol, 2.5 eq) in dioxane (60 mL) and H2O (6 mL) was stirred at 80 °C for 4 hours under N2. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na2SO4. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=10/0 to 3/1) to afford methyl 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3-carboxylate (M1, 5.60 g, 18.0 mmol, 87.40% yield) as a white solid. LCMS: m/z 302.0 (M+H)+. [0506] Preparation of methyl 5-(8-chloro-1,5-naphthyridin-2-yl)-2-methyl-pyrazole-3- carboxylate (M2)
Figure imgf000130_0001
[0507] Step 1. To a solution of 6-chloropyridin-3-amine (5 g, 38.9 mmol, 1 eq) in i-PrOH (100 mL) was added 5-(methoxymethylene)-2, 2-dimethyl-1,3-dioxane-4,6-dione (7.24 g, 38.9 mmol, 1 eq). The mixture was stirred at 80 °C for 5 hours, cooled to room temperature, and concentrated to provide 5-[[(6-chloro-3-pyridyl) amino] methylene]-2,2-dimethyl-1,3- dioxane-4,6-dione (8.8 g, 30.8 mmol, 79 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.29 (d, J = 14.4 Hz, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 14.4 Hz, 1H), 8.11 (dd, J = 2.8, 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 1.68 (s, 6H); LCMS: m/z 282.9 (M+H)+. [0508] Step 2. Diphenylether (400 mL) was heated to 220 °C and 5-[[(6-chloro-3- pyridyl)amino]methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (8.8 g, 31.1 mmol, 1 eq) was added into the mixture by portions. After finishing the addition, the mixture was stirred at 220 °C for 10 minutes. After the reaction was completed, the reaction solution was cooled to room temperature, and petroleum ether (1 L) was added into the reaction mixture to precipitate out a large amount of solid. The precipitate was collected via filtration, washed with petroleum ether, and dried under reduced pressure. The crude product was triturated with ethyl acetate (30 mL) at 25 °C to provide 6-chloro-1, 5-naphthyridin-4-ol (3.4 g, 16.9 mmol, 54% yield) was obtained as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.11 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 - 7.58 (m, 1H), 7.39 - 7.31 (m, 2H), 6.68 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.30 (s, 4H), 2.88 - 2.81 (m, 2H), 1.93 - 1.82 (m, 2H); LCMS: 181.1 (M+H)+. [0509] Step 3. To a solution of 6-chloro-1,5-naphthyridin-4-ol (1.6 g, 8.86 mmol, 1 eq) in ACN (15 mL) was added dropwise TMSBr (10.9 g, 70.9 mmol, 8 eq). The mixture was stirred at 85 °C for 16 hours. The mixture was cooled and filtered. The filtrate was concentrated to give 6-bromo-1, 5-naphthyridin-4-ol (2.8 g, crude) as brown solid. LCMS: 226.7 (M+H)+. [0510] Step 4. To a solution of 6-bromo-1, 5-naphthyridin-4-ol (2.8 g, 12.4 mmol, 1 eq) in toluene (30 mL) was added DIEA (6.43 g, 49.8 mmol, 8.7 mL, 4 eq) and POCl3 (5.72 g, 37.3 mmol, 3.47 mL, 3 eq). The mixture was stirred at 110 °C for 2 hours, cooled and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether/Ethyl acetate=0:1 to 1:1) to give 2-bromo-8-chloro-1, 5-naphthyridine (1.7 g, 5.93 mmol, 47.7% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.99 - 8.93 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.10 - 8.02 (m, 2H); LCMS: 244.8 (M+H)+. [0511] Step 5. A mixture of 2-bromo-8-chloro-1,5-naphthyridine (1.7 g, 6.98 mmol, 1 eq), methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-carboxylate (2.42 g, 9.08 mmol, 1.3 eq), KOAc (2.06 g, 21 mmol, 3 eq), Pd(dppf)Cl2.CH2Cl2 (570 mg, 698 umol, 0.1 eq) in dioxane (20 mL) and H2O (10 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 70 °C for 16 hours under N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (30 mL × 3) and water (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 0:1) to give methyl 5- (8-chloro-1,5-naphthyridin-2-yl)-2-methyl-pyrazole-3-carboxylate (800 mg, 2.40 mmol, 34% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.11 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 - 7.58 (m, 1H), 7.39 - 7.31 (m, 2H), 6.68 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.30 (s, 4H), 2.88 - 2.81 (m, 2H), 1.93 - 1.82 (m, 2H); LCMS: m/z 303.0 (M+H)+. [0512] Preparation of 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one (Ex.1)
Figure imgf000132_0001
[0513] Step 1. A mixture of 8-bromo-2-methoxy-1,5-naphthyridine (120 mg, 0.502 mmol, 1.00 eq), tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]carbamate (192 mg, 0.552 mmol, 1.10 eq), RuPhos Pd G3 (42.0 mg, 0.0502 mmol, 0.10 eq) and Cs2CO3 (491 mg, 1.51 mmol, 3.00 eq) in toluene (3.00 mL) was stirred at 110 °C for 20 hours under N2. On completion, the mixture was concentrated in vacuum. The mixture was purified by prep-TLC (Petroleum ether : Ethyl acetate=1:1) to give tert-butyl N-[3-[2-(3-chloro-4-fluoro-N-(6- methoxy-1,5-naphthyridin-4-yl)anilino)ethoxy]propyl]carbamate (70.0 mg, 0.139 mmol, 27.6% yield) as a yellow solid. LCMS: m/z 505.2 (M+H)+. [0514] Step 2. To a mixture of tert-butyl N-[3-[2-(3-chloro-4-fluoro-N-(6-methoxy-1,5- naphthyridin-4-yl)anilino)ethoxy]propyl]carbamate (115 mg, 0.228 mmol, 1.00 eq) in DCM (1.00 mL) was added a solution of HBr (1.49 g, 6.08 mmol, 1.00 mL, 33% purity, 27.0 eq) in HOAc slowly. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated in vacuum to give 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]-1,5-naphthyridin- 2-ol (105 mg, crude, HBr) as a yellow solid. LCMS : m/z 391.1 (M+1)+. [0515] Step 3. To a solution of 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]- 1,5-naphthyridin-2-ol (105 mg, 0.223 mmol, 1.00 eq, HBr) and DIEA (144 mg, 1.11 mmol, 0.194 mL, 5.00 eq) in DCM (2.00 mL) was added Boc2O (97.2 mg, 0.445 mmol, 0.102 mL, 2.00 eq) slowly. The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuum. The residue was purified by prep-TLC (Ethyl acetate) to give tert- butyl N-[3-[2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin-4- yl)anilino)ethoxy]propyl]carbamate (105 mg, 0.210 mmol, 94.4% yield) as a yellow solid. LCMS : m/z 491.2 (M+H)+. [0516] Step 4. To a solution of tert-butyl N-[3-[2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5- naphthyridin-4-yl)anilino)ethoxy]propyl]carbamate (105 mg, 0.214 mmol, 1.00 eq), 2,6- dimethylpyridine (920 mg, 8.59 mmol, 1.00 mL, 40.0 eq) and DMAP (52.0 mg, 0.428 mmol, 2.00 eq) in DCM (1.00 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (121 mg, 0.428 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 20 °C for 20 hours. On completion, to the mixture was added DCM (10.0 mL). The organic phase was washed with water (10.0 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether/Ethyl acetate=1/1) to give [8-[N-[2-[3- (tert-butoxycarbonylamino)-propoxy]ethyl]-3-chloro-4-fluoro-anilino]-1,5-naphthyridin-2- yl] trifluoromethanesulfonate (70.0 mg, 0.109 mmol, 51.1% yield) as a yellow solid. LCMS: m/z 623.1 (M+H)+. [0517] Step 5. A mixture of [8-[N-[2-[3-(tert-butoxycarbonylamino)propoxy]ethyl]-3-chloro- 4-fluoro-anilino]-1,5-naphthyridin-2-yl] trifluoromethanesulfonate (70.0 mg, 0.112 mmol, 1.00 eq), Pd(dppf)Cl2 (17.0 mg, 0.0225 mmol, 0.2 eq), TEA (510 mg, 5.03 mmol, 45.0 eq) in DMF (5.00 mL) and MeOH (10.0 mL) was stirred at 80 °C for 12 hours under CO (50 psi). On completion, the mixture was concentrated in vacuum and purified by prep-TLC (Petroleum ether : Ethyl acetate=1:3) to give methyl 8-[N-[2-[3-(tert- butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]-1,5-naphthyridine-2- carboxylate (60.0 mg, 0.110 mmol, 98.3% yield) as a yellow solid. LCMS: m/z 533.2 (M+1)+. [0518] Step 6-1. To a mixture of methyl 8-[N-[2-[3-(tert- butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]-1,5-naphthyridine-2- carboxylate (60.0 mg, 0.113 mmol, 1.00 eq) in MeOH (3.00 mL) and H2O (1.00 mL) was added LiOH•H2O (23.6 mg, 0.563 mmol, 5.00 eq). The mixture was stirred at 25 °C for 2 hours. On completion, MeOH was removed in vacuum. To the mixture was added water (5.00 mL) and HCl (1 N) until pH=5 ~ 6. The mixture was extracted with DCM (15.0 mL * 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 8-[N-[2-[3-(tert-butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro- anilino]-1,5-naphthyridine-2-carboxylic acid (50.0 mg, 0.0964 mmol, 85.6% yield) as a yellow solid. LCMS: m/z 519.2 (M+1)+. [0519] Step 6-2. To a mixture of 8-[N-[2-[3-(tert-butoxycarbonylamino)propoxy]ethyl]-3- chloro-4-fluoro-anilino]-1,5-naphthyridine-2-carboxylic acid (50.0 mg, 0.0964 mmol, 1.00 eq) and DCM (2.00 mL) was added HCl/dioxane (4 M, 1.72 mL, 71.6 eq) slowly at 0 °C. The mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuum to give 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]-1,5- naphthyridine-2-carboxylic acid (43.0 mg, 94.4 umol, 98.0% yield, HCl) as a yellow solid. LCMS: m/z 419.1 (M+H)+. [0520] Step 7. To a mixture of 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]- 1,5-naphthyridine-2-carboxylic acid (37.0 mg, 0.0813 mmol, 1.00 eq, HCl) in DCM (2.00 mL) was added DIEA (110 mg, 0.850 mmol, 10.0 eq) slowly, followed by FDPP (38.0 mg, 0.0975 mmol, 1.20 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuum. The mixture was purified by prep-HPLC to give Ex. 1 (14.7 mg, 0.0358 mmol, 44.1% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.00 - 9.83 (m, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.51 - 7.45 (m, 1H), 7.41 - 7.32 (m, 1H), 6.76 (d, J = 5.2 Hz, 1H), 4.48 - 4.31 (m, 2H), 3.89 (br s, 2H), 3.79 (br s, 2H), 3.53 - 3.46 (m, 2H), 1.88 - 1.80 (m, 2H); LCMS: m/z 401.1 (M+H)+. [0521] Preparation of 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido-[4,3-e][1,4,10]oxadiazacyclotridecin-9(1H)-one (Ex.2)
Figure imgf000134_0001
Figure imgf000135_0001
[0522] Step 1. A mixture of tert-butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]- propyl]carbamate (90 mg mg, 0.260 mmol, 1.15 eq), methyl 4-chloroquinoline-6-carboxylate (50.0 mg, 0.226 mmol, 1.00 eq), Pd2(dba)3 (15.0 mg, 0.016.4 mmol, 0.07 eq), tritert- butylphosphonium;tetrafluoroborate (10.0 mg, 0.0345 mmol, 0.15 eq) and K2CO3 (94.0 mg, 0.680 mmol, 3.01 eq) in toluene (2.00 mL) was stirred at 110 °C for 15 hours under N2. On completion, the mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/1 to 1/1) to give methyl 4-[N-[2-[3-(tert- butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]quinoline-6-carboxylate (2- 2, 75.0 mg, 0.124 mmol, 54.9% yield) as a yellow gum. 1H NMR (400 MHz, CDCl3-d) δ = 8.89 - 8.74 (m, 1H), 8.44 - 8.35 (m, 1H), 8.20 - 7.97 (m, 2H), 7.24 (br d, J = 5.2 Hz, 1H), 7.04 - 6.86 (m, 2H), 6.79 - 6.60 (m, 1H), 4.76 - 4.56 (m, 1H), 4.04 (br t, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.57 (t, J = 5.2 Hz, 2H), 3.38 (t, J = 6.0 Hz, 2H), 3.16 - 3.01 (m, 2H), 1.68 - 1.61 (m, 2H), 1.32 (s, 9H); LCMS: 532.2 (M+H)+. [0523] Ex.2 was prepared from 2-2 after hydrolysis of ester, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex.1.1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 8.82 – 8.11 (m, 2H), 8.04 – 7.68 (m, 2H), 7.46 – 7.14 (m, 2H), 7.14 – 6.31 (m, 2H), 4.18 – 3.86 (m, 2H), 3.80 (br s, 2H), 3.72 – 3.49 (m, 2H), 3.47 – 3.37 (m, 2H), 1.79 – 1.63 (m, 2H). LCMS: m/z 400.0 (M+H)+. [0524] Preparation of 15-(3-chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6- ethenopyrimido[4,5-e][1,4,10]oxadiazacyclotridecin-7(13H)-one (Ex.35)
Figure imgf000135_0002
[0525] Ex 35 was prepared using similar procedures as Ex. 2 using methyl 4- chloroquinazoline-6-carboxylate to replace methyl 4-chloroquinoline-6-carboxylate in Step 1. 1H NMR (400 MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.74 (s, 1H), 8.35 (dd, J = 1.6, 5.6 Hz, 1H), 8.11 (br d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 2.4, 6.4 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.41 - 7.37 (m, 1H), 4.72 (s, 2H), 4.40 (s, 2H), 3.92 (s, 2H), 3.76 (br d, J = 2.0 Hz, 2H), 1.88 - 1.83 (m, 1H). LCMS: m/z 401.1 (M+H)+. [0526] Preparation of 1-(3-chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H- 14,16-etheno-13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one (Ex.36)
Figure imgf000136_0001
[0527] A mixture of methyl 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3-carboxylate (M1, 200 mg, 0.663 mmol, 1 eq), tert-butyl N-[3-[2-(3-chloro-4-fluoro- anilino)ethoxy]propyl]carbamate (J1, 300 mg, 0.865 mmol, 1.3 eq), RuPhos-Pd-G3 (55.4 mg, 0.0663 mmol, 0.1 eq), Cs2CO3 (647.91 mg, 1.99 mmol, 3 eq) and in toluene (8 mL) was stirred at 110 °C for 16 hours under N2 atmosphere. The reaction mixture was concentrated in vacuum. The residue was purified by prep-HPLC to afford methyl 5-[4-[N-[2-[3-(tert- butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolyl]-2-methyl- pyrazole-3-carboxylate (110 mg, 0.180 mmol, 27.1% yield) as a yellow solid.1H NMR (400 MHz, CDCl3-d) δ = 8.84 - 8.54 (m, 2H), 8.36 - 8.07 (m, 1H), 8.02 - 7.79 (m, 1H), 7.60 (br d, J = 5.2 Hz, 1H), 7.54 - 7.28 (m, 1H), 7.25 - 7.03 (m, 2H), 6.81 (s, 1H), 5.31 (s, 1H), 4.32 (br d, J = 1.2 Hz, 1H), 4.22 - 4.12 (m, 3H), 3.94 (s, 3H), 3.74 (br s, 2H), 3.61 - 3.45 (m, 3H), 3.19 (br d, J = 5.6 Hz, 2H), 2.37 - 2.16 (m, 1H), 1.93 - 1.69 (m, 9H), 1.65 - 1.53 (m, 1H). LCMS: m/z 612.3 ( M+H)+. [0528] 36-1 was further converted to Ex 36 after hydrolysis, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex.1.1H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.23 - 8.15 (m, 2H), 8.09 - 8.00 (m, 1H), 7.60 - 7.44 (m, 2H), 7.43 - 7.28 (m, 1H), 7.23 - 7.14 (m, 1H), 6.70 - 6.62 (m, 1H), 4.08 (s, 3H), 3.99 (br s, 2H), 3.70 (br s, 2H), 3.47 - 3.46 (m, 4H), 2.03 - 1.97 (m, 2H). LCMS: m/z 480.2 (M+H)+. [0529] Preparation of 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro- 9H-14,16-etheno-13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9- one (Ex.37)
Figure imgf000137_0002
[0530] Ex 37 was prepared using similar methods as Ex.36 using J2 in Step 1.1H NMR (400 MHz, DMSO-d6) δ = 8.97 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.20 (dd, J = 1.6, 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 2.8, 6.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.21 (td, J = 3.6, 8.8 Hz, 1H), 6.69 (d, J = 4.8 Hz, 1H), 4.04 (s, 3H), 3.98 (br s, 2H), 3.69 (br s, 4H), 3.49 (br s, 2H), 3.01 (s, 3H), 2.16 (br d, J = 5.2 Hz, 2H) LCMS: m/z 494.2 (M+H)+. [0531] Preparation of 1-(3-chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro- 14,16-etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one (Ex.38)
Figure imgf000137_0001
[0532] 38-1 was prepared following similar methods as Ex.36 using J3 to replace J1. [0533] To a solution of 38-1 (50 mg, 0.0814 mmol, 1 eq) in DCM (3 mL) was added HBr/AcOH (1 mL). The mixture was stirred at 25 °C for 1 hour and then partitioned between dichloromethane (5 mL × 3) and water (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by reversed-phase HPLC to provide Ex.38 (4.04 mg, 0.0842 mmol, 10 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 5.2 Hz, 1H), 8.36 - 8.27 (m, 2H), 7.95 (t, J = 7.6 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.64 (s, 1H), 7.57 - 7.47 (m, 1H), 7.41 (dd, J = 4.0, 6.8 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 4.38 (d, J = 7.6 Hz, 2H), 4.10 (s, 3H), 3.54 - 3.48 (m, 2H), 3.11 - 3.05 (m, 2H), 2.65 (d, J = 4.4 Hz, 2H), 1.70 - 1.63 (m, 2H); LCMS: m/z 480.2 (M+1:480.2). [0534] Preparation of 1-(3-chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro- 13,15-etheno-12,9-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecin-8(5H)-one (Ex.39)
Figure imgf000138_0001
[0535] Ex 39 was prepared using similar methods as Ex.36 using J4 to replace J1.1H NMR (400 MHz, DMSO-d6) δ = 8.86 - 8.67 (m, 1H), 8.10 - 7.80 (m, 3H), 7.50 - 7.30 (m, 1H), 7.12 - 6.91 (m, 2H), 6.71 - 6.47 (m, 2H), 4.14 - 3.97 (m, 2H), 3.67 (s, 3H), 3.61 - 3.39 (m, 6H), 2.91 - 2.79 (m, 3H); LCMS: m/z 480.2 (M+H)+. [0536] Preparation of 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro- 2H-14,16-etheno-13,10-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacycloheptadecin- 7(6H)-one (Ex.40)
Figure imgf000139_0001
[0537] Step 1. To a mixture of methyl 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3- carboxylate (2.00 g, 6.63 mmol, 1 eq) and CaCl2 (2.21 g, 19.89 mmol, 3 eq) in EtOH (40 mL) was added NaBH4 (501 mg, 13.3 mmol, 2 eq) at 0 °C slowly. The mixture was stirred at 25 °C for 12 hours. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to afford compound [5-(4-chloro-6-quinolyl)-2-methyl- pyrazol-3-yl]methanol (1.70 g, 5.96 mmol, 89.8% yield) as a white solid. LCMS: m/z 274.1 ( M+H)+. [0538] Step 2. To a mixture of [5-(4-chloro-6-quinolyl)-2-methyl-pyrazol-3-yl]methanol (1.30 g, 4.75 mmol, 1 eq) and TEA (1.44 g, 14.3 mmol, 1.98 mL, 3 eq) in DCM (13 mL) was added MsCl (670 mg, 5.85 mmol, 1.23 eq) at 0 °C, the mixture was stirred at 25 °C for 1 hour. Additional MsCl (652 mg, 5.70 mmol,1.2 eq) was added at 0 °C and the mixture was stirred at 25 °C for another 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to provide 4-chloro- 6-[5-(chloromethyl)-1-methyl-pyrazol-3-yl]quinoline (1.60 g, 4.69 mmol, 98.8% yield, 85.7% purity) as a yellow solid. LCMS: m/z 291.9 ( M+H)+. [0539] Step 3. To a mixture of 4-chloro-6-[5-(chloromethyl)-1-methyl-pyrazol-3-yl]quinoline (1.33 g, 4.55 mmol, 1 eq) in THF (20 mL) was added MeNH2 (2 M, 30 mL, 13.2 eq), the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuum to afford 1-[5-(4-chloro-6-quinolyl)-2-methyl-pyrazol-3-yl]-N-methyl-methanamine (1.20 g, 3.85 mmol, 84.6% yield) as a yellow solid. LCMS: m/z 287.1 ( M+H)+. [0540] Step 4. To a mixture of 1-[5-(4-chloro-6-quinolyl)-2-methyl-pyrazol-3-yl]-N-methyl- methanamine (1.15 g, 4.01 mmol, 1 eq) in DCM (12 mL) was added DIEA (1.55 g, 12.0 mmol, 2.09 mL, 3 eq). The mixture was stirred at 0 °C. Then Boc2O (2.62 g, 12.0 mmol, 2.76 mL, 3 eq) was added, the mixture was stirred at 25 °C for 2 hours. The reaction filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford tert-butyl N-[[5-(4-chloro-6-quinolyl)-2-methyl-pyrazol-3- yl]methyl]-N-methyl-carbamate (720 mg, 1.75 mmol, 43.6% yield, 94.0% purity) was a yellow oil. LCMS: m/z 388.1 (M+H)+. [0541] Step 5. To a mixture of tert-butyl N-[[5-(4-chloro-6-quinolyl)-2-methyl-pyrazol-3- yl]methyl]-N-methyl-carbamate (300 mg, 0.775 mmol, 1 eq) and ethyl 2-[3-(3-chloro-4- fluoro-anilino)propoxy]acetate (270 mg, 0.931 mmol, 1.20 eq) in toluene (5 mL) was added Cs2CO3 (757 mg, 2.33 mmol, 3 eq) and RuPhos Pd G3 (64.0 mg, 0.0775 mmol, 0.1 eq). The mixture was stirred at 120 °C for 12 hours under N2. The reaction was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/0 to 1/1) to afford ethyl 2-[3-(N-[6-[5-[[tert- butoxycarbonyl(methyl)amino]methyl]-1-methyl-pyrazol-3-yl]-4-quinolyl]-3-chloro-4- fluoro-anilino)propoxy]acetate (68.0 mg, 0.957 mmol, 12.3% yield) as a yellow oil. LCMS: m/z 640.4 (M+H)+. [0542] Ex.40 was obtained from 40-5 after hydrolysis of ester, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex. 1.1H NMR (400 MHz, DMSO-d6) δ = 8.64 - 8.55 (m, 1H), 8.34 (s, 1H), 8.31 - 8.24 (m, 1H), 8.21 (br d, J = 8.4 Hz, 1H), 8.05 (br d, J = 8.8 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.50 - 7.41 (m, 1H), 7.36 - 7.30 (m, 1H), 6.81 (br d, J = 5.2 Hz, 1H), 6.53 (s, 1H), 5.17 (br d, J = 16.8 Hz, 1H), 4.74 (br d, J = 12.8 Hz, 1H), 4.15 - 4.00 (m, 2H), 3.89 (s, 3H), 3.80 - 3.66 (m, 3H), 3.64 - 3.55 (m, 5H), 2.67 - 2.65 (m, 2H). LCMS: m/z 480.2 (M+H)+. [0543] Preparation of 7-chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-etheno- 19,16-(metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one (Ex.41)
Figure imgf000141_0001
[0544] 41-1 was prepared using a similar method as 2-2 in Ex.2.41-1 was converted to 41-4 in three steps using the methods as conversion of 1-2 to 1-5 in Ex. 1. 41-4 was coupled with K1 to provide 41-5 using a similar method as 36-1 to 36-2 in Ex.36. Ex.41 was obtained from 41-5 after hydrolysis of ester, de-Boc, and macrocyclic amide formation as described in the conversion of 1-6 to Ex.1.1H NMR (400 MHz, DMSO-d6) δ = 9.61 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.64 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 5.32 (s, 2H), 4.72 (s, 2H), 4.15 (s, 3H), 3.94 (br t, J = 7.2 Hz, 2H). LCMS: m/z 453.2 (M+H)+. [0545] Preparation of N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16- etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)- yl]benzamide (Ex.42)
Figure imgf000142_0001
Figure imgf000143_0001
[0546] Step 1. To a solution of 6-chloroquinolin-4-ol (1 g, 5.57 mmol, 1 eq) in DMF (15 mL) was added PBr3 (1.96 g, 7.24 mmol, 1.3 eq) at 0 °C. The reaction was stirred at 20 °C for 2 hours. The reaction mixture was poured into 50 mL of water and solid was filtered to give 4- bromo-6-chloro-quinoline (0.85 g, 3.15 mmol, 56% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.74 (d, J = 4.4 Hz, 1H), 8.12 - 8.07 (m, 2H), 7.99 (d, J = 4.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H) [0547] Step 2. A solution of 4-bromo-6-chloro-quinoline (200 mg, 0.824 mmol, 1 eq), methyl 3-[2-[benzyloxycarbonyl-[3-(tert-butoxycarbonylamino)propyl]amino]ethylamino]benzoate (400 mg, 0.824 mmol, 1 eq), RuPhos Pd G3 (68.8 mg, 0.0824 mmol, 0.1 eq) and Cs2CO3 (805.2 mg, 2.28 mmol, 3 eq) in toluene (8 mL) was stirred at 120 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give methyl 3-[2-[benzyloxycarbonyl-[3-(tert- butoxycarbonylamino)propyl]amino]ethyl-(6-chloro-4-quinolyl)amino]benzoate (160 mg, 123.6 umol, 30% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.98 - 8.76 (m, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.59 - 7.40 (m, 3H), 7.32 - 7.18 (m, 6H), 7.00 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.98 (s, 2H), 4.14 - 4.03 (m, 2H), 3.75 (s, 3H), 3.55 (d, J = 6.4 Hz, 2H), 3.23 - 3.08 (m, 2H), 2.84 (d, J = 6.8 Hz, 2H), 1.55 (d, J = 5.6 Hz, 2H), 1.37 - 1.27 (m, 9H) [0548] Step 3. A solution of methyl 3-[2-[benzyloxycarbonyl-[3-(tert- butoxycarbonylamino)propyl]amino]ethyl-(6-chloro-4-quinolyl)amino]benzoate (160 mg, 0.243 mmol, 1 eq) in DCM (5 mL) and HCl/dioxane (2 mL) was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated to give the crude methyl 3-[2-[3- aminopropyl(benzyloxycarbonyl)amino]ethyl-(6-chloro-4-quinolyl)amino]benzoate (170 mg, crude) as a yellow oil. [0549] Step 4. To a solution of methyl 3-[2-[3-aminopropyl(benzyloxycarbonyl)amino]ethyl- (6-chloro-4-quinolyl)amino]benzoate (170 mg, 0.310 mmol, 1 eq), 3-borono-1-methyl-1H- pyrazole-5-carboxylic acid (118 mg, 0.696 mmol, 2.24 eq) and DIEA (80.3 mg, 0.621 mmol, 2 eq) in DMF (20 mL) was added T3P (148 mg, 0.466 mmol, 1.5 eq). The reaction was stirred at 20 °C for 0.5 hour. The reaction without work-up and used for next step directly. [0550] Step 5. A solution of [5-[3-[benzyloxycarbonyl-[2-(N-(6-chloro-4-quinolyl)-3- methoxycarbonyl-anilino)ethyl]amino]propylcarbamoyl]-1-methyl-pyrazol-3-yl]boronic acid (175 mg, 0.279 mmol, 1 eq), K3PO4 (179.6 mg, 3 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (21.9 mg, 0.1 eq) in THF (20 mL) and H2O (4 mL) was stirred at 70 °C for 1 hour. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/1 to 1/0) to give 42-6 (75 mg, 39.9% yield) as a yellow solid. LCMS: m/z 619.2) (M+H)+. [0551] Step 6. A solution of 42-6 (25 mg, 0.0404 mmol, 1 eq) and LiOH.H2O (3.39 mg, 0.0808 mmol, 2 eq) in THF (1 mL), MeOH (1 mL) and H2O (0.5 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give the crude 42-7 (25 mg, crude) as a yellow solid. [0552] Step 7. To a solution of 42-7 (25 mg, 0.0413 mmol, 1 eq) and cyclopropanamine (4.72 mg, 0.0826 mmol, 2 eq) in THF (1 mL) was added DIEA (10.6 mg, 0.0826 mmol, 2 eq) and T3P (19.7 mg, 0.062.0 mmol, 1.5 eq). The reaction was stirred at 20 °C for 0.5 hour. The reaction mixture was diluted with aq NaHCO3 (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude 42-8 (27 mg, crude) as a yellow solid. [0553] Step 8. To a solution of 42-8 (27 mg, 0.0419 mmol, 1 eq) in DCM (3 mL) was added HBr/HOAc (0.5 mL). The reaction was stirred at 20 °C for 0.5 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to provide Ex. 42 (1.86 mg, 0.0335 umol, 7.98% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.36 (s, 2H), 8.23 (d, J = 8.8 Hz, 1H), 8.10 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.41 - 7.36 (m, 1H), 6.62 (d, J = 5.2 Hz, 1H), 4.06 (s, 3H), 3.91 (d, J = 2.8 Hz, 2H), 3.44 (s, 2H), 2.87 (s, 3H), 2.80 (J = 3.6, 7.2 Hz, 2H), 1.87 (d, J = 8.0 Hz, 2H), 0.66 (d, J = 7.2 Hz, 2H), 0.58 - 0.49 (m, 2H); LCMS: m/z 510.2 (M+H)+. [0554] Preparation of 3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]-N-(propan-2- yl)benzamide (Ex.43)
Figure imgf000145_0001
[0555] Ex.43 was prepared following similar methods as Ex.42 using 2-propyamine for amide coupling with 42-7 in Step 7. 1H NMR (400 MHz, DMSO-d6) δ = 9.21 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.25 - 8.19 (m, 2H), 8.14 - 8.08 (m, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.67 - 7.60 (m, 2H), 7.48 - 7.42 (m, 1H), 7.41 - 7.37 (m, 1H), 6.62 (d, J = 4.8 Hz, 1H), 4.11 - 4.04 (m, 4H), 3.98 - 3.88 (m, 2H), 3.21 (d, J = 4.0 Hz, 4H), 2.87 ( s, 2H), 1.92 - 1.82 (m, 2H), 1.14 (d, J = 6.4 Hz, 6H); LCMS: m/z 512.5 (M+H)+. [0556] Preparation of N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide (Ex.44)
Figure imgf000145_0002
[0557] Ex.44 was prepared following similar methods as Ex.42 using methylamine for amide coupling with 42-7 in Step 7.1H NMR (400 MHz, DMSO-d6) δ = 9.22 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.49 - 8.37 (m, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.12 (t, J = 7.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.69 - 7.63 (m, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.41 - 7.34 (m, 1H), 6.65 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H), 3.99 - 3.86 (m, 2H), 3.25 (s, 4H), 2.93 - 2.85 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 1.93 - 1.84 (m, 2H); LCMS: m/z 484.2 (M+H)+. [0558] Preparation of 1-(3,4-dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro- 14,16-etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one (Ex.45)
Figure imgf000146_0001
[0559] Ex. 45 was prepared following similar methods as Ex. 36 using J8 to replace J1 followed by de-Cbz using the method as that in Ex. 38. 1H NMR (400 MHz, DMSO-d6) δ = 9.22 (d, J = 1.6 Hz, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.24 (dd, J = 1.6, 8.8 Hz, 1H), 8.12 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.68 - 7.58 (m, 2H), 6.77 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.91 (d, J = 0.8 Hz, 2H), 3.53 - 3.35 (m, 2H), 2.83 (s, 2H), 2.61 - 2.54 (m, 2H), 1.92 - 1.83 (m, 2H). LCMS: m/z 513.0 (M+H)+. [0560] Preparation of 1-(3-chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro- 14,16-etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one (Ex.46)
Figure imgf000146_0002
[0561] Ex. 46 was prepared following similar methods as Ex. 36 using J9 to replace J1 followed by de-Cbz using the method as that in Ex. 38. 1H NMR (400 MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.11 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 - 7.58 (m, 1H), 7.39 - 7.31 (m, 2H), 6.68 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.30 (s, 4H), 2.88 - 2.81 (m, 2H), 1.93 - 1.82 (m, 2H); LCMS: m/z 479.3 (M+H)+. [0562] Preparation of 2-[1-(3-chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11- octahydro-14,16-etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin- 8(9H)-yl]-N-methylacetamide (Ex.47)
Figure imgf000147_0001
[0563] 47-1 was prepared with similar methods as 36-1 in Ex.36 using J3 to replace J1. [0564] Step 1. To a solution of methyl 5-[4-[N-[2-[benzyloxycarbonyl-[3-(tert- butoxycarbonylamino)propyl]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolyl]-2-methyl- pyrazole-3-carboxylate (380 mg, 0.509 mmol, 1 eq) in DCM (2 mL) and HCl/dioxane (2 mL). The mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated to give a residue. The compound was used into the next step and without further purification to give methyl 5- [4-[N-[2-[3-aminopropyl(benzyloxycarbonyl)amino]ethyl]-4-chloro-3-fluoro-anilino]-6- quinolyl]-2-methyl-pyrazole-3-carboxylate (328 mg, 0.509 mmol, 100% yield) was obtained as yellow oil. [0565] Step 2. To a solution of methyl 5-[4-[N-[2-[3-aminopropyl(benzyloxycarbonyl)- amino]ethyl]-4-chloro-3-fluoro-anilino]-6-quinolyl]-2-methyl-pyrazole-3-carboxylate (289 mg, 0.448 mmol, 1 eq) and 2-bromo-N-methyl-acetamide (68.1 mg, 0.448 mmol, 1 eq) in DMSO (4 mL) was added DIEA (289 mg, 2.24 mmol, 5 eq). The mixture was stirred at 50 °C for 16 hr, quenched with water (40 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, EtOAc: MeOH = 1:0 to 1:1) to give methyl 5-[4-[N-[2-[benzyloxycarbonyl-[3-[[2-(methylamino)-2-oxo- ethyl]amino]propyl]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolyl]-2-methyl-pyrazole- 3-carboxylate (70 mg, 0.0661 mmol, 14% yield) as a yellow solid. LCMS: m/z 716.4 (MS+H)+. [0566] Step 3. To a solution of methyl 5-[4-[N-[2-[benzyloxycarbonyl-[3-[[2-(methylamino)- 2-oxo-ethyl]amino]propyl]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolyl]-2-methyl- pyrazole-3-carboxylate (70 mg, 0.0977 mmol, 1 eq) in MeOH (1 mL), H2O (0.5 mL) and THF (1 mL) was added LiOH.H2O (12.3 mg, 293 umol, 3 eq). The mixture was stirred at 25 °C for 0.5 hour. The mixture was concentrated to remove MeOH. The compound was used into the next step without further purification. [0567] Step 4. To a solution of 5-[4-[N-[2-[benzyloxycarbonyl-[3-[[2-(methylamino)-2-oxo- ethyl]amino]propyl]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolyl]-2-methyl-pyrazole- 3-carboxylic acid (68.6 mg, 0.0977 mmol, 1 eq) in THF (40 mL) was added T3P (46.6 mg, 0.146 mmol, 1.5 eq) and DIEA (37.9 mg, 0.293 mmol, 3 eq). The mixture was stirred at 0 °C for 3 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (SiO2, EtOAc: MeOH = 4:1) to give 47-5 (10 mg, 0.0139 mmol, 14% yield) as a white solid. LCMS: m/z 684.2 (MS+H)+. [0568] Step 5. To a solution of 47-5 (10 mg, 0.0146 mmol, 1 eq) in DCM (3 mL) and HBr/AcOH (1 mL). The mixture was stirred at 25 °C for 1 hour. the mixture was quenched with saturated solution of NaHCO3(10 mL) and extracted with dichloromethane(5 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give Ex. 47 (0.93 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.22 (d, J = 1.6 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.21 (dd, J = 1.6, 8.8 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.69 (s, 1H), 7.47 - 7.38 (m, 2H), 7.26 - 7.22 (m, 1H), 6.68 (d, J = 4.4 Hz, 1H), 4.02 (s, 3H), 3.86 (d, J = 4.4 Hz, 2H), 3.75 - 3.54 (m, 2H), 2.84 - 2.77 (m, 2H), 2.60 (s, 7H), 1.98-1.96 (m, 2H). LCMS: m/z 550.2 (MS+H)+. [0569] Preparation of 15-(3-chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15- octahydro-2,19-etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin- 7(5H)-one (Ex.48)
Figure imgf000149_0002
[0570] Ex. 48 was prepared as a yellow solid following similar methods as Ex.36 using M2 to replace M1 followed by de-Cbz using the method as that in Ex. 38. 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 5.2 Hz, 1H), 8.36 - 8.27 (m, 2H), 7.95 (t, J = 7.6 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.64 (s, 1H), 7.57 - 7.47 (m, 1H), 7.41 (dd, J = 4.0, 6.8 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 4.38 (d, J = 7.6 Hz, 2H), 4.10 (s, 3H), 3.54 - 3.48 (m, 2H), 3.11 - 3.05 (m, 2H), 2.65 (d, J = 4.4 Hz, 2H), 1.70 - 1.63 (m, 2H); LCMS: 480.2 (M+H)+. [0571] Preparation of N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11- ethenopyrido[4,3-e][1,9,4]dioxazacyclododecin-6-yl]prop-2-enamide (Ex.49)
Figure imgf000149_0001
Figure imgf000150_0001
[0572] Step 1. A solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-chloro-4-fluoro- aniline (1.7 g, 5.59 mmol, 1 eq) , 4-chloro-6-methoxy-quinoline (1.1 g, 5.68 mmol, 1.02 eq), RuPhos Pd G3 (200 mg, 0.239 mmol, 0.043 eq) and Cs2CO3 (5.47 g, 16.7 mmol, 3 eq) in Tol. (20 mL) was stirred at 120 °C for 12 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1to provide N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(3-chloro-4-fluoro-phenyl)-6- methoxy-quinolin-4-amine (2.2 g, 3.34 mmol, 59% yield, 70% purity) as a yellow oil. LCMS: m/z 461.4 (M+H)+. [0573] Step 2. A solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(3-chloro-4-fluoro- phenyl)-6-methoxy-quinolin-4-amine (2.2 g, 4.77 mmol, 1 eq) and CsF (2.17 g, 14.3 mmol, 3 eq) in DMSO (20 mL) was stirred at 20 °C for 12 hours. The reaction mixture was diluted with H2O (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to provide 2-(3-chloro-4-fluoro-N-(6-methoxy-4-quinolyl)anilino)ethanol (850 mg, 2.45 mmol, 51.37% yield) was obtained as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ = 8.73 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 2.8, 9.2 Hz, 1H), 7.20 (t, J = 9.2 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.65 (td, J = 3.6, 9.2 Hz, 1H), 4.94 (t, J = 5.2 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.64 - 3.58 (m, 5H); LCMS: m/z 346.8 (M+H)+. [0574] Step 3. To a solution of 2-(3-chloro-4-fluoro-N-(6-methoxy-4-quinolyl)anilino)ethanol (800 mg, 2.31 mmol, 1 eq) in DCM (20 mL) was added BBr3 (1 M, 6.92 mL, 3 eq) at 0 °C. The reaction was stirred at 20 °C for 12 hours under N2. The reaction mixture was quenched by added aq NaHCO3 (10 mL). The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide 4-[3- chloro-4-fluoro-N-(2-hydroxyethyl)anilino]quinolin-6-ol (600 mg, 1.73 mmol, 75.03% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 4.4 Hz, 1H), 7.25 (dd, J = 2.4, 9.2 Hz, 1H), 7.16 (t, J = 9.2 Hz, 1H), 6.89 (dd, J = 3.2, 6.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.54 - 6.46 (m, 1H), 4.88 (t, J = 5.2 Hz, 1H), 3.90 (t, J = 6.0 Hz, 2H), 3.59 (q, J = 6.0 Hz, 2H); LCMS: m/z 332.9 (M+H)+. [0575] Step 4. A solution of 4-[3-chloro-4-fluoro-N-(2-hydroxyethyl)anilino]quinolin-6-ol (600 mg, 1.80 mmol, 1 eq), 3-chloro-2-(chloromethyl)prop-1-ene (600 mg, 4.80 mmol, 2.66 eq) and K2CO3 (747 mg, 5.41 mmol, 3 eq) in DMF (10 mL) was stirred at 40 °C for 12 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/1 to 0/1) to provide 2-(3-chloro-N-[6-[2- (chloromethyl)allyloxy]-4-quinolyl]-4-fluoro-anilino)ethanol (350 mg, 0.797 mmol, 44% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41 (dd, J = 2.8, 9.2 Hz, 1H), 7.18 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 2.8, 6.2 Hz, 1H), 6.59 (td, J = 3.6, 8.8 Hz, 1H), 5.32 (s, 1H), 5.19 (d, J = 1.2 Hz, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.52 (s, 2H), 4.22 (s, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.61 (q, J = 6.0 Hz, 2H); LCMS: m/z 420.9 (M+H)+. [0576] Step 5. To a solution of 2-(3-chloro-N-[6-[2-(chloromethyl)allyloxy]-4-quinolyl]-4- fluoro-anilino)ethanol (300 mg, 0.712 mmol, 1 eq) in THF (60 mL) was added NaH (60.0 mg, 1.50 mmol, 60% purity, 2.11 eq) at 0 °C. The reaction was stirred at 20 °C for 6 hours. The reaction was quenched by aq NH4Cl (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to provide 49-5 (170 mg, 0.441 mmol, 62% yield) was obtained as a yellow oil. LCMS: m/z 384.9 (M+H)+. [0577] Step 6. A solution of 49-5 (170 mg, 0.441 mmol, 1 eq) , K2OsO4.2H2O (8.14 mg, 0.022 mmol, 0.05 eq) and NMO (155 mg, 1.33 mmol, 3 eq) in THF (3 mL) and H2O (0.5 mL) was stirred at 20 °C for 12 hours. The reaction mixture was diluted with aq Na2SO3 (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product 49-6 (180 mg, 0.412 mmol, 93.3% yield) as a brown solid which was used for next step without further purification. LCMS: m/z 418.9 (M+H)+. [0578] Step 7. To a solution of 49-6 (180 mg, 0.429 mmol, 1 eq) in THF (2 mL) and H2O (1 mL) was added NaIO4 (137 mg, 0.644 mmol, 1.5 eq). The reaction was stirred at 20 °C for 1 hours. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC(0.1% TFA condition) to provide 49-7 (50 mg, 0.116 mmol, 27.0% yield) as a yellow oil. LCMS: m/z 405.0 (M+H)+. [0579] Step 8. To a solution of 49-7 (35 mg, 0.0905 mmol, 1 eq) and ammonium acetate (13.9 mg, 0,180 mmol, 2 eq) in THF (1 mL) and MeOH (1 mL) was added NaBH3CN (8.53 mg, 0.135 mmol, 1.5 eq). The reaction was stirred at 20 °C for 12 hours. The reaction mixture was concentrated to provide a crude product 49-8 (30 mg, crude) as a yellow solid which was used without further purification. [0580] Step 9. To a solution of 49-8 (30 mg, 0.077 mmol, 1 eq) and NaHCO3 (6.50 mg, 0.077 mmol, 1 eq) in THF (1 mL) and H2O (1 mL) was added prop-2-enoyl chloride (8 mg, 0.088 mmol, 1.14 eq). The reaction was stirred at 20 °C for 0.1 hours. The reaction mixture was concentrated and purified by Prep-HPLC to provide Ex.49 (7.14 mg, 0.016 umol, 21% yield) as a yellow gum.1H NMR (400 MHz, DMSO-d6) δ = 8.92 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.43 (br d, J = 7.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.49 (t, J = 8.8 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.08 (d, J = 6.0 Hz, 1H), 6.37 (dd, J = 10.2, 17.2 Hz, 1H), 6.15 (dd, J = 2.0, 17.2 Hz, 1H), 5.64 (dd, J = 2.0, 10.0 Hz, 1H), 4.36 (br s, 2H), 4.02 (br s, 2H), 3.53 (br s, 2H), 3.51 (br s, 1H), 2.07 (s, 2H); LCMS: m/z 442.0 (M+1). [0581] Preparation of N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11- ethenopyrido[4,3-e][1,9,4]dioxazacyclododecin-6-yl]propenamide (Ex.50)
Figure imgf000153_0001
[0582] A suspension of Ex. 49 (1.05 mg, 0.00238 mmol) and 10% Pd/C (0.25 mg, 0.00024 mmol) in ethanol (0.1 mL) was stirred for 1 hour under a hydrogen balloon. The mixture was filtered, concentrated, and purified by reversed phase HPLC to Ex.50 (0.62 mg, 0.0014 mmol, 59%) as a colorless oil. LCMS: m/z 443.9 (M+H)+. [0583] Preparation of N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H- 9,11-ethenopyrido[4,3-i][1,5,8]oxadiazacyclododecin-6-yl]prop-2-enamide (Ex.51)
Figure imgf000153_0002
Figure imgf000154_0001
[0584] Step 1. 51-1 was prepared with a similar method as 49-1 in Ex. 49 using J11 to replace J10. LCMS: m/z 445.8 (M+H)+. [0585] Step 2. To a solution of tert-butyl N-[2-(3-chloro-4-fluoro-N-(6-methoxy-4- quinolyl)anilino)ethyl]carbamate (1.6 g, 3.59 mmol, 1 eq) in DMF (20 mL) was added NaH (260 mg, 6.50 mmol, 60% purity, 1.81 eq) and CH3I (611 mg, 4.31 mmol, 1.2 eq) at 0 °C. The reaction was stirred at 20 °C for 2 hours. The reaction was quenched by water (50 ml), diluted with H2O (100 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 0% to 20%) to provide tert-butyl N-[2-(3-chloro-4-fluoro-N-(6-methoxy-4- quinolyl)anilino)ethyl]-N-methyl-carbamate (1.5 g, 1.08 mmol, 30% yield) as a yellow oil. LCMS: m/z 460.0 (M+H)+. [0586] Step 3. A solution of tert-butyl N-[2-(3-chloro-4-fluoro-N-(6-methoxy-4- quinolyl)anilino)ethyl]-N-methyl-carbamate (1.5 g, 3.26 mmol, 1 eq) in HCl/dioxane (10 mL) and DCM (10 mL) was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated to give the crude product N'-(3-chloro-4-fluoro-phenyl)-N'-(6-methoxy-4-quinolyl)-N-methyl- ethane-1,2-diamine (1.2 g, crude) as a yellow solid, which was used directly without further purification. [0587] Step 4. To a solution of N'-(3-chloro-4-fluoro-phenyl)-N'-(6-methoxy-4-quinolyl)-N- methyl-ethane-1,2-diamine (1.2 g, 3.33 mmol, 1 eq) in DMSO (20 mL) was added DIEA (1.29 g, 10.00 mmol, 3 eq) at 0 °C. Then to the reaction was added 3-chloro-2-(chloromethyl)prop- 1-ene (4.32 g, 34.5 mmol, 10.4 eq). The reaction was stirred at 50 °C for 12 hours. The reaction was concentrated and purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=0% to 60%) to provide N'-(3-chloro-4-fluoro-phenyl)-N-[2-(chloromethyl)allyl]-N'- (6-methoxy-4-quinolyl)-N-methyl-ethane-1,2-diamine (0.9 g, 1.89 mmol, 56% yield) as a yellow oil.1H NMR (400 MHz, METHANOL-d4) δ = 8.64 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.33 (dd, J = 2.4, 9.2 Hz, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.99 (dd, J = 2.4, 6.0 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.83 - 6.76 (m, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.26 (s, 3H), 4.20 - 4.15 (m, 2H), 4.06 (br t, J = 6.4 Hz, 2H), 3.98 (s, 2H), 3.08 (s, 2H), 2.25 (s, 3H); LCMS: m/z 447.9 (M+H)+. [0588] Step 5. To a solution of N'-(3-chloro-4-fluoro-phenyl)-N-[2-(chloromethyl)allyl]-N'- (6-methoxy-4-quinolyl)-N-methyl-ethane-1,2-diamine (0.9 g, 2.01 mmol, 1 eq) in DCM (20 mL) was added BBr3 (1 M, 6.02 mL, 3 eq). The reaction was stirred at 40 °C for 2 hours. The reaction mixture was diluted with aq NaHCO3 (100 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product 4-[3-chloro-N-[2-[2- (chloromethyl)allyl-methyl-amino]ethyl]-4-fluoro-anilino]quinolin-6-ol (0.42 g, 0.928 mmol, 46% yield) as a yellow solid, which was used directly without further purification.1H NMR (400 MHz, METHANOL-d4) δ = 8.58 (d, J = 6.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.11 (qd, J = 4.0, 7.6 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 5.28 - 5.21 (m, 1H), 5.14 (s, 1H), 4.26 (t, J = 6.4 Hz, 2H), 4.05 - 3.96 (m, 2H), 3.20 (s, 2H), 2.84 (s, 2H), 2.37 (s, 3H); LCMS: m/z 434.0 (M+H)+. [0589] Step 6. To a solution of 4-[3-chloro-N-[2-[2-(chloromethyl)allyl-methyl-amino]ethyl]- 4-fluoro-anilino]quinolin-6-ol (0.3 g, 0.690 mmol, 1 eq) in DMF (60 mL) was added K2CO3 (114 mg, 0.828 mmol, 1.2 eq). The reaction was stirred at 80 °C for 1 hour, diluted with H2O (300 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 1/1) to provide 51-6 (0.1 g, 0.238 mmol, 34% yield) as a white solid. LCMS: m/z 398.0 (M+H)+. [0590] Ex.51 was obtained from 51-6 following similar methods as 49-5 to Ex.49.1H NMR (400 MHz, DMSO-d6) δ = 9.24 - 9.12 (m, 1H), 8.54 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.95 - 7.85 (m, 1H), 7.44 - 7.38 (m, 1H), 7.35 - 7.25 (m, 2H), 7.03 (s, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.41 - 6.22 (m, 1H), 6.20 - 6.07 (m, 1H), 5.70 - 5.56 (m, 1H), 4.59 - 4.40 (m, 2H), 4.34 (t, J = 4.8 Hz, 2H), 3.96 - 3.82 (m, 1H), 3.50 - 3.41 (m, 2H), 3.30 - 3.29 (m, 3H), 2.91 - 2.77 (m, 2H); LCMS: m/z 454.9 (M+H)+. [0591] Preparation of 15-(3-chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15- octahydro-2,19-etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin- 7(5H)-one (Ex.52)
Figure imgf000156_0001
[0592] Ex.52 was prepared as a yellow solid following similar methods as Ex.36 using M2 to replace M1 and J12 to replace J1. [0593] Preparation of 15-(4-chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15- octahydro-2,19-etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin- 7(5H)-one (Ex.53)
Figure imgf000156_0002
[0594] Ex.53 was prepared as a yellow solid following similar methods as Ex.36 using M2 to replace M1 and J13 to replace J1, followed by de-Cbz using the method as that in Ex.38. 1H NMR (400 MHz, DMSO-d6) δ = 8.49 (d, J = 5.2 Hz, 1H), 8.38 - 8.34 (m, 1H), 8.32 - 8.28 (m, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.52 (d, J = 11.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 4.36 - 4.29 (m, 2H), 4.10 (s, 3H), 3.51 - 3.47 (m, 2H), 3.13 - 3.08 (m, 2H), 2.65 (d, J = 4.8 Hz, 2H), 1.71 - 1.65 (m, 2H); LCMS: m/z 480.2 (M+H)+. [0595] Preparation of 15-(3,4-dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro- 2,19-etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one (Ex.54)
Figure imgf000157_0002
[0596] Ex.54 was prepared as an off-white solid, following similar methods as Ex.36 using M2 to replace M1 and J14 to replace J1, followed by de-Cbz using the method as that in Ex. 38.1H NMR (400 MHz, DMSO-d6) δ = 8.47 (d, J = 5.2 Hz, 1H), 8.37 - 8.34 (m, 1H), 8.30 - 8.25 (m, 1H), 7.98 - 7.92 (m, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 4.37 - 4.30 (m, 2H), 4.10 (s, 3H), 3.49 (d, J = 5.6 Hz, 2H), 3.11 - 3.05 (m, 2H), 2.66 - 2.62 (m, 2H), 1.70 - 1.59 (m, 2H); LCMS: 495.9 (M+H)+. [0597] Preparation of 15-(3-chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15- octahydro-2,19-etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin- 7(5H)-one (Ex.55)
Figure imgf000157_0001
[0598] Ex.55 was prepared as a yellow solid, following similar methods as Ex.36 using M2 to replace M1 and J15 to replace J1, followed by de-Cbz using the method as that in Ex. 38. 1H NMR (400 MHz, DMSO- d6) δ = 8.42 (d, J = 5.2 Hz, 1H), 8.35 - 8.19 (m, 2H), 7.69 (d, J = 6.4 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.36 (m, 1H), 6.62 (d, J = 5.2 Hz, 1H), 4.32 (t, J = 7.2 Hz, 2H), 4.07 (s, 3H), 3.67 (s, 2H), 3.11 - 3.02 (m, 2H), 2.99 (s, 3H), 2.65 (d, J = 8.8 Hz, 2H), 1.84 (d, J = 5.6 Hz, 2H); LCMS: m/z 494.2 (M+H)+. [0599] Preparation of 10-(3-chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14- ethenopyrido[3,4-d][1,3,6,9]oxatriazacyclododecin-8-one (Ex.56)
Figure imgf000158_0001
[0600] Step 1. A mixture of ethyl 2-(3-chloro-4-fluoro-anilino)acetate (2 g, 8.63 mmol, 1 eq), 8-chloro-2-methoxy-1,5-naphthyridine (1.85 g, 9.50 mmol, 1.1 eq), Cs2CO3 (8.44 g, 25.9 mmol, 3 eq), XPhos (412 mg, 0.863 mmol, 0.1 eq) and Pd(dba)2 (496 mg, 0.863 mmol, 0.1 eq) in dioxane (20 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (30 mL × 3) and water (40 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 1:1) to give ethyl 2-(3-chloro-4- fluoro-N-(6-methoxy-1,5-naphthyridin-4-yl)anilino)acetate (2 g, 4.41 mmol, 51% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 8.52 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.34 - 7.30 (m, 1H), 7.17 - 7.13 (m, 1H), 7.12 - 7.07 (m, 1H), 7.03 (d, J = 5.2 Hz, 1H), 5.02 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.52 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); LCMS: m/z 391.0 (M+H)+. [0601] Step 2. To a solution of ethyl 2-(3-chloro-4-fluoro-N-(6-methoxy-1,5-naphthyridin-4- yl)anilino)acetate (1.9 g, 4.87 mmol, 1 eq) in DCM (2 mL) was added BBr3 (1 M, 14.62 mL, 3 eq) at 0 °C. The reaction was stirred at 40 °C for 2 hours under N2. The reaction mixture was partitioned between ethyl acetate (30 mL × 3) and water (30 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 5:1) to give methyl 2- (3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin-4-yl)anilino)acetate (600 mg, 1.33 mmol, 27% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 8.53 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.26 - 7.15 (m, 1H), 6.79 (d, J = 9.6 Hz, 1H), 6.69 (d, J = 5.8 Hz, 1H), 6.40 (d, J = 3.2, 6.0 Hz, 1H), 4.56 (s, 2H), 3.70 (s, 3H); LCMS: m/z 361.9 (M+H)+. [0602] Step 3. To a solution of methyl 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin- 4-yl)anilino)acetate (500 mg, 1.38 mmol, 1 eq) in MeOH (5 mL) and H2O (2 mL) was added LiOH.H2O (174 mg, 4.15 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give a crude product 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5- naphthyridin-4-yl)anilino)acetic acid (400 mg, crude) as yellow solid and used for next step directly. LCMS: m/z 347.7 ( M+H)+. [0603] Step 4. To a solution of 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin-4- yl)anilino)acetic acid (400 mg, 1.15 mmol, 1 eq) and 3-aminopropan-1-ol (86.4 mg, 1.15 mmol, 1 eq) in DMF (5 mL) was added T3P (439 mg, 1.38 mmol, 1.2 eq) and DIEA (446 mg, 3.45 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, Ethyl acetate/MeOH=1:0 to 5:1) to give 2-(3-chloro-4- fluoro-N-(6-hydroxy-1,5-naphthyridin-4-yl)anilino)-N-(3-hydroxypropyl)acetamide (100 mg, 0.246 mmol, 22% yield) as a white solid. LCMS: m/z 404.8 (M+H)+. [0604] Step 5. A mixture of 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-naphthyridin-4- yl)anilino)-N-(3-hydroxypropyl)acetamide (100 mg, 0.247 mmol, 1 eq), DIAD (150 mg, 0.741 mmol, 3 eq), PPh3 (194 mg, 0.741 mmol, 3 eq) in THF (1 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 25 °C for 16 hours under N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (20 mL × 3) and water (40 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-TLC (SiO2, EtOAc: MeOH = 10:1) to give Ex.56 (60 mg, 0.152 mmol, 61% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ= 8.56 (d, J = 5.2 Hz, 1H), 8.51 (s, 1H), 8.27 (d, J = 9.2 Hz, 1H), 7.43 - 7.40 (m, 1H), 7.39- 7.36 (m, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 4.48 (s, 2H), 4.43 (t, J = 6.4Hz, 2H), 3.22 (s, 2H), 1.96 - 1.85 (m, 2H); LCMS: m/z 386.6 (M+H)+. [0605] Preparation of 1-(3-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11- ethenopyrido[4,3-i][1,5,8]oxadiazacyclododecin-3-one (Ex.57)
Figure imgf000160_0001
[0606] Ex.57 was prepared as an off-white solid, following similar methods as Ex.56 using 4-bromo-6-methoxyquinoline to replace 8-chloro-2-methoxy-1,5-naphthyridine. 1H NMR (400 MHz, DMSO-d6) δ = 8.69 (d, J = 4.8 Hz, 1H), 8.24 (t, J = 5.6 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.33 (s, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.28 - 3.21 (m, 2H), 1.91 - 1.81 (m, 2H); LCMS: m/z 386.6 (M+H)+. [0607] Preparation of 15-(3,4-dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15- octahydro-2,19-etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin- 7(5H)-one (Ex.58)
Figure imgf000160_0002
[0608] Ex.58 was prepared as a white solid following similar methods as Ex.36 using M2 to replace M1 and J16 to replace J1, followed by de-Cbz using the method as that in Ex.38.1H NMR (400 MHz, DMSO-d6) δ = 8.43 (d, J = 5.2 Hz, 1H), 8.36 - 8.33 (m, 1H), 8.32 - 8.26 (m, 1H), 8.23 (s, 1H), 7.93 (t, J = 6.8 Hz, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 6.55 (d, J = 5.6 Hz, 1H), 4.40 (s, 2H), 4.18 - 4.06 (m, 5H), 3.10 - 3.04 (m, 2H), 2.63 (d, J = 2.8 Hz, 2H), 1.69 - 1.64 (m, 2H); LCMS：m/z 514.1 (M+H)+. Screen assays Kinase Binding Assay [0609] Kinase binding assays are performed at Eurofins/DiscoveRx using the general KINOMEscan Protocol (Fabian, M. A. et al., “A small molecule-kinase interaction map for clinical kinase inhibitors,” Nat. Biotechnol. 2005, 23(3):329-36). For most assays, kinase- tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions are performed in polystyrene 96-well plates in a final volume of 0.135 mL. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates is measured by qPCR. Results for compounds tested in this assay at a given concentration are reported as “%Ctrl”, where lower numbers indicate stronger binding in the matrix. [0610] %Ctrl calculation: Biochemical Assay [0611] The inhibition activities against enzymatic kinases will be evaluated at Reaction Biology Corporation (www.reactionbiology.com) using HotSpot assay platfrom, a radiometric assay based on conventional filter-binding assays, that directly measures kinase catalytic activity toward a specific substrate (Anastassiadis T, et al. Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selectivity. Nat Biotechnol. 2011, 29:1039-45). Briefly, specific kinase / substrate pairs along with required cofactors are prepared in reaction buffer; 20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Compounds are delivered into the reaction, followed ~ 20 minutes later by addition of a mixture of ATP (Sigma, St. Louis MO) and 33P ATP (Perkin Elmer, Waltham MA) to a final concentration of 10 μM. Reactions are carried out at room temperature for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate is removed by extensive washing of filters in 0.75% phosphoric acid. After subtraction of background derived from control reactions containing inactive enzyme, kinase activity data is expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC50 values and curve fits are obtained using Prism (GraphPad Software). Cellular Assay [0612] The inhibition of cellular activity of wild-type and mutant EGFRs will be evaluated at ProQinase GmbH (www.proqinase.com) using ProQinase’s cellular phosphorylation assays that have been designed to measure compound activity in a physiological environment on a physiological substrate. The cellular kinase assays include EGFR wild-type, EGFR L858R mutant, EGFR T790M mutant, EGFR G719S mutant, EGFR L861Q mutant, EGFR Δ752-759 mutant, EGFR L858R/T790M mutant, EGFR Δ746-750/T790M mutant, EGFR Δ746- 750/C797S mutant, EGFR T790M/C797S/L858R mutant, EGFR Δ746-750/T790M/C797S mutant, and EGFR Δ747-749/A750P mutant. The detailed experimental protocols are available at ProQinase GmbH website. [0613] Table 1. The inhibition activities against WT and Mutant EGFR kinases
Figure imgf000162_0001
Figure imgf000163_0001
[0614] Table 2. The inhibition activities against WT and Mutant HER2 kinases and HER4 kinase
Figure imgf000163_0002

Claims

WHAT IS CLAIMED IS: 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000164_0001
wherein X is a -X1- or -X1-(ring A)-; X1 is -O-, -S-, -NR1-; each Y is independently a ring B or -C(O)NR2-; ring A is C6-C10 arylene or 5- to 10-membered heteroarylene, and wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each ring B is C6-C10 arylene or 5- to 10-membered heteroarylene, wherein each hydrogen atom in C6-C10 arylene or 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each L is independently -C(R3)(R4)-, -C(O)-, -O-, -N(R5)-, -S-, -S(O)- or -S(O)2-, provided that (L)n does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R5)- bond; Z1 is N or C(R6); Z2 is N or C(R7); Z3 is N or C(R8); Z4 is N or C(R9); Z5 is N or C(R10); Z6 is N or C(R11); provided that at least one of Z1-Z6 is N; each of R1, R2, and R5 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2; each R3 and R4 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRc, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, -NO2, or two of R3 and R4 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each of R6, R7, R8, R9, R10, and R11 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or R6 and R7, R7 and R8, or R10 and R11 taken together with the carbons to which they are attached form a C4-C6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or a C6-C10 aryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkylene-C6-C10 aryl, or 5- to 10- membered heteroaryl, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)-(H or C1-C6 alkyl), -OC(O)N(H or C1-C6 alkyl)2, -OC(O)N(C2-C6 alkylene), -OS(O)-(H or C1-C6 alkyl), -OS(O)2-(H or C1-C6 alkyl), -OS(O)N(H or C1-C6 alkyl)2, -OS(O)N(C2-C6 alkylene), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(C2-C6 alkylene), -S(H or C1-C6 alkyl), -S(O) (H or C1-C6 alkyl), -S(O)2(H or C1-C6 alkyl), -S(O)N(H or C1-C6 alkyl)2, -S(O)N(C2-C6 alkylene), -S(O)2N(H or C1-C6 alkyl)2, -S(O)2N(C2-C6 alkylene), -N(H or C1-C6 alkyl)2, -N(C2-C6 alkylene), -N(H or C1-C6 alkyl)C(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)O(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)C(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)-(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)2(H or C1-C6 alkyl), -N(H or C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)N(C2-C6 alkylene), -N(H or C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)S(O)2N(C2-C6 alkylene), -C(O)-(H or C1-C6 alkyl), -C(O)O(H or C1-C6 alkyl), -C(O)N(C2-C6 alkylene), -P(H or C1-C6 alkyl)2, -P(C2-C6 alkylene), -P(O)(H or C1-C6 alkyl)2, -P(O)(C2-C6 alkylene), -P(O)2(H or C1-C6 alkyl)2, -P(O)2(C2-C6 alkylene), -P(O)N(H or C1-C6 alkyl)2, -P(O)N(C2-C6 alkylene), -P(O)2N(H or C1-C6 alkyl)2, -P(O)2N(C2-C6 alkylene), -P(O)O(H or C1-C6 alkyl), -P(O)2O(H or C1-C6 alkyl), -CN, or -NO2; m is 0, 1, or 2; and n is 3, 4, 5, 6, 7, 8, or 9.
2. The compound of claim 1 having the formula II
Figure imgf000167_0001
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 having the formula III
Figure imgf000168_0001
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 having the formula IV
Figure imgf000168_0002
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 having the formula V
Figure imgf000168_0003
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 having the formula VI
Figure imgf000169_0001
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 having the formula VII
Figure imgf000169_0002
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 having the formula VIII
Figure imgf000169_0003
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 having the formula IX
Figure imgf000170_0001
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 having the formula X
Figure imgf000170_0002
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 havng the formula XI
Figure imgf000170_0003
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 having the formula XII
Figure imgf000171_0001
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 having the formula XIII
Figure imgf000171_0002
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 having the formula XIV
Figure imgf000171_0003
or a pharmaceutically acceptable salt thereof,.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.
16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is phenylene or pyridinylene, wherein each hydrogen atom in phenylene or pyridinylene is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl.
17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is a phenylene or a pyridinylene of the formula
Figure imgf000172_0001
wherein each hydrogen atom is independently optionally substituted by a deuterium, fluoro, chloro, bromo, or C1-C6 alkyl.
18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein ring A, when present, is
Figure imgf000173_0001
, , , , .
19. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X1 is –NR1-.
20. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is hydrogen, C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2.
21. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.
22. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2.
23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is phenyl or pyridinyl, wherein each hydrogen atom in phenyl or pyridinyl is independently optionally substituted by deuterium, fluoro, chloro, bromo, or C1-C6 alkyl.
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R1, when present, is of the formula
Figure imgf000174_0001
, , , ,
25. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X1 is -O-.
26. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X1 is -S-.
27. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring B, when present, is 5- to 10-membered heteroarylene, wherein each hydrogen atom in 5- to 10-membered heteroarylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.
28. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring B, when present, is phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene, wherein each hydrogen atom in phenylene, furanylene, thiophenylene, pyrrolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyrazolylene, imidazolylene, oxadiazolylene, thiadiazolylene, triazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, or triazinylene is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.
29. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring B, when present, is
Figure imgf000175_0001
Figure imgf000175_0002
30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z1 is N.
31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is C(R8), Z4 is N, Z5 is C(R10), and Z6 is C(R11).
32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is C(R8), Z4 is C(R9), Z5 is C(R10), and Z6 is C(R11).
33. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is N, Z4 is N, Z5 is C(R10), and Z6 is C(R11).
34. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein Z2 is C(R7), Z3 is N, Z4 is C(R9), Z5 is C(R10), and Z6 is C(R11).
35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, when present is H.
36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7, when present is H.
37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8, when present is H.
38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9, when present is H.
39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R10, when present is H or –OCH3.
40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R11, when present is H.
41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from the group consisting of -C(R3)(R4)-, -C(O)-, -O-, or -N(R5)-, provided that (L)n does not comprise a –O-O- or a –O-N(R5)- bond.
42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -(L)n- is -(CR3R4)3-, -(CR3R4)4-, -(CR3R4)5-, -(CR3R4)6-, -(CR3R4)7-, -(CR3R4)8-, -C(O)N(R5)-(CR3R4)2O(CR3R4)2-, -CR3R4-C(O)N(R5)-(CR3R4)2O-, -CR3R4-C(O)N(R5)-(CR3R4)3O-, -N(R5)-C(O)CR3R4O(CR3R4)2-, -CR3R4-N(R5)-C(O)(CR3R4)2O-, -CR3R4-N(R5)-C(O)(CR3R4)3O-, -CR3R4O(CR3R4)2-, -CR3R4-O(CR3R4)3-, -(CR3R4)2O-CR3R4-, -(CR3R4)3O-CR3R4-, -(CR3R4)2O(CR3R4)2-, -(CR3R4)3O(CR3R4)2-, -(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)5O(CR3R4)3-, -O-CR3R4- O(CR3R4)3-, -CR3R4-O(CR3R4)2O-, -CR3R4-O(CR3R4)3O-, -O(CR3R4)2O(CR3R4)3-, -(CR3R4)2O(CR3R4)3O-, -O-(CR3R4)2-, -(CR3R4)2O-, –O-(CR3R4)3-, -(CR3R4)3O-, -O-(CR3R4)2O(CR3R4)2-, -(CR3R4)2O(CR3R4)2O-, -CR3R4-N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)2-, -(CR3R4)2N(R5)-(CR3R4)3-, -(CR3R4)3O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)C(O)N(R5)-(CR3R4)-, -(CR3R4)2O(CR3R4)2C(O)N(R5)-(CR3R4)-, -(CR3R4)2N(R5)-(CR3R4)3-, -O-(CR3R4)2N(R5)-(CR3R4)2-, -CR3R4N(R5)-(CR3R4)2O-, -(CR3R4)2N(R5)-(CR3R4)2O-, or -(CR3R4)2N(R5)-(CR3R4)3O-.
43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, -NRcC(O)Rd, and -CN, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, - P(O)ORe, -P(O)2ORe, -CN, or -NO2.
44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -(L)n- comprises -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -C(O)NH-(CH2)2O(CH2)2-, -C(O)N(CH3)-(CH2)2O(CH2)2-, -NHC(O)CH2O(CH2)2-, -N(CH3)-C(O)CH2O(CH2)2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)2CH(CH3)-, -CH2OCH2CH(CH3)-CH2-, -CH2OCH(CH3)-(CH2)2-, -CH(CN)-O-(CH2)3-, -CH(CH3)-O-(CH2)3-, -CH2O(CH2)2-O-, -(CH2)2O(CH2)2-, -CH2-C(CH3)2-O(CH2)2-, -CH2-C(CH3)2-O(CH2)3-, -(CH2)2OCH2-, -(CH2)2O(CH2)2-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)3-, -(CH2)2OCH(CH3)-(CH2)2-, -(CH2)2OC(CH3)2-(CH2)2-, -(CH2)2O(CH2)2- CH(CH3)-, -(CH2)2O-(CH2)2-C(CH3)2-CH2-CH(CH3)-O-(CH2)3-, -CH2CH(CH3)-O(CH2)2-, -CH(CH3)-CH2O(CH2)2-, -O-(CH2)2-, –O-(CH2)3-, -O-CH2CH(OH)CH2-, -O-(CH2)2O(CH2)2-, -O-CH2CH(CH3)-O(CH2)2-, -O-CH(CH3)-CH2O(CH2)2-, -(CH2)2OCH2CH(NH-C(O)-CH=CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)-C(O)- CH=CH2)CH2O-, -(CH2)2OCH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2OCH2CH(N(CH3)- C(O)-CH2CH2)CH2O-, -(CH2)2NH-CH2CH(NH-C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2NH-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH=CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(NH-C(O)-CH2CH2)CH2O-, -(CH2)2N(CH3)-CH2CH(N(CH3)-C(O)-CH2CH2)CH2O-, -(CH2)3O(CH2)C(O)N(CH3)CH2-, -(CH2)3O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)C(O)N(CH3)CH2-, -(CH2)2O(CH2)C(O)N(H)CH2-, -(CH2)2O(CH2)2C(O)N(CH3)CH2-, -(CH2)2O(CH2)2C(O)N(H)CH2-, -O-(CH2)2NH-(CH2)2-, -O-CH2CH(CH3)-NH-(CH2)2-, -O-CH(CH3)-CH2NH-(CH2)2-, -CH2NH-(CH2)2-, -(CH2)2NH-(CH2)2-, -(CH2)2NH-(CH2)3-, -(CH2)2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)3-, -CH2CH(CH3)-NH-(CH2)2-, -CH(CH3)-CH2NH-(CH2)2-, -O-(CH2)2N(CH3)-(CH2)2-, -O-CH2CH(CH3)-N(CH3)-(CH2)2-, -O-CH(CH3)-CH2N(CH3)-(CH2)2-, -CH2N(CH3)-(CH2)2-, -(CH2)2N(CH3)-(CH2)2-, -CH2C(O)N(H)-(CH2)3O-, -CH2C(O)N(CH3)-(CH2)3O-, -CH2CH(CH3)-N(CH3)-(CH2)2-, or -O-CH(CH3)-CH2N(CH3)-(CH2)2-.
45. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 1-(3-chloro-4-fluorophenyl)-17-methoxy-2,3,5,6,7,8-hexahydro- 10,12-ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; 1-(3-chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; (3R)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; (3S)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; 1-(3-chloro-4-fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; (5S)-1-(3-chloro-4-fluorophenyl)-5-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; (7R)-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; 12-(3-chloro-4-fluorophenyl)-1-methyl-4,13,14,16-tetrahydro-1H-6,8- ethenopyrazolo[4,3-k]pyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-5(12H)-one; 14-(3-chloro-4-fluorophenyl)-5-methyl-5,9,10,12,13,14-hexahydro-2,18-etheno-3,6- (metheno)pyrido[3,4-l][1,4,7,8,11,14]oxapentaazacyclohexadecin-7(8H)-one; and 1-(3-chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7,10-hexahydro-12,9-(azeno)-13,15- ethenopyrido[3,4-l][1,4,7,14]oxatriazacyclohexadecin-8(5H)-one.
46. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18- ethenopyrazolo[4,3-f]pyrido[4,3-b][8,11,1,4]benzodioxadiazacyclotetradecine; 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrido[4,3-b][8,11,1]benzodioxazacyclotetradecine; 15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-f]pyrimido[4,5- b][8,11,1,4]benzodioxadiazacyclotetradecine; 7-chloro-15-methyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3- f]pyrimido[4,5-b][8,11,1]benzodioxazacyclotetradecine; 7,15-dimethyl-5,12,13,15-tetrahydro-10H-1,18-ethenopyrazolo[4,3-m]pyrido[3,4- f]pyrimido[4,5-i][1,4,8]dioxazacyclotetradecine; 7-chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-ethenodipyrido[4,3-b:2',3'- f][8,11,1]benzodioxazacyclotetradecine; 7-chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-ethenodibenzo[e,l]pyrido[3,4- i][1,4,8,11]dioxadiazacyclotetradecine; 7-chloro-6-fluoro-14-methyl-5,13,14,17-tetrahydro-10H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][14,1,8,11]benzoxatriazacycloheptadecin-15(12H)-one; 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][14,1,8,11]benzoxatriazacycloheptadecin-15(12H)-one; 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-1,20-etheno-19,16- (metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one; 7-chloro-6-fluoro-14-methyl-13,14-dihydro-10H,17H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; 7-chloro-8-fluoro-13,14-dihydro-10H,17H-19,16-(azeno)-1,20-ethenopyrido[4,3- b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; 7-chloro-6-fluoro-13,14-dihydro-10H,17H-19,16-(azeno)-1,20-ethenopyrido[4,3- b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; 7-chloro-6-fluoro-14,17-dimethyl-13,14-dihydro-10H,17H-19,16-(azeno)-1,20- ethenopyrido[4,3-b][1,14,8,11]benzodioxadiazacycloheptadecin-15(12H)-one; 16-chloro-17-fluoro-8-methyl-8,9,10,11,13,18-hexahydro-7H-4,6-ethenopyrido[4,3- b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; 16-chloro-17-fluoro-8,9,10,11,13,18-hexahydro-7H-4,6-ethenopyrido[4,3- b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; (13R)-16-chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; (13S)-16-chloro-17-fluoro-7-oxo-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecine-13-carbonitrile; (9R)-16-chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7H-4,6- ethenopyrido[4,3-b][11,1,4,7]benzoxatriazacyclotetradecin-7-one; 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7H,13H-4,6-ethenopyrido[4,3- , 1,7]benzodioxazacyclotetradecin-7-one; and 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7H,13H-4,6-ethenopyrido[4,3- b][11,1,7]benzoxathiazacyclotetradecin-7-one.
47. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12- ethenopyrido[4,3-e][1,4,7,10]oxatriazacyclotridecin-9(1H)-one; 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-ethenopyrido[4,3- e][1,4,10]oxadiazacyclotridecin-9(1H)-one; 15-(3-chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-ethenopyrimido[4,5- e][1,4,10]oxadiazacyclotridecin-7(13H)-one; 1-(3-chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-etheno- 13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one; 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16- etheno-13,10-(metheno)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecin-9-one; 1-(3-chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; 1-(3-chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-etheno- 12,9-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecin-8(5H)-one; 1-(3-chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-etheno- 13,10-(metheno)pyrido[3,4-l][1,4,7,8,14]oxatetraazacycloheptadecin-7(6H)-one; N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide; 3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]-N-(propan-2- yl)benzamide; N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-etheno-13,10- (metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-1(11H)-yl]benzamide; 1-(3,4-dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; 1-(3-chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-etheno- 13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-9(2H)-one; 2-[1-(3-chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16- etheno-13,10-(metheno)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecin-8(9H)-yl]-N- methylacetamide; 15-(3-chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno- 3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-ethenopyrido[4,3- e][1,9,4]dioxazacyclododecin-6-yl]prop-2-enamide; N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-ethenopyrido[4,3- e][1,9,4]dioxazacyclododecin-6-yl]propanamide; N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11- ethenopyrido[4,3-i][1,5,8]oxadiazacyclododecin-6-yl]prop-2-enamide; 15-(3-chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; 15-(4-chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno- 3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; 15-(3,4-dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-etheno-3,6- (metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; 15-(3-chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; 10-(3-chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-ethenopyrido[3,4- d][1,3,6,9]oxatriazacyclododecin-8-one; 1-(3-chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-ethenopyrido[4,3- i][1,5,8]oxadiazacyclododecin-3-one; 15-(3,4-dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19- etheno-3,6-(metheno)pyrido[3,4-f][1,2,5,8,11,15]hexaazacycloheptadecin-7(5H)-one; and 7-chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-etheno-19,16- (metheno)pyrido[4,3-b][14,1,4,7,8,11]benzoxapentaazacycloheptadecin-15(12H)-one.
48. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
49. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof.
50. A compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
51. A compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
52. Use of a compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130252961A1 (en) * 2012-03-06 2013-09-26 Pfizer Inc. Macrocyclic derivatives for the treatment of diseases
US20170320894A1 (en) * 2004-12-08 2017-11-09 Janssen Pharmaceutica Nv Macrocyclic quinazole derivatives and their use as mtki
US20190076436A1 (en) * 2017-03-16 2019-03-14 Array Biopharma Inc. Macrocyclic compounds as ros1 kinase inhibitors
US20190169207A1 (en) * 2014-01-24 2019-06-06 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170320894A1 (en) * 2004-12-08 2017-11-09 Janssen Pharmaceutica Nv Macrocyclic quinazole derivatives and their use as mtki
US20130252961A1 (en) * 2012-03-06 2013-09-26 Pfizer Inc. Macrocyclic derivatives for the treatment of diseases
US20190169207A1 (en) * 2014-01-24 2019-06-06 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US20190076436A1 (en) * 2017-03-16 2019-03-14 Array Biopharma Inc. Macrocyclic compounds as ros1 kinase inhibitors

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