WO2022246092A1 - Macrocyclic compounds for treating disease - Google Patents

Macrocyclic compounds for treating disease Download PDF

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Publication number
WO2022246092A1
WO2022246092A1 PCT/US2022/030077 US2022030077W WO2022246092A1 WO 2022246092 A1 WO2022246092 A1 WO 2022246092A1 US 2022030077 W US2022030077 W US 2022030077W WO 2022246092 A1 WO2022246092 A1 WO 2022246092A1
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alkyl
fluoro
compound
pharmaceutically acceptable
acceptable salt
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PCT/US2022/030077
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French (fr)
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Eugene Yuanjin Rui
Jingrong Jean Cui
Evan W. ROGERS
Dayong Zhai
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Blossomhill Therapeutics, Inc.
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Publication of WO2022246092A1 publication Critical patent/WO2022246092A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • Ras is a GTP-binding protein and regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc.
  • H-Ras, K-Ras, and N- Ras are the main members of Ras superfamily, which are tightly regulated by factors that switch off the GTPase activity.
  • Somatic mutations at codons 12, 13 and 61 in the RAS genes are associated with about 16% of all human cancers and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-related cancers (Prior I. A. et al, A comprehensive survey of Ras mutations in cancer. Cancer Res.
  • KRAS G12C mutants Recent successful inhibition of the KRAS G12C mutant by covalent chemical modifiers sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) in KRAS G12C mutated lung cancer patients has shed lights on targeting KRAS mutants for therapeutic invention. However, inhibitors targeting KRAS mutants without covalent formation at KRAS G12C are still absent.
  • next generation GTPase 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.
  • KRAS inhibitors that are potent against oncogenic driver KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like, as well as other emrging and established resistance mutations, while maintaining selectivity over wild type KRAS.
  • KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like as well as other emrging and established resistance mutations, while maintaining selectivity over wild type KRAS.
  • the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0006] wherei [0007] ring A is a 4- to 10-membered heterocycloalkylene, C6-C10 arylene, or 5- to 10- membered heteroarylene; [0008] ring B is a C 6 -C 10 aryl or 5- to 10-membered heteroaryl; [0009] each L is independently -C(R 4 )(R 5 )-, -C(O)-, -O-, -N(R 6 )-, -S-, -S(O)- or -S(O)2-, provided that (L) p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R 6 )- bond; [0010] X is a -O-, -S-, -NR
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, II [0031] wherein R 1 , R 2 , R 3 , B, L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0033] wherein R 1 , R 2 , R 3 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0034] In some embodiments, 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, [0037] wherein R 1 , R 2 , A, B, L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 . [0038] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , B, L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 .
  • the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, [0041] w , and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 . [0042] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [0045] wherein R 1 , R 2 , R 3 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0046] In some embodiments, 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, [0049] wherein R 1 , R 2 , R 3 , A, L, X, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, [0050] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof, [0053] wher p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 . [0054] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H- pyrrolizinylene group is optionally substituted as described herein with respect to R 3 .
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, [0057] wherein R 1 , R 2 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the pyrrolidinylene group is optionally substituted as described herein with respect to R 3 .
  • the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
  • the compound of Formula (I)-(XVI) 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)-(XVI) 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)-(XVI), 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)-(XVI), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XVI), 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 Ras, such as K-Ras, comprising contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I)-(XVI), 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.
  • a Ras such as K-Ras
  • contacting comprising contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I)-(XVI), 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.
  • ring A is a 4- to 10-membered heterocycloalkylene, C 6 -C 10 arylene, or 5- to 10- membered heteroarylene
  • ring B is a C 6 -C 10 aryl or 5- to 10-membered heteroaryl
  • each L is independently -C(R 4 )(R 5 )-, -C(O)-, -O-, -N(R 6 )-, -S-, -S(O)- or -S(O)2-, provided that (L)p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R 6 )
  • R 3 is -C 1 -C 6 alkylene-, -4- to 10-membered heterocycloalkylene-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C 1 -C 6 alkylene-, -4- to 10-membered heterocycloalkylene-, or -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkylene)- is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-R a , C6-C10 aryl, -C1-C6 alkyl-
  • R 3 is -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)- is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-R a , C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10- membered heterocycloalkyl,
  • a pharmaceutical composition comprising at least one compound of any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • 55. 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 53, or a pharmaceutically acceptable salt thereof.
  • 56. A compound of any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
  • the portion of A-B defined by the group or chemical structure A can be represented by , , or , where each of “-*”, “-**”, and “ ” represents a bond to A and the point of covalent bond attachmen t t B Alt ti l
  • the portion of A-B defined by the group or chemical structure B can be represented by , , or , where each of “-*”, “-**”, and “ ” represents a bond to B and [0168]
  • alkyl refers to a straight- or branched-chain monovalent hydrocarbon group.
  • alkylene refers to a straight- or branched-chain divalent 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.
  • 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 ((-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 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. [0170]
  • 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. 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 C 2 -C 12 alkenylene, or C 2 -C 6 alkenyl or C 2 -C 6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl.
  • alkynyl refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds.
  • alkynylene refers to a straight- or branched- chain divalent hydrocarbon group having one or more triple bonds.
  • 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 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. [0172]
  • the term “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 divalent 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 monovalent radicals of the following entities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:
  • a cyclopropyl moiety can be depicted by the structural formul .
  • a cyclopropylene moiety can be depicted by the structural formul .
  • a cycloalkyl or cycloalkylene group can be 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.
  • the term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents.
  • haloalkyl groups include –CF 3 , -(CH 2 )F, -CHF 2 , -CH 2 Br, -CH 2 CF 3 , and -CH2CH2F.
  • 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 -CH2C(H)(F)-.
  • aryl refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • arylene refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • aryl or “arylene”
  • aryl mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms
  • C6-C10 aryl monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms
  • divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms C 6 - C14 arylene
  • divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms C6-C10 arylene
  • aryl groups are phenyl, naphthalenyl and anthracenyl.
  • arylene groups are phenylene, naphthalenylene and anthracenylene. 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.
  • 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 divalent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • heterocycloalkyl or “heterocycloalkylene”
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • the ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: O H H H H N O N N N O , [0177]
  • a three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane.
  • a four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane.
  • a five-membered heterocycle 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 five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one.
  • a six-membered heterocycle 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 heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4- tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide.
  • a “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.
  • a hexahydro-1H-pyrrolizinyl moiety can be depicted by the structura n particular, an example of a hexahydro-1H-pyrrolizinylene .
  • 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.
  • 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 divalent 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.
  • the ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: [018 - 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 monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • Non-limiting examples of six-membered heteroarylene groups include divalent 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.
  • Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2- b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula .
  • an example of an isoquinolin-3(2H)-oneylene moiety can be depicted by the structural formu .
  • a eteroaryl 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.
  • substituted 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. [0186] 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. [0187] 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.
  • Certain chemical entities of Formula (I)-(XVI) may be depicted in two or more tautomeric forms.
  • tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tutomers, and the like.
  • T OM)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.
  • C1-C3 refers independently to embodiments that have one carbon member (C 1 ), embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C3).
  • Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • disubstituent –J-K- where J ⁇ K, refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member.
  • a compound portion –(L) p - having the formula -CH(CH 3 )-CH 2 O(CH 2 ) 2 N(CH 3 )C(O)-, connecting two rings, A and B, will be understood that -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, can include both of the embodiments A-CH(CH3)-CH2O(CH2)2N(CH3)C(O)-B and B-CH(CH3)-CH2O(CH2)2N(CH3)C(O)-A.
  • certain of the compounds described herein include one or more position that can exists as stereoisomers.
  • certina of the compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements.
  • a carbon atom that can exist in stereoisomeric arrangements that is depiected without showing any stereoisomeric arrangement includes as a disclosure each of eh possible stereoisomeric arrangements.
  • a carbon atom having four groups that can be priorized according to the Cahn-Ingold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical definition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown below where R a > R b > R c > R d according to the Cahn-Ingold Prelog Rules.
  • 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)-(XVI), 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)-(XVI)).
  • 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)-(XVI), 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)-(XVI) 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.
  • KRAS inhibitor includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the KRAS gene, called K-Ras, that is involved in the RAS/MAPK signaling pathway.
  • KRAS gene, K-Ras, and RAS/MAPK signaling pathway will be known and understood by one of skill in the art. It will be appreciated that KRAS mutations occur in approximately one in seven of all human metastatic cancers, and that those mutations can occur in a variety of locations in the KRAS gene coding sequence.
  • KRAS mutations primarily occur in KRAS codons 12 and 13, and also occur in codons 18, 61, 117, and 146 at low frequencies and have distinct effects on tumor cell signaling based on the codon and missense mutation.
  • KRAS mutations include, but are not limited to KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like.
  • KRAS G12D refers to inhibiting the protein encoded by the KRAS G12D gene, having a coding sequence (e.g. a guanine to adenine substitution, at position 35 on codon 12 of the KRAS coding sequence) that produces a K-Ras G12D protein, where a glysine at position 12 of the protein sequence is replaced by am aspartic acid.
  • a coding sequence e.g. a guanine to adenine substitution, at position 35 on codon 12 of the KRAS coding sequence
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0201] wherein R 1 , R 2 , R 3 , A, B, L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, II [0203] wherein R 1 , R 2 , R 3 , B, L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0205] wherei , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, [0207] wherein described herein.
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [0209] wherein R 1 , R 2 , A, B, L, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 .
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , B, L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 .
  • the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, [0213] w , and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 . [0214] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [0217] wherein R 1 , R 2 , R 3 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0218] In some embodiments, 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, [0221] wherein R 1 , R 2 , R 3 , A, L, X, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, [0222] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof, [0225] wher p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R 3 . [0226] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H- pyrrolizinylene group is optionally substituted as described herein with respect to R 3 .
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, [0229] wherein R 1 , R 2 , L, X, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein, and each hydrogen atom in the pyrrolidinylene group is optionally substituted as described herein with respect to R 3 . [0230] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
  • ring A is a 4- to 10-membered heterocycloalkylene, C 6 -C 10 arylene, or 5- to 10-membered heteroarylene.
  • ring A is a 4- to 10-membered heterocycloalkylene.
  • ring A is a mono-cyclic 4- to 10-membered heterocycloalkylene.
  • ring A is a bicyclic 5- to 10-membered heterocycloalkylene. In some embodiments, ring A is a fused bicyclic 5- to 10-membered heterocycloalkylene. In some embodiments, ring A is a bridged bicyclic 6- to 10-membered heterocycloalkylene. In some embodiments, ring A is a spiro bicyclic 6- to 10-membered heterocycloalkylene.
  • Ring A is a 4- to 10-membered heterocycloalkylene, such as a mono-cyclic 4- to 10-membered heterocycloalkylene or a bicyclic 5- to 10-membered heterocycloalkylene, including fused bicyclic 5- to 10-membered heterocycloalkylene, bridged bicyclic 6- to 10-membered heterocycloalkylene, and spiro bicyclic 6- to 10-membered heterocycloalkylene, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkylene, as described above, is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR c , -OC(O)
  • Ring A is a 4- to 10-membered heterocycloalkylene, such as a mono-cyclic 4- to 10-membered heterocycloalkylene or a bicyclic 5- to 10-membered heterocycloalkylene, including fused bicyclic 5- to 10-membered heterocycloalkylene, bridged bicyclic 6- to 10-membered heterocycloalkylene, and spiro bicyclic 6- to 10-membered heterocycloalkylene, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkylene, as described above, is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR c , -OC(O)
  • Ring A is azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5-dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1-dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3-dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4-thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3- oxazinan-2-on
  • Ring A is azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5-dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1-dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3-dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4-thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3- oxazinan-2-on
  • Ring A is azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5-dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1-dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3-dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4-thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3- oxazinan-2-on
  • Ring A is of the formula [0241] wherein each of * and ** is p f covalent attachment, each of X 1 -X 6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that two of X 1 -X 6 are independently -CH- o 1 6 N and the remaining X -X are -CH 2 -, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 ary
  • Ring A is of the formula [0243] wherein each of * and ** is p f covalent attachment, each of X 1 -X 6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that two of X 1 -X 6 are independently -CH- or -N- and the remaining X 1 -X 6 are -CH 2 -, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl,
  • Ring A is of the formula [0245] wherein each of * and ** is p f covalent attachment, each of X 1 -X 6 is independently -CH-, -CH 2 -, -O-, -S-, -N-, or -NH-, provided that two of X 1 -X 6 are independently -CH- or -N- and the remaining X 1 -X 6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-
  • Ring A is of the formula [0247] wherein * is a point of covalent attachmen a point of covalent attachment to (L) p , each of X 1 -X 6 is ind S-, -N-, or -NH-, provided that two of X 1 -X 6 are independently -CH- or -N- and the remaining X 1 -X 6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to
  • Ring A is of the formula [0249] wherein * is a point of covalent attachmen a point of covalent attachment to (L) p , each of X 1 -X 6 is ind S-, -N-, or -NH-, provided that two of X 1 -X 6 are independently -CH- or -N- and the remaining X 1 -X 6 are -CH 2 -, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10
  • Ring A is of the formula [0251] wherein each of * and ** is a po o covalent attachment, X 1 is -CH- or -N-, each of X 2 -X 6 is independently -CH-, -CH 2 -, -O-, -S-, -N-, or -NH-, provided that one of X 2 -X 6 is -CH- or -N- and the remaining X 2 -X 6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl
  • Ring A is of the formula [0253] wherein each of * and ** is a po o covalent attachment, X 1 is -CH- or -N-, each of X 2 -X 6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X 2 -X 6 is -CH- or -N- and the remaining X 2 -X 6 are -CH 2 -, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl
  • Ring A is of the formula [0255] wherein each of * and ** is a po o covalent attachment, X 1 is -CH- or -N-, each of X 2 -X 6 is independently -CH-, -CH 2 -, -O-, -S-, -N-, or -NH-, provided that one of X 2 -X 6 is -CH- or -N- and the remaining X 2 -X 6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl
  • * is a point of covalent attachmen a point of covalent attachment to (L) p
  • X 1 is -CH- or -N-, eac H-, -CH 2 -, -O-, -S-, -N-, or -NH-, provided that one of X 2 -X 6 is -CH- or -N- and the remaining X 2 -X 6 are -CH 2 -, -O-, -S-, or -NH-
  • Ring A does not include an O-O, O-S, O-N, or N-S bond
  • each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered
  • * is a point of covalent attachmen a point of covalent attachment to (L) p
  • X 1 is -CH- or -N-, eac H-, -CH 2 -, -O-, -S-, -N-, or -NH-, provided that one of X 2 -X 6 is -CH- or -N- and the remaining X 2 -X 6 are -CH 2 -, -O-, -S-, or -NH-
  • Ring A does not include an O-O, O-S, O-N, or N-S bond
  • each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered
  • * is a point of covalent attachmen a point of covalent attachment to (L) p
  • X 1 is -CH- or -N-, eac H-, -CH 2 -, -O-, -S-, -N-, or -NH-, provided that one of X 2 -X 6 is -CH- or -N- and the remaining X 2 -X 6 are -CH 2 -, -O-, -S-, or -NH-
  • Ring A does not include an O-O, O-S, O-N, or N-S bond
  • each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR c ,
  • Ring A is of the formula [0263] wherein each of * and ** is a point of covalent attachment, X 1 and X 5 are each independently -CH- or -N-, each of X 2 , X 3 , X 4 , or X 6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC
  • Ring A is of the formula [0269] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X 1 and X 5 are each in 2 3 of X , X , X 4 , and X 6 is independently -CH 2 -, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R 1 that is deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR c , -OC(O)R c , -OC(O)NR c R d
  • R 1 is not 4- to 10-membered heterocycloalkyl, -OC(O)R c , -S(O)2R c , -SR c , -NR c C(O)R d , -C(O)OR c , -C(O)R c , or –CN.
  • an R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl
  • one or more hydrogen atoms in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are substituted by halogen, -OS(O)2R e , -S(O)2R e , -SR e , -C(O)R e , -CN, or -NO2.
  • R 1 when X 4 is -NH-, then R 1 is not 4- to 10-membered heterocycloalkyl, -C(O)OR c , or -C(O)R c .
  • R 1 when X 4 is -NH- and R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, then one or more hydrogen atoms in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl are substituted by halogen, -OS(O)2R e , -S(O)2R e , -SR e , -C(O)R e , -CN, or -NO 2 .
  • R 1 is not 4- to 10-membered heterocycloalkyl, -OC(O)R c , -S(O)2R c , -SR c , -NR c C(O)R d , -C(O)OR c , -C(O)R c , or -CN.
  • X 4 is -CH 2 - and R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C6-C10 aryl, or 5- to 10-membered heteroaryl
  • one or more hydrogen atoms in C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl are substituted by halogen, -OS(O)2R e , -S(O)2R e , -SR e , -C(O)R e , -CN, or -NO2.
  • R 1 when an R 1 is attached to a X 2 , X 3 , X 4 , X 5 , or X 6 that is an -NH- , then R 1 is not -C(O)R c . In some embodiments, when an R 1 is attached to a X 4 that is an -NH- , then R 1 is not -C(O)R c . [0313] In some embodiments, when an R 1 is attached to a X 2 , X 3 , X 4 , X 5 , or X 6 that is an -NH- and R 1 is -C(O)R c , then R c is not C2-C6 alkenyl.
  • m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
  • Ring B is C 6 -C 10 aryl or 5- to 10-membered heteroaryl. In some embodiments, Ring B is mono- or bi-cyclic C6-C10 aryl or mono- or bi-cyclic 5- to 10- membered heteroaryl. [0318] In some embodiments, Ring B is mono- or bi-cyclic C6-C10 aryl. In some embodiments, Ring B is monocyclic C 6 -C 10 aryl. In some embodiments, Ring B is bicyclic C 6 -C 10 aryl.
  • Ring B is furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, isoquinolin-3(2H)-onyl, thieno[3,2- b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-benzo[d]imidazolyl, benzo[d]oxazolyl, or
  • each R 2 when present, is independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, -OH, and NH2. In some embodiments, each R 2 , when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -OH, and NH2. [0337] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • n is 3. In some embodiments, n is 4. [0338] In some embodiments, q is 0. In some embodiments, q is 1. [0339] In some embodiments, -X- is -O-, -S-, or–NR 7 -. In some embodiments, -X- is -O-. In some embodiments, -X- is -S-. In some embodiments, -X- is –NR 7 -.
  • R 3 is -C 1 -C 6 alkylene-, -C 2 -C 6 alkenylene-, -C 2 -C 6 alkynylene-, -C3-C6 cycloalkylene-, -(4- to 10-membered heterocycloalkylene)-, -C1-C6 alkylene-(4- to 10- membered heterocycloalkylene)-, -C 6 -C 10 arylene-, -C 1 -C 6 alkylene-(C 6 -C 10 arylene)-, -(5- to 10-membered heteroarylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 3 -C 6 cycloalkylene, 4- to 10-
  • R 3 is -C 1 -C 6 alkylene-, -(4- to 10-membered heterocycloalkylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-, -(4- to 10-membered heterocycloalkylene)-, and -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O- C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -
  • R 3 is of the formula , [0343] wherein * represents a point ttachment to –(L)p, “ ” is a point of covalent attachmen d each hydrogen atom is independently optionally substitut kyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -
  • R 3 is of the formula , [0345] wherein * represents a point tachment to –(L) p , “ ” is a point of covalent attachmen d each hydrogen atom is independently optionally substitut kyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-R a , C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, -C 1 -C 6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f ,
  • R 3 is of the formula , [0347] wherein * represents a point ttachment to –(L)p, “ ” is a point of covalent attachment d each hydrogen atom is independently optionally substitute kyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-R a , C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, -C 1 -C 6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(
  • R 3 is of the formula , [0349] wherein * represents a point o attachment to –(L)p, “ ” is a point of covalent attachmen d each hydrogen atom is independently optionally substitut kyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-R a , C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)
  • R 3 is of the formula , [0351] wherein each hydroge ionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e ,
  • R 3 is of * , [0353] wherein * is a point of and is a point of covalent attachmen X. [0354] In or C1-C6 alkyl. [0355] 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 1 is C(R 8 ). In some embodiments, Z 2 is C(R 9 ). In some embodiments, Z 3 is C(R 10 ). In some embodiments, Z 4 is C(R 11 ). In some embodiments, Z 5 is C(R 12 ).
  • any of the possible combinations of Z 1 -Z 7 as provided above can be combined.
  • Z 1 is N, and Z 2 is N.
  • Z 1 is N, Z 2 is N, Z 3 is C(R 10 ), Z 4 is N, and Z 5 is C(R 12 ).
  • Z 1 is N, Z 2 is N, Z 3 is C(R 10 ), Z 4 is C(R 11 ), and Z 5 is C(R 12 ).
  • Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is N, and Z 5 is C(R 12 ).
  • Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is C(R 11 ), and Z 5 is C(R 12 ). In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 10 ), Z 4 is C(R 11 ), and Z 5 is N. In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 10 ), Z 4 is N, and Z 5 is N. In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 10 ), Z 4 is N, and Z 5 is C(R 12 ). In some embodiments, Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is C(R 11 ), and Z 5 is C(R 12 ).
  • Z 1 is N
  • Z 2 is N
  • Z 3 is N
  • Z 4 is N
  • Z 5 is N.
  • R 8 when present, is H.
  • R 9 when present, is H.
  • R 10 when present, is H or F.
  • R 11 when present, is H.
  • R 12 when present, is H.
  • each L is independently -C(R 4 )(R 5 )-, -C(O)-, -O-, -N(R 6 )-, -S-, -S(O)- or -S(O) 2 -, provided that (L) p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O- N(R 6 )- bond.
  • each L is independently each L is independently -C(R 4 )(R 5 )-, -C(O)-, -O-, or -N(R 6 ), provided that (L)p does not comprise a –O-O- or a -O-N(R 6 )- bond, and the point of covalent attachment of R 3 to (L)p does not form a –O-O- or a –O-N- bond.
  • each L is independently -C(R 4 )(R 5 )-, -C(O)-, -O-, or -N(R 6 ), provided that (L) p does not comprise a –O-O- or a –O-N(R 6 )- bond, and the point of covalent attachment of R 3 to (L)p does not form a –O-O- or a –O-N- bond.
  • p is 4, 5, 6, 7, 8, or 9.
  • p is 5, 6, 7, 8, or 9.
  • p is 4, 5, 6, 7, or 8.
  • p is 5, 6, 7, or 8.
  • p is 6, 7, 8, or 9.
  • p is 5, 6, or 7. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9.
  • -(L)p- is -(CR 4 R 5 )4-, -(CR 4 R 5 )5-, -(CR 4 R 5 )6-, -(CR 4 R 5 )7-, -(CR 4 R 5 ) 8 -, -(CR 4 R 5 ) 9 -, -(CR 4 R 5 )C(O)N(R 6 )-(CR 4 R 5 ) 2 O-, -(CR 4 R 5 )N(R 6 )C(O)-(CR 4 R 5 ) 2 O-, -N(R 6 )-C(O)(CR 4 R 5 )2O(CR 4 R 5 )2-, -CR 4 R 5 O(CR 4 R 5 )2O-(CR 4 R 5 )2, -O(CR 4 R 5 )2O(CR 4 R 5 )2O-, -CR 4 R 5 O-CR 4 R 5 -C(O)N(R 6 )
  • -(L)p- is -(CR 4 R 5 )4-, -(CR 4 R 5 )5-, -(CR 4 R 5 )6-, -(CR 4 R 5 )7-, -(CR 4 R 5 ) 8 -, -(CR 4 R 5 ) 9 -, -(CR 4 R 5 )C(O)N(R 6 )-(CR 4 R 5 ) 2 O-, -(CR 4 R 5 )N(R 6 )C(O)-(CR 4 R 5 ) 2 O-, -N(R 6 )-C(O)(CR 4 R 5 ) 2 O(CR 4 R 5 ) 2 -, -CR 4 R 5 O(CR 4 R 5 ) 2 O-(CR 4 R 5 ) 2 -, -CR 4 R 5 O(CR 4 R 5 ) 2 O-(CR 4 R 5 ) 2 -, -CR 4 R 5 O(CR 4 R 5 ) 2 O-(CR 4 R
  • -(L)p- comprises -(CR 4 R 5 )4-, -(CR 4 R 5 )5-, -(CR 4 R 5 )6-, -(CR 4 R 5 ) 7 -, -(CR 4 R 5 ) 8 -, -(CR 4 R 5 ) 9 -, -CR 4 R 5 C(O)N(R 6 )-(CR 4 R 5 ) 2 OCR 4 R 5 -, -C(O)N(R 6 )-(CR 4 R 5 )2O(CR 4 R 5 )2-, -N(R 6 )-C(O)(CR 4 R 5 )2O(CR 4 R 5 )2-, -CR 4 R 5 O(CR 4 R 5 ) 2 O-(CR 4 R 5 ) 2 , -O(CR 4 R 5 ) 2 O(CR 4 R 5 ) 2 O-, -CR 4 R 5 O-CR 4 R 5 - C(O)
  • -(L)n- is -(L)p- is -(CR 4 R 5 )4-, -(CR 4 R 5 )5-, -(CR 4 R 5 )6-, -(CR 4 R 5 )7- , -(CR 4 R 5 ) 8 -, -(CR 4 R 5 ) 9 -, -CR 4 R 5 C(O)N(R 6 )-(CR 4 R 5 ) 2 OCR 4 R 5 -, -C(O)N(R 6 )- (CR 4 R 5 )2O(CR 4 R 5 )2-, -N(R 6 )-C(O)(CR 4 R 5 )2O(CR 4 R 5 )2-, -CR 4 R 5 O(CR 4 R 5 )2O-(CR 4 R 5 )2, -O(CR 4 R 5 ) 2 O(CR 4 R 5 ) 2 O-, -CR 4 R 5 O-CR 4 R 5 )
  • R 4 when present, is H, C1-C6 alkyl, -OH, or –OCH3. In some embodiments, R 4 , when present, is H, methyl, -OH, or –OCH 3 . In some embodiments, R 5 , when present, is H, C1-C6 alkyl, -OH, or –OCH3. In some embodiments, R 5 , when present, is H, methyl, -OH, or –OCH 3 . In some embodiments, R 6 , when present, is H or C 1 -C 6 alkyl. In some embodiments, R 6 , when present, is H or methyl.
  • -(L) p - is -CH 2 C(O)N(H)-(CH 2 ) 2 O-, -CH 2 C(O)N(CH 3 )- (CH2)2O-, -CH2C(O)N(CH2CH3)-(CH2)2O-, -CH2N(H)C(O)-(CH2)2O-, -CH2C(O)N(CH3)C(O)-(CH2)2O-, -CH2C(O)N(CH2CH3)C(O)-(CH2)2O-, -C(O)N(H)- (CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)3O-, -CH2O(CH2)2OCH2-, -(CH2)2O(CH2)2O-, -CH2O-CH2-C(O)N(H)-(CH2), -CH2-C(
  • -(L) p - is -CH 2 C(O)N(H)-(CH 2 ) 2 OCH 2 -, -C(O)N(H)- (CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)2O-(CH2)2, -O(CH2)2O(CH2)2O-, -CH 2 O-CH 2 -C(O)N(H)-(CH 2 ) 2 -, -CH 2 O(CH 2 ) 2 C(O)N(H)-CH 2 -, -CH 2 O(CH 2 ) 2 N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-,
  • the disclosure provides a compound selected from the group consisting of (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]
  • the disclosure provides a compound selected from the group consisting of (2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.1 2,7 .1 4,7 .0 20,25 ]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (2'R,4R,4'R,7S)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaaza
  • 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. [0370] 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 Ras, in particular K-Ras.
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like.
  • KRAS G12C KRAS G12D
  • KRAS G12V KRAS G12R
  • KRAS G12S KRAS G13C
  • KRAS G13D KRAS G13D
  • KRAS A18D KRAS Q61H, KRAS K117N, and the like.
  • methods of treating a target cancer are described.
  • 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.
  • the cell is preferably a cancer cell with abnormal signaling due to a mutation of KRAS, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like.
  • 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. Patients may also require chronic treatment on a long-term basis.
  • 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.
  • Compound I-1 and I-2 are prepared via conventional chemistry from commercially available materials. Under SN2 displacement reaction condition A, compounds I-1 and I-2 are converted to a product, I-3, which then reacts with I-4 (prepared from commercially available material) to generate I-5. Under palladium-catalyzed Suzuki coupling condition I-5 and a variety of boronic esters react to generate I-6. After deprotection step D and amide coupling step E, macrocycles I-8 is formed. Deprotection of Boc and MOM groups under acid condition F produces Compound 1, isolated as the desired diastereomer. [0392] Scheme II 2 are prepared via conventional chemistry from commercially available materials. Under SN2 displacement reaction conditions A and B, macrocycle II-4 is formed.
  • Step B tert-butyl 1-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (B1-3): To a suspension of tert-butyl (lR,5S)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-2, 1.0 eq.) in diethyl ether at -40 °C is added N1,N1,N2,N2-tetramethylethane-1,2-diamine (1.5 eq.), followed by slow addition of sec- butyllithium (1.5 eq.).
  • tert-butyl 1-(aminomethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate B1-4: Diisopropyl azodicarboxylate (1.0 eq.) is added slowly to a solution of triphenylphosphine (PPh3) (1.0 eq.), tert-butyl 1-(hydroxymethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-3, 1.0 eq.) and phthalimide (1.0 eq.) in toluene which is pre-cooled with a -5 °C.
  • PPh3 triphenylphosphine
  • phthalimide 1.0 eq.
  • tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate B1-5: Benzyl chloroformate (1.1 eq.) is added over 15 minutes to a stirred solution of tert-butyl 1-(aminomethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-4, 1.0 eq.) in EtOH/water (1:1 v/v) at 0 °C.
  • Step E tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1): To a solution of tert-butyl 1- ((((benzyloxy)carbonyl)amino)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1-5, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.).
  • Step B tert-butyl 1-((((benzyloxy)carbonyl)(methyl)amino)methyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B2): To a solution of tert-butyl 1- ((((benzyloxy)carbonyl)amino)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B2-1, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.).
  • Step o[3.2.1]octane-8- carboxylate (B3-1) To a solution of tert-butyl (lR,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (B1-2, 1.0 eq.) in THF at -78 °C is added N1,N1,N2,N2-tetramethylethane-1,2- diamine (1.5 eq.), followed by slow addition of sec-butyllithium (1.5 eq.). The mixture is warmed to 0 °C and maintained at that temperature for 30 min before cooling to -78 °C.
  • (2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-ol (C1-3): a solution of ethyl (2R,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (C1-2, 1.0 eq.) in THF is cooled to 0 0 C and lithium aluminum hydride (1M in THF) (3.0 eq.) is added dropwise. After stirred for 30 minutes, the mixture is heated to 70 °C for 2 hours. The mixture is diluted with ethyl ether, cooled to 0 °C and quenched by water, 15% aqueous NaOH followed by water.
  • Step C The vessel is warmed to room temperature and stirred for 30 minutes. To the mixture is added anhydrous magnesium sulfate. The mixture is stirred for 30 minutes before being filtered. The solution is concentrated, and the crude is used directly for the next step. [0410] Step C.
  • Step E methyl 3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propanoate (C1): a solution of methyl 3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoate (C1-5, 1.0 eq.) in THF is added tetra-n-butylammonium fluoride (1.0M in THF, 1.1 eq.).
  • Step B tert-butyl (2-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)ethyl)(methyl)carbamate (C3): a solution of tert-butyl (2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethyl)(methyl)carbamate (C3-1, 1.0 eq.) in THF is added tetra-n-butylammonium fluoride (1.0M in THF, 1.1 eq.).
  • Step A tert-butyl 1-(2-hydroxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (D1-1): To a suspension of tert-butyl (lR,5S)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-2, 1.0 eq.) in diethyl ether at -40 °C is added N1,N1,N2,N2-tetramethylethane-1,2-diamine (1.5 eq.), followed by slow addition of sec- butyllithium (1.5 eq.).
  • Step B The mixture is warmed to 0 °C and maintained at that temperature for 30 min before cooling to -78 °C. Then, the solution of ethylene oxide (1.5 equiv) in Et 2 O, which is pre-cooled to ⁇ 78° C., is transferred to the previous flask via a cannula under N2 and then BF 3 .Et 2 O (1.5 equiv) is added dropwise over 30 min. After stirring at ⁇ 78 °C for 2 h, the reaction mixture is slowly warmed to rt and water is carefully added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0421] Step B.
  • tert-butyl 1-(2-((methylsulfonyl)oxy)ethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate D1-2: To a solution of tert-butyl 1-(2- hydroxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D1-1, 1.0 eq.) and Et3N (3.0 eq.) in THF, is added methanesulfonyl chloride (1.2 eq.). After stirring for 1 hour, water is added to quench the reaction.
  • methanesulfonyl chloride 1.2 eq.
  • Step C methyl 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)acetate (D1-3): To the suspension of NaH (1.2 eq.) in THF, is slowly added while stirring the solution of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro- 1H-pyrrolizin-2-ol (C1-4, 1.0 eq.) in THF.
  • Step D 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)ethan-1-ol (D1-4): To the solution of methyl 2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)acetate (D1-3, 1.0eq.) in THF is slowly added LiBH4 (4.0 eq.).
  • Step E tert-butyl 1-(2-(2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethoxy)ethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D1-5): To the suspension of NaH (1.2 eq.) in THF, is slowly added while stirring the solution of 2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethan-1-ol (D1-4, 1.0 eq.) in THF.
  • tert-butyl 1-(((methylsulfonyl)oxy)methyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate D2-2: To a solution of tert-butyl 1- (hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1-3, 1.0 eq.) and Et3N (3.0 eq.) in THF, is added methanesulfonyl chloride (1.2 eq.). After stirring for 1 hour, water is added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound.
  • Step C tert-butyl 1-((3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)-3-trityl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D2-3): To the suspension of NaH (1.2 eq.) in THF, is slowly added while stirring the solution of 3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propan-1-ol (D2-1, 1.0 eq.) in THF.
  • Step B 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)acetic acid (D3-2): Typical ester hydrolysis is used to produce D3-2.
  • Step C 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)acetic acid
  • tert-butyl 2-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate (D5-2) D5-2 is synthesized from tert-butyl 4-tritylpiperazine-1-carboxylate (D5-1) using the same procedure as B1-3.
  • Step B tert-butyl 2-(((methylsulfonyl)oxy)methyl)-4-tritylpiperazine-1-carboxylate (D5-3): D5-3 is synthesized from tert-butyl 2-(hydroxymethyl)-4-tritylpiperazine-1- carboxylate (D5-2) using the same procedure as D2-2.
  • Step C Step C.
  • D5-4 is synthesized from tert-butyl 2- (((methylsulfonyl)oxy)methyl)-4-tritylpiperazine-1-carboxylate (D5-3) and 3-(((2R,7aR)-7a- (((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propan-1-ol (D2-1) using the same procedure as D2-3.
  • Step D tert-butyl 2-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propoxy)methyl)piperazine-1-carboxylate (D5): D5 is synthesized from tert-butyl 2- ((3-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propoxy)methyl)-4-tritylpiperazine-1-carboxylate (D5-4) using the same procedure as D2.
  • Step D tert-butyl 1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)-N-methylpropanamido)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D6): To a solution of tert-butyl 1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)-N-methylpropanamido)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D6-3, 1.0 eq.) in 1,
  • Step E After filtration to remove Pd/C catalyst, the solution is added NaOH solution to hydolyze the methyl ester. After neutralization with sodium bicarbonate solution, the mixture is evaporated to dryness. The mixture is mixed with MeOH and filtered to remove solid. This solution of crude product is used directely to the next step. [0454] Step E.
  • Step F (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one: Crude compound from Step E (tert-butyl (14R,20R)-26- fluoro-27-[8-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-10-oxo-13,22-dioxa- 2,9,16
  • Step A tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-((3- (((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)-N- methylpropanamido)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.0 eq.) and N,N-Diisopropylethylamine (6.0 eq.) in dichloromethane is added tert-butyl 1-((3-(((2R,7aR)-7a- (hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)-N-methylpropanamido)methyl
  • Step 2 To a solution of (cis)-ethyl-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H- pyrrolizine-8-carboxylate (16.6 g, 77.8 mmol, 1 eq) in MeOH (50 mL) was added NaBH 4 (4.42 g, 117 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 3 To a solution of (cis)-6-hydroxy-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin-3-one (12.6 g, 73.6 mmol, 1 eq) in THF (150 mL) was added BH 3 -Me 2 S (10 M, 36.80 mL, 5 eq) and the mixture was stirred at 60 °C for 3 h.
  • Step 5 To a solution of (cis)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-ol (16.3 g, 41.20 mmol, 1 eq) in THF (120 mL) was added tert-butyl prop-2-enoate (10.6 g, 82.4 mmol, 11.96 mL, 2 eq) and KOH (1.16 g, 20.6 mmol, 0.5 eq). The mixture was stirred at 25 °C for 16 h.
  • Step 3 To a solution of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl]-1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (924 mg, 1.13 mmol, 1 eq) and 2-[8-fluoro-3-(methoxymethoxy)-1-naphthyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (752 mg, 2.26 mmol, 2 eq.) in THF (15 mL) was added [2-(2-aminophenyl)
  • Step 4 To a solution of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[8-fluoro-3-(methoxymethoxy)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[[methyl-(2,2,2-trifluoroacetyl) amino] methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.203 mmol, 1 eq) in THF (4 mL) and H 2 O (0.5 mL) was added LiOH.H2O (25.5 mg, 0.608 mmol, 3 eq).
  • Step 3 To a solution of tert-butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (8.50 g, 35.4 mmol, 1 eq) in THF (100 mL) was added sat.
  • benzyl dihydro-3H-3a,7-ethano[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate 1,1-dioxide (620 mg, 1.83 mmol, 1 eq) was then added to the mixture and stirred at 25 °C for 1 h. On completion, the mixture was quenched by water (10 mL).
  • Step 2 To a solution of tert-butyl 1-[3-[[(2R,8R)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propoxymethyl]- 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (634 mg, 0.709 mmol, 1 eq) in THF (10 mL) was added pyridine-hydrofluoride (151 mg, 1.06 mmol, 70%, 1.5 eq).
  • Peak 1 tert-butyl (4R,7S,14R,20R)-27-chloro-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate) (26.0 mg, 12.5% yield) as brown solid [LC/MS: (M+1: 619.2)] and Peak 2 (tert-butyl (4S,7R,14R,20R)-27-chloro-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1
  • Step 4 To a solution of tert-butyl (tert-butyl (4R,7S,14R,20R)-27-chloro-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate (26.0 mg, 0.042 mmol, 1 eq) and 2-[8-fluoro-3-(methoxymethoxy)- 1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.9 mg, 0.084 mmol, 2 eq) in THF (1 mL) was added [2-(2-aminophenyl)phenyl]palladium(1
  • Step 7 Preparation of Cpd.6b and Cpd.6: To a solution of tert-butyl (4S,7R,14R,20R)- 26-fluoro-27-[8-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (28.0 mg, 0.0355 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 1.0 mL, 112 eq).
  • Step 5 To a solution of (4R,7S,14R,20R)-26-fluoro-27-(7-fluoro-3-hydroxy-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (racemic Peak 1, 25 mg, 0.029 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (22.3 mg, 0.147 mmol, 5 eq) at 25 °C.
  • Peak 1 (4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one as a brown solid.
  • Peak 2 (4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one as a brown solid.
  • reaction mixture was diluted with water (10 mL) and extraction workup with DCM followed by concentration under vacuum to afford tert-butyl 1-[[(2,2,2-trifluoroacetyl)amino]methyl] - 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.30 g, 46.8% yield) as light yellow solid.
  • Step 7 To a mixture of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl]-1-[[(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (385 mg, 0.479 mmol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan -2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (4
  • Step 9 To a mixture of tert-butyl 1-(aminomethyl)-3-[2-[[(2R,8R)-2-(3-tert-butoxy-3- oxo-propoxy) -1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, 0.293 mmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL, 68.1 eq).
  • Example 4 Preparation of 5-ethynyl-6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 30-a); and 5-ethynyl-6-fluoro-4-[(4S,7R,14S,20S)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .
  • Step 3 To a solution of 6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-2-ol (120 mg, 0.145 mmol, 1 eq) in DMSO (2 mL) was added CsF (176.3 mg, 8 eq).
  • Example 4 Preparation of 5-ethynyl-6-fluoro-4-[(4R,7S,14S,20S)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 30-c); and 5-ethynyl-6-fluoro-4-[(4S,7R,14R,20R)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20
  • Step 2 To a solution of tert-butyl (4S,7R,14R,20R)-26-fluoro-27-[7-fluoro-3- (methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (10.0 mg, 0.0103 mmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.0026 mL, 1 eq).
  • Step 3 To a solution of (4S,7R,14R,20R)-26-fluoro-27-[7-fluoro-3- (methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaene (58.0 mg, 0.0703 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (64.1 mg, 0.421 mmol, 6 eq).
  • Example 5 Preparation of 4-[(4R,7S,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 31-a); 4- [(4R,7S,14S,18S,20R)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30
  • Step 1 To le (10.2 g, 149 mmol, 2.03 eq) in DCM (150 mL) was added ethyl (2R,8R)-2-hydroxy-5-oxo- 2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate (15.7 g, 73.6 mmol, 1 eq) slowly at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was washed with water (100 mL * 2) and the organic phase was dried with anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum.
  • Step 2 To a solution of ethyl (2R,8R)-2-[tert-butyl(diphenyl)silyl]oxy-5-oxo-2,3,6,7- tetrahydro-1H-pyrrolizine-8-carboxylate (23.0 g, 50.9 mmol, 1 eq) in THF (250 mL) was added LDA (2 M, 38.2 mL, 1.5 eq) dropwise at -78 °C.
  • Step 11 To a solution of 3-benzyl 8-(tert-butyl) 1-((3-(((2R,6R,7aS)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.77 g, 2.13 mmol, 1 eq) in i-PrOH (20 mL) was added Pd/C (300 mg, 10%) and Pd(OH) 2 /C (300 mg, 10%) under H 2 .
  • Step 16 To a solution of tert-butyl (4R,7S,14R,18R,20S)-18,26-difluoro-27-[7-fluoro- 3-(methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.1 2,7 .1 4,7 .1 14,20 .0 16,20 .0 25,30 ]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (13.0 mg, 0.0132 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 1 mL, 304 eq).
  • Example 6 Preparation of (2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.1 2,7 .1 4,7 .0 20,25 ]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (Compound 32-a); and (2'R,4R,4'R,7S)-22-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaaza
  • Step 12 To a solution of (4'R)-4',21-difluoro-22-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]-1'-methyl-spiro[9,17-dioxa-2,13,19,23,26,27- hexazapentacyclo[16.7.1.1 2,7 .1 4,7 .0 20,25 ]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidine]-12-one (37 mg, 0.042 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.031 mL, 3 eq).
  • Step 13 To a solution of (4'R)-4',21-difluoro-22-(7-fluoro-3-hydroxy-8- ⁇ [tri(propan- 2-yl)silyl]ethynyl ⁇ naphthalen-1-yl)-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.1 2,7 .1 4,7 .0 20,25 ]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (7 mg, 0.0083 mmol, 1 eq) in DMSO (0.1 mL) was added CsF (2.52 mg, 0.017 mmol, 2 eq).
  • Step 8 To a mixture of tert-butyl 3-[2-[3-[(tert-butoxycarbonylamino)methyl]-4- methyl-piperazin -1-yl]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-1-[(3-tert-butoxy-3- oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.128 mmol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane (131 mg, 0.256 mmol, 2 eq) in THF (2 mL) was added Ad2
  • HTRF KRAS mutation nucleotide exchange assays [0613] The HTRF KRAS nucleotide exchange assays were performed at Reaction Biology. Briefly, purified KRAS G12D, KRAS G12C or KRAS WT proteins was mixed with a-GST Tb antibody in reaction buffer (20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40). Series dilution of indicated compounds were added to the reaction buffer using acoustic dispenser (ECHO, Labcyte).
  • acoustic dispenser ECHO, Labcyte
  • IC50 values were determined using sigmoidal dose response (variable slope) equation from Prism software (GraphPad Software, San Diego, CA).
  • Cell proliferation assays [0615] 2000 AGS or GP2D cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours. Cell proliferation was measured using CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) following the manufacturer’s protocol. IC50 values were determined using Prism software (GraphPad Software, San Diego, CA). [0616] Kinase phosphorylation assays: [0617] Half a million AGS or GP2D cells per well were seeded in 24-well plate for 2 hours prior to treatment.
  • Antibodies were incubated overnight at 4 o C, washed, incubated with corresponding HRP-conjugated secondary antibodies, and incubated with chemiluminescent substrate for 5 minutes at room temperature.
  • Chemiluminescent images were acquired with a C-DiGit Imaging System (LI-COR Biosciences, Lincoln, NE). The relative density of the chemiluminescent bands was quantified via Image Studio Digits from LI-COR (LI-COR Biosciences, Lincoln, NE). The results are shown in the table below with A: ⁇ 1 ⁇ M; B: ⁇ 1 to ⁇ 10 ⁇ M, C: ⁇ 10 ⁇ M.
  • Example KRAS(G12D) AGS Prolif. GP2D Prolif.

Abstract

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

Description

MACROCYCLIC COMPOUNDS FOR TREATING DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119(e) to U. S. Provisional Application Serial No. 63/191,630 filed on May 21, 2021 and U. S. Provisional Application Serial No.63/340,750 filed on May 11, 2022, the entire disclosures of which are incorporated herein by reference. TECHNICAL FIELD [0002] The present disclosure relates to biaryl macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer. BACKGROUND [0003] Ras is a GTP-binding protein and regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. H-Ras, K-Ras, and N- Ras are the main members of Ras superfamily, which are tightly regulated by factors that switch off the GTPase activity. Somatic mutations at codons 12, 13 and 61 in the RAS genes are associated with about 16% of all human cancers and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-related cancers (Prior I. A. et al, A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457−2467), including 86-96% in pancreatic cancers, 40-50% in colorectal cancers, and 27-39% in lung adenocarcinomas (Kessler D. et al. Drugging an undruggable pocket on KRAS Proc Natl Acad Sci U S A.2019, 116(32):15823-15829). Mutated RAS is locked in the constitutively activated GTP bound state and facilitates enhanced Ras signaling in cancer cells. Despite aggressive efforts in targeting KRAS mutants, there are no inhibitors that directly target RAS have been approved due to absence of good druggable binding pockets in RAS. Recent successful inhibition of the KRAS G12C mutant by covalent chemical modifiers sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) in KRAS G12C mutated lung cancer patients has shed lights on targeting KRAS mutants for therapeutic invention. However, inhibitors targeting KRAS mutants without covalent formation at KRAS G12C are still absent. Therefore, there is unmet medical need to develop new KRAS inhibitors that target KRAS mutants with good efficacy and safety profile for treating patients with KRAS mutant cancers [0004] Overall, it is urgent to develop next generation GTPase 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 of KRAS inhibitors that are potent against oncogenic driver KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like, as well as other emrging and established resistance mutations, while maintaining selectivity over wild type KRAS. SUMMARY [0005] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0006] wherei
Figure imgf000003_0001
[0007] ring A is a 4- to 10-membered heterocycloalkylene, C6-C10 arylene, or 5- to 10- membered heteroarylene; [0008] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0009] each L is independently -C(R4)(R5)-, -C(O)-, -O-, -N(R6)-, -S-, -S(O)- or -S(O)2-, provided that (L)p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R6)- bond; [0010] X is a -O-, -S-, -NR7-; [0011] Z1 is N or C(R8); [0012] Z2 is N or C(R9); [0013] Z3 is N or C(R10); [0014] Z4 is N or C(R11); [0015] Z5 is N or C(R12); [0016] provided that at least two of Z1-Z5 are N; [0017] each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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, or [0018] each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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, or [0019] each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe; [0020] each R2 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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; [0021] R3 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C3-C6 cycloalkylene-, -(4- to 10-membered heterocycloalkylene)-, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, -C6-C10 arylene-, -C1-C6 alkylene-(C6-C10 arylene)-, -(5- to 10- membered heteroarylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocycloalkylene, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene), C6-C10 arylene, -C1-C6 alkylene-(C6-C10 arylene), 5- to 10-membered heteroarylene, and -C1-C6 alkylene-(5- to 10-membered heteroarylene), is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; provided that the R3 and (L)p do not form a –O-O-, a –O-S-, a –S-S-, or a –O-N- bond; [0022] each R4 and R5 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)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 R4 and R5 taken together with the carbon or carbons to which they are attached form a C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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; [0023] each R6 and R7 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-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, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 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; [0024] each of R8, R9, R10, R11, and R12 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -OS(O)NRgRh, -OS(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; [0025] each Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-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, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2; [0026] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; [0027] n is 0, 1, 2, 3, or 4; [0028] p is 4, 5, 6, 7, 8, or 9; and [0029] q is 0 or 1. [0030] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000008_0001
II [0031] wherein R1, R2, R3, B, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0032] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000008_0002
[0033] wherein R1, R2, R3, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0034] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
[0035] wherein
Figure imgf000009_0001
described herein. [0036] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000009_0002
[0037] wherein R1, R2, A, B, L, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0038] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000010_0001
[0039] wherein R1, R2, B, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0040] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, [0041] w
Figure imgf000010_0002
, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0042] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
[0043] wherein
Figure imgf000011_0001
described herein. [0044] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000011_0002
[0045] wherein R1, R2, R3, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0046] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
[0047] w
Figure imgf000012_0001
, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0048] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000012_0002
[0049] wherein R1, R2, R3, A, L, X, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, [0050] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000013_0001
[0051] wherein R1, R2, R3, L, X, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0052] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof, [0053] wher
Figure imgf000013_0002
p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0054] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000014_0001
[0055] wherein R1, R2, L, X, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H- pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0056] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
Figure imgf000014_0002
[0057] wherein R1, R2, L, X, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the pyrrolidinylene group is optionally substituted as described herein with respect to R3. [0058] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
[0059] wherei , Z2, Z3, Z4 5
Figure imgf000015_0001
, Z , m, n, p, and q are as described herein, and each hydrogen atom in the piperazinylene group is optionally substituted as described herein with respect to R3. [0060] In certain embodiments of the above aspects, the compound of Formula (I)-(XVI) is a compound selected from those species described or exemplified in the detailed description below. [0061] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XVI) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient. [0062] In further aspects, the disclosure relates to a compound of Formula (I)-(XVI), or a pharmaceutically acceptable salt thereof, for use as a medicament. [0063] 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)-(XVI), or a pharmaceutically acceptable salt thereof. [0064] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XVI), 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. [0065] In further aspects, the disclosure relates to a method of inhibiting a Ras, such as K-Ras, comprising contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I)-(XVI), 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. [0066] 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. [0067] 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof, [0068] where
Figure imgf000016_0001
[0069] ring A is a 4- to 10-membered heterocycloalkylene, C6-C10 arylene, or 5- to 10- membered heteroarylene; [0070] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0071] each L is independently -C(R4)(R5)-, -C(O)-, -O-, -N(R6)-, -S-, -S(O)- or -S(O)2-, provided that (L)p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R6)- bond; [0072] X is a -O-, -S-, -NR7-; [0073] Z1 is N or C(R8); [0074] Z2 is N or C(R9); [0075] Z3 is N or C(R10); [0076] Z4 is N or C(R11); [0077] Z5 is N or C(R12); [0078] provided that at least two of Z1-Z5 are N; [0079] each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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, or [0080] each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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, or [0081] each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe; [0082] each R2 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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; [0083] R3 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C3-C6 cycloalkylene-, -(4- to 10-membered heterocycloalkylene)-, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, -C6-C10 arylene-, -C1-C6 alkylene-(C6-C10 arylene)-, -(5- to 10- membered heteroarylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocycloalkylene, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene), C6-C10 arylene, -C1-C6 alkylene-(C6-C10 arylene), 5- to 10-membered heteroarylene, and -C1-C6 alkylene-(5- to 10-membered heteroarylene), is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; provided that the R3 and (L)p do not form a –O-O-, a –O-S-, a –S-S-, or a –O-N- bond; [0084] each R4 and R5 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)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 R4 and R5 taken together with the carbon or carbons to which they are attached form a C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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; [0085] each R6 and R7 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-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, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 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; [0086] each of R8, R9, R10, R11, and R12 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -OS(O)NRgRh, -OS(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; [0087] each Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-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, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2; [0088] m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; [0089] n is 0, 1, 2, 3, or 4; [0090] p is 4, 5, 6, 7, 8, or 9; and [0091] q is 0 or 1. [0092] 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein ring A is 4- to 10-membered heterocycloalkylene. [0093] 3. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkylene, a fused bicyclic 5- to 10-membered heterocycloalkylene, a bridged bicyclic 6- to 10-membered heterocycloalkylene, or a spiro bicyclic 6- to 10-membered heterocycloalkylene. [0094] 4. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkylene. [0095] 5. The compound of any one of clauses 1-3, or a pharmaceutically acceptable salt thereof, wherein ring A is a bridged bi-cyclic 6- to 10-membered heterocycloalkylene. [0096] 6. The compound of any one of clauses 1-3, or a pharmaceutically acceptable salt thereof, wherein ring A is ,
Figure imgf000021_0001
[0097] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p.
Figure imgf000021_0002
[0098] 7. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is ,
Figure imgf000021_0003
[0099] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p.
Figure imgf000021_0004
[0100] 8. The compound of any one of clauses 1-3, or 5-7, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula ,
Figure imgf000021_0005
[0101] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p.
Figure imgf000022_0001
[0102] 9. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B is a C6-C10 aryl. [0103] 10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl or naphthyl. [0104] 11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring B is of the formula .
Figure imgf000022_0002
salt thereof, wherein ring B is a 5- to 10-membered heteroaryl. [0106] 13. The compound of any one of clauses 1-8, or 12, or a pharmaceutically acceptable salt thereof, wherein ring B is * ,
Figure imgf000022_0003
[0107] wherein * is a point of covalent attachmen .
Figure imgf000022_0004
[0108] 14. The compound of any one of clauses 1-8, 12, or 13, or a pharmaceutically acceptable salt thereof, wherein ring B is , or
Figure imgf000023_0001
[0109] wherein * is a point of covalent attachmen . [0110] 15. The compound of any one of the
Figure imgf000023_0002
a pharmaceutically acceptable salt thereof, wherein Z1 is N. [0111] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z2 is N. [0112] 17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is N, and Z5 is CR12. [0113] 18. The compound of any one of clauses 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is CR11, and Z5 is CR12. [0114] 19. The compound of any one of clauses 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is CR11, and Z5 is N. [0115] 20. The compound of any one of clauses 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is CR12. [0116] 21. The compound of any one of clauses 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is N. [0117] 22. The compound of any one of clauses 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is N, and Z5 is N. [0118] 23. The compound of any one of clauses 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is CR11, and Z5 is N. [0119] 24. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein q is 0. [0120] 25. The compound of any one of clauses 1-23, or a pharmaceutically acceptable salt thereof, wherein q is 1. [0121] 26. The compound of any one of clauses 1-23 or 25, or a pharmaceutically acceptable salt thereof, wherein X is O. [0122] 27. The compound of any one of clauses 1-23 or 25, or a pharmaceutically acceptable salt thereof, wherein X is –NR7-. [0123] 28. The compound of any one of clauses 1-23 or 25, or a pharmaceutically acceptable salt thereof, wherein X is -S-. [0124] 29. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3 is -C1-C6 alkylene-, -4- to 10-membered heterocycloalkylene-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-, -4- to 10-membered heterocycloalkylene-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)- is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkyl-(4- to 10- membered heterocycloalkyl), -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, -NReC(=NRf)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. [0125] 30. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3 is -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)- is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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. [0126] 31. The compound of any one of clauses 1-29, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, methyl, ethyl, propyl, or -CH2-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in methyl, ethyl, propyl, or –CH2-(4- to 10-membered heterocycloalkyl)-, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, or -C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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] 32. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3 is , [0128] wherein each hydrogen ato
Figure imgf000025_0001
ently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen X. [0129] 33. The compound of any
Figure imgf000025_0002
ses, or a pharmaceutically acceptable salt thereof, wherein R3 is ,
Figure imgf000025_0003
[0130] wherein each hydrogen atom is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen X. [0131] 34. The compound of any
Figure imgf000026_0001
ses, or a pharmaceutically acceptable salt thereof, wherein R3 is , [0132] wherein * is a
Figure imgf000026_0002
is a point of covalent attachmen X. [0133]
Figure imgf000026_0003
ne of clauses 1-29, or a pharmaceutically acceptable salt thereof, wherein R3 is [0134] wherein each hydrog
Figure imgf000026_0004
ptionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen X. [0135] 36. The compound of an
Figure imgf000027_0001
35, or a pharmaceutically acceptable salt thereof, wherein R3 is * [0136] wherein * is a point
Figure imgf000027_0002
)p, and is a point of covalent attachmen X. [0137] 37
Figure imgf000027_0003
one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each L is independently each L is independently -C(R4)(R5)-, -C(O)-, -O-, or -N(R6), provided that (L)p does not comprise a –O-O- or a –O-N(R6)- bond, and the point of covalent attachment of R3 to (L)p does not form a –O-O- or a –O-N- bond. [0138] 38. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein -(L)p- is -(CR4R5)4-, -(CR4R5)5-, -(CR4R5)6-, -(CR4R5)7-, -(CR4R5)8-, -(CR4R5)9-, -(CR4R5)C(O)N(R6)-(CR4R5)2O-, -(CR4R5)N(R6)C(O)-(CR4R5)2O-, -N(R6)-C(O)(CR4R5)2O(CR4R5)2-, -CR4R5O(CR4R5)2O-(CR4R5)2, -O(CR4R5)2O(CR4R5)2O-, -CR4R5O-CR4R5-C(O)N(R6)-(CR4R5)2-, -CR4R5O(CR4R5)2C(O)N(R6)-CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)3N(R6)C(O)-, -(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2N(R6)C(O)CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-CR4R5-, -O-(CR4R5)3C(O)N(R6)-, -(CR4R5)3O(CR4R5)2-, -(CR4R5)2O(CR4R5)3-, -O-CR4R5- O(CR4R5)3-, -CR4R5-O(CR4R5)2O-CR4R5-, -CR4R5-O(CR4R5)2O-, -CR4R5-O(CR4R5)3O-, -O(CR4R5)2O(CR4R5)3-, -(CR4R5)2O(CR4R5)3O-, -O-(CR4R5)3-, -(CR4R5)3O-, -O-(CR4R5)2O(CR4R5)2-, -(CR4R5)2O(CR4R5)2O-, -CR4R5-N(R6)-(CR4R5)2-, -CR4R5-O(CR4R5)3-, -(CR4R5)2O-CR4R5-, -(CR4R5)3O-CR4R5-, -CR4R5N(R6)-(CR4R5)2O-, -(CR4R5)2N(R6)C(O)-(CR4R5)O-, or -(CR4R5)2-C(O)N(R6)-(CR4R5)O-. [0139] 39. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein -(L)p- is -CH2C(O)N(H)-(CH2)2O-, -CH2C(O)N(CH3)- (CH2)2O-, -CH2C(O)N(CH2CH3)-(CH2)2O-, -CH2N(H)C(O)-(CH2)2O-, -CH2C(O)N(CH3)C(O)-(CH2)2O-, -CH2C(O)N(CH2CH3)C(O)-(CH2)2O-, -C(O)N(H)- (CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)3O-, -CH2O(CH2)2OCH2-, -(CH2)2O(CH2)2O-, -CH2O-CH2-C(O)N(H)-(CH2)2-, -CH2O(CH2)2C(O)N(H)-CH2-, -CH2O(CH2)2C(O)N(CH3)-CH2-, -CH2O(CH2)2N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(CH3)-CH2O(CH2)2N(H)C(O)-, -CH(OCH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(OCH3)-CH2O(CH2)2N(H)C(O)-, -O(CH2)2O(CH2)2N(H)C(O)-, --CH2O(CH2)2N(H)C(O)-CH2-, or -O-(CH2)3C(O)N(H)-. [0140] 40. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H or methyl. [0141] 41. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H. [0142] 42. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H. [0143] 43. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H. [0144] 44. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R10, when present, is H or F. [0145] 45. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R11, when present, is H. [0146] 46. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R12, when present, is H. [0147] 47. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R2, when present, is independently selected from the group consisting of fluoro, chloro, -OH, and NH2. [0148] 48. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2. [0149] 49. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. [0150] 50. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 1, or 2. [0151] 51. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein p is 6 or 7. [0152] 52. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1- yl)-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14S,20S)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-13,22-dioxa- 2,10,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-9-one; (4R,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14S,20S)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-10-methyl-13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 9-one; 5-fluoro-4-[(4S,7S,14R,20R)-26-fluoro-10,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-fluoro-4-[(4R,7S,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-fluoro-4-[(4R,7S,14S,20S)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 11-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-10-methyl- 13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 11-one; 5-fluoro-4-[(6R,13R,19R)-25-fluoro-8,12,21-trioxa-2,5,15,23,27,30- hexaazahexacyclo[20.7.1.12,6.113,19.015,19.024,29]dotriaconta-1(30),22,24,26,28-pentaen-26- yl]naphthalen-2-ol; (4S,7R,14R,20R)-27-(3-chloro-2-isopropyl-5-hydroxyphenyl)-26-fluoro- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(6-fluoro-5-methyl-1H-indazol-4-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-8- methylnaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-8-methylnaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoronaphthalen-1-yl)- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoronaphthalen-1-yl)-9-methyl-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-27-(7,8-difluoro-3-hydroxynaphthalen- 1-yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethyl-3-hydroxynaphthalen-1-yl)-26-fluoro-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-27-(8-chloro-3-hydroxynaphthalen-1- yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(3-hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; 5,6-difluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(4S,7R,14R,20R)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethyl-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-chloro-4-[(4S,7R,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 3-chloro-5-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-4-(propan-2-yl)phenol; (4S,7R,14R,20R)-26-fluoro-27-(7- fluoro-8-methylnaphthalen-1-yl)-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene; 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,31,33- pentaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; (4S,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4R,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; 5-ethynyl-6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4S,7R,14S,20S)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4R,7S,14S,20S)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 4-[(4R,7S,14R,18R,20S)-18,26-difluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(4R,7S,14S,18S,20R)-18,26-difluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; and 4- [(4S,7R,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol. [0153] 53. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (2'R,4R,4'R,7S)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (4S,7R,15S)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23- fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one; (4R,7S,15R)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa- 2,13,16,19,21,25,28,30-octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta- 1(28),20,22,24,26-pentaen-12-one; and (4S,7R,15R)-24-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one. [0154] 54. A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [0155] 55. 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 53, or a pharmaceutically acceptable salt thereof. [0156] 56. A compound of any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject. [0157] 57. A compound of any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject. [0158] 58. Use of a compound of any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. DETAILED DESCRIPTION [0159] 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. [0160] 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. [0161] 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. [0162] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. [0163] 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. [0164] 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. [0165] 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. [0166] 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). [0167] As used herein and in connection with chemical structures depicting the vaious embodiments described herein, “*”, “**”, and “ ”, each represent 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 imgf000035_0001
, or , where each of “-*”, “-**”, and “ ” represents a bond to A and the point of covalent bond attachmen
Figure imgf000035_0002
t t B Alt ti l , in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by , , or , where each of “-*”, “-**”, and “ ” represents a bond to B and
Figure imgf000035_0003
[0168] 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 [0169] The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain divalent 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 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. [0170] 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 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. [0171] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched- chain divalent 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 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. [0172] 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 divalent 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 monovalent radicals of the following entities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:
,
Figure imgf000037_0001
In particular, a cyclopropyl moiety can be depicted by the structural formul . In
Figure imgf000037_0002
particular, a cyclopropylene moiety can be depicted by the structural formul . It will be appreciated that a cycloalkyl or cycloalkylene group can be
Figure imgf000037_0003
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. [0173] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine. [0174] 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)-. [0175] The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term “arylene” refers to a divalent 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), monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10 aryl), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6- C14 arylene), divalent 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 arylene groups are phenylene, naphthalenylene and anthracenylene. 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. [0176] 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 divalent 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-membered), 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), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-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 or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: O H H H H N O N N N O ,
Figure imgf000038_0001
[0177] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle 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 five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one. A six-membered heterocycle 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 heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4- tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring. [0178] In particular, a hexahydro-1H-pyrrolizinyl moiety can be depicted by the structura n particular, an example of a hexahydro-1H-pyrrolizinylene
Figure imgf000039_0001
. or heterocycloalkylene group can be
Figure imgf000039_0002
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. [0180] 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 divalent 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. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: [018
Figure imgf000040_0001
- 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 monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of six-membered heteroarylene groups include divalent 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. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2- b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole. [0182] In particular, an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula . In particular, an example of an isoquinolin-3(2H)-oneylene moiety can be
Figure imgf000041_0001
depicted by the structural formu . [0183] It will be appreciated th
Figure imgf000041_0002
at a eteroaryl 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. [0184] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone. [0185] 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. [0186] 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. [0187] 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. [0188] Certain chemical entities of Formula (I)-(XVI) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tutomers, and the like.
Figure imgf000043_0001
[0189] In
Figure imgf000043_0002
t as the following tautome . [0190] T
Figure imgf000043_0003
OM)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-C3 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). [0191] 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 –J-K-, where J ≠ K, refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member. For example, in certain embodiments, where applicable, a compound portion –(L)p- having the formula -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, connecting two rings, A and B, will be understood that -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, can include both of the embodiments A-CH(CH3)-CH2O(CH2)2N(CH3)C(O)-B and B-CH(CH3)-CH2O(CH2)2N(CH3)C(O)-A. [0192] It will be appreciated that certain of the compounds described herein include one or more position that can exists as stereoisomers. For example, certina of the compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements. It will be appreciated that a carbon atom that can exist in stereoisomeric arrangements that is depiected without showing any stereoisomeric arrangement includes as a disclosure each of eh possible stereoisomeric arrangements. For example a carbon atom having four groups that can be priorized according to the Cahn-Ingold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical definition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown below
Figure imgf000044_0001
where Ra > Rb > Rc > Rd according to the Cahn-Ingold Prelog Rules. It will be further appreciated that certain of the compounds described herein can possess relative stereochemistry based on the arrangement of atoms in relation to a ring plane. It will be understood that a structure showing no particular stereochemical arrangement, such as includes and describes
Figure imgf000044_0002
ents, including all possible diastereomers including those shown below
.
Figure imgf000045_0001
the compounds represented by Formula (I)-(XVI), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts. [0194] 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. [0195] 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. [0196] For a compound of Formula (I)-(XVI) 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. [0197] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XVI), 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)-(XVI)). 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. [0198] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XVI), 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)-(XVI) 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). [0199] As used herein, the term “KRAS inhibitor” includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the KRAS gene, called K-Ras, that is involved in the RAS/MAPK signaling pathway. The terms KRAS gene, K-Ras, and RAS/MAPK signaling pathway will be known and understood by one of skill in the art. It will be appreciated that KRAS mutations occur in approximately one in seven of all human metastatic cancers, and that those mutations can occur in a variety of locations in the KRAS gene coding sequence. KRAS mutations primarily occur in KRAS codons 12 and 13, and also occur in codons 18, 61, 117, and 146 at low frequencies and have distinct effects on tumor cell signaling based on the codon and missense mutation. Examples of KRAS mutations include, but are not limited to KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. It will be understood by a person having ordinary skill in the art that reference to a inhibiting of KRAS mutations, such as KRAS G12D refers to inhibiting the protein encoded by the KRAS G12D gene, having a coding sequence (e.g. a guanine to adenine substitution, at position 35 on codon 12 of the KRAS coding sequence) that produces a K-Ras G12D protein, where a glysine at position 12 of the protein sequence is replaced by am aspartic acid. REPRESENTATIVE EMBODIMENTS [0200] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000047_0001
[0201] wherein R1, R2, R3, A, B, L, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0202] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000048_0001
II [0203] wherein R1, R2, R3, B, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0204] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0205] wherei
Figure imgf000048_0002
, m, n, p, and q are as described herein. [0206] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, [0207] wherein
Figure imgf000049_0001
described herein. [0208] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000049_0002
[0209] wherein R1, R2, A, B, L, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0210] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000050_0001
[0211] wherein R1, R2, B, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0212] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, [0213] w
Figure imgf000050_0002
, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0214] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
[0215] wherein
Figure imgf000051_0001
described herein. [0216] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000051_0002
[0217] wherein R1, R2, R3, L, X, X1, X2, X3, X4, X5, X6, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0218] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
[0219] w
Figure imgf000052_0001
, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0220] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000052_0002
[0221] wherein R1, R2, R3, A, L, X, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, [0222] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000053_0001
[0223] wherein R1, R2, R3, L, X, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0224] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof, [0225] wher
Figure imgf000053_0002
p, and q are as described herein, and each hydrogen atom in the hexahydro-1H-pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0226] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000054_0001
[0227] wherein R1, R2, L, X, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the hexahydro-1H- pyrrolizinylene group is optionally substituted as described herein with respect to R3. [0228] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
Figure imgf000054_0002
[0229] wherein R1, R2, L, X, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein, and each hydrogen atom in the pyrrolidinylene group is optionally substituted as described herein with respect to R3. [0230] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
[0231] wherei , Z2, Z3, Z4, Z5
Figure imgf000055_0001
, m, n, p, and q are as described herein, and each hydrogen atom in the piperazinylene group is optionally substituted as described herein with respect to R3. [0232] In some embodiments, ring A is a 4- to 10-membered heterocycloalkylene, C6-C10 arylene, or 5- to 10-membered heteroarylene. [0233] In some embodiments, ring A is a 4- to 10-membered heterocycloalkylene. In some embodiments, ring A is a mono-cyclic 4- to 10-membered heterocycloalkylene. In some embodiments, ring A is a bicyclic 5- to 10-membered heterocycloalkylene. In some embodiments, ring A is a fused bicyclic 5- to 10-membered heterocycloalkylene. In some embodiments, ring A is a bridged bicyclic 6- to 10-membered heterocycloalkylene. In some embodiments, ring A is a spiro bicyclic 6- to 10-membered heterocycloalkylene. [0234] In some embodiments, Ring A is a 4- to 10-membered heterocycloalkylene, such as a mono-cyclic 4- to 10-membered heterocycloalkylene or a bicyclic 5- to 10-membered heterocycloalkylene, including fused bicyclic 5- to 10-membered heterocycloalkylene, bridged bicyclic 6- to 10-membered heterocycloalkylene, and spiro bicyclic 6- to 10-membered heterocycloalkylene, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkylene, as described above, is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 10-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. [0235] In some embodiments, Ring A is a 4- to 10-membered heterocycloalkylene, such as a mono-cyclic 4- to 10-membered heterocycloalkylene or a bicyclic 5- to 10-membered heterocycloalkylene, including fused bicyclic 5- to 10-membered heterocycloalkylene, bridged bicyclic 6- to 10-membered heterocycloalkylene, and spiro bicyclic 6- to 10-membered heterocycloalkylene, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkylene, as described above, is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 10-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. [0236] In some embodiments, Ring A is a 4- to 10-membered heterocycloalkylene, such as a mono-cyclic 4- to 10-membered heterocycloalkylene or a bicyclic 5- to 10-membered heterocycloalkylene, including fused bicyclic 5- to 10-membered heterocycloalkylene, bridged bicyclic 6- to 10-membered heterocycloalkylene, and spiro bicyclic 6- to 10-membered heterocycloalkylene, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkylene, as described above, is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0237] In some embodiments, Ring A is azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5-dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1-dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3-dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4-thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3- oxazinan-2-onylene, piperazin-2-onylene, thiomorpholinylene, thiomorpholinylene 1,1- dioxide, 3,8-diazabycyclo[3.2.1]octanylene, or (1R,5S)-3,8-diazabicyclo[3.2.1]octanylene, wherein each hydrogen atom in azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5- dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1- dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3- dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4- thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3-oxazinan-2-onylene, piperazin-2-onylene, thiomorpholinylene, thiomorpholinylene 1,1-dioxide, 3,8- diazabycyclo[3.2.1]octanylene, and (1R,5S)-3,8-diazabicyclo[3.2.1]octanylene is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 10- 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. [0238] In some embodiments, Ring A is azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5-dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1-dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3-dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4-thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3- oxazinan-2-onylene, piperazin-2-onylene, thiomorpholinylene, thiomorpholinylene 1,1- dioxide, 3,8-diazabycyclo[3.2.1]octanylene, or (1R,5S)-3,8-diazabicyclo[3.2.1]octanylene, wherein each hydrogen atom in azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5- dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1- dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3- dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4- thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3-oxazinan-2-onylene, piperazin-2-onylene, thiomorpholinylene, thiomorpholinylene 1,1-dioxide, 3,8- diazabycyclo[3.2.1]octanylene, and (1R,5S)-3,8-diazabicyclo[3.2.1]octanylene is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 10-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. [0239] In some embodiments, Ring A is azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5-dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1-dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3-dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4-thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3- oxazinan-2-onylene, piperazin-2-onylene, thiomorpholinylene, thiomorpholinylene 1,1- dioxide, 3,8-diazabycyclo[3.2.1]octanylene, or (1R,5S)-3,8-diazabicyclo[3.2.1]octanylene, wherein each hydrogen atom in azitidinylene, oxtenanylene, thietanylene, pyrrolidinylene, tetrahydrofuranylene, 2,5-dihydro-1H-pyrrolylene, pyrazolidinylene, thiazolidinylene, 4,5- dihydro-1H-imidazolylene, dihydrothiophen-2(3H)-onylene, tetrahydrothiophenylene 1,1- dioxide, imidazolidin-2-onylene, pyrrolidin-2-onylene, dihydrofuran-2(3H)-onylene, 1,3- dioxolan-2-onylene, oxazolidin-2-onylene, piperidinylene, morpholinylene, 4H-1,4- thiazinylene, 1,2,3,4-tetrahydropyridinylene, piperazinylene, 1,3-oxazinan-2-onylene, piperazin-2-onylene, thiomorpholinylene, thiomorpholinylene 1,1-dioxide, 3,8- diazabycyclo[3.2.1]octanylene, and (1R,5S)-3,8-diazabicyclo[3.2.1]octanylene is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, or 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0240] In some embodiments, Ring A is of the formula [0241] wherein each of * and ** is
Figure imgf000060_0001
p f covalent attachment, each of X1-X6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that two of X1-X6 are independently -CH- o 1 6
Figure imgf000060_0002
N and the remaining X -X are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0242] In some embodiments, Ring A is of the formula [0243] wherein each of * and ** is
Figure imgf000061_0001
p f covalent attachment, each of X1-X6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that two of X1-X6 are independently -CH- or -N- and the remaining X1-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0244] In some embodiments, Ring A is of the formula [0245] wherein each of * and ** is
Figure imgf000062_0001
p f covalent attachment, each of X1-X6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that two of X1-X6 are independently -CH- or -N- and the remaining X1-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0246] In some embodiments, Ring A is of the formula
Figure imgf000062_0002
[0247] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, each of X1-X6 is ind
Figure imgf000062_0003
S-, -N-, or -NH-, provided that two of X1-X6 are independently -CH- or -N- and the remaining X1-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0248] In some embodiments, Ring A is of the formula
Figure imgf000063_0001
[0249] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, each of X1-X6 is ind
Figure imgf000063_0002
S-, -N-, or -NH-, provided that two of X1-X6 are independently -CH- or -N- and the remaining X1-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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, -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. [0250] In some embodiments, Ring A is of the formula [0251] wherein each of * and ** is a po
Figure imgf000064_0001
o covalent attachment, X1 is -CH- or -N-, each of X2-X6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X2-X6 is -CH- or -N- and the remaining X2-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0252] In some embodiments, Ring A is of the formula [0253] wherein each of * and ** is a po
Figure imgf000065_0001
o covalent attachment, X1 is -CH- or -N-, each of X2-X6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X2-X6 is -CH- or -N- and the remaining X2-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0254] In some embodiments, Ring A is of the formula [0255] wherein each of * and ** is a po
Figure imgf000066_0001
o covalent attachment, X1 is -CH- or -N-, each of X2-X6 is independently -CH-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X2-X6 is -CH- or -N- and the remaining X2-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, Ring A does not include more than two heteroatoms in the ring, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0256] In some embodiments, Ring A is of the formula
Figure imgf000067_0001
[0257] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X1 is -CH- or -N-, eac
Figure imgf000067_0002
H-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X2-X6 is -CH- or -N- and the remaining X2-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0258] In some embodiments, Ring A is of the formula
Figure imgf000068_0001
[0259] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X1 is -CH- or -N-, eac
Figure imgf000068_0002
H-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X2-X6 is -CH- or -N- and the remaining X2-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0260] In some embodiments, Ring A is of the formula
Figure imgf000069_0001
[0261] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X1 is -CH- or -N-, eac
Figure imgf000069_0002
H-, -CH2-, -O-, -S-, -N-, or -NH-, provided that one of X2-X6 is -CH- or -N- and the remaining X2-X6 are -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0262] In some embodiments, Ring A is of the formula
Figure imgf000069_0003
[0263] wherein each of * and ** is a point of covalent attachment, X1 and X5 are each independently -CH- or -N-, each of X2, X3, X4, or X6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0264] In some embodiments, Ring A is of the formula [0265] wherein each of * and **
Figure imgf000070_0001
p valent attachment, X1 and X5 are each independently -CH- or -N-, each of X2, X3, X4, or X6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0266] In some embodiments, Ring A is of the formula [0267] wherein each of * and **
Figure imgf000071_0001
s a po o covalent attachment, X1 and X5 are each independently -CH- or -N-, each of X2, X3, X4, or X6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0268] In some embodiments, Ring A is of the formula
Figure imgf000072_0001
[0269] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X1 and X5 are each in 2 3
Figure imgf000072_0002
of X , X , X4, and X6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0270] In some embodiments, Ring A is of the formula
Figure imgf000073_0001
[0271] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X1 and X5 are each in
Figure imgf000073_0002
of X2, X3, X4, and X6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0272] In some embodiments, Ring A is of the formula
Figure imgf000073_0003
[0273] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, X1 and X5 are each in 2 3
Figure imgf000074_0001
of X , X , X4, and X6 is independently -CH2-, -O-, -S-, or -NH-, Ring A does not include an O-O, O-S, O-N, or N-S bond, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0274] In some embodiments, Ring A is of the formula , [0275] wh
Figure imgf000074_0002
h hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0276] In some embodiments, Ring A is of the formula , [0277] wh
Figure imgf000075_0001
h hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0278] In some embodiments, Ring A is of the formula , [0279] wh
Figure imgf000076_0001
h hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0280] In some embodiments, Ring A is of the formula ,
Figure imgf000076_0002
[0281] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000076_0003
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0282] In some embodiments, Ring A is of the formula ,
Figure imgf000077_0001
[0283] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000077_0002
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0284] In some embodiments, Ring A is of the formula ,
Figure imgf000078_0001
[0285] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000078_0002
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0286] In some embodiments, Ring A is of the formula ,
Figure imgf000078_0003
[0287] wherein each of * and ** is a point of covalent attachment, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0288] In some embodiments, Ring A is of the formula , [0289]
Figure imgf000079_0001
ydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0290] In some embodiments, Ring A is of the formula , [0291]
Figure imgf000080_0001
ydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0292] In some embodiments, Ring A is of the formula ,
Figure imgf000080_0002
[0293] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000081_0001
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0294] In some embodiments, Ring A is of the formula ,
Figure imgf000081_0002
[0295] wherein * is a point of covalent attachment a point of covalent attachment to (L)p, and each hydrogen is i
Figure imgf000081_0003
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0296] In some embodiments, Ring A is of the formula ,
Figure imgf000082_0001
[0297] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000082_0002
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0298] In some embodiments, Ring A is of the formula , [0299] wherein each of *
Figure imgf000083_0001
and is a point of covalent attachment, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0300] In some embodiments, Ring A is of the formula , [0301] wherein each of *
Figure imgf000083_0002
and is a point of covalent attachment, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0302] In some embodiments, Ring A is of the formula , [0303] wherein each of *
Figure imgf000084_0001
and is a point of covalent attachment, and each hydrogen is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0304] In some embodiments, Ring A is of the formula ,
Figure imgf000085_0002
[0305] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000085_0001
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0306] In some embodiments, Ring A is of the formula ,
Figure imgf000085_0003
[0307] wherein * is a point of covalent attachmen a point of covalent attachment to (L)p, and each hydrogen is
Figure imgf000086_0001
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0308] In some embodiments, Ring A is of the formula ,
Figure imgf000086_0002
[0309] wherein * is a point of covalent attachment a point of covalent attachment to (L)p, and each hydrogen is i
Figure imgf000086_0003
uted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe. [0310] In some embodiments, R1 is not 4- to 10-membered heterocycloalkyl, -OC(O)Rc, -S(O)2Rc, -SRc, -NRcC(O)Rd, -C(O)ORc, -C(O)Rc, or –CN. In some embodiments, when an R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, then one or more hydrogen atoms in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are substituted by halogen, -OS(O)2Re, -S(O)2Re, -SRe, -C(O)Re, -CN, or -NO2. [0311] In some embodiments, when X4 is -NH-, then R1 is not 4- to 10-membered heterocycloalkyl, -C(O)ORc, or -C(O)Rc. In some embodiments, when X4 is -NH- and R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, then one or more hydrogen atoms in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are substituted by halogen, -OS(O)2Re, -S(O)2Re, -SRe, -C(O)Re, -CN, or -NO2. In some embodiments, when X4 is -CH2-, then R1 is not 4- to 10-membered heterocycloalkyl, -OC(O)Rc, -S(O)2Rc, -SRc, -NRcC(O)Rd, -C(O)ORc, -C(O)Rc, or -CN. In some embodiments, when X4 is -CH2- and R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, then one or more hydrogen atoms in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are substituted by halogen, -OS(O)2Re, -S(O)2Re, -SRe, -C(O)Re, -CN, or -NO2. [0312] In some embodiments, when an R1 is attached to a X2, X3, X4, X5, or X6 that is an -NH- , then R1 is not -C(O)Rc. In some embodiments, when an R1 is attached to a X4 that is an -NH- , then R1 is not -C(O)Rc. [0313] In some embodiments, when an R1 is attached to a X2, X3, X4, X5, or X6 that is an -NH- and R1 is -C(O)Rc, then Rc is not C2-C6 alkenyl. In some embodiments, when an R1 is attached to a X4 that is an -NH- and R1 is -C(O)Rc, then Rc is not C2-C6 alkenyl. [0314] In some embodiments, Ring A is a 5- to 10-membered mono- or bi-cyclic heteroarylene, wherein each hydrogen atom in 5- to 10-membered mono- or bi-cyclic heteroarylene is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0315] In some embodiments, Ring A is a C6-C10 mono-or bi-cyclic arylene, wherein each hydrogen atom in C6-C10 mono- or bi-cyclic arylene is independently optionally substituted by an R1 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0316] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0317] In some embodiments, Ring B is C6-C10 aryl or 5- to 10-membered heteroaryl. In some embodiments, Ring B is mono- or bi-cyclic C6-C10 aryl or mono- or bi-cyclic 5- to 10- membered heteroaryl. [0318] In some embodiments, Ring B is mono- or bi-cyclic C6-C10 aryl. In some embodiments, Ring B is monocyclic C6-C10 aryl. In some embodiments, Ring B is bicyclic C6-C10 aryl. [0319] In some embodiments, Ring B is a C6-C10 mono-or bi-cyclic aryl, wherein each hydrogen atom in C6-C10 mono- or bi-cyclic aryl is independently optionally substituted by an R2 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0320] In some embodiments, Ring B is phenyl or naphthyl, wherein each hydrogen atom in phenyl or naphthyl is independently optionally substituted by an R2 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0321] In some embodiments, Ring B is of the formula ,
Figure imgf000090_0001
[0322] wherein * is a point of covalent attachmen d each hydrogen atom is independently optionally substituted by a gen, C1-C6
Figure imgf000090_0002
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0323] In some embodiments, Ring B is of the formula ,
Figure imgf000091_0001
[0324] wherein each * is a point of covalent attachme d each hydrogen atom is independently optionally substituted b
Figure imgf000091_0002
alogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0325] In some embodiments, Ring B is of the formula
,
Figure imgf000092_0001
wherein * is a point of covalent attachmen . [0326] In some embodiments, Ring B is
Figure imgf000092_0002
embered heteroaryl. In some embodiments, Ring B is bicyclic 5- to 10-membered heteroaryl. [0327] In some embodiments, Ring B is monocyclic 5- to 10-membered heteroaryl, wherein each hydrogen atom in monocyclic 5- to 10-membered heteroaryl is independently optionally substituted by an R2 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0328] In some embodiments, Ring B is bicyclic 5- to 10-membered heteroaryl, wherein each hydrogen atom in bicyclic 5- to 10-membered heteroarylis independently optionally substituted by an R2 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0329] In some embodiments, Ring B is furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, isoquinolin-3(2H)-onyl, thieno[3,2- b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-benzo[d]imidazolyl, benzo[d]oxazolyl, or benzo[d]thiazolyl wherein each hydrogen atom in furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,8-naphthyridinyl, isoquinolin-3(2H)-onyl, thieno[3,2-b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-benzo[d]imidazolyl, benzo[d]oxazolyl, and benzo[d]thiazolyl is independently optionally substituted by an R2 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0330] In some embodiments, Ring B is of the formula
Figure imgf000094_0001
[0331] wherein * is a point of covalent attachmen d Y5 are each independently CH or N, and each
Figure imgf000094_0002
ly substituted by an R2 that is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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. [0332] In some embodiments, Ring B is of the formula * ,
Figure imgf000095_0001
[0333] wherein * is a point of covalent attachmen d each hydrogen atom is independently substituted by an R2 that
Figure imgf000095_0002
1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0334] In some embodiments, Ring B is of the formula , or
Figure imgf000096_0001
[0335] wherein * is a point of covalent attachmen d each hydrogen atom is independently substituted by an R2 that 1-C6 alkyl, C2-C6
Figure imgf000096_0002
alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- 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. [0336] In some embodiments, each R2, when present, is independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, -OH, and NH2. In some embodiments, each R2, when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -OH, and NH2. [0337] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0338] In some embodiments, q is 0. In some embodiments, q is 1. [0339] In some embodiments, -X- is -O-, -S-, or–NR7-. In some embodiments, -X- is -O-. In some embodiments, -X- is -S-. In some embodiments, -X- is –NR7-. [0340] In some embodiments, R3 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C3-C6 cycloalkylene-, -(4- to 10-membered heterocycloalkylene)-, -C1-C6 alkylene-(4- to 10- membered heterocycloalkylene)-, -C6-C10 arylene-, -C1-C6 alkylene-(C6-C10 arylene)-, -(5- to 10-membered heteroarylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocycloalkylene, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene), C6-C10 arylene, -C1-C6 alkylene-(C6-C10 arylene), 5- to 10-membered heteroarylene, and -C1-C6 alkylene-(5- to 10-membered heteroarylene), is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, -C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; provided that the R3 and (L)p do not form a –O-O-, a –O-S-, a –S-S-, or a –O-N- bond;. [0341] In some embodiments, R3 is -C1-C6 alkylene-, -(4- to 10-membered heterocycloalkylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-, -(4- to 10-membered heterocycloalkylene)-, and -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O- C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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. [0342] In some embodiments, R3 is of the formula , [0343] wherein * represents a point
Figure imgf000098_0001
ttachment to –(L)p, “ ” is a point of covalent attachmen d each hydrogen atom is independently optionally substitut kyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6
Figure imgf000098_0002
alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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. [0344] In some embodiments, R3 is of the formula , [0345] wherein * represents a point
Figure imgf000098_0003
tachment to –(L)p, “ ” is a point of covalent attachmen d each hydrogen atom is independently optionally substitut
Figure imgf000098_0004
kyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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. [0346] In some embodiments, R3 is of the formula , [0347] wherein * represents a point
Figure imgf000099_0001
ttachment to –(L)p, “ ” is a point of covalent attachment d each hydrogen atom is independently optionally substitute
Figure imgf000099_0002
kyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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. [0348] In some embodiments, R3 is of the formula , [0349] wherein * represents a point o
Figure imgf000099_0003
attachment to –(L)p, “ ” is a point of covalent attachmen d each hydrogen atom is independently optionally substitut
Figure imgf000099_0004
kyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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. [0350] In some embodiments, R3 is of the formula , [0351] wherein each hydroge
Figure imgf000100_0001
ionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen X. [0352] In some embodiments, R3 is of
Figure imgf000100_0002
* , [0353] wherein * is a point of
Figure imgf000100_0003
and is a point of covalent attachmen X. [0354] In
Figure imgf000100_0004
or C1-C6 alkyl. [0355] 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, Z1 is C(R8). In some embodiments, Z2 is C(R9). In some embodiments, Z3 is C(R10). In some embodiments, Z4 is C(R11). In some embodiments, Z5 is C(R12). In some embodiments, any of the possible combinations of Z1-Z7 as provided above can be combined. In some embodiments, Z1 is N, and Z2 is N. In some embodiments, Z1 is N, Z2 is N, Z3 is C(R10), Z4 is N, and Z5 is C(R12). In some embodiments, Z1 is N, Z2 is N, Z3 is C(R10), Z4 is C(R11), and Z5 is C(R12). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is N, and Z5 is C(R12). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is C(R11), and Z5 is C(R12). In some embodiments, Z1 is N, Z2 is N, Z3 is C(R10), Z4 is C(R11), and Z5 is N. In some embodiments, Z1 is N, Z2 is N, Z3 is C(R10), Z4 is N, and Z5 is N. In some embodiments, Z1 is N, Z2 is N, Z3 is C(R10), Z4 is N, and Z5 is C(R12). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is C(R11), and Z5 is C(R12). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is N, and Z5 is N. In some embodiments, R8, when present, is H. In some embodiments, R9, when present, is H. In some embodiments, R10, when present, is H or F. In some embodiments, R11, when present, is H. In some embodiments, R12, when present, is H. [0356] In some embodiments, each L is independently -C(R4)(R5)-, -C(O)-, -O-, -N(R6)-, -S-, -S(O)- or -S(O)2-, provided that (L)p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O- N(R6)- bond. In some embodiments, each L is independently each L is independently -C(R4)(R5)-, -C(O)-, -O-, or -N(R6), provided that (L)p does not comprise a –O-O- or a -O-N(R6)- bond, and the point of covalent attachment of R3 to (L)p does not form a –O-O- or a –O-N- bond. In some embodiments, each L is independently -C(R4)(R5)-, -C(O)-, -O-, or -N(R6), provided that (L)p does not comprise a –O-O- or a –O-N(R6)- bond, and the point of covalent attachment of R3 to (L)p does not form a –O-O- or a –O-N- bond. [0357] In some embodiments, p is 4, 5, 6, 7, 8, or 9. In some embodiments, p is 5, 6, 7, 8, or 9. In some embodiments, p is 4, 5, 6, 7, or 8. In some embodiments, p is 5, 6, 7, or 8. In some embodiments, p is 6, 7, 8, or 9. In some embodiments, p is 5, 6, or 7. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. [0358] In some embodiments, -(L)p- is -(CR4R5)4-, -(CR4R5)5-, -(CR4R5)6-, -(CR4R5)7-, -(CR4R5)8-, -(CR4R5)9-, -(CR4R5)C(O)N(R6)-(CR4R5)2O-, -(CR4R5)N(R6)C(O)-(CR4R5)2O-, -N(R6)-C(O)(CR4R5)2O(CR4R5)2-, -CR4R5O(CR4R5)2O-(CR4R5)2, -O(CR4R5)2O(CR4R5)2O-, -CR4R5O-CR4R5-C(O)N(R6)-(CR4R5)2-, -CR4R5O(CR4R5)2C(O)N(R6)-CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)3N(R6)C(O)-, -(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2N(R6)C(O)CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-CR4R5-, -O-(CR4R5)3C(O)N(R6)-, -(CR4R5)3O(CR4R5)2-, -(CR4R5)2O(CR4R5)3-, -O-CR4R5- O(CR4R5)3-, -CR4R5-O(CR4R5)2O-CR4R5-, -CR4R5-O(CR4R5)2O-, -CR4R5-O(CR4R5)3O-, -O(CR4R5)2O(CR4R5)3-, -(CR4R5)2O(CR4R5)3O-, -O-(CR4R5)3-, -(CR4R5)3O-, -O-(CR4R5)2O(CR4R5)2-, -(CR4R5)2O(CR4R5)2O-, -CR4R5-N(R6)-(CR4R5)2-, -CR4R5-O(CR4R5)3-, -(CR4R5)2O-CR4R5-, -(CR4R5)3O-CR4R5-, -CR4R5N(R6)-(CR4R5)2O-, -(CR4R5)2N(R6)C(O)-(CR4R5)O-, or -(CR4R5)2-C(O)N(R6)-(CR4R5)O-. [0359] In some embodiments, -(L)p- is -(CR4R5)4-, -(CR4R5)5-, -(CR4R5)6-, -(CR4R5)7-, -(CR4R5)8-, -(CR4R5)9-, -(CR4R5)C(O)N(R6)-(CR4R5)2O-, -(CR4R5)N(R6)C(O)-(CR4R5)2O-, -N(R6)-C(O)(CR4R5)2O(CR4R5)2-, -CR4R5O(CR4R5)2O-(CR4R5)2, -O(CR4R5)2O(CR4R5)2O-, -CR4R5O-CR4R5-C(O)N(R6)-(CR4R5)2-, -CR4R5O(CR4R5)2C(O)N(R6)-CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)3N(R6)C(O)-, -(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2N(R6)C(O)CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-CR4R5-, -O-(CR4R5)3C(O)N(R6)-, -(CR4R5)3O(CR4R5)2-, -(CR4R5)2O(CR4R5)3-, -O-CR4R5- O(CR4R5)3-, -CR4R5-O(CR4R5)2O-CR4R5-, -CR4R5-O(CR4R5)2O-, -CR4R5-O(CR4R5)3O-, -O(CR4R5)2O(CR4R5)3-, -(CR4R5)2O(CR4R5)3O-, -O-(CR4R5)3-, -(CR4R5)3O-, -O-(CR4R5)2O(CR4R5)2-, -(CR4R5)2O(CR4R5)2O-, -CR4R5-N(R6)-(CR4R5)2-, -CR4R5-O(CR4R5)3-, -(CR4R5)2O-CR4R5-, -(CR4R5)3O-CR4R5-, -CR4R5N(R6)-(CR4R5)2O-, -(CR4R5)2N(R6)C(O)-(CR4R5)O-, or -(CR4R5)2-C(O)N(R6)-(CR4R5)O-, wherein each of R4, R5, and R6 are as defined herein. [0360] In some embodiments, -(L)p- comprises -(CR4R5)4-, -(CR4R5)5-, -(CR4R5)6-, -(CR4R5)7-, -(CR4R5)8-, -(CR4R5)9-, -CR4R5C(O)N(R6)-(CR4R5)2OCR4R5-, -C(O)N(R6)-(CR4R5)2O(CR4R5)2-, -N(R6)-C(O)(CR4R5)2O(CR4R5)2-, -CR4R5O(CR4R5)2O-(CR4R5)2, -O(CR4R5)2O(CR4R5)2O-, -CR4R5O-CR4R5- C(O)N(R6)-(CR4R5)2-, -CR4R5O(CR4R5)2C(O)N(R6)-CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)3N(R6)C(O)-, -(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)2N(R6)C(O)-CR4R5-, -O-(CR4R5)3C(O)N(R6)-, -(CR4R5)3O(CR4R5)2-, -(CR4R5)2O(CR4R5)3-, -O-CR4R5- O(CR4R5)3-, -CR4R5-O(CR4R5)2O-, -CR4R5-O(CR4R5)3O-, -O(CR4R5)2O(CR4R5)3-, -(CR4R5)2O(CR4R5)3O-, -O-(CR4R5)3-, -(CR4R5)3O-, -O-(CR4R5)2O(CR4R5)2-, -(CR4R5)2O(CR4R5)2O-, -CR4R5-N(R6)-(CR4R5)2-, -CR4R5-O(CR4R5)3-, -(CR4R5)2O-CR4R5-, -(CR4R5)3O-CR4R5-, -CR4R5N(R6)-(CR4R5)2O-, -(CR4R5)2N(R6)-(CR4R5)2O-, or -(CR4R5)2N(R6)-(CR4R5)2O-, wherein each of R4, R5, and R6 are as defined herein. [0361] In some embodiments, -(L)n- is -(L)p- is -(CR4R5)4-, -(CR4R5)5-, -(CR4R5)6-, -(CR4R5)7- , -(CR4R5)8-, -(CR4R5)9-, -CR4R5C(O)N(R6)-(CR4R5)2OCR4R5-, -C(O)N(R6)- (CR4R5)2O(CR4R5)2-, -N(R6)-C(O)(CR4R5)2O(CR4R5)2-, -CR4R5O(CR4R5)2O-(CR4R5)2, -O(CR4R5)2O(CR4R5)2O-, -CR4R5O-CR4R5-C(O)N(R6)-(CR4R5)2-, -CR4R5O(CR4R5)2C(O)N(R6)-CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)3N(R6)C(O)-, -(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)2N(R6)C(O)-CR4R5-, -O-(CR4R5)3C(O)N(R6)-, -(CR4R5)3O(CR4R5)2-, -(CR4R5)2O(CR4R5)3-, -O-CR4R5- O(CR4R5)3-, -CR4R5-O(CR4R5)2O-, -CR4R5-O(CR4R5)3O-, -O(CR4R5)2O(CR4R5)3-, -(CR4R5)2O(CR4R5)3O-, -O-(CR4R5)3-, -(CR4R5)3O-, -O-(CR4R5)2O(CR4R5)2-, -(CR4R5)2O(CR4R5)2O-, -CR4R5-N(R6)-(CR4R5)2-, -CR4R5-O(CR4R5)3-, -(CR4R5)2O-CR4R5-, -(CR4R5)3O-CR4R5-, -CR4R5N(R6)-(CR4R5)2O-, -(CR4R5)2N(R6)-(CR4R5)2O-, or -(CR4R5)2N(R6)-(CR4R5)2O-, wherein each of R4, R5, and R6 are as defined herein. [0362] In some embodiments, R4, when present, is H, C1-C6 alkyl, -OH, or –OCH3. In some embodiments, R4, when present, is H, methyl, -OH, or –OCH3. In some embodiments, R5, when present, is H, C1-C6 alkyl, -OH, or –OCH3. In some embodiments, R5, when present, is H, methyl, -OH, or –OCH3. In some embodiments, R6, when present, is H or C1-C6 alkyl. In some embodiments, R6, when present, is H or methyl. [0363] In some embodiments, -(L)p- is -CH2C(O)N(H)-(CH2)2O-, -CH2C(O)N(CH3)- (CH2)2O-, -CH2C(O)N(CH2CH3)-(CH2)2O-, -CH2N(H)C(O)-(CH2)2O-, -CH2C(O)N(CH3)C(O)-(CH2)2O-, -CH2C(O)N(CH2CH3)C(O)-(CH2)2O-, -C(O)N(H)- (CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)3O-, -CH2O(CH2)2OCH2-, -(CH2)2O(CH2)2O-, -CH2O-CH2-C(O)N(H)-(CH2)2-, -CH2O(CH2)2C(O)N(H)-CH2-, -CH2O(CH2)2N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)- CH2O(CH2)2N(CH3)C(O)-, -CH(CH3)-CH2O(CH2)2N(H)C(O)-, -CH(OCH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(OCH3)-CH2O(CH2)2N(H)C(O)-, -O(CH2)2O(CH2)2N(H)C(O)-, --CH2O(CH2)2N(H)C(O)-CH2-, or -O-(CH2)3C(O)N(H)-. [0364] In some embodiments, -(L)p- is -CH2C(O)N(H)-(CH2)2OCH2-, -C(O)N(H)- (CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)2O-(CH2)2, -O(CH2)2O(CH2)2O-, -CH2O-CH2-C(O)N(H)-(CH2)2-, -CH2O(CH2)2C(O)N(H)-CH2-, -CH2O(CH2)2N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(CH3)-CH2O(CH2)2N(H)C(O)-, -CH(OCH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(OCH3)-CH2O(CH2)2N(H)C(O)-, -O(CH2)2O(CH2)2N(H)C(O)-, -CH2O(CH2)2N(H)C(O)-CH2-, or -O-(CH2)3C(O)N(H)-. [0365] In some embodiments, the disclosure provides a compound selected from the group consisting of (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14S,20S)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 9-one; (4R,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4R,7S,14S,20S)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-10-methyl- 13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 9-one; 5-fluoro-4-[(4S,7S,14R,20R)-26-fluoro-10,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-fluoro-4-[(4R,7S,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-fluoro-4-[(4R,7S,14S,20S)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 11-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-10-methyl- 13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 11-one; 5-fluoro-4-[(6R,13R,19R)-25-fluoro-8,12,21-trioxa-2,5,15,23,27,30- hexaazahexacyclo[20.7.1.12,6.113,19.015,19.024,29]dotriaconta-1(30),22,24,26,28-pentaen-26- yl]naphthalen-2-ol; (4S,7R,14R,20R)-27-(3-chloro-2-isopropyl-5-hydroxyphenyl)-26-fluoro- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(6-fluoro-5-methyl-1H-indazol-4-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-8- methylnaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-8-methylnaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoronaphthalen-1-yl)- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoronaphthalen-1-yl)-9-methyl-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-27-(7,8-difluoro-3-hydroxynaphthalen- 1-yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethyl-3-hydroxynaphthalen-1-yl)-26-fluoro-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-27-(8-chloro-3-hydroxynaphthalen-1- yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(3-hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; 5,6-difluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(4S,7R,14R,20R)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethyl-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-chloro-4-[(4S,7R,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 3-chloro-5-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-4-(propan-2-yl)phenol; (4S,7R,14R,20R)-26-fluoro-27-(7- fluoro-8-methylnaphthalen-1-yl)-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene; 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,31,33- pentaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; (4S,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4R,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; 5-ethynyl-6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4S,7R,14S,20S)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4R,7S,14S,20S)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 4-[(4R,7S,14R,18R,20S)-18,26-difluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(4R,7S,14S,18S,20R)-18,26-difluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; and 4- [(4S,7R,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; or a pharmaceutically acceptable salt thereof. [0366] In some embodiments, the disclosure provides a compound selected from the group consisting of (2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (2'R,4R,4'R,7S)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (4S,7R,15S)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23- fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one; (4R,7S,15R)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa- 2,13,16,19,21,25,28,30-octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta- 1(28),20,22,24,26-pentaen-12-one; and (4S,7R,15R)-24-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one, or a pharmaceutically acceptable salt thereof.. [0367] The following represent illustrative embodiments of compounds of Formula (I): Example Number Structure Name (ACD 2019)
Figure imgf000107_0001
(4S7S14R20R)-26-fluoro-27-(8-fluoro-3-
Figure imgf000108_0001
(4S7S14R20R)-26-fluoro-27-(8-fluoro-3-
Figure imgf000109_0001
,
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
[0368] 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 [0369] 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. [0370] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions. [0371] 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. [0372] 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. [0373] 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. [0374] 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. [0375] 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. [0376] 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. [0377] 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. [0378] 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. [0379] The term “subject” refers to a mammalian patient in need of such treatment, such as a human. [0380] 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. [0381] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target Ras, in particular K-Ras. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. In preferred embodiments, methods of treating a target cancer are described. [0382] 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 a mutation of KRAS, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. [0383] 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). [0384] 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 [0385] 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. [0386] 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 [0387] 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)-(XVI). [0388] 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: g grams e e uivalents
Figure imgf000123_0001
Me methyl Et thl
Figure imgf000124_0001
AcOH Acetic Acid DMA N N Di th lf id [038
Figure imgf000125_0002
9] 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: [0390] Scheme I
Figure imgf000125_0001
[0391] The general scheme I is using Compound 1 as an illustration. Compound I-1 and I-2 are prepared via conventional chemistry from commercially available materials. Under SN2 displacement reaction condition A, compounds I-1 and I-2 are converted to a product, I-3, which then reacts with I-4 (prepared from commercially available material) to generate I-5. under palladium-catalyzed Suzuki coupling condition I-5 and a variety of boronic esters react to generate I-6. After deprotection step D and amide coupling step E, macrocycles I-8 is formed. Deprotection of Boc and MOM groups under acid condition F produces Compound 1, isolated as the desired diastereomer. [0392] Scheme II
Figure imgf000126_0001
2 are prepared via conventional chemistry from commercially available materials. Under SN2 displacement reaction conditions A and B, macrocycle II-4 is formed. Under palladium- catalyzed Suzuki coupling condition II-4 and a variety of boronic esters react to generate II-5. After deprotection of Boc and MOM groups under acid condition D, Compound 10 is produced, isolated as the desired diastereomer. [0394] One of ordinary skill in the art will appreciate that the proposed target compounds can also be prepared using a different order of steps to introduce the substitutions on the bicyclic aromatic ring. For examples, the alternative schemes shown below are exemplary of variants of the processes for preparing the examples as described above. Table of Intermediates Name Structure Name Structure
Figure imgf000126_0002
Figure imgf000127_0001
[0395
Figure imgf000128_0002
] Preparation of intermediate B1 [0396] St
Figure imgf000128_0001
boxylate (B1- 2): tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1-1, 1.0 eq.) is dissolved in acetonitrile and cooled to 5-10°C whereupon triethylamine (4.0 eq.) is added, followed by drop wise addition of a solution of trityl chloride (1.1 eq.) in DCM. The reaction is stirred for 1 h at room temperature. The reaction mixture is cooled to approximately 0°C and then filtered. The filtrate is evaporated, and the residue is purified by chromatography to give the title compound. [0397] Step B. tert-butyl 1-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (B1-3): To a suspension of tert-butyl (lR,5S)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-2, 1.0 eq.) in diethyl ether at -40 °C is added N1,N1,N2,N2-tetramethylethane-1,2-diamine (1.5 eq.), followed by slow addition of sec- butyllithium (1.5 eq.). The mixture is warmed to 0 °C and maintained at that temperature for 30 min before cooling to -70 °C. Then, paraformaldehyde (10 eq.) is added over 5 minutes and the reaction mixture is warmed up to room temperature over 1 hour before quenched with water. Workup and chromatography purification afford the title compound. [0398] Step C. tert-butyl 1-(aminomethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (B1-4): Diisopropyl azodicarboxylate (1.0 eq.) is added slowly to a solution of triphenylphosphine (PPh3) (1.0 eq.), tert-butyl 1-(hydroxymethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-3, 1.0 eq.) and phthalimide (1.0 eq.) in toluene which is pre-cooled with a -5 °C. cooling bath at such a rate that temperature of the reaction mixture is kept between 15-25° C. The cooling bath is removed after the addition is finished and the reaction mixture is stirred for 1 h. The crude product obtained after reaction workup is mixed with EtOH and hydrazine (1.2 eq.). The mixture is refluxed for 1 hour. After cooled down, the solid is removed by filtration. And the solution is concentrated to dryness to give crude product, which is used for the next step directly without further purification. [0399] Step D. tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-5): Benzyl chloroformate (1.1 eq.) is added over 15 minutes to a stirred solution of tert-butyl 1-(aminomethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-4, 1.0 eq.) in EtOH/water (1:1 v/v) at 0 °C. After stirring for 1 h at 0 °C and 6 h at ambient temperature, the mixture is diluted with water. Extraction workup with EtOAc followed by chromatography afford the title product. [0400] Step E. tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1): To a solution of tert-butyl 1- ((((benzyloxy)carbonyl)amino)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1-5, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.). The solution is stirred until reaction completion and is then treated with NaHCO3 (3.0 eq.). The mixture is stirred for another 30 minutes and concentrated to dryness. The residue is mixed with dichloromethane and filtered through a celite plug. The filtrate is then concentrated to give crude title compound. [0401] Preparation of of intermediate B2: [0402]
Figure imgf000129_0001
3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B2-1): To the suspension of NaH (1.2 eq.) in anhydrous THF is added the solution of tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3- trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1-5, 1.0 eq.) in anhydrous THF at 00C, followed by addition of methyl iodide (1.2 eq.). After stirring at room temperature for 1 hour, reaction is quenched with water. EtOAc extraction workup followed by chromatography affords title compound. [0403] Step B. tert-butyl 1-((((benzyloxy)carbonyl)(methyl)amino)methyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B2): To a solution of tert-butyl 1- ((((benzyloxy)carbonyl)amino)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B2-1, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.). The solution is stirred until reaction completion and is then treated with NaHCO3 (3.0 eq.). The mixture is stirred for another 30 minutes and concentrated to dryness. The residue is mixed with dichloromethane, and filtered through a celite plug. The filtrate is then concentrated to give crude title compound. [0404] Preparation of Intermediate B3: [0405] Step
Figure imgf000130_0001
o[3.2.1]octane-8- carboxylate (B3-1): To a solution of tert-butyl (lR,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (B1-2, 1.0 eq.) in THF at -78 °C is added N1,N1,N2,N2-tetramethylethane-1,2- diamine (1.5 eq.), followed by slow addition of sec-butyllithium (1.5 eq.). The mixture is warmed to 0 °C and maintained at that temperature for 30 min before cooling to -78 °C. Then, ethyl 2-iodoacetate (2 eq.) is added over 5 minutes and the reaction mixture is warmed up to room temperature over 1 hour before quenched with water. Workup and chromatography purification afford the title compound. [0406] Step B. tert-butyl 1-(2-ethoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (B3): To a solution of tert-butyl 1-(2-ethoxy-2-oxoethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B3-1, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.). The solution is stirred until reaction completion and is then treated with NaHCO3 (3.0 eq.). The mixture is stirred for another 30 minutes and concentrated to dryness. The residue is mixed with dichloromethane, and filtered through a celite plug. The filtrate is then concentrated to give crude title compound. [0407] Preparation of Intermediate C1
[04 a(5H)-
Figure imgf000131_0001
carboxylate (C1-2): a solution of ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)- carboxylate (C1-1, 1.0 eq.) and catalytic amount of acetic acid in MeOH is added sodium cyanoborohydride (2.0 eq.) and the mixture is stirred until the reaction completioin. Water is then added to quench the reaction. Extraction workup with EtOAc, followed by chromatography afford the title compound. [0409] Step B. (2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-ol (C1-3): a solution of ethyl (2R,7aR)-2-hydroxy-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (C1-2, 1.0 eq.) in THF is cooled to 00C and lithium aluminum hydride (1M in THF) (3.0 eq.) is added dropwise. After stirred for 30 minutes, the mixture is heated to 70 °C for 2 hours. The mixture is diluted with ethyl ether, cooled to 0 °C and quenched by water, 15% aqueous NaOH followed by water. The vessel is warmed to room temperature and stirred for 30 minutes. To the mixture is added anhydrous magnesium sulfate. The mixture is stirred for 30 minutes before being filtered. The solution is concentrated, and the crude is used directly for the next step. [0410] Step C. (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin- 2-ol (C1-4): a solution of (2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-ol (C1-3, 1.0 eq.) and imidazole (2.0 eq.) in DMF is added tert-Butyldiphenyl-silyl-chloride (1.1 eq.). The reaction is stirred for 2 hours and then quenched with water. Extraction workup with EtOAc, followed by chromatography afford the title product. [0411] Step D. methyl 3-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)propanoate (C1-5): a solution of (2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (C1-4, 1.0 eq.) in t-BuOH are added cesium carbonate (1.1 eq.) and methyl acrylate (20 eq.). The solution is stirred at ambient temperature for 18 h. The suspension is then extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to remove solvent. The residue is purified by chromatography to afford the title product. [0412] Step E. methyl 3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propanoate (C1): a solution of methyl 3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoate (C1-5, 1.0 eq.) in THF is added tetra-n-butylammonium fluoride (1.0M in THF, 1.1 eq.). After stirring to reaction completion, the EtOAc extraction followed by chromatography affords the title product. [0413] Preparation of Intermediate C2:
Figure imgf000132_0001
1H-pyrrolizin-2-yl)oxy)ethyl)carbamate (C2-1): Sodium hydride (1.1 eq.) is placed in a dried flask which is then sealed and charged with N2. A solution of (2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-ol (C1-4, 1.0 eq.) in a minimal amount of THF is added to the flask and the solution stirred at room temperature for 30 minutes. The solution is then chilled to 0 C and a solution 2-(boc-amino) ethyl bromide (1.4 eq.) in a minimal amount of THF is added dropwise to the reaction and the solution is stirred at room temperature for an hour. The precipitate is filtered off and the filtrate diluted with ether and washed with water. The organic phase is dried and concentrated. The residue is purified by chromatography to afford the titled product. [0415] Step B. tert-butyl (2-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)ethyl)carbamate (C2): a solution of tert-butyl (2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethyl)carbamate (C2-1, 1.0 eq.) in THF is added tetra-n-butylammonium fluoride (1.0M in THF, 1.1 eq.). After stirring to reaction completion, the EtOAc extraction workup followed by chromatography affords the title product. [0416] Preparation of intermediate C3:
Figure imgf000132_0002
[0417] Step A. tert-butyl (2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro- 1H-pyrrolizin-2-yl)oxy)ethyl)(methyl)carbamate (C3-1): To the suspension of NaH (1.2 eq.) in anhydrous THF is added the solution of tert-butyl (2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethyl)carbamate (C2-1, 1.0 eq.) in anhydrous THF at 00C, followed by addition of methyl iodide (1.2 eq.). After stirring at room temperature for 1 hour, reaction is quenched with water. EtOAc extraction workup followed by chromatography affords title compound. [0418] Step B. tert-butyl (2-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)ethyl)(methyl)carbamate (C3): a solution of tert-butyl (2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethyl)(methyl)carbamate (C3-1, 1.0 eq.) in THF is added tetra-n-butylammonium fluoride (1.0M in THF, 1.1 eq.). After stirring to reaction completion, the EtOAc extraction followed by chromatography affords the title product. [0419] Preparation of intermediate D1:
Figure imgf000133_0001
[0420] Step A. tert-butyl 1-(2-hydroxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (D1-1): To a suspension of tert-butyl (lR,5S)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (B1-2, 1.0 eq.) in diethyl ether at -40 °C is added N1,N1,N2,N2-tetramethylethane-1,2-diamine (1.5 eq.), followed by slow addition of sec- butyllithium (1.5 eq.). The mixture is warmed to 0 °C and maintained at that temperature for 30 min before cooling to -78 °C. Then, the solution of ethylene oxide (1.5 equiv) in Et2O, which is pre-cooled to −78° C., is transferred to the previous flask via a cannula under N2 and then BF3.Et2O (1.5 equiv) is added dropwise over 30 min. After stirring at −78 °C for 2 h, the reaction mixture is slowly warmed to rt and water is carefully added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0421] Step B. tert-butyl 1-(2-((methylsulfonyl)oxy)ethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D1-2): To a solution of tert-butyl 1-(2- hydroxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D1-1, 1.0 eq.) and Et3N (3.0 eq.) in THF, is added methanesulfonyl chloride (1.2 eq.). After stirring for 1 hour, water is added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0422] Step C. methyl 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)acetate (D1-3): To the suspension of NaH (1.2 eq.) in THF, is slowly added while stirring the solution of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro- 1H-pyrrolizin-2-ol (C1-4, 1.0 eq.) in THF. After stirring for 30 minutes, methyl bromoacetate (1.2 eq.) is added. After reaction is complete, water is added to quench reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0423] Step D. 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)ethan-1-ol (D1-4): To the solution of methyl 2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)acetate (D1-3, 1.0eq.) in THF is slowly added LiBH4 (4.0 eq.). After the reduction reaction is complete, water is added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0424] Step E. tert-butyl 1-(2-(2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethoxy)ethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D1-5): To the suspension of NaH (1.2 eq.) in THF, is slowly added while stirring the solution of 2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)ethan-1-ol (D1-4, 1.0 eq.) in THF. After stirring for 30 minutes, the solution of tert-butyl 1-(2- ((methylsulfonyl)oxy)ethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D1-2, 1.0 eq.) in THF is added. When the reaction is complete, water is added to quench the reaction. Extraction workup followed by chromatography affords the title compound. [0425] Step F. tert-butyl 1-(2-(2-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)ethoxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D1): To the solution of tert-butyl 1-(2-(2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)ethoxy)ethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D1-5, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.). The solution is stirred until reaction completion of trityl deprotection and is then treated with Na2CO3 (3.0 eq.). After the extraction workup with EtOAc, the residue obtained is dissolved in THF, and nBu4NF (1.0M in THF, 1.2 eq.) is added. After the reaction is complete, solvent is removed and residue is purified by chromatogaphy to affford the product. [0426] Preparation of intermediate D2: Ph Ph Si Ph O Si Ph H [0427] Ste
Figure imgf000135_0001
ro-1H- pyrrolizin-2-yl)oxy)propan-1-ol (D2-1): To the solution of methyl 3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoate (C1-5, 1.0eq.) in THF is slowly added LiBH4 (4.0 eq.). After the reduction reaction is complete, water is added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0428] Step B. tert-butyl 1-(((methylsulfonyl)oxy)methyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D2-2): To a solution of tert-butyl 1- (hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1-3, 1.0 eq.) and Et3N (3.0 eq.) in THF, is added methanesulfonyl chloride (1.2 eq.). After stirring for 1 hour, water is added to quench the reaction. Extraction workup with EtOAc followed by chromatography affords the title compound. [0429] Step C. tert-butyl 1-((3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)-3-trityl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D2-3): To the suspension of NaH (1.2 eq.) in THF, is slowly added while stirring the solution of 3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propan-1-ol (D2-1, 1.0 eq.) in THF. After stirring for 30 minutes, the solution of tert-butyl 1- (((methylsulfonyl)oxy)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D2-2, 1.0 eq.) in THF is added. When the reaction is complete, water is added to quench the reaction. Extraction workup followed by chromatography affords the title compound. [0430] Step D. tert-butyl 1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D2): To the solution of tert-butyl 1-((3-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)propoxy)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D2-3, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.). The solution is stirred until reaction completion of trityl deprotection and is then treated with Na2CO3 (3.0 eq.). After the extraction workup with EtOAc, the residue obtained is dissolved in THF, and nBu4NF (1.0M in THF, 1.2 eq.) is added. After the reaction is complete, solvent is removed and residue is purified by chromatogaphy to affford the product. [0431] Preparation of intermediate D3:
[0432] Step
Figure imgf000137_0001
[3.2.1]octane-8- carboxylate (D3-1): tert-butyl 1-(2-((methylsulfonyl)oxy)ethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D1-2, 1.0 eq.), phthalimide (1.1 eq.) and Et3N (2.0 eq.) are mixed in DMF and stirred at room temperature until the reaction completion. After extraction workup with EtOAc, the residue is mixed with hydrazine (2.0 eq.) in the EtOH. The mixture is refluxed for until reaction completion. After cooling down, the precipitate is removed, and the filtrate is concentrated to give crude product, which is used directly to the next step. [0433] Step B. 2-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)acetic acid (D3-2): Typical ester hydrolysis is used to produce D3-2. [0434] Step C. tert-butyl 1-(2-(2-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)acetamido)ethyl)-3-trityl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D3-3): Typical amide coupling condition is used to couple D3-1 and D3-2 with HATU for the title compound. [0435] Step D. tert-butyl 1-(2-(2-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)acetamido)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D3): Same reaction condition is used as in D2 to produce the title compound. [0436] Preparation of Intermediate D4: [043
Figure imgf000138_0001
a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)-N- methylacetamido)ethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D4-1): Synthesis of D4-1 uses the same procedure as B2-1. [0438] Step B. tert-butyl 1-(2-(2-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)-N-methylacetamido)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D4): Synthesis of D4 uses the same reaction condition as for D2. [0439] Preparation of intermediate D5:
Figure imgf000138_0002
[0440] Step A. tert-butyl 2-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate (D5-2): D5-2 is synthesized from tert-butyl 4-tritylpiperazine-1-carboxylate (D5-1) using the same procedure as B1-3. [0441] Step B. tert-butyl 2-(((methylsulfonyl)oxy)methyl)-4-tritylpiperazine-1-carboxylate (D5-3): D5-3 is synthesized from tert-butyl 2-(hydroxymethyl)-4-tritylpiperazine-1- carboxylate (D5-2) using the same procedure as D2-2. [0442] Step C. tert-butyl 2-((3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)-4- tritylpiperazine-1-carboxylate (D5-4): D5-4 is synthesized from tert-butyl 2- (((methylsulfonyl)oxy)methyl)-4-tritylpiperazine-1-carboxylate (D5-3) and 3-(((2R,7aR)-7a- (((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propan-1-ol (D2-1) using the same procedure as D2-3. [0443] Step D. tert-butyl 2-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propoxy)methyl)piperazine-1-carboxylate (D5): D5 is synthesized from tert-butyl 2- ((3-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propoxy)methyl)-4-tritylpiperazine-1-carboxylate (D5-4) using the same procedure as D2. [0444] Preparation of Intermediate D6:
Figure imgf000139_0001
carboxylate (D6-1): A solution of tert-butyl 1- ((((benzyloxy)carbonyl)(methyl)amino)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (B2-1, 1.0 eq.) is dissolved in MeOH and hydrogenated in presence of Pd/C. After reaction completion, the solid is removed by filtration and the filtrate is concentrated to dryness to give the title compound. [0446] Step B. 3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)propanoic acid (D6-2): A solution of methyl 3-(((2R,7aR)-7a- (hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoate (C1, 1.0 eq.) in MeOH is added 1.0 M NaOH solution. And reaction mixture is stirred until hydrolysis completion. After neutralized with 1.0M HCl solution, the mixture is concentrated to dryness. The residue is mixed with MeOH and filtered to remove salt. After removing solvent, the solid is used directly for the next step. [0447] Step C. tert-butyl 1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)-N-methylpropanamido)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D6-3): A solution of tert-butyl 1-((methylamino)methyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D6-1, 1.0 eq.), 3-(((2R,7aR)-7a- (hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoic acid (D6-2, 1.0 eq.) and DIEA (4.0 eq.) in MeOH is added HATU (1.1 eq.) and stirred until reaction completion. After removing solvent, EtOAc is added. The mixture is washed with brine, dried over Na2SO4, and concentrated. The residue is purified by reverse phase flash chromatography to afford the title compound. [0448] Step D. tert-butyl 1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)-N-methylpropanamido)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D6): To a solution of tert-butyl 1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2- yl)oxy)-N-methylpropanamido)methyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (D6-3, 1.0 eq.) in 1,4-dioxane at room temperature is added 1M HCl (2.3 eq.). The solution is stirred until reaction completion and is then treated with NaHCO3 (3.0 eq.). The mixture is stirred for another 30 minutes and concentrated to dryness. The residue is mixed with dichloromethane, and filtered through a celite plug. The filtrate is then concentrated to give crude title compound. [0449] Preparation of (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)- 13,22-dioxa-2,9,16,24,28,31,33- h h l 217112714 7114 200162002530 i 131 23252729
Figure imgf000140_0001
Figure imgf000141_0001
fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (A1, 1.0 eq.) and N,N- Diisopropylethylamine (6.0 eq.) in dichloromethane is added tert-butyl 1- ((((benzyloxy)carbonyl)amino)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (B1, 1.0 eq.) at -40 °C. After stirring at -40 °C for 0.5 h, the mixture is diluted with water, extracted with dichloromethane. The combined organic layers is washed with brine, dried over Na2SO4, filtered and concentrated under vacuum, affording the title compound. [0451] Step B. tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3-(7-chloro-8-fluoro-2- (((2R,7aR)-2-(3-methoxy-3-oxopropoxy)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A mixture of tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 eq.), methyl 3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoate (C1, 2.0 eq.) and DIEA (3.0 eq.) in dioxane is stirred at 800C for 6 hours. After reaction completion, the mixture is diluted with water, extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated under vaccum. The crude product is purified by reverse phase chromatography to afford the tilte compound. [0452] Step C. tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3-(8-fluoro-7-(8-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aR)-2-(3-methoxy-3-oxopropoxy)tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate: A mixture of tert-butyl 1- ((((benzyloxy)carbonyl)amino)methyl)-3-(7-chloro-8-fluoro-2-(((2R,7aR)-2-(3-methoxy-3- oxopropoxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.0 eq.), 2-(8-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.3 eq.), K3PO4 (1.5 M solution, 3.0 eq.), Mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’- biphenyl)]palladium(II), [(Di(1-adamantyl)-butylphosphine)-2-(2’-amino-1,1’- biphenyl)]palladium(II) methanesulfonate (cataCXium-A-Pd-G3, CAS#1651823-59-4, MW:728.27) (0.1 eq) in THF is degassed and purged with nitrogen gas 3 times. The mixture is stirred at 60 °C for 2 hours under nitrogen atmosphere. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by reversed phase flash chromatography to give the title compound. [0453] Step D. 3-(((2R,7aR)-7a-(((4-(1-(aminomethyl)-8-(tert-butoxycarbonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthalen-1- yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propanoic acid: A solution of tert-butyl 1-((((benzyloxy)carbonyl)amino)methyl)-3-(8-fluoro-7-(8- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aR)-2-(3-methoxy-3- oxopropoxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.0 eq.) in MeOH is hydrogenated under Hydrogen gas in presence of Pd/C until reaction completion for Cbz deprotection. After filtration to remove Pd/C catalyst, the solution is added NaOH solution to hydolyze the methyl ester. After neutralization with sodium bicarbonate solution, the mixture is evaporated to dryness. The mixture is mixed with MeOH and filtered to remove solid. This solution of crude product is used directely to the next step. [0454] Step E. tert-butyl (14R,20R)-26-fluoro-27-[8-fluoro-3-(methoxymethoxy)naphthalen- 1-yl]-10-oxo-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate: A crude solution of 3-(((2R,7aR)-7a-(((4-(1-(aminomethyl)-8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(8-fluoro-3- (methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)propanoic acid in MeOH from Step D is added DIEA (1.0 eq.) and HATU (1.5 eq.) and stirred until reaction completion. After concentration to remove MeOH solvent, EtOAc is added. The resulting mixture is washed with brine and dried over Na2SO4. After removing solvent, the residue is used directly to the next step. [0455] Step F. (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one: Crude compound from Step E (tert-butyl (14R,20R)-26- fluoro-27-[8-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-10-oxo-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate) (1.0 eq.) is dissolved in MeOH/1,4-dioxane, and HCl solution is added and stirred until reaction completion. After removing solvent, the residue is purified by HPLC to afford the title compound. [0456] Compound 1-4 are produced with General Scheme I. Scheme A Numbe Intermeidat B C Compound # and Structure
Figure imgf000143_0001
[0457] Preparation of (4S,7R,14R,20R)-27-(3-chloro-2-isopropyl-5-hydroxyphenyl)-26- fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 10)
Figure imgf000144_0001
Figure imgf000144_0002
[0458] Step A. tert-butyl 3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-((3- (((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)-N- methylpropanamido)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.0 eq.) and N,N-Diisopropylethylamine (6.0 eq.) in dichloromethane is added tert-butyl 1-((3-(((2R,7aR)-7a- (hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)-N-methylpropanamido)methyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (D6, 1.0 eq.) at -40 °C. After stirring at -40 °C for 0.5 h, the mixture is diluted with water, extracted with dichloromethane. The combined organic layers is washed with brine, dried over Na2SO4, filtered and concentrated under vacuum, affording title compound. [0459] Step B. tert-butyl (14R,20R)-27-chloro-26-fluoro-9-methyl-10-oxo-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate: A solution of tert-butyl 3-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-1-((3-(((2R,7aR)-7a-(hydroxymethyl)hexahydro-1H- pyrrolizin-2-yl)oxy)-N-methylpropanamido)methyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.0 eq.), and DIEA (3.0 eq.) in dioxane is stirred at 80 0C for 6 hours. After reaction completion, the mixture is diluted with water, extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, and concentrated under vaccum. The crude product is purified by reverse phase chromatography to afford the tilte compound. [0460] Step C. tert-butyl (14R,20R)-27-[3-chloro-5-(methoxymethoxy)-2-(propan-2- yl)phenyl]-26-fluoro-9-methyl-10-oxo-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate: A mixture of the product from Step B (tert-butyl (14R,20R)-27- chloro-26-fluoro-9-methyl-10-oxo-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate) (1.0 eq.), 2-(3-chloro-2-isopropyl-5-(methoxymethoxy)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq.), K3PO4 (1.5 M solution, 3.0 eq.), and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II), [(Di(1-adamantyl)-butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (cataCXium-A-Pd-G3, CAS#1651823-59-4, MW:728.27) (0.1 eq.) in THF is degassed and purged with nitrogen gas 3 times. The mixture is stirred at 60 °C for 2 hours under nitrogen atmosphere. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue is purified by reversed phase flash chromatography to give the title compound. [0461] Step D. (4S,7R,14R,20R)-27-[3-chloro-5-hydroxy-2-(propan-2-yl)phenyl]-26-fluoro- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one: A solution of the product from Step C (tert-butyl (14R,20R)-27-[3-chloro-5- (methoxymethoxy)-2-(propan-2-yl)phenyl]-26-fluoro-9-methyl-10-oxo-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate) (1.0 eq.) is dissolved in MeOH/1,r-dioxane, and HCl solution is added and stirred until reaction completion. After removing solvent, the residue is purified by HPLC to afford the title compound. [0462] Compounds 5-27 are syntheized as Compound 10 using General Scheme II Scheme Core D Boronic acid Compound # and Structure intermediate intermediate
Figure imgf000145_0001
D3 Compound 7
Figure imgf000146_0001
D6 Compound 13 A1
Figure imgf000147_0001
D6 Compound 19
Figure imgf000148_0001
D2 Compound 25 O O
Figure imgf000149_0001
[0463] Chemical Synthesis: [0464] Example 1: Preparation of (4S,7R,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 2), (4S,7R,14S,20S)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 2-a), (4R,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1- yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 2-b, and (4R,7S,14S,20S)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen- 1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 2-c) [0465] Part 1. Preparation of intermediate (cis)-tert-butyl 3-[[8-(hydroxymethyl)-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoate;
Figure imgf000150_0001
(25.0 g, 118 mmol, 1 eq) in EtOH (250 mL) was added slowly NaBH4 (1.34 g, 35.5 mmol, 0.3 eq) at 0 °C under N2 and stirred at 0 °C for 10 min. The mixture was quenched by MeOH (30 mL) and concentrated under vacuum to give crude. The residue was purified by silica gel chromatography using petroleum ether(PE)/EtOAc to afford (cis)-ethyl-2-hydroxy-5-oxo- 2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate (16.8 g, 78.8 mmol, 66.6% yield) as colorless oil. [0467] Step 2. To a solution of (cis)-ethyl-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H- pyrrolizine-8-carboxylate (16.6 g, 77.8 mmol, 1 eq) in MeOH (50 mL) was added NaBH4 (4.42 g, 117 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was quenched by MeOH (30 mL) and concentrated under vacuum to give crude (cis)- 6-hydroxy-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin-3-one (12.6 g, crude) as colorless oil. [0468] Step 3. To a solution of (cis)-6-hydroxy-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H- pyrrolizin-3-one (12.6 g, 73.6 mmol, 1 eq) in THF (150 mL) was added BH3-Me2S (10 M, 36.80 mL, 5 eq) and the mixture was stirred at 60 °C for 3 h. On completion, the mixture was quenched by MeOH (50 mL) and 4 M HCl/dioxane (30 mL) added and stirred at 60 °C for 1 h. The mixture was then concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM. (cis)-8-(hydroxymethyl)-1, 2, 3, 5, 6, 7- hexahydropyrrolizin-2-ol (11.6 g, crude) was obtained as colorless oil. [0469] Step 4. To a solution of (cis)-8-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2-ol (11.6 g, 73.79 mmol, 1 eq) in DCM (150 mL) was added TEA (22.4 g, 221 mmol, 30.8 mL, 3 eq) and TBDPSCl (22.3 g, 81.2 mmol, 20.9 mL, 1.1 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using EtOAc in petroleum ether to give (cis)-8-[[tert-butyl (diphenyl) silyl] oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-ol (16.3 g, 41.2 mmol, 55.8% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.84 - 7.79 (m, 2H), 7.76 - 7.72 (m, 2H), 7.45 - 7.37 (m, 6H), 4.34 (s, 1H), 4.20 - 3.97 (m, 1H), 3.50 (d, J = 4.4 Hz, 2H), 3.34 - 3.25 (m, 1H), 3.04 - 2.92 (m, 1H), 2.83 - 2.68 (m, 2H), 2.24 - 2.16 (m, 1H), 1.96 - 1.88 (m, 1H), 1.84 - 1.74 (m, 1H), 1.69 - 1.61 (m, 1H), 1.57 - 1.50 (m, 2H), 1.09 (s, 9H). [0470] Step 5. To a solution of (cis)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-ol (16.3 g, 41.20 mmol, 1 eq) in THF (120 mL) was added tert-butyl prop-2-enoate (10.6 g, 82.4 mmol, 11.96 mL, 2 eq) and KOH (1.16 g, 20.6 mmol, 0.5 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using EtOAc in PE to give (cis)-tert-butyl 3-[[8-[[tert butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin- 2-yl]oxy]propanoate (17.5 g, 33.4 mmol, 81.1% yield) as colorless oil. [0471] Step 6. To a solution of (cis)-tert-butyl 3-[[8-[[tert-butyl(diphenyl)silyl]oxymethyl]- 1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propanoate (6.60 g, 12.6 mmol, 1 eq) in THF (60 mL) was added pyridine;hydrofluoride (2.68 g, 18.9 mmol, 2.43 mL, 70% purity, 1.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give (cis)-tert-butyl 3-[[8-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propanoate (3.20 g, 11.2 mmol, 88.9% yield) as yellow oil. 1H NMR (400 MHz, CD3OD) δ 4.26 (t, J = 4.4 Hz, 1H), 3.82 - 3.76 (m, 1H), 3.72 - 3.65 (m, 2H), 3.60 (d, J = 11.2 Hz, 2H), 3.36 - 3.32 (m, 1H), 3.20 - 3.10 (m, 2H), 2.49 (t, J = 6.0 Hz, 2H), 2.27 - 2.16 (m, 2H), 2.11 - 2.00 (m, 3H), 1.90 - 1.80 (m, 1H), 1.46. [0472] Part 2. Preparation of intermediate tert-butyl 1-[[methyl-(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.
Figure imgf000152_0001
[0473] Ste
Figure imgf000152_0002
ylate (28.0 g, 132 mmol, 1 eq) and TEA (16.0 g, 158 mmol, 22.0 mL, 1.2 eq) in DCM (660 mL) was added chloro(diphenyl)methyl]benzene (38.9 g, 139 mmol, 1.06 eq) and the reaction was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using EtOAc in PE to give tert-butyl 3-trityl-3, 8- diazabicyclo [3.2.1] octane-8-carboxylate (56.0 g, 123 mmol, 93.4% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 7.48 (s, 5H), 7.27 (s, 7H), 7.19 - 7.10 (m, 3H), 4.22 - 4.11 (m, 1H), 4.08 - 3.96 (m, 1H), 2.97 (d, J = 11.2 Hz, 2H), 2.41 - 2.31 (m, 2H), 2.03 - 1.95 (m, 2 H), 1.87 - 1.70 (m, 2 H), 1.26 (s, 9 H). [0474] Step 2. To a solution of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16.4 g, 36.2 mmol, 1 eq) and TMEDA (7.14 g, 61.5 mmol, 9.28 mL, 1.7 eq) in diethyl ether (170 mL) was added s-BuLi (1.3 M, 47.3 mL, 1.7 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 1.5 h. Then ethyl formate (8.04 g, 108 mmol, 8.73 mL, 3 eq) was added to the mixture at -10 °C for 30 min. On completion, the mixture was quenched by water (150 mL). Extraction workup with EtOAc followed by silica gel chromatography using EtOAc in PE afford tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.80 g, 14.1 mmol, 19.48% yield) as white solid.1H NMR (400 MHz, CDCl3) δ = 9.66 - 9.24 (m, 1H), 7.60 - 7.46 (m, 5H), 7.27 (s, 7H), 7.17 - 7.07 (m, 3H), 4.31 - 4.18 (m, 1H), 4.09 - 4.00 (m, 1H), 3.51 - 3.34 (m, 1H), 3.06 - 2.92 (m, 1H), 2.43 (s, 2H), 2.30 - 2.07 (m, 2H), 1.93 (d, J = 11.2 Hz, 1H), 1.78 (t, J = 12.4 Hz, 1H), 1.19 - 1.06 (m, 9H) [0475] Step 3. To a solution of tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (4.50 g, 9.32 mmol, 1 eq) in MeOH (50 mL) was added MeNH2 (2 M, 23.3 mL, 5 eq). After stirring at 20 °C for 3 h., the solution was cooled to 0 °C and added NaBH4 (459 mg, 12.1 mmol, 1.3 eq). The resulting solution was stirred at 20 °C for 1.5 h. On completion, the mixture was quenched by MeOH (20 mL) and concentrated under vacuum; the residue was purified by silica gel chromatography using EtOAc in PE to afford tert-butyl 1- (methylaminomethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.88 g, 7.80 mmol, 83.6% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 7.49 (s, 5H), 7.32 - 7.21 (m, 7H), 7.18 - 7.09 (m, 3H), 4.11 - 4.04 (m, 1H), 3.03 - 2.91 (m, 2H), 2.87 - 2.82 (m, 1H), 2.80 (d, J = 4.4 Hz, 2H), 2.48 - 2.42 (m, 1H), 2.39 (s, 3H), 2.37 - 2.31 (m, 1H), 2.27 - 2.17 (m, 1H), 1.86 - 1.79 (m, 1H), 1.75 - 1.68 (m, 1H), 1.17 (s, 9H). [0476] Step 4. To a solution of tert-butyl 1-(methylaminomethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3.88 g, 7.80 mmol, 1 eq) in DCM (70 mL) was added TEA (3.94 g, 38.9 mmol, 5.43 mL, 5 eq) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (2.46 g, 11.7 mmol, 1.63 mL, 1.5 eq). The mixture was stirred at 0 °C and warmed to 25 °C for 16 h. On completion, the mixture was diluted with water (40 mL) and extraction workup followed by silica gel chromatography using EtOAc in PE to give tert-butyl 1-[[methyl-(2,2,2- trifluoroacetyl)amino]methyl]-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.13 g, 5.27 mmol, 67.6% yield) as light yellow oil.1H NMR (400 MHz, CDCl3) δ 7.39 (s, 5H), 7.23 - 7.16 (m, 7H), 7.09 - 7.02 (m, 3H), 4.12 - 3.89 (m, 3H), 3.03 (d, J = 1.2 Hz, 3H), 2.90 - 2.80 (m, 2H), 2.41 - 2.27 (m, 1H), 2.22 - 2.11 (m, 1H), 1.95 - 1.73 (m, 4H), 1.09 (s, 9H). [0477] Step 5. To a solution of tert-butyl 1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3- trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.33 g, 5.61 mmol, 1 eq) in dioxane (40 mL) was added HCl/dioxane (1 M, 1 mL, 1.78e-1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched by NaHCO3 (10 mL) and water (40 mL). Extraction workup followed by silica gel chromatography to give tert-butyl 1-[[methyl-(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.60 g, 4.55 mmol, 81.2% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ = 4.26 - 4.14 (m, 2H), 3.26 - 3.20 (m, 3H), 3.10 - 3.00 (m, 2H), 2.80 - 2.71 (m, 2H), 2.07 - 1.93 (m, 2H), 1.93 - 1.77 (m, 2H), 1.56 - 1.38 (s, 9H) [0478] Part 3. Preparation of Compound 2, Compound 2-a, Compound 2-b and Compound 2- c.
Figure imgf000154_0001
Figure imgf000155_0001
3,8- diazabicyclo[3.2.1]octane-8carboxylate (1.53 g, 4.36 mmol, 1 eq) and DIEA (3.77 g, 29.2 mmol, 5.08 mL, 6.7 eq) in DCM (25 mL) was added 2,4,7-trichloro-8-fluoro-pyrido[4,3- d]pyrimidine (1.10 g, 4.36 mmol, 1 eq) at -40 °C for 1 h under N2. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)- 1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.2 g, 3.88 mmol, 88% yield) as yellow solid.1H NMR (400 MHz, CDCl3) δ 8.93 - 8.72 (m, 1H), 4.41 (d, J = 7.2 Hz, 3H), 4.21 - 4.12 (m, 1H), 3.72 (d, J = 12.0 Hz, 2H), 3.28 (d, J = 1.2 Hz, 3H), 2.08 - 1.61 (m, 5H), 1.55 (s, 9H). [0480] Step 2. The mixture of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.46 g, 2.57 mmol, 1 eq), tert-butyl 3-[[(2R,8R)-8-(hydroxymethyl)-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoate (1.47 g, 5.15 mmol, 2 eq) and DIEA (998 mg, 7.72 mmol, 1.34 mL, 3 eq) in dioxane (30 mL) was stirred at 80 °C for 16 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using EtOAc in PE to give tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo- propoxy)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl]-1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (924 mg, 1.13 mmol, 43.9% yield) as yellow oil. [0481] Step 3. To a solution of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl]-1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (924 mg, 1.13 mmol, 1 eq) and 2-[8-fluoro-3-(methoxymethoxy)-1-naphthyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (752 mg, 2.26 mmol, 2 eq.) in THF (15 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanesulfonate (82.4 mg, 0.113 mmol, 0.1 eq) and K3PO4 (2 M, 1.70 mL, 3 eq). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using EtOAc in PE to give tert-butyl 3-[2- [[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 8-fluoro-7-[8-fluoro-3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1- [[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (904 mg, 0.917 mmol, 80% yield) as yellow solid. [0482] Step 4. To a solution of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[8-fluoro-3-(methoxymethoxy)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[[methyl-(2,2,2-trifluoroacetyl) amino] methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.203 mmol, 1 eq) in THF (4 mL) and H2O (0.5 mL) was added LiOH.H2O (25.5 mg, 0.608 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated under vacuum to give tert-butyl 3-[2- [[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 8-fluoro-7-[8-fluoro-3-(methoxymethoxy)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1- (methylaminomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (181 mg, crude) as yellow solid. [0483] Step 5. To a solution of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[8-fluoro-3-(methoxymethoxy)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-(methylaminomethyl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (181 mg, 0.203 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 2.01 mL, 39.6 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated under vacuum to give 3-[[(2R,8R)-8-[[8-fluoro-7- (8-fluoro-3-hydroxy-1-naphthyl)-4-[1-(methylaminomethyl)-3,8-diazabicyclo[3.2.1] octan-3- yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propanoic acid (148 mg, crude, HCl) as yellow solid. LCMS: (M+1: 690.2) [0484] Step 6. Preparation of Cpd. 2, Cpd. 2-a, Cpd. 2-b, and Cpd. 2-c: To a solution of 3- [[(2R,8R)-8-[[8-fluoro-7-(8-fluoro-3-hydroxy-1-naphthyl)-4-[1-(methylaminomethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoic acid (147 mg, 0.202 mmol, 1 eq, HCl) in DMF (3 mL) was added DIEA (78.5 mg, 0.607 mmol, 3 eq) and HATU (92.4 mg, 0.243 mmol, 1.2 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated under vacuum and the residue was purified by Prep-HPLC to give two peaks of the desired product, Peak 1 and Peak 2. These two peaks were independently resolved by chiral SFC to give Cpd. 2-a and Cpd.2-b from peak 1 and Cpd.2-c and Cpd.2 from peak 2. [0485] Cpd. 2-a: 5.21 mg as white solid. (4S,7R,14S,20S)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one. 1H NMR (400 MHz, CD3OD) δ 9.13 - 9.02 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.32 (s, 1H), 7.15 (dd, J = 12.4, 2.4 Hz, 1H), 6.97 - 6.86 (m, 1H), 5.14 - 4.99 (m, 1H), 4.69 (dd, J = 10.8, 3.6 Hz, 1H), 4.40 (d, J = 13.8 Hz, 1H), 4.35 - 4.22 (m, 2H), 4.12 (t, J = 4.2 Hz, 1H), 4.03 (t, J = 9.2 Hz, 1H), 3.85 (t, J = 12.2 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.51 - 3.43 (m, 1H), 3.22 (d, J = 2.8 Hz, 3H), 3.20 - 3.07 (m, 2H), 2.97 - 2.72 (m, 4H), 2.56 - 2.32 (m, 3H), 2.02 - 1.65 (m, 8H). LC/MS: (M+1: 672.3) [0486] Cpd. 2-b: 4.15 mg as white solid. (4R,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one. 1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.38 (td, J = 7.6, 5.2 Hz, 1H), 7.33 (s, 1H), 7.16 (dd, J = 13.2, 2.4 Hz, 1H), 6.96 - 6.86 (m, 1H), 5.19 - 5.05 (m, 1H), 4.78 (s, 1H), 4.42 - 4.23 (m, 3H), 4.17 (t, J = 4.0 Hz, 1H), 4.04 (t, J = 9.6 Hz, 1H), 3.87 (t, J = 11.6 Hz, 1H), 3.69 (s, 1H), 3.57 - 3.41 (m, 2H), 3.21 (d, J = 2.4 Hz, 3H), 3.19 - 3.11 (m, 1H), 3.09 - 3.01 (m, 1H), 3.00 - 2.76 (m, 4H), 2.61 - 2.42 (m, 3H), 2.02 - 1.94 (m, 2H), 1.90 - 1.62 (m, 5H). LC/MS: (M+1: 672.4) [0487] Cpd. 2-c: 4.44 mg as yellow gum. (4R,7S,14S,20S)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one. 1H NMR (400 MHz, CD3OD) δ 9.27 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.40 (td, J = 8.0, 3.2 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.17 (dd, J = 12.0, 2.4 Hz, 1H), 6.92 (td, J = 12.4, 7.8 Hz, 1H), 5.22 (dd, J = 12.0, 2.8 Hz, 1H), 4.59 (dd, J = 19.2, 14.2 Hz, 1H), 4.45 (t, J = 10.2 Hz, 1H), 4.35 - 4.20 (m, 3H), 3.98 - 3.54 (m, 7H), 3.41 - 3.33 (m, 2H), 3.25 - 3.14 (m, 4H), 2.84 - 2.63 (m, 4H), 2.35 - 2.21 (m, 3H), 2.18 - 1.93 (m, 4H), 1.81 - 1.67 (m, 1H). LC/MS: (M+1: 672.3) [0488] Cpd. 2: 3.99 mg as yellow gum. (4S,7R,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one. 1H NMR (400 MHz, CD3OD) δ 9.36 - 9.22 (m, 1H), 7.67 - 7.56 (m, 1H), 7.42 - 7.38 (m, 1H), 7.37 - 7.32 (m, 1H), 7.21 - 7.11 (m, 1H), 6.92 (td, J = 12.4, 7.6 Hz, 1H), 5.27 - 5.18 (m, 1H), 4.65 - 4.54 (m, 1H), 4.51 - 4.43 (m, 1H), 4.38 - 4.18 (m, 3H), 3.98 - 3.60 (m, 6H), 3.43 - 3.34 (m, 2H), 3.26 - 3.16 (m, 4H), 2.84 - 2.63 (m, 4H), 2.35 - 1.94 (m, 7H), 1.83 - 1.69 (m, 1H). LC/MS: (M+1: 672.2) [0489] Example 2: Preparation of 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol (Compound 6); 5-fluoro-4- [(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 6-a); and 5-fluoro-4-[(4R,7S,14S,20S)-26-fluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol (Compound 6-b) [0490] Part 1. Preparation of intermediate tert-butyl 1-[3-[[(2R,8R)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propoxymethyl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate O TBDPSO TBDPSO OH
Figure imgf000158_0001
Figure imgf000159_0001
[0491] S
Figure imgf000159_0002
8R)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propanoate (9.20 g, 17.6 mmol, 1 eq.) in THF (90 mL) was added LAH (867 mg, 22.8 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. and quenched with water (30 ml). Extraction workup with DCM, followed by silica gel chromatography using MeOH in DCM to give 3-[[(2R,8R)- 8-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propan-1- ol (4.90 g, 10.8 mmol, 61.5% yield) as colorless oil. LCMS: (M+1: 454.8) [0492] Step 2. To a solution of tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (30.0 g, 62.2 mmol, 1 eq.) in DCM (300 mL) was added HCl/dioxane (4 M, 75 mL, 4.83 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, water (100 mL) was added and extraction work up with DCM followed by concentration under vacuum to give tert- butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.50 g, 35.4 mmol, 56.9% yield) as colorless oil. [0493] Step 3. To a solution of tert-butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (8.50 g, 35.4 mmol, 1 eq) in THF (100 mL) was added sat. NaHCO3 (108 g, 1.29 mol, 50 mL, 36.3 eq) and CbzCl (7.84 g, 45.9 mmol, 6.54 mL, 1.3 eq). The mixture was stirred at 25 °C for 1 h. Extraction workup with EtOAc and concentration under vacuum to give 3- benzyl 8-(tert-butyl) 1-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (14.0 g, crude) as colorless oil. [0494] Step 4. To a solution of 3-benzyl 8-(tert-butyl) 1-formyl-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (14.0 g, 37.4 mmol, 1 eq) in MeOH (150 mL) was added NaBH4 (2.12 g, 56.1 mmol, 1.5 eq). The mixture was stirred at 0 °C for 2 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give 3-benzyl 8-(tert-butyl) 1-(hydroxymethyl)- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.5 g, 30.6 mmol, 81.7% yield) as colorless oil. [0495] Step 5. To a solution of 3-benzyl 8-(tert-butyl) 1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.5 g, 30.6 mmol, 1 eq) in DCM (60 mL) was added HCl/dioxane (4 M, 45 mL, 5.89 eq). The mixture was stirred at 20 °C for 3 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give benzyl 1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (6.00 g, 21.7 mmol, 71.1% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.41 - 7.29 (m, 5H), 5.21 - 5.07 (m, 2H), 3.98 - 3.73 (m, 2H), 3.55 (s, 3H), 3.11 - 2.84 (m, 2H), 1.94 - 1.57 (m, 5H) [0496] Step 6. To a mixture of imidazole (12.2 g, 179 mmol, 9 eq) in DCM (55 mL) at -78 °C was added SOCl2 (7.10 g, 59.7 mmol, 4.33 mL, 3 eq) and the mixture was stirred at -78 °C for 1 h. Then benzyl 1-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.50 g, 19.9 mmol, 1 eq) in DCM (10 mL) was added at -78 °C and the reaction mixture was stirred at 25 °C for 16 h. On completion, the mixture was quenched by NH4Cl (50 mL). Extraction workup with EtOAc, followed by concentration under vacuum to give benzyl dihydro-3H- 3a,7-ethano[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate 1-oxide (6.30 g, 19.5 mmol, 98.2% yield) as light yellow oil. [0497] Step 7. To a solution of benzyl dihydro-3H-3a,7-ethano[1,2,3]oxathiazolo[3,4- a]pyrazine-5(4H)-carboxylate 1-oxide (6.30 g, 19.5 mmol, 1 eq) in MeCN (180 mL) and H2O (60 mL) was added NaIO4 (5.43 g, 25.4 mmol, 1.41 mL, 1.3 eq) and RuCl3.3H2O (102 mg, 0.391 mmol, 0.02 eq). The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched by water (30 mL). Extraction workup with EtOAc followed by silica gel chromatography using EtOAc in PE to give benzyl dihydro-3H-3a,7- ethano[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate 1,1-dioxide (4.00 g, 11.8 mmol, 60.5% yield) as white solid. LCMS: (M + Na: 360.9). [0498] Step 8. To a solution of 3-[[(2R,8R)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]- 1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propan-1-ol (831 mg, 1.83 mmol, 1 eq) in DMF (15 mL) was added NaH (147 mg, 3.66 mmol, 60% purity, 2 eq) at 0 °C for 30 min. Then benzyl dihydro-3H-3a,7-ethano[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate 1,1-dioxide (620 mg, 1.83 mmol, 1 eq) was then added to the mixture and stirred at 25 °C for 1 h. On completion, the mixture was quenched by water (10 mL). Extraction workup with EtOAc followed by silica gel chromatography using MeOH in DCM to give benzyl 1-[3-[[(2R,8R)-8- [[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.23 g, 1.73 mmol, 94.3% yield) as colorless oil. LCMS: (M+1: 712.8). [0499] Step 9. To a solution of benzyl 1-[3-[[(2R,8R)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propoxymethyl]- 3,8-diazabicyclo[3.2.1] octane-3-carboxylate (1.23 g, 1.73 mmol, 1 eq) in DCM (15 mL) was added Boc2O (754 mg, 3.46 mmol, 2 eq) and TEA (524 mg, 5.18 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give 3-benzyl 8-(tert-butyl) 1-((3-(((2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H- pyrrolizin-2-yl)oxy)propoxy)methyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (750 mg, 53.5% yield) as colorless oil. LCMS: (M+1: 812.8) [0500] Step 10. To a solution of 3-benzyl 8-(tert-butyl) 1-((3-(((2R,7aR)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (600 mg, 0.739 mmol, 1 eq) in i-PrOH (6 mL) was added Pd(OH)2/C (50.0 mg, 10%) and Pd/C (50.0 mg, 10%). The mixture was stirred at 25 °C for 3 hours under H2. On completion, the mixture was filtered and concentrated under vacuum to give tert-butyl 1-[3-[[(2R,8R)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, crude) as colorless oil. LCMS: (M+1: 678.9) [0501] Part 2. Preparation of Compound 6, Compound 6-a and Compound 6-b. Boc Cl Boc N N N N
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000163_0001
5 mmol, 1.3 eq) and DIEA (629 mg, 4.87 mmol, 6 eq) in DCM (15 mL) was added tert-butyl 1- [3-[[(2R,8R)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.811 mmol, 1 eq) at -40 °C for 1 h under N2. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give tert- butyl 1-[3-[[8-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (634 mg, 0.709 mmol, 87.4% yield) as brown oil. LCMS: (M+1: 893.6). [0503] Step 2. To a solution of tert-butyl 1-[3-[[(2R,8R)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propoxymethyl]- 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (634 mg, 0.709 mmol, 1 eq) in THF (10 mL) was added pyridine-hydrofluoride (151 mg, 1.06 mmol, 70%, 1.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction was concentrated and the residue was purified by silica gel chromatography using MeOH in DCM to give tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1-[3- [[(2R,8R)-8-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propoxymethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 47.3% yield) as yellow oil. LCMS: (M+1: 657.1). [0504] Step 3. To the solution of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin- 4-yl)-1-[3-[[(2R,8R)-8-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy] propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 0.335 mmol, 1 eq) in dioxane (22 mL) was added DIEA (173 mg, 1.34 mmol, 4 eq) and 4A MS (220 mg). The mixture was stirred at 100 °C for 16 h. On completion, the mixture was filtered, concentrated and the residue was purified by silica gel chromatography using MeOH in DCM to give Peak 1 (tert-butyl (4R,7S,14R,20R)-27-chloro-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate) (26.0 mg, 12.5% yield) as brown solid [LC/MS: (M+1: 619.2)] and Peak 2 (tert-butyl (4S,7R,14R,20R)-27-chloro-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate) (58.0 mg, 27.9% yield) as brown solid [LC/MS: (M+1: 619.2)]. [0505] Step 4. To a solution of tert-butyl (tert-butyl (4R,7S,14R,20R)-27-chloro-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate (26.0 mg, 0.042 mmol, 1 eq) and 2-[8-fluoro-3-(methoxymethoxy)- 1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.9 mg, 0.084 mmol, 2 eq) in THF (1 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane; methanesulfonate (3.06 mg, 0.0042 mmol, 0.1 eq) and K3PO4 (2 M, 0.063 mL, 3 eq). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH in DCM to give tert-butyl (4R,7S,14R,20R)-26-fluoro-27-[8-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (10.0 mg, 30.2% yield) as white solid. LCMS: (M+1 = 789.4). [0506] Step 5. To a solution of tert-butyl (4R,7S,14R,20R)-26-fluoro-27-[8-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate (10.0 mg, 0.0127 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.357 mL, 113 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated and the residue was triturated by DCM, and the filter cake was concentrated under vacuum to give 5-fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol (Cpd. 6-a) (4.62 mg, 54.8% yield) as white solid.1H NMR (400 MHz, CD3OD) δ 9.31 (d, J = 4.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.49 - 7.39 (m, 2H), 7.30 (dd, J = 14.4, 2.4 Hz, 1H), 7.04 - 6.94 (m, 1H), 5.70 (d, J = 14.4 Hz, 1H), 5.34 (dd, J = 17.2, 11.6 Hz, 1H), 4.80 - 4.72 (m, 1H), 4.55 - 4.45 (m, 2H), 4.42 - 4.32 (m, 2H), 4.10 (d, J = 11.2 Hz, 1H), 3.95 - 3.66 (m, 8H), 3.45 - 3.36 (m, 3H), 2.76 - 2.66 (m, 1H), 2.27 (d, J = 3.2 Hz, 5H), 2.14 - 1.92 (m, 5H). LC/MS: (M+1: 645.2) [0507] Step 6. To a solution of tert-butyl (4S,7R,14R,20R)-27-chloro-26-fluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (Peak 2, 38.0 mg, 0.0614 mmol, 1 eq) and 2-[8- fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (40.8 mg, 0.123 mmol, 2 eq.) in THF (1 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (4.5 mg, 0.0061 mmol, 0.1 eq) and K3PO4 (2 M, 0.0921 mL, 3 eq). The mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give tert-butyl (4S,7R,14R,20R)-26-fluoro-27-[8-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate (33.0 mg, 68.2% yield) as white solid. LCMS: (M+1: 789.3). [0508] Step 7. Preparation of Cpd.6b and Cpd.6: To a solution of tert-butyl (4S,7R,14R,20R)- 26-fluoro-27-[8-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (28.0 mg, 0.0355 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 1.0 mL, 112 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under vacuum; 15.05 mg of crude product was obtained. 13 mg out of this 15.05 mg was resolved by chiral SFC to afford 2.05 mg of 5- fluoro-4-[(4R,7S,14S,20S)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Cpd. 6-b) as off-white solid and 1.45 mg of 5-fluoro-4- [(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Cpd.6) as yellow gum were obtained. [0509] (Cpd.6-b): 1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.34 - 7.32 (m, 1H), 7.17 (dd, J = 17.2, 2.4 Hz, 1H), 6.95 - 6.87 (m, 1H), 5.35 - 5.28 (m, 1H), 5.25 - 5.17 (m, 1H), 4.56 (s, 2H), 4.36 - 4.30 (m, 2H), 4.27 - 4.23 (m, 1H), 3.98 - 3.87 (m, 2H), 3.70 - 3.64 (m, 5H), 3.53 - 3.46 (m, 1H), 2.71 - 2.61 (m, 2H), 2.52 (d, J = 13.6 Hz, 2H), 2.27 - 2.19 (m, 3H), 1.76 - 1.66 (m, 6H), 1.61 (d, J = 7.6 Hz, 2H). LC/MS: (M+1: 645.2) [0510] (Cpd.6): 1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.34 - 7.30 (m, 1H), 7.21 - 7.12 (m, 1H), 6.99 - 6.86 (m, 1H), 5.41 - 5.28 (m, 1H), 4.95 - 4.90 (m, 1H), 4.78 (s, 1H), 4.63 - 4.53 (m, 1H), 4.32 - 4.22 (m, 2H), 4.07 - 4.00 (m, 1H), 3.73 - 3.65 (m, 5H), 3.63 - 3.57 (m, 1H), 3.50 - 3.43 (m, 1H), 3.23 - 3.16 (m, 1H), 3.13 - 3.04 (m, 1H), 2.97 - 2.89 (m, 1H), 2.79 - 2.71 (m, 1H), 2.52 - 2.42 (m, 1H), 2.34 - 2.26 (m, 1H), 2.23 - 2.11 (m, 1H), 1.98 (d, J = 5.6 Hz, H), 1.96 - 1.73 (m, 6H), 1.69 - 1.60 (m, 2H). LC/MS: (M+1: 645.0) [0511] Example 3: Preparation of (4S,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 28-a); (4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 28-b); (4R,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 28-c); and (4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 28-d)
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000167_0003
Figure imgf000167_0002
Figure imgf000167_0004
O O [0512]
Figure imgf000168_0001
-propoxy)- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl]-1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (425 mg, 0.521 mmol, 1 eq.) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (534 mg, 1.04 mmol, 2 eq) in THF (10 mL) was added K3PO4 (2 M, 0.781 mL, 3 eq) and [2-(2- aminophenyl)phenyl] palladium(1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (56.9 mg, 0.0781 mmol, 0.15 eq). The mixture was degassed, purged with N23 times, and then stirred at 60 °C for 2 hrs. On completion, the reaction mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give tert-butyl 3-[2- [[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)-1,2,3,5,6,7-hexahydropyrrolizin -8-yl]methoxy]- 8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[[methyl-(2,2,2-trifluoroacetyl)amino]methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 73.4% yield, 99% purity) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J = 10.0 Hz, 1H), 7.79 (dd, J = 5.6, 9.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.37 - 7.28 (m, 2H), 5.34 - 5.28 (m, 2H), 4.93 - 4.77 (m, 1H), 4.51 - 3.96 (m, 8H), 3.65 -3.60 (m, 2H), 3.52 (s, 3H), 3.31 (s, 1H), 3.26 (s, 2H), 3.20 - 3.12 (m, 2H), 2.88 - 2.78 (m, 1H), 2.69 - 2.58 (m, 1H), 2.46 – 2.40 (m, 2H), 2.33 - 2.21 (m, 1H), 2.11 (d, J = 5.6 Hz, 1H), 2.05 (s, 1H), 1.95 - 1.81 (m, 4H), 1.76 - 1.63 (m, 2H), 1.60 (s, 4H), 1.55 - 1.50 (m, 9H), 1.42 (s, 9H), 1.27 (s, 1H), 0.87 - 0.83 (m, 18H). LCMS: (M+1:1166.9) [0513] Step 2. To a mixture of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[[methyl-(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (420 mg, 0.360 mmol, 1 eq) in THF (4 mL) and H2O (0.8 mL) was added LiOH.H2O (45.3 mg, 1.08 mmol, 3 eq). The mixture was stirred at 25 °C for 16 hrs. On completion, the reaction mixture was concentrated under vacuum to give tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo- propoxy)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1- (methylaminomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 84.4% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 5.6 Hz, 1H), 8.10 (dd, J = 6.0, 9.2 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.56 -7.50 (m, 1H), 7.35 -7.30 (m, 1H), 5.36 (s, 2H), 4.72 (d, J = 10.4 Hz, 1H), 4.41 - 4.30 (m, 1H), 4.28 - 4.02 (m, 4H), 3.66 (dd, J = 5.6, 12.0 Hz, 1H), 3.60 -3.58 (m, 1H), 3.56 - 3.49 (m, 2H), 3.43 (s, 3H), 3.05 - 2.89 (m, 4H), 2.81 - 2.63 (m, 2H), 2.39 - 2.27 (m, 6H), 2.08 - 1.97 (m, 2H), 1.94 - 1.81 (m, 4H), 1.80 - 1.69 (m, 3H), 1.63 - 1.53 (m, 3H), 1.46 (s, 9H), 1.33 -1.30 (m, 9H), 1.18 - 1.16 (m, 1H), 0.81 -0.80 (m, 18H). LCMS: (M+1:1070.9). [0514] Step 3. To a solution of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1- (methylaminomethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (350 mg, 0.327 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 0.082 mL, 1 eq) at 25 °C. The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated under vacuum to give 3-[[(2R,8R)-8-[[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1- naphthyl]-4-[1-(methylaminomethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propanoic acid (250 mg, 73.8% yield, 84% purity) as a yellow solid. LCMS: (M+1:871.5). [0515] Step 4. To a solution of 3-[[(2R,8R)-8-[[8-fluoro-7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]-4-[1-(methylaminomethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoic acid (250 mg, 0.287 mmol, 1 eq) and DIEA (111 mg, 0.862 mmol, 3 eq) in DMF (2 mL) was added HATU (131 mg, 0.345 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated and the crude product was purified by prep-HPLC to give Peak 1 (4R,7S,14R,20R)-26-fluoro- 27-(7-fluoro-3-hydroxy-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one (racemic, 30 mg, 10.2% yield) as a yellow solid [LCMS: (M+1:853.3)] and Peak 2 (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-3-hydroxy-8-{[tri(propan- 2-yl)silyl]ethynyl}naphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (racemic, 30 mg, 9.3% yield) as a yellow solid [LCMS: (M+1:853.3)]. [0516] Step 5. To a solution of (4R,7S,14R,20R)-26-fluoro-27-(7-fluoro-3-hydroxy-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (racemic Peak 1, 25 mg, 0.029 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (22.3 mg, 0.147 mmol, 5 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered, concentrated and the crude product was purified by prep-HPLC to give Peak 1’ (4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one as a brown solid. [0517] The racemic Peak 1’ was then resolved by chiral SFC to afford chiral Cpd. 28-a ((4S,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9-methyl- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one) and Cpd.28-b ((4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one). [0518] Cpd. 28-a: 1H NMR (400 MHz, CD3OD) δ 9.05 (d, J = 8.8 Hz, 1H), 7.85 -7.80 (m, 1H), 7.37 - 7.29 (m, 2H), 7.21 (dd, J = 2.4, 6.8 Hz, 1H), 5.03 - 4.96 (m, 1H), 4.73 (d, J = 14.4 Hz, 1H), 4.59 (d, J = 2.0 Hz, 2H), 4.44 - 4.32 (m, 2H), 4.28 - 4.20 (m, 1H), 4.12 (s, 1H), 4.04 (t, J = 8.6 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.73 - 3.68 (m, 1H), 3.50 - 3.45 (m, 1H), 3.37 (s, 1H), 3.22 (d, J = 4.4 Hz, 3H), 2.99 - 2.77 (m, 4H), 2.57 - 2.35 (m, 3H), 2.13 - 1.70 (m, 9H). LCMS: (M+1:696.2). [0519] Cpd. 28-b: 1H NMR (400 MHz, CD3OD) δ 9.05 (d, J = 8.6 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.37 - 7.29 (m, 2H), 7.21 (dd, J = 2.4, 6.8 Hz, 1H), 5.00 (s, 1H), 4.70 (d, J = 11.2 Hz, 1H), 4.64 - 4.56 (m, 2H), 4.45 - 4.33 (m, 2H), 4.28 - 4.20 (m, 1H), 4.13 (s, 1H), 4.05 (t, J = 9.6 Hz, 1H), 3.85 (dd, J = 12.4, 17.2 Hz, 1H), 3.70 (dd, J = 2.0, 6.8 Hz, 1H), 3.50 - 3.45 (m, 1H), 3.37 (s, 1H), 3.22 (d, J = 4.4 Hz, 3H), 2.97 - 2.79 (m, 4H), 2.57 - 2.36 (m, 3H), 2.07 - 1.73 (m, 9H). LCMS: (M+1: 696.2). [0520] Step 6. To a solution of (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-3-hydroxy-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (racemic Peak 2, 25 mg, 0.029 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (22.3 mg, 0.147 mmol, 5 eq) at 25 °C.The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered, concentrated, and the crude product was purified by prep-HPLC to give Peak 2’ (4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one as a brown solid. [0521] The racemic Peak 2’ was then resolved by chiral SFC to give Cpd. 28-c (4R,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9-methyl- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one) and Cpd. 28-d ((4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one). [0522] Cpd. 28-c: 1H NMR (400 MHz, CD3OD) δ 9.11 (d, J = 6.4 Hz, 1H), 7.85 -7.80 (m, 1H), 7.36 - 7.29 (m, 2H), 7.21 (dd, J = 2.4, 8.4 Hz, 1H), 5.07 (dd, J = 4.8, 11.2 Hz, 1H), 4.68 (dd, J = 2.8, 13.6 Hz, 1H), 4.64 - 4.54 (m, 1H), 4.32 (t, J = 12.0 Hz, 1H), 4.16 (t, J = 4.4 Hz, 1H), 4.05 (dd, J = 2.8, 11.2 Hz, 2H), 3.94 - 3.80 (m, 2H), 3.75 (t, J = 6.0 Hz, 1H), 3.70 - 3.63 (m, 1H), 3.41 (s, 1H), 3.24 (s, 3H), 3.19 - 3.12 (m, 2H), 2.97 (dd, J = 4.0, 11.2 Hz, 1H), 2.79 - 2.60 (m, 3H), 2.52 - 2.33 (m, 2H), 2.15 - 1.65 (m, 9H). LCMS: (M+1: 696.2). [0523] Cpd. 28-d: 1H NMR (400 MHz, CD3OD) δ 9.11 (d, J = 6.4 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.35 - 7.34 (m, 1H), 7.33 - 7.29 (m, 1H), 7.21 (dd, J = 2.4, 8.0 Hz, 1H), 5.07 (dd, J = 4.8, 11.2 Hz, 1H), 4.72 - 4.66 (m, 1H), 4.64 - 4.56 (m, 2H), 4.37 - 4.28 (m, 1H), 4.16 (t, J = 4.4 Hz, 1H), 4.05 (dd, J = 2.0, 11.2 Hz, 1H), 3.95 - 3.79 (m, 2H), 3.78 - 3.72 (m, 1H), 3.67 (d, J = 6.4 Hz, 1H), 3.41 (s, 1H), 3.24 (s, 3H), 3.19 - 3.13 (m, 2H), 3.01 - 2.93 (m, 1H), 2.69 (dd, J = 4.8, 7.2 Hz, 3H), 2.53 - 2.33 (m, 2H), 2.20 - 1.68 (m, 9H). LCMS: (M+1: 696.2). [0524] Example 4: Preparation of (4S,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 29-a); (4R,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 29-b); (4R,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1- yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 29-c); and (4S,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Compound 29-d)
Figure imgf000172_0001
Figure imgf000173_0001
[0525
Figure imgf000174_0001
8- carboxylate (4.40 g, 9.12 mmol, 1 eq) in THF (50 mL) was added MgSO4 (5.49 g, 45.5 mmol, 5 eq), TEA (1.85 g, 18.2 mmol, 2.54 mL, 2 eq) and NH2OH.HCl (696 mg, 10.0 mmol, 1.1 eq), and the mixture was stirred at 25 °C for 12 hours. On completion, the mixture was filtered and concentrated under vacuum to afford tert-butyl 1-[(E)-hydroxyiminomethyl]-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4.50 g, 9.04 mmol, 99.1% yield) as white solid. LCMS: (M+23: 520.2). [0526] Step 2. To a solution of tert-butyl 1-[(E)-hydroxyiminomethyl]-3-trityl-3,8- diazabicyclo[3.2.1] octane-8-carboxylate (4.50 g, 9.04 mmol, 1 eq) in MeOH (60 mL) was added Raney-Ni (1.00 g, 11.6 mmol, 1.29 eq) and NH3•H2O (1.27 g, 9.04 mmol, 1.39 mL, 25%, 1 eq). The reaction mixture was stirred at 25 °C for 2 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to afford tert-butyl 1-(aminomethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.00 g, 8.27 mmol, 91.4% yield) as white solid. LCMS: (M+1: 484.3). [0527] Step 3. To a mixture of tert-butyl 1-(aminomethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8- carboxylate (4.00 g, 8.27 mmol, 1 eq) and TEA (4.18 g, 41.3 mmol, 5.76 mL, 5 eq) in DCM (50 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (3.47 g, 16.5 mmol, 2.30 mL, 2 eq) at 0°C. The reaction mixture was then stirred at 25 °C for 12 hours. On completion, the reaction mixture was concentrated and the residue was purified by silica gel chromatography to afford tert-butyl 1-[[(2,2,2-trifluoroacetyl)amino]methyl]-3- trityl-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (1.10 g, 1.90 mmol, 22.9% yield) as white solid. LCMS: (M+23: 602.3). [0528] Step 4. To a mixture of tert-butyl 1-[[(2,2,2-trifluoroacetyl)amino]methyl]-3-trityl-3,8- diazabicyclo [3.2.1]octane-8-carboxylate (1.10 g, 1.90 mmol, 1 eq) in DCM (10 mL) was added HCl/dioxane (4 M, 1 mL, 2.11 eq) and stirred at 25 °C for 5 hours. On completion, the reaction mixture was diluted with water (10 mL) and extraction workup with DCM followed by concentration under vacuum to afford tert-butyl 1-[[(2,2,2-trifluoroacetyl)amino]methyl] - 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.30 g, 46.8% yield) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.40 (dd, J = 1.2, 2.4 Hz, 1H), 4.17 (d, J = 6.4 Hz, 1H), 3.87 (s, 1H), 3.51 (d, J = 11.2 Hz, 1H), 3.01 - 2.87 (m, 2H), 2.68 - 2.54 (m, 2H), 2.03 - 1.84 (m, 3H), 1.83 - 1.69 (m, 2H), 1.49 (s, 9H). [0529] Step 5. To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (187 mg, 0.741 mmol, 1 eq) and DIEA (478 mg, 3.71 mmol, 5 eq) in DCM (10 mL) at -40 °C was added tert-butyl 1-[[(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 0.741 mmol, 1 eq) and stirred for 1 hour. On completion, the reaction mixture was concentrated and the residue was purified by silica gel chromatography to afford tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1-[[(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 97.5% yield) as red solid.1H NMR (400 MHz, CDCl3) δ = 8.83 (s, 1H), 8.23 - 7.96 (m, 1H), 4.57 (d, J = 12.4 Hz, 1H), 4.50 - 4.41 (m, 2H), 3.98 (dd, J = 5.6, 13.6 Hz, 1H), 3.82 - 3.68 (m, 2H), 3.58 (d, J = 12.4 Hz, 1H), 2.07 - 1.95 (m, 1H), 1.93 - 1.82 (m, 2H), 1.70 - 1.60 (m, 1H), 1.55 (s, 9H). LCMS: (M+1: 553.1). [0530] Step 6. To a mixture of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-1-[[(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (370 mg, 0.668 mmol, 1 eq) and tert-butyl 3-[[(2R,8R)-8-(hydroxymethyl)-1,2,3,5,6,7- hexahydropyrrolizin -2-yl]oxy]propanoate (381 mg, 1.34 mmol, 2 eq.) in dioxane (8 mL) was added 4A MS and stirred at 25°C for 0.5 hour. DIEA (259 mg, 2.01 mmol, 3 eq) was then added and the mixture was stirred at 80 °C for 30 hours. On completion, the reaction mixture was concentrated and the residue was purified by silica gel chromatography to afford tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-1-[[(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 83.8% yield) as light yellow solid. LCMS: (M+1:802.4). [0531] Step 7. To a mixture of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl]-1-[[(2,2,2-trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (385 mg, 0.479 mmol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan -2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (491 mg, 0.959 mmol, 2 eq) in THF (8 mL) was added K3PO4 (2 M, 0.719 mL, 3 eq) and [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl) -butyl-phosphane;methanesulfonate (52.4 mg, 0.0719 mmol, 0.15 eq). The reaction mixture was stirred at 60 °C for 12 hours. On completion, the reaction mixture was concentrated and the residue was purified by silica gel chromatography to afford tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[[(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (360 mg, 65.1% yield) as red solid. LCMS: (M/2+1: 577.0). [0532] Step 8. To a mixture of tert-butyl 3-[2-[[(2R,8R)-2-(3-tert-butoxy-3-oxo-propoxy)- 1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[[(2,2,2- trifluoroacetyl)amino]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 0.295 mmol, 1 eq) in THF (5 mL) and H2O (1 mL) was added LiOH•H2O (37.1 mg, 0.885 mmol, 3 eq). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to afford tert-butyl 1-(aminomethyl)-3-[2-[[(2R,8R)-2-(3-tert- butoxy-3-oxo-propoxy)-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, 99.4% yield) as light yellow solid. LCMS: (M+1: 1056.6). [0533] Step 9. To a mixture of tert-butyl 1-(aminomethyl)-3-[2-[[(2R,8R)-2-(3-tert-butoxy-3- oxo-propoxy) -1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, 0.293 mmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL, 68.1 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to afford 3-[[(2R,8R)-8-[[4- [1-(aminomethyl)-3,8 -diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoic acid (260 mg, 99.2% yield, HCl) as light yellow solid. LCMS: (M+1: 586.4). [0534] Step 10. To a mixture of 3-[[(2R,8R)-8-[[4-[1-(aminomethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl] -8-fluoro-7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoic acid (250 mg, 0.280 mmol, 1 eq, HCl) and DIEA (72.4 mg, 0.560 mmol, 2 eq) in DMF (4 mL) was added HATU (138 mg, 0.364 mmol, 1.3 eq). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was quenched with water (0.05 mL) and concentrated in vacuo. The residue was purified by prep-HPLC to afford (4R,7R,14R,20R)-26-fluoro-27-(7-fluoro-3-hydroxy-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl)-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Peak 1, 20.0 mg, 8.52% yield) and (4S,7S,14R,20R)-26-fluoro-27-(7-fluoro-3- hydroxy-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Peak 2, 20.0 mg, 8.52% yield) as light yellow solid. Peak 1 LCMS: (M+1: 838.4); Peak 2 LCMS: (M+1: 838.5). [0535] Step 11. To a mixture of (7R,14R,20R)-26-fluoro-27-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl) -1-naphthyl]-13,22-dioxa-2,9,16,24,28,31,33- heptazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (20.0 mg, 0.0238 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (18.1 mg, 0.119 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was concentrated, and the residue was purified by prep-HPLC to afford racemic Peak 1’ (14.27 mg, 85.0% yield, 97% purity) as brown solid. LCMS: (M+1:682.3). [0536] The racemic Peak 1’ (12.0 mg) was then resolved by chiral SFC to afford (4S,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one (Cpd. 29-a, 5.27 mg) and (4R,7R,14R,20R)-27-(8-ethynyl- 7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Cpd.29-b, 5.46 mg) as brown solid. [0537] Cpd. 29-a: 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (s, 1H), 9.07 (d, J = 13.6 Hz, 1H), 8.10 (dd, J = 5.6, 6.4 Hz, 1H), 8.02 - 7.92 (m, 1H), 7.50 - 7.43 (m, 1H), 7.39 (s, 1H), 7.17 (d, J = 11.2 Hz, 1H), 5.04 - 4.80 (m, 1H), 4.35 (d, J = 6.4 Hz, 1H), 4.18 - 4.00 (m, 3H), 3.98 - 3.83 (m, 3H), 3.80 - 3.69 (m, 1H), 3.64 - 3.48 (m, 2H), 3.02 - 2.93 (m, 2H), 2.83 - 2.76 (m, 1H), 2.40 - 2.29 (m, 2H), 2.21 - 2.14 (m, 1H), 2.07 - 1.99 (m, 1H), 1.91 - 1.85 (m, 1H), 1.79 - 1.65 (m, 4H), 1.56 - 1.49 (m, 2H), 1.39 - 1.32 (m, 1H), 1.23 (s, 3H), 1.17 (d, J = 3.6 Hz, 1H). LCMS: (M+1: 682.2) [0538] Cpd.29-b: 1H NMR (400 MHz, DMSO-d6) δ = 10.22 - 10.08 (m, 1H), 9.11 - 9.00 (m, 1H), 8.16 - 8.06 (m, 1H), 8.01 - 7.93 (m, 1H), 7.46 (dt, J = 2.4, 8.4 Hz, 1H), 7.38 (s, 1H), 7.17 (d, J = 12.4 Hz, 1H), 5.00 - 4.82 (m, 1H), 4.40 - 4.20 (m, 1H), 4.17 - 3.99 (m, 3H), 3.97 - 3.83 (m, 3H), 3.80 - 3.69 (m, 1H), 3.62 - 3.51 (m, 1H), 2.97 (dd, J = 6.0, 12.4 Hz, 2H), 2.86 - 2.73 (m, 2H), 2.39 - 2.29 (m, 2H), 2.20 - 2.11 (m, 1H), 2.08 - 1.99 (m, 1H), 1.87 - 1.82 (m, 1H), 1.78 - 1.60 (m, 5H), 1.53 (d, J = 5.6 Hz, 2H), 1.39 - 1.32 (m, 1H), 1.23 (s, 3H). LCMS: (M+1: 682.3) [0539] Step 12. To a mixture of (4S,7S,14R,20R)-26-fluoro-27-(7-fluoro-3-hydroxy-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Peak 2, 20.0 mg, 0.0238 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (18.1 mg, 0.119 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was concentrated, and the residue was purified by prep-HPLC to afford racemic Peak 2’ (14.09 mg, 83.1% yield) as brown solid. LCMS: (M+1: 682.2). [0540] The racemic Peak 2’ (12.0 mg) was resolved by chiral SFC to afford (4R,7R,14S,20S)- 27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one (Cpd. 29-c) and (4S,7S,14R,20R)-27-(8-ethynyl-7-fluoro- 3-hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one (Cpd.29-d). [0541] Cpd. 29-c: 1H NMR (400 MHz, DMSO-d6) δ = 10.29 - 9.97 (m, 1H), 9.13 - 8.93 (m, 1H), 8.05 (s, 1H), 8.00 - 7.93 (m, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.17 (d, J = 13.6 Hz, 1H), 4.98 - 4.74 (m, 1H), 4.51 - 4.32 (m, 1H), 4.23 - 4.04 (m, 3H), 3.95 (s, 1H), 3.89 (d, J = 17.6 Hz, 1H), 3.73 (t, J = 8.4 Hz, 1H), 3.59 - 3.48 (m, 3H), 3.25 - 3.14 (m, 2H), 3.10 - 3.01 (m, 1H), 2.96 (d, J = 13.6 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.41 (d, J = 5.2 Hz, 1H), 2.34 - 2.23 (m, 1H), 2.13 (dd, J = 2.8, 4.8 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.87 - 1.73 (m, 5H), 1.69 - 1.61 (m, 1H), 1.56 - 1.45 (m, 2H), 1.41 - 1.25 (m, 1H). LCMS: (M+1: 682.2). [0542] Cpd. 29-d: 1H NMR (400 MHz, DMSO-d6) δ = 10.15 (s, 1H), 9.04 (d, J = 19.6 Hz, 1H), 8.06 (s, 1H), 8.01 - 7.93 (m, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J = 14.8 Hz, 1H), 4.99 - 4.68 (m, 1H), 4.54 - 4.32 (m, 1H), 4.21 - 4.06 (m, 2H), 4.01 - 3.82 (m, 2H), 3.80 - 3.69 (m, 1H), 3.61 - 3.47 (m, 3H), 3.26 - 3.15 (m, 2H), 3.12 - 3.02 (m, 1H), 2.97 (d, J = 12.0 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.49 - 2.37 (m, 2H), 2.28 (dd, J = 1.6, 14.8 Hz, 1H), 2.21 - 2.11 (m, 1H), 2.06 - 1.97 (m, 1H), 1.92 - 1.61 (m, 6H), 1.58 - 1.45 (m, 2H), 1.39 - 1.25 (m, 1H). LCMS: (M+1: 682.3). [0543] Example 4, Part 1: Preparation of 5-ethynyl-6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 30-a); and 5-ethynyl-6-fluoro-4-[(4S,7R,14S,20S)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 30-b)
Figure imgf000179_0001
[0544] Step 1. To a mixture of tert-butyl (4R,7S,14R,20R)-27-chloro-26-fluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (racemic Peak 1 as prepared in Cpd. 6, 140 mg, 0.226 mmol, 1 eq) and2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl] ethynyl-triisopropyl-silane (232 mg, 0.452 mmol, 2 eq) in dioxane (2 mL) and H2O (0.4 mL) was added K3PO4 (144 mg, 0.678 mmol, 3 eq) and di-tert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (14.7 mg, 0.0226 mmol, 0.1 eq). The mixture was degassed and purged with N2 3 times and stirred at 80 °C for 2 hours under microwave. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give tert-butyl (4R,7S,14R,20R)-26-fluoro-27-[7- fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (racemic, 150 mg, 68.4% yield) as brown solid. LCMS: (M+1: 969.4) [0545] Step 2. To a solution of tert-butyl (4R,7S,14R,20R)-26-fluoro-27-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (racemic, 140 mg, 0.144 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL, 55.4 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under vacuum to give crude 6-fluoro-4- [(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (120 mg, crude) as yellow solid. LCMS: (M+1: 825.5). [0546] Step 3. To a solution of 6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (120 mg, 0.145 mmol, 1 eq) in DMSO (2 mL) was added CsF (176.3 mg, 8 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was filtered, and the filtrate was purified by Prep-HPLC to give 50 mg of crude product. This crude was then separated by chiral SFC to give 5-ethynyl-6-fluoro-4-[(4S,7R,14S,20S)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Cpd. 30-a, 20.02 mg, 20.58% yield) as brown solid, and 5-ethynyl-6- fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Cpd.30-b, 22.86 mg, 23.4% yield) as brown solid. [0547] Cpd. 30-a: 1H NMR (400 MHz, CD3OD) δ 9.08 - 8.96 (m, 1H), 7.83 (d, J = 3.2 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.25 - 7.15 (m, 1H), 5.43 - 5.25 (m, 1H), 4.81 (s, 1H), 4.35 - 4.10 (m, 3H), 4.05 - 3.88 (m, 2H), 3.87 - 3.76 (m, 2H), 3.72 - 3.56 (m, 3H), 3.48 (d, J = 11.2 Hz, 1H), 3.42 - 3.33 (m, 2H), 3.22 - 3.09 (m, 2H), 2.92 - 2.83 (m, 1H), 2.78 - 2.68 (m, 1H), 2.48 - 2.34 (m, 1H), 2.24 (d, J = 14.4 Hz, 1H), 2.12 - 1.82 (m, 7H), 1.75 - 1.55 (m, 3H). LC/MS: (M+1: 669.2). [0548] Cpd. 30-b: 1H NMR (400 MHz, CD3OD) δ 9.13 - 8.94 (m, 1H), 7.91 - 7.78 (m, 1H), 7.36 - 7.27 (m, 2H), 7.26 - 7.16 (m, 1H), 5.46 - 5.26 (m, 1H), 4.37 - 4.11 (m, 3H), 4.07 - 3.77 (m, 4H), 3.72 - 3.54 (m, 3H), 3.48 (d, J = 11.2 Hz, 1H), 3.39 (d, J = 11.2 Hz, 2H), 3.26 - 3.10 (m, 2H), 2.93 (d, J = 8.4 Hz, 1H), 2.82 (d, J = 3.6 Hz, 1H), 2.49 - 2.37 (m, 1H), 2.29 (d, J = 14.4 Hz, 1H), 2.03 - 1.81 (m, 7H), 1.80 - 1.54 (m, 3H). LC/MS: (M+1: 669.4). [0549] Example 4, Part 2: Preparation of 5-ethynyl-6-fluoro-4-[(4R,7S,14S,20S)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 30-c); and 5-ethynyl-6-fluoro-4-[(4S,7R,14R,20R)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Compound 30-d)
Figure imgf000181_0001
Figure imgf000182_0001
trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (racemic Peak 2 as prepared in Cpd. 6, 66.0 mg, 0.106 mmol, 1 eq.) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (109 mg, 0.213 mmol, 2 eq) in dioxane (0.8 mL) and H2O (0.2 mL) was added K3PO4 (67.9 mg, 0.319 mmol, 3 eq) and di- tert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (6.95 mg, 0.0106 mmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 2 hours under microwave. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give tert-butyl (4S,7R,14R,20R)-26- fluoro-27-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate (50.0 mg, 48.4% yield) as brown solid. LCMS: (M+1: 969.4). [0551] Step 2. To a solution of tert-butyl (4S,7R,14R,20R)-26-fluoro-27-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (10.0 mg, 0.0103 mmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.0026 mL, 1 eq). The mixture was stirred at 25 °C for 6 h. On completion, the mixture was concentrated under vacuum to give (4S,7R,14R,20R)-26-fluoro- 27-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaene (8.00 mg, crude, HCl) as yellow solid. LCMS: (M+1: 825.3). [0552] Step 3. To a solution of (4S,7R,14R,20R)-26-fluoro-27-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene (58.0 mg, 0.0703 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (64.1 mg, 0.421 mmol, 6 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was filtered, and the filtrate was purified by Prep-HPLC to give 50 mg of crude product, which was then resolved by chiral SFC to afford 5-ethynyl-6-fluoro-4- [(4R,7S,14S,20S)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Cpd. 30-c, 4.55 mg) as brown solid, and 5-ethynyl-6-fluoro-4- [(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol (Cpd.30-d, 5.02 mg) as brown solid. [0553] Cpd.30-c: 1H NMR (400 MHz, CD3OD) δ 9.08 (d, J = 6.4 Hz, 1 H), 7.86 (dd, J = 8.8, 5.6 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.21 (dd, J = 10.4, 2.4 Hz, 1H), 5.35 - 5.20 (m, 1H), 5.07 (t, J = 10.4 Hz, 1H), 4.35 - 4.26 (m, 2H), 4.22 - 4.00 (m, 2H), 3.76 - 3.58 (m, 7H), 3.43 (s, 3H), 3.27 - 3.18 (m, 2H), 3.14 - 3.04 (m, 1H), 3.02 - 2.91 (m, 1H), 2.63 - 2.52 (m, 1H), 2.48 - 2.36 (m, 1H), 2.28 - 2.16 (m, 1H), 2.14 - 2.05 (m, 2H), 2.03 - 1.89 (m, 4H), 1.72 - 1.60 (m, 2H). LC/MS: (M+1: 669.1). [0554] Cpd.30-d: 1H NMR (400 MHz, CD3OD) δ 9.09 (d, J = 6.4 Hz, 1 H), 7.87 (dd, J = 8.8, 5.6 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.21 (dd, J = 9.6, 2.4 Hz, 1H), 5.36 - 5.20 (m, 1H), 5.09 (t, J = 10.4 Hz, 1H), 4.31 - 4.23 (m, 2H), 4.22 - 4.00 (m, 2H), 3.77 - 3.60 (m, 7H), 3.44 (s, 3H), 3.27 - 3.19 (m, 2H), 3.15 - 3.05 (m, 1H), 3.04 - 2.94 (m, 1H), 2.63 - 2.51 (m, 1H), 2.48 - 2.36 (m, 1H), 2.30 - 2.17 (m, 1H), 2.15 - 2.06 (m, 2H), 2.05 - 1.90 (m, 4H), 1.73 - 1.60 (m, 2H). LC/MS: (M+1: 669.1). [0555] Example 5: Preparation of 4-[(4R,7S,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 31-a); 4- [(4R,7S,14S,18S,20R)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 31-b); 4-[(4S,7R,14R,18R,20S)-18,26- difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 31-c)
Figure imgf000184_0001
Figure imgf000185_0008
Figure imgf000185_0001
Figure imgf000185_0003
Figure imgf000185_0002
Figure imgf000185_0004
Figure imgf000185_0005
Figure imgf000185_0006
Figure imgf000185_0007
[0556] Step 1. To
Figure imgf000186_0001
le (10.2 g, 149 mmol, 2.03 eq) in DCM (150 mL) was added ethyl (2R,8R)-2-hydroxy-5-oxo- 2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate (15.7 g, 73.6 mmol, 1 eq) slowly at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was washed with water (100 mL * 2) and the organic phase was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using EtOAc/PE to give compound ethyl (2R,8R)-2-[tert-butyl(diphenyl)silyl]oxy-5-oxo-2,3,6,7-tetrahydro-1H- pyrrolizine-8-carboxylate (66.0 g, 146 mmol, 99.2% yield) was obtained as a white solid. 1H NMR (400 MHz,CDCl3) δ = 7.67 - 7.56 (m, 4H), 7.49 - 7.33 (m, 6H), 4.51 (tt, J = 1.6, 5.6 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.69 (dd, J = 5.6, 12.4 Hz, 1H), 3.13 (d, J = 12.4 Hz, 1H), 2.87 - 2.72 (m, 1H), 2.71 - 2.64 (m, 1H), 2.49 - 2.29 (m, 2H), 2.10 - 1.98 (m, 1H), 1.72 - 1.66 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.04 (s, 9H). [0557] Step 2. To a solution of ethyl (2R,8R)-2-[tert-butyl(diphenyl)silyl]oxy-5-oxo-2,3,6,7- tetrahydro-1H-pyrrolizine-8-carboxylate (23.0 g, 50.9 mmol, 1 eq) in THF (250 mL) was added LDA (2 M, 38.2 mL, 1.5 eq) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 hour, and the solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (20.9 g, 66.2 mmol, 1.3 eq) in THF (150 mL) was then added at -78 °C. After stirring at 25 °C for 1 hour, the reaction mixture was poured into NH4Cl (aq.300 mL) and stirred for 10 min. Extraction workup with EtOAc followed by silica gel chromatography using EtOAc/PE to afford ethyl (2R,6R,8S)-2-[tert-butyl(diphenyl)silyl]oxy-6-fluoro-5-oxo-2,3,6,7-tetrahydro-1H- pyrrolizine-8-carboxylate (27.0 g, 57.5 mmol, 37.6% yield) as a yellow oil. LCMS: (M+1: 470.0). [0558] Step 3. To a solution of ethyl (2R,6R,8S)-2-[tert-butyl(diphenyl)silyl]oxy-6-fluoro-5- oxo-2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate (20.0 g, 42.6 mmol, 1 eq) in THF (200 mL) was added pyridine-hydrofluoride (18.1 g, 128 mmol, 16.4 mL, 70.0% purity, 3 eq). The mixture was stirred at 50 °C for 16 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using EtOAc/PE to afford ethyl (2R,6R,8S)- 6-fluoro-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate (4.00 g, 17.3 mmol, 40.6% yield) as white solid. LCMS: (M+1: 231.9). [0559] Step 4. To a solution of ethyl (2R,6R,8S)-6-fluoro-2-hydroxy-5-oxo-2,3,6,7- tetrahydro-1H-pyrrolizine-8-carboxylate (4.00 g, 17.3 mmol, 1 eq) in MeOH (40 mL) was added NaBH4 (982 mg, 25.9 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours and then quenched by water (5 mL). Extraction workup and concentration under vacuum to give (2R,6R,8S)-2-fluoro-6-hydroxy-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin- 3-one (4.0 g, crude) as white solid. 1H NMR (400 MHz, MeOD-d4) δ = 5.55 (t, J = 8.4 Hz, 0.5H), 5.46 - 5.36 (m, 0.5H), 4.56 - 4.46 (m, 1H), 4.06 - 3.94 (m, 1H), 3.76 (d, J = 11.6 Hz, 1H), 3.39 (d, J = 11.6 Hz, 1H), 2.91 (dd, J = 2.4, 12.8 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.04 - 1.86 (m, 3H) [0560] Step 5. To a solution of (2R,6R,8S)-2-fluoro-6-hydroxy-8-(hydroxymethyl)-2,5,6,7- tetrahydro-1H-pyrrolizin-3-one (4.00 g, 21.1 mmol, 1 eq) in THF (50 mL) was added BH3- Me2S (10 M, 10. mL, 5 eq) at 0 °C. The mixture was stirred at 60 °C for 16 h. On completion, the mixture was quenched by MeOH (50 mL) and added 4N HCl (50 mL) and stirred at 60 °C for 1 h. Extraction workup and concentration under vacuum to give (2R,6R,8S)-6-fluoro-8- (hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2-ol (3.60 g, crude) as white solid. [0561] Step 6. To a solution of (2R,6R,8S)-6-fluoro-8-(hydroxymethyl)-1,2,3,5,6,7- hexahydropyrrolizin-2-ol (3.60 g, 20.6 mmol, 1 eq) in DCM (40 mL) was added TEA (6.24 g, 61.6 mmol, 3 eq) and TBDPSCl (7.34 g, 26.7 mmol, 6.86 mL, 1.3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give (2R,6R,8S)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2-ol (3.10 g, 7.50 mmol, 36.5% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.84 - 7.71 (m, 4H), 7.46 - 7.31 (m, 6H), 5.27 - 5.03 (m, 1H), 4.40 - 4.26 (m, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.43 - 3.32 (m, 3H), 3.30 - 3.18 (m, 3H), 3.04 - 2.87 (m, 1H), 2.38 (t, J = 8.0 Hz, 1H), 2.26 - 2.20 (m, 2H), 2.05 (s, 4H), 1.68 (s, 1H), 1.67 - 1.57 (m, 2H), 1.08 (s, 9H) [0562] Step 7. To a solution of (2R,6R,8S)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-6-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-2-ol (2.40 g, 5.80 mmol, 1 eq) in THF (24 mL) was added KOH (130 mg, 2.32 mmol, 0.4 eq) and tert-butyl prop-2-enoate (1.49 g, 11.6 mmol, 1.68 mL, 2 eq). The mixture was stirred at 25 °C for 3 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using EtOAc/PE to give tert-butyl 3-[[(2R,6R,8S)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propanoate (2.00 g, 2.87 mmol, 49.4% yield) as colorless oil. LCMS (M+1: 542.7). [0563] Step 8. To a solution of tert-butyl 3-[[(2R,6R,8S)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propanoate (2.00 g, 3.69 mmol, 1 eq) in THF (20 mL) was added LiAlH4 (210 mg, 5.54 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hours. On completion, the mixture was quenched by water (20 mL). Extraction workup with EtOAc followed by silica gel chromatography using MeOH/DCM to give 3-[[(2R,6R,8S)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propan- 1-ol (1.40 g, 2.97 mmol, 80.4% yield) as colorless oil. LCMS: (M+1: 472.7) [0564] Step 9. To a solution of 3-[[(2R,6R,8S)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-6- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propan-1-ol (1.39 g, 2.96 mmol, 1 eq) in DMF (15 mL) was added NaH (236 mg, 5.91 mmol, 60% purity, 2 eq) at 0 °C and stirred for 10 min. Benzyl 4,4-dioxo-3-oxa-4λ6-thia-5,8-diazatricyclo[4.3.2.01,5]undecane-8-carboxylate (1.00 g, 2.96 mmol, 1 eq) was then added to the mixture and stirred at 25 °C for 16 h. On completion, the mixture was quenched by water (20 mL). Extraction workup with EtOAc followed by silica gel chromatography using MeOH/DCM to give benzyl 1-[3-[[(2R,6R,8S)- 8-[[tert-butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3,8-diazabicyclo [3.2.1]octane-3-carboxylate (2.37 g, crude) as yellow oil. LCMS: (M+1: 730.4). [0565] Step 10. To a solution of benzyl 1-[3-[[(2R,6R,8S)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3,8-diazabicyclo [3.2.1]octane-3-carboxylate (2.37 g, 3.25 mmol, 1 eq) in DCM (25 mL) was added TEA (985 mg, 9.74 mmol, 1.36 mL, 3 eq) and Boc2O (921 mg, 4.22 mmol, 1.3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give 3-benzyl 8-(tert-butyl) 1-((3-(((2R,6R,7aS)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.07 g, 2.49 mmol, 76.8% yield) as colorless oil. LCMS: (M+1: 831.1). [0566] Step 11. To a solution of 3-benzyl 8-(tert-butyl) 1-((3-(((2R,6R,7aS)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.77 g, 2.13 mmol, 1 eq) in i-PrOH (20 mL) was added Pd/C (300 mg, 10%) and Pd(OH)2/C (300 mg, 10%) under H2. The mixture was stirred at 20 °C for 2 h under 15 Psi. On completion, the mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl 1-((3-(((2R,6R,7aS)-7a-(((tert- butyldiphenylsilyl)oxy)methyl)-6-fluorohexahydro-1H-pyrrolizin-2-yl)oxy)propoxy)methyl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 94.3% yield) as colorless oil. LCMS: (M+1: 696.9). [0567] Step 12. To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (762 mg, 3.02 mmol, 1.5 eq) and DIEA (1.56 g, 12.1 mmol, 2.10 mL, 6 eq) in DCM (20 mL) at -40 °C, was added tert-butyl 1-[3-[[(2R,6R,8S)-8-[[tert-butyl(diphenyl)silyl]oxymethyl]-6-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-2-yl]oxy]propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.40 g, 2.01 mmol, 1 eq) and stirred at -40 °C for 1 h under N2. On completion, the reaction mixture was concentrated and the residue was purified by silica gel chromatography using EtOAc/PE to tert-butyl 1-[3-[[(2R,6R,8S)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.18 g, 1.29 mmol, 64.3% yield) as yellow oil. LCMS: (M+1: 912.6). [0568] Step 13. To a solution of tert-butyl 1-[3-[[(2R,6R,8S)-8-[[tert- butyl(diphenyl)silyl]oxymethyl]-6-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.18 g, 1.29 mmol, 1 eq) in THF (10 mL) was added pyridine-hydrofluoride (275 mg, 1.94 mmol, 70%, 1.5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to afford tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl)-1-[3-[[(2R,6R,8S)-6-fluoro-8-(hydroxymethyl)-1,2,3,5,6,7- hexahydropyrrolizin-2-yl]oxy]propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 73.9% yield) as off-white solid. LCMS: (M+1: 674.9). [0569] Step 14. To a solution of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-1-[3-[[(2R,6R,8S)-6-fluoro-8-(hydroxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2- yl]oxy]propoxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.208 mmol, 1 eq) in dioxane (0.5 mL) was added DIEA (80.6 mg, 0.623 mmol, 3 eq) and the mixture was stirred at 100 °C for 24 h. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give tert-butyl (14R,18R,20S)-27- chloro-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate (30.0 mg, 22.6% yield) as yellow oil. LCMS: (M+1: 637.2). [0570] Step 15. To a mixture of tert-butyl (14R,18R,20S)-27-chloro-18,26-difluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (25.0 mg, 0.0392 mmol, 1 eq) and 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl] ethynyl- triisopropyl-silane (40.2 mg, 0.0785 mmol, 2 eq) in dioxane (1 mL) and H2O (0.2 mL) was added K3PO4 (24.9 mg, 0.118 mmol, 3 eq) and ditert-butyl(cyclopentyl) phosphane;dichloropalladium;iron (2.56 mg, 0.00392 mmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 2 h under microwave. On completion, the mixture was concentrated and the residue was purified by silica gel chromatography using MeOH/DCM to give Peak 1 (tert-butyl (4R,7S,14R,18R,20S)-18,26- difluoro-27-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1- yl]-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate) (15.0 mg, 38.7% yield) as brown solid, and Peak 2 (tert-butyl (4S,7R,14R,18R,20S)-18,26-difluoro-27-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene-33-carboxylate) (15.0 mg, 38.7% yield) as brown solid. LCMS: (M+1: 987.0). [0571] Step 16. To a solution of tert-butyl (4R,7S,14R,18R,20S)-18,26-difluoro-27-[7-fluoro- 3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (13.0 mg, 0.0132 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 1 mL, 304 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated under vacuum to give 4-[(4R,7S,14R,18R,20S)- 18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (10.0 mg, crude) as yellow solid. LCMS: (M+1: 843.2). [0572] Step 17. To a solution of 4-[(4R,7S,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (Peak 1’, 10.0 mg, 0.0119 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (5.41 mg, 0.0356 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered, and the filtrate was purified by Prep-HPLC to give 4-[(4R,7S,14R,18R,20S)-18,26-difluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (racemic Cpd.30-a, 4.57 mg, 55.6% yield) as yellow solid.1H NMR (400 MHz, MeOD-d4) δ 9.06 (d, J = 18.4 Hz, 1H), 7.93 - 7.80 (m, 1H), 7.39 - 7.30 (m, 2H), 7.26 - 7.16 (m, 1H), 5.63 - 5.44 (m, 2H), 5.07 - 4.99 (m, 1H), 4.43 - 4.26 (m, 2H), 4.23 - 4.06 (m, 2H), 3.97 - 3.39 (m, 12H), 2.58 - 2.47 (m, 1H), 2.42 - 2.25 (m, 2H), 1.77 (s, 6H), 1.66 - 1.46 (m, 1H). LC/MS: (M+1: 687.5). [0573] Step 18. To a solution of tert-butyl (4S,7R,14R,18R,20S)-18,26-difluoro-27-[7-fluoro- 3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaene-33-carboxylate (racemic Peak 2, 150 mg, 0.152 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL, 52.7 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated under vacuum to give 4- [(4S,7R,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (130 mg, crude) as yellow solid. LCMS: (M+1: 843.3). [0574] Step 19. To a solution of 4-[(4S,7R,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (Peak 2’, 130 mg, 0.154 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (70.3 mg, 0.463 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was diluted with water (50 mL) and extracted with DCM (30 mL*3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give crude product, which was then separated by chiral SFC to give 4-[(4R,7S,14S,18S,20R)-18,26- difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. 31-b) (22.6 mg, 19.4% yield) as off-white solid, and 4-[(4S,7R,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Cpd. 31-c) (21.97 mg, 25.44% yield) as yellow solid. [0575] Cpd. 31-b: 1H NMR (400 MHz, CDCl3) δ 8.76 - 8.60 (m, 1H), 7.74 - 7.64 (m, 1H), 7.24 (s, 1H), 7.21 - 7.14 (m, 2H), 5.28 - 5.18 (m, 1H), 5.12 - 4.99 (m, 2H), 4.15 - 4.06 (m, 4H), 3.69 - 3.57 (m, 8H), 3.51 - 3.35 (m, 5H), 3.23 - 3.02 (m, 5H), 2.18 - 2.08 (m, 5H). LC/MS: (M+1: 687.3). [0576] Cpd. 31-c: 1H NMR (400 MHz, CDCl3) δ 8.73 - 8.60 (m, 1H), 7.69 (dd, J = 8.8, 6.0 Hz, 1H), 7.61 - 7.49 (m, 1H), 7.25 - 7.22 (m, 1H), 7.18 (t, J = 8.8 Hz, 2H), 5.28 - 5.17 (m, 1H), 5.12 - 5.00 (m, 2H), 4.13 - 4.00 (m, 4H), 3.61 (d, J = 4.4 Hz, 7H), 3.52 - 3.33 (m, 5H), 3.23 - 2.98 (m, 5H), 2.19 - 2.06 (m, 6H). LC/MS: (M+1: 687.2). [0577] Example 6: Preparation of (2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (Compound 32-a); and (2'R,4R,4'R,7S)-22-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (Compound 32-b)
Figure imgf000192_0001
Figure imgf000193_0001
dicarboxylate (20.0 g, 80.9 mmol, 1 eq) in THF (200 mL) was added dropwise LDA (2 M, 60.7 mL, 1.5 eq) at 0 °C, and the mixture was stirred at 0 °C for 1 hour, and chloromethoxymethylbenzene (15.2 g, 97.1 mmol, 13.5 mL, 1.2 eq) was then added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 6 hours. On completion, the reaction mixture was quenched by addition of NH4Cl (4 mL) and concentrated under reduced pressure to remove solvent, and then diluted with H2O (150mL). Extraction workup with EtOAc followed by silica gel chromatography to afford compound 1-(tert-butyl) 2-methyl (4R)-2- ((benzyloxy)methyl)-4-fluoropyrrolidine-1,2-dicarboxylate (15.0 g, 40.8 mmol, 50.5% yield) as a red oil.1H NMR (400 MHz, CDCl3) δ 7.39 - 7.29 (m, 5H), 5.34 - 5.09 (m, 1H), 4.78 - 4.65 (m, 1H), 4.54 (dd, J = 7.6 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.83 - 3.77 (m, 1H), 3.77 - 3.73 (m, 3H), 3.73 - 3.64 (m, 1H), 2.82 - 2.58 (m, 1H), 2.50 - 2.32 (m, 1H), 1.50 - 1.37 (m, 8H). [0579] Step 2. To a solution of 1-(tert-butyl) 2-methyl (4R)-2-((benzyloxy)methyl)-4- fluoropyrrolidine-1,2-dicarboxylate (15 g, 40.83 mmol, 1 eq) in DCM (150 mL) was added TFA (231 g, 2.03 mol, 49.6 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. Compound methyl (4R)-2-((benzyloxy)methyl)-4-fluoropyrrolidine-2-carboxylate (15 g, crude, TFA) was obtained as a red oil. [0580] Step 3. To a solution of methyl (4R)-2-((benzyloxy)methyl)-4-fluoropyrrolidine-2- carboxylate (15.0 g, 39.3 mmol, 1 eq, TFA) and HCHO (4.79 g, 59.0 mmol, 4.39 mL, 37% purity, 1.5 eq) in MeOH (150 mL) was added NaBH(OAc)3 (25.0 g, 118 mmol, 3 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (20 mL) and extraction workup with EtOAc followed by silica gel chromatography using EtOAc/PE to afford methyl (4R)-2-(benzyloxymethyl)-4-fluoro-1-methyl-pyrrolidine-2- carboxylate (8.3 g, 29.50 mmol, 75.00% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.39 - 7.29 (m, 5H), 5.28 - 5.06 (m, 1H), 4.60 - 4.48 (m, 2H), 3.76 - 3.72 (m, 4H), 3.61 (d, J = 9.6 Hz, 1H), 3.37 - 3.12 (m, 2H), 2.59 - 2.48 (m, 4H), 2.46 - 2.33 (m, 1H). [0581] Step 4. To the mixture of LAH (715 mg, 18.8 mmol, 1 eq) in 25 mL of THF was added a solution of methyl (4R)-2-(benzyloxymethyl)-4-fluoro-1-methyl-pyrrolidine-2-carboxylate (5.3 g, 18.84 mmol, 1 eq) in THF (25 mL) dropwise at 0 °C under N2 atmosphere and the resulting mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched by addition of NH4Cl (40 mL), filtered and concentrated under reduced pressure to give a residue. Compound [(4R)-2-(benzyloxymethyl)-4-fluoro-1-methyl-pyrrolidin-2- yl]methanol (4 g, crude) was obtained as yellow oil.1H NMR (400 MHz, CDCl3) δ 7.40 - 7.27 (m, 5H), 5.24 - 5.02 (m, 1H), 4.54 - 4.41 (m, 2H), 3.49 (d, J = 9.6 Hz, 1H), 3.38 - 3.29 (m, 2H), 3.28 - 3.18 (m, 2H), 3.18 - 3.03 (m, 1H), 2.46 - 2.37 (m, 1H), 2.36 (s, 3H), 2.31 - 2.17 (m, 1H). [0582] Step 5. To a solution of [(4R)-2-(benzyloxymethyl)-4-fluoro-1-methyl-pyrrolidin-2-yl] methanol (4 g, 15.79 mmol, 1 eq) in Toluene (4 mL) was added DPPA (6.52 g, 23.7 mmol, 5.13 mL, 1.5 eq) and DBU (4.81 g, 31.6 mmol, 4.76 mL, 2 eq). The mixture was stirred at 100 °C for 6 hours. On completion, the residue was diluted with H2O (40 mL) and extraction workup with EtOAc and concentration under reduced pressure to give compound (4R)-2- (azidomethyl)-2-(benzyloxymethyl)-4-fluoro-1-methyl-pyrrolidine (4 g, crude) as a red oil. [0583] Step 6. To a solution of (4R)-2-(azidomethyl)-2-(benzyloxymethyl)-4-fluoro-1- methyl-pyrrolidine (4.00 g, 14.4 mmol, 1 eq) and Boc2O (4.70 g, 21.56 mmol, 1.5 eq) in EtOH (1 mL) was added Pd/C (2.30 g, 28.7 mmol, 10%, 2 eq) under N2. The suspension was de- gassed and purged with H2 three times. The mixture was stirred under H2 (20 psi) at 25 °C for 1 hour. On completion, the reaction mixture was filtered and concentrated to give a residue, which was purified by prep-HPLC to afford compound tert-butyl N-[[(4R)-2- (benzyloxymethyl)-4-fluoro-1-methyl-pyrrolidin-2-yl] methyl] carbamate (3.00 g, 8.51 mmol, 59.2% yield) as a yellow oil. 1H NMR (400 MHz, MeOD-d4) δ = 7.38 - 7.29 (m, 5H), 5.30 - 5.12 (m, 1H), 4.54 - 4.49 (m, 2H), 3.68 - 3.52 (m, 2H), 3.45 - 3.35 (m, 2H), 3.25 - 3.19 (m, 2H), 2.64 - 2.59 (m, 3H), 2.48 (m, 1H), 2.27 - 2.12 (m, 1H), 1.43 (s, 9H) [0584] Step 7. To a solution of tert-butyl N-[[(4R)-2-(benzyloxymethyl)-4-fluoro-1-methyl- pyrrolidin-2-yl]methyl]carbamate (3.00 g, 8.51 mmol, 1 eq) in MeOH (30 mL) was added Pd/C (136.19 mg, 1.70 mmol, 10%, 0.2 eq) and Pd(OH)2/C (1.20 g, 1.70 mmol, 20%, 0.2 eq) under N2. The suspension was de-gassed and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 50 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC to afford tert-butyl N-[[(4R)-4-fluoro-2-(hydroxymethyl)-1-methyl-pyrrolidin-2-yl] methyl] carbamate (1.9 g, 7.24 mmol, 85.09% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.60 (s, 1H), 4.94 - 4.77 (m, 1H), 3.69 - 3.57 (m, 2H), 3.10 (t, J = 13.2 Hz, 1H), 2.72 (d, J = 11.6 Hz, 1H), 2.61 (t, J = 14.0 Hz, 1H), 2.34 (s, 3H), 2.28 - 2.08 (m, 1H), 1.94 (d, J = 10.0 Hz, 1H), 1.45 (s, 9H), 1.43 - 1.32 (m, 1H). [0585] Step 8. To a solution of tert-butyl 1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3-(2,7- dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.341 mmol, 1 eq.) in dioxane (2 mL) was added DIEA (88.2 mg, 0.682 mmol, 2 eq), 4A MS and tert-butyl N-[[(4R)-4-fluoro-2-(hydroxymethyl)-1-methyl-pyrrolidin-2- yl]methyl]carbamate (268 mg, 1.02 mmol, 3 eq) while stirring at 25 °C for 0.5 hour. After addition, the resulting mixture was stirred at 100 °C for 5.5 hours. On completion, the reaction was diluted with H2O (4 mL). Extraction workup with EtOAc followed by prep-HPLC to afford tert-butyl 3-[2-[[(4R)-2-[(tert-butoxycarbonylamino)methyl]-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-1-[(3-tert-butoxy- 3-oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 57.8% yield) as a yellow solid.1H NMR (400 MHz, CD3OD) δ 8.88 (s, 1H), 4.92 (m, 1H), 4.83 - 4.55 (m, 5H), 4.43 (d, J = 6.0 Hz, 1H), 4.12 (d, J = 9.6 Hz, 1H), 3.81 - 3.64 (m, 5H), 2.98 - 2.80 (m, 2H), 2.56 - 2.37 (m, 5H), 2.33 (s, 3H), 2.02 - 1.82 (m, 4H), 1.70 - 1.63 (m, 1H), 1.54 (s, 9H), 1.44 - 1.31 (m, 18H). [0586] Step 9. To a solution of tert-butyl 3-[2-[[(4R)-2-[(tert-butoxycarbonylamino)methyl]- 4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]- 1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.197 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 0.049 mL, 1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to afford compound 3-[[3-[2-[[(4R)-2-(aminomethyl)-4-fluoro-1- methyl-pyrrolidin-2-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octan-1-yl]methoxy]propanoic acid (130 mg, crude, HCl) as a red oil. LCMS: (M+1: 556.1). [0587] Step 10. To a solution of 3-[[3-[2-[[(4R)-2-(aminomethyl)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1] octan-1-yl]methoxy]propanoic acid (130 mg, 0.219 mmol, 1 eq, HCl) in DMF (2 mL) was added HATU (167 mg, 0.439 mmol, 2 eq) and DIEA (142 mg, 1.10 mmol, 5 eq). The mixture was stirred at 25 °C for 1 hour. On completion, extraction workup with EtOAc followed by prep-TLC afford compound (4'R)-22-chloro-4',21-difluoro-1'- methylspiro[9,17-dioxa-2,13,19,23,26,27-hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa- 1(26),18,20,22,24-pentaene-15,2'-pyrrolidin]-12-one (100 mg, 84.71% yield) as a yellow solid. LCMS: (M+1: 538.2). [0588] Step 11. A mixture of (4'R)-22-chloro-4',21-difluoro-1'-methylspiro[9,17-dioxa- 2,13,19,23,26,27-hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24- pentaene-15,2'-pyrrolidin]-12-one (50.0 mg, 0.0929 mmol, 1 eq), 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl] ethynyl- triisopropyl-silane (143 mg, 0.279 mmol, 3 eq), K3PO4 (2 M, 0.046 mL, 1 eq) and ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (60.6 mg, 0.0929 mmol, 1 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 1 hour under N2 atmosphere. On completion, extraction workup with EtOAc followed by prep-TLC afford compound (4'R)-4',21-difluoro-22-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]-1'-methyl-spiro[9,17-dioxa-2,13,19,23,26,27- hexazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidine]-12-one (17.0 mg, 20.6% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.96 - 8.89 (m, 1H), 7.77 (m, 1H), 7.49 (s, 1H), 7.32 (s, 1H), 6.55 - 6.45 (m, 1H), 5.29 (s, 3H), 5.01 - 4.92 (m, 1H), 4.91 - 4.76 (m, 1H), 4.72 - 4.34 (m, 2H), 4.22 - 4.07 (m, 3H), 3.92 - 3.69 (m, 4H), 3.56 - 3.44 (m, 5H), 3.26 - 3.12 (m, 1H), 2.98 - 2.74 (m, 4H), 2.41 (s, 3H), 2.30 - 2.10 (m, 2H), 2.09 - 2.00 (m, 4H), 1.87 - 1.69 (m, 2H), 0.94 - 0.87 (m, 18H). [0589] Step 12. To a solution of (4'R)-4',21-difluoro-22-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]-1'-methyl-spiro[9,17-dioxa-2,13,19,23,26,27- hexazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidine]-12-one (37 mg, 0.042 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.031 mL, 3 eq). The mixture was stirred at 25 °C for 1 hour and then concentrated under reduced pressure to afford crude product (4'R)-4',21-difluoro-22-(7-fluoro-3-hydroxy-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (36 mg, crude) as a yellow oil. [0590] Step 13. To a solution of (4'R)-4',21-difluoro-22-(7-fluoro-3-hydroxy-8-{[tri(propan- 2-yl)silyl]ethynyl}naphthalen-1-yl)-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (7 mg, 0.0083 mmol, 1 eq) in DMSO (0.1 mL) was added CsF (2.52 mg, 0.017 mmol, 2 eq). The mixture was stirred at 40 °C for 2 hours. On completion, the mixture was filtered and the filtrate was purified by prep-HPLC to give (4'R)-22-(8-ethynyl-7-fluoro- 3-hydroxynaphthalen-1-yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one (0.83 mg, 14.4% yield) as a red solid. LCMS: (M+1: 688.2). [0591] This red solid was separated by chiral SFC and further purified by prep-HPLC to afford Compound Cpd. 32-a [(2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 4',21-difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one] (2.01 mg, 7.08% yield) as a yellow solid, and Cpd.32-b [(2'R,4R,4'R,7S)- 22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21-difluoro-1'-methylspiro[9,17-dioxa- 2,13,19,23,26,27-hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24- pentaene-15,2'-pyrrolidin]-12-one] (0.73 mg, 2.57% yield) as a yellow solid. [0592] Cpd.32-a: 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 3.2 Hz, 1H), 7.55 (m, 1H), 7.21 - 7.05 (m, 3H), 6.48 (s, 1H), 5.00 - 4.74 (m, 2H), 4.54 (d, J = 12.8 Hz, 1H), 4.40 (m, 1H), 4.20 - 4.04 (m, 2H), 3.91 - 3.77 (m, 3H), 3.72 - 3.57 (m, 4H), 3.25 - 3.14 (m, 1H), 3.04 - 2.89 (m, 2H), 2.87 - 2.72 (m, 3H), 2.42 (s, 3H), 2.17 (s, 1H), 2.00 (d, J = 9.6 Hz, 2H), 1.78 (d, J = 12.0 Hz, 2H), 1.51 (m, 1H). LCMS: (M+1: 688.2). [0593] Cpd. 32-b: 1H NMR (400 MHz, DMSO-d6) δ 10.21 - 10.02 (m, 1H), 8.91 - 8.76 (m, 1H), 8.05 - 7.88 (m, 1H), 7.51 - 7.41 (m, 1H), 7.37 (s, 1H), 7.22 - 7.10 (m, 1H), 6.55 - 6.41 (m, 1H), 5.85 - 5.68 (m, 1H), 4.85 - 4.68 (m, 2H), 4.47 - 4.30 (m, 1H), 4.20 - 3.92 (m, 4H), 3.88 - 3.68 (m, 6H), 3.21 - 3.15 (m, 3H), 3.06 - 2.89 (m, 3H), 2.25 (s, 3H), 1.95 - 1.67 (m, 6H). LCMS: (M+1: 688.1). [0594] Example 6: Preparation of (4S,7R,15S)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen- 1-yl)-23-fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one (Compound 33-a); (4R,7S,15R)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23-fluoro- 16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one (Compound 33-b); and (4S,7R,15R)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23- fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one (Compound 33-c)
Figure imgf000198_0001
Figure imgf000199_0001
[0595] Step 1. To a mixture of pyrazin-2-ylmethanamine (10.0 g, 91.6 mmol, 1 eq) in IPA (70 mL) was added Boc2O (24.0 g, 109 mmol, 25.2 mL, 1.2 eq). The reaction mixture was stirred at 25 °C for 2 hours. On completion, extraction workup with EtOAc followed by silica gel chromatography using Petroleum/EtOAc to afford tert-butyl N-(pyrazin-2- ylmethyl)carbamate (19.0 g, 99% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.53 - 8.44 (m, 2H), 4.48 (d, J = 5.2 Hz, 2H), 1.45 (s, 9H). [0596] Step 2. To a mixture of tert-butyl N-(pyrazin-2-ylmethyl)carbamate (1.0 g, 4.78 mmol, 1 eq) in MeOH (32 mL) and H2O (2 mL) was added Pd/C (100 mg, 4.78 mmol, 10%, 1 eq), Pt/C (20.0 mg, 0.00476 mmol, 5%) and 1,1,2-trichloroethane (1.28 g, 9.56 mmol, 2 eq). The reaction mixture was stirred at 25°C for 12 hours under H2 (50 psi). On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to afford tert-butyl N-(piperazin-2-ylmethyl)carbamate (1.10 g, 91% yield, HCl) as brown solid.1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J = 5.6 Hz, 1H), 3.39 (s, 1H), 3.35 - 3.24 (m, 4H), 3.22 - 3.10 (m, 3H), 2.97 - 2.86 (m, 1H), 1.39 (s, 9H). [0597] Step 3. To a mixture of tert-butyl 1-(hydroxymethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8- carboxylate (2.00 g, 4.13 mmol, 1 eq) and tert-butyl prop-2- enoate (5.29 g, 41.2 mmol, 5.99 mL, 10 eq) in THF (10 mL) was added KOH (115 mg, 2.06 mmol, 0.5 eq). The reaction mixture was stirred at 25°C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford tert-butyl 1-[(3-tert-butoxy -3-oxo-propoxy)methyl]-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.65 g, 2.69 mmol, 65% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.12 (m, 15H), 4.08 - 3.96 (m, 2H), 3.75 - 3.64 (m, 1H), 3.59 - 3.46 (m, 2H), 3.45 - 3.38 (m, 1H), 2.97 (d, J = 10.8 Hz, 1H), 2.86 - 2.77 (m, 1H), 2.48 - 2.39 (m, 1H), 2.33 (t, J = 6.0 Hz, 1H), 2.18 - 2.11 (m, 1H), 1.96 - 1.86 (m, 2H), 1.69 (d, J = 10.8 Hz, 1H), 1.58 (d, J = 10.8 Hz, 1H), 1.41 - 1.32 (m, 9H), 1.10 (s, 9H) [0598] Step 4. The mixture of tert-butyl 1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3-trityl-3,8- diazabicyclo [3.2.1]octane-8-carboxylate (3.10 g, 5.06 mmol, 1 eq) in H2O (1 mL) and HOAc (36 mL) was stirred at 60°C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford tert-butyl 1-[(3-tert- butoxy-3- oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.20 g, 3.24 mmol, 64% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.16 (s, 2H), 4.01 - 3.85 (m, 1H), 3.74 - 3.61 (m, 3H), 3.02 - 2.92 (m, 1H), 2.87 - 2.81 (m, 1H), 2.70 - 2.63 (m, 1H), 2.50 - 2.42 (m, 2H), 2.02 - 1.96 (m, 3H), 1.74 - 1.56 (m, 2H), 1.48 - 1.43 (m, 18H). [0599] Step 5. To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (817 mg, 3.24 mmol, 1 eq) in DCM (15 mL) was added DIEA (2.09 g, 16.2 mmol, 2.82 mL, 5 eq) at -40°C. Then tert-butyl 1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.20 g, 3.24 mmol, 1 eq) was added at -40°C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford tert-butyl 1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3-(2,7- dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.30 g, 2.22 mmol, 68% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 4.63 - 4.37 (m, 2H), 4.32 - 4.27 (m, 1H), 4.04 - 3.98 (m, 1H), 3.78 - 3.49 (m, 5H), 2.42 (t, J = 6.0 Hz, 2H), 1.57 - 1.27 (m, 20H) [0600] Step 6. To a mixture of tert-butyl N-(piperazin-2-ylmethyl)carbamate (881 mg, 3.50 mmol, 2.57 eq, HCl) and DIEA (528 mg, 4.09 mmol, 3 eq) in DCM (10 mL) at -40 °C, was added tert-butyl 1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3-(2,7-dichloro-8-fluoro- pyrido[4,3-d] pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 1.36 mmol, 1 eq), and the reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to afford tert-butyl 3-[2-[3-[(tert-butoxycarbonylamino)methyl]piperazin-1- yl] -7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-1-[(3-tert-butoxy-3-oxo- propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (910 mg, 1.19 mmol, 87% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.00 - 6.83 (m, 1H), 4.73 - 4.41 (m, 3H), 4.34 - 4.16 (m, 2H), 4.02 - 3.93 (m, 1H), 3.72 - 3.52 (m, 4H), 3.50 - 3.35 (m, 1H), 3.03 - 2.86 (m, 4H), 2.70 - 2.53 (m, 3H), 2.49 - 2.44 (m, 1H), 2.39 (t, J = 5.6 Hz, 2H), 1.79 (s, 3H), 1.48 - 1.29 (m, 28H). LCMS: (M+1: 766.2) [0601] Step 7. To a mixture of tert-butyl 3-[2-[3-[(tert- butoxycarbonylamino)methyl]piperazin-1-yl]-7- chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl]-1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (880 mg, 1.15 mmol, 1 eq) and TEA (349 mg, 3.45 mmol, 3 eq) in MeOH (2 mL) was added HCHO (440 mg, 14.6 mmol, 12.7 eq) and HOAc (207 mg, 3.45 mmol, 3 eq). After stirring at 25°C for 0.5 hour, NaBH3CN (144 mg, 2.30 mmol, 2 eq) was added and stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with water (50 mL) and extraction workup with EtOAc followed by column chromatography afford tert-butyl 3-[2-[3-[(tert- butoxycarbonylamino)methyl]-4-methyl-piperazin-1-yl]-7-chloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl]-1-[(3-tert-butoxy-3-oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (630 mg, 70% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 6.92 - 6.73 (m, 1H), 4.65 - 4.40 (m, 3H), 4.33 - 4.20 (m, 2H), 4.06 - 3.92 (m, 1H), 3.75 - 3.57 (m, 4H), 3.47 - 3.35 (m, 1H), 3.29 (s, 3H), 3.22 - 3.12 (m, 1H), 2.93 - 2.86 (m, 1H), 2.85 - 2.79 (m, 1H), 2.42 - 2.37 (m, 2H), 2.25 (s, 3H), 2.17 - 2.10 (m, 1H), 2.08 - 1.99 (m, 1H), 1.91 (s, 1H), 1.86 - 1.74 (m, 2H), 1.66 - 1.55 (m, 1H), 1.46 (s, 9H), 1.40 (s, 9H), 1.34 (s, 9H). LCMS: (M+1: 780.2). [0602] Step 8. To a mixture of tert-butyl 3-[2-[3-[(tert-butoxycarbonylamino)methyl]-4- methyl-piperazin -1-yl]-7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl]-1-[(3-tert-butoxy-3- oxo-propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.128 mmol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane (131 mg, 0.256 mmol, 2 eq) in THF (2 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (14.0 mg, 0.0192 mmol, 0.15 eq) and K3PO4 (2 M, 0.192 mL, 3 eq). The reaction mixture was stirred at 60°C for 24 hours. On completion, the reaction mixture was diluted with water (20 mL) and extraction workup with EtOAc followed by column chromatography afford tert-butyl 3-[2-[3-[(tert-butoxycarbonylamino)methyl] -4- methyl-piperazin-1-yl]-8-fluoro-7-[7 -fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[(3-tert-butoxy-3-oxo- propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44.0 mg, 30.3% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.93 - 8.80 (m, 1H), 8.07 (dd, J = 6.0, 8.8 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.54 (t, J = 8.8 Hz, 1H), 7.33 - 7.26 (m, 1H), 6.99 - 6.68 (m, 1H), 5.36 (s, 2H), 4.80 - 4.42 (m, 4H), 4.39 - 4.28 (m, 1H), 4.09 - 3.97 (m, 3H), 3.72 - 3.59 (m, 4H), 3.43 (s, 2H), 3.29 (s, 8H), 2.30 - 2.23 (m, 4H), 1.99 (s, 1H), 1.46 (s, 8H), 1.39 (s, 4H), 1.36 - 1.30 (m, 12H), 1.16 (t, J = 7.2 Hz, 2H), 1.07 (s, 1H), 0.86 -0.80 (m, 18H), 0.57 - 0.45 (m, J = 5.4, 6.9 Hz, 4H), 0.07 (s, 1H), -0.06 (s, 1H). LCMS: (M/2+1:565.3) [0603] Step 9. To a mixture of tert-butyl 3-[2-[3-[(tert-butoxycarbonylamino)methyl]-4- methyl-piperazin-1 -yl]-8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[(3-tert-butoxy-3-oxo- propoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (34 mg, 0.030 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (2.5 M, 1 mL, 80.0 eq). The reaction mixture was stirred at 25°C for 1 hour and then concentrated in vacuo to afford 3-[[3-[2-[3-(aminomethyl)-4- methyl-piperazin -1-yl]-8-fluoro-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1- naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-1-yl]methoxy]propanoic acid (25.0 mg, 95.9% yield, HCl) as yellow solid. LCMS: (M+1: 829.4). [0604] Step 10. To a mixture of 3-[[3-[2-[3-(aminomethyl)-4-methyl-piperazin-1-yl]-8-fluoro- 7-[7-fluoro-3- hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4- yl]-3,8-diazabicyclo[3.2.1]octan-1-yl]methoxy]propanoic acid (25 mg, 0.029 mmol, 1 eq, HCl) in DMF (2 mL) was added HATU (21.9 mg, 0.0577 mmol, 1 eq) and DIEA (11.2 mg, 0.0866 mmol, 3 eq). The reaction mixture was stirred at 25°C for 1 hour, and then diluted with water and extracted with EtOAc. The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to afford 23-fluoro-24-(7-fluoro-3-hydroxy-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl)-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one (10 mg, 42.6% yield) as yellow solid. LCMS: (M+1: 811.6). [0605] Step 11. To a solution of 23-fluoro-24-(7-fluoro-3-hydroxy-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl)-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one (10 mg, 0.012 mmol, 1 eq) in DMSO (2 mL) was added CsF (5.62 mg, 0.0369 mmol, 3 eq). The reaction mixture was stirred at 25°C for 0.5 hour, and then filtered and concentrated in vacuo. The residue was purified by prep-HPLC to afford 24-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one as yellow solid. LCMS: (M+1: 655.3) [0606] This product was separated by chiral SFC to afford Peak 1 and Peak 2 [Cpd. 33-c, (4S,7R,15R)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa- 2,13,16,19,21,25,28,30-octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta- 1(28),20,22,24,26-pentaen-12-one]. [0607] Peak 1 was further separated by chiral SFC to afford Cpd. 33-a, [(4S,7R,15S)-24-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa- 2,13,16,19,21,25,28,30-octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta- 1(28),20,22,24,26-pentaen-12-one] and Cpd. 33-b, (4R,7S,15R)-24-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one. [0608] Cpd.33-a: 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 18.8 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.18 - 7.10 (m, 1H), 5.12 - 4.84 (m, 3H), 4.41 - 4.21 (m, 2H), 4.19 - 3.95 (m, 2H), 3.90 - 3.79 (m, 2H), 3.76 - 3.61 (m, 4H), 3.12 - 2.98 (m, 2H), 2.97 - 2.78 (m, 4H), 2.45 - 2.34 (m, 4H), 2.33 - 2.21 (m, 2H), 2.07 - 1.93 (m, 4H), 1.84 - 1.72 (m, 2H). LCMS: (M+1: 655.4) [0609] Cpd.33-b: 1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.83 (m, 1H), 7.99 - 7.94 (m, 1H), 7.49 - 7.43 (m, 1H), 7.39 - 7.35 (m, 1H), 7.14 (dd, J = 2.4, 18.0 Hz, 1H), 5.22 - 4.93 (m, 1H), 4.79 - 4.67 (m, 2H), 4.18 - 4.09 (m, 2H), 4.04 - 3.94 (m, 2H), 3.85 - 3.75 (m, 2H), 3.71 - 3.63 (m, 4H), 3.16 - 3.07 (m, 2H), 3.06 - 2.84 (m, 4H), 2.36 - 2.31 (m, 4H), 2.13 - 2.09 (m, 1H), 2.05 - 1.91 (m, 3H), 1.72 - 1.68 (m, 1H), 1.24 (s, 3H). LCMS: (M+1: 655.1) [0610] Cpd. 33-c: 1H NMR (400 MHz,CDCl3) δ 8.73 (dd, J = 4.2, 12.8 Hz, 1H), 7.89 - 7.79 (m, 1H), 7.36 - 7.26 (m, 2H), 7.18 (dd, J = 2.4, 18.0 Hz, 1H), 5.45 - 5.37 (m, 1H), 5.36 - 5.29 (m, 1H), 5.26 (s, 1H), 4.14 - 4.07 (m, 1H), 4.05 - 3.99 (m, 1H), 3.97 - 3.87 (m, 2H), 3.84 - 3.77 (m, 1H), 3.76 - 3.72 (m, 1H), 3.71 - 3.65 (m, 2H), 3.64 - 3.56 (m, 2H), 3.24 - 3.05 (m, 2H), 3.03 - 2.66 (m, 4H), 2.57 - 2.45 (m, 2H), 2.44 - 2.35 (m, 4H), 2.33 - 2.21 (m, 2H), 1.96 - 1.87 (m, 1H), 1.62 - 1.53 (m, 2H), 1.48 - 1.44 (m, 1H). LCMS: (M+1: 655.1) [0611] Biological Assays [0612] HTRF KRAS mutation nucleotide exchange assays: [0613] The HTRF KRAS nucleotide exchange assays were performed at Reaction Biology. Briefly, purified KRAS G12D, KRAS G12C or KRAS WT proteins was mixed with a-GST Tb antibody in reaction buffer (20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40). Series dilution of indicated compounds were added to the reaction buffer using acoustic dispenser (ECHO, Labcyte). The reactions were mixed and incubated at room temperature for 1 hour. Purified SOS1 proteins and GTP-DY-647P1 were introduced to initiate the exchange reaction. HTRF signals were quantified using a Envision (Perkin Elmer) for G12C assays (Ex/Em=(320-75/665-7.5; 615-8.5)) or a PHERAstar (BMG Labtech) for KRAS G12D (Ex/Em=(337/665; 620)). IC50 values were determined using sigmoidal dose response (variable slope) equation from Prism software (GraphPad Software, San Diego, CA). [0614] Cell proliferation assays: [0615] 2000 AGS or GP2D cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours. Cell proliferation was measured using CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) following the manufacturer’s protocol. IC50 values were determined using Prism software (GraphPad Software, San Diego, CA). [0616] Kinase phosphorylation assays: [0617] Half a million AGS or GP2D cells per well were seeded in 24-well plate for 2 hours prior to treatment. Cells were collected after a 4 hours treatment and lysed in RIPA buffer buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% Deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1X Halt protease and phosphatase inhibitors (Thermo Scientific). Protein lysates were resolved on 4–12% Bolt Bis-Tris gels with MES running buffer, transferred to nitrocellulose membrane using Trans-Blot Turbo Transfer System (BioRad, Hercules, CA), and detected with desired antibodies. Antibodies were incubated overnight at 4oC, washed, incubated with corresponding HRP-conjugated secondary antibodies, and incubated with chemiluminescent substrate for 5 minutes at room temperature. Chemiluminescent images were acquired with a C-DiGit Imaging System (LI-COR Biosciences, Lincoln, NE). The relative density of the chemiluminescent bands was quantified via Image Studio Digits from LI-COR (LI-COR Biosciences, Lincoln, NE). The results are shown in the table below with A: < 1 µM; B: ≥ 1 to < 10 µM, C: ≥ 10 µM. Example KRAS(G12D) AGS Prolif. GP2D Prolif.
Figure imgf000205_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000206_0001
ring A is a 4- to 10-membered heterocycloalkylene, C6-C10 arylene, or 5- to 10- membered heteroarylene; ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; each L is independently -C(R4)(R5)-, -C(O)-, -O-, -N(R6)-, -S-, -S(O)- or -S(O)2-, provided that (L)p does not comprise a –O-O-, a –O-S-, a –S-S-, or a –O-N(R6)- bond; X is a -O-, -S-, -NR7-; Z1 is N or C(R8); Z2 is N or C(R9); Z3 is N or C(R10); Z4 is N or C(R11); Z5 is N or C(R12); provided that at least two of Z1-Z5 are N; each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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, or each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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, or each R1 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -S(O)Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -N(C(O)Rc)(C(O)Rd), -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, - P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, or -NO2, or two of R1 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10- membered heterocycloalkyl is independently optionally substituted by deuterium, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)NReRf, -OS(O)2NReRf, -S(O)Re, -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)ORe, -C(O)NReRf, - PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, or -P(O)2ORe; each R2 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORc, -P(O)2ORc, -CN, or -NO2, or two of R2 taken together with the carbon or carbons to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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; R3 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C3-C6 cycloalkylene-, -(4- to 10-membered heterocycloalkylene)-, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, -C6-C10 arylene-, -C1-C6 alkylene-(C6-C10 arylene)-, -(5- to 10- membered heteroarylene)-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C3-C6 cycloalkylene, 4- to 10-membered heterocycloalkylene, -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene), C6-C10 arylene, -C1-C6 alkylene-(C6-C10 arylene), 5- to 10-membered heteroarylene, and -C1-C6 alkylene-(5- to 10-membered heteroarylene), is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1- C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; provided that the R3 and (L)p do not form a –O-O-, a –O-S-, a –S-S-, or a –O-N- bond; each R4 and R5 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=NRc)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(=NRc)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, - C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=NRc)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 R4 and R5 taken together with the carbon or carbons to which they are attached form a C6-C10 aryl, 5- to 10- membered heteroaryl, C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-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 R6 and R7 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-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, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 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 of R8, R9, R10, R11, and R12 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, - SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -OS(O)NRgRh, -OS(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; each Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-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, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1- C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1- C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; n is 0, 1, 2, 3, or 4; p is 4, 5, 6, 7, 8, or 9; and q is 0 or 1.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is 4- to 10-membered heterocycloalkylene.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkylene, a fused bicyclic 5- to 10-membered heterocycloalkylene, a bridged bicyclic 6- to 10-membered heterocycloalkylene, or a spiro bicyclic 6- to 10-membered heterocycloalkylene.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a mono-cyclic 4- to 10-membered heterocycloalkylene.
5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein ring A is a bridged bi-cyclic 6- to 10-membered heterocycloalkylene.
6. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring A is ,
Figure imgf000211_0001
wherein * is a point of covalent attachme a point of covalent attachment to (L)p.
Figure imgf000211_0002
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein ring A is ,
Figure imgf000211_0003
wherein * is a point of covalent attachme a point of covalent attachment to (L)p.
Figure imgf000211_0004
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula ,
Figure imgf000211_0005
wherein * is a point of covalent attachme a point of covalent attachment to (L)p.
Figure imgf000212_0001
9. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring B is a C6-C10 aryl.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein ring B is a phenyl or naphthyl.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein Ring B is of the formula ,
Figure imgf000212_0002
12. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- to 10-membered heteroaryl.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring B is * ,
Figure imgf000213_0001
wherein * is a point of covalent attachmen .
Figure imgf000213_0002
14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein ring B is , or
Figure imgf000213_0003
wherein * is a point of covalent attachmen .
Figure imgf000213_0004
15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z1 is N.
16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z2 is N.
17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is N, and Z5 is CR12.
18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is CR11, and Z5 is CR12.
19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is CR11, and Z5 is N.
20. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is CR12.
21. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is N.
22. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR10, Z4 is N, and Z5 is N.
23. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is CR11, and Z5 is N.
24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein q is 0.
25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein q is 1.
26. The compound of any one of claims 1-23 or 25, or a pharmaceutically acceptable salt thereof, wherein X is O.
27. The compound of any one of claims 1-23 or 25, or a pharmaceutically acceptable salt thereof, wherein X is –NR7-.
28. The compound of any one of claims 1-23 or 25, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
29. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is -C1-C6 alkylene-, -4- to 10-membered heterocycloalkylene-, or -C1-C6 alkylene- (4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-, -4- to 10-membered heterocycloalkylene-, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)- is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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.
30. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in -C1-C6 alkylene-(4- to 10-membered heterocycloalkylene)- is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1- C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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.
31. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, methyl, ethyl, propyl, or -CH2-(4- to 10-membered heterocycloalkylene)-, wherein each hydrogen atom in methyl, ethyl, propyl, or –CH2-(4- to 10-membered heterocycloalkyl)-, is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl- O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, or -C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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.
32. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is , wherein each hydrogen atom is indep
Figure imgf000216_0001
onally substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen or X.
Figure imgf000216_0002
33. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is , wherein each hydrogen
Figure imgf000216_0003
ted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen or X.
Figure imgf000217_0001
34. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is , wherein * is a point of c
Figure imgf000217_0002
oint of covalent attachment X.
Figure imgf000217_0003
35. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is wherein each hydrogen atom i
Figure imgf000217_0004
substituted by deuterium, halogen, C1-C6 alkyl, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 alkyl-O-C1-C6 alkyl, -C1-C6 alkyl-O-Ra, C6-C10 aryl, -C1-C6 alkyl-(C6-C10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkyl-(5- to 10-membered heterocycloalkyl), -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, -NReC(=NRf)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; wherein * is a point of covalent attachment to (L)p, and is a point of covalent attachmen or X.
Figure imgf000218_0001
36. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3 is * wherein * is a point of covalent
Figure imgf000218_0002
is a point of covalent attachment X.
Figure imgf000218_0003
37. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each L is independently each L is independently -C(R4)(R5)-, -C(O)-, -O-, or -N(R6), provided that (L)p does not comprise a –O-O- or a –O-N(R6)- bond, and the point of covalent attachment of R3 to (L)p does not form a –O-O- or a –O-N- bond.
38. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein -(L)p- is -(CR4R5)4-, -(CR4R5)5-, -(CR4R5)6-, -(CR4R5)7-, -(CR4R5)8-, -(CR4R5)9-, -(CR4R5)C(O)N(R6)-(CR4R5)2O-, -(CR4R5)N(R6)C(O)-(CR4R5)2O-, -N(R6)-C(O)(CR4R5)2O(CR4R5)2-, -CR4R5O(CR4R5)2O-(CR4R5)2, -O(CR4R5)2O(CR4R5)2O-, -CR4R5O-CR4R5-C(O)N(R6)-(CR4R5)2-, -CR4R5O(CR4R5)2C(O)N(R6)-CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-, -CR4R5O(CR4R5)3N(R6)C(O)-, -(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2O(CR4R5)2N(R6)C(O)-, -O(CR4R5)2N(R6)C(O)CR4R5-, -CR4R5O(CR4R5)2N(R6)C(O)-CR4R5-, -O-(CR4R5)3C(O)N(R6)-, -(CR4R5)3O(CR4R5)2-, -(CR4R5)2O(CR4R5)3-, -O-CR4R5- O(CR4R5)3-, -CR4R5-O(CR4R5)2O-CR4R5-, -CR4R5-O(CR4R5)2O-, -CR4R5-O(CR4R5)3O-, -O(CR4R5)2O(CR4R5)3-, -(CR4R5)2O(CR4R5)3O-, -O-(CR4R5)3-, -(CR4R5)3O-, -O-(CR4R5)2O(CR4R5)2-, -(CR4R5)2O(CR4R5)2O-, -CR4R5-N(R6)-(CR4R5)2-, -CR4R5-O(CR4R5)3-, -(CR4R5)2O-CR4R5-, -(CR4R5)3O-CR4R5-, -CR4R5N(R6)-(CR4R5)2O-, -(CR4R5)2N(R6)C(O)-(CR4R5)O-, or -(CR4R5)2C(O)N(R6)-(CR4R5)O-.
39. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein -(L)p- is -CH2C(O)N(H)-(CH2)2O-, -CH2C(O)N(CH3)-(CH2)2O-, -CH2C(O)N(CH2CH3)-(CH2)2O-, -CH2N(H)C(O)-(CH2)2O-, -CH2C(O)N(CH3)C(O)- (CH2)2O-, -CH2C(O)N(CH2CH3)C(O)-(CH2)2O-, -C(O)N(H)-(CH2)2O(CH2)2-, -N(H)-C(O)(CH2)2O(CH2)2-, -CH2O(CH2)3O-, -CH2O(CH2)2OCH2-, -(CH2)2O(CH2)2O-, -CH2O-CH2-C(O)N(H)-(CH2)2-, -CH2O(CH2)2C(O)N(H)-CH2-, -CH2O(CH2)2C(O)N(CH3)-CH2-, -CH2O(CH2)2N(H)C(O)-, -CH2O(CH2)3N(H)C(O)-, -(CH2)2O(CH2)2N(H)C(O)-, -CH(CH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(CH3)- CH2O(CH2)2N(H)C(O)-, -CH(OCH3)-CH2O(CH2)2N(CH3)C(O)-, -CH(OCH3)-CH2O(CH2)2N(H)C(O)-, -O(CH2)2O(CH2)2N(H)C(O)-, --CH2O(CH2)2N(H)C(O)-CH2-, or -O-(CH2)3C(O)N(H)-.
40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H or methyl.
41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H.
42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H.
43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H.
44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R10, when present, is H or F.
45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R11, when present, is H.
46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R12, when present, is H.
47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R2, when present, is independently selected from the group consisting of fluoro, chloro, -OH, and NH2.
48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.
49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1, or 2.
51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 6 or 7.
52. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14S,20S)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-13,22-dioxa- 2,10,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-9-one; (4R,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14S,20S)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-10-methyl-13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 9-one; 5-fluoro-4-[(4S,7S,14R,20R)-26-fluoro-10,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-fluoro-4-[(4R,7S,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-fluoro-4-[(4R,7S,14S,20S)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3- hydroxynaphthalen-1-yl)-13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 11-one; (4S,7S,14R,20R)-26-fluoro-27-(8-fluoro-3-hydroxynaphthalen-1-yl)-10-methyl- 13,22-dioxa-2,10,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 11-one; 5-fluoro-4-[(6R,13R,19R)-25-fluoro-8,12,21-trioxa-2,5,15,23,27,30- hexaazahexacyclo[20.7.1.12,6.113,19.015,19.024,29]dotriaconta-1(30),22,24,26,28-pentaen-26- yl]naphthalen-2-ol; (4S,7R,14R,20R)-27-(3-chloro-2-isopropyl-5-hydroxyphenyl)-26-fluoro- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(6-fluoro-5-methyl-1H-indazol-4-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-8- methylnaphthalen-1-yl)-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(7-fluoro-8-methylnaphthalen-1-yl)-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoronaphthalen-1-yl)- 9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(8-fluoronaphthalen-1-yl)-9-methyl-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-27-(7,8-difluoro-3-hydroxynaphthalen- 1-yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethyl-3-hydroxynaphthalen-1-yl)-26-fluoro-9-methyl-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4S,7R,14R,20R)-27-(8-chloro-3-hydroxynaphthalen-1- yl)-26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-26-fluoro-27-(3-hydroxynaphthalen-1-yl)-9-methyl-13,22-dioxa- 2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; 5,6-difluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(4S,7R,14R,20R)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethyl-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-chloro-4-[(4S,7R,14R,20R)-26-fluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 3-chloro-5-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-4-(propan-2-yl)phenol; (4S,7R,14R,20R)-26-fluoro-27-(7- fluoro-8-methylnaphthalen-1-yl)-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29- pentaene; 5-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,31,33- pentaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; (4S,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 26-fluoro-9-methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-9- methyl-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro-13,22- dioxa-2,9,16,24,28,31,33-heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-10-one; (4R,7R,14R,20R)-27-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-26-fluoro-13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4R,7R,14S,20S)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; (4S,7S,14R,20R)-27-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-26-fluoro- 13,22-dioxa-2,9,16,24,28,31,33- heptaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 10-one; 5-ethynyl-6-fluoro-4-[(4R,7S,14R,20R)-26-fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4S,7R,14S,20S)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4R,7S,14S,20S)-26- fluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(4S,7R,14R,20R)-26-fluoro-9,13,22-trioxa- 2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]naphthalen-2-ol; 4-[(4R,7S,14R,18R,20S)-18,26-difluoro- 9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(4R,7S,14S,18S,20R)-18,26-difluoro-9,13,22- trioxa-2,16,24,28,31,33-hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta- 1(31),23,25,27,29-pentaen-27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; and 4- [(4S,7R,14R,18R,20S)-18,26-difluoro-9,13,22-trioxa-2,16,24,28,31,33- hexaazaheptacyclo[21.7.1.12,7.14,7.114,20.016,20.025,30]tetratriaconta-1(31),23,25,27,29-pentaen- 27-yl]-5-ethynyl-6-fluoronaphthalen-2-ol.
53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of (2'R,4S,4'R,7R)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (2'R,4R,4'R,7S)-22-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4',21- difluoro-1'-methylspiro[9,17-dioxa-2,13,19,23,26,27- hexaazapentacyclo[16.7.1.12,7.14,7.020,25]octacosa-1(26),18,20,22,24-pentaene-15,2'- pyrrolidin]-12-one; (4S,7R,15S)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23- fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one; (4R,7S,15R)-24-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa- 2,13,16,19,21,25,28,30-octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta- 1(28),20,22,24,26-pentaen-12-one; and (4S,7R,15R)-24-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-23-fluoro-16-methyl-9-oxa-2,13,16,19,21,25,28,30- octaazahexacyclo[18.7.1.12,7.14,7.115,19.022,27]hentriaconta-1(28),20,22,24,26-pentaen-12-one.
54. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
55. 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 53, or a pharmaceutically acceptable salt thereof.
56. A compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
57. A compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
58. Use of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.
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