WO2023173017A1 - Kras inhibitors for treating disease - Google Patents

Kras inhibitors for treating disease Download PDF

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Publication number
WO2023173017A1
WO2023173017A1 PCT/US2023/064042 US2023064042W WO2023173017A1 WO 2023173017 A1 WO2023173017 A1 WO 2023173017A1 US 2023064042 W US2023064042 W US 2023064042W WO 2023173017 A1 WO2023173017 A1 WO 2023173017A1
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alkyl
fluoro
pyrido
pyrimidin
pyrrolizin
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PCT/US2023/064042
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French (fr)
Inventor
Jingrong Jean Cui
Evan W. ROGERS
Eugene Yuanjin Rui
Dayong Zhai
Anindya SARKAR
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Blossomhill Therapeutics, Inc.
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Publication of WO2023173017A1 publication Critical patent/WO2023173017A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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 on/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 mutant 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.
  • MRTX1133 has been reported as potent and highly selective noncovalent KRAS G12D inhibitor (Wang X.
  • intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate drug efficacy in mice. This suggests MRTX1133 may have poor bioavailability.
  • KRAS mutants such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D with good in vivo efficacy, safety, and predicted human oral pharmacokinetic profile for treating patients with KRAS mutant cancers.
  • the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0007] wherein [0008] X is a -O-, -S-, or -NR 4 -; [0009] Y is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, or –C(O)NR 10 -; [0010] Z 1 is N or C(R 5 ); [0011] Z 2 is N or C(R 6 ); [0012] Z 3 is N or C(R 7 ); [0013] Z 4 is N or C(R 8 ); [0014] Z 5 is N or C(R 9 ); [0015] provided that at least two of Z 1 -Z 5 are N; [0016] R 1 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alky
  • At least one hydrogen atom in the compound of the formula I is substituted by a deuterium. In some embodiments, at least one hydrogen atom in R 3 or R 11 in the compound of the formula I is substituted by a deuterium.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0031] wherein [0032] X is a -O-, -S-, or -NR 4 -; [0033] Z 1 is N or C(R 5 ); [0034] Z 2 is N or C(R 6 ); [0035] Z 3 is N or C(R 7 ); [0036] Z 4 is N or C(R 8 ); [0037] Z 5 is N or C(R 9 ); [0038] provided that at least two of Z 1 -Z 5 are N; [0039] each R 2 is independently 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, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -OR
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0052] wherein [0053] X is a -O-, -S-, or -NR 4 -; [0054] Z 1 is N or C(R 5 ); [0055] Z 2 is N or C(R 6 ); [0056] Z 3 is N or C(R 7 ); [0057] Z 4 is N or C(R 8 ); [0058] Z 5 is N or C(R 9 ); [0059] provided that at least two of Z 1 -Z 5 are N; [0060] each R 2 is independently 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, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -OR
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [0073] wherein R 2 , R 3 , R 11 , R a , R b , A, B, X, Y, 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, III [0075] wherein R 2 , R 3 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0076] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, IV [0077] wherein R 2 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein.
  • the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof, IVa [0079] wherein R 2 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0080] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, [0083] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0082] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, [0083] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein. [0084] In some embodiments, the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, VII [0087] wherein R 2 , R 3 , R 11 , R 12 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0088] 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 VIIIa, or a pharmaceutically acceptable salt thereof, VIIIa [0091] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0092] In some embodiments, the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [0095] wherein R 2 , R 3 , R 11 , R 13 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0096] 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 Xa, or a pharmaceutically acceptable salt thereof, [0099] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0100] In some embodiments, the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, [0103] wherein R 1 , R 2 , R 3 , R 10 , R a , R b , B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , n, p, and q are as described herein. [0104] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 3 , R 10 , R 11 , R a , R b , A, B, 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 XIII, or a pharmaceutically acceptable salt thereof, [0107] wherein R 2 , R 3 , R 10 , R 11 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof, XIV [0109] wherein R 2 , R 10 , R 11 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and q are as described herein.
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, XV [0111] wherein R 2 , R 3 , R 10 , R 11 , R 12 , R a , R b , A, 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 XVI, or a pharmaceutically acceptable salt thereof, XVI [0113] wherein R 2 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and q are as described herein. [0114] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof, [0117] wherein R 2 , R 10 , R 11 , R 13 , R a , R b , A, 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 XIX, or a pharmaceutically acceptable salt thereof, [0119] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0120] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof, XX [0121] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0122] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
  • XXI [0123] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof, XXII [0125] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof, XXIV [0129] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0130] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
  • XXV [0131] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof, XXVI [0133] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
  • XXVII [0135] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof, XXVIII [0137] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
  • XXIX [0139] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0140] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof, XXX [0141] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the compound of Formula (I)-(XXX) 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)-(XXX) 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)-(XXX), 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)-(XXX), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XXX), 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)-(XXX), 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
  • R 12 is H, deuterium, 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, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in 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, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C
  • R 3 when present, is -C 1 -C 6 alkyl or 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in -C 1 -C 6 alkyl and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 - C 6 alkyl, -OC 1 -C 6 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, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycl
  • each R 11 is independently 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, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR a R b , -OS(O) 2 NR a R b , -SR a , -S(O)R a ,
  • each R 2 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, -OR c , or -NR c R d .
  • Ring B is , [0210] wherein is a point of covalent attachment.
  • R 4 when present, is H or methyl.
  • a pharmaceutical composition comprising at least one compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • 39. 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 37, or a pharmaceutically acceptable salt thereof.
  • 40. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
  • 41. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
  • the portion of A-B defined by the group or chemical structure A can be represented by where each of “-*”, “-**”, and ” represents a bond to A and the point of covalent bond attachment to B.
  • the portion of A-B defined by the group or chemical structure B can be represented by , where each of “-*”, “-**”, and represents a bond to B and the point of covalent bond attachment to A.
  • 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 C 1 -C 20 alkyl or C 1 -C 20 alkylene, C 1 -C 12 alkyl or C 1 -C 12 alkylene, or C 1 -C 6 alkyl or C 1 -C 6 alkylene.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkylene groups examples include methylene (-CH 2 -), ethylene ((-CH 2 -) 2 ), n-propylene ((-CH 2 -) 3 ), iso-propylene ((-C(H)(CH 3 )CH 2 -)), n-butylene ((-CH 2 -)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkenyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C 2 -C 20 alkenyl, C 2 -C 12 alkenyl, or C 2 -C 6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein.
  • alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkynyl refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C 2 -C 2 0 alkynyl, C 2 -C 12 alkynyl, or C 2 -C 6 alkynyl.
  • alkynyl groups include acetylenyl (- C ⁇ CH) and propargyl (-CH 2 C ⁇ CH), but-3-yn-1,4-diyl (-C ⁇ C-CH 2 CH 2 -), and the like. It will be appreciated that an alkynyl group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0338] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle.
  • cycloalkyl In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” 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::
  • a cyclopropyl moiety can be depicted by the structural formula It will be appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein.
  • a cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF 3 , -(CH 2 )F, -CHF2, -CH 2 Br, -CH 2 CF 3 , and -CH 2 CH 2 F.
  • aryl refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • aryl mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C 6 -C 14 aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6- C 10 aryl).
  • aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein.
  • 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. .
  • 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).
  • heterocycloalkyl it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidine, and morpholine.
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • 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.
  • Examples, without limitations, of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane.
  • Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities: [0342]
  • 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 structural formula .
  • a heterocycloalkyl group can be unsubstituted or substituted as described herein.
  • a heterocycloalkyl 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.
  • 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.
  • 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: [0346]
  • a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle.
  • a five-membered heteroaryl 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.
  • a six-membered heteroaryl 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.
  • a “bicyclic heteroaryl” 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.
  • an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula .
  • a heteroaryl group can be unsubstituted or substituted as described herein.
  • a heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein.
  • a heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • substituted means that the specified group or moiety bears one, two, or three substituents.
  • substituted means that the specified group or moiety bears one or two substituents.
  • substituted means the specified group or moiety bears one substituent.
  • 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.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • 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 that can be incorporated into compounds of the disclosure 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.
  • Such 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.
  • detection or imaging techniques such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) 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.
  • Certain chemical entities of Formula (I)-(XXX) 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.
  • 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.
  • a ring option of isoquinolin-3(2H)-oneylene can exist as the following tautomers
  • the nomenclature “(ATOM)i-(ATOM)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.
  • C 1- C 3 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 (C 3 ).
  • the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XXX), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M.
  • 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
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXX), 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)-(XXX)).
  • 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)-(XXX), 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)-(XXX) 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, [0366] wherein R 1 , R 2 , R 3 , R a , R b , B, X, Y, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , n, p, and q are as described herein.
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [0368] wherein R 2 , R 3 , R 11 , R a , R b , A, B, X, Y, 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, III [0370] wherein R 2 , R 3 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0371] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, IV [0372] wherein R 2 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0373] In some embodiments, the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, V [0376] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0377] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof, [0380] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein. [0381] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof, VIII [0384] wherein R 2 , R 11 , R 12 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0385] In some embodiments, the disclosure provides a compound of the formula VIIIa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof, VIIIb [0388] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0389] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof, [0392] wherein R 2 , R 11 , R 13 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0393] In some embodiments, the disclosure provides a compound of the formula Xa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof, [0396] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0397] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof, [0400] wherein R 2 , R 3 , R 10 , R 11 , R a , R b , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0401] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof, XIV [0404] wherein R 2 , R 10 , R 11 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and q are as described herein.
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, XV [0406] wherein R 2 , R 3 , R 10 , R 11 , R 12 , R a , R b , A, 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 XVI, or a pharmaceutically acceptable salt thereof, XVI [0408] wherein R 2 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and q are as described herein.
  • the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof, [0410] wherein R 2 , R 3 , R 10 , R 11 , R 13 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0411] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof, XIX [0414] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0415] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof, XXI [0418] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0419] In some embodiments, the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof, XXIII [0422] wherein R 2 , R 3 , R 11 , R 12 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0423] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
  • XXIV [0424] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof, XXV [0426] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
  • XXVI [0428] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof, XXVII [0430] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof, [0434] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0435] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
  • Y is -S(O) 2 - or –C(O)NR 10 -. In some embodiments, Y is -S(O) 2 - . In some embodiments, Y is –C(O)NR 10 -. In some embodiments, Y is -S(O) 2 - or –C(O)NR 10 - , and R 1 is ring A.
  • Y is -S(O) 2 -, and R 1 is ring A. In some embodiments, Y is or –C(O)NR 10 -, and R 1 is ring A. In some embodiments, Y is -O-, -S-, -S(O)-, or -S(O) 2 - and R 1 is ring A. In some embodiments, Y is -O-, -S-, or -S(O)- , and R 1 is ring A. In some embodiments, Y is -O-, and R 1 is ring A. In some embodiments, Y is -S-, and R 1 is ring A. In some embodiments, Y is -S-, and R 1 is ring A.
  • Y is -S(O)-
  • R 1 is ring A.
  • Y is a bond
  • R 1 is ring A.
  • ring A is a C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R 11 .
  • ring A is an unsubstituted C 3 -C 8 cycloalkyl, or a C 3 -C 8 cycloalkyl substituted with one or more of R 11 .
  • ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with one or more of R 11 .
  • ring A is an unsubstituted C 6 -C 10 aryl, or a C 6 -C 10 aryl substituted with one or more of R 11 .
  • ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10- membered heteroaryl substituted with one or more of R 11 .
  • ring A is a C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted C 3 -C 8 cycloalkyl, or a C 3 -C 8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted C 6 -C 10 aryl, or a C 6 -C 10 aryl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is a 4- to 10-membered heterocycloalkyl that is not an unsubstituted or a substituted ring of the formula [0441]
  • A is 4- to 10-membered heterocycloalkylthat is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl.
  • ring A is a 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a fused bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bridged bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments, ring A is a spiro bicyclic 6- to 10-membered heterocycloalkyl. [0442] In some embodiments, Ring A is
  • Ring A is of the formula , or , [0444] wherein * is a point of covalent attachment to [0445] In some embodiments, Ring A is [0446] wherein * is a point of covalent attachment to and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6.
  • Ring A is azitidinyl, oxtenanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro-1H-pyrrolyl, pyrazolidinyl, thiazolidinyl, 4,5-dihydro-1H- imidazolyl, dihydrothiophen-2(3H)-onyl, tetrahydrothiophenyl 1,1-dioxide, imidazolidin-2- onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, 1,3-dioxolan-2-onyl, oxazolidin-2-onyl, piperidinyl, morpholinyl, 4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3- oxazinan-2-on
  • Ring A is
  • Ring A is
  • each R 11 is independently 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, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR a R b , -OS(O) 2 NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -NR a C(O)
  • m is 0. In some embodiments, m is one or more. 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 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
  • ring B is a C 6 -C 10 aryl or 5- to 10-membered heteroaryl, optionally substituted with one or more R 2 , R 12 , or R 13 .
  • ring B is a C 3 - C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl optionally substituted with one or more R 2 , R 12 , or R 13 .
  • Ring B is [0461] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0462] In some embodiments, Ring B is
  • Ring B is [0465] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0466] In some embodiments, Ring B is [0467] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0468] In some embodiments, Ring B is
  • Ring B is [0471] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0473] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0475] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0476] In some embodiments, Ring B is [0477] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0478] In some embodiments, Ring B is [0479] wherein wherein * is a point of covalent attachment to n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • each R 2 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OR c , or - CN.
  • each R 2 when present, is independently selected from the group consisting of fluoro, chloro, C 1 -C 6 alkyl, -OH, and -CN.
  • each R 2 when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -C ⁇ CH, -CN, and -OH.
  • R 12 is H, deuterium, 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, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in 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, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e ,
  • R 12 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 12 is H, deuterium, or methyl.
  • R 13 is H, deuterium, 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, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in 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, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f
  • R 13 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 13 is H, deuterium, or methyl. [0483] In some embodiments, n is 0. In some embodiments, n is one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. 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.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0484] In some embodiments, Ring B is [0485] wherein “ ” is a point of covalent attachment. [0486] In some embodiments, Ring B is
  • Ring B is of the formula [0489] wherein “ ” is a point of covalent attachment.
  • q is 0. In some embodiments, q is 1.
  • -X- is -O-, -S-, or–NR 4 -. In some embodiments, -X- is -O-. In some embodiments, -X- is -S-. In some embodiments, -X- is –NR 4 -.
  • R 4 is H, deuterium, 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, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in 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, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e ,
  • R 4 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 4 is H, deuterium, or methyl.
  • R 3 is -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, -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkyl), -C 6 -C 10 aryl, -C 1 -C 6 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C
  • R 3 is -C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, or -C 1 - C 6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, or -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 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), haloalky
  • R 3 is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 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, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C 1 -C 6 alkyl-(4- to 10- membered heterocycloalkyl), -OR e , -OC(O)R e
  • R 3 is [0497] wherein is a point of covalent attachment. [0498] In some embodiments, R 3 is [0499] wherein “ is a point of covalent attachment. [0500] In some embodiments, R 3 is [0501] wherein “ ” is a point of covalent attachment.
  • R 3 is –C 1 -C 6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C 1 -C 6 alkyl-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 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, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, or -C 1 -C 6 alkyl-
  • R 3 is of the formula [0504] wherein wherein ” is a point of covalent attachment, and each hydrogen atom is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 - C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, 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, -C 1 -C 6 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 the formula [0506] wherein wherein is a point of covalent attachment, and each hydrogen atom is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 - C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, 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, -C 1 -C 6 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 when present, is of the formula [0508] wherein is a point of covalent attachment.
  • R 3 when present, is of the formula [0510] wherein is a point of covalent attachment.
  • each R a , R b , R c , R d , R e , R f , R g , and R h is independently selected from the group consisting of H, deuterium, 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, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; or two of R a and R b , or R c and R d , or R e and R f , or R g and R h , taken together with the atom or atoms to which they are attached, combine to form a C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6
  • Z 1 is N. In some embodiments, Z 2 is N. In some embodiments, Z 3 is N. In some embodiments, Z 4 is N. In some embodiments, Z 5 is N. In some embodiments, Z 6 is N. In some embodiments, Z 7 is N. In some embodiments, Z 1 is C(R 5 ). In some embodiments, Z 2 is C(R 6 ). In some embodiments, Z 3 is C(R 7 ). In some embodiments, Z 4 is C(R 8 ). In some embodiments, Z 5 is C(R 9 ). In some embodiments, Z 6 is C(R 14 ). In some embodiments, Z 7 is C(R 15 ).
  • any of the possible combinations of Z 1 -Z 7 can be combined as embodiemnts.
  • Z 6 is N or C(R 14 ).
  • Z 7 is N or C(R 15 ).
  • Z 1 is N, and Z 2 is N.
  • Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is N, and Z 5 is C(R 9 ).
  • Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is C(R 8 ), and Z 5 is C(R 9 ).
  • Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is N, and Z 5 is C(R 9 ). In some embodiments, Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is C(R 8 ), and Z 5 is C(R 9 ). In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is C(R 8 ), and Z 5 is N. In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), 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 7 ), 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 7 ), Z 4 is N, and Z 5 is C(R 9 ).
  • Z 1 is N
  • Z 2 is N
  • Z 3 is N
  • Z 4 is C(R 8 )
  • Z 5 is C(R 9 ).
  • Z 1 is N
  • Z 2 is N
  • Z 3 is N
  • Z 4 is N
  • Z 5 is N.
  • each of R 5 , R 6 , R 7 , R 8 , R 9 , R 14 , and R 15 is independently H, 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, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR g , -OC(O)R g , -OC(O)NR g R h , -OS(O)R g , -OS(O) 2 R g , -SR g , -S(O)R g , -S(O) 2 R g , -S(O)NR g R h , -S(O) 2 NR g R h , -OS(O)NR g R g R
  • R 6 when present, is H.
  • R 7 when present, is H or F.
  • R 8 when present, is H.
  • R 9 when present, is H.
  • R 14 when present, is H.
  • R 15 when present, is H.
  • the disclosure provides a compound selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy ⁇ -4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0516] 3-[7-(8-ethynyl-7-fluoro
  • the disclosure provides a compound selected from the groups consisting of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0583] 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0584] 5-ethyl-4-[8-fluor
  • 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. [0620] 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.
  • the proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below.
  • Scheme I [0641] The general scheme I is used to prepare the products with general structure Ex. X.
  • the bicyclic aryl core I-1-1 and a variety of amines I-2 are either commercially available or prepared via conventional chemistry from commercially available materials.
  • DIPEA diisopropylethyl amine
  • the general scheme II is used to prepare the products with general structure Ex. X.
  • the bicyclic aryl core I-1-1, a variety of amines I-2, I-4 and boronic ester or acid are either commercially available or prepared via conventional chemistry from commercially available materials.
  • B under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 o C, compound II-1 and an amine or alcohol I-4 are converted to a product II-2.
  • Step 2 To a mixture of tert-butyl 8-fluoro-3-azabicyclo[3.2.1]octane-3-carboxylate (50.0 mg, 0.218 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 0.2 mL, 3.67 eq).
  • Step 4 To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (180 mg, 0.233 mmol, 1 eq) in DCM (2 mL) was added HCl/Dioxane (4 M, 0.3 mL, 5.16 eq).
  • Step 2 To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (2.30 g, 7.28 mmol, 1.0 eq) in dioxane (20 mL) was added DIEA (1.88 g, 14.6 mmol, 2.0 eq) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (1.27 g, 8.01 mmol, 1.1 eq). The mixture was stirred at 80 °C for 12 hours.
  • reaction mixture was partitioned between EtOAc (20 mL) and H 2 O (20 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 To a solution of (3R,4R)-4-fluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (60.0 mg, 0.743 mmol, 1.0 eq) in DCM (10 mL) was added HCl/Dioxane (4 M, 1 mL).
  • Step 1 A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.80 g, 4.10 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.15 g, 6.15 mmol, 1.5 eq), K3PO4 (2.61 g, 12.3 mmol, 3.0 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphan
  • Step 2 To a mixture of 3-azabicyclo[3.1.1]heptane (8.62 mg, 0.0645 mmol, 1.45 eq, HCl) and 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (35.0 mg, 0.0443 mmol, 1 eq) in DMF (1 mL) was added K 2 CO 3 (18.3 mg, 0.133 mmol, 3 eq).
  • Step 3 To a solution of 2-[8-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7- yl]-2-fluoro-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (50.0 mg, 0.064 mmol, 1 eq) and DCM (1 mL) was added HCl/dioxane (4 M, 0.206 mL, 13 eq), the resulting mixture was stirred at 23 °C for 1.5 h.
  • Step 1 To a solution of [5-chloro-6-fluoro-4-(trifluoromethylsulfonyloxy)-2- naphthyl] acetate (50.0 mg, 0.129 mmol, 1 eq) in THF (1 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (16.3 mg, 0.388 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1h. On completion, the mixture was quenched with HCl (1N, 5 mL) and extracted with ethyl acetate (2 mL ⁇ 3).
  • Step 1 A mixture of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (200 mg, 0.605 mmol, 1.2 eq), DIEA (391 mg, 3.03 mmol, 6 eq) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then piperidine (43.0 mg, 0.504 mmol, 1 eq) was added to the mixture at -40 °C. The mixture was stirred at -40 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 3 To the solution of tert-butyl 7-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-1,7- diazaspiro[4.4]nonane-1-carboxylate (150 mg, 0.178 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 20 eq).
  • Step 1 To a mixture of tert-butyl 1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine- 6- carboxylate (460 mg, 2.03 mmol, 2 eq) and 7-chloro-8-fluoro-2-[[(2R,8S)-2- fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (445 mg, 1.02 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (421 mg, 3.05 mmol, 3 eq).
  • Step 3 To a solution of tert-butyl 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,4,4a,5,7,7a-hexahydro- 2H-pyrrolo[3,4-b]pyridine-6-carboxylate (400 mg, 0.437 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 1.19 mL, 10.8 eq).
  • Step 4 To a solution of 4-[4-(2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b]pyridin-1-yl)- 8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (352 mg, 0.437 mmol, 1 eq, HCl) in DCM (4 mL) was added Ac2O (111 mg, 1.09 mmol, 2.5 eq) and TEA (221 mg, 2.19 mmol, 5 eq) at 0 °C.
  • Step 1 To a solution of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (800 mg, 1.10 mmol, 1 eq) in DCM (20 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (587 mg, 1.64 mmol, 1.5 eq) and DIEA (283 mg, 2.19 mmol, 2 eq), DMAP (26.7 mg, 0.219 mmol, 0.2 eq).
  • Step 1 To a solution of 1H-indol-3-yl acetate (248 mg, 1.42 mmol, 2.00 eq) in dioxane (4.50 mL) was added 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (300 mg, 0.708 mmol, 1 eq), Cs2CO3 (461 mg, 1.42 mmol, 2 eq) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (68.9 mg, 0.0708 mmol, 0.1 eq).
  • Step 5 A mixture of 2-[2-fluoro-8-[8-fluoro-5-methoxy-2-methylsulfonyl-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (240 mg, 0.331 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (158 mg, 0.993 mmol, 3 eq), t-BuOK (111 mg, 0.993 mmol, 3 eq) in Toluene (3 mL) was degassed and purged with N2 for 3 times at 0 °C, and then the mixture was stirred at 25 °C under N 2 atmosphere for 1 h.
  • KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G12D/T35S or KRAS WT proteins were 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).
  • Serial dilutions of indicated compounds were prepared in DMSO and added to the KRAS /a-GST Tb antibody mixture using acoustic dispenser (ECHO, Beckman).
  • Method A Two thousand KRAS mutant cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours at 37°C and 5% CO 2 .
  • 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).
  • Method B Two thousand KRAS mutant cells per well were seeded in 96-well black plate and then treated with indicated compounds for 5 days at 37°C and 5% CO 2 .
  • Ex.1 was administered to female BALB/c mice via oral gavage at the dose level of 50 mg/kg. Mouse plasma was collected before the dose and at 15 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after the dose. For each time points, blood samples were collected from three mice into tubes containing K2-EDTA, followed by gentle mixing to assure distribution of the anti-coagulant. Immediately after a blood sample was collected and mixed, it was placed on ice. Blood samples were subsequently centrifuged at 4 oC for 10 minutes at 5,000 rpm. The plasma was harvested into pre-labeled tubes and stored at -80 oC. Frozen plasma samples were shipped to Integrated Analytical Solutions, Inc. for bioanalysis of Ex.1 by LC/MS/MS. Non-compartment analysis method of Phoenix 64 software (Certara, Inc) was used to calculate various pharmacokinetic parameters and the results were summarized in the Table below:

Abstract

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

Description

KRAS INHIBITORS 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.63/318,352 filed on March 9, 2022, and U. S. Provisional Application Serial No. 63/359,805 filed on July 9, 2022, the entire disclosures of which are incorporated herein by reference. TECHNICAL FIELD [0002] The present disclosure relates to diaryl compounds targeting KRAS, pharmaceutical compositions containing the compounds, and methods of using such 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 on/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. [0004] Direct targeting of mutant KRAS has previously proven challenging because of its high affinity for nucleotide and the lack of tractable binding pockets for small-molecule inhibitors. 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. The increased understanding of structural elements of the KRAS switch II pocket made it possible to design KRAS inhibitors selective for different mutant variants. MRTX1133 has been reported as potent and highly selective noncovalent KRAS G12D inhibitor (Wang X. et al, Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor, J. Med. Chem.2022, 65: 3123–3133). However, intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate drug efficacy in mice. This suggests MRTX1133 may have poor bioavailability. [0005] Therefore, there is unmet medical need to develop new noncovalent KRAS inhibitors that can selectively target KRAS mutants such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D with good in vivo efficacy, safety, and predicted human oral pharmacokinetic profile for treating patients with KRAS mutant cancers. SUMMARY [0006] In one aspect, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0007] wherein
Figure imgf000003_0001
[0008] X is a -O-, -S-, or -NR4-; [0009] Y is a bond, -O-, -S-, -S(O)-, -S(O)2-, or –C(O)NR10-; [0010] Z1 is N or C(R5); [0011] Z2 is N or C(R6); [0012] Z3 is N or C(R7); [0013] Z4 is N or C(R8); [0014] Z5 is N or C(R9); [0015] provided that at least two of Z1-Z5 are N; [0016] R1 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or ring A, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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; and when Y is a bond, -O-, –S-, or –S(O)-, then R1 is ring A; [0017] 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 atoms 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, -Re, -Rf, -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; [0018] R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-( C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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; [0019] each of R4 and R10 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, -Re, -Rf, 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 R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10- membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl 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, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10- membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0020] each of R5, R6, R7, R8, and R9 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; [0021] ring A is a C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each of C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R11; [0022] each R11 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, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, - C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, - P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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 two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0023] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0024] 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; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a 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, 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0025] n is 0, 1, 2, 3, 4, 5, 6, or 7; [0026] p is 0 or 1; and [0027] q is 0, 1, or 2; [0028] and wherein the compound is not of the formula
Figure imgf000007_0001
Figure imgf000008_0002
[0029] In some embodiments, at least one hydrogen atom in the compound of the formula I is substituted by a deuterium. In some embodiments, at least one hydrogen atom in R3 or R11 in the compound of the formula I is substituted by a deuterium. [0030] In another aspect, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0031] wherein
Figure imgf000008_0001
[0032] X is a -O-, -S-, or -NR4-; [0033] Z1 is N or C(R5); [0034] Z2 is N or C(R6); [0035] Z3 is N or C(R7); [0036] Z4 is N or C(R8); [0037] Z5 is N or C(R9); [0038] provided that at least two of Z1-Z5 are N; [0039] 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 atoms 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, -Re, -Rf, -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; [0040] R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10- membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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; [0041] R4 is 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, -Re, -Rf, 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 R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10- membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10- membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl 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, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0042] each of R5, R6, R7, R8, and R9 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; [0043] ring A is a 4- to 10-membered heterocycloalkyl that is unsubstituted or is substituted with one or more of R11; [0044] each R11 is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -OH, -OC1-C6 alkyl, -CN, -C(O)NRaRb, or -NRaC(O)Rb, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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 two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0045] ring B is a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; [0046] 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; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a 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, 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0047] m is 0, 1, 2, 3, 4, 5, or 6; [0048] n is 0, 1, 2, 3, 4, 5, 6, or 7; and [0049] p is 0 or 1; [0050] provided that when p is 1, then at least one hydrogen atom in R3 is substituted by deuterium. [0051] In another aspect, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000012_0001
[0052] wherein [0053] X is a -O-, -S-, or -NR4-; [0054] Z1 is N or C(R5); [0055] Z2 is N or C(R6); [0056] Z3 is N or C(R7); [0057] Z4 is N or C(R8); [0058] Z5 is N or C(R9); [0059] provided that at least two of Z1-Z5 are N; [0060] 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 atoms 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, -Re, -Rf, -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; [0061] R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10- membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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; [0062] R4 is 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, -Re, -Rf, 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 R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10- membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10- membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl 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, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0063] each of R5, R6, R7, R8, and R9 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; [0064] ring A is a 4- to 10-membered heterocycloalkyl that is unsubstituted or is substituted with one or more of R11; [0065] each R11 is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -OH, -OC1-C6 alkyl, -CN, -C(O)NRaRb, or -NRaC(O)Rb, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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 two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0066] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0067] 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; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a 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, 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0068] m is 0, 1, 2, 3, 4, 5, or 6; [0069] n is 0, 1, 2, 3, 4, 5, 6, or 7; and [0070] p is 0 or 1; [0071] provided that when p is 1, then at least one hydrogen atom in R3 is substituted by deuterium. [0072] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000016_0001
[0073] wherein R2, R3, R11, Ra, Rb, A, B, X, Y, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0074] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000016_0002
III [0075] wherein R2, R3, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0076] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
Figure imgf000017_0001
IV [0077] wherein R2, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0078] In some embodiments, the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof,
Figure imgf000017_0002
IVa [0079] wherein R2, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0080] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000018_0001
[0081] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0082] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000018_0002
[0083] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0084] In some embodiments, the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof,
Figure imgf000019_0001
VIa [0085] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0086] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
Figure imgf000019_0002
VII [0087] wherein R2, R3, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0088] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000020_0001
VIII [0089] wherein R2, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0090] In some embodiments, the disclosure provides a compound of the formula VIIIa, or a pharmaceutically acceptable salt thereof,
Figure imgf000020_0002
VIIIa [0091] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0092] In some embodiments, the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof,
Figure imgf000021_0001
VIIIb [0093] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0094] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000021_0002
[0095] wherein R2, R3, R11, R13, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0096] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
Figure imgf000022_0001
[0097] wherein R2, R11, R13, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0098] In some embodiments, the disclosure provides a compound of the formula Xa, or a pharmaceutically acceptable salt thereof,
Figure imgf000022_0002
[0099] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0100] In some embodiments, the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof,
Figure imgf000023_0001
[0101] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0102] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000023_0002
[0103] wherein R1, R2, R3, R10, Ra, Rb, B, X, Z1, Z2, Z3, Z4, Z5, n, p, and q are as described herein. [0104] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000024_0001
[0105] wherein R2, R3, R10, R11, Ra, Rb, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0106] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000024_0002
[0107] wherein R2, R3, R10, R11, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, p, and q are as described herein. [0108] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000025_0001
XIV [0109] wherein R2, R10, R11, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and q are as described herein. [0110] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
Figure imgf000025_0002
XV [0111] wherein R2, R3, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0112] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000026_0001
XVI [0113] wherein R2, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0114] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000027_0001
[0115] wherein R2, R3, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0116] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000027_0002
[0117] wherein R2, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0118] In some embodiments, the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0001
[0119] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0120] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0002
XX [0121] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0122] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
Figure imgf000029_0001
XXI [0123] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0124] In some embodiments, the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof,
Figure imgf000029_0002
XXII [0125] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0126] In some embodiments, the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000030_0001
XXIII [0127] wherein R2, R3, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0128] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000030_0002
XXIV [0129] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0130] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
Figure imgf000031_0001
XXV [0131] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0132] In some embodiments, the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000031_0002
XXVI [0133] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0134] In some embodiments, the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000032_0001
XXVII [0135] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0136] In some embodiments, the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000032_0002
XXVIII [0137] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0138] In some embodiments, the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000033_0001
XXIX [0139] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0140] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
Figure imgf000033_0002
XXX [0141] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0142] In certain embodiments of the above aspects, the compound of Formula (I)-(XXX) is a compound selected from those species described or exemplified in the detailed description below. [0143] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XXX) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient. [0144] In further aspects, the disclosure relates to a compound of Formula (I)-(XXX), or a pharmaceutically acceptable salt thereof, for use as a medicament. [0145] 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)-(XXX), or a pharmaceutically acceptable salt thereof. [0146] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XXX), 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. [0147] 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)-(XXX), 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. [0148] 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. [0149] 1. A compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000034_0001
[0150] wherein [0151] X is a -O-, -S-, or -NR4-; [0152] Z1 is N or C(R5); [0153] Z2 is N or C(R6); [0154] Z3 is N or C(R7); [0155] Z4 is N or C(R8); [0156] Z5 is N or C(R9); [0157] provided that at least two of Z1-Z5 are N; [0158] 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 atoms 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, -Re, -Rf, -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; [0159] R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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; [0160] R4 is 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, -Re, -Rf, 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 R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl 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, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; [0161] each of R5, R6, R7, R8, and R9 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; [0162] ring A is a 4- to 10-membered heterocycloalkyl that is unsubstituted or is substituted with one or more of R11; [0163] each R11 is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -OH, -OC1-C6 alkyl, -CN, -C(O)NRaRb, or -NRaC(O)Rb, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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 two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; [0164] ring B is a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; [0165] 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; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a 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, 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; [0166] m is 0, 1, 2, 3, 4, 5, or 6; [0167] n is 0, 1, 2, 3, 4, 5, 6, or 7; and [0168] p is 0 or 1; [0169] provided that when p is 1, then at least one hydrogen atom in R3 is substituted by deuterium. [0170] 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula V, VII, IX, XIX, XXI, XXIII, XXV, XXVII, or XXIX,
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
[0171] wherein [0172] Z6 is N or C(R14); [0173] Z7 is N or C(R15); [0174] R12 is 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, -Re, -Rf, 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; [0175] R13 is 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, -Re, -Rf, 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; and [0176] each of R14 and R15 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. [0177] 3. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(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, 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. [0178] 4. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is -C1-C6 alkyl or 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in -C1-C6 alkyl and 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, 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. [0179] 5. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000043_0003
[0180] wherein
Figure imgf000043_0004
is a point of covalent attachment. [0181] 6. The compound of any one of clauses 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is –C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C1-C6 alkyl-(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. [0182] 7. The compound of any one of clauses 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000043_0001
[0183] 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, 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, and is a point of covalent attachment.
Figure imgf000043_0002
[0184] 8. The compound of any one of clauses 1 to 4, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000044_0001
[0185] wherein “ ” is a point of covalent attachment. [0186] 9. The compound of any one of clauses 1 to 4, 6 to 8, wherein the compound is of the formula IVa, VIa, VIIIb, Xb, XX, XXII, XXIV, XXVI, XXVIII, or XXX,
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
[0187] or a pharmaceutically acceptable salt thereof. [0188] 10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2. [0189] 11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. [0190] 12. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R11 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, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, - Re, -Rf, 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, -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; wherein each Ra, Rb, Re, and Rf, is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1- C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; or two of Ra and Rb, or Re and Rf, taken together with the atom or atoms to which they are attached, combine to form a 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, 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(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, or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0191] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula
Figure imgf000048_0001
Figure imgf000049_0003
, [0192] wherein * is a point of covalent attachment to
Figure imgf000049_0001
. [0193] 14. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein ring A is of the formula
Figure imgf000049_0002
Figure imgf000050_0001
[0194] wherein * is a point of covalent attachment to
Figure imgf000050_0002
[0195] 15. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z1 is N. [0196] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z2 is N. [0197] 17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is N, and Z5 is CR9. [0198] 18. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is CR9. [0199] 19. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is N. [0200] 20. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is CR9. [0201] 21. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is N. [0202] 22. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is N, and Z5 is N. [0203] 23. The compound of any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is CR8, and Z5 is N. [0204] 24. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein X is -O-. [0205] 25. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X is –NR4-. [0206] 26. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X is -S-. [0207] 27. The compound of any one of clauses 1 to 23, or a pharmaceutically acceptable salt thereof, wherein p is 0. [0208] 28. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently deuterium, halogen, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, -ORc, or -NRcRd. [0209] 29. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring B is
Figure imgf000051_0001
Figure imgf000052_0001
, [0210] wherein
Figure imgf000052_0002
is a point of covalent attachment. [0211] 30. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R4, when present, is H or methyl. [0212] 31. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H. [0213] 32. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H. [0214] 33. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or F. [0215] 34. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H. [0216] 35. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H. [0217] 36. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0218] 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0219] 3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-ol; [0220] (3S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3- ol; [0221] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(4-fluoropiperidin-1-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol; [0222] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(8-fluoro-3-azabicyclo[3.2.1]octan-3-yl)-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0223] (1R,5S,8S)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]-3-azabicyclo[3.2.1]octan-8-ol; [0224] (3R,4R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-4- fluoropiperidin-3-ol; [0225] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0226] 4-[4-(azetidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0227] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0228] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3R)-3-methoxypyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0229] 4-[4-(azepan-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0230] 4-[4-(2-azabicyclo[2.2.1]heptan-2-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0231] 4-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0232] (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidine- 3-carbonitrile; [0233] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0234] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl]-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0235] (2R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-N-(propan- 2-yl)piperidine-2-carboxamide; [0236] 4-[4-(8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0237] 4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0238] 4-[2-(1,7-diazaspiro[4.4]nonan-7-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0239] 4-{2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0240] (3S)-3-{[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl]amino}-N,5-dimethylhexanamide; [0241] (2R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-N- methylpiperidine-2-carboxamide; [0242] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; [0243] 5,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0244] 7-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,3-benzothiazol-2-amine; [0245] 4-[4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0246] 5-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0247] 8-chloro-7-fluoro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]isoquinolin-3-amine; [0248] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0249] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3S)-3-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0250] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3R)-3-methoxypiperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0251] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3S)-3-methoxypiperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0252] 4-[4-(3-ethoxypiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0253] 2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}- 6-(piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carbonitrile; [0254] (4R)-2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-6-(piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7- tetrahydro-1-benzothiophene-3-carbonitrile; [0255] (4S)-2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-6-(piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7- tetrahydro-1-benzothiophene-3-carbonitrile; [0256] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3R)-3-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0257] 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0258] 7-(4-chloro-1H-indol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; [0259] 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0260] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2H10)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0261] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0262] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- (2H3)methylpiperidin-3-ol; [0263] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- (2H3)methylpiperidin-3-ol; [0264] (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0265] 7-ethynyl-6-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1H-indazol-3- amine; [0266] 7-ethynyl-6-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1H-indazol-3- amine; [0267] (1R)-4-chloro-3-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl](1-2H)-1H-inden-1-ol; [0268] 8-ethynyl-7-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]isoquinolin-3- amine; [0269] 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- amine; [0270] 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0271] 5-ethynyl-6-fluoro-4-{8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7- yl}naphthalen-2-ol; [0272] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0273] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2S)-2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0274] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(2R)-2-(hydroxymethyl)piperidin-1-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; [0275] 5-ethynyl-6-fluoro-4-(8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)meth}oxy)-4-[(2S)-2-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; [0276] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[3-(methoxymethyl)-2-methyl-2,4,5,6-tetrahydro-7H- pyrazolo[3,4-b]pyridin-7-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0277] 4-[4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5- ethynyl-6-fluoronaphthalen-2-ol; [0278] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(3aR,7aR)-hexahydrofuro[2,3-c]pyridin-6(2H)-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; [0279] 1-{(4aS,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3- d]pyrimidin-4-yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; [0280] N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-yl}-N-methylacetamide; [0281] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(5S)-2-oxa-6-azaspiro[4.5]decan-6-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; [0282] (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]- 2,6-diazaspiro[4.5]decan-3-one; [0283] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(4R,5S)-4-fluoro-1-methyl-1,7- diazaspiro[4.4]nonan-7-yl]-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; and [0284] 4-{2-[(3S)-3-(dimethylamino)-3-(fluoromethyl)pyrrolidin-1-yl]-8-fluoro-4-(piperidin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0285] or a pharmaceutically acceptable salt thereof. [0286] 37. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0287] 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0288] 5-ethyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0289] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0290] 5-chloro-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0291] 4-[6-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0292] 5-ethynyl-6-fluoro-4-[8-fluoro-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0293] N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin- 3-yl}-N-methylacetamide; [0294] (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6- diazaspiro[4.5]decan-3-one; [0295] (5R)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6- diazaspiro[4.5]decan-3-one; [0296] 1-{(4aR,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; [0297] 1-{(4aS,7aS)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; [0298] (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0299] 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-methylnaphthalen-2-ol; [0300] 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0301] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0302] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-amine; [0303] 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0304] 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0305] 7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidine; [0306] 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0307] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{3-[(methanesulfonyl)methyl]piperidin-1-yl}pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; [0308] 4-{2-[(2S,4S)-4-(dimethylamino)-2-methylpyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0309] 1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,2-dihydro-3H-indol-3-one; [0310] 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0311] 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3-methylpiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0312] 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0313] 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0314] 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoronaphthalen-2-ol; [0315] 4-[4-(5-chloro-2,3-dihydro-1H-indol-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0316] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0317] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-5-methoxy-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol; [0318] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; and [0319] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[3-(methoxymethyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4- b]pyridin-7-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. [0320] 38. A pharmaceutical composition comprising at least one compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. [0321] 39. 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 37, or a pharmaceutically acceptable salt thereof. [0322] 40. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject. [0323] 41. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject. [0324] 42. Use of a compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. DETAILED DESCRIPTION [0325] 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. [0326] 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. [0327] 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. [0328] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. [0329] 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. [0330] 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. [0331] 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. [0332] 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). [0333] As used herein and in connection with chemical structures depicting the vaious embodiments described herein, “*”, “**”, and
Figure imgf000062_0001
“ ”, 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 imgf000062_0002
Figure imgf000062_0003
where each of “-*”, “-**”, and
Figure imgf000062_0004
” represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion of A-B defined by the group or chemical structure B can be represented by
Figure imgf000062_0007
Figure imgf000062_0005
, where each of “-*”, “-**”, and
Figure imgf000062_0006
represents a bond to B and the point of covalent bond attachment to A. [0334] 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 [0335] 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. [0336] The term “alkenyl” refers to a straight- or branched-chain mono-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” to a specific range of atoms, such as C2-C20 alkenyl, C2-C12 alkenyl, or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein. An alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0337] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C2-C20 alkynyl, C2-C12 alkynyl, or C2-C6 alkynyl. 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 group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0338] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” 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::
Figure imgf000064_0001
In particular, a cyclopropyl moiety can be depicted by the structural formula
Figure imgf000064_0002
It will be appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein. A cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0339] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine. [0340] 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 “aryl” refers to a monovalent 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” 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), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10 aryl).Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein. An aryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0341] 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. . In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” 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 to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples, without limitations, of mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidine, and morpholine. Polycyclic ring systems include fused, bridged, and spiro systems. In some embodiments, it can be advantageous to limit the number of atoms in a bicyclic “heterocycloalkyl” to a specific range of ring atoms, such as from 5 to 10 ring atoms (5- to 10-membered), or 6 to 10 ring atoms (6- to 10-membered). 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. Examples, without limitations, of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities:
Figure imgf000065_0001
[0342] 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. [0343] In particular, a hexahydro-1H-pyrrolizinyl moiety can be depicted by the structural formula
Figure imgf000066_0001
. [0344] It will be appreciated that a heterocycloalkyl group can be unsubstituted or substituted as described herein. A heterocycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0345] 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. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” to a specific range of atom members, such as 5- to 10-membered heteroaryl. 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. 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:
Figure imgf000067_0001
[0346] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle. A five-membered heteroaryl 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. A six-membered heteroaryl 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. A “bicyclic heteroaryl” 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. [0347] In particular, an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula
Figure imgf000067_0002
. [0348] It will be appreciated that a heteroaryl group can be unsubstituted or substituted as described herein. A heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0349] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0350] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone. [0351] 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. [0352] 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. [0353] 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. [0354] Certain chemical entities of Formula (I)-(XXX) 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 imgf000069_0001
[0355] In particular, a ring option of isoquinolin-3(2H)-oneylene can exist as the following tautomers
Figure imgf000069_0002
[0356] The nomenclature “(ATOM)i-(ATOM)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). [0357] [0358] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XXX), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts. [0359] 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. [0360] 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. [0361] For a compound of Formula (I)-(XXX) 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. [0362] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXX), 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)-(XXX)). 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. [0363] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXX), 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)-(XXX) 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). [0364] 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 [0365] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000072_0001
[0366] wherein R1, R2, R3, Ra, Rb, B, X, Y, Z1, Z2, Z3, Z4, Z5, n, p, and q are as described herein. [0367] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000072_0002
[0368] wherein R2, R3, R11, Ra, Rb, A, B, X, Y, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0369] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000073_0001
III [0370] wherein R2, R3, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0371] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
Figure imgf000073_0002
IV [0372] wherein R2, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0373] In some embodiments, the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof,
Figure imgf000074_0001
IVa [0374] wherein R2, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0375] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000074_0002
V [0376] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0377] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000075_0001
[0378] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0379] In some embodiments, the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof,
Figure imgf000075_0002
[0380] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0381] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
Figure imgf000076_0001
VII [0382] wherein R2, R3, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0383] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000076_0002
VIII [0384] wherein R2, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0385] In some embodiments, the disclosure provides a compound of the formula VIIIa, or a pharmaceutically acceptable salt thereof,
Figure imgf000077_0001
VIIIa [0386] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0387] In some embodiments, the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof,
Figure imgf000077_0002
VIIIb [0388] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0389] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000078_0002
[0390] wherein R2, R3, R11, R13, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0391] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
Figure imgf000078_0001
[0392] wherein R2, R11, R13, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0393] In some embodiments, the disclosure provides a compound of the formula Xa, or a pharmaceutically acceptable salt thereof,
Figure imgf000079_0001
[0394] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0395] In some embodiments, the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof,
Figure imgf000079_0002
[0396] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0397] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000080_0001
[0398] wherein R1, R2, R3, R10, Ra, Rb, B, X, Z1, Z2, Z3, Z4, Z5, n, p, and q are as described herein. [0399] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000080_0002
[0400] wherein R2, R3, R10, R11, Ra, Rb, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0401] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000081_0001
XIII [0402] wherein R2, R3, R10, R11, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, p, and q are as described herein. [0403] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000081_0002
XIV [0404] wherein R2, R10, R11, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and q are as described herein. [0405] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
Figure imgf000082_0001
XV [0406] wherein R2, R3, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0407] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000082_0002
XVI [0408] wherein R2, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0409] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000083_0001
[0410] wherein R2, R3, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0411] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000084_0001
XVIII [0412] wherein R2, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0413] In some embodiments, the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000084_0002
XIX [0414] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0415] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
Figure imgf000085_0001
[0416] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0417] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
Figure imgf000085_0002
XXI [0418] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0419] In some embodiments, the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof,
Figure imgf000086_0001
XXII [0420] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0421] In some embodiments, the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000086_0002
XXIII [0422] wherein R2, R3, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0423] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000087_0001
XXIV [0424] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0425] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
Figure imgf000087_0002
XXV [0426] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0427] In some embodiments, the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000088_0001
XXVI [0428] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0429] In some embodiments, the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000088_0002
XXVII [0430] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0431] In some embodiments, the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000089_0001
[0432] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0433] In some embodiments, the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000089_0002
[0434] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0435] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
Figure imgf000090_0001
XXX [0436] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0437] In some embodiments, Y is -S(O)2- or –C(O)NR10-. In some embodiments, Y is -S(O)2- . In some embodiments, Y is –C(O)NR10-. In some embodiments, Y is -S(O)2- or –C(O)NR10- , and R1 is ring A. In some embodiments, Y is -S(O)2-, and R1 is ring A. In some embodiments, Y is or –C(O)NR10-, and R1 is ring A. In some embodiments, Y is -O-, -S-, -S(O)-, or -S(O)2- and R1 is ring A. In some embodiments, Y is -O-, -S-, or -S(O)- , and R1 is ring A. In some embodiments, Y is -O-, and R1 is ring A. In some embodiments, Y is -S-, and R1 is ring A. In some embodiments, Y is -S(O)- , and R1 is ring A. In some embodiments, Y is a bond, and R1 is ring A. [0438] In some embodiments, ring A is a C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each of C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R11. In some embodiments, ring A is an unsubstituted C3-C8 cycloalkyl, or a C3-C8 cycloalkyl substituted with one or more of R11. In some embodiments, ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with one or more of R11. In some embodiments, ring A is an unsubstituted C6-C10 aryl, or a C6-C10 aryl substituted with one or more of R11. In some embodiments, ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10- membered heteroaryl substituted with one or more of R11. [0439] In some embodiments, ring A is a C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein each of C3-C8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 of R11. In some embodiments, ring A is an unsubstituted C3-C8 cycloalkyl, or a C3-C8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R11. In some embodiments, ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R11. In some embodiments, ring A is an unsubstituted C6-C10 aryl, or a C6-C10 aryl substituted with 1, 2, 3, 4, 5, or 6 of R11. In some embodiments, ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R11. [0440] In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl that is not an unsubstituted or a substituted ring of the formula
Figure imgf000091_0001
[0441] In some embodiments, A is 4- to 10-membered heterocycloalkylthat is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments, ring A is a 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a fused bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bridged bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments, ring A is a spiro bicyclic 6- to 10-membered heterocycloalkyl. [0442] In some embodiments, Ring A is
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
wherein * is a point of covalent attachment to
Figure imgf000094_0002
, and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. [0443] In some embodiments, Ring A is is of the formula
Figure imgf000094_0003
Figure imgf000095_0004
, or , [0444] wherein * is a point of covalent attachment to
Figure imgf000095_0001
[0445] In some embodiments, Ring A is
Figure imgf000095_0002
[0446] wherein * is a point of covalent attachment to and m is 0 or one
Figure imgf000095_0003
or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. [0447] In some embodiments, Ring A is azitidinyl, oxtenanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro-1H-pyrrolyl, pyrazolidinyl, thiazolidinyl, 4,5-dihydro-1H- imidazolyl, dihydrothiophen-2(3H)-onyl, tetrahydrothiophenyl 1,1-dioxide, imidazolidin-2- onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, 1,3-dioxolan-2-onyl, oxazolidin-2-onyl, piperidinyl, morpholinyl, 4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3- oxazinan-2-onyl, piperazin-2-onyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, 3,8- diazabycyclo[3.2.1]octanyl, or (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, wherein each hydrogen atom in azitidinyl, oxtenanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro- 1H-pyrrolyl, pyrazolidinyl, thiazolidinyl, 4,5-dihydro-1H-imidazolyl, dihydrothiophen-2(3H)- onyl, tetrahydrothiophenyl 1,1-dioxide, imidazolidin-2-onyl, pyrrolidin-2-onyl, dihydrofuran- 2(3H)-onyl, 1,3-dioxolan-2-onyl, oxazolidin-2-onyl, piperidinyl, morpholinyl, 4H-1,4- thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3-oxazinan-2-onyl, piperazin-2-onyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, 3,8-diazabycyclo[3.2.1]octanyl, or (1R,5S)- 3,8-diazabicyclo[3.2.1]octanyl, is independently optionally substituted by an R11. [0448] In some embodiments, Ring A is
Figure imgf000096_0001
Figure imgf000097_0001
[0449] wherein * is a point of covalent attachment t
Figure imgf000097_0002
[0450] In some embodiments, Ring A is
Figure imgf000097_0003
Figure imgf000098_0001
[0451] wherein * is a point of covalent attachment to
Figure imgf000098_0002
[0452] In some embodiments, Ring A is
Figure imgf000099_0001
Figure imgf000100_0001
[0453] wherein * is a point of covalent attachment to
Figure imgf000100_0002
[0454] In some embodiments, Ring A is
Figure imgf000100_0003
[0455] wherein * is a point of covalent attachment to
Figure imgf000100_0004
[0456] In some embodiments, each R11 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, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, - C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, - P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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 two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0457] In some embodiments, each R11 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, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, - Re, -Rf, 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, -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; wherein each Ra, Rb, Re, and Rf, is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1- C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; or two of Ra and Rb, or Re and Rf, taken together with the atom or atoms to which they are attached, combine to form a 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, 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(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, or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group. [0458] In some embodiments, m is 0. In some embodiments, m is one or more. 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 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0459] In some embodiments, ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl, optionally substituted with one or more R2, R12, or R13. In some embodiments, ring B is a C3- C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl optionally substituted with one or more R2, R12, or R13. [0460] In some embodiments, Ring B is
Figure imgf000102_0001
[0461] wherein wherein * is a point of covalent attachment to , n is 0 or
Figure imgf000102_0002
one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0462] In some embodiments, Ring B is
Figure imgf000103_0001
[0463] wherein wherein * is a point of covalent attachment to , n is 0 or
Figure imgf000103_0002
one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0464] In some embodiments, Ring B is
Figure imgf000103_0003
[0465] wherein wherein * is a point of covalent attachment to
Figure imgf000103_0004
, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0466] In some embodiments, Ring B is
Figure imgf000103_0005
[0467] wherein wherein * is a point of covalent attachment to , n is 0 or
Figure imgf000103_0006
one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0468] In some embodiments, Ring B is
Figure imgf000104_0001
[0469] wherein wherein * is a point of covalent attachment to n is 0 or
Figure imgf000104_0002
one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0470] In some embodiments, Ring B is
Figure imgf000104_0003
[0471] wherein wherein * is a point of covalent attachment to
Figure imgf000104_0004
, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0472] In some embodiments, Ring B is
Figure imgf000104_0005
[0473] wherein wherein * is a point of covalent attachment to , n is 0 or
Figure imgf000104_0006
one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0474] In some embodiments, Ring B is
Figure imgf000104_0007
[0475] wherein wherein * is a point of covalent attachment to
Figure imgf000105_0001
, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0476] In some embodiments, Ring B is
Figure imgf000105_0002
[0477] wherein wherein * is a point of covalent attachment to
Figure imgf000105_0003
, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0478] In some embodiments, Ring B is
Figure imgf000105_0004
[0479] wherein wherein * is a point of covalent attachment to
Figure imgf000105_0005
n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0480] In some embodiments, 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 atoms 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, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each R2 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc, or - CN. In some embodiments, each R2, when present, is independently selected from the group consisting of fluoro, chloro, C1-C6 alkyl, -OH, and -CN. In some embodiments, each R2, when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -C≡CH, -CN, and -OH. [0481] In some embodiments, R12 is 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, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, - NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. In some embodiments, R12 is H, deuterium, or C1-C6 alkyl. In some embodiments, R12 is H, deuterium, or methyl. [0482] In some embodiments, R13 is 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, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, - NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. In some embodiments, R13 is H, deuterium, or C1-C6 alkyl. In some embodiments, R13 is H, deuterium, or methyl. [0483] In some embodiments, n is 0. In some embodiments, n is one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. 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 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0484] In some embodiments, Ring B is
Figure imgf000107_0001
[0485] wherein
Figure imgf000107_0002
“ ” is a point of covalent attachment. [0486] In some embodiments, Ring B is
Figure imgf000107_0003
Figure imgf000108_0001
[0487] wherein “ ” is a point of covalent attachment. [0488] In some embodiments, Ring B is of the formula
Figure imgf000108_0002
[0489] wherein “ ” is a point of covalent attachment.
Figure imgf000108_0003
[0490] In some embodiments, q is 0. In some embodiments, q is 1. [0491] In some embodiments, -X- is -O-, -S-, or–NR4-. In some embodiments, -X- is -O-. In some embodiments, -X- is -S-. In some embodiments, -X- is –NR4-. [0492] In some embodiments, R4 is 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, -Re, -Rf, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, - NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, - P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe’, -CN, or -NO2. In some embodiments, R4 is H, deuterium, or C1-C6 alkyl. In some embodiments, R4 is H, deuterium, or methyl. [0493] In some embodiments, R3 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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. [0494] In some embodiments, R3 is -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1- C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(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, 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. [0495] In some embodiments, R3 is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 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, 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. [0496] In some embodiments, R3 is
Figure imgf000110_0001
[0497] wherein
Figure imgf000110_0003
is a point of covalent attachment. [0498] In some embodiments, R3 is
Figure imgf000110_0002
[0499] wherein “
Figure imgf000111_0001
is a point of covalent attachment. [0500] In some embodiments, R3 is
Figure imgf000111_0002
[0501] wherein “
Figure imgf000111_0003
” is a point of covalent attachment. [0502] In some embodiments, R3 is –C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C1-C6 alkyl-(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. [0503] In some embodiments, R3 is of the formula
Figure imgf000111_0004
[0504] wherein wherein
Figure imgf000111_0005
” is a point of covalent attachment, and 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, 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. [0505] In some embodiments, R3 is of the formula
Figure imgf000111_0006
[0506] wherein wherein
Figure imgf000112_0001
is a point of covalent attachment, and 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, 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. [0507] In some embodiments, R3, when present, is of the formula
Figure imgf000112_0002
[0508] wherein
Figure imgf000112_0003
is a point of covalent attachment. [0509] In some embodiments, R3, when present, is of the formula
Figure imgf000112_0004
[0510] wherein
Figure imgf000112_0005
is a point of covalent attachment. [0511] In some embodiments, 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; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a 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, 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, or Re and Rf taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl. [0512] In some embodiments, Z1 is N. In some embodiments, Z2 is N. In some embodiments, Z3 is N. In some embodiments, Z4 is N. In some embodiments, Z5 is N. In some embodiments, Z6 is N. In some embodiments, Z7 is N. In some embodiments, Z1 is C(R5). In some embodiments, Z2 is C(R6). In some embodiments, Z3 is C(R7). In some embodiments, Z4 is C(R8). In some embodiments, Z5 is C(R9). In some embodiments, Z6 is C(R14). In some embodiments, Z7 is C(R15). In some embodiments, any of the possible combinations of Z1-Z7 can be combined as embodiemnts. In some embodiments, Z6 is N or C(R14). In some embodiments, Z7 is N or C(R15). In some embodiments, Z1 is N, and Z2 is N. In some embodiments, Z1 is N, Z2 is N, Z3 is C(R7), Z4 is N, and Z5 is C(R9). In some embodiments, Z1 is N, Z2 is N, Z3 is C(R7), Z4 is C(R8), and Z5 is C(R9). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is N, and Z5 is C(R9). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is C(R8), and Z5 is C(R9). In some embodiments, Z1 is N, Z2 is N, Z3 is C(R7), Z4 is C(R8), and Z5 is N. In some embodiments, Z1 is N, Z2 is N, Z3 is C(R7), Z4 is N, and Z5 is N. In some embodiments, Z1 is N, Z2 is N, Z3 is C(R7), Z4 is N, and Z5 is C(R9). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is C(R8), and Z5 is C(R9). In some embodiments, Z1 is N, Z2 is N, Z3 is N, Z4 is N, and Z5 is N. [0513] In some embodiments, each of R5, R6, R7, R8, R9, R14, and R15 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 [0514] In some embodiments, R5, when present, is H. In some embodiments, R6, when present, is H. In some embodiments, R7, when present, is H or F. In some embodiments, R8, when present, is H. In some embodiments, R9, when present, is H. In some embodiments, R14, when present, is H. In some embodiments, R15, when present, is H. [0515] In some embodiments, the disclosure provides a compound selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0516] 3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-ol; [0517] (3S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3- ol; [0518] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(4-fluoropiperidin-1-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol; [0519] 5-ethynyl-6-fluoro-4-[8-fluoro-4-(8-fluoro-3-azabicyclo[3.2.1]octan-3-yl)-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol; [0520] (1R,5S,8S)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]-3-azabicyclo[3.2.1]octan-8-ol; [0521] (3R,4R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-4- fluoropiperidin-3-ol; [0522] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0523] 4-[4-(azetidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0524] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0525] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3R)-3-methoxypyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0526] 4-[4-(azepan-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0527] 4-[4-(2-azabicyclo[2.2.1]heptan-2-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0528] 4-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0529] (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidine- 3-carbonitrile; [0530] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0531] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl]-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0532] (2R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-N-(propan- 2-yl)piperidine-2-carboxamide; [0533] 4-[4-(8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0534] 4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0535] 4-[2-(1,7-diazaspiro[4.4]nonan-7-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0536] 4-{2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0537] (3S)-3-{[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl]amino}-N,5-dimethylhexanamide; [0538] (2R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-N- methylpiperidine-2-carboxamide; [0539] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; [0540] 5,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0541] 7-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,3-benzothiazol-2-amine; [0542] 4-[4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0543] 5-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0544] 8-chloro-7-fluoro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]isoquinolin-3-amine; [0545] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0546] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3S)-3-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0547] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3R)-3-methoxypiperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0548] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3S)-3-methoxypiperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0549] 4-[4-(3-ethoxypiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0550] 2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}- 6-(piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carbonitrile; [0551] (4R)-2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-6-(piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7- tetrahydro-1-benzothiophene-3-carbonitrile; [0552] (4S)-2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-6-(piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7- tetrahydro-1-benzothiophene-3-carbonitrile; [0553] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(3R)-3-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0554] 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0555] 7-(4-chloro-1H-indol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; [0556] 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0557] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2H10)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0558] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0559] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- (2H3)methylpiperidin-3-ol; [0560] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- (2H3)methylpiperidin-3-ol; [0561] (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0562] 7-ethynyl-6-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1H-indazol-3- amine; [0563] 7-ethynyl-6-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1H-indazol-3- amine; [0564] (1R)-4-chloro-3-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl](1-2H)-1H-inden-1-ol; [0565] 8-ethynyl-7-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]isoquinolin-3- amine; [0566] 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- amine; [0567] 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0568] 5-ethynyl-6-fluoro-4-{8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7- yl}naphthalen-2-ol; [0569] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2R)-2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0570] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(2S)-2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0571] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(2R)-2-(hydroxymethyl)piperidin-1-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; [0572] 5-ethynyl-6-fluoro-4-(8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)meth}oxy)-4-[(2S)-2-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; [0573] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[3-(methoxymethyl)-2-methyl-2,4,5,6-tetrahydro-7H- pyrazolo[3,4-b]pyridin-7-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0574] 4-[4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5- ethynyl-6-fluoronaphthalen-2-ol; [0575] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(3aR,7aR)-hexahydrofuro[2,3-c]pyridin-6(2H)-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; [0576] 1-{(4aS,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- ({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3- d]pyrimidin-4-yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; [0577] N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-yl}-N-methylacetamide; [0578] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(5S)-2-oxa-6-azaspiro[4.5]decan-6-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; [0579] (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]- 2,6-diazaspiro[4.5]decan-3-one; [0580] 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(4R,5S)-4-fluoro-1-methyl-1,7- diazaspiro[4.4]nonan-7-yl]-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; and [0581] 4-{2-[(3S)-3-(dimethylamino)-3-(fluoromethyl)pyrrolidin-1-yl]-8-fluoro-4-(piperidin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0582] or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a compound selected from the groups consisting of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0583] 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0584] 5-ethyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0585] 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0586] 5-chloro-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0587] 4-[6-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; [0588] 5-ethynyl-6-fluoro-4-[8-fluoro-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0589] N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin- 3-yl}-N-methylacetamide; [0590] (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6- diazaspiro[4.5]decan-3-one; [0591] (5R)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6- diazaspiro[4.5]decan-3-one; [0592] 1-{(4aR,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; [0593] 1-{(4aS,7aS)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; [0594] (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0595] 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-methylnaphthalen-2-ol; [0596] 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0597] (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; [0598] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-amine; [0599] 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0600] 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0601] 7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidine; [0602] 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0603] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{3-[(methanesulfonyl)methyl]piperidin-1-yl}pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol; [0604] 4-{2-[(2S,4S)-4-(dimethylamino)-2-methylpyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; [0605] 1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,2-dihydro-3H-indol-3-one; [0606] 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0607] 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3-methylpiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0608] 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0609] 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0610] 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6- fluoronaphthalen-2-ol; [0611] 4-[4-(5-chloro-2,3-dihydro-1H-indol-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; [0612] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; [0613] 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-5-methoxy-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol; [0614] 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; and [0615] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[3-(methoxymethyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4- b]pyridin-7-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol, [0616] or a pharmaceutically acceptable salt thereof. [0617] The following represent illustrative embodiments of compounds of Formula (I):
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
and pharmaceutically acceptable salts thereof. [0618] 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 [0619] 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. [0620] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions. [0621] 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. [0622] 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. [0623] 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. [0624] 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. [0625] 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. [0626] 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. [0627] 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. [0628] 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. [0629] The term “subject” refers to a mammalian patient in need of such treatment, such as a human. [0630] 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. [0631] 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. [0632] 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. [0633] 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). [0634] 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 [0635] 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. [0636] 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 [0637] 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)-(XXX). [0638] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0002
[0639] The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below. [0640] Scheme I
Figure imgf000148_0001
[0641] The general scheme I is used to prepare the products with general structure Ex. X. The bicyclic aryl core I-1-1 and a variety of amines I-2 are either commercially available or prepared via conventional chemistry from commercially available materials. A: under basic condition such as diisopropylethyl amine (DIPEA) in dichloromethane at reduced temperature such as -40oC, compound I-1-1 and amine I-2 are converted to a product I-3. B: under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 oC, compound I-3 and an amine or alcohol I-4 are converted to a product I-5. C: under palladium-catalyzed Suzuki coupling condition, compound I-5 and a boronic ester I-6 are converted to a product which is de-protected, if required, to provide the final product Ex.
Figure imgf000149_0001
[0643] The general scheme II is used to prepare the products with general structure Ex. X. The bicyclic aryl core I-1-1, a variety of amines I-2, I-4 and boronic ester or acid are either commercially available or prepared via conventional chemistry from commercially available materials. A: 2,2,2-trifluoroethanol is deprotonated with a base such as NaH in an appropriate solvent such as 2-me-THF and then reacted with I-1-1 in dichloromethane at reduced temperature such as -40oC to a product II-1. B: under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 oC, compound II-1 and an amine or alcohol I-4 are converted to a product II-2. C: under palladium-catalyzed Suzuki coupling condition, compound II-2 and a boronic ester I-6 are converted to II-3. D: under basic condition, such as CsF in DMF, the amine I-2 will react with II-3 to provide a product which is deprotected, if required, to afford the final product Ex. X. [0644] Preparation of 3-azabicyclo[3.2.1]octan-8-yloxy-tert-butyl-diphenyl-silane (I-3-2)
Figure imgf000149_0002
[0645] Step 1. To a mixture of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 4.44 mmol, 1 eq) in MeOH (10 mL) was added NaBH4 (168 mg, 4.44 mmol, 1 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hour. On completion, the reaction mixture was quenched by addition of sat. aqueous NH4Cl (10 mL) and mixture was filtered. The filtrate was diluted with H2O (5 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give to afford tert-butyl 8-hydroxy-3- azabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 4.40 mmol, 99% yield) as a white solid. [0646] Step 2. To a mixture of tert-butyl 8-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (600 mg, 2.64 mmol, 1 eq) and imidazole (359 mg, 5.28 mmol, 2 eq) in DCM (8 mL) was added TBDPSCl (798 mg, 2.90 mmol, 746 uL, 1.1 eq) at 0 °C slowly. The mixture was stirred at 25 °C for 12 hours. On completion, the residue was purified by flash silica gel chromatography to afford tert-butyl 8-[tert-butyl(diphenyl)silyl]oxy-3- azabicyclo[3.2.1]octane-3-carboxylate (900 mg, 1.93 mmol, 73% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 7.62 - 7.57 (m, 4H), 7.36 - 7.25 (m, 6H), 3.86 (t, J = 5.2 Hz, 1H), 3.67 - 3.56 (m, 1H), 3.54 - 3.38 (m, 3H), 1.85 - 1.61 (m, 2H), 1.43 - 1.34 (m, 13H), 1.02 (s, 9H). [0647] Step 3. To a mixture of tert-butyl 8-[tert-butyl(diphenyl)silyl]oxy-3- azabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 2.15 mmol, 1 eq) in DCM (10 mL) was added HCl/EtOAc (4 M, 2 mL, 3.73 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to afford 3- azabicyclo[3.2.1]octan-8-yloxy-tert-butyl-diphenyl-silane (890 mg, crude, HCl) as a yellow solid. LCMS: m/z 366.1 (M+1). [0648] The following TBDPS hydroxy piperidine derivatives were prepared using similar methods as I-3-2:
Figure imgf000150_0001
[0649] Preparation of 8-fluoro-3-azabicyclo[3.2.1]octane (I-6-2). [0650]
Figure imgf000150_0002
[0651] Step 1. To a mixture of tert-butyl 8-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (100 mg, 0.440 mmol, 1 eq.) in toluene (1 mL) was added DBU (201 mg, 1.32 mmol, 3 eq) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (199 mg, 0.660 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate= 2:1) to afford tert-butyl 8-fluoro-3-azabicyclo[3.2.1]octane-3-carboxylate (50.0 mg, 0.218 mmol, 49 % yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 4.84 - 4.58 (m, 1H), 4.04 - 3.78 (m, 2H), 2.99 - 2.75 (m, 2H), 2.35 (s, 2H), 1.95 - 1.77 (m, 2H), 1.62 - 1.51 (m, 2H), 1.46 (s, 8H). [0652] Step 2. To a mixture of tert-butyl 8-fluoro-3-azabicyclo[3.2.1]octane-3-carboxylate (50.0 mg, 0.218 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 0.2 mL, 3.67 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to afford compound 8-fluoro-3-azabicyclo[3.2.1]octane (80.0 mg, crude) as a yellow oil which was used directly in the next step. [0653] Preparation of 1-(methoxymethyl)-3-azabicyclo [3.2.1] octane (I-17-2)
Figure imgf000151_0001
[0654] Step 1. To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.2.1]octane-3- carboxylate (200 mg, 0.829 mmol, 1 eq) in DMF (4 mL) at 0 °C was added NaH (49.7 mg, 1.24 mmol, 60% purity, 1.5 eq) and the mixture was stirred for 0.5 h followed by addition of MeI (176 mg, 1.24 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was slowly added to water (30 mL), extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 1-(methoxymethyl)-3- azabicyclo[3.2.1]octane-3-carboxylate (130 mg, 509 umol, 61.4% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 3.93 - 3.68 (m, 2H), 3.33 (s, 3H), 3.28 (s, 2H), 2.88 - 2.67 (m, 2H), 2.22 (d, J = 16.4 Hz, 1H), 1.79 - 1.63 (m, 2H), 1.53 (d, J = 11.2 Hz, 2H), 1.45 (s, 9H), 1.43 - 1.38 (m, 2H) [0655] Step 2. To a solution of tert-butyl 1-(methoxymethyl)-3-azabicyclo [3.2.1]octane-3- carboxylate (130 mg, 0.509 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL, 7.86 eq) at 0 °C, and then the mixture was stirred at 0-25 °C for 1h. On completion, the reaction mixture was concentrated in vacuo to give 1-(methoxymethyl)-3-azabicyclo [3.2.1] octane (110 mg, crude) as a white oil.1H NMR (400 MHz, CDCl3) δ = 3.63 (s, 1H), 3.25 - 3.22 (m, 3H), 3.22 - 3.19 (m, 2H), 3.19 - 3.08 (m, 2H), 3.04 - 2.86 (m, 2H), 2.43 - 2.31 (m, 1H), 2.09 - 1.97 (m, 3H), 1.58 - 1.43 (m, 3H) [0656] [0657] General Method A [0658] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol (Ex.1)
Figure imgf000152_0001
[0659] Step 1. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (0.70 g, 2.77 mmol, 1 eq) in DCM (30 mL) was added TEA (1.40 g, 13.9 mmol, 5 eq) at -40 °C followed by addition of a solution of piperidine (260 mg, 3.05 mmol, 1.1 eq) in DCM (4 mL) under N2. The mixture was stirred at -40 °C for 1 hour and partitioned between DCM (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 2,7-dichloro-8-fluoro-4-(1-piperidyl)pyrido[4,3- d]pyrimidine (680 mg, crude) as a white solid. LCMS: m/z 300.9 (M+1). [0660] Step 2. To a solution of 2,7-dichloro-8-fluoro-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (610 mg, 2.03 mmol, 1 eq) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (645 mg, 4.05 mmol, 2 eq) in dioxane (7 mL) was added DIEA (785 mg, 6.08 mmol, 3 eq). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was partitioned between EtOAc (10 mL* 2) and H2O (15 mL). The organic phase was separated, washed with brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 7-chloro-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1- piperidyl)pyrido[4,3-d]pyrimidine (620 mg, 1.46 mmol, 72.2% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.71 (s, 1H), 5.41 - 5.04 (m, 1H), 4.32 - 4.22 (m, 1H), 4.19 - 4.09 (m, 1H), 3.86 – 3.92 (m, 4H), 3.28 - 3.20 (m, 2H), 3.19 - 3.12 (m, 1H), 3.03 - 2.88 (m, 1H), 2.22 - 2.08 (m, 2H), 1.99 - 1.91 (m, 2H), 1.87 - 1.72 (m, 8H). [0661] Step 3. To a solution of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (620 mg, 1.46 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 (900 mg, 1.76 mmol, 1.2 eq) in dioxane (7 mL) and H2O (1.4 mL) was added Cs2CO3 (1.43 g, 4.39 mmol, 3 eq), and ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (95.3 mg, 0.146 mmol, 0.1 eq) under N2. The mixture was stirred at 100 °C for 12 hours. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (200 mg, 0.258 mmol, 17.7% yield) as a black brown oil.1H NMR (400 MHz, CDCl3) δ = 9.02 (s, 1H), 7.85 - 7.71 (m, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.32 - 7.28 (m, 1H), 5.31 - 5.28 (m, 2H), 3.92 ( d, J = 3.2 Hz, 6H), 3.52 - 3.51 (m, 1H), 3.53 - 3.49 (m, 2H), 3.27 - 3.14 (m, 3H), 3.03 - 2.95 (m, 1H), 2.23 - 2.11 (m, 2H), 1.86 - 1.75 (m, 8H), 1.61 (s, 6H), 1.42 - 1.16 (m, 18H). [0662] Step 4. To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (180 mg, 0.233 mmol, 1 eq) in DCM (2 mL) was added HCl/Dioxane (4 M, 0.3 mL, 5.16 eq). The mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue (200 mg, crude) was used for next step directly as a yellow solid. LCMS: m/z 730.5 (M+1). [0663] Step 5. To a solution of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (180 mg, 0.247 mmol, 1 eq) in DMSO (1.5 mL) was added CsF (187 mg, 1.23 mmol, 5 eq). The mixture was stirred at 25 °C for 0.5 hour. The resulting mixture was filtered and the filtrate was purified by prep-HPLC to give Ex.1 (33 mg, 0.0521 mmol, 21.1% yield) as a yellow solid. [0664] General Method B [0665] Preparation of (3R,4R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin- 4-yl]-4-fluoropiperidin-3-ol (Ex.8) [0666]
Figure imgf000154_0001
[0667] Step 1. To a solution of 2,2,2-trifluoroethanol (1.19 g, 11.9 mmol, 1.0 eq) in 2- MeTHF (10 mL) was added NaH (713 mg, 17.8 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. Then the mixture was added to the solution of 2,4,7- trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (3.00 g, 11.9 mmol, 1.0 eq) in 2-Me-THF (20 mL) at -40 °C. The mixture was stirred at -40 °C for 1 hr, quenched with sat. aqueous NH4Cl (30 mL), and extracted with ethyl acetate (25 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was triturated with PE at 25 oC for 30 min and filtered to give 2,7-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.52 g, 7.51 mmol, 63.2% yield) as an off-white solid.1H NMR (400 MHz, CDCl3) δ = 9.18 (s, 1H), 7.37 - 7.36 (m, 1H), 5.09 (q, J = 8.0 Hz, 2H). [0668] Step 2. To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (2.30 g, 7.28 mmol, 1.0 eq) in dioxane (20 mL) was added DIEA (1.88 g, 14.6 mmol, 2.0 eq) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (1.27 g, 8.01 mmol, 1.1 eq). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was then partitioned between EtOAc (10 mL* 2) and H2O (15 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (2.00 g, 4.56 mmol, 62.6% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.99 (s, 1H), 5.40 - 5.22 (m, 1H), 5.02 (q, J = 8.0 Hz, 2H), 4.40 - 4.34 (m, 2H), 3.35 - 3.26 (m, 2H), 3.24 - 3.19 (m, 1H), 3.01 (dt, J = 5.6, 9.6 Hz, 1H), 2.26 (dd, J = 10.0, 14.4 Hz, 2H), 2.17 - 2.10 (m, 2H), 2.01 - 1.96 (m, 2H). [0669] Step 3. A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.80 g, 4.10 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.15 g, 6.15 mmol, 1.5 eq), K3PO4 (2.61 g, 12.3 mmol, 3.0 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (299 mg, 0.410 mmol, 0.1 eq) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere in microwave. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (2.31 g, 2.49 mmol, 60.7% yield) was obtained as a brown oil.1H NMR (400 MHz, CDCl3) δ = 9.24 (s, 1H), 7.80 (dd, J = 6.0, 9.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.32 (s, 1H), 7.31 - 7.28 (m, 1H), 5.33 - 5.28 (m, 2H), 5.18 - 5.09 (m, 1H), 5.05 - 4.91 (m, 2H), 4.44 - 4.26 (m, 2H), 3.51 (s, 3H), 3.29 - 3.24 (m, 2H), 3.20 - 3.15 (m, 1H), 2.99 (td, J = 4.8, 9.2 Hz, 1H), 2.22 - 2.07 (m, 3H), 1.96 (td, J = 6.0, 11.6 Hz, 3H), 0.87 (d, J = 7.6 Hz, 9H), 0.84 (d, J = 7.6 Hz, 9H), 0.58 - 0.49 (m, 3H). LCMS: m/z 789.5 (M+1). [0670] Step 4. To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (100 mg, 0.126 mmol, 1.0 eq) in DMF (2 mL) was added K2CO3 (87.6 mg, 0.634 mmol, 5.0 eq) and (3R,4R)-4- fluoropiperidin-3-ol (39.5 mg, 0.254 mmol, 2.0 eq, HCl salt). The mixture was stirred at 80 °C for 3 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 5 (3R,4R)-4- fluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3- d]pyrimidin-4-yl]piperidin-3-ol (60.0 mg, 0.0609 mmol, 48.0% yield) was obtained as a colorless oil. LCMS: m/z 808.3 (M+1). [0671] Step 5. To a solution of (3R,4R)-4-fluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (60.0 mg, 0.743 mmol, 1.0 eq) in DCM (10 mL) was added HCl/Dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 1 h and concentrated to give (3R,4R)-4-fluoro-1-[8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-hydroxy-8- (2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (100 mg, crude) as a yellow solid. LCMS: m/z 764.3 (M+1). [0672] Step 6. To a solution of (3R,4R)-4-fluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (100 mg, 0.131 mmol, 1.0 eq) in DMSO (2 mL) was added CsF (99.4 mg, 0.655 mmol, 5.0 eq). The mixture was stirred at 25 °C for 2 hr. The residue was purified by prep-HPLC to give (3R,4R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-4-fluoro- piperidin-3-ol (Ex.8, 8.27 mg, 0.12 mmol, 9.18% yield, formic acid salt) was obtained as a yellow solid. [0673] The following examples were made following General Method A or B as indicated in the Table:
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
[0674] General Method C [0675] Preparation of 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl- 6-fluoronaphthalen-2-ol (Ex.71)
Figure imgf000172_0001
[0676] Step 1. A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.80 g, 4.10 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.15 g, 6.15 mmol, 1.5 eq), K3PO4 (2.61 g, 12.3 mmol, 3.0 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (299 mg, 0.410 mmol, 0.1 eq) in dioxane (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere in microwave. The mixture was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 0/1) to give 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (2.31 g, 2.49 mmol, 60.7% yield) as a brown oil.1H NMR (400 MHz, CDCl3) δ = 9.24 (s, 1H), 7.80 (dd, J = 6.0, 9.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.32 (s, 1H), 7.31 - 7.28 (m, 1H), 5.33 - 5.28 (m, 2H), 5.18 - 5.09 (m, 1H), 5.05 - 4.91 (m, 2H), 4.44 - 4.26 (m, 2H), 3.51 (s, 3H), 3.29 - 3.24 (m, 2H), 3.20 - 3.15 (m, 1H), 2.99 (td, J = 4.8, 9.2 Hz, 1H), 2.22 - 2.07 (m, 3H), 1.96 (td, J = 6.0, 11.6 Hz, 3H), 0.87 (d, J = 7.6 Hz, 9H), 0.84 (d, J = 7.6 Hz, 9H), 0.58 - 0.49 (m, 3H); LCMS: m/z 789.5 (M+1). [0677] Step 2. To a mixture of 3-azabicyclo[3.1.1]heptane (8.62 mg, 0.0645 mmol, 1.45 eq, HCl) and 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (35.0 mg, 0.0443 mmol, 1 eq) in DMF (1 mL) was added K2CO3 (18.3 mg, 0.133 mmol, 3 eq). The resulting mixture was stirred at 80 °C for 1 h. On completion, the reaction mixture was partitioned between ethyl acetate (2 mL × 3) and water (4 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE/THF=1:0 to 2:1) to give 2-[8-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahy dropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-2-fluoro-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (50.0 mg, crude) as yellow solid. LCMS: m/z 786.2 (M+1). [0678] Step 3. To a solution of 2-[8-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7- yl]-2-fluoro-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (50.0 mg, 0.064 mmol, 1 eq) and DCM (1 mL) was added HCl/dioxane (4 M, 0.206 mL, 13 eq), the resulting mixture was stirred at 23 °C for 1.5 h. On completion, the mixture was concentrated to give 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (40.0 mg, 53.9 umol, 84% yield) as yellow solid. LCMS: m/z : 742.3 (M+1). [0679] Step 4. The mixture of 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro- 5-(2-triisopropylsilylethynyl)naphthalen-2-ol (40.0 mg, 1 eq) and CsF (57.3 mg, 7 eq) in DMSO (1 mL) was stirred at 40 °C for 12 h. On completion, the mixture was filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC purification (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(TFA)-ACN];B%: 20%- 50%,10min) to give Ex.71 TFA salt (8.31 mg, 26% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.28 - 10.12 (m, 1H), 9.49 (s, 1H), 7.99 (dd, J = 5.6, 9.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 5.66 - 5.46 (m, 1H), 4.68 - 4.54 (m, 2H), 4.39 - 4.17 (m, 4H), 3.95 (s, 1H), 3.92 - 3.70 (m, 5H), 3.35 - 3.23 (m, 2H), 2.35 - 2.31 (m, 1H), 2.27 - 2.10 (m, 5H), 2.09 - 1.98 (m, 1H), 1.53 - 1.45 (m, 2H); LCMS: m/z 586.2 (M+1). [0680] General Method D [0681] Preparation of 5-ethyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.72)
Figure imgf000174_0001
[0682] Step 1. A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (100 mg, 0.236 mmol, 1 eq), 2-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (121 mg, 0.354 mmol, 1.5 eq), Ad2nBuP Pd G3 (17.2 mg, 0.0236 mmol, 0.1 eq), K3PO4 (150 mg, 0.708 mmol, 3 eq) in THF (2 mL) and H2O (0.4 mL) was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give 7-[8-ethyl-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- (1-piperidyl)pyrido[4,3-d]pyrimidine (105 mg, 0.174 mmol, 73% yield) as a white solid. LCMS: m/z 605.0 (M+1). [0683] Step 2. To a solution of 7-[8-ethyl-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3- d]pyrimidine (105 mg, 0.174 mmol, 1 eq) in DCM (9 mL) was added HCl/dioxane (1 mL). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by Prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (FA)- CAN]; B%: 21%-51%, 9min) to give Ex.72 formic acid salt (71.4 mg, 73% yield) as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ = 9.04 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 5.58 – 5.39 (m, 1H), 4.61 – 4.55 (m, 1H), 4.54 – 4.48 (m, 1H), 4.07 (s, 4H), 3.86 – 3.59 (m, 3H), 2.66 – 2.43 (m, 2H), 2.43 – 2.18 (m, 6H), 2.14 – 2.03 (m, 1H), 1.85 (s, 6H), 0.89 (dt, J = 1.2, 7.6 Hz, 3H); LCMS: m/z 560.4 (M+1). [0684] Preparation of 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.73)
Figure imgf000175_0001
[0685] Ex.73 was prepared following a similar procedure as General Method D.1H NMR (400 MHz, DMSO-d6) δ = 10.31 (s, 1H), 9.08 (s, 1H), 7.87 - 7.82 (m, 1H), 7.44 - 7.35 (m, 3H), 7.14 (d, J = 2.4 Hz, 1H), 5.66 - 5.47 (m, 1H), 4.64 - 4.53 (m, 2H), 4.03 - 3.92 (m, 4H), 3.88 - 3.74 (m, 2H), 2.26 - 2.10 (m, 4H), 2.09 - 1.99 (m, 2H), 1.76 (s, 7H), 1.23 (s, 1H). LCMS: m/z 566.4 (M+1). [0686] Preparation of 5-chloro-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol (Ex.74)
Figure imgf000176_0001
[0687] Step 1. To a solution of [5-chloro-6-fluoro-4-(trifluoromethylsulfonyloxy)-2- naphthyl] acetate (50.0 mg, 0.129 mmol, 1 eq) in THF (1 mL) and H2O (0.5 mL) was added LiOH.H2O (16.3 mg, 0.388 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1h. On completion, the mixture was quenched with HCl (1N, 5 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=3:1) to give (8-chloro-7-fluoro-3-hydroxy-1-naphthyl) trifluoromethanesulfonate (50 mg, crude) as a white solid. [0688] Step 2. To a mixture of (8-chloro-7-fluoro-3-hydroxy-1-naphthyl) trifluoromethanesulfonate (50.0 mg, 0.145 mmol, 1 eq) and DIEA (56.3 mg, 0.435 mmol, 3 eq) in DCM (0.5 mL) was added MOMCl (23.0 mg, 0.285 mmol, 1.97 eq) at 0 °C, the mixture was stirred at 0°C for 1 h. On completion, the mixture was quenched with sat. NH4Cl (1 mL) and extracted with DCM (0.5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give [8-chloro-7-fluoro-3- (methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (45.1 mg, 0.116 mmol, 80 % yield) as a colorless oil. [0689] Step 3. To a solution of [8-chloro-7-fluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (24.0 mg, 0.0617 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (23.5 mg, 0.0926 mmol, 1.5 eq) in METHOXY-CYCLOPENTANE (0.7 mL) was added KOAc (24.2 mg, 0.247 mmol, 4 eq) and dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane; methanesulfonate;[2-[2- (methylamino)phenyl]phenyl]palladium(1+) (5.68 mg, 0.00617 umol, 0.1 eq) was stirred at 80 °C for 3 h under N2. On completion, the mixture was filtered and concentrated. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate=5:1) to give 2-[8-chloro-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (18 mg, 0.0491 mmol, 79 % yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.64 (dd, J = 5.2, 9.2 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.32 - 7.29 (m, 1H), 5.32 - 5.28 (m, 2H), 3.51 (s, 3H), 1.46 (s, 12H). [0690] Ex.74 was then prepared following similar reaction conditions as in General Method D to give a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.44 - 10.18 (m, 1H), 9.09 (s, 1H), 7.96 (dd, J = 5.6, 9.2 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1H),7.44 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 5.66 - 5.48 (m, 1H), 4.66 - 4.52 (m, 2H), 3.98 (s, 4H), 3.92 - 3.66 (m, 4H), 3.32 (s, 1H), 2.69 - 2.55 (m, 1H), 2.37 - 2.29 (m, 1H), 2.24 - 2.11 (m, 2H), 2.09 - 1.98 (m, 1H), 1.76 (s, 6H). LCMS: m/z 584.3 (M+1). [0691] Preparation of 4-[6-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-(piperidin-1-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.75)
Figure imgf000178_0001
[0692] Step 1. A mixture of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (200 mg, 0.605 mmol, 1.2 eq), DIEA (391 mg, 3.03 mmol, 6 eq) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then piperidine (43.0 mg, 0.504 mmol, 1 eq) was added to the mixture at -40 °C. The mixture was stirred at -40 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 7-bromo-2,6-dichloro-8-fluoro-4-(1-piperidyl)quinazoline (205 mg, 0.475 mmol, 94% yield) as a yellow solid. LCMS: m/z 379.7 (M+1). [0693] Ex.75 was then prepared following similar reaction conditions as Steps 2-5 in General Method A to give an off-white solid.1H NMR (400 MHz, MeOD-d4) δ = 7.84 (dd, J = 5.6, 9.2 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.34 - 7.27 (m, 2H), 7.04 (d, J = 2.4 Hz, 1H), 5.41 - 5.21 (m, 1H), 4.33 - 4.18 (m, 2H), 3.90 - 3.83 (m, 4H), 3.27 (d, J = 4.0 Hz, 1H), 3.25 - 3.18 (m, 2H), 2.31 (brd, J = 6.4 Hz, 4H), 2.04 - 1.97 (m, 2H), 1.83 (br s, 6H), 1.36 - 1.26 (m, 2H). LCMS: m/z 607.3 (M+1). [0694] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-(1-methyl-1,7-diazaspiro[4.4]nonan- 7-yl)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.116)
Figure imgf000179_0001
[0695] Step 1. To a solution of 2,7-dichloro-8-fluoro-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (300 mg, 0.996 mmol, 1 eq) in dioxane (6 mL) was added tert-butyl 1,7- diazaspiro[4.4]nonane-1-carboxylate (270 mg, 1.20 mmol, 1.2 eq) and DIEA (257 mg, 1.99 mmol, 2 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was concentrated and purified by column chromatography (SiO2, PE:THF=1:0 to 5:1) to give tert- butyl 7-[7-chloro-8-fluoro-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-1,7- diazaspiro[4.4]nonane-1-carboxylate (480 mg, 98% yield) as a yellow solid. LCMS: m/z 490.8 (M+1). [0696] Step 2. The mixture of tert-butyl 7-[7-chloro-8-fluoro-4-(1-piperidyl)pyrido[4,3- d]pyrimidin -2-yl]-1,7-diazaspiro[4.4]nonane-1-carboxylate (280 mg, 0.570 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 (438 mg, 0.855 mmol, 1.5 eq) in THF (4 mL) was added K3PO4 (1.5 M, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(1+);bis (1-adamantyl)-butyl- phosphane; methanesulfonate (41.5 mg, 0.057 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 N2 atmosphere. On completion, the mixture was filtered, concentrated, and purified by column chromatography (SiO2, PE:THF=1:0 to 4:1) to give tert-butyl 7-[8-fluoro-7- [7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-1,7- diazaspiro[4.4]nonane-1-carboxylate (380 mg, 79% yield) as a yellow solid. LCMS: m/z 841.4 (M+1). [0697] Step 3. To the solution of tert-butyl 7-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-1,7- diazaspiro[4.4]nonane-1-carboxylate (150 mg, 0.178 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 20 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 4-[2-(1,7-diazaspiro[4.4] nonan-7-yl)-8-fluoro-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2- ol HCl salt (130 mg, 99% yield) as a yellow solid. LCMS: m/z 697.4 (M+1). [0698] Step 4. To the mixture of 4-[2-(1,7-diazaspiro[4.4]nonan-7-yl)-8-fluoro-4-(1- piperidyl)pyrido [4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2- ol HCl salt (130 mg, 0.177 mmol, 1 eq) and HCHO (26.6 mg, 0.886 mmol, 5 eq) in MeOH (1.5 mL) was added AcOK (173 mg, 1.77 mmol, 10 eq). The mixture was stirred at 25 °C for 0.2 h followed by addition of NaBH3CN (33.4 mg, 0.531 mmol, 3 eq). The mixture was stirred at 25 °C for 12 h, quenched with water (0.2 mL), and concentrated. The residue was purified by column chromatography (SiO2, PE:THF=1:0 to 1:3) to give 6-fluoro-4-[8-fluoro- 2-(1- methyl-1,7-diazaspiro[4.4]nonan-7-yl)-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5- (2-triisopropylsilylethynyl)naphthalen-2-ol (126 mg, 99% yield) as a white solid. LCMS: m/z 711.4 (M+1). [0699] Ex.76 was then prepared following similar reaction conditions as Step 4 in General Method A to give a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.34 - 10.12 (m, 1H), 8.84 (s, 1H), 8.01 - 7.95 (m, 1H), 7.47 (t, J = 8.8 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.20 (s, 1H), 4.03 (s, 2H), 3.85 (s, 6H), 3.75 - 3.65 (m, 2H), 3.37 - 3.22 (m, 1H), 2.80 (s, 3H), 2.35 - 2.16 (m, 2H), 2.15 - 1.95 (m, 4H), 1.75 (s, 6H). LCMS: m/z 555.3 (M+1). [0700] General Method E [0701] Preparation of N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin- 4-yl]piperidin-3-yl}-N-methylacetamide (Ex.77)
Figure imgf000181_0001
[0702] Step 1. The mixture of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydrop yrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]- 6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (150 mg, 0.190 mmol, 1 eq), tert-butyl N-methyl-N-[(3R)-3-piperidyl]carbamate (40.8 mg, 0.190 mmol, 1 eq), K2CO3 (131 mg, 0.951 mmol, 5 eq) in DMF (3 mL) was stirred at 80 °C for 2 hours. On completion, the mixture was diluted by ethyl acetate (50 mL) and washed with brine (50 mL). The organic layers were combined, dried by sodium sulfate, and filtered. The filtrated was concentrated in vacuo and purified by column chromatography (SiO2, petroleum ether : ethyl acetate=1:0 to 1:1) to give tert-butyl N-[(3R)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]-N-methyl- carbamate (140 mg, 0.155 mmol, 81.5% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.15 - 9.05 (m, 1H), 8.17 - 8.06 (m, 1H), 7.80 - 7.70 (m, 1H), 7.60 - 7.52 (m, 1H), 7.38 - 7.31 (m, 1H), 5.36 (s, 2H), 4.58 - 4.36 (m, 2H), 4.07 - 3.91 (m, 3H), 3.43 (s, 3H), 3.28 (s, 8H), 2.80 (d, J = 9.2 Hz, 7H), 1.48 - 1.38 (m, 9H), 1.17 (t, J = 7.2 Hz, 2H), 0.91 - 0.78 (m, 21H), 0.50 (qd, J = 7.2, 15.2 Hz, 3H). LCMS: m/z 903.4 (M+1). [0703] Step 2. A mixture of tert-butyl N-[(3R)-1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3-piperidyl]-N-methyl- carbamate (50 mg, 0.0554 mmol, 1 eq), HCl/dioxane (4 M, 0.0138 mL, 1 eq) in DCM (1 mL) was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated under reduced pressure to give a 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]meth oxy]-4-[(3R)-3-(methylamino)-1-piperidyl]pyrido[4,3- d]pyrimidin-7-yl]-5-(2-triiso propylsilylethynyl)naphthalen-2-ol (40 mg, 0.0527 mmol, 95.2% yield) as a brown solid. LCMS: m/z 759.4 (M+1). [0704] Step 3. The mixture of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-[(3R)-3-(methylamino)-1-piperidyl]pyrido[4,3- d]pyrimidin-7-yl]-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (40 mg, 0.0527 mmol, 1 eq), CsF (40.0 mg, 0.264 mmol, 5 eq) in DMSO (2 mL) was stirred at 25 °C for 12 hours. On completion, the mixture was diluted by ethyl acetate (50 mL) and water (50 mL). The separated organic layer was washed by brine (50 mL), dried by sodium sulfate, filtered and concentrated in vacuo to give the compound 5-ethynyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-[(3R)-3-(methylamino)-1- piperidyl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (30 mg, 0.0498 mmol, 94.5% yield) as a yellow solid. LCMS: m/z 603.4 (M+1). [0705] Step 4. A mixture of 5-ethynyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-[(3R)-3-(methylamino)-1-piperidyl]pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol (30 mg, 0.0498 mmol, 1 eq), Ac2O (5.08 mg, 0.0498 mmol, 1 eq), TEA (15.1 mg, 0.149 mmol, 3 eq) in DCM (1 mL) was stirred at 25 °C for 1 hour. On completion, the mixture was diluted by dichloromethane (50 mL) and water (50 mL). The separated organic layer was washed with brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo to give [4-[4-[(3R)-3-[acetyl(methyl)amino]-1-piperidyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-2-naphthyl] acetate (30 mg, 0.0437 mmol, 87.8% yield) as a yellow solid. LCMS: m/z 687.3 (M+1). [0706] Step 5. The mixture of [4-[4-[(3R)-3-[acetyl(methyl)amino]-1-piperidyl]-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7- yl]-5-ethynyl-6-fluoro-2-naphthyl] acetate (30 mg, 0.0437 mmol, 1 eq), K2CO3 (18.1 mg, 0.131 mmol, 3 eq) in MeOH (2 mL) was stirred at 25 °C for 1 hour. On completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Ultimate C18150*25 mm*5 um; mobile phase: [water(FA)-ACN]; B%: 14%-44%, 10 min) to give Ex.77 formic acid salt (1.15 mg, 3.81% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.12 - 8.97 (m, 1H), 8.40 - 8.39 (m, 1H), 7.95 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (br t, J = 8.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.23 - 7.14 (m, 1H), 5.37 - 5.14 (m, 1H), 4.63 - 4.45 (m, 1H), 4.44 - 4.34 (m, 1H), 4.33 - 4.19 (m, 1H), 4.12 (br d, J = 10.8 Hz, 1H), 4.04 - 3.88 (m, 2H), 3.49 (br s, 3H), 3.07 (br d, J = 9.2 Hz, 3H), 3.01 - 2.97 (m, 1H), 2.93 (d, J = 2.8 Hz, 2H), 2.87 - 2.77 (m, 2H), 2.14 - 2.08 (m, 1H), 2.05 - 1.89 (m, 5H), 1.85 - 1.71 (m, 4H). LCMS: m/z 645.4 (M+1). [0707] Preparation of (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]-2,6-diazaspiro[4.5]decan-3-one (Ex.78) and (5R)-6-[7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6-diazaspiro[4.5]decan-3-one (Ex.79)
Figure imgf000183_0001
[0708] Ex.78 and 79 were prepared following similar reaction conditions as in General Method A starting with racemic 2,6-diazaspiro[4.5]decan-3-one to give the following arbitrarily assigned diastereomers that were separated by HPLC: (5S)-6-[7-(8-ethynyl-7- fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6-diazaspiro[4.5]decan-3-one (10.1 mg, 23% yield) 1
Figure imgf000184_0001
H NMR (499 MHz, DMSO-d6 ) δ = 10.80 (br d, J = 1.1 Hz, 1H), 10.60 - 9.92 (m, 1H), 9.07 (s, 1H), 7.99 (dd, J = 5.9, 9.2 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.23 - 7.17 (m, 1H), 5.75 - 5.54 (m, 1H), 4.59 - 4.51 (m, 2H), 3.92 - 3.84 (m, 3H), 3.80 - 3.74 (m, 2H), 3.72 - 3.66 (m, 1H), 3.57 - 3.49 (m, 1H), 3.41 (br dd, J = 4.1, 10.1 Hz, 1H), 3.31 (br s, 1H), 2.97 - 2.86 (m, 1H), 2.69 - 2.60 (m, 1H), 2.45 - 2.31 (m, 2H), 2.30 - 2.12 (m, 3H), 2.12 - 2.03 (m, 2H), 2.01 - 1.95 (m, 1H), 1.84 - 1.70 (m, 4H); LCMS: m/z 643.0 (M+1) and (5R)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl]-2,6-diazaspiro[4.5]decan-3-one (8.6 mg, 19.6% yield) 1H NMR (499 MHz, DMSO-d6 ) δ = 10.79 (br d, J = 5.5 Hz, 1H), 10.48 - 9.93 (m, 1H), 9.07 (s, 1H), 7.99 (dd, J = 5.9, 9.2 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.21 - 7.17 (m, 1H), 5.74 - 5.54 (m, 1H), 4.60 - 4.53 (m, 2H), 4.11 - 3.95 (m, 1H), 3.89 - 3.85 (m, 2H), 3.81 - 3.76 (m, 2H), 3.76 - 3.63 (m, 2H), 3.59 - 3.47 (m, 1H), 3.41 (br dd, J = 4.1, 9.9 Hz, 1H), 3.31 (br s, 1H), 2.97 - 2.85 (m, 2H), 2.68 - 2.56 (m, 1H), 2.47 - 2.29 (m, 2H), 2.24 - 2.03 (m, 4H), 1.85 - 1.72 (m, 4H); LCMS: m/z 643.0 (M+1). [0709] General Method F [0710] Preparation of 1-{(4aR,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl]octahydro-6H-pyrrolo[3,4-b]yrrolid-6-yl}ethan-1-one (Ex.80) and 1- {(4aS,7aS)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]octahydro- 6H-pyrrolo[3,4-b]yrrolid-6-yl}ethan-1-one (Ex.81)
Figure imgf000185_0001
[0711] Step 1. To a mixture of tert-butyl 1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine- 6- carboxylate (460 mg, 2.03 mmol, 2 eq) and 7-chloro-8-fluoro-2-[[(2R,8S)-2- fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (445 mg, 1.02 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (421 mg, 3.05 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL X 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE:THF=1:0 to 2:1) to give tert-butyl 1-[7-chloro-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4- b]pyridine-6-carboxylate (415 mg, 72% yield) as a yellow oil. LCMS: m/z 565.1 (M+1). [0712] Step 2. To a mixture of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl - 1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (523 mg, 1.02 mmol, 1.5 eq) and tert-butyl 1-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4- b]pyridine-6-carboxylate (385 mg, 0.681 mmol, 1 eq) in THF (6 mL) was added K3PO4 (1.5 M, 1.36 mL, 3 eq) and [2-(2-aminophenyl)phenyl] palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanesulfonate (49.6 mg, 0.0681 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 N2 atmosphere. On completion, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE:THF=1:0 to 2:1) to give tert-butyl 1-[8- fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7- [7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]- 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-6-carboxylate (540 mg, 86% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 9.15 - 9.00 (m, 1H), 8.13 - 8.07 (m, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.35 (d, J = 10.4 Hz, 1H), 5.75 (s, 1H), 5.36 (s, 3H), 5.27 - 4.95 (m, 1H), 4.45 - 3.98 (m, 3H), 3.84 - 3.69 (m, 1H), 3.43 (s, 3H), 3.22 - 3.11 (m, 3H), 2.90 - 2.83 (m, 1H), 2.21 - 1.99 (m, 4H), 1.94 - 1.77 (m, 5H), 1.60 - 1.47 (m, 2H), 1.44 - 1.39 (m, 9H), 1.35 (s, 3H), 0.85 - 0.79 (m, 18H), 0.52 - 0.43 (m, 3H). [0713] Step 3. To a solution of tert-butyl 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,4,4a,5,7,7a-hexahydro- 2H-pyrrolo[3,4-b]pyridine-6-carboxylate (400 mg, 0.437 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 1.19 mL, 10.8 eq). The mixture was stirred at 25 °C for 1 h, and concentrated to give 4-[4-(2,3,4,4a,5,6,7,7a- octahydropyrrolo[3,4-b]pyridin-1-yl)-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin- 7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2-ol HCl salt (352 mg, 99% yield) as a yellow solid. LCMS: m/z 771.4 (M+1). [0714] Step 4. To a solution of 4-[4-(2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b]pyridin-1-yl)- 8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (352 mg, 0.437 mmol, 1 eq, HCl) in DCM (4 mL) was added Ac2O (111 mg, 1.09 mmol, 2.5 eq) and TEA (221 mg, 2.19 mmol, 5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h, quenched with water (10 mL), and extracted with DCM (10 mL X 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give [4-[4-(6-acetyl- 3,4,4a,5,7,7a-hexahydro-2H-pyrrolo [3,4-b]pyridin-1-yl)-8-fluoro-2- [[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)-2-naphthyl] acetate (400 mg, crude) as orange oil. LCMS: m/z 855.4 (M+1). [0715] Step 5. To a solution of [4-[4-(6-acetyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4- b]pyridin-1- yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)-2-naphthyl] acetate (200 mg, 0.233 mmol, 1 eq) in DMSO (4 mL) was added CsF (177 mg, 1.17 mmol, 5 eq). The mixture was stirred at 40 °C for 12 h, filtered, and concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(TFA)-ACN];B%: 12%-42%,10min) followed by purification with SFC (column: REGIS (R,R)WHELK-O1(250mm*25mm, 10 um);mobile phase: [ACN/EtOH(0.1%NH3H2O)];B%: 60%-60%,A3;30min) to give the arbitrarily assigned diastereomer Ex.80 or Ex.81 (14.83 mg, 7% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.23 - 10.11 (m, 1H), 9.09 - 8.95 (m, 1H), 8.02 - 7.93 (m, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.23 - 7.14 (m, 1H), 5.38 - 4.99 (m, 2H), 4.41 - 4.25 (m, 1H), 4.19 - 4.10 (m, 1H), 4.08 - 3.96 (m, 2H), 3.90 - 3.82 (m, 1H), 3.69 - 3.42 (m, 3H), 3.12 - 3.06 (m, 2H), 3.02 (s, 1H), 2.88 - 2.78 (m, 1H), 2.14 (s, 1H), 2.07 (d, J = 6.0 Hz, 1H), 2.00 (d, J = 6.8 Hz, 2H), 1.96 (d, J = 2.8 Hz, 2H), 1.87 - 1.76 (m, 5H), 1.57 - 1.48 (m, 1H), 1.27 - 1.18 (m, 2H), 0.88 - 0.76 (m, 1H); LCMS: m/z 657.3 (M+1). Another diastereomer Ex.81 or Ex.80 was also obtained from SFC purification (3.93 mg, 1% yield, 97% purity). 1H NMR (400 MHz, MeOD-d4) δ = 9.13 - 9.02 (m, 1H), 7.91 - 7.86 (m, 1H), 7.38 - 7.32 (m, 2H), 7.25 - 7.19 (m, 1H), 5.67 - 5.27 (m, 2H), 4.73 - 4.65 (m, 2H), 4.54 - 4.44 (m, 1H), 4.04 - 3.84 (m, 5H), 3.73 - 3.65 (m, 2H), 3.58 - 3.42 (m, 4H), 2.64 - 2.55 (m, 2H), 2.47 - 2.41 (m, 1H), 2.37 - 2.29 (m, 2H), 2.16 - 2.09 (m, 4H), 2.04 - 1.97 (m, 2H), 1.91 - 1.83 (m, 1H), 1.72 - 1.64 (m, 1H); LCMS: m/z 657.3 (M+1). [0716] Preparation of (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]-3-methylpiperidin-3-ol (Ex.82)
Figure imgf000188_0001
[0717] Ex.82 was prepared following similar reaction conditions as in General Method C. 1H NMR (400 MHz, DMSO-d6 ) δ = 10.21 (br d, J = 6.0 Hz, 1H), 9.37 - 9.12 (m, 1H), 7.99 (dd, J = 6.0, 8.8 Hz, 1H), 7.54 - 7.35 (m, 2H), 7.21 (dd, J = 2.4, 17.6 Hz, 1H), 5.68 - 5.46 (m, 1H), 4.65 - 4.53 (m, 2H), 4.52 - 4.37 (m, 1H), 4.17 (br d, J = 13.2 Hz, 1H), 4.05 (br d, J = 14.0 Hz, 1H), 3.91 (s, 1H), 3.75 (br s, 4H), 3.66 - 3.60 (m, 2H), 3.35 - 3.24 (m, 3H), 2.25 - 2.12 (m, 2H), 2.11 - 1.97 (m, 2H), 1.77 - 1.59 (m, 3H), 1.18 (br d, J = 16.4 Hz, 3H); LCMS: m/z 604.3 (M+1). [0718] Preparation of 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-methylnaphthalen-2-ol (Ex. 83) and 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-
Figure imgf000188_0002
Figure imgf000188_0003
[0719] Step 1. To a mixture of 7-[8-chloro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2- [[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1- piperidyl)pyrido[4,3-d]pyrimidine (60.0 mg, 0.983 mmol, 1 eq, the intermediate for the preparation of Ex.73) and potassium trifluoro(methyl)boranuide (239 mg, 1.97 mmol, 20 eq) in dioxane (3.6 mL) and H2O (0.7 mL) was added Pd(OAc)2 (2.21 mg, 0.00983 mmol, 0.1 eq), bis(1-adamantyl)-butyl-phosphane (7.05 mg, 0.0196 mmol, 0.2 eq) and Cs2CO3 (96.1 mg, 0.295 mmol, 3 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 100 °C for 2 h under N2 atmosphere. On completion, the mixture was filtered, concentrated, and purified by column chromatography (SiO2, PE:THF=1:0 to 1:3) to give a crude product. The crude product was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 45%- 45%,C5.5;39min) to give 8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (10.0 mg, 16% yield) as a colorless oil; LCMS: m/z 576.2 (M+1) and 8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methoxy]-7- [3-(methoxymethoxy)-8-methyl-1- naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (10.0 mg, 15% yield) as colorless oil. LCMS: m/z 590.2 (M+1). [0720] Step 2. To a solution of 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]-7-[3-(methoxymethoxy)-8-methyl-1-naphthyl]-4-(1- piperidyl)pyrido[4,3-d]pyrimidine (10.0 mg, 16.9 umol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.100 mL, 23 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated and purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(TFA)-ACN];B%: 22%-52%,8min) to give Ex.83 TFA salt (2.33 mg, 20% yield) as a white solid.1H NMR (400 MHz, DMSO-d6 ) δ = = 10.02 - 9.88 (m, 1H), 9.12 - 9.08 (m, 1H), 7.68 (br d, J = 8.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.06 (br d, J = 6.4 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 5.66 - 5.49 (m, 1H), 4.64 - 4.53 (m, 2H), 3.98 (br s, 4H), 3.91 - 3.82 (m, 3H), 3.38 - 3.24 (m, 2H), 2.37 - 2.29 (m, 1H), 2.23 - 2.12 (m, 2H), 2.09 - 2.00 (m, 1H), 1.87 (s, 3H), 1.81 - 1.72 (m, 7H); LCMS: m/z 546.4 (M+1). [0721] 8-Fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[3- (methoxymethoxy)-1-naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine was converted to Ex. 84 following a similar procedure. H NMR (400 MHz, DMSO-d6 ) δ = = 10.15 - 9.91 (m, 1H), 9.19 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.53 (br d, J = 8.0 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.33 - 7.21 (m, 3H), 5.67 - 5.49 (m, 1H), 4.66 - 4.55 (m, 2H), 4.00 (br s, 4H), 3.85 (br d, J = 17.6 Hz, 3H), 3.35 - 3.25 (m, 1H), 2.36 - 2.30 (m, 1H), 2.23 - 2.11 (m, 2H), 2.10 - 2.01 (m, 1H), 1.77 (br s, 7H); LCMS: m/z 532.5 (M+1). [0722] Preparation of (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl]-3-methylpiperidin-3-ol (Ex.85)
Figure imgf000190_0001
[0723] Ex.85 was prepared following similar procedure to step 1 in General Method F and steps 1-2 in General Method D.1H NMR (400 MHz, METHANOL-d4 ) δ = 9.25 (s, 1H), 7.68 (dd, J = 6.0, 8.8 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 5.58 - 5.39 (m, 1H), 4.63 - 4.55 (m, 2H), 4.54 - 4.46 (m, 1H), 4.33 (br t, J = 12.0 Hz, 1H), 3.71 - 3.57 (m, 4H), 3.50 - 3.39 (m, 1H), 2.52 - 2.39 (m, 3H), 2.36 - 2.28 (m, 1H), 2.26 - 2.11 (m, 5H), 1.90 - 1.72 (m, 4H), 1.29 (d, J = 8.8 Hz, 4H), 0.87 - 0.74 (m, 3H). LCMS: m/z 608.3 (M+1). [0724] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- amine (Ex 86)
Figure imgf000191_0001
[0725] Step 1. To a solution of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (800 mg, 1.10 mmol, 1 eq) in DCM (20 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (587 mg, 1.64 mmol, 1.5 eq) and DIEA (283 mg, 2.19 mmol, 2 eq), DMAP (26.7 mg, 0.219 mmol, 0.2 eq). The mixture was stirred at 25 °C for 3 h. On completion, the mixture was concentrated in vacuo and purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3:1 to 1:1) to give [6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl] methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2-triisopropylsilylethynyl)-2- naphthyl] trifluoromethanesulfonate (800 mg, 0.928 mmol, 85% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.49 (d, J = 2.8 Hz, 1H), 8.39 (dd, J = 6.0, 9.2 Hz, 1H), 7.84 – 7.75 (m, 2H), 5.41 – 5.21 (m, 1H), 4.18 – 4.08 (m, 2H), 4.05 – 3.97 (m, 2H), 3.92 (s, 4H), 3.20 – 3.09 (m, 3H), 3.08 – 3.02 (m, 1H), 2.92 – 2.81 (m, 2H), 2.19 – 2.00 (m, 4H), 1.94 – 1.84 (m, 2H), 1.77 (s, 5H), 0.84 (dd, J = 7.2, 10.4 Hz, 18H). [0726] Step 2. A mixture of [6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)-2-naphthyl] trifluoromethanesulfonate (750 mg, 0.870 mmol, 1 eq) Pd2(dba)3 (79.6 mg, 0.087 mmol, 0.1 eq), Cs2CO3 (793 mg, 2.44 mmol, 2.8 eq), tert-butyl carbamate (244 mg, 2.09 mmol, 2.4 eq) and Xantphos (151 mg, 0.261 mmol, 0.3 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. On completion, the mixture was concentrated in vacuo and purified by column chromatography (SiO2, DCM/MeOH=20:1 to 10:1) to give tert-butyl N-[6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2-triisopropylsilylethynyl)-2- naphthyl] carbamate (650 mg, 0.784 umol, 90% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.86 - 9.76 (m, 1H), 9.07 - 8.98 (m, 1H), 8.30 - 8.19 (m, 1H), 8.12 - 8.02 (m, 1H), 7.62 - 7.54 (m, 2H), 6.14 (d, J = 4.8 Hz, 3H), 5.46 - 5.18 (m, 1H), 3.95 - 3.87 (m, 4H), 3.58 - 3.55 (m, 1H), 3.20 - 3.01 (m, 3H), 2.85 (d, J = 6.4 Hz, 1H), 2.19 - 2.00 (m, 3H), 1.82 - 1.70 (m, 8H), 1.50 (s, 9H), 0.83 (dd, J = 7.6, 11.2 Hz, 18H), 0.53 - 0.47 (m, 2H). [0727] The final steps were performed using procedures similar to the final steps in General procedure A to give Ex.85 formic acid salt (20.36 mg, 30% yield) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ = 9.01 - 8.92 (m, 1H), 8.15 (s, 1H), 7.82 - 7.73 (m, 1H), 7.38 - 7.28 (m, 1H), 7.10 - 7.01 (m, 1H), 5.71 - 5.57 (m, 2H), 5.39 - 5.19 (m, 1H), 4.17 - 4.00 (m, 2H), 3.97 - 3.85 (m, 5H), 3.14 - 3.01 (m, 3H), 2.89 - 2.79 (m, 1H), 2.18 - 1.98 (m, 3H), 1.89 - 1.71 (m, 9H). LCMS: m/z 573.2 (M+H). [0728] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (Ex.87)
Figure imgf000192_0001
[0729] Ex.87 was prepared following the procedures of General Method C using (3R)-3- fluoropiperidine.1H NMR (400 MHz, DMSO-d6) δ = 10.73 - 9.81 (m, 1H), 9.04 (d, J = 12.0 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.50 - 7.43 (m, 1H),7.41 - 7.37 (m, 1H), 7.24 - 7.17 (m, 1H), 5.40 - 5.18 (m, 1H), 5.11 - 4.92 (m, 1H), 4.43 - 4.30 (m, 1H), 4.29 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 4.07 - 3.96 (m, 2H), 3.95 - 3.82 (m, 2H), 3.63 - 3.57 (m, 2H), 3.11 - 3.07 (m, 2H), 3.02 (s, 1H), 2.08 - 1.94 (m,5H), 1.89 - 1.71 (m, 4H). LCMS: m/z 592.3 (M+1). [0730] Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (Ex.88)
Figure imgf000193_0001
[0731] Ex.88 was prepared following the procedures of General Method C using (3R)-3- fluoropiperidine and the appropriate boronic ester.1H NMR (400 MHz, DMSO-d6) δ = 10.73 - 9.81 (m, 1H), 9.04 (d, J = 12.0 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.50 - 7.43 (m, 1H),7.41 - 7.37 (m, 1H), 7.24 - 7.17 (m, 1H), 5.40 - 5.18 (m, 1H), 5.11 - 4.92 (m, 1H), 4.43 - 4.30 (m, 1H), 4.29 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 4.07 - 3.96 (m, 2H), 3.95 - 3.82 (m, 2H), 3.63 - 3.57 (m, 2H), 3.11 - 3.07 (m, 2H), 3.02 (s, 1H), 2.08 - 1.94 (m,5H), 1.89 - 1.71 (m, 4H). LCMS: m/z 592.3 (M+1). [0732] Preparation of 7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidine (Ex.89)
Figure imgf000193_0002
[0733] To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (7.8 mg, 0.00989 mmol) and piperidine (4.21 mg, 0.0494 mmol) in DMF (0.12 mL) was added Cesium fluoride (9.01 mg, 0.0593 mmol) at 23 °C was stirred for 2 hr. After completion, the mixture was poured into water (1 mL), and extracted with DCM (3 x 5 mL). The combined organic phases were washed with water (2 x 5 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by using preparative HPLC (C18, 0- 100% MeCN in water with 0.035% TFA) to Ex.89 TFA salt (4.01 mg, 53.40% yield).1H NMR (600 MHz, DMSO-d6 ) δ = 10.86 (br d, J = 1.9 Hz, 1H), 9.06 (s, 1H), 8.12 (dd, J = 5.9, 9.2 Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.57 (t, J = 8.9 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 5.64 - 5.51 (m, 1H), 5.39 (d, J = 1.0 Hz, 2H), 4.66 - 4.54 (m, 2H), 4.01 (d, J = 0.8 Hz, 1H), 4.00 - 3.93 (m, 4H), 3.91 - 3.80 (m, 4H), 3.45 (s, 3H), 2.60 - 2.53 (m, 1H), 2.50 - 2.48 (m, 1H), 2.37 - 2.29 (m, 1H), 2.23 - 2.14 (m, 2H), 2.10 - 2.00 (m, 1H), 1.78 (br s, 6H). LCMS: m/z 618.0 (M+1). [0734] Preparation of 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5- ethynyl-6-fluoronaphthalen-2-ol (Ex.90)
Figure imgf000194_0001
[0735] Ex.90 was prepared following the procedures of General Method A starting with 3,3- difluoropiperidine.1H NMR (400 MHz, DMSO-d6) δ = 10.25 - 10.07 (m, 1H), 9.06 (s, 1H), 7.99 (dd, J = 6.0, 8.9 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H),7.41 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.38 - 5.21 (m, 1H), 4.33 - 4.11 (m, 2H), 4.03 - 3.86 (m, 3H), 3.13 - 3.07 (m,2H), 3.03 (s, 1H), 2.84 (d, J = 6.01H), 2.30 - 2.21 (m, 2H), 2.14 (s, 1H), 2.08 - 1.98 (m, 4H), 1.89 - 1.76 (m, 3H). LCMS: m/z 612.3 (M+1). [0736] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-{3-[(methanesulfonyl)methyl]piperidin-1-yl}pyrido[4,3- d]pyrimidin-7-yl)naphthalen-
Figure imgf000194_0002
[0737] Ex.91 was prepared following the procedures of General Method A starting with racemic 33-[(Methylsulfonyl)methyl]piperidine.1H NMR (400 MHz, DMSO-d6 ) δ = 10.41 - 9.93 (m, 1H), 9.05 - 8.96 (m, 1H), 8.20 - 8.15 (m, 1H), 7.96 (dd, J = 5.9, 9.2 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.39 - 7.35 (m, 1H), 7.21 - 7.15 (m, 1H), 5.37 - 5.15 (m, 1H), 4.73 - 4.53 (m, 1H), 4.43 - 4.26 (m, 1H), 4.19 - 4.00 (m, 2H), 3.98 - 3.86 (m, 1H), 3.19 - 3.13 (m, 2H), 3.07 - 2.97 (m, 6H), 2.85 - 2.77 (m, 1H), 2.18 - 1.93 (m, 5H), 1.87 - 1.66 (m, 5H), 1.62 - 1.46 (m, 1H). LCMS: m/z 666.3 (M+1). [0738] Preparation of 4-{2-[(2S,4S)-4-(dimethylamino)-2-methylpyrrolidin-1-yl]-8-fluoro-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.92)
Figure imgf000195_0001
[0739] Step 1. To a solution of 2,7-dichloro-8-fluoro-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (220 mg, 0.730 mmol, 1 eq) in dioxane (5 mL) was added DIEA (94.4 mg, 0.730 mmol, 1 eq) and tert-butyl N-[(3S,5S)-5-methylpyrrolidin-3-yl]carbamate (219 mg, 1.10 mmol, 1.5 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was concentrated and purified by column chromatography (SiO2, PE/THF=3:1 to 3:1) to give tert-butyl N- [(3S,5S)-1-[7-chloro-8-fluoro-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-5-methyl- pyrrolidin-3-yl]carbamate (330 mg, 0.709 mmol, 97% yield) as a white solid. LCMS: m/z 465.2 (M+1). [0740] Step 2. To a solution of tert-butyl N-[(3S,5S)-1-[7-chloro-8-fluoro-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-5-methyl-pyrrolidin-3-yl]carbamate (310 mg, 0.666 mmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 1 mL, 6.20 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give crude (3S,5S)- 1-[7-chloro-8-fluoro-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-5-methyl-pyrrolidin-3- amine HCl salt (300 mg) as a white solid. LCMS: m/z 365.1 (M+1). [0741] Step 3. To a solution of (3S,5S)-1-[7-chloro-8-fluoro-4-(1-piperidyl)pyrido[4,3- d]pyrimidin-2-yl]-5-methyl-pyrrolidin-3-amine (300 mg, 0.822 mmol, 1 eq) in MeOH (5 mL) was added HCHO (123 mg, 4.11 mmol, 5 eq) and AcOK (806 mg, 8.22 mmol, 10 eq). The mixture was stirred for 0.5 h followed by addition of NaBH3CN (51.6 mg, 0.822 mmol, 1 eq) at 0 °. The mixture was stirred at 25 °C for 12 h. On completion, water（2 ml）was added and the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give (3S,5S)-1-[7-chloro-8-fluoro-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-N,N,5-trimethyl-pyrrolidin-3-amine (198 mg, 0.503 umol, 61% yield) as a yellow solid. LCMS: m/z 393.2 (M+1). [0742] The remaining steps were performed with procedures similar to those of General Method A to give Ex.92 (34.0 mg, 48% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.82 - 8.66 (m, 1H), 8.19 (s, 1H), 7.95 (dd, J = 6.0, 9.1 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H),7.36 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 4.44 - 4.32 (m, 1H), 4.04 - 3.97 (m, 1H), 3.78 (br s, 4H), 3.33 - 3.22 (m, 2H),3.00 - 2.90 (m, 1H), 2.19 (s, 6H), 2.00 - 1.86 (m, 2H), 1.73 (br s, 6H), 1.37 - 1.24 (m, 3H). LCMS: m/z 543.2 (M+1). [0743] Preparation of 1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,2-dihydro-3H-indol-3-one (Ex.93)
Figure imgf000197_0001
[0744] Step 1. To a solution of 1H-indol-3-yl acetate (248 mg, 1.42 mmol, 2.00 eq) in dioxane (4.50 mL) was added 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (300 mg, 0.708 mmol, 1 eq), Cs2CO3 (461 mg, 1.42 mmol, 2 eq) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (68.9 mg, 0.0708 mmol, 0.1 eq). The mixture was stirred at 90 °C for 16 h under N2 atmosphere. On completion, the mixture was concentrated in reduced pressure and purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give [1-[8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3- d]pyrimidin-7-yl]indol-3-yl] acetate (0.207 g, 0.368 mmol, 52% yield) as a brown solid. LCMS: m/z 563.3 (M+1). [0745] Step 2. To a solution of 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl] methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]indol-3-yl] acetate (200 mg, 0.355 mmol, 1 eq) in H2O (1.50 mL) and EtOH (1.50 mL) was added Na2SO3 (112 mg, 0.888 mmol, 2.5 eq). The mixture was stirred at 70 °C for 48 h. On completion, the mixture was concentrated under vacuum and purified by prep-HPLC purification (column: Phenomenex Luna C18150*25mm*10um;mobile phase:[water(FA)- ACN];B%: 10%-40%,8min) to give Ex.93 (1.00 mg, 1.43% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.86 - 10.43 (m, 1H), 8.99 - 8.88 (m, 1H), 7.85 - 7.76 (m, 1H), 7.43 - 7.33 (m, 1H), 7.02 -6.95 (m, 1H), 6.78 - 6.57 (m, 1H), 5.63 - 5.44 (m, 1H), 4.62 - 4.45 (m, 2H), 4.08 - 3.89 (m, 8H), 2.19 - 2.01 (m, 4H), 1.74 (d, J = 11.2 Hz, 9H). LCMS: m/z 521.1 (M+1). [0746] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1- yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Ex.94) and 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3- fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.95)
Figure imgf000198_0001
[0747] Examples 94 and 95 were prepared following the procedures of General Method A starting with racemic 3-fluoro-3-methylpiperidine followed by SFC separation of the final mixture to give the arbitrarily assigned diastereomers Ex.94 or Ex.95.1H NMR (400 MHz, DMSO-d6 ) δ = 10.29 - 10.10 (m, 1H), 9.15 - 8.88 (m, 1H), 8.06 - 7.91 (m, 1H), 7.54 - 7.15 (m, 3H), 5.40 - 5.13 (m, 1H), 4.62 - 4.35 (m, 2H), 4.20 - 4.00 (m, 2H), 3.99 - 3.77 (m, 1H), 3.16 - 2.97 (m, 4H), 2.88 - 2.78 (m, 1H), 2.17 - 2.11 (m, 1H), 2.08 - 1.96 (m, 4H), 1.85 - 1.73 (m, 4H), 1.46 - 1.37 (m, 3H), 1.30 - 1.15 (m, 2H); LCMS: m/z 606.2 (M+1) and Ex.95 or Ex.94: 1H NMR (400 MHz, DMSO-d6 ) δ = 10.22 (d, J = 5.6 Hz, 1H), 9.09 (d, J = 19.2 Hz, 1H), 8.05 - 7.92 (m, 1H), 7.55 - 7.13 (m, 3H), 5.65 - 5.33 (m, 1H), 4.65 - 4.39 (m, 4H), 3.99 - 3.71 (m, 3H), 3.69 - 3.55 (m, 2H), 2.99 - 2.84 (m, 1H), 2.30 - 2.24 (m, 1H), 2.15 - 1.90 (m, 6H), 1.87 - 1.73 (m, 2H), 1.46 - 1.38 (m, 3H), 1.24 - 1.22 (m, 2H). LCMS: m/z 606.2 (M+1). [0748] Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol (Ex.96) and 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3- methylpiperidin-1-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.97)
Figure imgf000199_0001
[0749] Examples 96 and 97 were prepared following the procedures of General Method A starting with racemic 3-fluoro-3-methylpiperidine and the appropriate boronic ester. The final mixture was seperated by SFC to give the arbitrarily assigned diastereomers Ex.96 or Ex.97: 1H NMR (400 MHz, DMSO-d6 ) δ = 9.11 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 7.85 - 7.70 (m, 1H), 7.44 - 7.29 (m, 2H), 7.08 - 6.96 (m, 1H), 5.42 - 5.11 (m, 1H), 4.58 - 4.42 (m, 2H), 4.17 - 4.04 (m, 2H), 3.14 - 3.06 (m, 3H), 3.01 (s, 1H), 2.86 - 2.79 (m, 1H), 2.38 - 2.28 (m, 1H), 2.17 - 2.08 (m, 2H), 2.08 - 2.04 (m, 1H), 2.04 - 1.94 (m, 3H), 1.88 - 1.72 (m, 5H), 1.44 - 1.36 (m, 3H), 1.23 (s, 1H), 0.78 - 0.66 (m, 3H); LCMS: m/z 610.0 (M+1) and Ex.97 or Ex.96: 1H NMR (400 MHz, DMSO-d6 ) δ = 9.11 (s, 1H), 8.23 (s, 1H), 7.84 - 7.72 (m, 1H), 7.42 - 7.27 (m, 2H), 7.04 (d, J = 4.4 Hz, 1H), 5.44 - 5.15 (m, 1H), 4.60 - 4.44 (m, 2H), 4.19 - 4.03 (m, 2H), 3.08 (d, J = 9.2 Hz, 3H), 3.01 (s, 1H), 2.85 - 2.79 (m, 1H), 2.17 - 2.10 (m, 2H), 2.07 - 1.97 (m, 4H), 1.86 - 1.73 (m, 5H), 1.44 - 1.36 (m, 3H), 1.23 (s, 2H), 0.77 - 0.68 (m, 3H); LCMS: m/z 610.2 (M+1). [0750] Preparation of 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5- ethyl-6-fluoronaphthalen-2-ol (Ex.98)
Figure imgf000199_0002
[0751] Ex.98 was prepared following the procedures of General Method A.1H NMR (400 MHz, DMSO-d6 ) δ = 9.99 (s, 1H), 9.12 (s, 1H), 7.88 - 7.70 (m, 1H), 7.45 - 7.28 (m, 2H), 7.04 (d, J = 2.4 Hz, 1H), 5.37 - 5.12 (m, 1H), 4.35 - 4.17 (m, 2H), 4.01 - 3.91 (m, 2H), 3.10 - 2.99 (m, 4H), 2.86 - 2.80 (m, 1H), 2.36 - 2.31 (m, 1H), 2.28 - 2.19 (m, 2H), 2.15 - 2.11 (m, 1H), 2.06 (d, J = 2.4 Hz, 1H), 2.00 - 1.96 (m, 2H), 1.87 - 1.75 (m, 3H), 1.23 (s, 1H), 0.76 - 0.67 (m, 3H). LCMS: m/z 616.2 (M+1). [0752] Preparation of 4-[4-(5-chloro-2,3-dihydro-1H-indol-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]p yrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.99)
Figure imgf000200_0001
[0753] Ex.99 was prepared following General Method A. 1H NMR (400 MHz, DMSO-d6) δ = 10.30 - 10.09 (m, 1H), 9.27 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 6.0, 9.2 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.41 (d, J = 2.4 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 5.37 - 5.20 (m, 1H), 4.91 - 4.71 (m, 1H), 4.71 - 4.57 (m, 1H), 4.22 - 4.05 (m, 3H), 3.15 - 3.05 (m, 3H), 3.02 (s, 1H), 2.87 - 2.80 (m, 1H), 2.19 - 2.10 (m, 1H), 2.10 - 1.95 (m, 3H), 1.88 - 1.76 (m, 3H). LCMS: m/z 642.1 (M+1). [0754] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3- b]199yrrolid-4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.100)
Figure imgf000200_0002
[0755] Ex.100 was prepared following General Method A. 1H NMR (499 MHz, DMSO-d6 ) δ = 10.82 (br s, 1H), 9.21 (s, 1H), 7.99 (dd, J = 5.9, 9.2 Hz, 1H), 7.86 (s, 1H), 7.48 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 5.63 (br s, 1H), 5.58 - 5.47 (m, 1H), 4.67 - 4.54 (m, 4H), 4.33 (ddd, J = 3.1, 6.2, 12.0 Hz, 3H), 4.20 - 4.14 (m, 1H), 4.11 - 4.06 (m, 1H), 3.92 - 3.84 (m, 1H), 3.31 (br d, J = 5.2 Hz, 2H), 2.93 - 2.79 (m, 3H), 2.58 - 2.52 (m, 1H), 2.40 - 2.24 (m, 2H), 2.21 - 2.05 (m, 4H). LCMS: m/z 626.0 (M+1). [0756] Preparation of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-5-methoxy-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl]naphthalen-2-ol (Ex.101)
Figure imgf000201_0001
[0757] Step 1. To a solution of 5,7-dichloro-8-fluoro-2-methylsulfanyl-3H-pyrido[4,3- d]pyrimidin-4-one (1.23, 4.39 mmol, 1 eq) in DMA (12 mL) was added NaOMe (474 mg, 8.78 mmol, 2 eq) and MeOH (141 mg, 4.39 mmol, 1 eq). The mixture was stirred at 50 °C for 1 h. On completion, the reaction mixture was added H2O (50 mL) and to adjust pH to 3 with HCl (1 N), filtered and the filtered cake was concentrated in vacuum to give 7-chloro-8- fluoro-5-methoxy-2-methylsulfanyl-3H-pyrido[4,3-d]pyrimidin-4-one (1.05 g, 3.81 mmol, 87% yield) as brown solid.1H NMR (400 MHz, DMSO-d6) δ = 13.04 (s, 1H), 3.92 (s, 3H), 2.58 (s, 3H). LCMS: m/z 276.1 (M+1). [0758] Step 2. To a solution of 7-chloro-8-fluoro-5-methoxy-2-methylsulfanyl-3H- pyrido[4,3-d]pyrimidin-4-one (1.03 g, 3.74 mmol, 1 eq) in ACN (8.50 mL) was added POCl3 (687 mg, 4.48 mmol, 1.2 eq) and DIEA (1.45 g, 11.2 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. Then the piperidine (318 mg, 3.74 mmol, 1 eq) was added at -10 °C. Then the mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EA (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 7-chloro-8- fluoro-5-methoxy-2-methylsulfanyl-4-(1-piperidyl) pyrido[4,3-d]pyrimidine (1.1 g, 3.21 mmol, 86% yield) as orange solid. LCMS: m/z 343.0 (M+1). [0759] Step 3. A mixture of 7-chloro-8-fluoro-5-methoxy-2-methylsulfanyl-4-(1- piperidyl)pyrido [4,3-d]pyrimidine (1.0 g, 2.92 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 (2.24 g, 4.38 mmol, 1.5 eq), K3PO4 (1.86 g, 8.75 mmol, 3 eq), Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (212 mg, 0.292 mmol, 0.1 eq) in THF (10 mL) and H2O (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 2-[2-fluoro-8-[8-fluoro-5-methoxy-2-methylsulfanyl-4-(1-piperidyl)pyrido[4,3-d]pyrimidin- 7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (1.70 g, 2.45 mmol, 84% yield) as brown solid. LCMS: m/z 693.3 (M+1). [0760] Step 4. To a solution of 2-[2-fluoro-8-[8-fluoro-5-methoxy-2-methylsulfanyl-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (300 mg, 0.433 mmol, 1 eq) in DCM (5 mL) was added m-CPBA (220 mg, 1.08 mmol, 85% purity, 2.5 eq) at 0 °C, and stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition Na2SO3 (10 mL) at 0 °C, and then diluted with H2O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give 2-[2- fluoro-8-[8-fluoro-5-methoxy-2-methylsulfonyl-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]- 6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (300 mg, 0.414 mmol, 96% yield) as orange oil. [0761] Step 5. A mixture of 2-[2-fluoro-8-[8-fluoro-5-methoxy-2-methylsulfonyl-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (240 mg, 0.331 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (158 mg, 0.993 mmol, 3 eq), t-BuOK (111 mg, 0.993 mmol, 3 eq) in Toluene (3 mL) was degassed and purged with N2 for 3 times at 0 °C, and then the mixture was stirred at 25 °C under N2 atmosphere for 1 h. On completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EA (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1/0 to 0/1) to give 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxy-4-(1-piperidyl)pyrido[4,3- d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (200 mg, 0.249 mmol, 75% yield) as yellow oil. LCMS: m/z 804.2 (M+1). [0762] Step 6. The remaing steps followed similar reaction conditions as Steps 4 in General Method A to give Ex.101 as a yellow solid.1H NMR (400 MHz, MeOD-d4) δ = 7.86 (dd, J = 5.6, 9.2 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.27 - 7.23 (m, 1H), 5.67 - 5.46 (m, 1H), 4.74 - 4.64 (m, 2H), 4.06 (s, 3H), 4.05 - 3.99 (m, 1H), 3.98 - 3.88 (m, 2H), 3.84 (br d, J = 7.6 Hz, 4H), 3.50 - 3.41 (m, 2H), 2.77 - 2.56 (m, 2H), 2.47 - 2.12 (m, 4H), 1.87 - 1.76 (m, 6H). LCMS: m/z 603.2 (M+1). [0763] Preparation of 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-
b]203yrrolid-4-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (Ex.102)
Figure imgf000204_0001
[0764] A suspension of 5-ethynyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-methyl-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (5 mg, 0.00799 mmol) and Palladium, 10% on carbon (0.85 mg, 0.00799 mmol) in ethanol (0.04 mL) was stirred under Hydrogen balloon (1 atmosphere) at 23 °C for 3.5 h . Upon completion, the solvent was evaporated and the residue was purified by preparative HPLC (C18, 10- 100% acetonitrile in water with 0.035% TFA) to Ex.102 as TFA salt (3.32 mg, 0.00446 μmol, 57% yield).1H NMR (600 MHz, DMSO-d6 ) δ = 10.72 - 10.66 (m, 1H), 9.99 (br s, 1H), 9.28 (s, 1H), 7.88 (s, 1H), 7.82 - 7.76 (m, 1H), 7.41 - 7.33 (m, 2H), 7.03 (d, J = 2.5 Hz, 1H), 5.63 (br s, 1H), 5.55 (br s, 1H), 4.68 - 4.55 (m, 2H), 4.34 - 4.22 (m, 2H), 3.94 - 3.84 (m, 2H), 3.82 - 3.78 (m, 1H), 3.37 - 3.28 (m, 2H), 2.86 (br t, J = 6.3 Hz, 2H), 2.82 - 2.69 (m, 3H),
2.63 - 2.52 (m, 2H), 2.41 - 2.30 (m, 2H), 2.26 - 2.16 (m, 3H), 1.19 (br t, J = 7.3 Hz, 1H), 0.76 (t, J = 7.4 Hz, 3H). LCMS: m/z 630.0 (M+1). [0765] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[3-(methoxymethyl)-1-methyl-1,4,5,6-tetrahydro-7H- pyrazolo[3,4-b]pyridin-7-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.103)
Figure imgf000205_0001
[0766] Example 103 was synthesized using procedures similar to those of General Method A as a yellow solid.1
Figure imgf000205_0002
H NMR (400 MHz, METHANOL-d4 ) δ = 9.17 (s, 1H), 7.89 (dd, J = 5.6, 9.1 Hz, 1H), 7.41 – 7.31 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H), 5.55 – 5.38 (m, 1H), 4.66 – 4.50 (m, 3H), 4.45 (s, 2H), 4.42 – 4.27 (m, 2H), 3.80 – 3.61 (m, 3H), 3.46 (s, 3H), 3.42 (d, J = 6 Hz, 1H), 3.40 (s, 3H), 2.73 (br t, J = 6.4 Hz, 2H), 2.60 – 2.44 (m, 2H), 2.36 – 2.19 (m, 3H), 2.10 – 1.99 (m, 3H). LCMS: m/z :670.3 (M+1). [0767] Screen Assays [0768] Screen Assays [0769] HTRF KRAS mutation nucleotide exchange assays: [0770] The HTRF KRAS nucleotide exchange assays were performed at Reaction Biology. Briefly, purified GST tagged KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G12D/T35S or KRAS WT proteins were 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). Serial dilutions of indicated compounds were prepared in DMSO and added to the KRAS /a-GST Tb antibody mixture using acoustic dispenser (ECHO, Beckman). Compounds were incubated with KRAS/a-GST Tb antibody at room temperature for one hour. Purified SOS1 proteins and GTP-DY-647P1 mix was introduced to initiate the exchange reaction. HTRF signals were quantified 20-60 minutes later. The background subtracted signals are converted to % activity relative to DMSO controls. Data is analyzed using GraphPad Prism 4 with “sigmoidal dose-response (variable slope) equation to obtain compound IC50 values.
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
[0771] Cell proliferation assays: [0772] Method A: Two thousand KRAS mutant cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours at 37°C and 5% CO2. 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).
Figure imgf000208_0002
Figure imgf000209_0001
Figure imgf000210_0001
[0773] Method B: Two thousand KRAS mutant cells per well were seeded in 96-well black plate and then treated with indicated compounds for 5 days at 37°C and 5% CO2. 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).
Figure imgf000211_0001
[0774] Inhibition of phosphorylation of ERK (Thr202/Tyr204) using In-Cell Western [0775] KRAS mutant cells were plated in clear bottom 96 well plates at a density of 50,000- 120,000 cells per well. Cells were allowed to attach overnight and then treated with compounds for 3 hours. After treatment, cells were fixed with 10% buffered formalin for 20 minutes at room temperature, washed with PBS, and then permeabilized with ice cold 100% methanol for 10 minutes to overnight at -20°C. Odyssey Blocking Buffer (LiCOR Biosciences: 927-60001) was added to each well for 1 hour at room temperature prior to incubation with primary antibodies overnight at 4°C. The primary antibodies used were as follows: Phospho-ERK (Cell Signaling: CS-9101) diluted to 1:250 and β-actin (Cell Signaling: CS-3700 ) diluted to 1:2000 in Odyssey Blocking Buffer + 0.05% Tween20. Plates were washed 3X with Wash Buffer (PBS+0.1% Tween20) and incubated with secondary antibodies for 2 hours at room temperature. The following secondary antibodies were used: goat anti-rabbit-800 (LI-COR: 926-32211) and goat anti-mouse-680 (LICOR: 926-68070) both diluted to 1:2000 in Odyssey Blocking Buffer + 0.05% Tween20. The plates were washed 3X with Wash Buffer before imaged on LiCOR Odyssey M Imaging System. Phospho-ERK signal was normalized to β-actin signal for each well and the percent of DMSO control values were calculated. IC50 values were calculated using the sigmoidal dose-response (variable slope) equation in GraphPad Prism 4.
Figure imgf000212_0001
[0776] Mouse oral PK evaluation of Ex.1 [0777] Ex.1 was administered to female BALB/c mice via oral gavage at the dose level of 50 mg/kg. Mouse plasma was collected before the dose and at 15 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after the dose. For each time points, blood samples were collected from three mice into tubes containing K2-EDTA, followed by gentle mixing to assure distribution of the anti-coagulant. Immediately after a blood sample was collected and mixed, it was placed on ice. Blood samples were subsequently centrifuged at 4 ºC for 10 minutes at 5,000 rpm. The plasma was harvested into pre-labeled tubes and stored at -80 ºC. Frozen plasma samples were shipped to Integrated Analytical Solutions, Inc. for bioanalysis of Ex.1 by LC/MS/MS. Non-compartment analysis method of Phoenix 64 software (Certara, Inc) was used to calculate various pharmacokinetic parameters and the results were summarized in the Table below:
Figure imgf000212_0002

Claims

WHAT IS CLAIMED IS: 1. A compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000213_0001
wherein X is a -O-, -S-, or -NR4-; Z1 is N or C(R5); Z2 is N or C(R6); Z3 is N or C(R7); Z4 is N or C(R8); Z5 is N or C(R9); provided that at least two of Z1-Z5 are N; 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 atoms 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, -Re, -Rf, -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 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10- membered heterocycloalkyl), C6-C10 aryl, -C1-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -C1-C6 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, 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; R4 is 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, -Re, -Rf, 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 R1 and R10 taken together with the atom or atoms to which they are attached combine to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl 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, or two hydrogen atoms on a single carbon atom of the monocyclic 4- to 10-membered heterocycloalkyl, fused bicyclic 5- to 10-membered heterocycloalkyl, or bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; each of R5, R6, R7, R8, and R9 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; ring A is a 4- to 10-membered heterocycloalkyl that is unsubstituted or is substituted with one or more of R11; each R11 is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 10- membered heterocycloalkyl, -OH, -OC1-C6 alkyl, -CN, -C(O)NRaRb, or -NRaC(O)Rb, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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 two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; ring B is a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; 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; or two of Ra and Rb, or Rc and Rd, or Re and Rf, or Rg and Rh, taken together with the atom or atoms to which they are attached, combine to form a 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, 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo groups or an alkenyl; m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, 6, or 7; and p is 0 or 1; provided that when p is 1, then at least one hydrogen atom in R3 is substituted by deuterium.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula V, VII, IX or XIX
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
wherein Z6 is N or C(R14); Z7 is N or C(R15); R12 is 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, -Re, -Rf, 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; R13 is 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, -Re, -Rf, 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; and each of R14 and R15 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.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkyl, 4- to 10- membered heterocycloalkyl, or -C1-C6 alkylene-(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, 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. 4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is -C1-C6 alkyl or 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in -C1-C6 alkyl and 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,
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.
5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000221_0001
wherein “ ” is a point of covalent attachment.
6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is –C1-C6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C1-C6 alkyl-(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.
7. The compound of any one of claims 1 to 4 or 6, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000222_0001
, 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, 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, and “ ” is a point of covalent attachment.
8. The compound of any one of claims 1 to 4, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000222_0002
wherein “ ” is a point of covalent attachment.
9. The compound of any one of claims 1 to 4, 6 to 8, wherein the compound is of the formula IVa, VIa, VIIIb, Xb, or XXa, or a pharmaceutically acceptable salt thereof,
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
or a pharmaceutically acceptable salt thereof.
10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.
11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R11 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, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaC(O)Rb, -N(C(O)Ra)(C(O)Rb), NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, or two of R11 taken together with the atom or atoms to which they are attached or three of R11 taken together with the atoms 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, -Re, -Rf, 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, -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; wherein each Ra, Rb, Re, and Rf, is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1- C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl; or two of Ra and Rb, or Re and Rf, taken together with the atom or atoms to which they are attached, combine to form a 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, 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(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, or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group.
13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is of the formula
Figure imgf000227_0001
wherein * is a point of covalent attachment to
Figure imgf000228_0001
14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is of the formula
Figure imgf000228_0002
Figure imgf000229_0001
wherein * is a point of covalent attachment to
Figure imgf000229_0002
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 CR7, Z4 is N, and Z5 is CR9.
18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is CR9.
19. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is N.
20. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is CR9.
21. The compound of any one of claims 1 to 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 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is N, and Z5 is N.
23. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is CR8, and Z5 is N.
24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X is –NR4-.
26. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
27. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein p is 0.
28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -ORc, or -NRcRd.
29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is
Figure imgf000231_0001
wherein is a point of covalent attachment.
30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R4, when present, is H or methyl.
31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H.
32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H.
33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or F.
34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H.
35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H.
36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2- ol; 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; 3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-ol; (3S)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3- ol; 5-ethynyl-6-fluoro-4-[8-fluoro-4-(4-fluoropiperidin-1-yl)-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-4-(8-fluoro-3-azabicyclo[3.2.1]octan-3-yl)-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]naphthalen- 2-ol; (1R,5S,8S)-3-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- azabicyclo[3.2.1]octan-8-ol; (3R,4R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-4- fluoropiperidin-3-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[1-(hydroxymethyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 4-[4-(azetidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-methoxypyrrolidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- ol; 4-[4-(azepan-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[4-(2-azabicyclo[2.2.1]heptan-2-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; 4-[4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidine- 3-carbonitrile; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[1-(methoxymethyl)-3-azabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)- yl]-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; (2R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-N-(propan- 2-yl)piperidine-2-carboxamide; 4-[4-(8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; 4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-8-fluoro-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[2-(1,7-diazaspiro[4.4]nonan-7-yl)-8-fluoro-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7- yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-{2-[(3R,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; (3S)-3-{[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-2-yl]amino}-N,5-dimethylhexanamide; (2R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-N- methylpiperidine-2-carboxamide; 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; 5,6-difluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 7-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,3-benzothiazol-2-amine; 4-[4-(4,4-difluoropiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 8-chloro-7-fluoro-1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]isoquinolin-3-amine; 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3S)-3-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-methoxypiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3S)-3-methoxypiperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-[4-(3-ethoxypiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-6- (piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carbonitrile; (4R)-2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-6- (piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carbonitrile; (4S)-2-amino-4-{3-[2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-6- (piperidin-1-yl)pyrimidin-4-yl]-1,2,4-oxadiazol-5-yl}-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carbonitrile; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(3R)-3-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 7-(4-chloro-1H-indol-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidine; 5-ethynyl-6-fluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2H10)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- (2H3)methylpiperidin-3-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- (2H3)methylpiperidin-3-ol; (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; 7-ethynyl-6-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1H-indazol-3-amine; 7-ethynyl-6-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1H-indazol-3-amine; (1R)-4-chloro-3-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl](1-2H)-1H-inden-1-ol; 8-ethynyl-7-fluoro-1-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]isoquinolin-3-amine; 5-ethynyl-1,6-difluoro-4-[8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-amine; 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7- yl}naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2R)-2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(2S)-2-(methoxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-[(2R)-2-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl}naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)meth}oxy)-4-[(2S)-2-(hydroxymethyl)piperidin-1-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-[3-(methoxymethyl)-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[3,4- b]pyridin-7-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; 4-[4-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6- fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-[(3aR,7aR)-hexahydrofuro[2,3-c]pyridin-6(2H)-yl]pyrido[4,3- d]pyrimidin-7-yl}naphthalen-2-ol; 1-{(4aS,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4- yl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4- yl]piperidin-3-yl}-N-methylacetamide; 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)-4-[(5S)-2-oxa-6-azaspiro[4.5]decan-6-yl]pyrido[4,3-d]pyrimidin-7- yl}naphthalen-2-ol; (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]- 2,6-diazaspiro[4.5]decan-3-one; 5-ethynyl-6-fluoro-4-{8-fluoro-2-[(4R,5S)-4-fluoro-1-methyl-1,7-diazaspiro[4.4]nonan-7-yl]- 4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; and 4-{2-[(3S)-3-(dimethylamino)-3-(fluoromethyl)pyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; 5-ethyl-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-chloro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-chloro-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-[6-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- (piperidin-1-yl)quinazolin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; N-{(3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]piperidin-3- yl}-N-methylacetamide; (5S)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6- diazaspiro[4.5]decan-3-one; (5R)-6-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-2,6- diazaspiro[4.5]decan-3-one; 1-{(4aR,7aR)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]octahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; 1-{(4aS,7aS)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]octahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl}ethan-1-one; (3R)-1-[7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl]-5-methylnaphthalen-2-ol; 4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-3- methylpiperidin-3-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-amine; 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoropiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin-1-yl)pyrido[4,3- d]pyrimidine; 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{3-[(methanesulfonyl)methyl]piperidin-1-yl}pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; 4-{2-[(2S,4S)-4-(dimethylamino)-2-methylpyrrolidin-1-yl]-8-fluoro-4-(piperidin-1- yl)pyrido[4,3-d]pyrimidin-7-yl}-5-ethynyl-6-fluoronaphthalen-2-ol; 1-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(piperidin- 1-yl)pyrido[4,3-d]pyrimidin-7-yl]-1,2-dihydro-3H-indol-3-one; 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3R)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoro-3-methylpiperidin-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; 4-[4-(3,3-difluoropiperidin-1-yl)-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoronaphthalen-2-ol; 4-[4-(5-chloro-2,3-dihydro-1H-indol-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-5-methoxy-4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-(1-methyl-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)pyrido[4,3- d]pyrimidin-7-yl]naphthalen-2-ol; and 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[3-(methoxymethyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin- 7-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol.
38. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
39. 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 37, or a pharmaceutically acceptable salt thereof.
40. A compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
41. A compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
42. Use of a compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.
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