WO2023173014A1 - Kras inhibitors and their use - Google Patents

Kras inhibitors and their use Download PDF

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Publication number
WO2023173014A1
WO2023173014A1 PCT/US2023/064038 US2023064038W WO2023173014A1 WO 2023173014 A1 WO2023173014 A1 WO 2023173014A1 US 2023064038 W US2023064038 W US 2023064038W WO 2023173014 A1 WO2023173014 A1 WO 2023173014A1
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alkyl
fluoro
diazabicyclo
pyrrolizin
octan
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PCT/US2023/064038
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French (fr)
Inventor
Jingrong Jean Cui
Evan W. ROGERS
Eugene Yuanjin Rui
Dayong Zhai
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Blossomhill Therapeutics, Inc.
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Publication of WO2023173014A1 publication Critical patent/WO2023173014A1/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

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
  • 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, [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, [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. [0078] 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, [0081] wherein R 2 , R 11 , 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 VII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof, [0085] 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. [0086] 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, [0089] 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. [0090] 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, [0093] 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. [0094] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
  • 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, [0097] 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, [0099] 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, [0101] 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, [0103] 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. [0104] 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, [0107] 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. [0108] 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, [0111] 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. [0112] 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, [0115] wherein R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0116] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXV, 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 , Z 6 , Z 7 , m, n, and p are as described herein. [0120] In some embodiments, the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof, [0123] wherein R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0124] In some embodiments, 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, [0127] 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. [0128] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein.
  • the disclosure provides a compound of the formula XXXI, or a pharmaceutically acceptable salt thereof, [0131] wherein R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein.
  • the compound of Formula (I)-(XXXIII) 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)-(XXXIII) 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)-(XXXIII), 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)-(XXXIII), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XXXIII), 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)-(XXXIII), 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
  • each of 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 , -S(O) 2 NR g R h , -S(O) 2 NR g R h , -S(O) 2 NR
  • 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
  • R 11 is -C 1 -C 6 alkylOC 1 -C 6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, -C 1 -C 6 alkylOC s -C 6 cycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen, C 1 -C 6 alkylS(O) 2 C 1 -C 6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, or 5- to 10-membered heterocycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen. [0181] 14.
  • 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 .
  • 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 [0199] 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 20 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. [0275]
  • 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 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 –CF3, -(CH 2 )F, -CHF2, -CH 2 Br, -CH 2 CF3, 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: [0279] 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: [0283]
  • 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)-(XXXIII) 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 .
  • (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.
  • the term 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)-(XXXIII), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXXIII), 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)-(XXXIII)).
  • 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)-(XXXIII), 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)-(XXXIII) 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, [0303] 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. [0304] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0307] wherein R 2 , R 3 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0308] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [0311] 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. [0312] 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 VII, or a pharmaceutically acceptable salt thereof, [0315] 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. [0316] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [0319] 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. [0320] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, [0323] 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. [0324] 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, [0327] 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, [0329] 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, [0331] 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, [0333] 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. [0334] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
  • 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.
  • the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof, [0337] 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, and q are as described herein.
  • the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof, [0339] 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. [0340] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof, [0341] 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. [0342] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof, [0345] wherein R 2 , R 3 , 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. [0346] In some embodiments, 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, [0349] wherein R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein. [0350] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof, [0353] 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. [0354] In some embodiments, the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof, [0357] wherein R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein. [0358] In some embodiments, the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof, [0361] wherein R 2 , R 11 , X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0362] In some embodiments, the disclosure provides a compound of the formula XXXI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXXII, or a pharmaceutically acceptable salt thereof, [0365] 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. [0366] In some embodiments, the disclosure provides a compound of the formula XXXIII, 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-, 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(O)- , and R 1 is ring A. In some embodiments, Y is a bond, and 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 , ,
  • 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.
  • Ring A is , 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. [0374] In some embodiments, Ring A is , , , , , [0375] 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 [0378] wherein * is a point of covalent attachment to [0379] In some embodiments, Ring A is , [0380] wherein * is a point of covalent attachment to [0381] In some embodiments, Ring A is is an unsubstituted C 6 -C 10 aryl or a C 6 -C 10 aryl substituted with one or more of R 11 . In some embodiments, Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R 11 , or naphthyl substituted with one or more of R 11 .
  • Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R 11 , or naphthyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • Ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with one or more of R 11 .
  • Ring A is an substituted 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 of the formula [0384] wherein * is a point of covalent attachment to and m is 0 or one or more. In some embodiments, m is 0, 1, 2, or 3. [0385] In some embodiments, Ring A is of the formula , , , , , , , , [0386] wherein * is a point of covalent attachment to [0387] In some embodiments, ring A is of the formula , [0388] wherein * is a point of covalent attachment to and [0389] each R 11 is attached to a carbon atom of ring A, and each R 11 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or 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,
  • 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 . In some embodiments, 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • each R 11 is independently deuterium, halogen, C 1 -C 6 alkyl, C2- 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)R
  • At least one R 11 is -C 1 -C 6 alkylOC 1 -C 6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, -C 1 -C 6 alkylOCs-C6 cycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen, or C 1 -C 6 alkylS(O) 2 C 1 -C 6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen.
  • At least one R 11 is -CH 2 -O-CH 3, -CH 2 -O-CD 3, -CH 2 - O-CF3, -CH 2 -O-CHF2, -CH 2 -O-cyclopropyl, -CH 2 CH 2 -O-CH3, -CH 2 CH 2 -O-CD3, -CH 2 CH 2 -O-CF 3, -CH 2 CH 2 -O-CHF 2, -CH 2 CH 2 -O-cyclopropyl , -CH 2 -O-CH 2 CH 3 , or –CH 2 S(O) 2 CH 3 .
  • m is 0. In some embodiments, m is one or more.
  • 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, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4.
  • m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0404] In some embodiments, ring B is a C 6 -C 10 aryl or 5- to 10-membered heteroaryl, optuionally substituted with one or more R 2 , R 12 , or R 13 . [0405] In some embodiments, Ring B is [0406] wherein * is a point of covalent attachment to , R 2 , Z 6 , and Z 7 are as described herein, and n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0408] wherein * is a point of covalent attachment to 2 6 7 , R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, or 4. [0409] In some embodiments, Ring B is [0410] wherein * is a point of covalent attachment to 2 6 7 R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0412] wherein * is a point of covalent attachment to , R 2 , Z 6 , and Z 7 are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0413] In some embodiments, Ring B is [0414] wherein * is a point of covalent attachment to 2 6 7 , R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0416] wherein * is a point of covalent attachment to 2 6 7 R , Z , and Z are as described herein, 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, C2- C 6 alkenyl, C 2 -C 6 alkynyl, -OR c , or -NR c R d .
  • 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. In some embodiments, each R 2 , when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -CF 3 , -C ⁇ CH, - CN, -NH 2 , -OH, -OCH3, and -OC(O)N(CH3) 2 .
  • 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. [0421] 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. [0422] In some embodiments, Ring B is , , , , , , [0423] In some embodiments, Ring B is [0424] wherein is a point of covalent attachment. [0425] In some embodiments, Ring B is [0426] wherein is a point of covalent attachment. [0427] In some embodiments, q is 0. In some embodiments, q is 1. [0428] In some embodiments, -X- is -O-, -S-, or–NR 4 -. In some embodiments, -X- is -O-.
  • -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,
  • 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 C1- C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C 3
  • R 3 is -C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, or -C 1 - C6 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 , , , [0434] wherein is a point of covalent attachment. [0435] In some embodiments, R 3 is , , [0436] 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 –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 , [0440] wherein 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 , -OS(O)NR e R
  • R 3 is of the formula , [0442] wherein 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 , -OS(O)NR e R
  • R 3 is of the formula , [0444] wherein 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 , -OS(O)NR e R
  • R 3 is of the formula , [0446] wherein 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 , -OS(O)NR e R
  • 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 , -OS(
  • R 5 when present, is H.
  • 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.
  • R a and R b when present, are each independently H, deuterium, methyl, ethyl, or isopropyl.
  • R a when present, is H, deuterium, methyl, ethyl, or isopropyl.
  • R b when present, is H, deuterium, methyl, ethyl, or isopropyl.
  • 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-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0454] 5-ethynyl-6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy ⁇ -4-[(1R,5S)-1- ⁇ [( 2 H3)methyloxy]methyl ⁇ -3,8-diazabicyclo[3.2.1
  • 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. [0507] 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 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 oC, compound II-1 and an amine or alcohol I-4 are converted to a product II-2.
  • 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.
  • C under basic condition, the amine I- 2 will react with II-2 to provide a product III-1.
  • Step 1 To a solution of 3-benzyl 8-(tert-butyl) 1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.5 g, 30.6 mmol, 1 eq) in DCM (60 mL) was added HCl/dioxane (4 M, 45 mL, 5.89 eq). The mixture was stirred at 20 °C for 3 h.
  • Step 5 To a solution of benzyl (1R,5S)-1- ⁇ [( 2 H3)methyloxy]methyl ⁇ -3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1 eq) in DCM is added Boc2O (1.5 eq), DMAP (0.1 eq) and TEA (2 eq). The mixture is stirred at 25 °C for 16 h. On completion, the reaction mixture is concentrated under reduced pressure to remove solvent.
  • Step 1 To a solution of benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1 ⁇ 6 - [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate (50 mg, 0.148 mmol, 1 eq.) in DMF (0.5 mL) was added methylsulfanylsodium (20.7 mg, 0.296 mmol, 2 eq) at 25 oC and the reaction mixture was stirred for 1 h. Then HCl (6 M, 0.1 mL, 4.06 eq) was added at 25 °C.
  • Step 1 To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (650 mg, 2.57 mmol, 1.1 eq) in DCM (24 mL) was added DIEA (1.82 g, 14.0 mmol, 2.45 mL, 6 eq). Then tert-butyl (1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 2.34 mmol, 1 eq.) was added into the mixture at -40 °C for 1 h under N 2 . On completion, the mixture was concentrated under reduced pressure to give a residue.
  • Step 3 A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (640 mg, 1.08 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 (1.10 g, 2.15 mmol, 2 eq), K 3 PO 4 (685 mg, 3.23 mmol, 3
  • Step 5 A mixture of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-2-ol (70.0 mg, 0.0874 mmol, 1 eq) and CsF (79.7 mg, 0.524 mmol, 6 eq) in DMSO (1 mL) was stirred at 25 °C for 2 h.
  • Step 1 Na (816 mg, 35.5 mmol, 841 uL, 10 eq) was added to trideuterio(deuteriooxy)methane (10.7 g, 296 mmol, 12.0 mL, 83.3 eq) at 0 °C, and the mixture was stirred at 0 ⁇ 25 °C for 1 h.
  • Step 4 To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (905 mg, 3.59 mmol, 1.5 eq) in DCM (14 mL) was added DIEA (1.85 g, 14.34 mmol, 2.50 mL, 6 eq). Then tert-butyl (1R,5S)-1- ⁇ [( 2 H 3 )methyloxy]methyl ⁇ -3,8-diazabicyclo[3.2.1]octane-8- carboxylate (620 mg, 2.39 mmol, 1 eq) was added into the mixture at -40 °C for 1 h under N 2 .
  • Step 3 To a mixture of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-( ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]( 2 H 2 )methyl ⁇ oxy)pyrido[4,3-d]pyrimidin-4-yl]-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 334 umol, 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 (171 mg, 334 umol, 1 eq) in THF (5
  • Step 2 To a mixture of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-( ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]( 2 H 2 )methyl ⁇ oxy)pyrido[4,3-d]pyrimidin-4-yl]-1- ⁇ [( 2 H 3 )methyloxy]methyl ⁇ -3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.183 mmol, 1 eq) and ⁇ [2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-1-yl]ethynyl ⁇ tri(propan-2-yl)silane (187 mg, 0.366
  • Step 1 To a solution of benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1 ⁇ 6 - [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate (2.8 g, 8.27 mmol, 1 eq) in DMF (28 mL) was added cyclopropanol (480 mg, 8.27 mmol, 1 eq), and then NaH (496 mg, 12.4 mmol, 60% purity, 1.5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h.
  • Step 1 A mixture of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-(2,7-dichloro- 8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.201 mmol, 1 eq.), [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]( 2 H 2 )methanol (48.5 mg, 0.301 mmol, 1.5 eq), and DIEA (77.8 mg, 0.602 mmol, 105 uL, 3 eq.) in dioxane (0.5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N 2 atmosphere.
  • Step 2 To a solution of tert-butyl (1R,5S)-1-[(difluoromethoxy)methyl]-3-(7-[8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0629] (250 mg, 0.302 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 1 mL, 13.3 eq).The mixture was stirred at 25 °C for 1 hr.
  • Step 3 To a solution of ⁇ [2-fluoro-6-methoxy-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl ⁇ tri(propan-2-yl)silane (73.7 mg, 0.152 mmol, 1.3 eq) in dioxane (0.5 mL) was added tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.117 mmol, 1 eq), K 3 PO 4 (1.5 M, 3 eq) and
  • Step 5 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-2-yl dimethylcarbamate (65 mg, 0.0745 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (33.97 mg, 0.224 mmol, 3 eq).
  • Step 2 To a mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 10.68 mmol, 1 eq.) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (216 mg, 0.672 mmol, 4 eq), and K 3 PO 4 (107.01 mg, 504.12 umol, 3 eq) in H 2 O (0.4 mL) and dioxane (2 mL) was added [2-(2-(2-(
  • Step 5 To a solution of SOCl 2 (3.91 g, 32.86 mmol, 3 eq) in DCM (20 mL) was added IMIDAZOLE (6.71 g, 98.5 mmol, 9 eq) at -68 °C and stirred for 1 h, then benzyl 1-(1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3.18 g, 10.95 mmol, 1 eq) in DCM (10 mL) was added at -68 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 12 To a solution of tert-butyl 3-[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]-1-[1- (trideuteriome thoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 245 umol, 1 eq) in dioxane (2 mL) was added 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (188 mg, 367 umol, 1.5 eq) and K3PO4 (
  • Step 1 To a solution of tert-butyl 3-[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]-1-[1- (trideuteriome thoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 212 umol, 1 eq) in dioxane (2 mL) was added 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (114 mg, 318 umol, 1.5 eq) and K3PO4 (1.5 M, 424 uL, 3 eq) and [2-
  • Step 2 To a solution of tert-butyl 3-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- l]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 135 umol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 33.9 uL, 1 eq).
  • Step 3 The above solid was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um);mobile phase: [Neu-MeOH];B%: 35%-35%,A2.2;30min) to give 5- ethyl-6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy ⁇ -4-[(1S,5R)-1- ⁇ 1-[( 2 H 3 )methyloxy]ethyl ⁇ -3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.27, 4.69 mg, 7.04 ⁇ mol, 15% yield) as a yellow solid and 5-e
  • Step 1 A mixture of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (5.00 g, 13.9 mmol, 1 eq), DIEA (10.8 g, 83.7 mmol, 6 eq), Tf 2 O (15.7 g, 55.8 mmol, 4 eq) in DCM (20 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 0 °C for 12 hours.
  • Step 1 To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (92.6 mg, 582 ⁇ mol, 2 eq) in THF (2.00 mL) was added t-BuOK (65.3 mg, 582 ⁇ mol, 2.00 eq). The mixture was stirred at 0 °C for 0.5 h.
  • Step 1 To a mixture of 2,6-dichloro-4-methyl-pyridine (23.0 g, 141 mmol, 1 eq) in PMBNH 2 (121 g, 888 mmol, 115 mL, 6.26 eq) was stirred at 120 °C for 12 hours. On completion, the reaction mixture was diluted with ACN (100 mL). White solid was formed and filtered afford to 6-chloro-N-[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (23.0 g, 87.5 mmol, 61% yield) as white solid.
  • Step 1 To a solution of benzyl (1R,6S)-4,4-dioxo-3-oxa-4thia-5,8-diazatricyclo [4.3.2.01,5]undecane-8-carboxylate (1.00 g, 3.00 mmol, 1 eq) and cyclopropanol (171 mg, 3.00 mmol, 1 eq) in DMF (10 mL) was added NaH (177 mg, 4.00 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h.
  • Step 7 To a solution of tert-butyl (1R,5S)-1-(cyclopropoxymethyl)-3-[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]quinazolin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 237 ⁇ mol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 593 ⁇ L, 10 eq).
  • Step 8 To a solution of 4-[4-[(1R,5S)-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy] quinazolin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (170 mg, 206 ⁇ mol, 1 eq) in DMSO (1 mL) was added CsF (375 mg, 2 mmol, 12 eq).
  • Step 6 To a solution of tert-butyl 3-(7-chloro-8-fluoro-2- ⁇ [(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4- yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1, 200 mg, 329 ⁇ mol, 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 (203 mg, 395 ⁇ mol, 1.2 eq) in dioxane (2 mL) was added K 3 PO 4 (3 M, 3 M, 3
  • Step 7 To a solution of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-1-yl]-2- ⁇ [(2Z)-2-(fluoromethylidene)tetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 230 ⁇ mol, 1 eq) in DCM (2.5 mL) was added HCl/dioxane (4 M, 57.46 ⁇ L, 1 eq).
  • Step 8 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ -4-[1-(methoxymethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5- ⁇ [tri(propan-2- yl)silyl]ethynyl ⁇ naphthalen-2-ol (250 mg, 307 ⁇ mol, 1 eq) in DMSO (2 mL) was added CsF (280 mg, 1.84 mmol, 68.1 ⁇ L, 6 eq).
  • Step 1 To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-[[(2E)-2- (fluoromethylidene)tetrahydro- lH-pyrrolizin-7 a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin- 4-yl)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 2 from Ex.
  • Step 2 To a solution of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen- 1 -yl] -2- ⁇ [(2E)-2-(fluoromethylidene)tetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[ 4, 3-d]pyrimidin-4-yl )- 1 -(methoxy methyl )-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 690 ⁇ mol, 1 eq) in DCM (7 mL) was added HCI/dioxane (4 M, 172 ⁇ L, 1 eq).
  • the filtrate was purified by prep-HPLC purification (column: Phenomenex luna Cis 150 * 25 mm * 10 um; mobile phase: [water (FA)-ACN]; gradient: 5%-35% B over 8 min) to give 5-ethynyl-6-fluoro-4-(8-fluoro-2- ⁇ [(2E)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5 H)-y 1 ] methoxy ⁇ -4- [ 1 -(methoxymethyl)-
  • Step 4 The above solid was separated by prep-HPLC purification (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 um);mobile phase: [CO 2 -ACN/MeOH(0.1% NH 3 H 2 O)]; B%: 40%, isocratic elution mode).
  • Step 1 To a solution of [(2Z)-2-(fluoromethylidene)tetrahydro- 1H-pyrrol izi n-7a( 5H)- yl]methanol (104 mg, 609 ⁇ mol, 1.5 eq) in THF (2 mL) was added NaH (32.5 mg, 812 ⁇ mol , 60% purity, 2 eq) at 0 °C for 0.5 h and then tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro- quinazolin-4-yl)-l-(cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 406 ⁇ mol, 1 eq, from BHT-WX-5260) was added at 0 °C.
  • Step 2 A mixture of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2- ⁇ [(2Z)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)- 1 - [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 148 ⁇ mol, 1 eq), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- naphthyl]ethynyl-triisopropyl-silane (114 mg, 222 ⁇ mol , 1.5 eq), K 3 PO 4 (94.1 mg, 443 ⁇ mol , 3 eq), [
  • Step 3 To a solution of tert-butyl (1R,5S)-l-[(cyclopropyloxy)methyl]-3-(8-fluoro-7- [7-fluoro-3 -(methoxymethoxy)- 8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen- 1 -yl] -2- ⁇ [(2Z)- 2-(fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60.0 mg, 61 ⁇ mol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.5 mL, 32.74 eq).
  • Step 4 To a solution of 4-(4- ⁇ (1R,5S)-L[(cyclopropyloxy)methyl]-3,8- diazabicyclo
  • Step 1 A mixture of tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2- yl)carbamate (100 mg, 269 ⁇ mol , 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (103 mg, 404 ⁇ mol , 1.5 eq), KOAc (79.3 mg, 808 ⁇ mol, 3 eq), Pd(PPh 3 ) 2 Cl 2 (18.9 mg, 26.9 ⁇ mol, 0.1 eq) in dioxane (1 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 80 °C for 2 h under N 2 atmosphere.
  • Step 2 A mixture of tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (80.0 mg, 191 ⁇ mol, 1 eq), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (59.4 mg, 95.6 ⁇ mol , 0.5 eq), K 3 PO 4 (122 mg, 574 ⁇ mol, 3 eq), and [2-(2-aminophen-2-
  • Step 3 To a solution of tert-butyl (1R,5S)-3-(7- ⁇ 2-[(tert-butoxycarbonyl)amino]-3- cyano-7-fluoro-l-benzothiophen-4-yl)-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l-[(cyclopropyloxy)methyl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 39.9 ⁇ mol , 1 eq) in DCM (0.5 mL) was added HCI/dioxane (4 M, 0.5 mL, 50.1 eq).
  • Step 1 A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy )quinazolin-4-yl)- 1 - [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 196 ⁇ mol, 1 eq), tert-butyl N- [3-cyano-7-fluoro-4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)benzothiophen-2-yl
  • Step 2 To a solution of tert-butyl (1R,5S)-3-(7- ⁇ 2-[(tert-butoxycarbonyl)amino]-3- cyano-7-fluoro-l-benzothiophen-4-yl)-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 80.0 ⁇ mol , 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.5 mL, 25 eq).
  • Step 1 To a solution of benzyl (lR,6S)-4,4-dioxo-3-oxa-4thia-5,8-diazatricyclo [4.3.2.01, 5]undecane-8-carboxylate (1.50 g, 4.43 mmol, 1 eq) in DMF (15 mL) was added sodium;methanolate (718 mg, 13.3 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h.
  • Step 2 To a solution of benzyl (lR,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 3.44 mmol, 1 eq) in DCM (10 mL) was added Boc 2 O (2.25 g, 10.3 mmol, 3 eq) and TEA (2.09 g, 20.6 mmol, 6 eq). The mixture was stirred at 25 °C for 2 h.
  • Step 3 To a solution of O3-benzyl 08-tert-butyl (1R,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (800 mg, 2.05 mmol, 1 eq) in i-PrOH (8 mL) was added Pd/C (100 mg, 93.9 ⁇ mol , 10% purity, 4.59e-2 eq) and Pd(OH) 2 (100 mg, 71.2 ⁇ mol, 10% purity, 3.48 e-2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 at 25 °C for 1 h.
  • Step 5 A mixture of [2-(fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)- yl]methanol (132 mg, 775 ⁇ mol, 2.00 eq) and t-BuOK (43.5 mg, 388 ⁇ mol , 1.00 eq) in THF (2 mL) was degassed and purged with N 2 for 3 times at 0 °C for 0.5 h, then tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 388 ⁇ mol, 1.00 eq) was added to the mixture, the mixture was stirred at 0 °C for 1.5 h under N2 atmosphere.
  • Step 6 To a miture of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2- ⁇ [(2Z)-2- (fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25.0 mg, 38.4 ⁇ mol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- naphthyl]ethynyl-triisopropyl-silane (29.5 mg, 57.6 ⁇ mol, 1.5 eq) in dioxane (0.5 mL) and H 2 O (0.1 mL
  • Step 7 To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-
  • Step 8 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2Z)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5H)-yl]methoxy ⁇ -4- [(1R,5S)- 1 - (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5- ⁇ [tri(propan-2- yl)silyl]ethynyl ⁇ naphthalen-2-ol (15.0 mg, 18.4 ⁇ mol, 1.00 eq) in DMSO (0.5 mL) was added CsF (33.7 mg, 221 ⁇ mol, 12 eq).
  • Step 1 To a solution of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2- ⁇ [(2E)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5H)-yl]methoxy ⁇ quinazolin-4-yl)- 1 - (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.0 mg, 115 ⁇ mol, 1 eq, from BHT-WX-5262_P1) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-naphthyl]ethynyl-triisopropyl-silane (88.6 mg, 173 ⁇ mol, 1.50 eq) in dioxane (1
  • Step 1 A mixture of N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6- tributylstannyl-5-(trifluoromethyl)pyridin-2-amine (100 mg, 142 ⁇ mol, 1 eq), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (84.4 mg, 142 ⁇ mol, 1 eq), Cui (27.0 mg, 142 ⁇ mol, 1 eq), Xphos Pd G4 (12.2 mg, 14.2 ⁇ mol, 0.1 eq) and TEA (28.7
  • Ex. 43 was syntheized using the same chemistry as Ex. 42.
  • Ex. 44 was synthesized using the same chemistry as Ex. 42.
  • Step 1 A mixture of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 g, 44.0 mmol, 1 eq) in Et 2 O (200 mL) was degassed and purged with N2 for 3 times, then TMEDA (25.6 g, 220 mmol, 33.2 mL, 5 eq) and s-BuLi (1.3 M, 57.5 mL, 1.7 eq) was added at -40 °C and stirred for 2 h, then 4-[tert-butyl(dimethyl)silyl]oxybutanal (26.7 g, 132 mmol, 3 eq) was added at -40 °C, and then the mixture was stirred at -40 °C for 1 h under N 2 atmosphere.
  • reaction mixture was quenched by addition NH4CI (100 mL) at 0 °C, and then diluted with H 2 O (200 mL) and extracted with EA (150 mL * 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of tert-butyl l-[4-[tert-butyl(dimethyl)silyl]oxy-l-hydroxy- butyl]-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (18 g, 27.4 mmol, 1 eq) in DMSO (100 mL) was added CsF (12.5 g, 82.2 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was diluted with H 2 O (150 mL) and extracted with EA (100 mL * 3).
  • Step 3 To a solution of tert-butyl l-(l,4-dihydroxybutyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (9.3 g, 17.1 mmol, 1 eq) in pyridine (90 mL) was added benzenesulfonyl chloride (9.08 g, 51.4 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was diluted with H 2 O (100 mL) and extracted with EA (100 mL * 3).
  • Step 4 To a solution of tert-butyl l-[(2R)-tetrahydrofuran-2-yl]-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1, 1.35 g, 2.57 mmol, 1 eq) in DCM (14 mL) was added HOAc (7.34 g, 122 mmol, 7.00 mL, 47.5 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was diluted with water (50 mL) and extracted with DCM (20 mL x3).
  • Step 5 A mixture of tert-butyl l-[(2R)-tetrahydrofuran-2-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (570 mg, 2.02 mmol, 1 eq), 7-bromo-2,4-dichloro-8- fluoro-quinazoline (896 mg, 3.03 mmol, 1.5 eq), and DIEA (783 mg, 6.06 mmol, 1.05 mL, 3 eq) in DCM (6 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at -40 °C for Ih under N 2 atmosphere.
  • Step 6 To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-l- [(2R)-tetrahydrofuran-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (670 mg, 1.24 mmol, 1 eq), [(2R,8S)-2-fhioro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (295 mg, 1.85 mmol, 1.5 eq) in dioxane (7 mL) was added KF (216 mg, 3.71 mmol, 3 eq) and 1,4,7,10,13,16-hexaoxacyclooctadecane (163 mg, 618 qmol, 0.5 eq).
  • Step 7 SFC separation: The solid obtained above was separated by SFC (Column: Chiralpak AD-3 50x4.6mm I.D., 3um , Mobile phase: Phase A for CO 2 , and Phase B for EtOH(0.05%DEA); Gradient elutiomB in A from 5% to 40%, Flow rate: 3mL/min;Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar) to give tert-butyl (1S,5R)-3-(7-bromo-8- fluoro-2- ⁇ [(2R,7aS) - 2- 13 uorotetrahydro- 1H-pyrrol izin-7 a(5H)-yl]methoxy ⁇ quinazolin-4-yl)- l-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1-a, 230 mg, 346 ⁇ mol
  • Step 8 A mixture of tert-butyl (1S,5R)-3-(7-bromo-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-l-[(27?)-oxolan-2-yl]-
  • Step 9 To a solution of tert-butyl (1S,5R)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-l-yl]-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-l-[(27?)-oxolan-2-yl]-
  • Step 10 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇
  • Step 11 A mixture of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-l-[(2S)-oxolan-2-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1-b, 270 mg, 406 ⁇ mol, 1 eq), 2-[2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-naphthyl] ethynyl-triisopropyl-silane (312 mg, 609 ⁇ mol, 1.5 eq), K 3 PO 4 (259 mg, 1.22 mmol,
  • Step 12 To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-l-yl]-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ quinazolin-4-yl)-l-[(2S)-oxolan-2-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 309 ⁇ mol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 1 mL, 12.9 eq).
  • Step 13 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4- ⁇ (1R,5S)-l-[(2S)-oxolan-2-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl ⁇ quinazolin-7-yl)-5- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen- 2-ol (250 mg, 303 ⁇ mol, 1 eq) in DMSO (2 mL) was added CsF (276 mg, 1.82 mmol, 6 eq).
  • Ex. 47 and Ex. 48 were synthesized using the same chemistry as Ex. 45 and Ex. 46 using intermediate Peak 2 from Ex. 45 synthesis.
  • Ex. 49 was synthesized using the same chemistry as Ex. 38.
  • Ex. 50 was synthesized using the same chemistry as Ex. 39.
  • 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.
  • 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-l,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.
  • Step 3 A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-l,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-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (3.15 g, 6.15 mmol, 1.5 eq), K 3 PO 4 (2.61 g, 12.3 mmol, 3.0 eq), [2-(2-aminophenyl)phenyl]palladium(l+);bis(l- adamantyl)-butyl-
  • 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 4 To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-l-naphthyl]ethynyl-triisopropyl-silane (1.0 eq) in DMF is added K 2 CO 3 (5.0 eq) and tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (2.0 eq).
  • Step 5 To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)- 8- ⁇ [tri(propan-2-yl)silyl]ethynyl ) naphthalen- 1 -yl] -2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 eq) in DCM is added HCl/Dioxane (4 M, 6 eq.).
  • Step 6 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4- ⁇ (1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl ⁇ pyrido[4,3-d]pyrimidin-7-yl)-5- ⁇ [tri(propan-2- yl)silyl]ethynyl ⁇ naphthalen-2-ol (1.0 eq) in DMSO is added CsF (5.0 eq).
  • Step 1 The mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (406 mg, 0.925 mmol, 1 eq), tert-butyl l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 0.925 mmol, 1 eq) and K 2 CO 3 (383 mg, 2.77 mmol, 3 eq) in DMF (6.5 mL) was stirred at 80 °C for 1 h.
  • Step 2 The mixture of tert-butyl 3-(7-chloro-8-fluoro-2-[
  • Step 3 To a solution of give tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)- 8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen- 1 -yl] -2- ⁇ [(2R, 7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l-(2-methoxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.313 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 0.782 mL, 10 eq), the reaction was stirred at 25 °C for 1 h.
  • Step 4 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4-[l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-5- [ [tri(propan-2-yl)silyl]ethynyl )naphthalen-2-ol (270 mg, 0.331 mmol, 1 eq) in DMSO (3 mL) was added CsF (352 mg, 2.32 mmol, 7 eq), the reaction was stirred at 25 °C for 16 h.
  • Step 1 To a solution of benzyl (3aR,7S)-l,l-dioxodihydro-1H,3H-3a,7-ethano-l ⁇ 6 - [l,2,3]oxathiazolo[3,4- ⁇ ]pyrazine-5(4H)-carboxylate (50 mg, 0.148 mmol, 1 eq.) in DMF (0.5 mL) was added methylsulfanylsodium (20.7 mg, 0.296 mmol, 18.8 uL, 2 eq), and the mixture was stirred at 25 °C for 1 h. Then HC1 (6 M, 0.1 mL, 4.06 eq) was added at 25 °C.
  • Step 2 To a solution of benzyl (1R,5S)-l-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (10 mg, 0.0326 mmol, 1 eq) in DCM (0.5 mL) was added TEA (9.91 mg, 0.0979 mmol, 13.6 uL, 3 eq) and Boc 2 O (10.7 mg, 0.049 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h.
  • Step 3 To a solution of 3-benzyl 8-tert-butyl (1R,5S)-l-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (300 mg, 0.738 mmol, 1 eq) in DCM (5 mL) was added m-CPBA (375 mg, 1.84 mmol, 85% purity, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition of sat.
  • m-CPBA 375 mg, 1.84 mmol, 85% purity, 2.5 eq
  • Step 4 A mixture of 3-benzyl 8-tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (290 mg, 0.661 mmol, 1 eq), Pd/C (30 mg, 10% purity), Pd(OH) 2 /C (30 mg, 10% purity) in i-PrOH (5 mL) was degassed and purged with H 2 for 3 times, and then the mixture was stirred at 25 °C for 2 h under H 2 (15 psi) atmosphere. On completion, the reaction mixture was filtrated.
  • Step 5 To a solution of tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.230 mmol, 1 eq) in DMF (0.5 mL) was added K 2 CO 3 (95.4 mg, 0.690 mmol, 3 eq) and 7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy ) -4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (80.7 mg, 0.184 mmol, 0.8 eq).
  • Step 6 A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7a 1 S')-2- f I uorotetrahydro- 1 H-pyrrolizi n-7a(5H)-yl ] methoxy ⁇ pyrido
  • Step 7 To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-l-yl]-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (69 mg, 0.0695 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 0.8 mL, 46.1 eq).
  • Step 8 To a solution of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4- ⁇ (1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl ⁇ pyrido[4,3-d]pyrimidin-7-yl)-5- ⁇ [tri(propan-2- yl)silyl]ethynyl ⁇ naphthalen-2-ol (55 mg, 0.0648 mmol, 1 eq) in DMSO (1 mL) was added CsF (118 mg, 0.777 mmol, 12 eq).
  • Step 1 To a solution of benzyl l,l-dioxodihydro-lH,3H-3a,7-ethano-l ⁇ 6 - [l,2,3]oxathiazolo[3,4- ⁇ ]pyrazine-5(4H)-carboxylate (82.0 mg, 0.242 mmol, 1 eg.) and cyclopropanol (14.1 mg, 0.242 mmol, 1 eg.) in DMF (1 mL) was added NaH (14.5 mg, 0.364 mmol, 60% purity, 1.5 eg.) at 0 °C. The mixture was stirred at 25 °C for 1 h.
  • Step 5 A mixture of tert-butyl 3-(7-chloro-8-lluoro-2-[
  • Step 6 To a solution of tert-butyl l-[(cyclopropyloxy)methyl]-3-(8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-l-yl]-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.0463 mmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.1 mL, 8.63 eq).
  • Step 7 To a solution of 4-(4- ⁇ l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl ⁇ -8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5- ⁇ [tri(propan-2- yl)silyl]ethynyl ⁇ naphthalen-2-ol (38.0 mg, 0.046 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (21.0 mg, 0.138 mmol, 3 eq).
  • Step 1 To a solution of 3-benzyl 8-tert-butyl ( 1R,5S)- 1 -(hydroxy methyl )-3 ,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1 g, 2.66 mmol, 1 eq.) in DCM (5 mL) and H 2 O (5 mL) was added [bromo(difluoro)methyl]-trimethyl-silane (1.08 g, 5.31 mmol, 2 eq) and KOAc (1.04 g, 10.63 mmol, 4 eq). The mixture was stirred at 25 °C for 16 hr.
  • Step 2 A mixture of 3-benzyl 8-tert-bulyl ( 1R,5S)- l -
  • Step 3 To a solution of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (40.0 mg, 0.0912 mmol, 1 eq.), tert-butyl (1R,5S)-l-[(difluoromethoxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (53.3 mg, 0.182 mmol, 2 eq) in DMF (0.5 mL) was added K 2 CO 3 (37.8 mg, 0.273 mmol, 3 eq).
  • Step 4 A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- ⁇ [(2R,7aS)-2- fl uorotetrahydro- 1 H-pyrrolizi n-7a(5H)-yl
  • Step 1 To a mixture of tert-butyl 3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (13.0 g, 28.6 mmol, 1 eq.) and TMEDA (5.65 g, 48.6 mmol, 1.7 eq) in Et 2 O (250 mL) was added s-BuLi (1.3 M, 37.4 mL, 1.7 eq) at -40 °C under N 2 atmosphere. The reaction mixture was stirred at -40 °C for 1 h under N2 atmosphere.
  • Step 2 To a mixture of tert-butyl l-(4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -l- hydroxybutyl)-3-(triphenylmethyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (12.0 g, 18.2 mmol, 1 eq) in DMSO (120 mL) was added CsF (13.8 g, 91.3 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the residue was diluted with water (150 mL) and extracted with EA (2 X 150 mL).
  • Step 3 To a mixture of tert-butyl l-(l,4-dihydroxybutyl)-3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (9.40 g, 17.3 mmol, 1 eq) in Pyridine (100 mL) was added TsCl (1.22 g, 17.3 mmol, 1 eq). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the residue was diluted with water (90 mL) and extracted with EA (2 X 90 mL). The combined organic layers was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give a residue.
  • Step 4 To a mixture of tert-butyl l-(oxolan-2-yl)-3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2.50 g, 4.76 mmol, 1 eq) in DCM (25 mL) was added HOAc (13.1 g, 218 mmol, 45 eq). The reaction mixture was stirred at 50 °C for 2 hours. On completion, the residue was diluted with water (40 mL) and extracted with EA (2 X 40 mL).
  • Step 6 To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2- ⁇ [(2R,7a5)-2-fluorotetrahydro- l H-pyrrolizin-7a(5H)-yl
  • Step 7 To a mixture of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen- 1 -yl] -2- ⁇ [(2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.411 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 2 mL, 19 eq).
  • Step 8 To a mixture of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy ⁇ -4-[l-(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-5- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-2-ol (15.0 mg, 0.0181 mmol, 1 eq) in DMSO (1 mL) was added CsF (13.7 mg, 0.0906 umol, 5 eq).
  • Step 9 To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2- ⁇ [(2R,7a>S')-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan- 2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.805 mmol, 1 eq) and ⁇ [2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl]ethynyl ⁇ tri(propan-2-yl)silane (1.24 g, 2.42 mmol, 3 eq) in dioxane (10 mL) and H 2 O
  • Step 10 To a mixture of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- ⁇ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-l-yl]-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (520 mg, 0.535 mmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL, 14 eq).
  • Step 11 To a mixture of 6-fluoro-4-(8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7 a( 5H)- y 1 ]methoxy ⁇ -4- [ 1 -(oxolan-2-yl)-3, 8-diazabicyclo[3.2.1 ]octan-3 - y l ] py ri do 14.3 -z/ 1 py ri m i di n -7- y 1 ) -5 - [ [tri(propan-2-yl)silyl]ethynyl ⁇ naphthalen-2-ol (40 mg, 0.0483 mmol, 1 eq) in DMSO (2 mL) was added CsF (36.7 mg, 0.241 mmol, 5 eq).
  • 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 MgCl 2 , 1 mM DTT, 0.05% BSA, 0.0025% NP40).
  • 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 P-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.
  • Phospho-ERK Cell Signaling: CS-9101
  • P-actin Cell Signaling: CS-3700
  • 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.
  • blood samples were collected from three mice into tubes containing K2-EDTA, followed by gentle mixing to assure distribution of the anti-coagulant.
  • a blood sample was collected and mixed, it was placed on ice.
  • Blood samples were subsequently centrifuged at 4 °C for 10 minutes at 5,000 rpm.
  • the plasma was harvested into pre-labeled tubes and stored at -80 °C.
  • 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 was used to calculate various pharmacokinetic parameters and the results were summarized in the Table below:

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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 AND THEIR USE 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, U. S. Provisional Application Serial No.63/359,806 filed on July 9, 2022, and U. S. Provisional Application Serial No.63/381,056 filed on October 26, 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,
Figure imgf000003_0001
[0007] wherein [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_0001
[0029] In some embodiments, each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; provided that at least one R11 is a 4- to 10-membered heterocycloalkyl or at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re, wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10- membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; 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. [0030] In another aspect, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000009_0001
[0031] wherein [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 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 of the formula
Figure imgf000011_0001
, [0044] wherein * is a point of covalent attachment, [0045] each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; provided that at least one R11 is a 4- to 10-membered heterocycloalkyl or at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re, wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10- membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; 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; [0046] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0047] 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; 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; [0048] m is 1, 2, 3, 4, 5, or 6; [0049] n is 0, 1, 2, 3, 4, 5, 6, or 7; and [0050] p is 0 or 1. [0051] In another aspect, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000013_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 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 of the formula
Figure imgf000016_0001
, [0065] wherein * is a point of covalent attachment, [0066] each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; provided that at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; [0067] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0068] 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; 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; [0069] m is 1, 2, 3, 4, 5, or 6; [0070] n is 0, 1, 2, 3, 4, 5, 6, or 7; and [0071] p is 0 or 1. [0072] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000017_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 imgf000018_0001
[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 imgf000018_0002
[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 V, or a pharmaceutically acceptable salt thereof,
Figure imgf000019_0001
[0079] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0080] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000019_0002
[0081] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0082] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
Figure imgf000020_0001
[0083] wherein R2, R3, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0084] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000020_0002
[0085] wherein R2, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0086] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000021_0001
[0087] wherein R2, R3, R11, R13, 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 X, or a pharmaceutically acceptable salt thereof,
Figure imgf000021_0002
[0089] wherein R2, R11, R13, 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 XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000022_0001
[0091] wherein R1, R2, R3, R10, Ra, Rb, B, X, Z1, Z2, Z3, Z4, Z5, n, p, and q are as described herein. [0092] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000022_0002
[0093] wherein R2, R3, R10, R11, Ra, Rb, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0094] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000023_0001
[0095] 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. [0096] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000023_0002
[0097] wherein R2, R10, R11, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and q are as described herein. [0098] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
Figure imgf000024_0002
[0099] wherein R2, R3, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0100] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000024_0001
Figure imgf000025_0001
[0101] wherein R2, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0102] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000025_0002
[0103] wherein R2, R3, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0104] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000026_0002
[0105] wherein R2, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0106] In some embodiments, the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000026_0001
[0107] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0108] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
Figure imgf000027_0001
[0109] wherein R2, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0110] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
Figure imgf000027_0002
[0111] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0112] In some embodiments, the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0001
[0113] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0114] In some embodiments, the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000028_0002
[0115] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0116] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000029_0002
[0117] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0118] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
Figure imgf000029_0001
[0119] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0120] In some embodiments, the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000030_0001
[0121] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0122] In some embodiments, the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000030_0002
[0123] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0124] In some embodiments, the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000031_0001
[0125] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0126] In some embodiments, the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000031_0002
[0127] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0128] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
Figure imgf000032_0001
[0129] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0130] In some embodiments, the disclosure provides a compound of the formula XXXI, or a pharmaceutically acceptable salt thereof,
Figure imgf000032_0002
[0131] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0132] In certain embodiments of the above aspects, the compound of Formula (I)-(XXXIII) is a compound selected from those species described or exemplified in the detailed description below. [0133] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XXXIII) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient. [0134] In further aspects, the disclosure relates to a compound of Formula (I)-(XXXIII), or a pharmaceutically acceptable salt thereof, for use as a medicament. [0135] 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)-(XXXIII), or a pharmaceutically acceptable salt thereof. [0136] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XXXIII), 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. [0137] 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)-(XXXIII), 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. [0138] 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. [0139] 1. A compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000033_0001
[0140] wherein [0141] X is a -O-, -S-, or -NR4-; [0142] Z1 is N or C(R5); [0143] Z2 is N or C(R6); [0144] Z3 is N or C(R7); [0145] Z4 is N or C(R8); [0146] Z5 is N or C(R9); [0147] provided that at least two of Z1-Z5 are N; [0148] 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; [0149] 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; [0150] 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; [0151] 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; [0152] ring A is of the formula
Figure imgf000036_0001
, [0153] wherein * is a point of covalent attachment to
Figure imgf000036_0002
, [0154] each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; provided that at least one R11 is a 4- to 10-membered heterocycloalkyl or at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re, wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10- membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; 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; [0155] ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl; [0156] 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; 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; [0157] m is 1, 2, 3, 4, 5, or 6; [0158] n is 0, 1, 2, 3, 4, 5, 6, or 7; and [0159] p is 0 or 1. [0160] 2. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula V, XIX, XXII, XXVI, XXIX, or XXXII
Figure imgf000038_0001
Figure imgf000039_0001
[0161] wherein [0162] Z6 is N or C(R14); [0163] Z7 is N or C(R15); and [0164] 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. [0165] 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. [0166] 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. [0167] 5. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R3, when present, is
Figure imgf000041_0001
, , , [0168] wherein
Figure imgf000041_0003
is a point of covalent attachment. [0169] 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 –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. [0170] 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 imgf000041_0002
, [0171] 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, or two hydrogen atoms taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl optionally substituted with deuterium or fluorine; and
Figure imgf000042_0003
is a point of covalent attachment. [0172] 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 imgf000042_0001
[0173] wherein
Figure imgf000042_0004
is a point of covalent attachment. [0174] 9. The compound of any one of clauses 1 to 4, 6 to 8, wherein the compound is of the formula IV, VI, XX, XXI, XXIII, or XXIV,
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
[0175] or a pharmaceutically acceptable salt thereof. [0176] 10. The compound of any one of clauses 1 to 4, 6 to 9, wherein the compound is of the formula XXVII, XXVIII, XXX, or XXXI,
Figure imgf000044_0002
Figure imgf000045_0001
[0177] or a pharmaceutically acceptable salt thereof. [0178] 11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein m is 1. [0179] 12. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3. [0180] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein at least one R11 is -C1-C6 alkylOC1-C6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, -C1-C6 alkylOCs-C6 cycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen, C1-C6 alkylS(O)2C1-C6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, or 5- to 10-membered heterocycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen. [0181] 14. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein at least one R11 is -CH2-O-CH3, -CH2-O-CD3, -CH2-O-CF3, - CH2-O-CHF2, -CH2-O-cyclopropyl, -CH2CH2-O-CH3, -CH2CH2-O-CD3, -CH2CH2-O-CF3, - CH2CH2-O-CHF2, -CH2CH2-O-cyclopropyl, -CH2-O-CH2CH3,–CH2S(O)2CH3, -furanyl, or - oxetanyl. [0182] 15. The compound of any one of the preceding clauses, wherein ring A is of the formula
Figure imgf000046_0001
Figure imgf000047_0001
[0183] wherein * is a point of covalent attachment to
Figure imgf000047_0002
[0184] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z1 is N. [0185] 17. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z2 is N. [0186] 18. 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. [0187] 19. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is CR9. [0188] 20. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is N. [0189] 21. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is CR9. [0190] 22. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is N. [0191] 23. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is N, and Z5 is N. [0192] 24. The compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is CR8, and Z5 is N. [0193] 25. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein X is -O-. [0194] 26. The compound of any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X is –NR4-. [0195] 27. The compound of any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X is -S-. [0196] 28. The compound of any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, wherein p is 0. [0197] 29. 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. [0198] 30. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring B is
Figure imgf000048_0001
[0199] wherein
Figure imgf000048_0002
is a point of covalent attachment. [0200] 31. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R4, when present, is H or methyl. [0201] 32. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H. [0202] 33. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H. [0203] 34. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or F. [0204] 35. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H. [0205] 36. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H. [0206] 37. The compound of clause 1, 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- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol; [0207] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0208] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0209] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0210] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan- 3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0211] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(trifluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octan- 3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0212] 7-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-1,3-benzothiazol-2-amine; [0213] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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; [0214] 4-(4-{1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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; [0215] 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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; [0216] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0217] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0218] 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-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; [0219] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol; [0220] 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol; [0221] 7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; [0222] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidine; [0223] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl dimethylcarbamate; [0224] 3-chloro-5-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline; [0225] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0226] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0227] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- 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-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0229] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(oxetan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0230] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0231] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0232] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0233] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[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-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine; [0235] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]quinazolin-7-yl)naphthalen-2-ol; [0236] 6-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; [0237] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol; [0238] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0239] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0240] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0241] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0242] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; [0243] 2-amino-4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-7-fluoro-1-benzothiophene-3-carbonitrile; [0244] 2-amino-4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3- yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin- 7-yl)-7-fluoro-1-benzothiophene-3-carbonitrile; [0245] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]quinazolin-7-yl)naphthalen-2-ol; [0246] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]quinazolin-7-yl)naphthalen-2-ol; [0247] 6-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)- 4-methyl-5-(trifluoromethyl)pyridin-2-amine; [0248] 7-(3-chloro-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; [0249] 7-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; [0250] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-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-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0252] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0253] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0254] 2-amino-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-1-benzothiophene-3-carbonitrile; and [0255] 2-amino-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7- yl)-1-benzothiophene-3-carbonitrile; [0256] or a pharmaceutically acceptable salt thereof. [0257] 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. [0258] 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. [0259] 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. [0260] 41. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject. [0261] 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 [0262] 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. [0263] 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. [0264] 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. [0265] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense. [0266] 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. [0267] 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. [0268] 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. [0269] 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). [0270] As used herein and in connection with chemical structures depicting the vaious embodiments described herein, “*”, “**”, and
Figure imgf000055_0007
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 imgf000055_0003
Figure imgf000055_0001
, , where each of “-*”, “-**”, and
Figure imgf000055_0002
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 imgf000055_0004
Figure imgf000055_0006
where each of “-*”, “-**”, and
Figure imgf000055_0005
represents a bond to B and the point of covalent bond attachment to A. [0271] 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 [0272] 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. [0273] 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. [0274] 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. [0275] 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 imgf000057_0001
In particular, a cyclopropyl moiety can be depicted by the structural formula
Figure imgf000057_0002
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. [0276] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine. [0277] 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. [0278] 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 imgf000058_0001
[0279] 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. [0280] In particular, a hexahydro-1H-pyrrolizinyl moiety can be depicted by the structural formula
Figure imgf000059_0001
. [0281] 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. [0282] 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 imgf000060_0001
[0283] 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. [0284] In particular, an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula
Figure imgf000061_0001
. [0285] 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. [0286] 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. [0287] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone. [0288] 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. [0289] 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. [0290] 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. [0291] Certain chemical entities of Formula (I)-(XXXIII) 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 imgf000062_0002
[0292] In particular, a ring option of isoquinolin-3(2H)-oneylene can exist as the following tautomers
Figure imgf000062_0001
. [0293] 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). [0294] [0295] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XXXIII), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts. [0296] 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. [0297] 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. [0298] For a compound of Formula (I)-(XXXIII) 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. [0299] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXXIII), 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)-(XXXIII)). 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. [0300] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXXIII), 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)-(XXXIII) 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). [0301] 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 [0302] In some embodiments, the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000065_0001
[0303] wherein R1, R2, R3, Ra, Rb, B, X, Y, Z1, Z2, Z3, Z4, Z5, n, p, and q are as described herein. [0304] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000066_0001
[0305] wherein R2, R3, R11, Ra, Rb, A, B, X, Y, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0306] In some embodiments, the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000066_0002
[0307] wherein R2, R3, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0308] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof,
Figure imgf000067_0001
[0309] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0310] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000067_0002
[0311] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0312] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
Figure imgf000068_0001
[0313] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0314] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
Figure imgf000068_0002
[0315] wherein R2, R3, R11, R12, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0316] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000069_0001
[0317] wherein R2, R11, R12, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0318] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
Figure imgf000069_0002
[0319] wherein R2, R3, R11, R13, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0320] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
Figure imgf000070_0001
[0321] wherein R2, R11, R13, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0322] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
Figure imgf000070_0002
[0323] wherein R1, R2, R3, R10, Ra, Rb, B, X, Z1, Z2, Z3, Z4, Z5, n, p, and q are as described herein. [0324] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
Figure imgf000071_0001
[0325] wherein R2, R3, R10, R11, Ra, Rb, A, B, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0326] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000071_0002
[0327] 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. [0328] In some embodiments, the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000072_0001
[0329] wherein R2, R10, R11, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and q are as described herein. [0330] In some embodiments, the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof,
Figure imgf000072_0002
[0331] wherein R2, R3, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0332] In some embodiments, the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000073_0001
[0333] wherein R2, R10, R11, R12, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0334] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000074_0001
[0335] wherein R2, R3, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, p, and q are as described herein. [0336] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000074_0002
[0337] wherein R2, R10, R11, R13, Ra, Rb, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and q are as described herein. [0338] In some embodiments, the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000075_0002
[0339] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0340] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
Figure imgf000075_0001
[0341] wherein R2, R11, A, B, X, Z1, Z2, Z3, Z4, Z5, m, and n are as described herein. [0342] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
Figure imgf000076_0001
[0343] wherein R2, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0344] In some embodiments, the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof,
Figure imgf000076_0002
[0345] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0346] In some embodiments, the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000077_0001
[0347] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0348] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
Figure imgf000077_0002
[0349] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0350] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
Figure imgf000078_0001
[0351] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0352] In some embodiments, the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
Figure imgf000078_0002
[0353] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0354] In some embodiments, the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
Figure imgf000079_0001
[0355] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0356] In some embodiments, the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000079_0002
[0357] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0358] In some embodiments, the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
Figure imgf000080_0001
[0359] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, n, and p are as described herein. [0360] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
Figure imgf000080_0002
[0361] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0362] In some embodiments, the disclosure provides a compound of the formula XXXI, or a pharmaceutically acceptable salt thereof,
Figure imgf000081_0001
[0363] wherein R2, R11, X, Z1, Z2, Z3, Z4, Z5, Z6, Z7, m, and n are as described herein. [0364] In some embodiments, the disclosure provides a compound of the formula XXXII, or a pharmaceutically acceptable salt thereof,
Figure imgf000081_0002
[0365] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0366] In some embodiments, the disclosure provides a compound of the formula XXXIII, or a pharmaceutically acceptable salt thereof,
Figure imgf000082_0001
[0367] wherein R2, R3, R11, A, X, Z1, Z2, Z3, Z4, Z5, m, n, and p are as described herein. [0368] 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-, 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. [0369] 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. [0370] 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. [0371] 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 imgf000083_0001
[0372] 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. [0373] In some embodiments, Ring A is
Figure imgf000084_0001
Figure imgf000085_0001
, ,
Figure imgf000086_0001
wherein * is a point of covalent attachment to
Figure imgf000086_0002
and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. [0374] In some embodiments, Ring A is
Figure imgf000087_0002
, , , , , [0375] wherein * is a point of covalent attachment to
Figure imgf000087_0003
, and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. [0376] 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 as defined herein. [0377] In some embodiments, Ring A is
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
[0378] wherein * is a point of covalent attachment to
Figure imgf000089_0003
[0379] In some embodiments, Ring A is
Figure imgf000089_0002
, [0380] wherein * is a point of covalent attachment to
Figure imgf000089_0004
[0381] In some embodiments, Ring A is is an unsubstituted C6-C10 aryl or a C6-C10 aryl substituted with one or more of R11. In some embodiments, Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R11, or naphthyl substituted with one or more of R11. In some embodiments, Ring A is a unsubstituted phenyl, unsubstituted naphthyl, phenyl substituted with 1, 2, 3, 4, or 5 of R11, or naphthyl substituted with 1, 2, 3, 4, 5, or 6 of R11. [0382] In some embodiments, Ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with one or more of R11. In some embodiments, Ring A is an substituted 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R11. [0383] In some embodiments, Ring A is of the formula
Figure imgf000090_0001
[0384] wherein * is a point of covalent attachment to
Figure imgf000090_0003
and m is 0 or one or more. In some embodiments, m is 0, 1, 2, or 3. [0385] In some embodiments, Ring A is of the formula
Figure imgf000090_0002
, , , , , , ,
Figure imgf000091_0001
, , , [0386] wherein * is a point of covalent attachment to
Figure imgf000091_0003
[0387] In some embodiments, ring A is of the formula
Figure imgf000091_0002
, [0388] wherein * is a point of covalent attachment to
Figure imgf000091_0004
and [0389] each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; provided that at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl. [0390] In some embodiments, ring A is of the formula
Figure imgf000092_0001
[0391] wherein * is a point of covalent attachment to
Figure imgf000092_0002
and [0392] each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; provided that at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl. [0393] In some embodiments, ring A is of the formula
Figure imgf000093_0001
or [0394] wherein * is a point of covalent attachment to
Figure imgf000093_0002
and [0395] each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; provided that at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl. [0396] In some embodiments, ring A is of the formula [0397]
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0001
, , , , , , [0398] wherein * is a point of covalent attachment to
Figure imgf000095_0002
[0399] 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 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 of R11. [0400] 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. [0401] 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. [0402] In some embodiments, at least one R11 is -C1-C6 alkylOC1-C6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, -C1-C6 alkylOCs-C6 cycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen, or C1-C6 alkylS(O)2C1-C6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen. In some embodiments, at least one R11 is -CH2-O-CH3, -CH2-O-CD3, -CH2- O-CF3, -CH2-O-CHF2, -CH2-O-cyclopropyl, -CH2CH2-O-CH3, -CH2CH2-O-CD3, -CH2CH2-O- CF3, -CH2CH2-O-CHF2, -CH2CH2-O-cyclopropyl, -CH2-O-CH2CH3, or –CH2S(O)2CH3. [0403] 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, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. [0404] In some embodiments, ring B is a C6-C10 aryl or 5- to 10-membered heteroaryl, optuionally substituted with one or more R2, R12, or R13. [0405] In some embodiments, Ring B is
Figure imgf000097_0001
[0406] wherein * is a point of covalent attachment to
Figure imgf000098_0004
, R2, Z6, and Z7 are as described herein, and n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0407] In some embodiments, Ring B is
Figure imgf000098_0001
[0408] wherein * is a point of covalent attachment to 2 6 7
Figure imgf000098_0005
, R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, or 4. [0409] In some embodiments, Ring B is
Figure imgf000098_0002
[0410] wherein * is a point of covalent attachment to 2 6 7
Figure imgf000098_0006
R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0411] In some embodiments, Ring B is
Figure imgf000098_0003
[0412] wherein * is a point of covalent attachment to
Figure imgf000099_0003
, R2, Z6, and Z7 are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0413] In some embodiments, Ring B is
Figure imgf000099_0001
[0414] wherein * is a point of covalent attachment to 2 6 7
Figure imgf000099_0004
, R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0415] In some embodiments, Ring B is
Figure imgf000099_0002
[0416] wherein * is a point of covalent attachment to 2 6 7
Figure imgf000099_0005
R , Z , and Z are as described herein, n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0417] 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. [0418] In some embodiments, each R2 is independently deuterium, halogen, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, -ORc, or -NRcRd. 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. In some embodiments, each R2, when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -CF3, -C≡CH, - CN, -NH2, -OH, -OCH3, and -OC(O)N(CH3)2. [0419] 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. [0420] 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. [0421] 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. [0422] In some embodiments, Ring B is
Figure imgf000101_0001
, , , , , , , ,
Figure imgf000102_0001
[0423] In some embodiments, Ring B is
Figure imgf000102_0002
[0424] wherein
Figure imgf000102_0003
is a point of covalent attachment. [0425] In some embodiments, Ring B is
Figure imgf000103_0001
[0426] wherein
Figure imgf000103_0002
is a point of covalent attachment. [0427] In some embodiments, q is 0. In some embodiments, q is 1. [0428] 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-. [0429] 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. [0430] 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. [0431] 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. [0432] 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. [0433] In some embodiments, R3 is
Figure imgf000105_0001
, , , [0434] wherein
Figure imgf000105_0003
is a point of covalent attachment. [0435] In some embodiments, R3 is
Figure imgf000105_0002
, , [0436] wherein
Figure imgf000105_0004
is a point of covalent attachment. [0437] 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. [0438] 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; or two hydrogen atoms taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl otionally substituted with deuterium or fluorine. [0439] In some embodiments, R3 is of the formula
Figure imgf000106_0001
, [0440] 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. [0441] In some embodiments, R3 is of the formula
Figure imgf000106_0002
, [0442] 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; or two hydrogen atoms taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl otionally substituted with deuterium or fluorine. [0443] In some embodiments, R3 is of the formula
Figure imgf000107_0001
, [0444] 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. [0445] In some embodiments, R3 is of the formula
Figure imgf000107_0002
, [0446] 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; or two hydrogen atoms taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl otionally substituted with deuterium or fluorine. [0447] In some embodiments, R3 is of the formula
Figure imgf000108_0001
[0448] 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. [0449] 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. [0450] 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. [0451] 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. [0452] In some embodiments, Ra and Rb, when present, are each independently H, deuterium, methyl, ethyl, or isopropyl. In some embodiments, Ra, when present, is H, deuterium, methyl, ethyl, or isopropyl. In some embodiments, Rb, when present, is H, deuterium, methyl, ethyl, or isopropyl. [0453] 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-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0454] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0455] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0456] 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol; [0457] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan- 3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [0458] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(trifluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octan- 3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0459] 7-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-1,3-benzothiazol-2-amine; [0460] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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; [0461] 4-(4-{1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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; [0462] 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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; [0463] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0464] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; [0465] 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-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; [0466] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol; [0467] 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol; [0468] 7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; [0469] 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidine; [0470] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl dimethylcarbamate; [0471] 3-chloro-5-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline; [0472] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0473] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0474] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0475] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0476] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(oxetan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0477] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0478] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0479] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0480] 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0481] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine; [0482] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]quinazolin-7-yl)naphthalen-2-ol; [0483] 6-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; [0484] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol; [0485] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0486] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0487] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0488] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; [0489] 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; [0490] 2-amino-4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-7-fluoro-1-benzothiophene-3-carbonitrile; [0491] 2-amino-4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3- yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin- 7-yl)-7-fluoro-1-benzothiophene-3-carbonitrile; [0492] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]quinazolin-7-yl)naphthalen-2-ol; [0493] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]quinazolin-7-yl)naphthalen-2-ol; [0494] 6-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)- 4-methyl-5-(trifluoromethyl)pyridin-2-amine; [0495] 7-(3-chloro-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; [0496] 7-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; [0497] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0498] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0499] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0500] 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3- yl}quinazolin-7-yl)naphthalen-2-ol; [0501] 2-amino-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-1-benzothiophene-3-carbonitrile; and [0502] 2-amino-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7- yl)-1-benzothiophene-3-carbonitrile; [0503] or a pharmaceutically acceptable salt thereof. [0504] The following represent illustrative embodiments of compounds of Formula (I):
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
and pharmaceutically acceptable salts thereof. [0505] 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 [0506] 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. [0507] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions. [0508] 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. [0509] 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. [0510] 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. [0511] 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. [0512] 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. [0513] 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. [0514] 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. [0515] 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. [0516] The term “subject” refers to a mammalian patient in need of such treatment, such as a human. [0517] 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. [0518] 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. [0519] 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. [0520] 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). [0521] 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 [0522] 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. [0523] 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 [0524] 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)-(XXXIII). [0525] 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 imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
AcOH Acetic Acid
Figure imgf000132_0002
[0526] The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below. [0527] Scheme I
Figure imgf000132_0001
[0528] 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 80ºC, 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-protection if is required to provide the final product Ex. X. [0529] Scheme II
Figure imgf000133_0001
[0530] 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 de-protection if is required to afford the final product Ex. X. [0531] Scheme III
Figure imgf000133_0002
[0532] The general scheme III is used to prepare the products with general structure Ex. X. The bicyclic aryl core I-1-1, a variety of alcohol or amines 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 alcohol or amine I-4 are converted to a product II-2. C: under basic condition, the amine I- 2 will react with II-2 to provide a product III-1. D: under palladium-catalyzed Suzuki coupling condition, compound III-1 and a boronic ester I-6 are converted to a product which is de-protection if is required to afford the final product Ex. X. Intermediate Table
Figure imgf000134_0001
Figure imgf000135_0002
[0533] Preparation of tert-butyl (1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (I-1-2):
Figure imgf000135_0001
[0534] Step 1. To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28.0 g, 132 mmol, 1 eq) and TEA (16.0 g, 158 mmol, 22.0 mL, 1.2 eq) in DCM (660 mL) was added chloro(diphenyl)methyl]benzene (38.9 g, 139 mmol, 1.06 eq) and the reaction was stirred at 25 °C for 16 h. On completion, the mixture was concentrated under vacuum to give crude. The residue was purified by combi flash (120 g silica gel column, EtOAc in PE from 0% to 30%) to give tert-butyl 3-trityl-3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (56.0 g, 123 mmol, 93.4% yield) as white solid.1H NMR (400 MHz, CDCl3) δ 7.48 (s, 5H), 7.27 (s, 7H), 7.19 - 7.10 (m, 3H), 4.22 - 4.11 (m, 1H), 4.08 - 3.96 (m, 1H), 2.97 (d, J = 11.2 Hz, 2H), 2.41 - 2.31 (m, 2H), 2.03 - 1.95 (m, 2 H), 1.87 - 1.70 (m, 2 H), 1.26 (s, 9 H) [0535] Step 2. To a solution of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16.4 g, 36.2 mmol, 1 eq) and TMEDA (7.14 g, 61.5 mmol, 9.28 mL, 1.7 eq) in diethyl ether (170 mL) was added s-BuLi (1.3 M, 47.3 mL, 1.7 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 1.5 h. Then ethyl formate (8.04 g, 108 mmol, 8.73 mL, 3 eq.) was added to the mixture at -10 °C for 30 min. On completion, the reaction mixture was quenched with water (150 mL) and extracted with EtOAc (70 mL*3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give crude. The residue was purified by combi flash (120 g silica gel column, EtOAc in PE from 0%). tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.80 g, 14.1 mmol, 19.48% yield) as white solid.1H NMR (400 MHz, CDCl3) δ = 9.66 - 9.24 (m, 1H), 7.60 - 7.46 (m, 5H), 7.27 (s, 7H), 7.17 - 7.07 (m, 3H), 4.31 - 4.18 (m, 1H), 4.09 - 4.00 (m, 1H), 3.51 - 3.34 (m, 1H), 3.06 - 2.92 (m, 1H), 2.43 (s, 2H), 2.30 - 2.07 (m, 2H), 1.93 (d, J = 11.2 Hz, 1H), 1.78 (t, J = 12.4 Hz, 1H), 1.19 - 1.06 (m, 9H) [0536] Step 3. To a solution of tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (30.0 g, 62.2 mmol, 1 eq.) in DCM (300 mL) was added HCl/dioxane (4 M, 75 mL, 4.83 eq). The mixture was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was mixed with water (100 mL) and the organic and aqueous layers were separated. The aqueous layer was extracted by DCM (40 mL*4). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give tert-butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.50 g, 35.4 mmol, 56.9% yield) as colorless oil. [0537] Step 4. To a solution of tert-butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (8.50 g, 35.4 mmol, 1 eq) in THF (100 mL) was added sat. NaHCO3 (108 g, 1.29 mol, 50 mL, 36.3 eq) and CbzCl (7.84 g, 45.9 mmol, 6.54 mL, 1.3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was extracted with EtOAc (40 mL*4). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give 3-benzyl 8-tert-butyl 1-formyl-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (14.0 g, crude) as colorless oil. [0538] Step 5. To a solution of 3-benzyl 8-tert-butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane- 3,8-dicarboxylate (14.0 g, 37.4 mmol, 1 eq) in MeOH (150 mL) was added NaBH4 (2.12 g, 56.1 mmol, 1.5 eq). The mixture was stirred at 0 °C for 2 h. On completion, the mixture was concentrated under vacuum to give crude. This crude residue was purified by combi flash (40 g silica gel column, MeOH in DCM from 0% to 10%) to give 3-benzyl 8-tert-butyl 1- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.5 g, 30.6 mmol, 81.7% yield) as colorless oil. Chiral SFC resolution afforded 3-benzyl 8-tert-butyl (1R,5S)-1- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate. [0539] Step 6. To a solution of 3-benzyl 8-tert-butyl (1R,5S)-1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (4.90 g, 13.0 mmol, 1 eq.) in DCM (100 mL) was added TMSCHN2 (2 M, 13.0 mL, 2 eq) and BF3•Et2O (1.85 g, 13.0 mmol, 1.61 mL, 1 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. On completion, the reaction mixture was quenched by addition H2O 200 mL at 20 °C and extracted with DCM (50 mL * 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give 3-benzyl 8-tert-butyl (1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.10 g, 2.82 mmol, 22% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.29 (m, 5H), 5.25 - 5.07 (m, 2H), 4.25 (d, J = 15.2 Hz, 1H), 3.98 - 3.66 (m, 4H), 3.38 (s, 3H), 3.20 - 2.97 (m, 2H), 2.11 - 1.75 (m, 4H), 1.48 - 1.46 (m, 9H). [0540] Step 7. To a solution of 3-benzyl 8-tert-butyl (1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.05 g, 2.69 mmol, 1 eq) in i-PrOH (21 mL) was added Pd/C (420 mg, 10% purity) and Pd(OH)2/C (420 mg, 2.99 mmol, 1.11 eq). The reaction mixture was degassed and purged with H2 for 3 times, and then stirred at 20 °C for 1h under H2 atmosphere under 15 psi. On completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (655 mg, 2.56 mmol, 95% yield) as a light yellow oil. NMR (400 MHz, DMSO-d6) δ = 3.97 (br d, J = 6.3 Hz, 1H), 3.69 (br d, J = 8.1 Hz, 1H), 3.49 (d, J = 9.4 Hz, 1H), 3.24 (s, 3H), 2.73 (br d, J = 12.4 Hz, 1H), 2.69 - 2.63 (m, 1H), 2.60 - 2.54 (m, 1H), 2.49 - 2.41 (m, 1H), 2.00 - 1.88 (m, 1H), 1.85 - 1.69 (m, 2H), 1.68 - 1.54 (m, 1H), 1.40 (s, 9H). [0541] Preparation of tert-butyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (I-2-2):
Figure imgf000137_0001
Figure imgf000138_0001
[0542] Step 1. To a solution of 3-benzyl 8-(tert-butyl) 1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (11.5 g, 30.6 mmol, 1 eq) in DCM (60 mL) was added HCl/dioxane (4 M, 45 mL, 5.89 eq). The mixture was stirred at 20 °C for 3 h. On completion, the mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using MeOH in DCM to give benzyl 1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (6.00 g, 21.7 mmol, 71.1% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.29 (m, 5H), 5.21 - 5.07 (m, 2H), 3.98 - 3.73 (m, 2H), 3.55 (s, 3H), 3.11 - 2.84 (m, 2H), 1.94 - 1.57 (m, 5H). Chiral version benzyl (1R,5S)-1- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was prepared using this same procedure for racemic version. [0543] Step 2. To a mixture of imidazole (12.2 g, 179 mmol, 9 eq) in DCM (55 mL) at -78 °C was added SOCl2 (7.10 g, 59.7 mmol, 4.33 mL, 3 eq) and the mixture was stirred at -78 °C for 1 h. Then benzyl 1-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.50 g, 19.9 mmol, 1 eq) in DCM (10 mL) was added at -78 °C and the reaction mixture was stirred at 25 °C for 16 h. On completion, the mixture was quenched by aqueous NH4Cl (50 mL). Extraction workup with EtOAc, followed by concentration under vacuum to give benzyl dihydro-3H-3a,7-ethano[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate 1-oxide (6.30 g, 19.5 mmol, 98.2% yield) as light yellow oil. The chiral version benzyl (3aR,7S)-1- oxodihydro-1H,3H-3a,7-ethano-1λ4-[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate was prepared using this same procedure. [0544] Step 3. To a solution of benzyl dihydro-3H-3a,7-ethano[1,2,3]oxathiazolo[3,4- a]pyrazine-5(4H)-carboxylate 1-oxide (6.30 g, 19.5 mmol, 1 eq) in MeCN (180 mL) and H2O (60 mL) was added NaIO4 (5.43 g, 25.4 mmol, 1.41 mL, 1.3 eq) and RuCl3.3H2O (102 mg, 0.391 mmol, 0.02 eq). The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched by water (30 mL). Extraction workup with EtOAc followed by silica gel chromatography using EtOAc in PE to give benzyl dihydro-3H-3a,7- ethano[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate 1,1-dioxide (4.00 g, 11.8 mmol, 60.5% yield) as white solid. LCMS: (M + Na: 360.9). The chiral version benzyl (3aR,7S)- 1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6-[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)- carboxylate was prepared using this same procedure. [0545] Step 4. To a solution of benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6- [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate (1 eq) and (2H3)methanol (1 eq) in DMF is added NaH (1.5 eq) at 0 °C. The mixture is stirred at 25 °C for 1 h. On completion, the reaction mixture is concentrated to give a benzyl (1R,5S)-1-{[(2H3)methyloxy]methyl}- 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. [0546] Step 5. To a solution of benzyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1 eq) in DCM is added Boc2O (1.5 eq), DMAP (0.1 eq) and TEA (2 eq). The mixture is stirred at 25 °C for 16 h. On completion, the reaction mixture is concentrated under reduced pressure to remove solvent. The residue is purified by column chromatography to give 3-benzyl 8-tert-butyl (1R,5S)-1-{[(2H3)methyloxy]methyl}- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate. [0547] Step 6. A mixture of 3-benzyl 8-tert-butyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1 eq), Pd/C, and Pd(OH)2 in t-BuOH is degassed and purged with H2 for 3 times, and then the mixture is stirred at 25 °C for 1 h under H2 (15 psi). On completion, the reaction mixture is filtered and the filtrate is concentrated in vacuum to give product tert-butyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. [0548] tert-butyl (1R,5S)-1-[(trifluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (I-6-2) is prepared using similar procedure as I-2-2. [0549] Preparation of tert-butyl (1R,5S)-1-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (I-5-2).
Figure imgf000140_0001
[0550] Step 1. To a solution of benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6- [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate (50 mg, 0.148 mmol, 1 eq.) in DMF (0.5 mL) was added methylsulfanylsodium (20.7 mg, 0.296 mmol, 2 eq) at 25 ºC and the reaction mixture was stirred for 1 h. Then HCl (6 M, 0.1 mL, 4.06 eq) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give benzyl (1R,5S)-1-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (40 mg, 0.131 mmol, 88% yield) as white solid. LCMS: (M+1 = 307.0) [0551] Step 2. To a solution of benzyl (1R,5S)-1-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (10 mg, 0.0326 mmol, 1 eq) in DCM (0.5 mL) was added TEA (9.91 mg, 0.0979 mmol, 3 eq) and Boc2O (10.7 mg, 0.049 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was added H2O (10 mL), extracted with EA (10 mL*2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum to give 3-benzyl 8-tert-butyl (1R,5S)-1-[(methylsulfanyl)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (13 mg, 0.032 mmol, 98.0% yield) as white solid. LCMS: (M+Na = 429.1) [0552] Step 3. To a solution of 3-benzyl 8-tert-butyl (1R,5S)-1-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.0 eq.) in CH2Cl2 is added m-chloroperbenzoic acid (2.2 eq.) at room temperature and the mixture is stirred for 16 h. The reaction mixture is filtered, washed with aqueous NaHCO3, and brine, and the organic phase is separated, dried (Na2SO4) and concentrated in vacuo affording 3-benzyl 8-tert-butyl (1R,5S)-1- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate. [0553] Step 4. A mixture of 3-benzyl 8-tert-butyl (1R,5S)-1-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1 eq), Pd/C, and Pd(OH)2 in t-BuOH is degassed and purged with H2 for 3 times, and then the mixture is stirred at 25 °C for 1 h under H2 (15 psi). On completion, the reaction mixture is filtered and the filtrate is concentrated in vacuum to give product tert-butyl (1R,5S)-1-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (I-5-2). [0554] Preparation of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (I-8-2) and tert-butyl 1-[(cyclopropyloxy)methyl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-8a-2):
Figure imgf000141_0001
[0555] Step 1. To a solution of benzyl 1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6- [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate (82.0 mg, 0.242 mmol, 1 eq.) and cyclopropanol (14.1 mg, 0.242 mmol, 1 eq) in DMF (1 mL) was added NaH (14.5 mg, 0.364 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated to give a benzyl 1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (76 mg, 0.240 mmol, 99% yield) as yellow oil which was used into the next step without further purification. LCMS: (M+1: 317.1). Chiral version benzyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-3- carboxylate is prepared with this same procedure from benzyl (3aR,7S)-1,1-dioxodihydro- 1H,3H-3a,7-ethano-1λ6-[1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate. [0556] Step 2. To a solution of benzyl 1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (187 mg, 0.591 mmol, 1 eq) in DCM (2 mL) was added Boc2O (193 mg, 0.887 mmol, 1.5 eq), DMAP (7.22 mg, 0.059 mmol, 0.1 eq) and TEA (120 mg, 1.18 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, PE/THF=1/0 to 0/1) to give 3-benzyl 8-tert- butyl 1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (159 mg, 382 umol, 65% yield) as light yellow oil. LCMS: (M+23: 439.1). The chiral version 3-benzyl 8-tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate is prepared using this same procedure. [0557] Step 3. A mixture of 3-benzyl 8-tert-butyl 1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (159 mg, 0.382 mmol, 1 eq), Pd/C (0.0160 g, 10% purity, 1.00 eq), Pd(OH)2 (0.0160 g, 10% purity, 1.00 eq) in t-BuOH (10 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 1 h under H2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuum to give product tert-butyl 1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (I-8a-2, 100 mg, 0.354 mmol, 93% yield) as light yellow oil. LCMS: (M-100+1: 183.1). The chiral version tert-butyl (1R,5S)-1- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-8-2) is prepared using this same procedure from benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6- [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate. [0558] Preparation of tert-butyl (1R,5S)-1-[(difluoromethoxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (I-9-2):
Figure imgf000142_0001
[0559] Step 1. To a solution of 3-benzyl 8-tert-butyl (1R,5S)-1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1 g, 2.66 mmol, 1 eq.) in DCM (5 mL) and H2O (5 mL) was added [bromo(difluoro)methyl]-trimethyl-silane (1.08 g, 5.31 mmol, 2 eq) and KOAc (1.04 g, 10.63 mmol, 4 eq). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 80:20) to give 3-benzyl 8-tert-butyl (1R,5S)-1-[(difluoromethoxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (130 mg, 0.304 mmol, 11% yield) as a colorless oil. LCMS: (M+23:449.2) [0560] Step 2. A mixture of 3-benzyl 8-tert-butyl (1R,5S)-1-[(difluoromethoxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (130 mg, 0.304 mmol, 1 eq), Pd/C (20 mg, 0.304 mmol, 10% purity) in i-PrOH (1.5 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 2 hrs. under H2 atmosphere (15 psi). The mixture was filtered, and the filtrate was concentrated in vacuum to give tert-butyl (1R,5S)-1- [(difluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65 mg, 0.222 mmol, crude) as a yellow oil. LCMS: (M+1:293.0), which is used directly to the next step. [0561] Preparation of tert-butyl 1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (I-10-2):
Figure imgf000143_0001
[0562] Step 1. To a solution of methoxymethyl(triphenyl)phosphonium;bromide (1.55 g, 4.01 mmol, 3 eq) in THF (15 mL) was added KHMDS (1 M, 4.01 mL, 3 eq) slowly at 0 °C, the resulting mixture was stirred at 25 °C for 30 min, then 3-benzyl 8-tert-butyl 1-formyl-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (500 mg, 1.34 mmol, 1 eq.) in THF (10 mL) was added to the mixture and stirred for 30 min at -78 °C, the resulting mixture was allowed to warm to 25 °C and stirred for another 1 h. On completion, the mixture was quenched with water (75 mL) and extracted with ethyl acetate (35 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=6:1) to give 3-benzyl 8-tert-butyl 1- [(E)-2-methoxyethenyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (500 mg, 1.24 mmol, 93% yield) as a white solid. LCMS: (M+1:402.8). [0563] Step 2. To a solution of 3-benzyl 8-tert-butyl 1-[(E)-2-methoxyethenyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (450 mg, 1.12 mmol, 1 eq) in i-PrOH (4.5 mL) was added Pd/C (200 mg, 1.12 mmol, 10% purity, 1 eq) at 25 °C, the reaction was stirred at 25 °C for 1 h under H2 (15 psi). On completion, the mixture was filtered and concentrated to give tert-butyl 1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (I-10-2, 280 mg, 1.04 mmol, 93% yield) as a white oil. [0564] General Method A [0565] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.1)
Figure imgf000144_0001
[0566] Step 1. To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (650 mg, 2.57 mmol, 1.1 eq) in DCM (24 mL) was added DIEA (1.82 g, 14.0 mmol, 2.45 mL, 6 eq). Then tert-butyl (1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 2.34 mmol, 1 eq.) was added into the mixture at -40 °C for 1 h under N2. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 2.22 mmol, 95% yield) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.91 (s, 1H), 4.78 - 4.69 (m, 1H), 4.51 - 4.42 (m, 2H), 4.11 - 4.05 (m, 1H), 3.81 - 3.73 (m, 1H), 3.69 (d, J = 9.4 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.38 (s, 3H), 2.04 - 1.96 (m, 2H), 1.85 - 1.77 (m, 1H), 1.70 - 1.62 (m, 1H), 1.53 (s, 9H). [0567] Step 2. A mixture of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoro-pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (950 mg, 2.01 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (640 mg, 4.02 mmol, 2 eq), DIEA (1.04 g, 8.05 mmol, 1.40 mL, 4 eq) in dioxane (19 mL) was stirred at 80 °C for 16 h. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900 mg, 1.51 mmol, 75% yield) as a light yellow solid. LCMS: (M+1: 595.4). [0568] Step 3. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (640 mg, 1.08 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 (1.10 g, 2.15 mmol, 2 eq), K3PO4 (685 mg, 3.23 mmol, 3 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanesulfonate (78.3 mg, 0.108 mmol, 0.1 eq) in dioxane (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 mixture was dried over anhydrous Na2SO4, filtered, and the solid was washed with EtOAc (10 mL*3). The combined organic layer was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (12 g silica gel column, THF in PE from 0-100%) to give tert-butyl (1R,5S)-3-(8- fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin- 4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3 g, crude) as a light yellow oil. LCMS: (M+1: 945.5). [0569] Step 4. To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.106 mmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 1 mL, 37.8 eq), and then the mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under reduced pressure to give a 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (72.0 mg, 0.0899 mmol, 85% yield) as a yellow solid. LCMS: (M+1: 801.4). [0570] Step 5. A mixture of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (70.0 mg, 0.0874 mmol, 1 eq) and CsF (79.7 mg, 0.524 mmol, 6 eq) in DMSO (1 mL) was stirred at 25 °C for 2 h. On completion, the mixture was filtered and the filtrate was purified by reversed-phase HPLC column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 7%-37%,58 min] to give 5-ethynyl-6-fluoro-4-(8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (20.09 mg, 0.0312 mmol, 35.6% yield, 100% purity) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.20 (br s, 1H), 8.03 - 7.93 (m, 1H), 7.46 (br t, J = 8.9 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.19 (br s, 1H), 5.38 - 5.19 (m, 1H), 4.57 - 4.50 (m, 1H), 4.42 (br s, 1H), 3.88 (br s, 2H), 3.75 - 3.59 (m, 3H), 3.57 - 3.46 (m, 3H), 3.34 (s, 3H), 3.21 - 3.08 (m, 2H), 3.08 - 2.98 (m, 1H), 2.84 (br d, J = 5.6 Hz, 1H), 2.15 (br s, 1H), 2.07 (br s, 1H), 2.01 (br s, 1H), 1.90 - 1.67 (m, 6H), 1.54 (br d, J = 8.9 Hz, 1H). LCMS: (M+1: 645.3). [0571] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.2)
Figure imgf000146_0001
Figure imgf000147_0001
[0572] Step 1. Na (816 mg, 35.5 mmol, 841 uL, 10 eq) was added to trideuterio(deuteriooxy)methane (10.7 g, 296 mmol, 12.0 mL, 83.3 eq) at 0 °C, and the mixture was stirred at 0 ~ 25 °C for 1 h. Then the mixture above was added to the solution of benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6-[1,2,3]oxathiazolo[3,4- a]pyrazine-5(4H)-carboxylate (1.20 g, 3.55 mmol, 1 eq) in DMF (12 mL) at 0 °C. And then the mixture was stirred at 20 °C for 1 h. On completion, 1 M HCl was added until pH = 3, and the mixture was stirred at 20 °C for 1 h. This mixture was concentrated under reduced pressure to give benzyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate (1 g, 3.41 mmol, 96% yield) as a colorless oil. [0573] Step 2. To a solution of benzyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1 g, 3.41 mmol, 1 eq) in DCM (10 mL) was added Boc2O (744 mg, 3.41 mmol, 783 uL, 1 eq) and TEA (2.41 g, 23.9 mmol, 3.32 mL, 7 eq), and the mixture was stirred at 0 °C for 1 h. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give 3-benzyl 8-tert-butyl (1R,5S)- 1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.3 g, 3.30 mmol, 97% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.29 (m, 5H), 5.22 - 5.09 (m, 2H), 4.25 (br d, J = 14.8 Hz, 1H), 4.00 (br d, J= 12.8 Hz, 1H), 3.92 (br d, J = 12.4 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.80 - 3.74 (m, 1H), 3.72 - 3.66 (m, 1H), 3.17 - 2.99 (m, 2H),2.04 - 1.82 (m, 3H), 1.47 (s, 9H). LCMS: (M-56:338.1) [0574] Step 3. To a solution of 3-benzyl 8-tert-butyl (1R,5S)-1-{[(2H3)methyloxy]methyl}- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1 g, 2.54 mmol, 1 eq) in i-PrOH (10 mL) was added Pd/C (200 mg, 2.54 mmol, 10% purity, 1.00 eq) and Pd(OH)2 (200 mg, 1.42 mmol, 0.56 eq), and the mixture was degassed and purged with H2 for 3 times and then stirred at 20 °C for 1h under H2 atmosphere under 15 psi. On completion, the mixture was filtered and concentrated under reduced pressure to give tert-butyl (1R,5S)-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (620 mg, 2.39 mmol, 94% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 4.23 - 3.90 (m, 1H), 3.85 - 3.44 (m, 2H), 3.09 - 2.74 (m, 1H), 2.06 - 1.69 (m, 2H), 1.67 - 1.49 (m, 2H), 1.48 - 1.26 (m, 9H). LCMS: (M-56+1:204.1). [0575] Step 4. To a mixture of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (905 mg, 3.59 mmol, 1.5 eq) in DCM (14 mL) was added DIEA (1.85 g, 14.34 mmol, 2.50 mL, 6 eq). Then tert-butyl (1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (620 mg, 2.39 mmol, 1 eq) was added into the mixture at -40 °C for 1 h under N2. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (12 g silica gel column, THF in PE from 0-100%) to give tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (190 mg, 399 umol, 17% yield) as a light yellow oil. [0576] 1H NMR (400 MHz, CDCl3) δ = 4.83 - 4.67 (m, 1H), 4.51 - 4.40 (m, 2H), 4.16 - 4.03 (m, 1H), 3.79 - 3.73 (m, 1H),3.68 (d, J = 9.2 Hz, 1H), 3.55 (br d, J = 12.8 Hz, 1H), 2.04 - 1.98 (m, 2H), 1.84 - 1.76 (m, 1H), 1.69 - 1.64 (m, 1H), 1.53 (s, 9H). LCMS: m/z 475.1 (M+1). [0577] Step 5. To a solution of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (185 mg, 389 umol, 1 eq) and [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methanol (124 mg, 778 umol, 2 eq) in dioxane (4 mL) was added DIEA (201 mg, 1.56 mmol, 271 uL, 4 eq). The mixture was stirred at 80 °C for 16 h. On completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (12g silica gel column, THF in PE from 0-100%) to givetert-butyl (1R,5S)-3-(7- chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (135 mg, 226 umol, 58% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.78 (s, 1H), 5.43 - 5.15 (m, 1H), 4.63 (br d, J = 12.8 Hz, 1H), 4.50 - 4.39 (m, 2H),4.37 - 4.26 (m, 1H), 4.12 - 4.00 (m, 1H), 3.65 (s, 2H), 3.55 - 3.47 (m, 1H), 3.35 - 3.17 (m, 2H), 3.06 - 2.95 (m, 1H), 2.36 - 2.27(m, 1H), 2.25 - 2.09 (m, 2H), 2.03 - 1.80 (m, 6H), 1.53 (s, 9H), 1.44 (s, 2H). LCMS: m/z 598.4 (M+1). [0578] Step 6. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 201 umol, 1 eq), {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (206 mg, 401 umol, 2 eq), K3PO4 (128 mg, 602 umol, 3 eq), and [2-(2-aminophenyl)phenyl]palladium(1+), bis(1-adamantyl)-butyl- phosphane;methanesulfonate (14.6 mg, 20.1 umol, 0.1 eq) in dioxane (2 mL) and H2O (0.4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (12g silica gel column, THF in PE from 0-100%) to give tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 190 umol, 95% yield) as a yellow oil. [0579] 1H NMR (400 MHz, CDCl3) δ = 7.37 (br s, 3H), 7.27 (s, 1H), 4.47 (d, J = 4.8 Hz, 5H), 4.44 (s, 2H), 3.87 (s, 6H),3.55 - 3.46 (m, 3H), 3.01 - 2.85 (m, 1H), 2.73 (br s, 8H), 1.73 (br s, 6H), 1.45 (s, 18H), 1.30 - 1.23 (m, 1H), 1.11 (d, J = 6.8 Hz,9H). LCMS: m/z 948.4 (M+1). [0580] Step 7. To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170 mg, 179 umol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 44.8 uL, 1 eq). The mixture was stirred at 20 °C for 0.5 h. On completion, the mixture was concentrated under reduced pressure to give 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (140 mg, 174 umol, 97 % yield) as a brown solid. LCMS: m/z 805.3 (M+1). [0581] Step 8. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (140 mg, 174 umol, 1 eq) in DMSO (2 mL) was added CsF (159 mg, 1.04 mmol, 6 eq), and the mixture was stirred at 25 °C for 0.75 h. On completion, the mixture was filtered to remove CsF. The solution was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 3%- 33%,10min) to give5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (57.75 mg, 83.25 umol, 47.81% yield, as formic acid salt) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.15 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.39 (d, J =2.4 Hz, 1H), 7.19 (s, 1H), 5.40 - 5.18 (m, 1H), 4.59 - 4.47 (m, 1H), 4.43 - 4.33 (m, 1H), 4.16 (dd, J = 3.6, 10.4 Hz, 1H), 4.08 -4.02 (m, 1H), 3.93 - 3.87 (m, 1H), 3.53 - 3.47 (m, 5H), 3.16 - 3.00 (m, 4H), 2.87 - 2.80 (m, 1H), 2.15 (br d, J = 4.4 Hz, 1H), 2.09- 1.97 (m, 2H), 1.89 - 1.69 (m, 6H), 1.57 - 1.45 (m, 1H). LCMS: m/z 648.2 (M+1). [0582] Preparation of 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol (Ex.3)
Figure imgf000150_0001
[0583] Step 1. To a solution of ethyl (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-8- carboxylate (3.4 g, 16.90 mmol, 1 eq) in MeOD (40 mL) at 0°C was added sodium borodeuteride (958.80 mg, 25.34 mmol, 1.5 eq). The mixture was stirred at 25°C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (12 g silica gel, MeOH in DCM from 0% to 100%) to give [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methanol (1.5 g, 9.30 mmol, 55.07% yield) as a white oil.1H NMR (400 MHz, DMSO-d6) δ = 5.32 - 5.06 (m, 1H), 3.35 (s, 3H), 3.01 - 2.97 (m, 1H), 2.92 (s, 1H), 2.81 - 2.72 (m, 1H), 2.08 - 1.92 (m, 1H), 1.85 - 1.72 (m, 3H), 1.65 - 1.61 (m, 1H). [0584] Step 2. To a solution of [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methanol [0585] (202.2 mg, 1.27 mmol, 1 eq.) in THF (15 mL) was added NaH (66 mg, 1.65 mmol, 60 % purity, 1.3 eq). The mixture was stirred at 0 °C for 1 hour, tert-butyl (1R,5S)-3-(2,7- dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 1.27 mmol, 1 eq) was then added into the mixture. The mixture was stirred at 0 °C for 1 hour. On completion the reaction mixture was quenched by addition of H2O (100 mL) at 25 °C, and then diluted with EA 100 mL and extracted with EA (200 mL * 3). The combined organic layers were washed with NaCl.aq 200 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 43% yield, 96 % purity) as yellow solid. LCMS: m/z 472.0 (M+1). [0586] Step 3. To a mixture of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 334 umol, 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 (171 mg, 334 umol, 1 eq) in THF (5 mL) and H2O (1 mL) was added tripotassium;phosphate (213 mg, 1.00 mmol, 3 eq) and [2-(2- aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane;methanesulfonate (121.97 mg, 167.48 umol, 0.5 eq). The mixture was stirred at 80 °C for 12 hours. On completion the reaction mixture was quenched by addition H2O (3 mL), and then diluted with H2O (10 mL) and extracted with EA (10mL * 3). The combined organic layers were washed with sat. NaCl 10 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:2) to give the compound tert-butyl (1R,5S)-3-{8-fluoro-7- [7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2- ({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3- d]pyrimidin-4-yl}-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 31% yield) as a yellow solid. LCMS: m/z 947.4 (M+1). [0587] Step 4. To a solution of tert-butyl (1R,5S)-3-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl}-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 95 umol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 23.7 uL) .The mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give the compound 6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl}-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (70 mg, 91% yield) as a yellow solid. [0588] LCMS: m/z 803.3 (M+1). [0589] Step 5. To a solution of 6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl}-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (70 mg, 87.1 umol, 1 eq) in DMSO (2 mL) was added CsF (66.2 mg, 435 umol, 5 eq). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC(column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(FA)-ACN]; B%: 3%-33%,min) to give the compound 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol (12.2 mg, 20% yield, 98.6% purity, as formic acid salt) as white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.30 - 10.03 (m, 1H), 9.04 (s, 1H), 7.98 (dd, J = 6.0, 9.2 Hz, 1H), 7.47 (t, J = 8.8 Hz, 1H),7.40 (d, J = 2.4 Hz, 1H), 7.22 - 7.16 (m, 1H), 5.38 - 5.19 (m, 1H), 4.58 - 4.31 (m, 2H), 3.96 - 3.85 (m, 1H), 3.60 (s, 2H), 3.50 -3.46 (m, 2H), 3.44 (s, 1H), 3.40 (s, 3H), 3.12 - 3.07 (m, 2H), 3.02 (s, 1H), 2.87 - 2.79 (m, 1H), 2.14 (d, J = 4.0 Hz, 1H), 2.06 (d,J = 2.4 Hz, 1H), 2.01 (d, J = 8.8 Hz, 1H), 1.87 (d, J = 5.2 Hz, 1H), 1.82 - 1.74 (m, 3H), 1.71 - 1.65 (m, 2H), 1.51 - 1.43 (m, 1H),1.24 (s, 1H). [0590] LCMS: m/z 647.4 (M+1). [0591] Preparation of 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl}naphthalen-2-ol (Ex.4)
Figure imgf000153_0001
[0592] Step 1. The mixture of tert-butyl (1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.294 mmol, 1 eq.), [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methanol (104 mg, 0.647 mmol, 2.2 eq.) and DIEA (152 mg, 1.18 mmol, 205 uL, 4 eq.) in dioxane (2 mL) was stirred at 80 °C for16 h. The reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (20 g silica gel column, MeOH in DCM from 0% to 10%) to give tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2- ({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3- d]pyrimidin-4-yl]-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (146 mg, 0.227 mmol, 77.4% yield, 93.7% purity) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.78 (s, 1H), 5.41 - 5.18 (m, 1H), 4.63 (d, J = 13.2 Hz, 1H), 4.52 - 4.36 (m, 2H), 4.05 (d, J = 9.2 Hz, 1H), 3.73 - 3.62 (m, 2H), 3.50 (d, J = 13.2 Hz, 1H), 3.39 - 3.15 (m, 3H), 3.06 - 2.95 (m, 1H), 2.24 - 2.08 (m, 2H), 2.01 - 1.91 (m, 4H), 1.64 (d, J = 10.4 Hz, 4H), 1.53 (s, 9H). LCMS: m/z 600.3 (M+1). [0593] Step 2. To a mixture of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 0.183 mmol, 1 eq) and {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (187 mg, 0.366 mmol, 2 eq) ,K3PO4 (2 M, 304 uL, 3.32 eq) in dioxane (1.5 mL) was added [2-(2- aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane;methanesulfonate (20.0 mg, 27.4 umol, 0.15 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 10 h under microwave. The reaction mixture was concentrated in vacuo to give the residue. The residue was purified by silica gel chromatography (40 g silica gel column, MeOH in DCM from 0% to 10%) to give tert-butyl (1R,5S)-3-{8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2- ({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3- d]pyrimidin-4-yl}-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.110 mmol, 60.4% yield, 87.8% purity). [0594] 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.13 (d, J = 14.4 Hz, 1H), 7.79 (ddd, J = 1.2, 5.6, 9.2 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 2.4, 6.4 Hz, 1H), 7.33 - 7.29 (m, 1H), 5.32 - 5.28 (m, 2H), 4.88 - 4.75 (m, 1H), 4.48 - 4.41 (m, 1H), 4.38 - 4.16 (m, 1H), 4.09 - 3.99 (m, 1H), 3.76 (d, J = 9.6 Hz, 1H), 3.51 (s, 3H), 3.39 dd, J = 6.8, 12.4 Hz, 1H), 3.32 - 3.19 (m, 2H), 3.07 - 2.98 (m, 1H), 2.35 - 2.16 (m, 3H), 2.03 (d, J = 4.0 Hz, 6H), 1.91 - 1.85 (m, 2H), 1.25 (s, 9H), 0.97 - 0.93 (m, 2H), 0.89 - 0.84 (m, 18H), 0.60 - 0.50 (m, 3H). LCMS: m/z 950.5 (M+1). [0595] Step 3. To a solution of tert-butyl (1R,5S)-3-{8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl}-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.105 mmol, 1 eq) in DCM (5 mL) was added HCl/dixoane (4 M, 1 mL, 38.0eq) at 25 °C and the mixture was stirred for 1 h. The reaction mixture was then concentrated in vacuum to give tert-butyl (1R,5S)-3-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl]-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl}-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (84.8 mg, 0.100 mmol, 95.6% yield, HCl) as a yellow solid. LCMS: m/z 806.5 (M+1). [0596] Step 4. To a solution of 6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl}-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (84.8 mg, 0.100 mmol, 1 eq, HCl) in DMSO (1 mL) was added CsF (305.78 mg, 2.01 mmol, 20 eq), and the mixture was stirred at 25 °C for 2 h .The reaction mixture was filtered to remove CsF, and the filtrate was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 4%-34%, 58min) to give Ex.4, 5-ethynyl-6-fluoro-4-{8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)-4-[(1R,5S)-1- {[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl}naphthalen-2-ol (30.33 mg, 0.0423 mmol, 42.01% yield, 97% purity, as formic acid salt) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.18 (s, 1H), 7.97 (dd, J = 6.0, 8.8 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.39 (s, 1H), 7.18 (s, 1H), 5.43 - 5.13 (m, 1H), 4.56 - 4.47 (m, 1H), 4.42 - 4.33 (m, 1H), 3.94 - 3.87 (m, 2H), 3.57 (d, J = 11.6 Hz, 1H), 3.50 - 3.44 (m, 3H), 3.13 - 3.01 (m, 3H), 2.87 - 2.80 (m, 1H), 2.15 - 1.97 (m, 3H), 1.92 - 1.64 (m, 7H), 1.51 - 1.42 (m, 1H). LCMS: m/z 650.3 (M+1). [0597] Preparation of 7-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-1,3-benzothiazol-2-amine (Ex.7)
Figure imgf000155_0001
[0598] Step 1. To A mixture of tert-butyl [7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamate (66.25 mg, 0.168 mmol, 1 eq.), tert- butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (100 mg, 0.168 mmol, 1 eq.) , [2-(2-aminophenyl)phenyl] palladium(1+) ; bis(1-adamantyl)-butyl-phosphane;methanesulfonate (12.24 mg, 16.80 umol, 0.1 eq) , and K3PO4 (107.01 mg, 504.13 umol, 3 eq) in H2O (0.3 mL) and dioxane (1.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 C for 16 hrs under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (20 mL × 3) and water (20 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 0:1) to give tert-butyl (1R,5S)- 3-(7-{2-[(tert-butoxycarbonyl)amino]-7-fluoro-1,3-benzothiazol-4-yl}-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (48 mg, 34.54% yield) as yellow oil. LCMS: m/z 827.2 (M+1). [0599] Step 2. To a solution of tert-butyl (1R,5S)-3-(7-{2-[(tert-butoxycarbonyl)amino]-7- fluoro-1,3-benzothiazol-4-yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 24.19 umol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.1 mL). The mixture was stirred at 25 C for 1 hr. On completion, the reaction mixture was partitioned between ethyl acetate (10 mL × 3) and water (10mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The crude product was purified by reversed-phase HPLC(column: Phenomenex Luna C1850*25mm*10um;mobile phase: [column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(FA)-CN];B%: 0%- 30%,15min) to give Ex.7, 7-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)-1,3-benzothiazol-2-amine (7.51 mg, 45% yield, 98% purity, as formic acid salt) as off-white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.43 (dd, J = 5.6, 8.4 Hz, 1H), 7.07 (t, J = 8.8 Hz,1H), 5.43 - 5.04 (m, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.18 - 3.99 (m, 2H), 3.60 - 3.52 (m, 8H), 3.32 (s, 3H), 3.10 - 3.07 (m, 1H),3.16 - 3.00 (m, 4H), 2.88 - 2.78 (m, 1H), 2.14 - 1.97 (m, 2H), 1.88 - 1.69 (m, 3H), 1.64 - 1.57 (m, 1H), 1.51 - 1.38 (m, 1H). LCMS: m/z 627.2 (M+1). [0600] Preparation of 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[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 (Ex.8)
Figure imgf000157_0001
[0601] Step 1. To a solution of benzyl (3aR,7S)-1,1-dioxodihydro-1H,3H-3a,7-ethano-1λ6- [1,2,3]oxathiazolo[3,4-a]pyrazine-5(4H)-carboxylate (2.8 g, 8.27 mmol, 1 eq) in DMF (28 mL) was added cyclopropanol (480 mg, 8.27 mmol, 1 eq), and then NaH (496 mg, 12.4 mmol, 60% purity, 1.5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition 6 M HCl (5 mL) at 0 °C and stirred for 0.5 h, and then mixture was concentrated under reduced pressure to remove solvent to give benzyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (2.5 g, 7.90 mmol, 96% yield) as brown oil. LCMS: (M+1 = 317.1). [0602] Step 2. To a solution of benzyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (2.5 g, 7.90 mmol, 1 eq) in DCM (25 mL) was added Boc2O (2.59 g, 11.9 mmol, 2.72 mL, 1.5 eq) and TEA (1.60 g, 15.8 mmol, 2.20 mL, 2 eq). The mixture was stirred at 25 °C for 16 h. 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 3-benzyl 8-tert- butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.34 g, 5.62 mmol, 71% yield) as yellow oil. LCMS: (M-100+1 = 317.0). [0603] Step 3. A mixture of 3-benzyl 8-tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.34 g, 5.62 mmol, 1 eq), Pd/C (200 mg, 10% purity, 1.00 eq), Pd(OH)2 (200 mg, 0.142 mmol, 10% purity) in i-PrOH (25 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 1 h under H2 atmosphere (15 psi). On completion, the mixture was filtrated to remove Pd/C and Pd(OH)2. And the filtrate was concentrated under reduced pressure to remove solvent to give tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.53 g, 5.42 mmol, 96% yield) as colorless oil.1H NMR (400 MHz, CDCl3) δ = 4.15 (br s, 1H), 4.07 - 3.96 (m, 1H), 3.79 - 3.72 (m, 1H), 3.32 - 3.24 (m, 1H), 3.05- 2.90 (m, 2H), 2.59 (dd, J = 2.0, 12.4 Hz, 2H), 1.96 - 1.92 (m, 2H), 1.71 - 1.64 (m, 2H), 1.48 (s, 8H), 1.21 (d, J = 6.0 Hz, 2H), 0.60 - 0.40 (m, 4H). [0604] Step 4. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.98 g, 7.86 mmol, 1.5 eq) in DCM (20 mL) was added DIEA (4.06 g, 31.5 mmol, 5.48 mL, 6 eq) and tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.48 g, 5.24 mmol, 1 eq) at -40 °C under N2 atmosphere. The mixture was stirred at -40 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1/0 to 0/1) to give tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-(2,7-dichloro- 8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 4.82 mmol, 92% yield) as yellow oil. LCMS: (M+1 = 498.1). [0605] Step 5. A mixture of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-(2,7-dichloro- 8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.3 g, 4.61 mmol, 1 eq), [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methanol (1.10 g, 6.92 mmol, 1.5 eq), and DIEA (1.79 g, 13.84 mmol, 2.41 mL, 3 eq) in dioxane (10 mL) was stirred at 80 °C for 16 h. 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 tert-butyl (1R,5S)-3-(7-chloro-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.32 g, 3.74 mmol, 81% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.75 (S, 1H), 5.40 - 5.19 (m, 1H), 4.61 - 4.53 (m, 1H), 4.49 - 4.37 (m, 2H), 4.30 -4.10 (m, 4H), 3.82 - 3.77 (m, 1H), 3.67 - 3.50 (m, 2H), 3.35 - 3.16 (m, 4H), 3.05 - 2.95 (m, 1H), 2.16 - 2.10 (m, 1H), 1.94 (br t, J= 6.4 Hz, 2H), 1.90 - 1.79 (m, 2H), 1.66 - 1.56 (m, 4H), 1.53 (s, 9H), 0.60 - 0.45 (m, 4H). LCMS: (M+1 = 621.4). [0606] Step 6. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.32 g, 3.74 mmol, 1 eq), {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (2.88 g, 5.61 mmol, 1.5 eq), K3PO4 (2.38 g, 11.2 mmol, 3 eq), and Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (272 mg, 0.374 mmol, 0.1 eq) and H2O (4 mL) in dioxane (20 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 under microwave. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give tert-butyl (1R,5S)- 1-[(cyclopropyloxy)methyl]-3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.04 g, 3.13 mmol, 84% yield) as brown oil. LCMS: (M+1 = 971.5). [0607] Step 7. To a solution of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-(8-fluoro-7- [7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3 g, 3.09 mmol, 1 eq) in DCM (30 mL) was added HCl/dioxane (4 M, 6 mL, 7.77 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (2.5 g, 3.02 mmol, 98% yield) as yellow solid. [0608] LCMS: (M+1 = 827.6). [0609] Step 8. To a solution of 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[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)-6-fluoro-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (2.5 g, 3.02 mmol, 1 eq) in DMSO (25 mL) was added CsF (2.75 g, 18.1 mmol, 6 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated to remove CsF. The solution was purified by prep-HPLC(column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(FA)-ACN];B%: 0%- 30%,20min) to give Ex.8, 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[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 (1.46 g, 2.02 mmol, 66.96% yield, 99.12% purity, as formic acid salt).1H NMR (400 MHz, METHANOL-d4) δ = 9.14 - 9.01 (m, 1H), 8.36 - 8.29 (m, 1H), 7.94 - 7.83 (m, 1H), 7.41 - 7.28 (m, 2H), 7.26 - 7.18 (m, 1H), 5.65 - 5.41 (m, 1H), 4.73 (br d, J = 13.6 Hz, 2H), 4.67 - 4.55 (m, 2H), 4.00 - 3.67 (m, 9H), 3.48 - 3.36 (m, 3H), 2.71 - 2.21 (m, 6H), 2.17 - 2.00 (m, 2H), 1.98 - 1.86 (m, 2H), 1.81 - 1.69 (m, 1H), 0.71 - 0.48 (m, 4H). LCMS: (M+1 = 671.2). [0610] Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.11)
Figure imgf000160_0001
[0611] Step 1. The mixture of 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (60.5 mg, 0.168 mmol, 1 eq.), tert-butyl (1R,5S)-3- (7-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (100 mg, 0.168 mmol, 1 eq.), Ad2nBuP Pd G3(cataCXium® A Pd G3) (12.2 mg, 0.0168 mmol, 0.1 eq.), and K3PO4 (107 mg, 0.504 mmol, 3 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 12 hours under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1:0 to 0:1) to give compound tert-butyl (1R,5S)-3-(7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 0.164 mmol, 97.6% yield) as a yellow solid. [0612] 1H NMR (400 MHz, DMSO-d6) δ = 9.16 (s, 1H), 7.94 - 7.86 (m, 1H), 7.68 (br s, 1H), 7.43 (br t, J = 9.2 Hz, 1H), 7.24 (br d, J = 7.2 Hz, 1H), 5.36 - 5.33 (m, 2H), 3.65 - 3.57 (m, 3H), 3.43 (d, J = 2.0 Hz, 3H), 1.89 - 1.76 (m, 12H), 1.47 (br s, 20H), 1.17 (dt, J = 2.0, 7.2 Hz, 3H), 0.74 (br t, J = 7.2 Hz, 3H). LCMS: m/z 793.2 (M+1). [0613] Step 2. The mixture of tert-butyl (1R,5S)-3-(7-[8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 75.7 umol, 1 eq) and HCl/dioxane (4 M, 19 uL) in DCM (2 mL) was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 um; mobile phase: [water(FA)-ACN]; B%: 5%-35%, 10 min) to give Ex.11, 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (23.9 mg, 0.0344 mmol, 45.46% yield, as formic acid salt).
Figure imgf000161_0001
NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.18 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.03 (t, J = 2.4 Hz, 1H), 5.37 - 5.18 (m, 1H), 4.57 - 4.38 (m, 2H), 4.22 - 4.13 (m, 1H), 4.04 (br dd, J = 4.0, 10.4 Hz, 1H), 3.47 (br d, J = 11.2 Hz, 3H), 3.45 - 3.39 (m, 3H), 3.32 (s, 3H), 3.09 (br d, J = 8.0 Hz, 2H), 3.01 (br s, 1H), 2.88 - 2.78 (m, 1H), 2.40 - 2.25 (m, 1H), 2.18 - 2.11 (m, 2H), 2.06 (br d, J = 2.0 Hz, 1H), 1.99 (br s, 1H), 1.87 - 1.72 (m, 4H), 1.69 - 1.57 (m, 2H), 1.53 - 1.39 (m, 1H), 0.72 (dt, J = 2.4, 7.2 Hz, 3H). LCMS: m/z 649.3 (M+1). [0614] Preparation of 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-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 (Ex.13)
Figure imgf000162_0001
[0615] Step 1. A mixture of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-(2,7-dichloro- 8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.201 mmol, 1 eq.), [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methanol (48.5 mg, 0.301 mmol, 1.5 eq), and DIEA (77.8 mg, 0.602 mmol, 105 uL, 3 eq.) in dioxane (0.5 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 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 tert-butyl (1R,5S)-3-[7-chloro-8- fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 128 umol, 64% yield) as colorless oil. LCMS: (M+1 = 623.4). [0616] Step 2. A mixture of tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-({[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl]-1- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (72 mg, 0.116 mmol, 1 eq), {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (88.8 mg, 0.173 mmol, 1.5 eq), K3PO4 (73.6 mg, 347 umol, 3 eq), and [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)- butyl-phosphane;methanesulfonate (8.41 mg, 11.6 umol, 0.1 eq) and H2O (0.2 mL) in dioxane (1 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 under microwave. On completion, the reaction mixture was diluted with H2O (30 mL) and extracted with EA 60 mL (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give tert-butyl (1R,5S)-1- [(cyclopropyloxy)methyl]-3-{8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl]-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (82 mg, 0.0843 mmol, 73% yield). LCMS: (M+1 = 973.6). [0617] Step 3. To a solution of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-{8-fluoro-7- [7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2- ({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3- d]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (74 mg, 0.076 mmol, 1 eq) in DCM (1.0 mL) was added HCl/dioxane (4 M, 0.2 mL, 10.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (60 mg, 0.0724 mmol, 95% yield) as yellow solid. LCMS: (M+1 = 829.5). [0618] Step 4. To a solution of 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-({[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl](2H2)methyl}oxy)pyrido[4,3-d]pyrimidin-7-yl]-6-fluoro-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (60 mg, 0.0724 umol, 1 eq) in DMSO (1 mL) was added CsF (132 mg, 0.868 mmol, 12 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated to remove CsF. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 6%- 36%,10min) to give Ex.13, 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-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 [0619] (17.2 mg, 0.0237 mmol, 32.79% yield, 99.17% purity, as formic acid salt) as yellow solid.1H NMR (400 MHz, MeOH-d4) δ = 9.08 - 9.02 (m, 1H), 7.92 - 7.82 (m, 1H), 7.39 - 7.31 (m, 2H), 7.26 - 7.19 (m, 1H), 5.54 - 5.35 (m, 1H), 4.73 - 4.62 (m, 2H), 3.83 - 3.72 (m, 3H), 3.71 - 3.68 (m, 2H), 3.68 - 3.61 (m, 2H), 3.60 - 3.52 (m, 2H), 3.41(tdd, J = 3.2, 6.0, 9.2 Hz, 1H), 3.36 (s, 1H), 3.29 - 3.20 (m, 1H), 2.58 - 2.37 (m, 2H), 2.31 - 2.25 (m, 1H), 2.23 - 2.12 (m, 2H),2.10 - 1.94 (m, 2H), 1.89 - 1.76 (m, 2H), 1.75 - 1.63 (m, 1H), 0.64 - 0.50 (m, 4H). LCMS: (M+1 = 673.4). [0620] Preparation of 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol (Ex.14)
Figure imgf000164_0001
[0621] Step 1. To a solution of {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (2.00 g, 3.90 mmol, 1 eq) in DMSO (20 mL) was added CsF (1.78 g, 11.7 mmol, 432 uL, 3 eq). 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 (50 mL * 3). The combined organic layers were washed with H2O (50 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-[8- ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.39 g, 3.86 mmol, crude) as white solid. LCMS: m/z 357.0 (M+1). [0622] Step 2. A mixture of 2-[8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.39 g, 3.90 mmol, 1 eq), and Pd/C (0.139 g, 3.90 mmol, 10% purity, 1 eq) in MeOH (14 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 4 h under H2 atmosphere (15 psi). On completion. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 0/1) to give 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1- yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (799 mg, 2.22 mmol, 57% yield) as colorless oil. 1H NMR (400 MHz, CDCl3-d) δ = 7.58 (dd, J = 5.6, 8.8 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.21 (t, J = 9.2 Hz, 1H), 5.33 - 5.24 (m, 2H), 3.56 - 3.47 (m, 3H), 3.21 - 3.08 (m, 2H), 1.47 - 1.44 (m, 12H), 1.32 - 1.25 (m, 3H). [0623] Step 3. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.0805 mmol, 1 eq), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (43.5 mg, 0.121 mmol, 1.5 eq), [2-(2-aminophenyl)phenyl]palladium (1+);bis(1-adamantyl)-butyl-phosphane;methanesulfonate (5.86 mg, 0.00805 mmol, 0.1 eq), and K3PO4 (51.3 mg, 0.242 mmol, 3 eq) and H2O (0.2 mL) in dioxane (1 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 under microwave. On completion. The reaction mixture was diluted with H2O (5 mL) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=1/0 to 0/1) to give tert-butyl (1R,5S)-1- [(cyclopropyloxy)methyl]-3-(7-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (14.0 mg, 0.0171 mmol, 21% yield). LCMS: m/z 819.6 (M+1). [0624] Step 4. To a solution of tert-butyl (1R,5S)-1-[(cyclopropyloxy)methyl]-3-(7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate [0625] (9.0 mg, 0.011 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 0.4 mL, 146 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)- ACN];B%: 18%-38%,58min) to give Ex.14, 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol (1.81 mg, 2.68 umol, 24% yield) as off-white solid.1H NMR (400 MHz, MeOH-d4) δ = 9.14 - 9.08 (m, 1H), 7.73 - 7.65 (m, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.05 (s, 1H), 5.56 - 5.38 (m, 1H), 4.58 - 4.46 (m, 4H), 3.96 - 3.87 (m, 2H), 3.81 - 3.73 (m, 2H), 3.72 - 3.69 (m, 2H), 3.64 (br s, 1H), 3.35 (s, 4H), 2.50 - 2.42 (m, 2H), 2.30 (br d, J = 8.4 Hz, 4H), 2.09 - 1.98 (m, 2H), 1.90 - 1.79 (m, 2H), 1.75 - 1.64 (m, 1H), 0.83 - 0.77 (m, 3H), 0.63 - 0.50 (m, 4H). LCMS: m/z 675.4 (M+1). [0626] Preparation of 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8- diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol (Ex.15)
Figure imgf000166_0001
[0627] Step 1. To a solution of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- [(difluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.317 mmol, 1 eq.), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (171 mg, 0.475 mmol, 1.5 eq) in H2O (0.6 mL) and dioxane (3 mL) was added K3PO4 (202 mg, 0.951 mmol, 3 eq), and [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanesulfonate(23.1 mg, 0.0317 mmol, 0.1 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 2 hr under N2 atmosphere in Microwave. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 1:1) to give tert- butyl (1R,5S)-1-[(difluoromethoxy)methyl]-3-(7-[8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (260 mg, 272.90 umol, 86% yield) as a black brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.17 (s, 1H), 7.97 - 7.81 (m, 1H), 7.63 (s, 1H), 7.49 - 7.41 (m, 1H), 7.28 - 7.19 (m, 1H), 7.14 - 7.05 (m, 1H), 7.13 - 6.53 (m, 2H), 4.58 - 4.44 (m, 2H), 4.42 - 4.31 (m, 1H), 4.22 - 4.12 (m, 2H), 4.06 (br dd, J = 4.8, 10.0 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.80 - 3.52 (m, 4H), 3.13 - 3.03 (m, 4H), 2.87 - 2.79 (m, 1H), 2.22 - 2.12 (m, 4H), 1.98 - 1.88 (m, 5H), 1.84 - 1.72 (m, 4H), 1.25 - 1.14 (m, 3H), 1.07 (s, 9H). [0628] Step 2. To a solution of tert-butyl (1R,5S)-1-[(difluoromethoxy)methyl]-3-(7-[8- ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0629] (250 mg, 0.302 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 1 mL, 13.3 eq).The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated to give a residue. The mixture was further purification by pre-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 12%-42%,58min) to give Ex.15, 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol (33.12 mg, 0.0479 umol, 15.9% yield, 99% purity) as a white solid. [0630] 1H NMR (400 MHz, MeOH-d4) δ = 9.20 - 9.02 (m, 1H), 7.79 - 7.63 (m, 1H), 7.36 - 7.32 (m, 1H), 7.31 - 7.22 (m, 1H), 7.12 - 7.03 (m, 1H), 6.75 - 6.31 (m, 1H), 5.64 - 5.40 (m, 1H), 4.82 - 4.75 (m, 1H), 4.68 - 4.53 (m, 3H), 4.13 - 4.01 (m, 2H), 3.92- 3.74 (m, 4H), 3.72 - 3.65 (m, 1H), 3.41 - 3.28 (m, 2H), 2.60 - 2.41 (m, 3H), 2.40 - 2.32 (m, 1H), 2.31 - 2.09 (m, 4H), 2.06 -1.86 (m, 2H), 1.85 - 1.65 (m, 2H), 0.88 - 0.71 (m, 3H). LCMS: m/z 685.2 (M+1). [0631] Preparation of 7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine (Ex.16)
Figure imgf000167_0001
[0632] Step 1. To a solution of {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (200 mg, 0.390 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 10 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (180 mg, 0.384 mmol, 98% yield) as a yellow solid. LCMS: m/z 469.1 (M+1). [0633] Step 2. To a solution of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (180 mg, 0.384 mmol, 1 eq) in DMF (2 mL) was added K2CO3 (132 mg, 0.96 mmol, 2.5 eq) and CH3I (81.8 mg, 0.576 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was partitioned between ethyl acetate (5 mL × 3) and water (5 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF = 4:1 to 4:1) to give {[2-fluoro-6- methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}tri(propan- 2-yl)silane (83.0 mg, 172 umol, 45% yield) as a brown solid.1H NMR (400 MHz, DMSO- d6) δ = 7.95 (dd, J = 6.0, 9.0 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 2.4Hz, 1H), 3.86 (s, 3H), 1.36 - 1.32 (m, 12H), 1.13 - 1.06 (m, 21H). [0634] Step 3. To a solution of {[2-fluoro-6-methoxy-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (73.7 mg, 0.152 mmol, 1.3 eq) in dioxane (0.5 mL) was added tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.117 mmol, 1 eq), K3PO4 (1.5 M, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane; methanesulfonate (8.57 mg, 11.7 umol, 0.1 eq) under N2.The mixture was stirred at 80 °C for 2 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=1:1 to 1:1) to give tert-butyl (1R,5S)-3-[8-fluoro-7-(7-fluoro-3-methoxy-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1- yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 109 umol, 93% yield) as a yellow solid. [0635] LCMS: m/z 915.4 (M+1). [0636] Step 4. To a solution of tert-butyl (1R,5S)-3-[8-fluoro-7-(7-fluoro-3-methoxy-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.0874 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 0.2 mL, 9 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 8-fluoro-7-(7-fluoro-3-methoxy-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidine (60.0 mg, 0.0736 mmol, 84% yield) as a yellow solid. LCMS: m/z 815.2 (M+1). [0637] Step 5. To a solution of 8-fluoro-7-(7-fluoro-3-methoxy-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl)-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidine (60.0 mg, 0.0736 mmol, 1 eq) in DMSO (2 mL) was added CsF (78.2 mg, 0.515 mmol, 7 eq) .The mixture was stirred at 40 °C for 1 h . On completion, the mixture was filtered to give a solution. The solution was purified by reversed phase column (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 11%- 41%,58min) to give Ex.16, 7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine (7.07 mg, 0.0107 mmol, 14% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.15 - 8.04 (m, 1H), 7.64 (br s, 1H), 7.54 (br t, J = 8.4 Hz, 1H), 7.29 (br s, 1H),5.42 - 5.16 (m, 1H), 4.57 - 4.29 (m, 2H), 4.22 - 4.08 (m, 1H), 4.05 - 3.87 (m, 6H), 3.32 (br s, 2H), 3.15 - 2.95 (m, 4H), 2.16 -1.93 (m, 4H), 1.89 - 1.58 (m, 7H), 1.56 - 1.34 (m, 2H), 1.23 (br s, 3H). LCMS: m/z 659.4 (M+1). [0638] Preparation of 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine (Ex.17)
Figure imgf000169_0001
[0639] Step 1. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.134 mmol, 1 eq.), {[2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl]ethynyl}tri(propan-2-yl)silane (79.0 mg, 0.174 mmol, 1.3 eq), [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane; methanesulfonate (9.79 mg, 0.0134 mmol, 0.1 eq) and K3PO4 (85.6 mg, 0.403 mmol, 3 eq) in H2O (0.4 mL) and dioxane (2 mL) was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 14 hours under N2 atmosphere. On completion, the reaction mixture was partitioned between ethyl acetate (10 mL × 3) and water (10 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 0:1) to give tert- butyl (1R,5S)-3-[8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-7-(7-fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)pyrido[4,3- d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 16% yield) as yellow oil. LCMS: m/z 885.2 (M+1). [0640] Step 2. To a solution of tert-butyl (1R,5S)-3-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7-(7-fluoro-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [0641] (15.0 mg, 0.0169 mmol, 1 eq) in DCM (1.50 mL) was added HCl/dioxane (4.00 M, 0.04 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give 8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-7-(7-fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-4-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine (12.0 mg, 90% yield) as yellow oil. [0642] LCMS: m/z 785.5 (M+1). [0643] Step 3. To a solution of 8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-7-(7-fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine (7.00 mg, 0.00892 mmol, 1 eq) in DMSO (1.00 mL) was added CsF (6.77 mg, 0.0445 mmol, 5 eq). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was partitioned between ethyl acetate (10 mL × 3) and water (10mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* 10um; mobile phase: [water(FA)-ACN]; B%: 12%-42%,58min) to give Ex.17, 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidine (4.08 mg, 6.05 umol, 67% yield, 100% purity, as formic acid salt).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.19 (dd, J = 2.4, 5.6 Hz, 2H), 7.72 - 7.57 (m, 3H), 5.52 - 5.51 (m, 1H), 5.38 - 5.18 (m, 1H), 4.61 - 4.30 (m, 2H), 4.22 - 3.98 (m, 3H), 3.61 (d, J = 10.8 Hz, 5H), 3.33 (s, 3H), 3.12 - 3.06 (m, 2H), 3.02 (s, 1H), 2.87 - 2.77 (m, 1H), 2.15 - 1.96 (m, 3H), 1.88 - 1.65 (m, 6H), 1.51 - 1.42 (m, 1H), 1.29 - 1.20 (m, 1H). LCMS: m/z 629.3 (M+1). [0644] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-yl dimethylcarbamate (Ex.18)
Figure imgf000171_0001
[0645] Step 1. To a solution of {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl]ethynyl}tri(propan-2-yl)silane (400 mg, 0.780 mmol, 1 eq) in MeOH (4 mL) was added 4-methylbenzenesulfonic acid (26.88 mg, 0.156 mmol, 0.2 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was concentrated to give 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (400 mg, 0.853 mmol, crude) as a yellow oil. LCMS: m/z 469.3 (M+1). [0646] Step 2. To a solution of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (200 mg, 0.427 umol, 1 eq), TEA (129.60 mg, 1.28 mmol, 178.26 uL, 3 eq) in DCM (2 mL) was added N,N-dimethylcarbamoyl chloride (68.86 mg, 0.640 mmol, 58.86 uL, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 1:1) to give 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-yl dimethylcarbamate (180 mg, 0.333 mmol, 78% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 7.71 (dd, J = 5.7, 8.9 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.27 - 7.22 (m, 1H), 3.14 (s, 3H), 3.09 - 3.00 (m, 3H), 1.43 (s, 12H), 1.16 (s, 21H). LCMS: m/z 540.3 (M+1). [0647] Step 3. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.126 mmol, 1 eq), 6- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-yl dimethylcarbamate (102.00 mg, 0.189 mmol, 1.5 eq), K3PO4 (80.26 mg, 0.378 mmol, 3 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (9.18 mg, 0.0126 mmol, 0.1 eq) in H2O (0.2 mL), dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hr under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH=1:0 to 0:1) to give tert-butyl (1R,5S)-3-[7-(3-[(dimethylcarbamoyl)oxy]-7- fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.082 mmol, 65% yield) as a yellow solid. LCMS: m/z 972.5 (M+1). [0648] Step 4. To a solution of tert-butyl (1R,5S)-3-[7-(3-[(dimethylcarbamoyl)oxy]-7- fluoro-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 0.0771 mmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 19.29 uL, 1 eq) .The mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated to give 6-fluoro-4-(8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-yl dimethylcarbamate (65 mg, 0.074 mmol, 96% yield). LCMS: m/z 872.6 (M+1). [0649] Step 5. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-yl dimethylcarbamate (65 mg, 0.0745 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (33.97 mg, 0.224 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC purification (Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 8%-38%,10min) to give Ex.18, 5-ethynyl-6-fluoro-4-(8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-yl dimethylcarbamate (14.56 mg, 0.02 mmol, 27.3% yield,100% purity, as formic acid salt) as a yellow solid.1H NMR (400 MHz, MeOH-d4) δ = 9.09 - 9.01 (m, 1H), 8.55 - 8.48 (m, 1H), 8.13 - 8.02 (m, 1H), 7.92 - 7.85 (m, 1H),7.52 - 7.43 (m, 2H), 5.47 - 5.24 (m, 1H), 4.71 - 4.55 (m, 2H), 4.46 - 4.28 (m, 2H), 3.79 - 3.68 (m, 2H), 3.66 - 3.60 (m, 1H), 3.58- 3.51 (m, 2H), 3.50 - 3.35 (m, 7H), 3.21 - 3.15 (m, 3H), 3.14 - 3.08 (m, 1H), 3.05 - 2.99 (m, 3H), 2.48 - 2.15 (m, 3H), 2.14 -1.89 (m, 4H), 1.87 - 1.60 (m, 3H). LCMS: m/z 716.4 (M+1). [0650] Preparation of 3-chloro-5-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline (Ex.19)
Figure imgf000173_0001
[0651] Step 1. A mixture of 3-bromo-5-chloro-4-(trifluoromethyl)aniline (1.5 g, 5.47 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.53 g, 6.01 mmol, 1.1 eq), Pd(dppf)Cl2.CH2Cl2 (223 mg, 0.273 mmol, 0.05 eq), and KOAc (1.61 g, 16.4 mmol, 3 eq) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then stirred at 90 °C for 12 hr under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE:THF = 100:1-100:5) to give 3-chloro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (550 mg, 1.71 mmol, 45.8% yield) as yellow solid.1H NMR (400 MHz, CDCl3-d) δ = 6.74 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 4.31 - 3.59 (m, 2H), 1.36 (s, 12H). LCMS: m/z 321.7 (M+1). [0652] Step 2. To a mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 10.68 mmol, 1 eq.) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (216 mg, 0.672 mmol, 4 eq), and K3PO4 (107.01 mg, 504.12 umol, 3 eq) in H2O (0.4 mL) and dioxane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl- phosphane;methanes [0653] ulfonate (18.3 mg, 25.2 umol, 0.15 eq). The mixture was degassed and purged with N2 for 3 times, and then stirred at 60 °C for 2 h under microwave. On completion, the reaction mixture was concentrated.The residue was purified by column chromatography (4 g silica gel column, MeOH in DCM from 0% to 10%) to give tert-butyl (1R,5S)-3-(7-[5- amino-3-chloro-2-(trifluoromethyl)phenyl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (126 mg, 141 umol, 84% yield) as a yellow oil.1H NMR (400 MHz, CDCl3-d) δ = 8.99 (s, 1H), 6.99 (s, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.52 (s, 1H), 5.41 - 5.21 (m, 1H), 4.65 - 4.18 (m, 6H), 4.04 (dd, J = 5.2, 6.0 Hz, 1H), 3.85 - 3.49 (m, 4H), 3.39 (s, 3H), 3.20 (d, J = 9.2 Hz, 1H), 2.31 (s, 1H), 2.25 (s, 1H), 2.20 - 2.13 (m, 2H), 2.03 - 1.92 (m, 6H), 1.44 (s, 9H). LCMS: m/z 754.3 (M+1). [0654] Step 3. A mixture of tert-butyl (1R,5S)-3-(7-[5-amino-3-chloro-2- (trifluoromethyl)phenyl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (100 mg, 0.133 mmol, 1 eq) in DCM (5 mL) was added HCl/dixoane (4 M, 2 mL, 60.3 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated. The residue was then purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 5%- 35%,8min) to give Ex.19, 3-chloro-5-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline (37.40 mg, 0.0524 mmol, 39.48% yield, 98% purity, as formic acid salt) as a white solid.1H NMR (400 MHz, DMSO- d6) δ = 9.04 (s, 1H), 8.14 (s, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.47 (s, 1H), 6.32 (s, 2H), 5.39 - 5.11 (m, 1H), 4.47 - 4.36 (m, 1H), 4.18 - 3.98 (m, 2H), 3.62 - 3.55 (m, 2H), 3.45 (s, 3H), 3.12 - 3.06 (m, 3H), 3.01 (s, 1H), 2.89 - 2.76 (m, 2H), 2.17 - 1.95 (m, 4H), 1.90 - 1.70 (m, 5H), 1.68 - 1.56 (m, 2H), 1.50 - 1.39 (m, 1H). LCMS: m/z 654.2 (M+1). [0655] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.25) and 5- ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.26)
Figure imgf000175_0001
Figure imgf000176_0001
[0656] Step 1. To a solution of tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (10.0 g, 20.7 mmol, 1 eq) in DCM (100 mL) was added HCl/dioxane (4 M, 10 mL, 1.93 eq). The mixture was stirred at 25 °C for 0.2 h. On completion, the reaction mixture was partitioned between DCM (100 mL × 3) and water (150 mL), adjust pH to 9 with saturated NaHCO3 aqueous solution. Then the reaction mixture was partitioned between（ DCM:MeOH=10:1）(100 mL × 6) and water (150 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 1-formyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.05 g, 16.8 mmol, 81% yield) as a colorless oil. [0657] Step 2. To a solution of tert-butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (4.05 g, 16.8 mmol, 1 eq) in THF (20 mL) was added NaHCO3 (41.6 g, 495 mmol, 19 mL, 29.4 eq) and CbzCl (3.74 g, 21.9 mmol, 1.3 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was partitioned between ethyl acetate (25 mL × 3) and water (25 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=3:1 to 3:1) to give O3-benzyl O8-tert- butyl 1-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (6.67 g, crude) as a white solid. LCMS: (M+23: 397.1). [0658] Step 3. To a solution of O3-benzyl O8-tert-butyl 1-formyl-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (6.17 g, 16.4 mmol, 1 eq) in THF (120 mL) was added MeMgBr (3 M, 6.59 mL, 1.2 eq) under N2. The mixture was stirred at 0 °C for 4 h. On completion, the reaction mixture was partitioned between ethyl acetate (150 mL × 3) and water (150 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=4:1 to 4:1) to give O3-benzyl O8-tert-butyl 1-(1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (3.59 g, 9.19 mmol, 56% yield) as a yellow oil. LCMS: (M+23: 413.2). [0659] Step 4. To a solution of O3-benzyl O8-tert-butyl 1-(1-hydroxyethyl)-3,8-diazabicyclo [3.2.1]octane-3,8-dicarboxylate (3.29 g, 8.43 mmol, 1 eq) in DCM (30 mL) was added HCl/dioxane (4 M, 3 mL, 1.42 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was concentrated to give benzyl 1-(1-hydroxyethyl)-3,8-diazabicyclo [3.2.1]octane-3-carboxylate (3.18 g, crude) as a white solid. LCMS: (M+1: 291.2). [0660] Step 5. To a solution of SOCl2 (3.91 g, 32.86 mmol, 3 eq) in DCM (20 mL) was added IMIDAZOLE (6.71 g, 98.5 mmol, 9 eq) at -68 °C and stirred for 1 h, then benzyl 1-(1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3.18 g, 10.95 mmol, 1 eq) in DCM (10 mL) was added at -68 °C. The mixture was stirred at 25 °C for 2 h. On completion, the mixture was quench with water (15 mL), then partitioned between DCM (40 mL × 3) and water (30 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=3:1 to 3:1) to give benzyl 2-methyl-4-oxo-3-oxa-4λ4-thia- 5,8-diazatricyclo[4.3.2.01,5] undecane-8-carboxylate (1.74 g, 5.17 mmol, 47% yield) as a white solid. LCMS: (M+23: 359.1). [0661] Step 6. To a solution of benzyl 2-methyl-4-oxo-3-oxa-4λ4-thia-5,8-diazatricyclo [4.3.2.01,5]undecane-8-carboxylate (1.74 g, 5.17 mmol, 1 eq) in ACN (63 mL) and H2O (2.5 mL) was added NaIO4 (1.44 g, 6.72 mmol, 1.3 eq) and RuCl3 (21.4 mg, 103 umol, 0.02 eq). The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was quenched by water (20 mL) and extratced with EtOAc (20 mL*3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give crude. The residue was purified by column chromatography (SiO2, PE:THF=2:1 to 2:1) to give benzyl 2- methyl-4,4-dioxo-3-oxa-4λ6-thia-5,8-diazatricyclo[4.3.2.01,5]undecane-8-carboxylate (1.40 g, 3.97 mmol, 77% yield) as a yellow oil. LCMS: (M+23: 375.1). [0662] Step 7. To mixture of Na (587 mg, 25.5 mmol, 10 eq) in CD3OD (4.44 g, 123 mmol, 5 mL, 48.2 eq) at 0°C was added DMF (10 mL), and then benzyl 2-methyl-4,4-dioxo-3-oxa- 4λ6-thia-5,8-diazatricyclo[4.3.2.01,5]undecane-8-carboxylate (900 mg, 2.55 mmol, 1 eq). And the mixture was stirred at 20 °C for 1 h. On completion, the mixture was concentrated to give benzyl 1-[1-(trideuteriomethoxy)ethyl]-3,8-diazabicy clo[3.2.1]octane-3-carboxylate (785 mg, crude) as a white solid. LCMS: (M+1: 308.2). [0663] Step 8. To a solution of benzyl 1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (785 mg, 2.55 mmol, 1 eq) in DCM (1 mL) was added Boc2O (1.67 g, 7.66 mmol, 3 eq) and TEA (258 mg, 2.55 mmol, 1 eq). The mixture was stirred at 25 °C for 6 h. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=8:1 to 8:1)to give O3-benzyl O8-tert-butyl 1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicyclo [3.2.1]octane-3,8-dicarboxylate (451 mg, 1.11 mmol, 43.34% yield) as a white solid. LCMS: (M+23: 430.2). [0664] Step 9. To a solution of O3-benzyl O8-tert-butyl 1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (410 mg, 1.01 mmol, 1 eq) in i-PrOH (4 mL) was added Pd/C (200 mg, 1.01 mmol, 10% purity, 1 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h under H2 (15 psi). On completion, the mixture was filtered, and the filtrate was concentrated to give tert-butyl 1-[1-(trideuteriomethoxy)ethyl]-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (274 mg, crude) as a white solid. [0665] Step 10. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (234 mg, 929 umol, 1 eq) in DCM (3 mL) was added DIEA (120 mg, 929 umol, 1 eq) and tert-butyl 1- [1-(trideuteriomethoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (254 mg, 929 umol, 1 eq). The mixture was stirred at -40 °C for 2 h under N2. On completion, the reaction mixture was partitioned between DCM (5 mL × 3) and water (5 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=1:1 to 1:1) to give tert- butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1-[1-(trideuteriomethoxy)ethyl]- 3,8-diazabicyclo[3.2.1] octane-8-carboxylate (332 mg, 678 umol, 73% yield) as a white solid. LCMS: (M+1: 489.1) [0666] Step 11. To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (147 mg, 925 umol, 1.5 eq) in THF (3 mL) was added NaH (49.3 mg, 1.23 mmol, 60% purity, 2 eq) at 0 °C, after addition, the mixture was stirred at 25 °C for 0.5 h, and then a solution of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1-[1- (trideuteriome thoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (302 mg, 617 umol, 1 eq) in THF (3 mL) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1.5 h. On completion, the mixture was quenched by water (8 mL) and extratced with EtOAc (8 mL*3). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give crude. The residue was purified by column chromatography (SiO2, PE/THF=1:0 to 1:1) to give tert-butyl 3-[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]-1-[1-(trideuteriomethoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (329 mg, 537 umol, 87% yield) as a white solid. LCMS: (M+1: 612.4). [0667] Step 12. To a solution of tert-butyl 3-[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]-1-[1- (trideuteriome thoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 245 umol, 1 eq) in dioxane (2 mL) was added 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (188 mg, 367 umol, 1.5 eq) and K3PO4 (1.5 M, 490 uL, 3 eq) and [2-(2-aminophenyl) phenyl] palladium(1+);bis(1- adamantyl)-butyl-phosphane; methanesulf onate (17.8 mg, 24.5 umol, 0.1 eq). The mixture was stirred at 80 °C for 3 h under N2. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=2:1 to 2:1) to give tert-butyl 3-[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]-1-[1- (trideuteriomethoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (168 mg, 174 umol, 71% yield) as a yellow solid. LCMS: (M+1: 962.8). [0668] Step 13. To a solution of tert-butyl 3-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydrop yrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethyn yl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-1-[1- (trideuteriomethoxy)ethyl]-3,8-dia zabicyclo[3.2.1]octane-8-carboxylate (150 mg, 155 umol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL, 51.3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 6-fluoro-4-[8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-[1-[1- (trideuteriomethoxy) ethyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl]- 5-(2-triiso propylsilylethynyl)naphthalen-2-ol (170 mg, crude) as a yellow solid. LCMS: (M+1: 818.5). [0669] Step 14. To a solution of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydr opyrrolizin-8-yl]methoxy]-4-[1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicyclo[3.2.1] octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (170 mg, 207 umol, 1 eq) in DMSO (2 mL) was added CsF (157 mg, 1.04 mmol, 5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered to remove CsF. The filrate was purified by reversed phase column(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 5%-35%, 8min) to give 5-ethynyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-[1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicy clo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol (2.69 mg, 4.07 μmol, 2% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ = 9.04 (d, J = 3.2 Hz, 1H), 8.17 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (t, J = 9.2 Hz,1H), 7.39 (d, J = 2.4 Hz, 1H), 7.19 (br s, 1H), 5.41 - 5.18 (m, 1H), 4.60 - 4.46 (m, 1H), 4.44 - 4.27 (m, 1H), 4.19 - 4.12 (m, 1H), 4.09 (dd, J = 4.0, 10.0 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.94 - 3.80 (m, 2H), 3.48 (br d, J = 12.0 Hz, 3H), 3.15 - 3.02 (m, 3H), 2.90 -2.78 (m, 1H), 2.16 - 1.96 (m, 3H), 1.87 - 1.63 (m, 6H), 1.57 - 1.45 (m, 1H), 1.20 (dd, J = 4.4, 6.0 Hz, 3H). LCMS: (M+1: 662.5). [0670] Step 15. SFC separation: The residue was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [Neu-MeOH];B%: 35%- 35%,A2.2;30min) to give 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.25, 15.16 mg, 22.91 μmol, 25.27% yield) and 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{1- [(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (Ex.26, 24.34 mg, 36.78 μmol, 40.57% yield). [0671] Ex.25: 1H NMR (400 MHz, DMSO-d6) δ = 10.24 - 10.08 (m, 1H), 9.03 (br s, 1H), 8.13 - 7.91 (m, 1H), 7.46 (br t, J = 8.8 Hz, 1H), 7.39(br s, 1H), 7.19 (br s, 1H), 5.37 - 5.15 (m, 1H), 4.58 - 4.26 (m, 2H), 4.15 - 4.02 (m, 2H), 3.96 - 3.79 (m, 1H), 3.63 - 3.52 (m,2H), 3.50 - 3.44 (m, 1H), 3.18 - 2.94 (m, 4H), 2.83 (br d, J = 6.0 Hz, 1H), 2.24 - 1.89 (m, 4H), 1.88 - 1.62 (m, 6H), 1.52 - 1.44(m, 1H), 1.23 - 1.17 (m, 3H). LCMS: (M+1: 662.4). Ex.26: 1H NMR (400 MHz, DMSO-d6) δ = 10.30 - 10.04 (m, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.02 - 7.92 (m, 1H), 7.46 (t, J = 9.2 Hz,1H), 7.39 (d, J = 2.4 Hz, 1H), 7.19 (br d, J = 3.2 Hz, 1H), 5.37 - 5.16 (m, 1H), 4.57 - 4.27 (m, 2H), 4.19 - 4.12 (m, 1H), 4.06 -3.99 (m, 1H), 3.95 - 3.81 (m, 1H), 3.68 - 3.56 (m, 3H), 3.14 - 3.00 (m, 4H), 2.87 - 2.79 (m, 1H), 2.20 - 1.94 (m, 4H), 1.87 - 1.63(m, 6H), 1.54 - 1.48 (m, 1H), 1.22 - 1.18 (m, 3H). LCMS: (M+1: 662.4). Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.27) and 5-ethyl-6-fluoro-4-(8-fluoro- 2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{1- [(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol (Ex.28)
Figure imgf000181_0001
[0672] Step 1. To a solution of tert-butyl 3-[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]-1-[1- (trideuteriome thoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 212 umol, 1 eq) in dioxane (2 mL) was added 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (114 mg, 318 umol, 1.5 eq) and K3PO4 (1.5 M, 424 uL, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane; methanesulfo nate (15.5 mg, 21.2 umol, 0.1 eq). The mixture was stirred at 80 °C for 3 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1 to 1:1) to give tert-butyl 3-[7-[8- ethyl-7-fluoro-3-(methoxymethoxy)-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]-1-[1- (trideuteriomethoxy)ethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (125 mg, 154 umol, 72% yield) as a yellow solid. LCMS: (M+1: 810.5). [0673] Step 2. To a solution of tert-butyl 3-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- l]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1-[1-(trideuteriomethoxy)ethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 135 umol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 33.9 uL, 1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give a residue. The residue was purified by reversed phase column(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 5%-35%,8min) to give 5-ethyl-6-fluoro-4-[8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-(1-{1-[(2H3)methyloxy]ethyl}-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol. (6.45 mg, 9.69 umol, 7.13% yield) as a brown solid. [0674] Step 3. The above solid was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um);mobile phase: [Neu-MeOH];B%: 35%-35%,A2.2;30min) to give 5- ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.27, 4.69 mg, 7.04 μmol, 15% yield) as a yellow solid and 5-ethyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.28, 14.62 mg, 21.9 μmol, 49% yield) as a yellow solid. [0675] Ex.27: 1H NMR (400 MHz, DMSO-d6) δ = 9.10 (d, J = 4.4 Hz, 1H), 8.16 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.39 - 7.28 (m, 2H),7.07 - 6.99 (m, 1H), 5.21 (br s, 1H), 5.42 - 5.14 (m, 1H), 4.54 - 4.40 (m, 2H), 4.23 - 4.01 (m, 3H), 3.37 (br dd, J = 0.8, 6.4 Hz,3H), 3.10 (br d, J = 8.8 Hz, 2H), 3.02 (s, 1H), 2.89 - 2.78 (m, 1H), 2.22 - 2.10 (m, 2H), 2.09 - 1.93 (m, 2H), 1.91 - 1.43 (m, 8H),1.19 (dd, J = 3.2, 6.3 Hz, 3H), 0.72 (dt, J = 2.0, 7.3 Hz, 3H). LCMS: (M+1:666.5). [0676] Ex.28: 1H NMR (400 MHz, DMSO-d6) δ = 9.09 (br d, J = 4.4 Hz, 1H), 7.80 - 7.72 (m, 1H), 7.39 - 7.29 (m, 2H), 7.03 (br s, 1H), 5.43 -5.15 (m, 1H), 4.57 - 4.37 (m, 2H), 4.19 - 4.04 (m, 3H), 3.38 - 3.32 (m, 3H), 3.03 - 2.94 (m, 2H), 2.87 - 2.79 (m, 1H), 2.22 - 1.94(m, 5H), 1.90 - 1.64 (m, 4H), 1.63 - 1.44 (m, 2H), 1.37 (s, 4H), 1.22 - 1.14 (m, 3H), 0.72 (br t, J = 6.0 Hz, 3H). LCMS: (M+1:666.4). [0677] [0678] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine (Ex.29)
Figure imgf000182_0001
Figure imgf000183_0001
[0679] Step 1. A mixture of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (5.00 g, 13.9 mmol, 1 eq), DIEA (10.8 g, 83.7 mmol, 6 eq), Tf2O (15.7 g, 55.8 mmol, 4 eq) in DCM (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 12 hours. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1:0 to 10:1) to give [6-fluoro- 4-(trifluoromethylsulfonyloxy)-5-(2-triisopropylsilyle thynyl)-2-naphthyl] trifluoromethanesulfonate (8 g, 12.8 mmol, 92% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.53 (d, J = 2.4 Hz, 1H), 8.37 (dd, J = 5.6, 9.2 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.85 (t, J = 9.2 Hz, 1H), 1.16 (br d, J = 6.4 Hz, 3H), 1.12 - 1.08 (m, 18H). [0680] Step 2. A mixture of [6-fluoro-4-(trifluoromethylsulfonyloxy)-5-(2- triisopropylsilylethynyl)-2-naphthyl] trifluoromethanesulfonate (6.00 g, 9.60 mmol, 1 eq), diphenylmethanimine (2.10 g, 11.6 mmol, 1.2 eq), Cs2CO3 (9.42 g, 28.9 mmol, 3 eq) in Tol. (12 mL). And then the mixture was added 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-2H- imidazole;3-chloropyridine;dichloropalladium (382 mg, 482 umol, 0.05 eq). At last, the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 hours under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with dichloromethane (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give compound [3- (benzhydrylideneamino)-7-fluoro-8-(2-triisopropylsilylethynyl)-1-naphthyl] trifluoromethanesulfonate (640 mg, 979 μmol, 10% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.94 (dd, J = 5.6, 9.2 Hz, 1H), 7.76 - 7.64 (m, 3H), 7.62 - 7.45 (m, 5H), 7.30 (br t, J = 5.6 Hz, 4H), 7.24 - 7.16 (m, 2H), 1.14 - 1.08 (m, 21H). LCMS: (M+1: 654.3) [0681] Step 3. A mixture of [3-(benzhydrylideneamino)-7-fluoro-8-(2- triisopropylsilylethynyl)-1-naphthyl] trifluoromethanesulfonate (240 mg, 367 μmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (186 mg, 734 μmol, 2 eq), APhos Pd G3 (23.3 mg, 36.7 μmol, 0.1 eq), AcOK (108 mg, 1.10 mmol, 3 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hours under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1:0 to 19:1) to give compound N-[6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-triisopro pylsilylethynyl)-2- naphthyl]-1,1-diphenyl-methanimine (180 mg, 285 μmol, 78% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.70 (br d, J = 7.2 Hz, 2H), 7.51 - 7.40 (m, 5H), 7.34 - 7.27 (m, 5H), 7.19 (br dd, J = 2.0, 7.2 Hz, 2H), 1.27 (s, 12H), 1.17 (s, 21H). LCMS: (M+1: 632.4). [0682] Step 4. A mixture of N-[6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (2-triisopropylsilylethynyl)-2-naphthyl]-1,1-diphenyl-methanimine (160 mg, 253 μmol, 1.3 eq), tert-butyl (1R,5S)-3-[7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexa hydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (116 mg, 195 μmol, 1eq, from BHT-WX-B5075), Ad2nBuP Pd G3(cataCXium® A Pd G3) (14.2 mg, 19.5 μmol, 0.1 eq), APhos Pd G3 (12.4 mg, 19.5 μmol, 0.1 eq), K3PO4 (124 mg, 584 μmol, 3 eq) in dioxane (2.5 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hours under N2 atmosphere. On completion, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1:0 to 1:4) to give compound tert-butyl (1R,5S)-3-[7-[3-(benzhydrylideneamino)-7- fluoro-8-(2-triisopropylsilylethynyl)-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]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 93.9 μmol, 48% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.12 (d, J = 3.2 Hz, 1H), 7.94 (dd, J = 6.0, 9.2 Hz, 1H), 7.75 - 7.64 (m, 2H), 7.57 - 7.53 (m, 1H), 7.52 - 7.45 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.34 - 7.30 (m, 3H), 7.24 - 7.18 (m, 2H), 7.09 (dd, J = 2.0, 7.2 Hz, 1H), 5.38 - 5.20 (m, 1H), 4.39 (br d, J = 5.2 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.03 (q, J = 7.2 Hz, 2H), 1.46 (d, J = 1.6 Hz, 12H), 1.07 (s, 21H). LCMS: (M+1: 1064.6). [0683] Step 5. A mixture of tert-butyl (1R,5S)-3-[7-[3-(benzhydrylideneamino)-7-fluoro-8- (2-triisopropylsilylethynyl)-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]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 75.2 μmol, 1 eq), CsF (57.1 mg, 376 μmol, 5 eq) in DMSO (2 mL) was degassed, and then the mixture was stirred at 25 °C for 2 hours. On completion, the mixture was diluted by ethyl acetate (10 mL) and water (10 mL), then washed by brine (10 mL). The organic layers was dried by sodium sulfate, concentrated in vacuo to give the compound tert-butyl (1R,5S)-3-[7-[3-(benzhydrylideneamino)-8- ethynyl-7-fluoro-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]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (68.0 mg, 74.9 μmol, 99% yield) as a yellow solid. LCMS: (M+1: 908.4). [0684] Step 6. A mixture of tert-butyl (1R,5S)-3-[7-[3-(benzhydrylideneamino)-8-ethynyl-7- fluoro-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]meth oxy]pyrido[4,3-d]pyrimidin-4-yl]-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (68.0 mg, 74.9 μmol, 1 eq), TFA (13.5 mmol, 1 mL) in DCM (1 mL) was degassed, and then the mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 um; mobile phase: [water(FA)-ACN]; B%: 4%-34%, 15 mins) to give compound 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine (6.87 mg, 9.96 μmol, 13.30% yield, FA) as a brown gum.1H NMR (400 MHz, DMSO-d6) δ = 9.02 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.33 (t, J = 9.2 Hz, 1H), 7.04 (s, 2H), 5.62 (br s, 2H), 5.41 - 5.18 (m, 1H), 4.58 - 4.44 (m, 1H), 4.41 - 4.30 (m, 1H), 4.14 (d, J = 10.4 Hz, 1H), 4.06 - 3.97 (m, 2H), 3.87 - 3.75 (m, 2H), 3.09 (br d, J = 10.8 Hz, 3H), 3.04 - 3.00 (m, 2H), 2.89 - 2.78 (m, 2H), 2.19 - 1.95 (m, 4H), 1.89 - 1.62 (m, 7H), 1.53 - 1.40 (m, 2H), 1.25 (t, J = 7.2 Hz, 1H). LCMS: (M+1: 644.4). [0685] [0686] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]quinazolin-7-yl)naphthalen-2-ol (Ex.30)
Figure imgf000186_0001
[0687] Step 1. To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (92.6 mg, 582 μmol, 2 eq) in THF (2.00 mL) was added t-BuOK (65.3 mg, 582 μmol, 2.00 eq).The mixture was stirred at 0 °C for 0.5 h. Then tert-butyl (1R,5S)-3-(7- bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (150 mg, 291 μmol, 1 eq) was added to the mixture. The reaction was stirred at 0 °C for 1 h. On completion, the mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2,DCM: MeOH= 10:1) to give tert-butyl (1R,5S)-3- [7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.120 g, 187 μmol, 64% yield) as a yellow oil. LCMS: (M+1:638.3). [0688] Step 2. A mixture of tert-butyl (1R,5S)-3-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 172 μmol, 1.00 eq), 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl] ethynyl- triisopropyl-silane (106 mg, 207 μmol, 1.20 eq), Cs2CO3 (169 mg, 517 μmol, 3.00 eq), ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (11.2 mg, 17.2 μmol, 0.1 eq) in dioxane (2 mL) and H2O (0.4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1h under N2 atmosphere. On completion, the reaction was concentrated under vacuum. The residue was purified by column chromatography (SiO2,Petroleum ether/Ethyl acetate=1/0 to 0/1) to give tert-butyl (1R,5S)-3-[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]quinazolin-4-yl]-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.09 g, 95.3 μmol, 55% yield) as a yellow oil. LCMS: (M+1:944.6). [0689] Step 3. A solution of tert-butyl (1R,5S)-3-[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]quinazolin-4-yl]-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.08 g, 84.7 μmol, 1 eq) in HCl/dioxane (0.5 mL) and DCM (0.5 mL) was stirred at 25 °C for 1 h. On completion, the reaction was concentrated under vacuum to give 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl]-5-(2-triisopropylsilylethynyl) naphthalen-2-ol (67.0 mg, 83.8 μmol, 98% yield) as a white solid. LCMS: (M+1:800.4). [0690] Step 4. 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-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo [3.2.1]octan-3-yl]quinazolin-7-yl]-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (57.0 mg, 71.3 μmol, 1 eq) in DMSO (0.5 mL) was added CsF (32.5 mg, 214 μmol, 3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:5%-35% B over 10 min) to give 5-ethynyl- 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo [3.2.1]octan-3-yl]quinazolin-7-yl]naphthalen- 2-ol (22.180 mg, 31.64 μmol, 44.40% yield, 98.378% purity, FA) as a white solid.1H NMR (400 MHz, MeOD-d4) δ = 7.88 - 7.81 (m, 2H), 7.38 - 7.27 (m, 3H), 7.10 (d, J = 2.4 Hz, 1H), 5.55 - 5.36 (m, 1H), 4.65 - 4.46 (m, 4H), 3.90 - 3.73 (m, 2H), 3.72 - 3.50 (m, 7H), 3.45 (s, 3H), 3.25 - 3.21 (m, 1H), 2.68 - 2.65 (m, 1H), 2.62 - 2.42 (m, 2H), 2.39 - 2.28 (m, 1H), 2.27 - 2.16 (m, 2H), 2.09 - 1.88 (m, 4H), 1.78 - 1.67 (m, 1H). LCMS: (M+1:644.3). [0691] [0692] Preparation of 6-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[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)-4-methyl-5-(trifluoromethyl)pyridin-2- amine (Ex.31)
Figure imgf000187_0001
Figure imgf000188_0001
Step 1. To a mixture of 2,6-dichloro-4-methyl-pyridine (23.0 g, 141 mmol, 1 eq) in PMBNH2 (121 g, 888 mmol, 115 mL, 6.26 eq) was stirred at 120 °C for 12 hours. On completion, the reaction mixture was diluted with ACN (100 mL). White solid was formed and filtered afford to 6-chloro-N-[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (23.0 g, 87.5 mmol, 61% yield) as white solid.1
Figure imgf000188_0002
NMR (400 MHz, DMSO-d6) δ 7.49 - 7.41 (m, 3H), 6.99 - 6.92 (m, 3H), 6.38 - 6.26 (m, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 2.12 (s, 2H). LCMS: (M+1 = 263.0). Step 2. The reaction of 6-chloro-N-[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (23.0 g, 87.5 mmol, 1 eq) in THF (200 mL) was added PMB-Cl (16.4 g, 105 mmol, 14.2 mL, 1.2 eq) and t-BuOK (14.7 g, 131 mmol, 1.5 eq). The reaction mixture was stirred at 25°C for 12 hours. On completion, the residue was diluted with water (120 mL) and extracted with EA(2 X 120 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography afford to 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (28.0 g, 73.1 mmol, 83% yield) as yellow oil.1H
Figure imgf000188_0003
NMR (400 MHz, DMSO-d6) δ 7.27 - 7.21 (m, 4H), 7.15 (d, J = 8.8 Hz, 1H), 6.94 - 6.85 (m, 5H), 4.32 (s, 4H), 3.74 (s, 6H), 3.24 (s, 3H). Step 3. The reaction of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2- amine (27.0 g, 70.5 mmol, 1 eq)in DMF (300 mL) was added NIS (19.0 g, 84.6 mmol, 1.2 eq). The reaction mixture was stirred at 25°C for 1 hour. On completion, the reaction mixture was diluted with water (100 mL). White solid was formed and filtered afford to 6-chloro-5- iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (18.0 g, 35.3 mmol, 50% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.16 (d, J = 8.8 Hz, 4H), 6.88 (d, J = 8.8 Hz, 4H), 6.63 (s, 1H), 4.61 (s, 4H), 3.73 (s, 6H), 2.27 (s, 3H). LCMS: (M+1 = 509.1). Step 4. To a mixture of 6-chloro-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl- pyridin-2- amine (11.0 g, 21.6 mmol, 1 eq) in DMF (100 mL) was added CuI (10.2 g, 54.0 mmol, 2.5 eq) and HMPA (19.3 g, 108 mmol, 18.9 mL, 5 eq). The reaction mixture was stirred at 25 °C for 0.8 hour. Then the reaction mixture was added methyl 2,2-difluoro-2- fluorosulfonyl-acetate (12.4 g, 64.8 mmol, 8.25 mL, 3 eq) dropwise at 90°C. The reaction mixture was stirred at 90°C for 11.2 hours. On completion, the residue was diluted with water (100 mL) and extracted with EA(2 X 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography afford to 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]- 4-methyl-5-(trifluoromethyl)pyridin-2-amine (9.00 g, 19.9 mmol, 92% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 4.69 (s, 1H), 3.61 (s, 3H), 3.43 (s, 2H), 2.88 (s, 3H), 1.38 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H). LCMS: (M+1 = 451.2). Step 5. The mixture of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5- (trifluoromethyl) pyridin-2-amine (4.00 g, 8.87 mmol, 1 eq) in HBr (59.6 g, 243 mmol, 40 mL, 33% purity, 27.4 eq) was stirred at 90°C for 1 hour. On completion, the reaction mixture was diluted with water (10 mL) and acidified with NaOH(15%) till pH = 7-8, The residue was diluted with water (40 mL) and extracted with EA(2 X 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated afford to 6-chloro-4-methyl-5- (trifluoromethyl)pyridin-2-amine (2 g, crude) as brown solid. LCMS: (M+1 = 211.1). Step 6. The mixture of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5- (trifluoromethyl) pyridin-2-amine (2.00 g, 4.44 mmol, 1 eq) in ACN (30 mL) was added acetyl bromide (8.18 g, 66.5 mmol, 5.38 mL, 15 eq). The reaction mixture was stirred at 90°C for 1 hour. On completion, the reaction mixture was quenched with EtOH (30 mL)and Acidified basified with NaOH( 15% )till pH = 7-8,The residue was diluted with water (30 mL) and extracted with EA(2 X 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo afford to N-[6-bromo-4-methyl-5- (trifluoromethyl)-2-pyridyl]acetamide (2.00 g, crude) as yellow solid. LCMS: (M+1 = 297.1). Step 7. The mixture of N-[6-bromo-4-methyl-5-(trifluoromethyl)-2-pyridyl]acetamide (2.00 g, 6.73 mmol, 1 eq) in THF (10 mL) and MeOH (10 mL) and H2O (5 mL) was added LiOH.H2O (564 mg, 13.4 mmol, 2 eq). The reaction mixture was stirred at 25°C for 1 hour. On completion, the residue was diluted with water (30 mL) and extracted with EA(2 X 30 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography afford to 6-bromo-4- methyl-5- (trifluoromethyl)pyridin-2-amine (1.40 g, 5.49 mmol, 81% yield) as yellow solid. Step 8. To a mixture of 6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (1.50 g, 5.88 mmol, 1 eq) in THF (15 mL) was added t-BuOK (1.65 g, 14.7 mmol, 2.5 eq) and PMB-Cl (2.21 g, 14.1 mmol, 1.92 mL, 2.4 eq). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the residue was diluted with water (40 mL) and extracted with EA(2 X 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography afford to 6- bromo-N,N-bis[(4- methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (1.30 g, 2.62 mmol, 44% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.24 (dd, J = 2.8, 8.8 Hz, 4H), 6.97 - 6.93 (m, 4H), 6.70 (s, 1H), 4.73 (s, 4H), 3.79 (s, 6H), 2.39 - 2.35 (m, 3H). LCMS: (M+1 = 496.9). Step 9. A mixture of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5- (trifluoromethyl)pyridin-2-amine (500 mg, 1.01 mmol, 1 eq), Pd2(dba)3 (92.4 mg, 101 μmol, 0.1 eq), tributyl(tributylstannyl)stannane (1.76 g, 3.03 mmol, 1.52 mL, 3 eq), LiCl (214 mg, 5.05 mmol, 103 μL, 5 eq) and P(Cy)3 (56.6 mg, 202 μmol, 65.5 μL, 0.2 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 16 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). N,N-bis[(4-methoxyphenyl)methyl]-4- methyl-6-tributylstannyl-5-(trifluoromethyl)pyridin-2-amine (427 mg, 605 μmol, 60% yield) was obtained as yellow oil. LCMS: (M+1 = 707.0). Step 10. A mixture of N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-5- (trifluoromethyl)pyridin-2-amine (100 mg, 142 μmol, 1 eq), tert-butyl 3-[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]-1-(cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (88.0 mg, 142 μmol, 1 eq, from BHT-WX-5129), CuI (27.0 mg, 142 μmol, 1 eq), Xphos Pd G4 (12.2 mg, 14.2 μmol, 0.1 eq) and TEA (28.7 mg, 284 μmol, 39.5 μL, 2 eq) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 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/THF=1/0 to 0/1). tert-butyl 3-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]- 4-methyl-3-(trifluoromethyl)-2-pyridyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1-(cyclopropoxymethyl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 9.44 μmol, 7% yield, 9% purity) was obtained as white solid. LCMS: (M+1 = 1001.5). Step 11. To a solution of tert-butyl (1R,5S)-3-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4- methyl-3-(trifluoromethyl)-2-pyridyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1-(cyclopropoxymethyl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90.0 mg, 89.9 μmol, 1 eq) in TFA (1.54 g, 13.5 mmol, 1 mL, 150 eq). The mixture was stirred at 60 °C for 3 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:0%-30% B over 9 min).6-(4-{(1R,5S)-1- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-4-methyl- 5-(trifluoromethyl)pyridin-2-amine (2 mg, 2.83 μmol, 3.15% yield, 100% purity, FA) was obtained as white solid.1H NMR (400 MHz, MeOH-d4) δ = 9.17 - 9.01 (m, 1H), 6.69 - 6.58 (m, 1H), 5.58 - 5.39 (m, 1H), 4.72 - 4.61 (m, 2H), 4.59 - 4.46 (m, 2H), 3.83 (br d, J = 4.8 Hz, 1H), 3.80 - 3.73 (m, 2H), 3.71 (d, J = 4.0 Hz, 2H), 3.69 - 3.61 (m, 4H), 3.45 - 3.39 (m, 1H), 3.31 - 3.26 (m, 1H), 2.54 - 2.47 (m, 2H), 2.47 - 2.44 (m, 3H), 2.36 - 2.29 (m, 1H), 2.27 - 2.18 (m, 2H), 2.13 - 2.05 (m, 1H), 2.03 - 1.96 (m, 1H), 1.89 - 1.78 (m, 2H), 1.73 - 1.63 (m, 1H), 0.65 - 0.59 (m, 2H), 0.57 - 0.50 (m, 2H). LCMS: (M+1 = 661.2). [0693] Preparation of 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Ex.32)
Figure imgf000191_0001
Figure imgf000192_0001
[0694] Step 1. To a solution of benzyl (1R,6S)-4,4-dioxo-3-oxa-4thia-5,8-diazatricyclo [4.3.2.01,5]undecane-8-carboxylate (1.00 g, 3.00 mmol, 1 eq) and cyclopropanol (171 mg, 3.00 mmol, 1 eq) in DMF (10 mL) was added NaH (177 mg, 4.00 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition 6 M HCl 2 mL at 0 °C and stirred for 0.5 h, and then the mixture was concentrated under reduced pressure to give benzyl (1R,5S)-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (800 mg, 3.00 mmol, 86% yield) as brown oil. LCMS: (M+1 = 317.2). [0695] Step 2. To a solution of benzyl (1R,5S)-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (800 mg, 3.00 mmol, 1 eq) in DCM (1 mL) was added tert-butoxycarbonyl tert-butyl carbonate (828 mg, 4.00 mmol, 1.5 eq) and TEA (511 mg, 5 mmol, 704 μL, 2 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was quenched with water (20 mL) and extracted with DCM (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 4:1) to give O3-benzyl O8-tert-butyl (1R,5S)-1- (cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (820 mg, 2 mmol, 78% yield) as off-white oil. LCMS: (M+23 = 439.1). [0696] Step 3. A mixture of O3-benzyl O8-tert-butyl (1R,5S)-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (820 mg, 2.00 mmol, 1 eq), Pd/C (209 mg, 197 μmol, 10% purity, 0.1 eq), and Pd(OH)2 (276 mg, 197 μmol, 10% purity, 0.1 eq) in i-PrOH (8 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 1 h under H2 atmosphere (15 psi). On completion, the mixture was filtrated to remove Pd/C and Pd(OH)2. Then the mixture was concentrated under reduced pressure to give tert- butyl (1R,5S)-1-(cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (500 mg, 2.00 mmol, 90% yield) as off-white oil. LCMS: (M+1-100 = 183.2). [0697] Step 4. A mixture of tert-butyl (1R,5S)-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1] octane-8-carboxylate (450 mg, 2.00 mmol, 1 eq), 7-bromo-2,4-dichloro- 8-fluoro-quinazoline (707 mg, 3.00 mmol, 1.5 eq), and DIEA (1.24 g, 10 mmol, 1.67 mL, 6 eq) in DCM (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at -40 °C for 1 h under N2 atmosphere. On completion, the mixture was quenched with water (20 mL) and extracted with DCM (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 0:1) to give tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-quinazolin -4-yl)-1- (cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900 mg, 2.00 mmol, 99% yield, 95% purity) as yellow solid. LCMS: (M+1 =543.0) [0698] Step 5. To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (147 mg, 923 μmol, 1 eq) in THF (5 mL) was added NaH (73.8 mg, 2 mmol, 60% purity, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h, and then tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1-(cyclopropoxymethyl)-3,8- diazabicyclo [3.2.1]octane-8-carboxylate (500 mg, 923 μmol, 1 eq) was added with at 0 °C. The mixture was stirred at 0 °C for 0.5 h. On completion, the mixture was added with 5 mL sat. NH4Cl and 5 mL H2O. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 0:1) to give tert-butyl (1R,5S)-3-[7- bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-1-(cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (470 mg, 707 μmol, 75% yield) as yellow solid. LCMS: (M+1 =666.3). [0699] Step 6. A mixture of tert-butyl (1R,5S)-3-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 226 μmol, 1 eq), 2-[2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl- triisopropyl-silane (173 mg, 339 μmol, 1.5 eq), [2-(2- aminophenyl)phenyl]palladium(1+);bis(1-adamantyl)-butyl-phosphane; methanesulfonate (16.4 mg, 23.0 μmol, 0.1 eq), and K3PO4 (144 mg, 677 μmol, 3 eq) in dioxane (1 mL) and H2O (0.2 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 mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 0:1) to give tert- butyl (1R,5S)-1-(cyclopropoxymethyl)-3-[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]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (230 mg, 220 μmol, 98% yield, 93% purity) as brown solid. LCMS: (M+1 =970.4). [0700] Step 7. To a solution of tert-butyl (1R,5S)-1-(cyclopropoxymethyl)-3-[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]quinazolin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 237 μmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 593 μL, 10 eq). The mixture was stirred at 25 °C for 10 min. On completion, the reaction mixture was concentrated under reduced pressure to give 4-[4- [(1R,5S)-1-(cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (180 mg, 218 μmol, 92% yield) as yellow solid. LCMS: (M+1 =826.4). [0701] Step 8. To a solution of 4-[4-[(1R,5S)-1-(cyclopropoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy] quinazolin-7-yl]-6-fluoro-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (170 mg, 206 μmol, 1 eq) in DMSO (1 mL) was added CsF (375 mg, 2 mmol, 12 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated. The residue was purified by prep-HPLC(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [n-Heptane- IPA(0.1%FA)];gradient:9%-39% B over 11 min) to give 4-(4-{(1R,5S)-1- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol (35.27 mg, 48.72 μmol, 23.67% yield, 98.87% purity, FA) as white solid.1H NMR (400 MHz, MeOD-d4) δ = 7.87 - 7.79 (m, 2H), 7.34 - 7.28 (m, 3H), 7.11 - 7.08 (m, 1H), 5.51 - 5.34 (m, 1H),4.56 - 4.50 (m, 2H), 4.49 - 4.45 (m, 1H), 3.75 (s, 1H), 3.68 (s, 2H), 3.62 - 3.51 (m, 4H), 3.48 (d, J = 13.2 Hz, 1H), 3.43 -3.37 (m, 2H), 3.21 (d, J = 10.4 Hz, 2H), 2.54 - 2.38 (m, 2H), 2.32 - 2.26 (m, 1H), 2.22 - 2.13 (m, 2H), 2.04 - 1.94 (m, 2H),1.91 - 1.84 (m, 2H), 1.72 - 1.54 (m, 1H), 0.63 - 0.58 (m, 2H), 0.52 (d, J = 5.6 Hz, 2H). LCMS: (M+1 =670.3). [0702] [0703] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (Ex.33) and 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.34)
Figure imgf000195_0001
Figure imgf000196_0001
[0704] Step 1. To a solution of tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1] octane-8- carboxylate (4.90 g, 10.2 mmol, 1 eq) in MeOH (30 mL), DCM (20 mL) was added NaBH4 (1.15 g, 30.5 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture diluted with sat. NH4Cl 50 mL and extracted with EA (100 mL * 3). The combined organic layers were washed with H2O 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EA=1:0 to 10:1). Compound ert-butyl 1- (hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (3.50 g, 6.50 mmol, 64.0% yield, 90.0% purity) was obtained as a white solid.
Figure imgf000196_0002
NMR (400 MHz, DMSO-d6) δ = 7.73 - 7.52 (m, 1H), 7.54 - 7.42 (m, 10H), 7.41 - 7.24 (m, 5H), 4.85 - 4.75 (m, 1H), 4.20 (J = 7.2 Hz, 2H), 3.88 - 3.81 (m, 1H), 3.15 (J = 10.8 Hz, 2H), 3.05 - 2.94 (m, 2H), 2.48 - 2.48 (m, 1H), 2.50 (d, J = 2.0 Hz, 1H), 2.38 - 2.31 (m, 1H), 1.28 - 1.26 (m, 9H). [0705] Step 2. To a solution oftert-butyl 1-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (2.37 g, 4.89 mmol, 1 eq) and 4A MS (237 mg, 4.89 mmol, 1 eq) in DCM (25 mL) was added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (2.10 g, 9.78 mmol, 2 eq) and trimethyloxonium;tetrafluoroborate (1.01 g, 6.85 mmol, 1.4 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture diluted with H2O 15 mL and extracted with DCM (30 mL * 3). The combined organic layers were washed with H2O 20 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 10:1). Compound tert-butyl 1-(methoxymethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2.14 g, crude) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.40 (s, 11H), 7.19 - 7.13 (m, 3H), 6.98 - 6.87 (m, 1H), 3.68 - 3.56 (m, 1H), 3.21 - 3.14 (m, 3H), 2.99 - 2.90 (m, 1H), 2.86 - 2.79 (m, 1H), 2.74 - 2.73 (m, 2H), 2.37 - 2.30 (m, 1H), 2.23 - 2.09 (m, 1H), 1.95 - 1.88 (m, 2H), 1.74 - 1.66 (m, 1H), 1.63 - 1.57 (m, 1H), 1.09 (s, 9H). [0706] Step 3. To a solution of tert-butyl 1-(methoxymethyl)-3-trityl-3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (2.50 g, 5.01 mmol, 1 eq) in DCM (25 mL) was added HCl/dioxane (4 M, 5.00 mL, 3.99 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture diluted with H2O 100 * 3 mL, adjust PH to a weak base (PH=8) and extracted with DCM (200 mL * 3)/MeOH(20 mL * 3). The combined organic layers were washed with H2O 8 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 1-(methoxymethyl)-3, 8-diazabicyclo[3.2.1] octane-8-carboxylate (1.25 g, crude) as a brown oil.1H NMR (400 MHz, DMSO-d6) δ = 3.86 - 3.79 (m, 1H), 3.59 - 3.51 (m, 1H), 3.38 - 3.32 (m, 1H), 3.10 (s, 3H), 2.60 (s, 3H), 2.58 - 2.49 (m, 2H), 1.82 - 1.73 (m, 1H), 1.70 - 1.57 (m, 2H), 1.53 - 1.43 (m, 1H), 1.29 - 1.24 (m, 9H). [0707] Step 4. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (1.85 g, 7.31 mmol, 1.5 eq) and DIEA (1.89 g, 14.6 mmol, 2.55 mL, 3 eq) in DCM (12.5 mL) at -40 °C was added tert-butyl 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.25 g, 4.88 mmol, 1 eq). The mixture was stirred at -40 °C for 1 hr. The reaction was concentrated in vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:0 to 4:1) to give tert-butyl 3-(2,7- dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.91 g, 3.84 mmol, 78.8% yield, 95% purity) as a red solid. LCMS: (M+1:472.1). [0708] Step 5. To a solution of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4- yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.12 mmol, 1 eq) and [(6Z)-6-(fluoromethylene)-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methanol (544 mg, 3.18 mmol, 1.5 eq) in ACN (10 mL) was added DIEA (821 mg, 6.35 mmol, 1.11 mL, 3 eq). The mixture was stirred at 80 °C for 16 hr. The reaction was concentrated in vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 1:1) to give tert-butyl 3-(7-chloro-8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1, 870 mg, 1.29 mmol, 60.9% yield, 90% purity) as an orange oil and tert-butyl 3-(7-chloro-8-fluoro-2- {[(2E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 2, 600 mg, 988 μmol) as an orange oil. Peak 1: NMR (400 MHz, CDCl3) δ = 8.79 (s, 1H), 6.75 - 6.35 (m, 1H), 4.73 - 4.63 (m, 1H), 4.48 - 4.39 (m, 2H), 4.06 (d, J = 10.0 Hz, 1H), 3.69 (d, J = 9.6 Hz, 2H), 3.58 - 3.47 (m, 2H), 3.38 (s, 3H), 2.83 - 2.70 (m, 1H), 2.55 - 2.36 (m, 1H), 2.28 (s, 1H), 2.05 - 1.91 (m, 4H), 1.87 - 1.80 (m, 2H), 1.71 - 1.65 (m, 2H), 1.53 (s, 9H), 1.44 (d, J = 0.4 Hz, 4H). Peak 2: 1H NMR (400 MHz, CDCl3) δ = 8.78 (s, 1H), 6.75 - 6.45 (m, 1H), 5.31 (s, 1H), 4.65 (d, J = 6.8, 12.6 Hz, 1H), 4.44 - 4.38 (m, 2H), 4.33 - 4.26 (m, 1H), 4.08 - 4.02 (m, 1H), 3.72 - 3.66 (m, 2H), 3.53 - 3.47 (m, 1H), 3.37 (s, 3H), 3.33 - 3.26 (m, 1H), 2.94 - 2.85 (m, 1H), 2.71 - 2.62 (m, 1H), 2.56 - 2.46 (m, 1H), 2.25 - 2.15 (m, 1H), 2.02 - 1.93 (m, 4H), 1.88 (s, 3H), 1.80 - 1.74 (m, 1H), 1.70 - 1.66 (m, 1H), 1.52 (s, 9H). [0709] Step 6. To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1, 200 mg, 329 μmol, 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 (203 mg, 395 μmol, 1.2 eq) in dioxane (2 mL) was added K3PO4 (3 M, 329 μL, 3 eq) and [2-(2-aminophenyl) phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (24.0 mg, 32.9 μmol, 11 μL, 0.1 eq) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hr under N2 atmosphere. The reaction was concentrated in vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=1:0 to 1:1) to give tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (234 mg, 244.5 μmol, 74.2% yield) as a orange oil. 1H NMR (400 MHz, DMSO-d6) δ = 9.21 - 9.16 (m, 1H), 8.15 - 8.06 (m, 1H), 7.79 - 7.72 (m, 1H), 7.60 - 7.52 (m, 1H), 7.40 - 7.31 (m, 1H), 6.66 - 6.62 (m, 1H), 5.38 - 5.35 (m, 2H), 3.73 - 3.67 (m, 2H), 3.63 (d, J = 9.4 Hz, 2H), 3.44 - 3.42 (m, 4H), 3.05 - 2.97 (m, 2H), 2.40 - 2.31 (m, 2H), 2.20 - 2.16 (m, 2H), 1.48 - 1.45 (m, 9H), 1.37 - 1.34 (m, 9H), 1.25 - 1.22 (m, 1H), 1.20 - 1.14 (m, 1H), 1.08 - 1.05 (m, 1H), 0.85 - 0.76 (m, 21H), 0.52 - 0.43 (m, 3H). [0710] Step 7. To a solution of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-1-yl]-2-{[(2Z)-2-(fluoromethylidene)tetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 230 μmol, 1 eq) in DCM (2.5 mL) was added HCl/dioxane (4 M, 57.46 μL, 1 eq). The mixture was stirred at 25 °C for 8 hr. The reaction was concentrated in vaccum to give 6-fluoro-4-(8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[1-(methoxymethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (260 mg, crude) as an orange oil. LCMS: (M+1:813.4). [0711] Step 8. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[1-(methoxymethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (250 mg, 307 μmol, 1 eq) in DMSO (2 mL) was added CsF (280 mg, 1.84 mmol, 68.1 μL, 6 eq). The mixture was stirred at 25 °C for 2 hr. The reaction solution is filtered. The filtrate was purified by prep-HPLC purification (column: Phenomenex Luna C18150 * 25mm * 10um; mobile phase: [water (FA)-ACN]; gradient:5%- 35% B over 8 min) to give 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z,7aS)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[1-(methoxymethyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 144.02 μmol, 46.84% yield, 94.58% purity) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ = 9.06 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 7.87 (dd, J = 5.6, 9.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.90 - 6.61 (m, 1H), 4.76 - 4.64 (m, 2H), 4.53 - 4.47 (m, 2H), 4.18 - 4.09 (m, 1H), 3.89 - 3.73 (m, 4H), 3.72 - 3.66 (m, 1H), 3.62 - 3.58 (m, 2H), 3.45 (d, J = 2.4 Hz, 3H), 3.05 - 2.96 (m, 1H), 2.87 (br d, J = 15.6 Hz, 1H), 2.62 (br d, J = 15.2 Hz, 1H), 2.25 (br dd, J = 6.4, 11.6 Hz, 1H), 2.18 - 2.09 (m, 1H), 2.08 - 1.98 (m, 3H), 1.93 - 1.83 (m, 2H), 1.79 - 1.67 (m, 1H). LCMS: (M+1:657.4). Step 9. The above solid was separated by prep-HPLC purification (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 um);mobile phase: [CO2-ACN/MeOH (0.1% NH3H2O)];B%:40%, isocratic elution mode). Compound 5-ethynyl-6-fluoro-4-(8-fluoro-2- {[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (Ex.33, 25.73 mg, 37.34 μmol, 24.52% yield, 95.29% purity) was obtained as an orange solid and 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.34, 26.22 mg, 38.04 μmol, 24.98% yield, 95.28% purity) as an orange solid. Ex.33: NMR (400 MHz, DMSO-d6) δ = 9.01 (d, J = 4.0 Hz, 1H), 7.86 (dd, J = 5.6, 9.2 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.78 - 6.52 (m, 1H), 4.72 - 4.58 (m, 2H), 4.35 - 4.24 (m, 2H), 3.85 (br d, J = 14.4 Hz, 1H), 3.72 - 3.66 (m, 2H), 3.63 - 3.57 (m, 1H), 3.55 - 3.51 (m, 2H), 3.47 (br d, J = 15.6 Hz, 2H), 3.42 (d, J = 3.2 Hz, 3H), 3.37 - 3.35 (m, 1H), 3.19 - 3.12 (m, 1H), 2.77 - 2.68 (m, 2H), 2.45 (br d, J = 16.0 Hz, 1H), 2.18 - 2.10 (m, 1H), 2.04 - 1.82 (m, 6H). LCMS: (M+1:657.4). Ex.34: 1H NMR (400 MHz, DMSO-d6) δ = 9.02 - 8.88 (m, 1H), 7.86 - 7.64 (m, 1H), 7.32 - 7.19 (m, 2H), 7.15 - 7.05 (m, 1H), 6.82 - 6.49 (m, 1H), 4.66 - 4.51 (m, 2H), 4.43 - 4.33 (m, 2H), 4.08 - 3.96 (m, 1H), 3.80 - 3.45 (m, 7H), 3.38 - 3.33 (m, 3H), 3.28 - 3.25 (m, 1H), 2.94 - 2.83 (m, 1H), 2.79 - 2.71 (m, 1H), 2.55 - 2.46 (m, 1H), 2.20 - 2.10 (m, 1H), 2.02 - 1.87 (m, 4H), 1.83 - 1.72 (m, 2H), 1.69 - 1.57 (m, 1H). LCMS: (M+1:657.4). [0712] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1S,5R)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (Ex.35) and 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.36).
Figure imgf000200_0001
[0713] Step 1. To a solution of tert-butyl 3-(7-chloro-8-fluoro-2-[[(2E)-2- (fluoromethylidene)tetrahydro- lH-pyrrolizin-7 a(5H)-yl]methoxy }pyrido[4,3-d]pyrimidin- 4-yl)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 2 from Ex. 33, 600 mg, 988 μmol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-naphthyl]ethynyl-triisopropyl-silane (608 mg, 1.19 mmol, 1.2 eq) in dioxane (6 mL) was added K3PO4 (3 M, 988 μL, 3 eq) and [2-(2- aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane;methanesulfonate (71.9 mg, 98.8 μmol, 33.5 μL, 0.1 eq) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hr under N2 atmosphere. The reaction was concentrated in vaccum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=l:0 to 1:1). Compound tert-butyl 3-(8-fluoro- 7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl)naphthalen-l-yl]-2- {[(2E)-2-
(fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (673 mg, 541 μmol, 54.8% yield, 77% purity) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ = 9.22 - 9.15 (m, 1H), 8.14 - 8.05 (m, 1H), 7.77 - 7.70 (m, 1H), 7.60 - 7.51 (m, 1H), 7.40 - 7.31 (m, 1H), 6.96 - 6.84 (m, 2H), 6.76 - 6.61 (m, 1H), 5.43 - 5.29 (m, 3H), 4.08 - 3.99 (m, 6H), 3.66 - 3.61 (m, 2H), 3.44 - 3.41 (m, 4H), 2.20 - 2.17 (m, 1H), 1.35 (s, 9H), 1.15 - 1.14 (m, 1H), 1.21 -
1.13 (m, 4H), 1.08 - 1.05 (m, 1H), 0.91 - 0.86 (m, 4H), 0.84 - 0.76 (m, 21H), 0.53 - 0.43 (m, 3H).
[0714] Step 2. To a solution of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- { [tri(propan-2-yl)silyl]ethynyl } naphthalen- 1 -yl] -2- { [(2E)-2-(fluoromethylidene)tetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy }pyrido[ 4, 3-d]pyrimidin-4-yl )- 1 -(methoxy methyl )-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 690 μmol, 1 eq) in DCM (7 mL) was added HCI/dioxane (4 M, 172 μL, 1 eq). The mixture was stirred at 25 °C for 8 hr. The reaction was concentrated in vaccum to give a 6-fluoro-4-(8-fluoro-2-{[(2E)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5 H)-y 1 ] methoxy } -4- [ 1 -(methoxymethyl)-
3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (630 mg, crude) as an orange oil. LCMS: (M+l:813.3).
[0715] Step 3. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2E)-2-
( fluoromethylidene)tetrahydro- 1 H-pyrrol izi n-7 a(5H)-yl]methoxy } -4- [ 1 -(methoxymethyl)-
3.8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (620 mg, 763 μmol, 1 eq) in DMSO (3 mL) was added CsF (695 mg, 4.58 mmol, 169 pL, 6 eq). The mixture was stirred at 25 °C for 2 hr. The reaction solution is filtered. The filtrate was purified by prep-HPLC purification (column: Phenomenex luna Cis 150 * 25 mm * 10 um; mobile phase: [water (FA)-ACN]; gradient: 5%-35% B over 8 min) to give 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5 H)-y 1 ] methoxy } -4- [ 1 -(methoxymethyl)-
3.8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (200 mg, 279.06 μmol, 36.59% yield, 91.63% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO- d6) δ = 9.05 (d, J = 2.4 Hz, 1H), 8.45 (s, 1H), 7.87 (dd, J = 5.8, 9.2 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.22 (s, 1H), 6.96 - 6.69 (m, 1H), 4.75 - 4.64 (m, 2H), 4.61 - 4.43 (m, 2H), 4.06 - 3.97 (m, 1H), 3.86 - 3.76 (m, 2H), 3.75 - 3.62 (m, 3H), 3.60 - 3.56 (m, 2H), 3.44 (d, J = 2.8 Hz, 3H), 2.99 - 2.90 (m, 2H), 2.78 - 2.69 (m, 1H), 2.32 - 2.22 (m, 1H),
2.14 - 1.97 (m, 4H), 1.93 - 1.80 (m, 2H), 1.76 - 1.67 (m, 1H). LCMS: (M+L657.2).
[0716] Step 4. The above solid was separated by prep-HPLC purification (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 um);mobile phase: [CO2-ACN/MeOH(0.1% NH3H2O)]; B%: 40%, isocratic elution mode). Compound 5-ethynyl-6-fluoro-4-(8-fluoro-2- { [(2E)-2-(fluoromethylidene)tetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy } -4- |( 1S,5R)- l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-
2-ol (Ex. 35, 38.87 mg, 56.53 μmol, 18.56% yield, 95.50% purity) was obtained as an orange oil and 5-ethynyl-6-fluoro-4-(8-fluoro-2-{ [(2E)-2-(fluoromethylidene)tetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-
3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 36, 40.31 mg, 61.38 μmol, 20.15% yield, 100% purity) as an orange oil.
Ex. 35: 1H NMR (400 MHz, DMSO-d6) δ = 9.00 (d, J = 4.1 Hz, 1H), 7.86 (dd, J = 5.6, 9.2 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.84 - 6.59 (m, 1H), 4.71 - 4.55 (m, 2H), 4.39 - 4.24 (m, 2H), 3.75 - 3.65 (m, 3H), 3.60 (br dd, J = 5.6, 12.5 Hz, 1H), 3.52 (s, 2H), 3.41 (d, J = 3.2 Hz, 3H), 3.36 - 3.34 (m, 1H), 3.16 - 3.09 (m, 1H), 2.84 (br d, J = 16.4 Hz, 1H), 2.73 - 2.64 (m, 1H), 2.55 (br d, J = 16.4 Hz, 1H), 2.19 - 2.11 (m, 1H), 1.78 (dt, J = 4.4, 13.5 Hz, 7H), 1.68 - 1.57 (m, 1H). LCMS: (M+1:657.2).
Ex. 36: 1H NMR (400 MHz, DMSO-d6) δ = 9.02 (d, J = 4.0 Hz, 1H), 7.86 (dd, J = 5.6, 9.2 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.87 - 6.61 (m, 1H), 4.72 - 4.57 (m, 2H), 4.42 - 4.28 (m, 2H), 3.77 - 3.66 (m, 3H), 3.62 (br dd, J = 2.4, 12.1 Hz, 1H), 3.53 (s, 2H), 3.42 (d, J = 3.2 Hz, 3H), 3.37 - 3.34 (m, 2H), 3.22 - 3.15 (m, 1H), 2.86 (br d, J = 16.4 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.59 (br d, J = 16.4 Hz, 1H), 2.22 - 2.14 (m, 1H), 2.00 - 1.88 (m, 4H), 1.85 - 1.75 (m, 2H), 1.64 (br dd, J = 8.8, 12.9 Hz, 1H). LCMS: (M+1:657.2).
[0717] Preparation of 4-(4-{(1R,5S)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Ex. 37)
Figure imgf000204_0001
[0718] Step 1. To a solution of [(2Z)-2-(fluoromethylidene)tetrahydro- 1H-pyrrol izi n-7a( 5H)- yl]methanol (104 mg, 609 μmol, 1.5 eq) in THF (2 mL) was added NaH (32.5 mg, 812 μmol , 60% purity, 2 eq) at 0 °C for 0.5 h and then tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro- quinazolin-4-yl)-l-(cyclopropoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220 mg, 406 μmol, 1 eq, from BHT-WX-5260) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the mixture was added with sat. NH4CI (1 mL) and H2O (1 mL). 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 to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l:O to 0: 1) to give tert-butyl ( 1R,5S)-3-(7-bromo-8-fluoro-2- { [(2Z)-2-(fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7a(5H)-yl ]methoxy }quinazolin-4-yl)- l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 177 μmol, 44% yield) as white solid. LCMS: (M+l = 678.0).
[0719] Step 2. A mixture of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7a(5H)-yl]methoxy } quinazolin-4-yl)- 1 - [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 148 μmol, 1 eq), 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- naphthyl]ethynyl-triisopropyl-silane (114 mg, 222 μmol , 1.5 eq), K3PO4 (94.1 mg, 443 μmol , 3 eq), [2-(2-aminophenyl)phenyl]palladium( 1 +) ;bis( 1 -adamantyl)-butyl- phosphane;methanesulfonate (10.8 mg, 15 μmol , 0.1 eq) in dioxane (1 mL) and H2O (0.2 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 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 to give a residue. The residue was purified by column chromatography (SiO2. Petroleum ether/THF= 1 :0 to 0:1) to give tert- butyl (1R,5S)-l-[(cyclopropyloxy)methyl]-3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- { [tri(propan-2-yl)silyl]ethynyl } naphthalen- 1 -yl] -2- { [(2Z)-2-(fluoromethylidene)tetrahydro- 1 H-pyrrol i zi n-7 a( 5H)-y 11 methoxy } quinazolin-4-yl)-3 , 8-diazabicyclo [3.2.1 ]octane- 8- carboxylate (120 mg, 122 μmol, 83% yield) as yellow solid. LCMS: (M+l = 982.0).
[0720] Step 3. To a solution of tert-butyl (1R,5S)-l-[(cyclopropyloxy)methyl]-3-(8-fluoro-7- [7-fluoro-3 -(methoxymethoxy)- 8- { [tri(propan-2-yl)silyl]ethynyl } naphthalen- 1 -yl] -2- { [(2Z)- 2-(fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60.0 mg, 61 μmol, 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.5 mL, 32.74 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give 4-(4- {(1R,5S)-L[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2Z)- 2-(fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)-6- fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (45.0 mg, 54.0 μmol, 88% yield, crude) as yellow solid. LCMS: (M+l=838.3).
[0721] Step 4. To a solution of 4-(4-{(1R,5S)-L[(cyclopropyloxy)methyl]-3,8- diazabicyclo|3.2.1 |ocian-3-yl}-8-fluoro-2-{ |(2Z)-2-(fluoromelhylidenejleirahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)-6-fluoro-5-{[tri(propan-2- yl)silyl]ethynyl[naphthalen-2-ol (45.0 mg, 54.0 μmol, 1 eq) in DMSO (0.5 mL) was added CsF (97.9 mg, 644 μmol, 12 eq). The mixture was stirred at 25 °C for 1 h. On completion, the residue was purified by Prep-HPLC (column: Welch ultimate Cl 8 150*25mm* 7um; mobile phase: [water(FA)-ACN]; gradient: 8%-38% B over 10 min) to give 4-(4-{(1R,5S)-l- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol (4.19 mg, 5.76 μmol, 10.72% yield, 100% purity, FA) as off-white solid. 1H NMR (400 MHz, MeOD-d4) δ = 7.88 - 7.77 (m, 2H), 7.35 - 7.27 (m, 3H), 7.13 - 7.08 (m, 1H), 6.95 - 6.67 (m, 1H), 4.63 - 4.41 (m, 4H), 4.10 - 3.98 (m, 1H), 3.80 - 3.72 (m, 1H), 3.71 - 3.66 (m, 2H), 3.66 - 3.59 (m, 2H), 3.58 - 3.46 (m, 2H), 3.45 - 3.37 (m, 2H), 3.26 - 3.19 (m, 1H), 3.01 - 2.89 (m, 2H), 2.74 (br d, J = 16 Hz, 1H), 2.27 (br d, 7 = 2.4 Hz, 1H), 2.13 - 1.85 (m,6H), 0.65 - 0.46 (m, 4H). LCMS: (M+l =682.4).
[0722] Preparation of 2-amino-4-(4-{(1R,5S')-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-
7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-7-yl)-7-fluoro- l -benzolhiophene-3-carbonilrile (Ex. 38)
Figure imgf000206_0001
[0723] Step 1. A mixture of tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2- yl)carbamate (100 mg, 269 μmol , 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (103 mg, 404 μmol , 1.5 eq), KOAc (79.3 mg, 808 μmol, 3 eq), Pd(PPh3)2Cl2 (18.9 mg, 26.9 μmol, 0.1 eq) in dioxane (1 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 concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (90.0 mg, 215 μmol, 80% yield) as white solid. LCMS: (M+23 = 441.1).
[0724] Step 2. A mixture of tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (80.0 mg, 191 μmol, 1 eq), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (59.4 mg, 95.6 μmol , 0.5 eq), K3PO4 (122 mg, 574 μmol, 3 eq), and [2-(2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl- phosphane;methanesulfonate (13.9 mg, 19.1 μmol , 0.1 eq) in dioxane (1 mL) and H2O (0.2 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 20 mL and extracted with EA 45 mL (15 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give tert-butyl (1R,5S)-3-(7-{2-[(tert-butoxycarbonyl)amino]-3-cyano-7-fluoro-l-benzothiophen- 4-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 79.8 μmol , 42% yield) as colorless oil. LCMS: (M+l = 877.3).
[0725] Step 3. To a solution of tert-butyl (1R,5S)-3-(7-{2-[(tert-butoxycarbonyl)amino]-3- cyano-7-fluoro-l-benzothiophen-4-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-[(cyclopropyloxy)methyl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 39.9 μmol , 1 eq) in DCM (0.5 mL) was added HCI/dioxane (4 M, 0.5 mL, 50.1 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:12%-42% B over 8 min) to give 2-amino-4- (4-{(1R,5S)-l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7- yl)-7-fluoro-l-benzothiophene-3-carbonitrile (1.18 mg, 1.63 μmol, 4.09% yield, 100% purity, FA) as orange solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.08 (s, 2H), 7.44 - 7.38 (m, 1H), 7.18 - 7.11 (m, 1H), 5.38 - 5.18 (m, 1H), 4.52 - 4.33 (m, 2H), 4.17 - 4.00 (m, 2H), 3.54 - 3.51 (m, 4H), 3.10 - 3.07 (m, 2H), 3.01 (br s, 1H), 2.87 - 2.78 (m, 2H), 2.16 - 2.11 (m, 1H), 2.06 - 1.98 (m, 2H), 1.89 - 1.67 (m, 5H), 1.59 - 1.48 (m, 2H), 1.48 - 1.33 (m, 2H), 0.53 - 0.49 (m, 2H), 0.48 - 0.44 (m, 2H). LCMS: (M+l = 677.2).
[0726] Preparation of 2-amino-4-(4-{(1R,5S)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-
7a(5H)-yl]methoxy)quinazolin-7-yl)-7-fluoro-l-benzothiophene-3-carbonitrile (Ex. 39)
Figure imgf000207_0001
[0727] Step 1. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy )quinazolin-4-yl)- 1 - [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 196 μmol, 1 eq), tert-butyl N- [3-cyano-7-fluoro-4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)benzothiophen-2-yl]carbamate (123 mg, 293 μmol, 1.5 eq), CS2CO3 (191 mg, 587 μmol, 3 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (12.8 mg, 20 μmol , 0.1 eq) in dioxane (1 mL) and H2O (0.2 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 mixture was quenched with water (20 mL) and extracted with DCM (25 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=l :0 to 0: 1) to give tert-butyl (1R,5S)-3-(7-{2-[(tert-butoxycarbonyl)amino]-3-cyano-7-fluoro-l- benzothiophen-4-yl)-8-fluoro-2-[[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}quinazolin-4-yl)-l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (149 mg, 170 μmol, 87% yield) as yellow solid. LCMS: (M+l = 876.3).
[0728] Step 2. To a solution of tert-butyl (1R,5S)-3-(7-{2-[(tert-butoxycarbonyl)amino]-3- cyano-7-fluoro-l-benzothiophen-4-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 80.0 μmol , 1 eq) in DCM (1 mL) was added HCl/dioxane (4 M, 0.5 mL, 25 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water (FA)-ACN]; gradient: 10%- 40% B over 8 min) to give 2-amino-4-(4-{(1R,5S)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy)quinazolin-7-yl)-7-fluoro-l-benzothiophene-3-carbonitrile (Ex. 39, 7.83 mg, 11.59 μmol, 14.50% yield, 100% purity) as white solid. 1H NMR (400 MHz, MeOD-d4) δ = 7.89 - 7.83 (m, 1H), 7.34 - 7.22 (m, 2H), 7.07 - 7.01 (m, 1H), 5.55 - 5.36 (m, 1H), 4.64 - 4.55 (m, 2H), 4.55 - 4.42 (m, 2H), 3.80 - 3.71 (m, 2H), 3.70 - 3.63 (m, 4H), 3.62 - 3.46 (m, 2H), 3.40 (d, J = 2.4 Hz, 1H), 2.44 (s, 2H), 2.41 - 2.28 (m, 1H), 2.27 - 2.15 (m, 2H), 2.10 - 1.94 (m, 2H), 1.92 - 1.82 (m, 2H), 1.65 (s, 1H), 1.50 -1.13 (m, 1H), 0.61 (s, 2H), 0.52 (d, J = 6.0 Hz, 2H). LCMS: (M+l =676.5).
[0729] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-
(fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5H)-yl]methoxy } -4- [( 1R,5S)- 1 - (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)naphthalen-2-ol (Ex. 40)
Figure imgf000209_0001
[0730] Step 1. To a solution of benzyl (lR,6S)-4,4-dioxo-3-oxa-4thia-5,8-diazatricyclo [4.3.2.01, 5]undecane-8-carboxylate (1.50 g, 4.43 mmol, 1 eq) in DMF (15 mL) was added sodium;methanolate (718 mg, 13.3 mmol, 3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixure was filtered and concentrated to give benzyl (1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 3.44 mmol, 77% yield) as a white solid. LCMS: (M+l = 293.9).
[0731] Step 2. To a solution of benzyl (lR,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 3.44 mmol, 1 eq) in DCM (10 mL) was added Boc2O (2.25 g, 10.3 mmol, 3 eq) and TEA (2.09 g, 20.6 mmol, 6 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was quenched with water (20 mL) and extracted with DCM (25 mL x3 ), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=4:0 to 10:1) to give O3-benzyl 08-tert-butyl (1R,5S)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (800 mg, 1.91 mmol, 55% yield, 93% purity) as a colorless liquid. LCMS: (M-100+1 = 291.1).
[0732] Step 3. To a solution of O3-benzyl 08-tert-butyl (1R,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (800 mg, 2.05 mmol, 1 eq) in i-PrOH (8 mL) was added Pd/C (100 mg, 93.9 μmol , 10% purity, 4.59e-2 eq) and Pd(OH)2 (100 mg, 71.2 μmol, 10% purity, 3.48 e-2 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 at 25 °C for 1 h. On completion, the mixture was filtrated to remove Pd/C and Pd(OH)2/C, and the mixture was concentrated under reduced pressure to give tert-butyl (1R,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1.29 mmol, 63% yield) as colorless oil. [0733] Step 4. To a mixture of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (519 mg, 1.76 mmol, 1.5 eq) in DCM (5 mL) was added tert-butyl (1R,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 1.17 mmol, 1 eq) and DIEA (907 mg, 7.02 mmol, 6.00 eq). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at -40 °C for 1 h under N2 atmosphere. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=4:l to 1:1) to give tert-butyl (1R,5S)-3-(7- bromo-2-chloro-8-fluoro-quinazolin-4-yl)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (500 mg, 949 μmol, 81% yield, 98% purity) as a yellow solid. LCMS: (M+l =517.0).
[0734] Step 5. A mixture of [2-(fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)- yl]methanol (132 mg, 775 μmol, 2.00 eq) and t-BuOK (43.5 mg, 388 μmol , 1.00 eq) in THF (2 mL) was degassed and purged with N2 for 3 times at 0 °C for 0.5 h, then tert-butyl (1R,5S)-3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 388 μmol, 1.00 eq) was added to the mixture, the mixture was stirred at 0 °C for 1.5 h under N2 atmosphere. On completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM/MeOH=10:l to 1:1) to tert-butyl (lR,55)-3-(7-bromo-8-fluoro-2-{ [(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1, 30.0 mg, 41.5 μmol, 11% yield, 90% purity) and tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-{ [(2E)-2- (fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 2, 80 mg, 119 μmol, 31% yield, 97% purity) as a yellow solid. LCMS: (M+l =652.1).
[0735] Step 6. To a miture of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy }quinazolin-4-yl)-l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25.0 mg, 38.4 μmol, 1 eq) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- naphthyl]ethynyl-triisopropyl-silane (29.5 mg, 57.6 μmol, 1.5 eq) in dioxane (0.5 mL) and H2O (0.1 mL) was added K3PO4 (24.5 mg, 115 μmol, 3.00 eq) and [2-(2- aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane;methanesulfo nate (2.80 mg, 3.84 μmol, 0.1 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=1:1 to 1:1) to give tert-butyl (1R,5S)-3-(8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{[(2Z)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7a(5H)-yl]methoxy } quinazolin-4-yl)- 1 - (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 12.6 μmol, 33% yield, 60% purity) as a yellow solid. LCMS: (M+l= 956.5).
[0736] Step 7. To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-|7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy }quinazolin-4-yl)-l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 20.9 μmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (2.50 M, 169 pL, 20.3 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtered and concentrated to give 6-fluoro-4- (8-fluoro-2- { [(2Z)-2-(fluoromethylidene)tetrahydro- 1H-pyrrolizin-7 a(5H)-yl]methoxy } -4- [(1R,5S)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5- {[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (15.0 mg, 18.4 μmol, 88% yield) as a white solid. LCMS: (M+l= 812.4).
[0737] Step 8. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5H)-yl]methoxy } -4- [(1R,5S)- 1 - (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (15.0 mg, 18.4 μmol, 1.00 eq) in DMSO (0.5 mL) was added CsF (33.7 mg, 221 μmol, 12 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixure was filtered. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:7%- 37% B over 10 min) to give 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2- (fluoromethylidene)tetrahydro-lH-pyrrolizin-7 a(5H)-yl]methoxy } -4- [(1R,5S)- 1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)naphthalen-2-ol (3.16 mg, 15.3 μmol, 82.56% yield, 100% purity) as a brown gum. 'H NMR (400 MHz, DMSO-d6) δ = 7.99 - 7.92 (m, 1H), 7.75 - 7.69 (m, 1H), 7.45 (t, J = 9.2 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H),7.23 - 7.16 (m, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.87 - 6.61 (m, 1H), 4.38 - 4.23 (m, 2H), 4.08 - 3.99 (m, 2H), 3.85 - 3.79 (m, 1H), 3.70 (br d, J = 15.2 Hz, 2H), 3.56 (br s, 2H), 3.32 (s, 3H), 3.27 (br d, J= 6.0 Hz, 3H), 3.03 - 2.97 (m, 1H), 2.57 (br d, J= 8.0 Hz, 2H), 2.54 (s, 1H), 2.34 - 2.28 (m, 1H), 2.00 - 1.65 (m, 8H), 1.51 - 1.42 (m, 1H). LCMS: (M+l= 656.2).
[0738] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-
(fluoromethylidene)tetrahydro-lH-pyrrolizin-7 a(5H)-yl]methoxy } -4- [( 1R,5S)- 1-
(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)naphthalen-2-ol (Ex. 41)
Figure imgf000212_0001
[0739] Step 1. To a solution of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-{[(2E)-2- (fluoromethylidene)tetrahydro- 1 H-pyrrolizin-7 a(5H)-yl]methoxy } quinazolin-4-yl)- 1 - (methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.0 mg, 115 μmol, 1 eq, from BHT-WX-5262_P1) and 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l-naphthyl]ethynyl-triisopropyl-silane (88.6 mg, 173 μmol, 1.50 eq) in dioxane (1 mL) and H2O (0.2 mL). Then was added K3PO4 (73.4 mg, 346 μmol, 3 eq) and [2-(2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane; methanesulfonate (8.40 mg, 11.5 μmol, 0.1 eq). The mixture was stirred at 80 °C for 2 h. On d]pyrimidin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Ex. 42)
Figure imgf000213_0001
[0743] Step 1. A mixture of N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6- tributylstannyl-5-(trifluoromethyl)pyridin-2-amine (100 mg, 142 μmol, 1 eq), tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (84.4 mg, 142 μmol, 1 eq), Cui (27.0 mg, 142 μmol, 1 eq), Xphos Pd G4 (12.2 mg, 14.2 μmol, 0.1 eq) and TEA (28.7 mg, 284 μmol, 39.5 pL, 2 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16 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/THF=l/0 to 0/1) to give tertbutyl (1R,5S)-3-(7-[6-{bis[(4-methoxyphenyl)methyl]amino}-4-methyl-3- (trifluoromethyl)pyridin-2-yl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 51.3 μmol, 36% yield) as yellow oil. LCMS: (M+l = 975.5). [0744] Step 2. A solution of tert-butyl (1R,5S)-3-(7-[6-{bis[(4- methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-8-fluoro-2- { [(2R,7aS)-2-fluoro tetrahydro- 1 H-pyrrolizin-7a(5H)-yl]methoxy]pyrido[4,3-d]pyrimidin-4- yl)-l-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 46.2 μmol, 1 eq) in TFA (1.54 g, 13.5 mmol, 1 mL, 292 eq) was stirred at 60 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:6%-36% B over 10 min) to give 6-(8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-l- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-4-methyl- 5-(trifluoromethyl)pyridin-2-amine (2.94 mg, 4.15 μmol, 8.99% yield, 96.08% purity, formic acid salt) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.03 - 8.98 (m, 1H), 6.82 - 6.73 (m, 2H), 6.53 - 6.46 (m, 1H), 5.38 - 5.16 (m, 1H), 4.52 - 4.30 (m, 2H), 4.13 (d, J = 10.4 Hz, 1H), 4.01 (d, J = 10.4 Hz, 1H), 3.60 - 3.55 (m, 6H), 3.32 - 3.31 (m, 3H), 3.10 - 3.05 (m, 2H), 3.01 (s, 1H), 2.86 - 2.78 (m, 1H), 2.36 (br d, J= 1.2 Hz, 3H), 2.16 - 2.09 (m, 1H), 2.08 - 1.96 (m, 2H), 1.86 - 1.69 (m, 4H), 1.66 - 1.54 (m, 2H), 1.49 - 1.38 (m, 1H). LCMS: (M+l = 635.2).
[0745] Preparation of 7-(3-chloro-8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-l- (methoxymethyl)-3,8-diazabicyclo[3.2. 1 |octan-3-yl |pyrido|4,3-d]pyrimidine (Ex. 43)
Ex. 43 was syntheized using the same chemistry as Ex. 42.
Preparation of 7-(8-ethynyl-3,7-difluoronaphthalen-l-yl)-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-l-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine (Ex. 44)
Ex. 44 was synthesized using the same chemistry as Ex. 42.
[0746] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{ |(2R,7aS)-2-fluoroletrahydro- I H- pyrrolizin-7a(5H)-yl | methoxy } -4- { (1S,5R)- 1 -[(27?)-oxolan-2-yl]-3, 8- diazabicyclo[3.2.1]octan-3-yl)quinazolin-7-yl)naphthalen-2-ol (Ex. 45) and 5-ethynyl-6- fluoro-4-(8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-4-
{(1R,5S)-l-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7- yl)naphthalen-2-ol (Ex. 46)
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
[0747] Step 1. A mixture of tert-butyl 3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 g, 44.0 mmol, 1 eq) in Et2O (200 mL) was degassed and purged with N2 for 3 times, then TMEDA (25.6 g, 220 mmol, 33.2 mL, 5 eq) and s-BuLi (1.3 M, 57.5 mL, 1.7 eq) was added at -40 °C and stirred for 2 h, then 4-[tert-butyl(dimethyl)silyl]oxybutanal (26.7 g, 132 mmol, 3 eq) was added at -40 °C, and then the mixture was stirred at -40 °C for 1 h under N2 atmosphere. On completion, the reaction mixture was quenched by addition NH4CI (100 mL) at 0 °C, and then diluted with H2O (200 mL) and extracted with EA (150 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reversed (H2O/ACN=l/0 to 0/1) to give tert-butyl 1 - [4- [tert-butyl(dimethyl)silyl]oxy- 1 -hydroxy-butyl] -3 -trityl- 3 , 8- diazabicyclo[3.2.1] octane-8-carboxylate (18 g, 27.4 mmol, 62% yield) as brown oil. LCMS: (M+l = 657.4).
[0748] Step 2. To a solution of tert-butyl l-[4-[tert-butyl(dimethyl)silyl]oxy-l-hydroxy- butyl]-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (18 g, 27.4 mmol, 1 eq) in DMSO (100 mL) was added CsF (12.5 g, 82.2 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was diluted with H2O (150 mL) and extracted with EA (100 mL * 3). The combined organic layers were washed with H2O (100 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give tert-butyl l-(l,4-dihydroxybutyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (11.4 g, 21.0 mmol, 77% yield) as yellow oil. LCMS: (M+l = 543.5).
[0749] Step 3. To a solution of tert-butyl l-(l,4-dihydroxybutyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (9.3 g, 17.1 mmol, 1 eq) in pyridine (90 mL) was added benzenesulfonyl chloride (9.08 g, 51.4 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EA (100 mL * 3). The combined organic layers were washed with H2O (50 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give tert-butyl l-[(2R)-tetrahydrofuran-2-yl]-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (Peak 1, 1.55 g, 2.81 mmol, 16% yield, 95% purity) as white solid and tert-butyl l-[(2S)-tetrahydrofuran-2-yl]-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 2, 5.4 g, 10.3 mmol, 60% yield) as white solid. LCMS: (M+l = 525.4).
[0750] Step 4. To a solution of tert-butyl l-[(2R)-tetrahydrofuran-2-yl]-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1, 1.35 g, 2.57 mmol, 1 eq) in DCM (14 mL) was added HOAc (7.34 g, 122 mmol, 7.00 mL, 47.5 eq). The mixture was stirred at 25 °C for 16 h. On completion, the mixture was diluted with water (50 mL) and extracted with DCM (20 mL x3). The water phase was treated with NaHCO3 to adjust PH to 7 and extracted with DCM (20 mL*2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give tert-butyl l-[(2R)-tetrahydrofuran-2-yl]-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (620 mg, 2.20 mmol, 85% yield) as white solid. 1 H NMR (400 MHz, CDCl3) δ = 4.90 - 4.76 (m, 1H), 4.23 - 4.18 (m, 1H), 3.93 - 3.81 (m, 2H), 3.09 - 2.99 (m, 2H), 2.64 - 2.50 (m, 2H), 2.15 - 2.06 (m, 2H), 2.02 - 1.86 (m, 4H), 1.86 - 1.78 (m, 1H), 1.69 - 1.62 (m, 1H), 1.50 - 1.44 (m, 9H).
[0751] Step 5. A mixture of tert-butyl l-[(2R)-tetrahydrofuran-2-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (570 mg, 2.02 mmol, 1 eq), 7-bromo-2,4-dichloro-8- fluoro-quinazoline (896 mg, 3.03 mmol, 1.5 eq), and DIEA (783 mg, 6.06 mmol, 1.05 mL, 3 eq) in DCM (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at -40 °C for Ih 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=l/O to 0/1) to give tert-butyl 3-(7- bromo-2-chloro-8-fluoro-quinazolin-4-yl)-l-[(2R)-tetrahydrofuran-2-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (970 mg, 1.79 mmol, 89% yield) as brown solid. LCMS: (M+l = 542.9).
[0752] Step 6. To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-l- [(2R)-tetrahydrofuran-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (670 mg, 1.24 mmol, 1 eq), [(2R,8S)-2-fhioro-l,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (295 mg, 1.85 mmol, 1.5 eq) in dioxane (7 mL) was added KF (216 mg, 3.71 mmol, 3 eq) and 1,4,7,10,13,16-hexaoxacyclooctadecane (163 mg, 618 qmol, 0.5 eq). The mixture was stirred at 100 °C for 72 h. On completion, the mixture was concentrated in vacuum to give a residue. The residue was purified by combi flash (20 g silica gel column, EtOAc in PE from 0% to 100%) to give tert-butyl 3-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-l-[(2R)-tetrahydrofuran-2-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 828 pmol, 67% yield) as light yellow solid.
[0753] Step 7. SFC separation: The solid obtained above was separated by SFC (Column: Chiralpak AD-3 50x4.6mm I.D., 3um , Mobile phase: Phase A for CO2, and Phase B for EtOH(0.05%DEA); Gradient elutiomB in A from 5% to 40%, Flow rate: 3mL/min;Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar) to give tert-butyl (1S,5R)-3-(7-bromo-8- fluoro-2- { [(2R,7aS) - 2- 13 uorotetrahydro- 1H-pyrrol izin-7 a(5H)-yl]methoxy }quinazolin-4-yl)- l-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1-a, 230 mg, 346 μmol, 40% yield) was obtained as yellow oil and tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(2S)- oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1-b, 300 mg, 451 μmol, 53% yield) was obtained as yellow oil.
Peak 1-a: LCMS: (M+l = 666.1) Peak 1-b: LCMS: (M+l = 666.0)
[0754] Step 8. A mixture of tert-butyl (1S,5R)-3-(7-bromo-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(27?)-oxolan-2-yl]-
3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1-a, 230 mg, 346 μmol, 1 eq), 2-[2-fluoro- 6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-naphthyl] ethynyl- triisopropyl-silane (266 mg, 519 μmol , 1.5 eq), K3PO4 (220 mg, 1.04 mmol, 3 eq), [2-(2- aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane; methanesulfonate (25.2 mg, 34.6 μmol, 0.1 eq) and H2O (0.6 mL) in dioxane (3 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 concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=l/0 to 0/1) to give tert-butyl (1S,5R)-3-(8-fluoro-7-[7-fhroro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(27?)-oxolan-2-yl]-
3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 309 μmol, 89% yield) as brown oil. LCMS: (M+l = 970.4).
[0755] Step 9. To a solution of tert-butyl (1S,5R)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(27?)-oxolan-2-yl]-
3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 278 μmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 1 mL, 14.4 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give 6-fluoro-4- (8-fluoro-2- { | (2R,7aS)-2- 1’1 uorotetrahydro- I H-pyrrol i zi n-7 a( 5 H)-y 1 ] methoxy } - 4 - { ( 1 S,5R)- 1 - [(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-([tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (225 mg, 272 μmol, 98% yield) as brown solid. LCMS: (M+l = 826.4).
[0756] Step 10. To a solution of 6-fluoro-4-(8-fluoro-2-{ |(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-{(1S,5R)-l-[(27?)-oxolan-2-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen- 2-ol (225 mg, 272 μmol, 1 eq) in DMSO (2 mL) was added CsF (248 mg, 1.63 mmol, 6 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated to remove CsF. The filtrate was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:3%-33% B over 9 min) to give 5- ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1S,5R)-l-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin- 7-yl)naphthalen-2-ol (Ex. 45, 135.32 mg, 187.77 μmol, 68.94% yield, 99.32% purity, FA) as yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.18 - 8.16 (m, 1H), 7.96 (dd, J = 6.0, 9.2 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.45 (t, J = 8.8 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.19 (br t, J = 7.6 Hz, 1H), 7.07 (s, 1H), 5.38 - 5.19 (m, 1H), 4.32 - 4.16 (m, 2H), 4.11 - 4.01 (m, 2H), 3.90 (br s, 1H), 3.82 - 3.77 (m, 2H), 3.74 - 3.65 (m, 2H), 3.61 (br d, J = 6.4 Hz, 2H), 3.50 - 3.38 (m, 4H), 3.10 (br d, J= 11.6 Hz, 2H), 3.04 - 3.00 (m, 1H), 2.89 - 2.79 (m, 1H), 2.17 - 2.11 (m, 1H), 2.01 (br s, 1H), 1.88 - 1.82 (m, 4H), 1.80 - 1.74 (m, 4H), 1.53 - 1.42 (m, 1H).
LCMS: (M+l = 670.3).
[0757] Step 11. A mixture of tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(2S)-oxolan-2-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Peak 1-b, 270 mg, 406 μmol, 1 eq), 2-[2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-naphthyl] ethynyl-triisopropyl-silane (312 mg, 609 μmol, 1.5 eq), K3PO4 (259 mg, 1.22 mmol, 3 eq), [2-(2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane; methanesulfonate (29.6 mg, 40.6 μmol, 0.1 eq) and H2O (0.6 mL) in dioxane (3 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 concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/THF= 1/0 to 0/1) to give tert-butyl ( 1R,5S)-3-(8-fluoro-7-|7-lluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(2S)-oxolan-2-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (360 mg, 371 μmol, 91% yield) as brown oil. LCMS: (M+l = 970.8).
[0758] Step 12. To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-4-yl)-l-[(2S)-oxolan-2-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 309 μmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 1 mL, 12.9 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to give 6-fluoro-4- (8-fluoro-2- { [(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy } -4- { (1R,5S)- 1- [(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-{ [tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (250 mg, 303 μmol, 98% yield) as brown solid. LCMS: (M+l = 826.3).
[0759] Step 13. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-{(1R,5S)-l-[(2S)-oxolan-2-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)-5-{ [tri(propan-2-yl)silyl]ethynyl}naphthalen- 2-ol (250 mg, 303 μmol, 1 eq) in DMSO (2 mL) was added CsF (276 mg, 1.82 mmol, 6 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated to remove CsF. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:9%-39% B over 11 min) to give 5-ethynyl- 6-fluoro-4-(8-fluoro-2- { | (2/?,7 a5)-2-fluorotetrahydro- 1 H-pyrrol i zi n-7a( 5H)-yl | methoxy } -4- {(1R,5S)-l-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin-7-yl)naphthalen- 2-ol (Ex. 46, 125.17 mg, 173.02 μmol, 57.17% yield, 98.94% purity, FA) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.17 (br d, J = 5.6 Hz, 1H), 7.95 (dd, J = 6.0, 9.2 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.45 (t, J = 9.2 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.19 (br t, J = 7.6 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 5.36 - 5.19 (m, 1H), 4.34 - 4.17 (m, 2H), 4.14 - 3.97 (m, 2H), 3.93 - 3.88 (m, 1H), 3.84 - 3.77 (m, 2H), 3.72 - 3.60 (m, 2H), 3.52 - 3.38 (m, 2H), 3.13 - 3.06 (m, 2H), 3.03 (br s, 1H), 2.88 - 2.79 (m, 1H), 2.16 - 2.11 (m, 1H), 2.06 (br s, 1H), 2.03 - 1.91 (m, 2H), 1.87 - 1.72 (m, 10H), 1.48 (br s, 1H). LCMS: EC3248-1027-P3A1 (M+l = 670.2)
[0760] Ex. 47 and Ex. 48 were synthesized using the same chemistry as Ex. 45 and Ex. 46 using intermediate Peak 2 from Ex. 45 synthesis.
[0761] Ex. 49 was synthesized using the same chemistry as Ex. 38. [0762] Ex. 50 was synthesized using the same chemistry as Ex. 39.
[0763] General Method B [0764] Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7 a( 5 H)-y 1 ] methoxy } -4- { ( 1R,5S)- 1 - [(methanesulfonyl)methyl] -3 ,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 5)
Figure imgf000222_0001
[0765] 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 NH4CI (30 mL), and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was triturated with PE at 25 °C 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. NMR (400 MHz, CDCI3) δ = 9.18 (s, 1H), 7.37 - 7.36 (m, 1H), 5.09 (q, J = 8.0 Hz, 2H).
[0766] 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-l,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-
I,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, CDCI3) 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, 7 = 5.6, 9.6 Hz, 1H), 2.26 (dd, 7 = 10.0, 14.4 Hz, 2H), 2.17 - 2.10 (m, 2H), 2.01 - 1.96 (m, 2H).
[0767] Step 3. A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-l,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-l,3,2- dioxaborolan-2-yl)naphthalen-l-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(l+);bis(l- 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-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-l-naphthyl]ethynyl-triisopropyl-silane (2.31 g, 2.49 mmol, 60.7% yield) was obtained as a brown oil. 1 H NMR (400 MHz, CDCI3) δ = 9.24 (s, 1H), 7.80 (dd, 7 = 6.0, 9.2 Hz, 1H), 7.53 (d, 7 = 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, 7 = 4.8, 9.2 Hz, 1H), 2.22 - 2.07 (m, 3H), 1.96 (td, 7= 6.0,
II.6 Hz, 3H), 0.87 (d, 7 = 7.6 Hz, 9H), 0.84 (d, 7 = 7.6 Hz, 9H), 0.58 - 0.49 (m, 3H). LCMS: m/z 789.5 (M+l).
[0768] Step 4. To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-l-naphthyl]ethynyl-triisopropyl-silane (1.0 eq) in DMF is added K2CO3 (5.0 eq) and tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (2.0 eq). The mixture is stirred at 80 °C for 3 h. The mixture was quenched with water. Extraction workup with EtOAc followed by column chromatography to give tertbutyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl] ethynyl } naphthalen- 1 -yl] -2- { [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-4pyrimidin-4-yl)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo [3.2.1 ] octane- 8-carboxylate.
[0769] Step 5. To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)- 8- { [tri(propan-2-yl)silyl]ethynyl ) naphthalen- 1 -yl] -2- { [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 eq) in DCM is added HCl/Dioxane (4 M, 6 eq.). The mixture was stirred at 25 °C for 1 h and concentrated to give 6-fluoro-4-(8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-l-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan-3- yl)pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol.
[0770] Step 6. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-{(1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (1.0 eq) in DMSO is added CsF (5.0 eq). The mixture is stirred at 25 °C for 2 hr. The residue is purified by prep-HPLC to give 5-ethynyl-6-fluoro-4- (8-fluoro-2- { [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7 a(5H)-yl]methoxy } -4- { ( XR,5S)- 1 - [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol.
[0771] General Method C:
[0772] Preparation of 4-(4-{(1R,5S)-l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Ex. 8):
Figure imgf000224_0001
Figure imgf000225_0001
[0773] Step 1. The mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (406 mg, 0.925 mmol, 1 eq), tert-butyl l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (250 mg, 0.925 mmol, 1 eq) and K2CO3 (383 mg, 2.77 mmol, 3 eq) in DMF (6.5 mL) was stirred at 80 °C for 1 h. On completion, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (5 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1) to give tert-butyl 3-(7-chloro-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5/f)-yl]methoxy}pyrido[4,3- d]pyrimidin-4-yl)-l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (475 mg, 0.780 mmol, 84% yield) as a yellow oil. LCMS: m/z 609.1 (M+l). Absolute chiral version tert-butyl ( I.S'.5.S')-3-(7-chloro-8-fluoro-2-{ [(2R,7aS)-2-fluoroieirahydro- l H-pyrrolizin- 7a(5H)-yl|melhoxy}pyrido|4,3-d]pyrimidin-4-yl)-l -(2-melhoxyelhyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate is prepared using similar procedure.
[0774] Step 2. The mixture of tert-butyl 3-(7-chloro-8-fluoro-2-[ |(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(2- methoxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (420 mg, 690 umol, 1 eq), 2-[2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-naphthyl] ethynyl-triisopropyl-silane (353 mg, 690 umol, 1 eq), K3PO4 (1.5 M, 1.38 mL, 3 eq) and [2- (2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane;methanesulfonate (50.2 mg, 69.0 umol, 0.1 eq) in THF (10 mL) was stirred at 80 °C for 2 h under N2. On completion, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:THF=1:1) to give tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- yl)silyl] ethynyl } naphthalen- 1 -yl] -2- { [(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (650 mg, 678 umol, 98% yield) as a yellow solid. LCMS: m/z 959.9 (M+l). The absolute chiral version tert-butyl (1S,5S)-3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)- 8- { [tri(propan-2-yl)silyl]ethynyl } naphthalen- 1 -yl] -2- { [(2R,7aS)-2-fluorotetrahydro- 1H- pynolizin-7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(2-methoxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate is prepared using similar procedure.
[0775] Step 3. To a solution of give tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)- 8- { [tri(propan-2-yl)silyl]ethynyl } naphthalen- 1 -yl] -2- { [(2R, 7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(2-methoxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.313 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 0.782 mL, 10 eq), the reaction was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy ) -4- [l-(2-methoxyethyl)-3 ,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (270 mg, crude) as a yellow solid. LCMS: m/z 815.5 (M+l). The absolute chiral version 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ) -4- [( 1S,5S)- l-(2-methoxyethyl)-3 ,8-diazabicyclo[3.2. l]octan- 3 -yl]pyrido [4,3-d]pyrimidin-7-yl)-5- { [tri(propan-2-yl)silyl]ethynyl }naphthalen-2-ol is prepared using similar procedure.
[0776] Step 4. To a solution of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-5- [ [tri(propan-2-yl)silyl]ethynyl )naphthalen-2-ol (270 mg, 0.331 mmol, 1 eq) in DMSO (3 mL) was added CsF (352 mg, 2.32 mmol, 7 eq), the reaction was stirred at 25 °C for 16 h. On completion, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (column: Welch Ultimate C18 150*25mm*5um;mobile phase: [water(TFA)-ACN];B%: 10%-40%,10min). to give 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[l-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 10, 50.77 mg, 0.077.1 mmol, 23% yield) as an orange solid. !H NMR (400 MHz, DMSO-d6) δ = 11.20 - 10.83 (m, 1H), 10.45 - 10.09 (m, 1H), 9.56 - 9.33 (m, 2H), 9.17 (s, 1H), 8.02 - 7.94 (m, 1H), 7.52 - 7.37 (m, 2H), 7.19 (s, 1H), 5.78 - 5.46 (m, 1H), 4.87 - 4.64 (m, 2H), 4.61 (br s, 2H), 4.24 (br s, 1H), 3.90 - 3.84 (m, 2H), 3.81 - 3.74 (m, 2H), 3.57 (br d, J = 6.0 Hz, 3H), 3.29 (d, J = 6.4 Hz, 3H), 2.60 - 2.53 (m, 1H), 2.37 - 2.29 (m, 1H), 2.22 - 2.03 (m, 8H), 1.96 - 1.79 (m, 2H). LCMS: m/z 659.1 (M+l). The absolute chiral version 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy } -4- [( 1S, 5S)- l-(2-methoxyethyl)-3 ,8-diazabicyclo[3.2. l]octan- 3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol is prepared using similar procedure.
[0777] Preparation of 5-ethynyL6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-{(1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 5)
Figure imgf000227_0001
[0778] Step 1. To a solution of benzyl (3aR,7S)-l,l-dioxodihydro-1H,3H-3a,7-ethano-lλ6- [l,2,3]oxathiazolo[3,4-α]pyrazine-5(4H)-carboxylate (50 mg, 0.148 mmol, 1 eq.) in DMF (0.5 mL) was added methylsulfanylsodium (20.7 mg, 0.296 mmol, 18.8 uL, 2 eq), and the mixture was stirred at 25 °C for 1 h. Then HC1 (6 M, 0.1 mL, 4.06 eq) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give benzyl (1R,5S)- 1- [(methylsulfanyl)methyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (40 mg, 0.131 mmol, 88% yield) as white solid. LCMS: (M+l = 307.0).
[0779] Step 2. To a solution of benzyl (1R,5S)-l-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (10 mg, 0.0326 mmol, 1 eq) in DCM (0.5 mL) was added TEA (9.91 mg, 0.0979 mmol, 13.6 uL, 3 eq) and Boc2O (10.7 mg, 0.049 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 3-benzyl 8-tert-butyl (1R,5S)-l-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (13 mg, 0.032 mmol, 98% yield) as white solid. LCMS: (M-100+ 1 = 307.0).
[0780] Step 3. To a solution of 3-benzyl 8-tert-butyl (1R,5S)-l-[(methylsulfanyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (300 mg, 0.738 mmol, 1 eq) in DCM (5 mL) was added m-CPBA (375 mg, 1.84 mmol, 85% purity, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was quenched by addition of sat. Na2SO4 30 mL at 0°C, and then diluted with H2O 50 mL and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/0 to 0/1) to give 3-benzyl 8-tert-butyl (1R,5S)-1- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (290 mg, 0.661 mmol, 90% yield) as colorless oil.
[0781] LCMS: (M-100+1 =339.0).
[0782] Step 4. A mixture of 3-benzyl 8-tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (290 mg, 0.661 mmol, 1 eq), Pd/C (30 mg, 10% purity), Pd(OH)2/C (30 mg, 10% purity) in i-PrOH (5 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 2 h under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtrated. And the filtrated was concentrated under reduced pressure to remove solvent to give tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (174 mg, 0.572 mmol, 86% yield) as colorless oil.
[0783] Step 5. To a solution of tert-butyl (1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.230 mmol, 1 eq) in DMF (0.5 mL) was added K2CO3 (95.4 mg, 0.690 mmol, 3 eq) and 7-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy ) -4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (80.7 mg, 0.184 mmol, 0.8 eq). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was diluted with H2O 20 mL and extracted with EA (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/THF=l/0 to 0/1) to give tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-4- yl)-l-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 109 umol, 47% yield). LCMS: (M+l = 643.2). [0784] Step 6. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7a1S')-2- f I uorotetrahydro- 1 H-pyrrolizi n-7a(5H)-yl ] methoxy } pyrido| 4,3-d]pyrimidi n-4-yl )- 1 - [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (63 mg, 0.098 mmol, 1 eq), {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl]ethynyl}tri(propan-2-yl)silane (75.31 mg, 0.147 mmol, 1.5 eq), K3PO4 (62.4 mg, 0.294 mmol, 3 eq), [2-(2-aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)- butyl-phosphane;methanesulfonate (7.13 mg, 0.0098 mmol, 0.1 eq) in dioxane (1 mL) and H2O (0.2 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 under microwave. On completion, the reaction mixture was diluted with H2O 20 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate— 1/0 to 0/1) to give tert-butyl ( lR,5.S')-3-(8-fluoro-7-|7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (85 mg, 85.6 umol, 87% yield) as colorless solid.
[0785] LCMS: (M+l= 993.3).
[0786] Step 7. To a solution of tert-butyl (1R,5S)-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (69 mg, 0.0695 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 0.8 mL, 46.1 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated to give 6-fluoro-4- (8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-4-{(1R,5S')-l- [(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)- 5-{ [tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (55 mg, 64.8 umol, 93% yield) as yellow solid. LCMS: (M+l = 849.3).
[0787] Step 8. To a solution of 6-fluoro-4-(8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-4-{(1R,5S)-l-[(methanesulfonyl)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (55 mg, 0.0648 mmol, 1 eq) in DMSO (1 mL) was added CsF (118 mg, 0.777 mmol, 12 eq). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was filtrated and the filtrate was purified by prep-HPLC(column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(TFA)-ACN];B%: 5%-35%,10min) to give Ex. 5, 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-l-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan-3- yl)pyrido[4,3-7]pyrimidin-7-yl)naphthalen-2-ol (33.81 mg, 41.91 umol, 64.70% yield, TFA) as yellow solid.
[0788] 1H NMR (400 MHz, MeOD-d4) δ = 9.12 (d, J = 2.4 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.37 - 7.31(m, 1H), 7.25 - 7.17 (m, 1H), 5.77 - 5.68 (m, 1H), 5.68 - 5.51 (m, 1H), 4.84 - 4.77 (m, 2H), 4.75 (br s, 2H), 4.34 - 4.24 (m, 2H),4.06 - 3.98 (m, 2H), 3.97 - 3.89 (m, 4H), 3.48 (dt, 7 = 5.6, 10.8 Hz, 1H), 3.23 (s, 3H), 2.69 (br d, J = 3.6 Hz, 1H), 2.66 - 2.56 (m,2H), 2.51 - 2.42 (m, 1H), 2.22 (br d, J= 12.4 Hz, 6H), 2.03 - 1.92 (m, 1H). LCMS: (M+l = 693.3).
[0789] Preparation of 4-(4-{l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl|- 8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Ex. 8a)
Figure imgf000230_0001
[0790] Step 1. To a solution of benzyl l,l-dioxodihydro-lH,3H-3a,7-ethano-lλ6- [l,2,3]oxathiazolo[3,4-α]pyrazine-5(4H)-carboxylate (82.0 mg, 0.242 mmol, 1 eg.) and cyclopropanol (14.1 mg, 0.242 mmol, 1 eg.) in DMF (1 mL) was added NaH (14.5 mg, 0.364 mmol, 60% purity, 1.5 eg.) at 0 °C. The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated to give a benzyl l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (76 mg, 0.240 mmol, 99% yield) as yellow oil which was used into the next step without further purification. LCMS: m/z 317.1 (M+l). [0791] Step 2. To a solution of benzyl l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (187 mg, 0.591 mmol, 1 eq) in DCM (2 mL) was added Boc2O (193 mg, 0.887 mmol, 204 uL, 1.5 eq), DMAP (7.22 mg, 0.0591 mmol, 0.1 eq) and TEA (120 mg, 1.18 mmol, 165 uL, 2 eq). The mixture was stirred at 25 °C for 16 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, PE/THF=l/0 to 0/1) to give 3- benzyl 8-tert-butyl l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (159 mg, 382 umol, 65% yield) as light yellow oil. LCMS: (M+23: 439.1). [0792] Step 3. A mixture of 3-benzyl 8-tert-butyl l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (159 mg, 0.382 mmol, 1 eq), Pd/C (0.0160 g, 10% purity, 1.00 eq), Pd(OH)2 (16 mg, 10% purity, 1.00 eq) in t-BuOH (10 mL) was degassed and purged with H2 for 3 times, and then stirred at 25 °C for 1 h under H2 (15 psi). On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuum to give product tert-butyl l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (100 mg, 354 umol, 93% yield) as light-yellow oil. LCMS: (M-100+1: 183.1). [0793] Step 4. To a solution of 7-chloro-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl |melhoxy }-4-(2,2,2-lrifluoroelhoxy)pyrido|4,3-d]pyrimidine (82.9 mg, 0.189 mmol, 1 eq.) in DMF (0.1 mL) was added K2CO3 (78.3 mg, 0.567 mmol, 3 eq) and tert-butyl l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80.0 mg, 0.283 mmol, 1.5 eq). The mixture was stirred at 80 °C for 1 h. On completion, the reaction mixture was diluted with H2O (5 mL) and extracted with EA 30 mL (10 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/THF=l/0 to 0/1) to give tert-butyl 3-(7-chloro-8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (96.0 mg, 0.155 mmol, 82% yield) as colorless oil.
[0794] LCMS: m/z 621.1 (M+l).
[0795] Step 5. A mixture of tert-butyl 3-(7-chloro-8-lluoro-2-[ |(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l- [(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (86 mg, 0.138 mmol, 1 eq), {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl]ethynyl}tri(propan-2-yl)silane (106 mg, 0.208 mmol, 1.5 eq), [2-(2- aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane; methanesulfonate (10.1 mg, 0.0139 mmol, 0.1 eq), and K3PO4 (88.2 mg, 0.415 mmol, 3 eq) in H2O (0.2 mL) and dioxane (1 mL) was degassed and purged with N2 for 3 times, and then stirred at 80 °C for 2 h under N2 atmosphere under microwave. On completion, the reaction mixture was diluted with H2O (5 mL) and extracted with EA (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l/O to 0/1) to give tert-butyl l-[(cyclopropyloxy)methyl]-3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (108 mg, 0.111 mmol, 80% yield) as light yellow solid. LCMS: m/z 972.6 (M+l).
[0796] Step 6. To a solution of tert-butyl l-[(cyclopropyloxy)methyl]-3-(8-fluoro-7-[7- fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2- { [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.0463 mmol, 1 eq) in DCM (0.5 mL) was added HCl/dioxane (4 M, 0.1 mL, 8.63 eq). The mixture was stirred at 25 °C for 1 h. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent. 4-(4-{ l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-6-fluoro-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (38.0 mg, 46.0 umol, 99% yield) was obtained as yellow solid. LCMS: m/z 827.1 (M+l).
[0797] Step 7. To a solution of 4-(4-{ l-[(cyclopropyloxy)methyl]-3,8- diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-{ [tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (38.0 mg, 0.046 mmol, 1 eq) in DMSO (0.5 mL) was added CsF (21.0 mg, 0.138 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was filtered, and the filtrate was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, lOmin). 4-(4-{ l-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2-{ [(2R,7aS)- 2-lluorotetrahydro- l H-pyrrolizin-7a(5H)-yl |methoxy }pyrido|4,3-d]pyrimidin-7-yl )-5- ethynyl-6-fluoronaphthalen-2-ol (Ex. 8a, 2.92 mg) was obtained as red solid. 1H NMR (400 MHz, MeOD-d4) 0= 9.11 (d, J = 4.0 Hz, 1H), 7.89 (dd, J = 5.6, 9.2 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 5.68 - 5.48 (m, 1H), 4.73 (s, 2H), 4.28 (t, J = 6.8 Hz, 1H), 4.03 (d, J = 7.6 Hz, 1H), 3.93 (d, J = 8.4 Hz, 4H), 3.86 (d, J = 10.8 Hz, 2H), 3.54 - 3.42 (m, 3H), 3.34 - 3.32 (m, 1H), 2.69 - 2.54 (m, 2H), 2.49 - 2.41 (m, 1H), 2.35 (dd, J = 6.8, 10.8 Hz, 2H), 2.29 - 2.17 (m, 3H), 2.16 (s, 2H), 2.01 - 1.89 (m, 1H), 0.71 - 0.66 (m, 2H), 0.61 - 0.57 (m, 2H). LCMS: m/z 670.7 (M+l).
[0798] The remaining product from prep-HPLC purification was used for SFC separation exploration.
[0799] Preparation of 4-(4-{( l R,5.S)-l -[(difluoromethoxy)melhyl]-3,8- diazabicyclo|3.2.1 |ocian-3-yl}-8-fluoro-2-{ |(2R,7aS)-2-fluoroieirahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Ex. 9)
Figure imgf000233_0001
[0800] Step 1. To a solution of 3-benzyl 8-tert-butyl ( 1R,5S)- 1 -(hydroxy methyl )-3 ,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1 g, 2.66 mmol, 1 eq.) in DCM (5 mL) and H2O (5 mL) was added [bromo(difluoro)methyl]-trimethyl-silane (1.08 g, 5.31 mmol, 2 eq) and KOAc (1.04 g, 10.63 mmol, 4 eq). The mixture was stirred at 25 °C for 16 hr. On completion, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l:0 to 80:20) to give (1S,5R)- 3-benzyl 8-tert-butyl (1R,5S)-l-[(difluoromethoxy)methyl]-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (130 mg, 0.304 mmol, 11% yield) as a colorless oil. LCMS: (M+23:449.2).
[0801] Step 2. A mixture of 3-benzyl 8-tert-bulyl ( 1R,5S)- l -|(dilluoromeihoxyimelhyl |-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (130 mg, 0.305 mmol, 1 eq), Pd/C (20 mg, 0.305 mmol, 10% purity) in i-PrOH (1.5 mL) was degassed and purgedwith H2 for 3 times, and then the mixture was stirred at 25 °C for 2 hrs. under H2 atmosphere (15 psi). The mixture was filtered, and the filtrate was concentrated in vacuum to give tert-butyl (1R,5S)-1- [(difluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65 mg, 0.222 mmol, crude) as a yellow oil. LCMS: m/z 293.0 (M+l).
[0802] Step 3. To a solution of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-l,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (40.0 mg, 0.0912 mmol, 1 eq.), tert-butyl (1R,5S)-l-[(difluoromethoxy)methyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (53.3 mg, 0.182 mmol, 2 eq) in DMF (0.5 mL) was added K2CO3 (37.8 mg, 0.273 mmol, 3 eq). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (20 mL*2) and dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by Prep-TLC (SiO2, DCM: MeOH = 90:10) to give tert-butyl (lR,55)-3-(7-chloro-8-fluoro-2-{[(2R,7a5)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l- [(difluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45.0 mg, 0.071 mmol, 78% yield) as a yellow oil.
[0803] LCMS: m/z 631.2 (M+l).
[0804] Step 4. A mixture of tert-butyl (1R,5S)-3-(7-chloro-8-fluoro-2-{[(2R,7aS)-2- fl uorotetrahydro- 1 H-pyrrolizi n-7a(5H)-yl | methoxy } pyrido[ 4,3-d]pyrimidi n-4-yl )- 1 - [(difluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40.0 mg, 0.0634 mmol, 1 eq), {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl]ethynyl}tri(propan-2-yl)silane (48.7 mg, 0.0951 mmol, 1.5 eq), [2-(2- aminophenyl)phenyl]palladium(l+);bis(l-adamantyl)-butyl-phosphane; methanesulfonate (4.62 mg, 0.00634 mmol, 0.1 eq), and K3PO4 (40.4 mg, 0.190 mmol, 3 eq) in dioxane (0.5 mL), H2O (0.1 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. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l :0 to 60:40) to give tert-butyl (1 R,5 S)- 1 - [(difluoromethoxy)methyl]-3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2- d]pyrimidin-7-yl)naphthalen-2-ol (Ex.21), 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-{(1S,5R)-1-[(2S)-oxolan-2-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex.22) and 5- ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Ex.23)
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
[0809] Step 1. To a mixture of tert-butyl 3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (13.0 g, 28.6 mmol, 1 eq.) and TMEDA (5.65 g, 48.6 mmol, 1.7 eq) in Et2O (250 mL) was added s-BuLi (1.3 M, 37.4 mL, 1.7 eq) at -40 °C under N2 atmosphere. The reaction mixture was stirred at -40 °C for 1 h under N2 atmosphere. Then 4-{[tert-butyl(dimethyl)silyl]oxy]butanal (17.3 g, 85.7 mmol, 3 eq) was added under N2 atmosphere. The reaction mixture was stirred at -40 °C for 7 h under N2 atmosphere. On completion, the residue was diluted with water (200 mL) and extracted with EA (2 * 200 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (neutral condition) chromatography to afford tert-butyl l-(4-{[tert-butyl(dimethyl)silyl]oxy]-l- hydroxybutyl)-3-(triphenylmethyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (14.0 g, 21.3 mmol, 74% yield) as yellow solid.
[0810] 1 H NMR (400 MHz, DMSO-d6) δ = 7.65 - 6.96 (m, 15H), 4.04 (d, J = 7.2 Hz, 1H), 3.57 - 3.51 (m, 2H), 2.90 - 2.81 (m, 1H), 2.42 - 2.38 (m, 1H), 2.20 - 2.10 (m, 1H), 1.89 - 1.80 (m, 1H), 1.73 - 1.62 (m, 3H), 1.53 - 1.37 (m, 3H), 1.10 (d, J = 11.2 Hz, 9H), 0.88 - 0.84 (m, 13H), 0.05 - 0.01 (m, 9H). LCMS: m/z 657.5 (M+l). [0811] Step 2. To a mixture of tert-butyl l-(4-{ [tert-butyl(dimethyl)silyl]oxy}-l- hydroxybutyl)-3-(triphenylmethyl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate (12.0 g, 18.2 mmol, 1 eq) in DMSO (120 mL) was added CsF (13.8 g, 91.3 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the residue was diluted with water (150 mL) and extracted with EA (2 X 150 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to afford tert-butyl l-(l,4-dihydroxybutyl)- 3-(triphenylmethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (9.40 g, 17.3 mmol, 94% yield) as yellow solid.
[0812] 'H NMR (400 MHz, DMSO-d6) δ = 7.56 - 7.09 (m, 15H), 4.32 - 4.25 (m, 1H), 4.01
(q, J= 7.2 Hz, 1H), 2.81 (d, 7 = 10.8 Hz, 1H), 2.53 (s, 1H), 2.41 - 2.29 (m, 1H), 2.20 - 2.08 (m, 1H), 2.00 - 1.93 (m, 1H), 1.92 (s, 2H), 1.59 - 1.53 (m, 1H), 1.47 - 1.31 (m, 2H), 1.14 - 1.05 (m, 9H), 0.85 - 0.82 (m, 6H). LCMS: m/z 543.4 (M+l).
[0813] Step 3. To a mixture of tert-butyl l-(l,4-dihydroxybutyl)-3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (9.40 g, 17.3 mmol, 1 eq) in Pyridine (100 mL) was added TsCl (1.22 g, 17.3 mmol, 1 eq). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the residue was diluted with water (90 mL) and extracted with EA (2 X 90 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (neutral condition) chromatography to afford tert-butyl l-(oxolan-2-yl)-3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4.50 g, 8.58 mmol, 49% yield) as yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.54 - 7.06 (m, 15H), 3.99 (s, 2H), 3.74 (d, J = 6.8 Hz, 1H), 3.46 (d, J = 7.2 Hz, 2H), 3.08 (d, J = 10.4 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.38 - 2.24 (m, 1H), 2.19 - 2.07 (m, 1H), 1.90 - 1.77 (m, 2H), 1.77 - 1.56 (m, 5H), 1.13 - 0.99 (m, 9H). LCMS: m/z 525.4 (M+l).
[0814] Step 4. To a mixture of tert-butyl l-(oxolan-2-yl)-3-(triphenylmethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (2.50 g, 4.76 mmol, 1 eq) in DCM (25 mL) was added HOAc (13.1 g, 218 mmol, 45 eq). The reaction mixture was stirred at 50 °C for 2 hours. On completion, the residue was diluted with water (40 mL) and extracted with EA (2 X 40 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to afford tert-butyl L(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.90 g, 3.19 mmol, 66% yield) as yellow oil. ' H NMR (400 MHz, DMSO-d6) δ = 4.43 - 4.20 (m, 1H), 4.05 - 3.96 (m, 1H), 3.81 - 3.72 (m, 1H), 3.66 - 3.57 (m, 1H), 2.86 - 2.69 (m, 4H), 1.84 (d, J = 5.6, 11.2 Hz, 5H), 1.76 - 1.67 (m, 4H), 1.46 - 1.42 (m, 9H). LCMS: m/z 283.2 (M+l). [0815] Step 5. To a mixture of tert-butyl l-(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate
[0816] (0.90 g, 3.19 mmol, 1 eq) and 7-chloro-8-fluoro-2-{ [(2R,7aS)-2-fluorotetrahydro-17:/- pyrrolizin-7a(5H)-yl |melhoxy}-4-(2,2,2-lrifluoroelhoxy)pyrido|4,3-7|pyrimidine (1.12 g, 2.55 mmol, 0.8 eq) in DMF (20 mL) was added K2CO3 (1.32 g, 9.56 mmol, 3 eq). The reaction mixture was stirred at 80 °C for 0.5 hour. On completion, the residue was diluted with water (40 mL) and extracted with EA (2 X 40 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford two isomers of tert-butyl 3-(7-chloro-8-fluoro- 2-{ [(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin- 4-yl)-l-(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. [0817] Isomer 1: (350 mg, 563 umol, 17% yield) as yellow solid.
[0818] 1 H NMR (400 MHz, DMSO-d6) δ = 8.94 (s, 1H), 5.40 - 5.19 (m, 1H), 4.77 (t, 7 = 7.6 Hz, 1H), 4.47 - 4.33 (m, 2H), 4.29 (d, J = 6.2 Hz, 1H), 4.18 - 4.13 (m, 1H), 4.11 - 4.05 (m, 1H), 3.78 - 3.65 (m, 3H), 3.53 (d, J = 12.6 Hz, 1H), 3.14 - 3.07 (m, 2H), 3.04 (s, 1H), 2.89 - 2.81 (m, 1H), 2.19 - 2.11 (m, 1H), 2.09 - 2.03 (m, 3H), 2.02 - 1.96 (m, 1H), 1.83 (t, 7 = 7.2, 14.2 Hz, 6H), 1.76 - 1.66 (m, 2H), 1.57 - 1.50 (m, 1H), 1.46 (s, 9H). LCMS: m/z 621.2 (M+l).
[0819] Isomer 2: (1.00 g, 1.61 mmol, 50% yield) as yellow oil.
[0820] 1 H NMR (400 MHz, DMSO-d6) δ = 8.93 (s, 1H), 5.36 - 5.14 (m, 1H), 4.61 (d, 7 = 11.6 Hz, 1H), 4.50 - 4.37 (m, 2H), 4.24 (d, 7 = 1.6 Hz, 1H), 4.12 - 4.04 (m, 1H), 3.76 - 3.69 (m, 1H), 3.68 - 3.54 (m, 3H), 3.05 (d, 7 = 6.0 Hz, 2H), 2.98 (s, 1H), 2.86 (s, 2H), 2.83 - 2.75 (m, 1H), 2.70 (s, 2H), 2.13 - 2.07 (m, 1H), 2.01 (br s, 1H), 1.87 (s, 2H), 1.83 - 1.67 (m, 7H), 1.58 (t, 7 = 8.0 Hz, 1H), 1.45 (s, 8H). LCMS: m/z 621.3 (M+l).
[0821] Step 6. To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2-{[(2R,7a5)-2-fluorotetrahydro- l H-pyrrolizin-7a(5H)-yl |methoxy }pyrido|4,3-7|pyrimidin-4-yl)- l-(oxolan- 2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.966 mmol, 1 eq) and {[2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl]ethynyl}tri(propan-2-yl)silane (1.49 g, 2.90 mmol, 3 eq) in dioxane (10 mL) and H2O (2 mL) was added K3PO4 (615 mg, 2.90 mmol, 3 eq) and ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (62.9 mg, 96.6 umol, 0.1 eq). The reaction mixture was stirred at 80 °C for 8 hours under N2. On completion, the residue was diluted with water (30 mL) and extracted with EA (2 X 30 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford tert-butyl 3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{ [(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan- 2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (420 mg, 0.432 mmol, 44% yield) as yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.19 (d, 7 = 13.6 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.74 (d, 7 = 2.4 Hz, 1H), 7.56 (t, 7 = 8.8 Hz, 1H), 7.35 (t, 7 = 2.4 Hz, 1H), 5.36 (s, 2H), 4.80 (t, 7 = 6.0 Hz, 1H), 4.73 - 4.64 (m, 1H), 4.45 - 4.31 (m, 1H), 4.22 - 4.11 (m, 1H), 4.08 - 3.97 (m, 2H), 3.86 - 3.77 (m, 1H), 3.76 - 3.68 (m, 1H), 3.43 (s, 3H), 3.10 (s, 2H), 3.03 (s, 1H), 2.89 - 2.81 (m, 1H), 2.52 - 2.51 (m, 2H), 2.49 - 2.48 (m, 2H), 2.13 (s, 1H), 2.11 - 2.00 (m, 2H), 1.99 - 1.95 (m, 2H), 1.92 - 1.86 (m, 2H), 1.81 (dd, 7 = 7.2, 14.0 Hz, 4H), 1.66 - 1.54 (m, 1H), 1.46 (d, 7 = 3.2 Hz, 9H), 1.20 - 1.14 (m, 1H), 0.91 - 0.76 (m, 18H), 0.55 - 0.40 (m, 3H). LCMS: m/z 971.5 (M+l). [0822] Step 7. To a mixture of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- { [tri(propan-2-yl)silyl]ethynyl } naphthalen- 1 -yl] -2- { [(2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H)-yl]methoxy)pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.411 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 2 mL, 19 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to afford 6-fluoro-4-(8- fluoro-2- { [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7 a(5H)-yl]methoxy ) -4- [ 1 -(oxolan-2- yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2- yl)silyl]ethynyl}naphthalen-2-ol (340 mg, 411 umol, 99% yield) as yellow solid. LCMS: m/z 827.5 (M+l).
[0823] Step 8. To a mixture of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-4-[l-(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (15.0 mg, 0.0181 mmol, 1 eq) in DMSO (1 mL) was added CsF (13.7 mg, 0.0906 umol, 5 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was filtered and the filtrate was purified by prep-HPLC (column: Welch Ultimate Cl 8 150*25mm*5um;mobile phase: [water(FA)-ACN];B%: 5%-35%,10min) to afford 5-ethynyl- 6-fluoro-4-(8-fluoro-2- { [(2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl]methoxy ) -4- [l-(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol (4.19 mg, 0.00585 mmol, 32% yield, as formic acid salt) as yellow solid. !H NMR (400 MHz, DMSO-d6) δ = 9.03 (d, J = 3.2 Hz, 1H), 8.20 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (s, 1H), 5.38 - 5.18 (m, 1H), 4.52 - 4.43 (m, 1H), 4.35 - 4.27 (m, 1H), 4.17 - 4.10 (m, 1H), 4.07 - 4.00 (m, 1H), 3.93 - 3.87 (m, 2H), 3.83 - 3.76 (m, 2H), 3.69 (dd, J = 6.4, 14.2 Hz, 3H), 3.09 (br d, J = 9.2 Hz, 2H), 3.02 (s, 1H), 2.87 - 2.79 (m, 1H), 2.17 - 2.08 (m, 1H), 2.06 (s, 1H), 2.00 (d, J = 2.0 Hz, 1H), 1.96 - 1.89 (m, 1H), 1.89 - 1.81 (m, 4H), 1.81 - 1.76 (m, 2H), 1.74 (d, J= 8.0 Hz, 1H), 1.70 - 1.59 (m, 2H), 1.51 - 1.38 (m, 1H). LCMS: m/z 671.2 (M+l).
[0824] The product was further purified and separated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um); mobile phase: [0.1%NH3H2O IPA]; B%: 45%- 45%,A2.7;90min) to afford 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy)-4-{(1S,5R)-l-[(2R)-oxolan-2-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 20) and 5- ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-l-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 21) as yellow solid. [0825] Ex. 20: NMR (400 MHz, DMSO-d6) δ = 0.21 - 10.12 (m, 1H), 9.06 - 9.00 (m, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (s, 1H), 5.38 - 5.19 (m, 1H), 4.53 - 4.44 (m, 1H), 4.35 - 4.26 (m, 1H), 4.15 - 4.09 (m, 1H), 4.08 - 4.02 (m, 1H), 3.94 - 3.85 (m, 2H), 3.83 - 3.76 (m, 1H), 3.72 - 3.66 (m, 1H), 3.63 - 3.53 (m, 2H), 3.51 - 3.43 (m, 1H), 3.13 - 3.06 (m, 2H), 3.02 (s, 1H), 2.86 - 2.79 (m, 1H), 2.15 - 2.11 (m, 1H), 2.08 - 2.04 (m, 1H), 2.00 (s, 1H), 1.96 - 1.89 (m, 1H), 1.88 - 1.81 (m, 4H), 1.80 - 1.76 (m, 2H), 1.70 - 1.61 (m, 2H), 1.50 - 1.39 (m, 1H), 1.26 - 1.19 (m, 1H). LCMS: m/z 671.4 (M+l).
[0826] Ex. 21: 1H NMR (400 MHz, DMSO-d6) δ = 10.37 - 10.09 (m, 1H), 9.04 (s, 1H), 7.98 (dd, J = 5.7, 9.2 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 2.5, 4.8 Hz, 1H), 5.37 - 5.20 (m, 1H), 4.67 - 4.27 (m, 2H), 4.16 (dd, J = 5.2, 10.3 Hz, 1H), 4.02 (dd, J = 4.6, 10.3 Hz, 1H), 3.97 - 3.85 (m, 2H), 3.82 - 3.74 (m, 1H), 3.70 - 3.54 (m, 3H), 3.43 (br d, J = 13.0 Hz, 1H), 3.15 - 3.06 (m, 2H), 3.04 - 2.99 (m, 1H), 2.88 - 2.80 (m, 1H), 2.17 - 2.11 (m, 1H), 2.09 - 2.04 (m, 1H), 2.03 - 1.96 (m, 1H), 1.93 - 1.71 (m, 8H), 1.68 - 1.62 (m, 1H), 1.60 - 1.49 (m, 2H).
[0827] LCMS: m/z 671.4 (M+l).
[0828] Step 9. To a mixture of tert-butyl 3-(7-chloro-8-fluoro-2-{[(2R,7a>S')-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan- 2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.805 mmol, 1 eq) and { [2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl]ethynyl}tri(propan-2-yl)silane (1.24 g, 2.42 mmol, 3 eq) in dioxane (10 mL) and H2O (2 mL) was added K3PO4 (512 mg, 2.42 mmol, 3 eq) and ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (52.4 mg, 80.5 umol, 0.1 eq). The reaction mixture was stirred at 80 °C for 2 hours under N2. On completion, the residue was diluted with water (30 mL) and extracted with EA (2 X 30 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford tert-butyl 3-(8-fluoro-7-[7-fluoro-3- (methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl]naphthalen-l-yl]-2-{[(2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan- 2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (570 mg, 0.586 mmol, 72% yield) as yellow solid.
[0829] 1 H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.10 (dd, J = 6.0, 9.2 Hz, 1H), 7.74 (d, 7 = 1.6 Hz, 1H), 7.56 (t, J= 8.8 Hz, 1H), 7.37 (dd, J= 2.4, 12.8 Hz, 1H), 5.36 (s, 2H), 4.97 - 4.65 (m, 1H), 4.50 (s, 1H), 4.41 - 4.21 (m, 2H), 4.16 - 4.08 (m, 1H), 4.07 - 3.99 (m, 2H), 3.86 - 3.69 (m, 2H), 3.69 - 3.59 (m, 1H), 3.43 (s, 3H), 3.13 - 3.04 (m, 2H), 3.02 (s, 1H), 2.87 - 2.79 (m, 1H), 2.16 - 2.10 (m, 1H), 2.09 - 2.03 (m, 1H), 2.03 - 1.99 (m, 1H), 1.97 - 1.93 (m, 1H), 1.91 - 1.73 (m, 8H), 1.65 - 1.52 (m, 1H), 1.46 (s, 9H), 1.17 (t, J = 7.2 Hz, 2H), 0.80 (t, J = 8.0 Hz, 18H), 0.55 - 0.40 (m, 3H). LCMS: m/z 971.5 (M+l).
[0830] Step 10. To a mixture of tert-butyl 3-(8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- { [tri(propan-2-yl)silyl]ethynyl}naphthalen-l-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl)-l-(oxolan-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (520 mg, 0.535 mmol, 1 eq) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL, 14 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was diluted with water (10 mL) and acidified with NaHCO3 to pH = 8-9, the residue was diluted with water (30 mL) and extracted with EA (2 X 30 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to afford 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[l-(oxolan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7- yl)-5-{ [tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (400 mg, 0.483 mmol, 90% yield) as yellow solid.
[0831] LCMS: m/z 827.4 (M+l).
[0832] Step 11. To a mixture of 6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7 a( 5H)- y 1 ]methoxy } -4- [ 1 -(oxolan-2-yl)-3, 8-diazabicyclo[3.2.1 ]octan-3 - y l ] py ri do 14.3 -z/ 1 py ri m i di n -7- y 1 ) -5 - [ [tri(propan-2-yl)silyl]ethynyl }naphthalen-2-ol (40 mg, 0.0483 mmol, 1 eq) in DMSO (2 mL) was added CsF (36.7 mg, 0.241 mmol, 5 eq). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];B%: 5%-35%,8min) to afford 5-ethynyl-6-fluoro-4- (8-fluoro-2- { [(2R,7aS)-2- fl uoroietrahydro- I H-pyrrol i zi n-7 a(5 H)-y 1 ] methoxy } -4- [ l-(oxolan- 2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (16.0 mg, 22.2 umol, 45% yield, as formic acid) as yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.17 (d, J = 3.2 Hz, 1H), 9.04 (s, 1H), 8.03 - 7.94 (m, 1H), 7.50 - 7.44 (m, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.19 (s, 1H), 5.40 - 5.17 (m, 1H), 4.63 - 4.29 (m, 2H), 4.20 - 4.10 (m, 1H), 4.09 - 4.00 (m, 1H), 3.97 - 3.85 (m, 2H), 3.82 - 3.75 (m, 1H), 3.70 - 3.55 (m, 4H), 3.12 - 3.07 (m, 2H), 3.04 - 3.00 (m, 1H), 2.86 - 2.81 (m, 1H), 2.16 - 2.11 (m, 1H), 2.06 (s, 1H), 2.03 - 1.97 (m, 1H), 1.95 - 1.72 (m, 8H), 1.69 - 1.61 (m, 1H), 1.60 - 1.50 (m, 2H). LCMS: m/z 671.2 (M+l).
[0833] The product was purified and separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [ACN/MeOH(0.1%NH3H2O)];B%: 50%- 50%,A4;50min) afford to 5-elhynyl-6-lliioro-4-(8-fluoro-2-{ [(2R,7aS)-2-lluoroieirahydro- lH-pyrrolizin-7a(5H)-yl ]melhoxy}-4-[( 1S,5R)- l-|(2S)-oxolan-2-yl |-3,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 22) as yellow solid and 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl]methoxy}-4-{(1R,5S)-l-[(2R)-oxolan-2-yl]-3,8- diazabicyclo[3.2.1]octan-3-yl}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Ex. 23) as yellow solid.
[0834] Ex. 22: 1H NMR (400 MHz, DMSO-d6) δ = 10.23 - 10.09 (m, 1H), 9.04 (s, 1H), 7.98 (dd, J = 6.0, 9.2 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.19 (t, J = 2.4 Hz, 1H), 5.37 - 5.17 (m, 1H), 4.67 - 4.27 (m, 2H), 4.17 - 4.02 (m, 2H), 3.97 - 3.85 (m, 2H), 3.82 - 3.74 (m, 1H), 3.70 - 3.53 (m, 3H), 3.47 - 3.39 (m, 1H), 3.09 (d, 7= 8.8 Hz, 2H), 3.02 (s, 1H), 2.90 - 2.79 (m, 1H), 2.17 - 2.10 (m, 1H), 2.06 (d, 7= 2.4 Hz, 1H), 2.03 - 1.97 (m, 1H), 1.93 - 1.73 (m, 8H), 1.69 - 1.62 (m, 1H), 1.59 - 1.49 (m, 2H). LCMS: m/z 671.4 (M+l). [0835] Ex. 23: H NMR (400 MHz, DMSO-d6) δ = 10.37 - 10.09 (m, 1H), 9.04 (s, 1H), 7.98 (dd, 7 = 5.6, 9.2 Hz, 1H), 7.47 (t, 7 = 9.2 Hz, 1H), 7.39 (d, 7 = 2.4 Hz, 1H), 7.19 (dd, 7 = 2.4, 4.8 Hz, 1H), 5.37 - 5.20 (m, 1H), 4.67 - 4.27 (m, 2H), 4.16 (dd, 7 = 5.2, 10.3 Hz, 1H), 4.02 (dd, 7 = 4.4, 10.3 Hz, 1H), 3.97 - 3.85 (m, 2H), 3.82 - 3.74 (m, 1H), 3.70 - 3.54 (m, 3H), 3.43 (d, 7= 13.2 Hz, 1H), 3.15 - 3.06 (m, 2H), 3.04 - 2.99 (m, 1H), 2.88 - 2.80 (m, 1H), 2.17 - 2.11 (m, 1H), 2.09 - 2.04 (m, 1H), 2.03 - 1.96 (m, 1H), 1.93 - 1.71 (m, 8H), 1.68 - 1.62 (m, 1H), 1.60 - 1.49 (m, 2H).
[0836] LCMS: m/z 671.4 (M+l).
[0837] The following examples were made following General Method A or B or C as indicated in the Table:
Figure imgf000244_0001
Figure imgf000245_0001
1.83 - 1.72 (m, 1H), 1.71 - 1.61 (m, 1H).
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
3.06 (m, 2H), 3.04 - 2.99 (m, 1H), 2.88 - 2.80 (m, 1H), 2.17 - 2.11 (m, 1H), 2.09 -
Figure imgf000250_0001
2.88 - 2.80 (m, 1H), 2.17 - 2.11 (m, 1H), 2.09 - 2.04 (m, 1H), 2.03 - 1.96 (m, 1H), 1.93 - 1.71 (m, 8H), 1.68 - 1.62 (m, 1H), 1.60 - 1.49 (m, 2H).
Figure imgf000251_0001
Figure imgf000252_0001
A 31 N N 661.2 3.83 (br d, J = 4.8 Hz, 1H), N O 3.80 - 3.73 (m, 2H), 3.71 (d, N N F J = 4.0 Hz, 2H), 3.69 - 3.61 (m, 4H), 3.45 - 3.39 (m, 1H), NH2 F 3.31 - 3.26 (m, 1H), 2.54 -
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
2.16 - 2.11 (m, 1H), 2.06 - 1.98 (m, 2H), 1.89 - 1.67 (m, 5H), 1.59 - 1.48 (m, 2H), 1.48 - 1.33 (m, 2H), 0.53 - 0.49 (m, 2H), 0.48 - 0.44 (m, 2H).
Figure imgf000256_0001
d6) δ = 8.19 (s, 1H), 8.00 - 7.94 (m, 1H), 7.72 (br d, J = 8.4 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.39 -7.34 (m, 1H), 7.24 - 7.15 (m, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.95 - 6.69 A 41 656.2 (m, 1H), 4.38 - 4.22 (m, 2H), 4.10 - 3.97 (m, 2H), 3.87 - 3.79 (m, 1H), 3.60 - 3.52 (m, 3H), 3.48 - 3.41 (m, 4H), 3.20 (br d, J = 14.0 Hz, 2H), 3.01 - 2.94 (m, 1H), 2.72 - 2.65 (m, 2H),2.43 - 2.31 (m, 2H), 2.03 - 1.69 (m, 8H), 1.47 (br s, 1H).
Figure imgf000257_0001
1H), 2.25 - 2.20 (m, 1H), 2.18 - 2.10 (m, 1H), 2.03 -
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Ex.10 6.05 7.83 Ex.11 4.74 4.897 Ex.14 6.86 5.292 Ex.15 2.26 1.677 Ex.16 172.5 1937
Figure imgf000261_0001
e line (KRAS G12D) (KRAS G12V) (KRAS G13D) (KRAS G12R) Ex.1 4.35 307.6 256.8 >10,000 Ex.2 2.46 304.4
Figure imgf000262_0002
[0838] Screen Assays
[0839] HTRF KRAS mutation nucleotide exchange assays:
[0840] 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 S0S1 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 imgf000262_0001
Figure imgf000263_0001
[0841] Cell proliferation assays:
[0842] 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 imgf000263_0002
n plasma x.1 by Inc) was rized in the mated T1/2 h h h h h
Figure imgf000264_0001
[0843] Inhibition of phosphorylation of ERK (Thr202/Tyr204) using In-Cell Western
[0844] 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 P-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 imgf000265_0001
[0845] Mouse oral PK evaluation of Ex. 1
[0846] 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 °C for 10 minutes at 5,000 rpm. The plasma was harvested into pre-labeled tubes and stored at -80 °C. 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 imgf000266_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of the formula III, or a pharmaceutically acceptable salt thereof,
Figure imgf000267_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 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 of the formula
Figure imgf000269_0001
, wherein * is a point of covalent attachment to
Figure imgf000269_0002
each R11 is attached to a carbon atom of ring A, and each R11 is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, or 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; or two of R11 taken together with the carbon atom to which they are attached form an oxo group or an alkenyl group; provided that at least one R11 is a 4- to 10-membered heterocycloalkyl or at least one R11 is a C1-C6 alkyl having at least one hydrogen atom substituted by a -ORe, wherein Re is not H, or substituted by a -S(O)2Re, wherein when Re is 4- to 10-membered heterocycloalkyl or 5- to 10- membered heteroaryl, then the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is covalently attached to –S(O)2- by a carbon atom in the 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; 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; ring B is a 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, or -Re and -Rf taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1- C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS(O)2N(H or C1-C6 alkyl)2, - SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)-C1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1- C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1- C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)N(H or C1- C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, - P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN, or -NO2; m is 1, 2, 3, 4, 5, or 6; n is 0, 1,
2,
3, 4, 5, 6, or 7; and p is 0 or 1. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula V, XIX, XXII, XXVI, or XXIX,
Figure imgf000271_0001
Figure imgf000272_0001
wherein Z6 is N or C(R14); Z7 is N or C(R15); 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 imgf000274_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 –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 imgf000274_0002
, 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, or two hydrogen atoms taken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl otionally substituted with deuterium or fluorine; and
Figure imgf000275_0003
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 imgf000275_0001
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 IV, VI, XX, XXI, XXIII, or XXIV,
Figure imgf000275_0002
Figure imgf000276_0001
Figure imgf000277_0001
or a pharmaceutically acceptable salt thereof.
10. The compound of any one of claims 1 to 4, 6 to 9, wherein the compound is of the formula XXVII, XXVIII, XXX, or XXXI,
Figure imgf000277_0002
Figure imgf000278_0001
or a pharmaceutically acceptable salt thereof.
11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 1.
12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.
13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one R11 is -C1-C6 alkylOC1-C6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, -C1-C6 alkylOCs-C6 cycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen, C1-C6 alkylS(O)2C1-C6 alkyl wherein each hydrogen is independently optionally substituted with D or halogen, or 5- to 10-membered heterocycloalkyl wherein each hydrogen is independently optionally substituted with D or halogen.
14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one R11 is -CH2-O-CH3, -CH2-O-CD3, -CH2-O-CF3, -CH2-O-CHF2, - CH2-O-cyclopropyl, -CH2CH2-O-CH3, -CH2CH2-O-CD3, -CH2CH2-O-CF3, -CH2CH2-O-CHF2, -CH2CH2-O-cyclopropyl, -CH2-O-CH2CH3,–CH2S(O)2CH3, -furanyl, or -oxetanyl.
15. The compound of any one of the preceding claims, wherein ring A is of the formula
Figure imgf000279_0001
Figure imgf000280_0001
wherein * is a point of covalent attachment to
Figure imgf000280_0002
16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z1 is N.
17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z2 is N.
18. 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.
19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is CR9.
20. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is CR8, and Z5 is N.
21. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is CR9.
22. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is N, and Z5 is N.
23. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is CR7, Z4 is N, and Z5 is N.
24. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z3 is N, Z4 is CR8, and Z5 is N.
25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X is –NR4-.
27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
28. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein p is 0.
29. 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.
30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is
Figure imgf000282_0001
wherein
Figure imgf000282_0002
is a point of covalent attachment.
31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R4, when present, is H or methyl.
32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5, when present, is H.
33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, when present, is H.
34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7, when present, is H or F.
35. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8, when present, is H.
36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9, when present, is H.
37. The compound of claim 1, 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-[(1R,5S)-1- (methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-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-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octan-3- 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-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- 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-[(1R,5S)-1-{[(2H3)methyloxy]methyl}-3,8-diazabicyclo[3.2.1]octan- 3-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-{(1R,5S)-1-[(methanesulfonyl)methyl]-3,8-diazabicyclo[3.2.1]octan-3- 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-{(1R,5S)-1-[(trifluoromethoxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3- 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- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)- 1,3-benzothiazol-2-amine; 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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; 4-(4-{1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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; 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[1-(2-methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-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-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol; 4-[4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-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; 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol; 4-(4-{(1R,5S)-1-[(difluoromethoxy)methyl]-3,8-diazabicyclo[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-ethyl-6-fluoronaphthalen-2-ol; 7-(8-ethynyl-7-fluoro-3-methoxynaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; 7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidine; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-yl dimethylcarbamate; 3-chloro-5-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)- 4-(trifluoromethyl)aniline; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1S,5R)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-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-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-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-{(1S,5R)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-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-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-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-[(1R,5S)-1-(oxetan-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-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-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- 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-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- 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-[(1S,5R)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- 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-[(1R,5S)-1-{1-[(2H3)methyloxy]ethyl}-3,8-diazabicyclo[3.2.1]octan-3- 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-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-amine; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7- yl)naphthalen-2-ol; 6-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2- {[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)-5-ethynyl- 6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1S,5R)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8-fluoro-2- {[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol; 2-amino-4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[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)-7-fluoro-1-benzothiophene-3-carbonitrile; 2-amino-4-(4-{(1R,5S)-1-[(cyclopropyloxy)methyl]-3,8-diazabicyclo[3.2.1]octan-3-yl}-8- fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}quinazolin-7-yl)- 7-fluoro-1-benzothiophene-3-carbonitrile; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2Z)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]quinazolin-7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2E)-2-(fluoromethylidene)tetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]quinazolin-7-yl)naphthalen-2-ol; 6-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)- 1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)-4- methyl-5-(trifluoromethyl)pyridin-2-amine; 7-(3-chloro-8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidine; 7-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy}-4-[(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]pyrido[4,3-d]pyrimidine; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1S,5R)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin- 7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin- 7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-1-[(2S)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin- 7-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl]methoxy}-4-{(1R,5S)-1-[(2R)-oxolan-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl}quinazolin- 7-yl)naphthalen-2-ol; 2-amino-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrido[4,3-d]pyrimidin-7-yl)- 1-benzothiophene-3-carbonitrile; and 2-amino-4-(8-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-4- [(1R,5S)-1-(methoxymethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]quinazolin-7-yl)-1- benzothiophene-3-carbonitrile; or a pharmaceutically acceptable salt thereof.
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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