WO2023173014A1 - Inhibiteurs de kras et leur utilisation - Google Patents

Inhibiteurs de kras et leur utilisation 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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English (en)
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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/fr

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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

La présente invention concerne des composés diaryles ciblant KRAS, des compositions pharmaceutiques contenant les composés, et des procédés d'utilisation de tels composés pour traiter une maladie, telle que le cancer.
PCT/US2023/064038 2022-03-09 2023-03-09 Inhibiteurs de kras et leur utilisation WO2023173014A1 (fr)

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