WO2023173017A1 - Inhibiteurs de kras pour le traitement d'une maladie - Google Patents

Inhibiteurs de kras pour le traitement d'une maladie Download PDF

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WO2023173017A1
WO2023173017A1 PCT/US2023/064042 US2023064042W WO2023173017A1 WO 2023173017 A1 WO2023173017 A1 WO 2023173017A1 US 2023064042 W US2023064042 W US 2023064042W WO 2023173017 A1 WO2023173017 A1 WO 2023173017A1
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alkyl
fluoro
pyrido
pyrimidin
pyrrolizin
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PCT/US2023/064042
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English (en)
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Jingrong Jean Cui
Evan W. ROGERS
Eugene Yuanjin Rui
Dayong Zhai
Anindya SARKAR
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Blossomhill Therapeutics, Inc.
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Publication of WO2023173017A1 publication Critical patent/WO2023173017A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Ras is a GTP-binding protein and regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc.
  • H-Ras, K-Ras, and N- Ras are the main members of Ras superfamily, which are tightly regulated by factors that switch on/off the GTPase activity.
  • Somatic mutations at codons 12, 13 and 61 in the RAS genes are associated with about 16% of all human cancers and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-related cancers (Prior I. A. et al, A comprehensive survey of Ras mutations in cancer. Cancer Res.
  • KRAS G12C mutant Recent successful inhibition of the KRAS G12C mutant by covalent chemical modifiers sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) in KRAS G12C mutated lung cancer patients has shed lights on targeting KRAS mutants for therapeutic invention. However, inhibitors targeting KRAS mutants without covalent formation at KRAS G12C are still absent.
  • MRTX1133 has been reported as potent and highly selective noncovalent KRAS G12D inhibitor (Wang X.
  • intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate drug efficacy in mice. This suggests MRTX1133 may have poor bioavailability.
  • KRAS mutants such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D with good in vivo efficacy, safety, and predicted human oral pharmacokinetic profile for treating patients with KRAS mutant cancers.
  • the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0007] wherein [0008] X is a -O-, -S-, or -NR 4 -; [0009] Y is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, or –C(O)NR 10 -; [0010] Z 1 is N or C(R 5 ); [0011] Z 2 is N or C(R 6 ); [0012] Z 3 is N or C(R 7 ); [0013] Z 4 is N or C(R 8 ); [0014] Z 5 is N or C(R 9 ); [0015] provided that at least two of Z 1 -Z 5 are N; [0016] R 1 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alky
  • At least one hydrogen atom in the compound of the formula I is substituted by a deuterium. In some embodiments, at least one hydrogen atom in R 3 or R 11 in the compound of the formula I is substituted by a deuterium.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0031] wherein [0032] X is a -O-, -S-, or -NR 4 -; [0033] Z 1 is N or C(R 5 ); [0034] Z 2 is N or C(R 6 ); [0035] Z 3 is N or C(R 7 ); [0036] Z 4 is N or C(R 8 ); [0037] Z 5 is N or C(R 9 ); [0038] provided that at least two of Z 1 -Z 5 are N; [0039] each R 2 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -OR
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0052] wherein [0053] X is a -O-, -S-, or -NR 4 -; [0054] Z 1 is N or C(R 5 ); [0055] Z 2 is N or C(R 6 ); [0056] Z 3 is N or C(R 7 ); [0057] Z 4 is N or C(R 8 ); [0058] Z 5 is N or C(R 9 ); [0059] provided that at least two of Z 1 -Z 5 are N; [0060] each R 2 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10- membered heteroaryl, -OR
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [0073] wherein R 2 , R 3 , R 11 , R a , R b , A, B, X, Y, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, III [0075] wherein R 2 , R 3 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0076] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, IV [0077] wherein R 2 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein.
  • the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof, IVa [0079] wherein R 2 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0080] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, [0083] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0082] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, [0083] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein. [0084] In some embodiments, the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof, VII [0087] wherein R 2 , R 3 , R 11 , R 12 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0088] In some embodiments, the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIIIa, or a pharmaceutically acceptable salt thereof, VIIIa [0091] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0092] In some embodiments, the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof, [0095] wherein R 2 , R 3 , R 11 , R 13 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0096] In some embodiments, the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula Xa, or a pharmaceutically acceptable salt thereof, [0099] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0100] In some embodiments, the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof, [0103] wherein R 1 , R 2 , R 3 , R 10 , R a , R b , B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , n, p, and q are as described herein. [0104] In some embodiments, the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof,
  • R 2 , R 3 , R 10 , R 11 , R a , R b , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof, [0107] wherein R 2 , R 3 , R 10 , R 11 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof, XIV [0109] wherein R 2 , R 10 , R 11 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and q are as described herein.
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, XV [0111] wherein R 2 , R 3 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof, XVI [0113] wherein R 2 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and q are as described herein. [0114] In some embodiments, the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof, [0117] wherein R 2 , R 10 , R 11 , R 13 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof, [0119] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0120] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof, XX [0121] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0122] In some embodiments, the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof,
  • XXI [0123] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof, XXII [0125] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof, XXIV [0129] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0130] In some embodiments, the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof,
  • XXV [0131] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof, XXVI [0133] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof,
  • XXVII [0135] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof, XXVIII [0137] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof,
  • XXIX [0139] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0140] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof, XXX [0141] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the compound of Formula (I)-(XXX) is a compound selected from those species described or exemplified in the detailed description below.
  • the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XXX) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.
  • the disclosure relates to a compound of Formula (I)-(XXX), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XXX), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(XXX), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.
  • the disclosure relates to a method of inhibiting a Ras, such as K-Ras, comprising contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I)-(XXX), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • a Ras such as K-Ras
  • R 12 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C
  • R 3 when present, is -C 1 -C 6 alkyl or 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in -C 1 -C 6 alkyl and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 - C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycl
  • each R 11 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR a R b , -OS(O) 2 NR a R b , -SR a , -S(O)R a ,
  • each R 2 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, -OR c , or -NR c R d .
  • Ring B is , [0210] wherein is a point of covalent attachment.
  • R 4 when present, is H or methyl.
  • a pharmaceutical composition comprising at least one compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
  • 39. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof.
  • 40. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
  • 41. A compound of any one of clauses 1 to 37, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
  • the portion of A-B defined by the group or chemical structure A can be represented by where each of “-*”, “-**”, and ” represents a bond to A and the point of covalent bond attachment to B.
  • the portion of A-B defined by the group or chemical structure B can be represented by , where each of “-*”, “-**”, and represents a bond to B and the point of covalent bond attachment to A.
  • alkyl refers to a straight- or branched-chain monovalent hydrocarbon group.
  • alkylene refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C 1 -C 20 alkyl or C 1 -C 20 alkylene, C 1 -C 12 alkyl or C 1 -C 12 alkylene, or C 1 -C 6 alkyl or C 1 -C 6 alkylene.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkylene groups examples include methylene (-CH 2 -), ethylene ((-CH 2 -) 2 ), n-propylene ((-CH 2 -) 3 ), iso-propylene ((-C(H)(CH 3 )CH 2 -)), n-butylene ((-CH 2 -)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkenyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C 2 -C 20 alkenyl, C 2 -C 12 alkenyl, or C 2 -C 6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein.
  • alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • alkynyl refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C 2 -C 2 0 alkynyl, C 2 -C 12 alkynyl, or C 2 -C 6 alkynyl.
  • alkynyl groups include acetylenyl (- C ⁇ CH) and propargyl (-CH 2 C ⁇ CH), but-3-yn-1,4-diyl (-C ⁇ C-CH 2 CH 2 -), and the like. It will be appreciated that an alkynyl group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0338] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle.
  • cycloalkyl In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms.
  • Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems.
  • Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities::
  • a cyclopropyl moiety can be depicted by the structural formula It will be appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein.
  • a cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF 3 , -(CH 2 )F, -CHF2, -CH 2 Br, -CH 2 CF 3 , and -CH 2 CH 2 F.
  • aryl refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • aryl mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C 6 -C 14 aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6- C 10 aryl).
  • aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein.
  • heterocycloalkyl refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. .
  • ring atoms such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6- membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered).
  • heterocycloalkyl it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidine, and morpholine.
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • Examples, without limitations, of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane.
  • Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities: [0342]
  • a three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of three- membered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane.
  • a four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane.
  • a five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2- one, and oxazolidin-2-one.
  • a six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heterocycle groups include mono- valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4- tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide.
  • a “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.
  • a hexahydro-1H-pyrrolizinyl moiety can be depicted by the structural formula .
  • a heterocycloalkyl group can be unsubstituted or substituted as described herein.
  • a heterocycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heteroaryl refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle.
  • a 5- to 10-membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • the ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities: [0346]
  • a “monocyclic” heteroaryl can be an aromatic five- or six- membered heterocycle.
  • a five-membered heteroaryl can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-liniting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a six-membered heteroaryl can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • a “bicyclic heteroaryl” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring.
  • Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5- naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H- pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula .
  • a heteroaryl group can be unsubstituted or substituted as described herein.
  • a heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein.
  • a heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • substituted means that the specified group or moiety bears one, two, or three substituents.
  • substituted means that the specified group or moiety bears one or two substituents.
  • substituted means the specified group or moiety bears one substituent.
  • Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Certain chemical entities of Formula (I)-(XXX) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. can exist in different tautomeric forms.
  • tautomers can generally be considered to be the same chemical compound.
  • examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tutomers, and the like.
  • a ring option of isoquinolin-3(2H)-oneylene can exist as the following tautomers
  • the nomenclature “(ATOM)i-(ATOM)j” with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized.
  • C 1- C 3 refers independently to embodiments that have one carbon member (C 1 ), embodiments that have two carbon members ( C 2 ), and embodiments that have three carbon members (C 3 ).
  • the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XXX), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXX), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XXX)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXX), and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XXX) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med.
  • KRAS inhibitor includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the KRAS gene, called K-Ras, that is involved in the RAS/MAPK signaling pathway.
  • KRAS gene, K-Ras, and RAS/MAPK signaling pathway will be known and understood by one of skill in the art. It will be appreciated that KRAS mutations occur in approximately one in seven of all human metastatic cancers, and that those mutations can occur in a variety of locations in the KRAS gene coding sequence.
  • KRAS mutations primarily occur in KRAS codons 12 and 13, and also occur in codons 18, 61, 117, and 146 at low frequencies and have distinct effects on tumor cell signaling based on the codon and missense mutation.
  • KRAS mutations include, but are not limited to KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like.
  • KRAS G12D refers to inhibiting the protein encoded by the KRAS G12D gene, having a coding sequence (e.g. a guanine to adenine substitution, at position 35 on codon 12 of the KRAS coding sequence) that produces a K-Ras G12D protein, where a glysine at position 12 of the protein sequence is replaced by am aspartic acid.
  • a coding sequence e.g. a guanine to adenine substitution, at position 35 on codon 12 of the KRAS coding sequence
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0366] wherein R 1 , R 2 , R 3 , R a , R b , B, X, Y, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , n, p, and q are as described herein.
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [0368] wherein R 2 , R 3 , R 11 , R a , R b , A, B, X, Y, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, III [0370] wherein R 2 , R 3 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0371] In some embodiments, the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, IV [0372] wherein R 2 , R 11 , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0373] In some embodiments, the disclosure provides a compound of the formula IVa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, V [0376] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and p are as described herein. [0377] In some embodiments, the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIa, or a pharmaceutically acceptable salt thereof, [0380] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, and n are as described herein. [0381] In some embodiments, the disclosure provides a compound of the formula VII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIII, or a pharmaceutically acceptable salt thereof, VIII [0384] wherein R 2 , R 11 , R 12 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0385] In some embodiments, the disclosure provides a compound of the formula VIIIa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula VIIIb, or a pharmaceutically acceptable salt thereof, VIIIb [0388] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0389] In some embodiments, the disclosure provides a compound of the formula IX, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula X, or a pharmaceutically acceptable salt thereof, [0392] wherein R 2 , R 11 , R 13 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0393] In some embodiments, the disclosure provides a compound of the formula Xa, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula Xb, or a pharmaceutically acceptable salt thereof, [0396] wherein R 2 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, and n are as described herein. [0397] In some embodiments, the disclosure provides a compound of the formula XI, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XII, or a pharmaceutically acceptable salt thereof, [0400] wherein R 2 , R 3 , R 10 , R 11 , R a , R b , A, B, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0401] In some embodiments, the disclosure provides a compound of the formula XIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XIV, or a pharmaceutically acceptable salt thereof, XIV [0404] wherein R 2 , R 10 , R 11 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , m, n, and q are as described herein.
  • the disclosure provides a compound of the formula XV, or a pharmaceutically acceptable salt thereof, XV [0406] wherein R 2 , R 3 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein.
  • the disclosure provides a compound of the formula XVI, or a pharmaceutically acceptable salt thereof, XVI [0408] wherein R 2 , R 10 , R 11 , R 12 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and q are as described herein.
  • the disclosure provides a compound of the formula XVII, or a pharmaceutically acceptable salt thereof, [0410] wherein R 2 , R 3 , R 10 , R 11 , R 13 , R a , R b , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, p, and q are as described herein. [0411] In some embodiments, the disclosure provides a compound of the formula XVIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XIX, or a pharmaceutically acceptable salt thereof, XIX [0414] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0415] In some embodiments, the disclosure provides a compound of the formula XX, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXI, or a pharmaceutically acceptable salt thereof, XXI [0418] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0419] In some embodiments, the disclosure provides a compound of the formula XXII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXIII, or a pharmaceutically acceptable salt thereof, XXIII [0422] wherein R 2 , R 3 , R 11 , R 12 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0423] In some embodiments, the disclosure provides a compound of the formula XXIV, or a pharmaceutically acceptable salt thereof,
  • XXIV [0424] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXV, or a pharmaceutically acceptable salt thereof, XXV [0426] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVI, or a pharmaceutically acceptable salt thereof,
  • XXVI [0428] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVII, or a pharmaceutically acceptable salt thereof, XXVII [0430] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein.
  • the disclosure provides a compound of the formula XXVIII, or a pharmaceutically acceptable salt thereof,
  • the disclosure provides a compound of the formula XXIX, or a pharmaceutically acceptable salt thereof, [0434] wherein R 2 , R 3 , R 11 , A, X, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , m, n, and p are as described herein. [0435] In some embodiments, the disclosure provides a compound of the formula XXX, or a pharmaceutically acceptable salt thereof,
  • Y is -S(O) 2 - or –C(O)NR 10 -. In some embodiments, Y is -S(O) 2 - . In some embodiments, Y is –C(O)NR 10 -. In some embodiments, Y is -S(O) 2 - or –C(O)NR 10 - , and R 1 is ring A.
  • Y is -S(O) 2 -, and R 1 is ring A. In some embodiments, Y is or –C(O)NR 10 -, and R 1 is ring A. In some embodiments, Y is -O-, -S-, -S(O)-, or -S(O) 2 - and R 1 is ring A. In some embodiments, Y is -O-, -S-, or -S(O)- , and R 1 is ring A. In some embodiments, Y is -O-, and R 1 is ring A. In some embodiments, Y is -S-, and R 1 is ring A. In some embodiments, Y is -S-, and R 1 is ring A.
  • Y is -S(O)-
  • R 1 is ring A.
  • Y is a bond
  • R 1 is ring A.
  • ring A is a C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more of R 11 .
  • ring A is an unsubstituted C 3 -C 8 cycloalkyl, or a C 3 -C 8 cycloalkyl substituted with one or more of R 11 .
  • ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with one or more of R 11 .
  • ring A is an unsubstituted C 6 -C 10 aryl, or a C 6 -C 10 aryl substituted with one or more of R 11 .
  • ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10- membered heteroaryl substituted with one or more of R 11 .
  • ring A is a C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each of C 3 -C 8 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted C 3 -C 8 cycloalkyl, or a C 3 -C 8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted 4- to 10-membered heterocycloalkyl, or a 4- to 10-membered heterocycloalkyl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted C 6 -C 10 aryl, or a C 6 -C 10 aryl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is an unsubstituted 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, 5, or 6 of R 11 .
  • ring A is a 4- to 10-membered heterocycloalkyl that is not an unsubstituted or a substituted ring of the formula [0441]
  • A is 4- to 10-membered heterocycloalkylthat is a mono-cyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, a bridged bicyclic 6- to 10-membered heterocycloalkyl, or a spiro bicyclic 6- to 10-membered heterocycloalkyl.
  • ring A is a 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a mono-cyclic 4- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a fused bicyclic 5- to 10-membered heterocycloalkyl. In some embodiments, ring A is a bridged bicyclic 6- to 10-membered heterocycloalkyl. In some embodiments, ring A is a spiro bicyclic 6- to 10-membered heterocycloalkyl. [0442] In some embodiments, Ring A is
  • Ring A is of the formula , or , [0444] wherein * is a point of covalent attachment to [0445] In some embodiments, Ring A is [0446] wherein * is a point of covalent attachment to and m is 0 or one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6.
  • Ring A is azitidinyl, oxtenanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro-1H-pyrrolyl, pyrazolidinyl, thiazolidinyl, 4,5-dihydro-1H- imidazolyl, dihydrothiophen-2(3H)-onyl, tetrahydrothiophenyl 1,1-dioxide, imidazolidin-2- onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, 1,3-dioxolan-2-onyl, oxazolidin-2-onyl, piperidinyl, morpholinyl, 4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3- oxazinan-2-on
  • Ring A is
  • Ring A is
  • each R 11 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR a R b , -OS(O) 2 NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -NR a C(O)
  • m is 0. In some embodiments, m is one or more. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
  • ring B is a C 6 -C 10 aryl or 5- to 10-membered heteroaryl, optionally substituted with one or more R 2 , R 12 , or R 13 .
  • ring B is a C 3 - C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl optionally substituted with one or more R 2 , R 12 , or R 13 .
  • Ring B is [0461] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0462] In some embodiments, Ring B is
  • Ring B is [0465] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0466] In some embodiments, Ring B is [0467] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0468] In some embodiments, Ring B is
  • Ring B is [0471] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0473] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • Ring B is [0475] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0476] In some embodiments, Ring B is [0477] wherein wherein * is a point of covalent attachment to , n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. [0478] In some embodiments, Ring B is [0479] wherein wherein * is a point of covalent attachment to n is 0 or one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
  • each R 2 is independently deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OR c , or - CN.
  • each R 2 when present, is independently selected from the group consisting of fluoro, chloro, C 1 -C 6 alkyl, -OH, and -CN.
  • each R 2 when present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, iso-propyl, -C ⁇ CH, -CN, and -OH.
  • R 12 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e ,
  • R 12 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 12 is H, deuterium, or methyl.
  • R 13 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f
  • R 13 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 13 is H, deuterium, or methyl. [0483] In some embodiments, n is 0. In some embodiments, n is one or more. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. [0484] In some embodiments, Ring B is [0485] wherein “ ” is a point of covalent attachment. [0486] In some embodiments, Ring B is
  • Ring B is of the formula [0489] wherein “ ” is a point of covalent attachment.
  • q is 0. In some embodiments, q is 1.
  • -X- is -O-, -S-, or–NR 4 -. In some embodiments, -X- is -O-. In some embodiments, -X- is -S-. In some embodiments, -X- is –NR 4 -.
  • R 4 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -R e , -R f , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e ,
  • R 4 is H, deuterium, or C 1 -C 6 alkyl. In some embodiments, R 4 is H, deuterium, or methyl.
  • R 3 is -C 1 -C 6 alkyl, -C 2 -C 6 alkenyl, -C 2 -C 6 alkynyl, -C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkyl), -C 6 -C 10 aryl, -C 1 -C 6 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in C 1 - C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C
  • R 3 is -C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, or -C 1 - C 6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C 1 -C 6 alkyl, 4- to 10-membered heterocycloalkyl, or -C 1 -C 6 alkylene-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, - C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalky
  • R 3 is 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C 1 -C 6 alkyl-(4- to 10- membered heterocycloalkyl), -OR e , -OC(O)R e
  • R 3 is [0497] wherein is a point of covalent attachment. [0498] In some embodiments, R 3 is [0499] wherein “ is a point of covalent attachment. [0500] In some embodiments, R 3 is [0501] wherein “ ” is a point of covalent attachment.
  • R 3 is –C 1 -C 6 alkyl-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl, or –C 1 -C 6 alkyl-(4- to 10-membered heterocycloalkyl), is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-R a , C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, or -C 1 -C 6 alkyl-
  • R 3 is of the formula [0504] wherein wherein ” is a point of covalent attachment, and each hydrogen atom is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 - C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, -C 1 -C 6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e
  • R 3 is of the formula [0506] wherein wherein is a point of covalent attachment, and each hydrogen atom is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-O-C 1 - C 6 alkyl, -OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, C 6 -C 10 aryl, -C 1 -C 6 alkyl-(C 6 -C 10 aryl), haloalkyl, C 3 -C 6 cycloalkyl, 5- to 10-membered heteroaryl, -C 1 -C 6 alkyl-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e ,
  • R 3 when present, is of the formula [0508] wherein is a point of covalent attachment.
  • R 3 when present, is of the formula [0510] wherein is a point of covalent attachment.
  • each R a , R b , R c , R d , R e , R f , R g , and R h is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; or two of R a and R b , or R c and R d , or R e and R f , or R g and R h , taken together with the atom or atoms to which they are attached, combine to form a C 3 -C 6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6
  • Z 1 is N. In some embodiments, Z 2 is N. In some embodiments, Z 3 is N. In some embodiments, Z 4 is N. In some embodiments, Z 5 is N. In some embodiments, Z 6 is N. In some embodiments, Z 7 is N. In some embodiments, Z 1 is C(R 5 ). In some embodiments, Z 2 is C(R 6 ). In some embodiments, Z 3 is C(R 7 ). In some embodiments, Z 4 is C(R 8 ). In some embodiments, Z 5 is C(R 9 ). In some embodiments, Z 6 is C(R 14 ). In some embodiments, Z 7 is C(R 15 ).
  • any of the possible combinations of Z 1 -Z 7 can be combined as embodiemnts.
  • Z 6 is N or C(R 14 ).
  • Z 7 is N or C(R 15 ).
  • Z 1 is N, and Z 2 is N.
  • Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is N, and Z 5 is C(R 9 ).
  • Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is C(R 8 ), and Z 5 is C(R 9 ).
  • Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is N, and Z 5 is C(R 9 ). In some embodiments, Z 1 is N, Z 2 is N, Z 3 is N, Z 4 is C(R 8 ), and Z 5 is C(R 9 ). In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is C(R 8 ), and Z 5 is N. In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is N, and Z 5 is N. In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is N, and Z 5 is N. In some embodiments, Z 1 is N, Z 2 is N, Z 3 is C(R 7 ), Z 4 is N, and Z 5 is C(R 9 ).
  • Z 1 is N
  • Z 2 is N
  • Z 3 is N
  • Z 4 is C(R 8 )
  • Z 5 is C(R 9 ).
  • Z 1 is N
  • Z 2 is N
  • Z 3 is N
  • Z 4 is N
  • Z 5 is N.
  • each of R 5 , R 6 , R 7 , R 8 , R 9 , R 14 , and R 15 is independently H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 10- membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR g , -OC(O)R g , -OC(O)NR g R h , -OS(O)R g , -OS(O) 2 R g , -SR g , -S(O)R g , -S(O) 2 R g , -S(O)NR g R h , -S(O) 2 NR g R h , -OS(O)NR g R g R
  • R 6 when present, is H.
  • R 7 when present, is H or F.
  • R 8 when present, is H.
  • R 9 when present, is H.
  • R 14 when present, is H.
  • R 15 when present, is H.
  • the disclosure provides a compound selected from the group consisting of 5-ethynyl-6-fluoro-4-[8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl]methoxy ⁇ -4-(piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol; 4-[4-(3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0516] 3-[7-(8-ethynyl-7-fluoro
  • the disclosure provides a compound selected from the groups consisting of 5-ethynyl-6-fluoro-4-(8-fluoro-4-[(3S)-3-fluoropiperidin-1-yl]-2- ⁇ [(2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 2-ol; [0583] 4-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2- ⁇ [(2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl]methoxy ⁇ pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2- ol; [0584] 5-ethyl-4-[8-fluor
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient.
  • compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. [0620] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • the term “subject” refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • cancer includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congen
  • cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.
  • Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources.
  • Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.
  • Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
  • Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
  • the compounds and pharmaceutical compositions of the disclosure specifically target Ras, in particular K-Ras.
  • these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like.
  • KRAS G12C KRAS G12D
  • KRAS G12V KRAS G12R
  • KRAS G12S KRAS G13C
  • KRAS G13D KRAS G13D
  • KRAS A18D KRAS Q61H, KRAS K117N, and the like.
  • methods of treating a target cancer are described.
  • an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably a cancer cell with abnormal signaling due to a mutation of KRAS, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like.
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the disclosure, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g.
  • crizotinib Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids.
  • suitable combination agents include anti-inflammatories such as NSAIDs.
  • the pharmaceutical compositions of the disclosure may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • the proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below.
  • Scheme I [0641] The general scheme I is used to prepare the products with general structure Ex. X.
  • the bicyclic aryl core I-1-1 and a variety of amines I-2 are either commercially available or prepared via conventional chemistry from commercially available materials.
  • DIPEA diisopropylethyl amine
  • the general scheme II is used to prepare the products with general structure Ex. X.
  • the bicyclic aryl core I-1-1, a variety of amines I-2, I-4 and boronic ester or acid are either commercially available or prepared via conventional chemistry from commercially available materials.
  • B under basic conditions such as diisopropylethylamine in dioxane at elevated temperature such as 80 o C, compound II-1 and an amine or alcohol I-4 are converted to a product II-2.
  • Step 2 To a mixture of tert-butyl 8-fluoro-3-azabicyclo[3.2.1]octane-3-carboxylate (50.0 mg, 0.218 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 0.2 mL, 3.67 eq).
  • Step 4 To a solution of 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6- (methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (180 mg, 0.233 mmol, 1 eq) in DCM (2 mL) was added HCl/Dioxane (4 M, 0.3 mL, 5.16 eq).
  • Step 2 To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (2.30 g, 7.28 mmol, 1.0 eq) in dioxane (20 mL) was added DIEA (1.88 g, 14.6 mmol, 2.0 eq) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (1.27 g, 8.01 mmol, 1.1 eq). The mixture was stirred at 80 °C for 12 hours.
  • reaction mixture was partitioned between EtOAc (20 mL) and H 2 O (20 mL) and extracted with EtOAc (20 mL). The combined organic phase was washed with brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 To a solution of (3R,4R)-4-fluoro-1-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]piperidin-3-ol (60.0 mg, 0.743 mmol, 1.0 eq) in DCM (10 mL) was added HCl/Dioxane (4 M, 1 mL).
  • Step 1 A mixture of 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.80 g, 4.10 mmol, 1.0 eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.15 g, 6.15 mmol, 1.5 eq), K3PO4 (2.61 g, 12.3 mmol, 3.0 eq), [2-(2-aminophenyl)phenyl]palladium(1+);bis(1- adamantyl)-butyl-phosphan
  • Step 2 To a mixture of 3-azabicyclo[3.1.1]heptane (8.62 mg, 0.0645 mmol, 1.45 eq, HCl) and 2-[2-fluoro-8-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1- naphthyl]ethynyl-triisopropyl-silane (35.0 mg, 0.0443 mmol, 1 eq) in DMF (1 mL) was added K 2 CO 3 (18.3 mg, 0.133 mmol, 3 eq).
  • Step 3 To a solution of 2-[8-[4-(3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7- yl]-2-fluoro-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (50.0 mg, 0.064 mmol, 1 eq) and DCM (1 mL) was added HCl/dioxane (4 M, 0.206 mL, 13 eq), the resulting mixture was stirred at 23 °C for 1.5 h.
  • Step 1 To a solution of [5-chloro-6-fluoro-4-(trifluoromethylsulfonyloxy)-2- naphthyl] acetate (50.0 mg, 0.129 mmol, 1 eq) in THF (1 mL) and H 2 O (0.5 mL) was added LiOH.H 2 O (16.3 mg, 0.388 mmol, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1h. On completion, the mixture was quenched with HCl (1N, 5 mL) and extracted with ethyl acetate (2 mL ⁇ 3).
  • Step 1 A mixture of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (200 mg, 0.605 mmol, 1.2 eq), DIEA (391 mg, 3.03 mmol, 6 eq) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then piperidine (43.0 mg, 0.504 mmol, 1 eq) was added to the mixture at -40 °C. The mixture was stirred at -40 °C for 2 h under N2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 3 To the solution of tert-butyl 7-[8-fluoro-7-[7-fluoro-3-(methoxymethoxy)-8- (2-triisopropylsilylethynyl)-1-naphthyl]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-2-yl]-1,7- diazaspiro[4.4]nonane-1-carboxylate (150 mg, 0.178 mmol, 1 eq) in DCM (2 mL) was added HCl/dioxane (4 M, 20 eq).
  • Step 1 To a mixture of tert-butyl 1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine- 6- carboxylate (460 mg, 2.03 mmol, 2 eq) and 7-chloro-8-fluoro-2-[[(2R,8S)-2- fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (445 mg, 1.02 mmol, 1 eq) in DMF (10 mL) was added K2CO3 (421 mg, 3.05 mmol, 3 eq).
  • Step 3 To a solution of tert-butyl 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]pyrido[4,3-d]pyrimidin-4-yl]-3,4,4a,5,7,7a-hexahydro- 2H-pyrrolo[3,4-b]pyridine-6-carboxylate (400 mg, 0.437 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 1.19 mL, 10.8 eq).
  • Step 4 To a solution of 4-[4-(2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b]pyridin-1-yl)- 8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3- d]pyrimidin-7-yl]-6-fluoro-5-(2-triisopropylsilylethynyl)naphthalen-2-ol (352 mg, 0.437 mmol, 1 eq, HCl) in DCM (4 mL) was added Ac2O (111 mg, 1.09 mmol, 2.5 eq) and TEA (221 mg, 2.19 mmol, 5 eq) at 0 °C.
  • Step 1 To a solution of 6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-5-(2- triisopropylsilylethynyl)naphthalen-2-ol (800 mg, 1.10 mmol, 1 eq) in DCM (20 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (587 mg, 1.64 mmol, 1.5 eq) and DIEA (283 mg, 2.19 mmol, 2 eq), DMAP (26.7 mg, 0.219 mmol, 0.2 eq).
  • Step 1 To a solution of 1H-indol-3-yl acetate (248 mg, 1.42 mmol, 2.00 eq) in dioxane (4.50 mL) was added 7-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-(1-piperidyl)pyrido[4,3-d]pyrimidine (300 mg, 0.708 mmol, 1 eq), Cs2CO3 (461 mg, 1.42 mmol, 2 eq) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]- 4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium (68.9 mg, 0.0708 mmol, 0.1 eq).
  • Step 5 A mixture of 2-[2-fluoro-8-[8-fluoro-5-methoxy-2-methylsulfonyl-4-(1- piperidyl)pyrido[4,3-d]pyrimidin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl- triisopropyl-silane (240 mg, 0.331 mmol, 1 eq), [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (158 mg, 0.993 mmol, 3 eq), t-BuOK (111 mg, 0.993 mmol, 3 eq) in Toluene (3 mL) was degassed and purged with N2 for 3 times at 0 °C, and then the mixture was stirred at 25 °C under N 2 atmosphere for 1 h.
  • KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G12D/T35S or KRAS WT proteins were mixed with a-GST Tb antibody in reaction buffer (20 mM Hepes, pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.05% BSA, 0.0025% NP40).
  • Serial dilutions of indicated compounds were prepared in DMSO and added to the KRAS /a-GST Tb antibody mixture using acoustic dispenser (ECHO, Beckman).
  • Method A Two thousand KRAS mutant cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours at 37°C and 5% CO 2 .
  • Cell proliferation was measured using CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) following the manufacturer’s protocol.
  • IC50 values were determined using Prism software (GraphPad Software, San Diego, CA).
  • Method B Two thousand KRAS mutant cells per well were seeded in 96-well black plate and then treated with indicated compounds for 5 days at 37°C and 5% CO 2 .
  • Ex.1 was administered to female BALB/c mice via oral gavage at the dose level of 50 mg/kg. Mouse plasma was collected before the dose and at 15 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after the dose. For each time points, blood samples were collected from three mice into tubes containing K2-EDTA, followed by gentle mixing to assure distribution of the anti-coagulant. Immediately after a blood sample was collected and mixed, it was placed on ice. Blood samples were subsequently centrifuged at 4 oC for 10 minutes at 5,000 rpm. The plasma was harvested into pre-labeled tubes and stored at -80 oC. Frozen plasma samples were shipped to Integrated Analytical Solutions, Inc. for bioanalysis of Ex.1 by LC/MS/MS. Non-compartment analysis method of Phoenix 64 software (Certara, Inc) was used to calculate various pharmacokinetic parameters and the results were summarized in the Table below:

Abstract

La présente invention concerne des composés diaryle ciblant KRAS, des compositions pharmaceutiques contenant les composés, et des méthodes d'utilisation de tels composés pour traiter une maladie, telle que le cancer.
PCT/US2023/064042 2022-03-09 2023-03-09 Inhibiteurs de kras pour le traitement d'une maladie WO2023173017A1 (fr)

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WO2024041606A1 (fr) * 2022-08-24 2024-02-29 泰励生物科技（上海）有限公司 Composé ayant une activité tumorale de mutant anti-kras

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WO2024041606A1 (fr) * 2022-08-24 2024-02-29 泰励生物科技（上海）有限公司 Composé ayant une activité tumorale de mutant anti-kras
CN117186095A (zh) * 2023-11-02 2023-12-08 南方科技大学 靶向kras蛋白g12d突变体的共价抑制剂

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