WO2023059792A1 - Composés de dégradation de la protéine 3 non structurale de coronavirus - Google Patents

Composés de dégradation de la protéine 3 non structurale de coronavirus Download PDF

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WO2023059792A1
WO2023059792A1 PCT/US2022/045889 US2022045889W WO2023059792A1 WO 2023059792 A1 WO2023059792 A1 WO 2023059792A1 US 2022045889 W US2022045889 W US 2022045889W WO 2023059792 A1 WO2023059792 A1 WO 2023059792A1
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compound
mmol
variant
independently selected
alkyl
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Martin Duplessis
Ronan Patrick HANLEY
Yanke LIANG
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C4 Thrapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • SARS-CoV-2 severe acute respiratory syndrome coronavirus-2
  • COVID-19 the resulting illness coronavirus disease 2019
  • SARS-CoV-2 quickly spread across the world and on March 11, 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic.
  • SARS-CoV-2 can cause a wide range of symptoms ranging from mild, cold-like symptoms to severe hospitalization, ventilation, and even death. The virus may cause long-term damage to the lungs, heart, and brain.
  • Coronaviruses are enveloped viruses with a single-strand, positive-sense RNA genome.
  • the genome of SARS-CoV-2 is among the largest known RNA viruses in the world and includes approximately 30 kilobases.
  • SARS-CoV-2 is a coronavirus (CoV), which is in the order Nidovirales, family Coronaviridae, subfamily Coronavirinae.
  • coronaviruses include: Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Bat SARS-like coronavirus WIV1 (Bat SL-CoV-WIVl), alpha coronaviruses 229E (HCoV-229E), New Haven coronavirus NL63 (HCoV-NL63), beta coronaviruses OC43 (HCoV-OC43), coronavirus HKIJ I (HCoV-HKU 1 ), and Middle East Respiratory Syndrome coronavirus (MERS-CoV).
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • Bat SARS-like coronavirus WIV1 Bat SARS-like coronavirus WIV1
  • HoV-229E alpha coronaviruses 229E
  • HoV-NL63 New Haven coronavirus NL63
  • beta coronaviruses OC43 HCoV-OC43
  • coronavirus HKIJ I
  • SARS-CoV-2 Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 exhibits a faster human-to-human transmission rate (Huang et al., Lancet 2020, 395, 497), making it particularly dangerous and challenging to contain. CoVs are often enzootic, crossing the animal-human species barrier (Lau et al., PNAS 2005, 102, 14040-5; Rest et al., Infect Genet Evol. 2003, 3, 219-25). Cross-species barrier jumps are responsible for CoVs such as the SARS CoV and the Middle Eastern respiratory syndrome CoV (MERS) to manifest as virulent human viruses (Schoeman and Fielding, Virology 2019, 16, 69). Genome sequencing has revealed that SARS-CoV-2 is approximately 96% identical at the whole-genome level to a bat coronavirus (Zhou et al. Nature 2020, 579, 270) and therefore most likely originated in bats.
  • MERS Middle Eastern respiratory syndrome CoV
  • SARS-CoV-2 enters cells through endocytosis or fusion with the cell membrane by binding to angiotensin converting enzyme 2 (ACE2) receptors. Spike glycoproteins on the surface of the virus envelope then bind to the ACE2 receptor.
  • the human transmembrane protease serine 2 cleaves and activates the spike protein (Luan et al. Biochem. Biophys. Res. Commun. 2020: 527, 165; Hoffman, M. et al. Cell, 2020, 181, 271; Yang et al. Int. J. Biol. Sci. 2020, 16, 1724). Once in the host’s cells SARS-CoV-2 replicates and spreads rapidly.
  • Dana-Farber Cancer Institute, Inc. filed a patent application published as WO 2022/081827 which describes the use of protein degraders to treat viral disorders including SARS-CoV-2.
  • Kymera Therapeutics, Inc. has also described degraders for the treatment of SARS-CoV-2 in a patent application published as WO 2021/231778.
  • Patent applications filed by C4 Therapeutics, Inc. that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation include: WO 2022/032026 titled “Advantageous Therapies For Disorders Mediated By Ikaros or Aiolos”; WO 2022/081925 titled “Tricyclic Ligands for Degradation of IKZF2 or IKZF4”; WO 2022/081927 titled “Tricyclic Compounds to Degrade Neosubstrates for Medical Use”; WO 2022/081928 titled “Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins”; WO 2021/255212 titled “BRAF Degraders”; WO 2021/255213 titled “Heterobifunctional Compounds as Degraders of BRAF”; WO 2021/178920 titled “Compounds for Targeted Degradation of BRD9”; WO 2021/127561 titled “Isoindolinone
  • the present invention provides compounds and their compositions, uses and manufacture that cause degradation of a coronavirus non- structural protein 3 (NSP3) for example SARS-CoV- 2 NSP3.
  • NSP3 coronavirus non- structural protein 3
  • a compound of the present invention can be administered in an effective amount to treat a patient with a coronavirus for example SARS-CoV-2 (also known as COVID19).
  • SARS-CoV-2 also known as COVID19
  • compounds of the present invention exhibit antiviral activity.
  • NSP3 is a useful protein target for the treatment of coronaviruses via targeted protein degradation.
  • NSP3 is a key component for coronavirus replication. It is composed of various domains, the organization of which differs by genus. Despite its structural complexity, eight domains of the NSP3 complex are conserved between the various CoVs: the ubiquitin-like domain 1 (Ubll), the Glu-rich acidic domain (also called “hypervariable region”), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papainlike protease (PLpro), the NSP3 ectodomain (3Ecto, also called “zinc-finger domain”), as well as the domains Y1 and CoV-Y of unknown functions. Neuman, Antiviral Research, 135, 97-107, 2016.
  • NSP3 is essential to viral survival, displays evidence of multiple functions or scaffolding roles in the virus that can amplify the impact of NSP3 degrader action, the targeted domain of NSP3 diverges from human paralogs that might impact selectivity profiles, and there is structural evidence of conserved functional or surface-exposed binding sites for ligand discovery.
  • Baez- Santos YM et al. Antiviral Research, 2015, 115, 21-38; O'Donoghue SI et al., Mol Syst Biol., 2021, 17(9); Lei J et al., Antiviral Research, 2018, 149, 58-74; and Shan H et al., Cell Chem Biol., 2021, 28(6), 855-865.
  • Ligands have been developed for the PLpro domain of NSP3.
  • This domain includes a cysteine protease that mediates viral replication by processing of viral polyproteins, in addition to being an essential protease in the formation of the replicase transcriptase complex (RTC).
  • RTC replicase transcriptase complex
  • PLpro also functions as a deubiquitinase and a delSGylase, acting as a major antagonist to host immune response by interfering with IRF3/NF-kB activation and IFN antiviral signaling via de- ubiquitination (DUB).
  • PLpro cleaves the isopeptide bond that ligates ubiquitin (Ub) and ubiquitin-like proteins (UbL) such as interferon-stimulated gene product 15 (ISG15) to lysine sidechains of host proteins Barretto et. al. Journal of Virology, 79(24), 15189-98, 2005.
  • NSP3 ligands include those described in Shen et al. “Potent, Novel SARS- CoV-2 PLpro Inhibitors Block Viral Replication in Monkey and Human Cell Cultures” preprint doi.org/10.1101/2021.02.13.431008. Additional NSP3 ligands are described in Santos et al., J. Med. Chem., 2014, 57, 2393-2412.
  • a compound of the present invention is used to treat a coronavirus variant for example a SARS-CoV-2 variants selected from alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, omicron, and zeta.
  • SARS-CoV-2 alpha variants include B.1.1.7 and Q.1-Q.8.
  • Non limiting examples of SARS-CoV-2 beta variants include B.1.351, B.1.351.2, and B.1.351.3.
  • Non limiting examples of SARS-CoV-2 gamma variants include P.l, P.1.1, and P.1.2.
  • Non limiting examples of SARS-CoV-2 delta variants include B.1.617.2 and AY.1.
  • Non limiting examples of SARS-CoV-2 epsilon variants include B.1.427 and B.1.429.
  • Non limiting examples of SARS-CoV-2 eta variants include B. 1.525.
  • Non limiting examples of SARS- CoV-2 iota variants include B.1.526.
  • Non limiting examples of SARS-CoV-2 kappa variants include B.1.617.1.
  • Non limiting examples of SARS-CoV-2 mu variants include B.1.621 and B.1.621.1.
  • Non limiting examples of SARS-CoV-2 zeta variants include P.2.
  • Non limiting examples of SARs-CoV2 omicron variants include B.1.1.529 and sub-lineage variants BA.l, BA.2, BA.2.12.1, BA.2.75, BA.3, BA.4, and BA.5.
  • a compound of the present invention is used to treat a coronavirus other than SARS-CoV-2.
  • Additional examples of coronaviruses include: Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Bat SARS-like coronavirus WIV1 (Bat SL-CoV-WIVl), alpha coronaviruses 229E (HCoV-229E), New Haven coronavirus NL63 (HCoV-NL63), beta coronaviruses OC43 (HCoV-OC43), coronavirus HKIJ I (HCoV-HKU 1), and Middle East Respiratory Syndrome coronavirus (MERS-CoV).
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • Bat SARS-like coronavirus WIV1 Bat SARS-like coronavirus WIV1 (Bat SL-CoV-WIVl)
  • alpha coronaviruses 229E HoV-229E
  • the compounds of the present invention include a NSP3 Targeting Ligand, a heterocyclic moiety, and a Linker that links them. More specifically a compound of Formula A is provided: or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein:
  • Heterocyclic Moiety is selected from: , or S;
  • X 3 , X 4 , X 5 , and X 6 are independently selected from N, CH, and CR 5 , wherein one of X 3 , X 4 , X 5 , and X 6 is a carbon atom that is attached to Linker; R 1 , R 3 , R 4 , and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 3 and R 4 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R 1 and R 6 are combine together to form a 1 or 2-carbon bridge; for example or R 1 and R 3 are combine together to form a 3-6 membered fused ring; for example each R 2 is selected from hydrogen, alkyl, haloal
  • R 5 independently selected from R 5 ; independently selected from R 5 ; and each of which R 18 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ; for example includes but does not include
  • Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with one R 12 substituent;
  • Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1,
  • R 12 is the attachment point to Linker
  • R 7 and R 8 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R 14 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 , -OR 7 , and -SR 7 each of which is optionally substituted with 1, 2,
  • each R 10 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , -OC(O)R 14 , -OC(S)R 14 , -OS(O)R 14 , -OS(O) 2 R 14 , -NR 11 C(O)R 14 , -NR 11 C(S)R 14 , -NR 11 S(O)R 14 , -NR 11 S(O) 2 R 14 , -P(O)(R 14 ) 2 , -NR 11 P(O)(R 14 ) 2 , and -OP(O)(
  • R 11 and R 13 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14 , -C(S)R 14 , -S(O)R 14 ,
  • each R 14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ; each R 15 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2;
  • Linker is a bivalent chemical group
  • NSP3 Targeting Ligand is selected from:
  • y is 0 or 1
  • Fused Cycle is a fused aryl, heteroaryl, cycloalkyl, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ;
  • X 16 is selected from
  • X 17 is selected from CR 33 R 34 , C(O), C(S), S(O), and S(O) 2 ;
  • X 18 is selected from CR 30 , CH, and N; each x is independently 0, 1, 2, 3, or 4;
  • X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are independently selected from N, CH, and CR 28 ; or X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are independently selected from N, CH, and CR 28 wherein no more than three of X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are N; in certain embodiments no more than two of X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are N; in certain embodiments only one of X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are N;
  • R 27 is selected from , and , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 29 ; each R 28 , R 29 , and R 30 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , - C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9
  • Linker is selected from wherein: X 1 and X 2 are independently at each occurrence selected from bond, heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S;
  • R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 26 )O-,
  • R 26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and
  • R 40 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSChalkenyl, -N(alkyl)SO2alkenyl, -NHSChalkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl.
  • NSP3 Targeting Ligand is selected from:
  • NSP3 Targeting Ligand is selected from:
  • a compound of Formula B is provided: or a pharmaceutically acceptable salt, N-oxide , isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein: Heterocyclic Moiety is In certain embodiments NSP3 Targeting Ligand B is selected from:
  • NSP3 Targeting Ligand c is selected from:
  • the compound of the present invention provides multiple advantages over traditional antiviral treatment of a coronavirus for example SARS CoV-2.
  • a NSP3 degrading compound of the present invention may a) overcome resistance in certain cases; b) prolong the kinetics of drug effect by destroying the protein, thus requiring resynthesis of the protein even after the compound has been metabolized; c) target all functions of the protein at once rather than a specific catalytic activity or binding event; d) require a smaller dose; e) require less frequent dosing; f) require a shorter dosing period; g) cause fewer side effects; and/or h) have increased potency compared to traditional antiviral agents due to the possibility of the compound of the present invention acting catalytically.
  • a compound of the present invention includes a NSP3 Targeting Ligand that reversibly, non-covalently binds with moderate potency (Kd ⁇ 1 pM).
  • Variables within the formulas described herein are selected such that the resulting compound is sufficiently stable for example stable enough to maintain a shelf life of at least two, three, four, or five months under ambient conditions.
  • One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions.
  • all R groups, with or without optional substituents should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted with alkyl is redundant; however, for example, alkoxy substituted with alkoxy is not redundant and aryl substituted with aryl is also not redundant).
  • a compound of the present invention or its pharmaceutically acceptable salt and/or its pharmaceutically acceptable composition thereof can be used to treat a coronavirus, for example SARS CoV-2. Therefore, in some embodiments a method to treat a host with SARS CoV-2 is provided that includes administering an effective amount of the compound of the present invention or its pharmaceutically acceptable salt to a patient in need thereof, typically a human, optionally in a pharmaceutically acceptable composition.
  • a compound of the present invention has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • the compound of the present invention includes a deuterium or multiple deuterium atoms.
  • Compounds of the present invention may offer important clinical benefits to patients, in particular for the rapid treatment of SARS CoV-2 infection.
  • the present invention thus includes at least the following features:
  • a compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof;
  • a compound of the present invention or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof for the treatment of a coronavirus;
  • a method of treating a coronavirus comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative), or prodrug thereof to a patient in need thereof;
  • composition comprising an effective host-treating amount of a compound of the present invention, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof together and a pharmaceutically acceptable carrier;
  • a compound of the present invention as a mixture of enantiomers or diastereomers (as relevant), including as a racemate;
  • FIG. 1 is a line graph showing the degradation of NSP3 in cereblon positive and cereblon negative HEK293 cell lines.
  • the cells were incubated with varying concentrations of Compound 5.
  • the HEK293 cells were incubated for 6 hours.
  • the x-axis is concentration measured in nanomolarity and the y-axis is % response.
  • the experimental procedure is provided in Example 216.
  • FIG. 2A and FIG. 2B are line graphs showing cell viability in the presence of Compound 5 in cereblon positive and cereblon negative HEK293 cell lines.
  • the cells were incubated with varying concentrations of Compound 5.
  • the HEK293 cells were incubated for 6 or 24 hours.
  • the x-axis is concentration measured in nanomolarity and the y-axis is % response.
  • the experimental procedure is provided in Example 217.
  • FIG. 3 is a line graph showing the proportion of NSP3 in a ternary complex with cereblon and Compound 5.
  • the cells were incubated with varying concentrations of Compound 5.
  • the x- axis is concentration measured in nanomolarity and the y-axis is fraction of ternary complex formed.
  • the experimental procedure is provided in Example 218.
  • FIG. 4 is a line graph showing the degradation of NSP3 by Compound 24 in NSP3 UBL2_PLpro-HA HiBiT 293T cell lines.
  • the cells were incubated with varying concentrations of Compound 24 for 6 hours and 24 hours.
  • the x-axis is concentration measured in micromolarity and the y-axis is % response (Emax).
  • the experimental procedure is provided in Example 216.
  • FIG. 5 is a line graph showing mean plasma concentrations versus time (hours) profile of Compound 92 after IV (1 mg/kg) and PO (10 mg/kg) administration in male ICR-CD1 mice. The experimental procedure and related results are provided in Example 219.
  • FIG. 6 is a line graph showing mean plasma concentrations versus time (hours) profile of Compound 93 after IV (1 mg/kg) and PO (10 mg/kg) administration in male ICR-CD1 mice.
  • the experimental procedure and related results are provided in Example 219.
  • FIG. 7 depicts Formula A of the present invention.
  • the compounds in any of the Formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, A-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context.
  • the present invention includes a compound of the present invention with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F 31 P, 32 P, 35 S, 36 C1, and 125 I respectively.
  • isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention 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.
  • the isotopic substitution occurs on one or more variables selected from Heterocyclic Moiety, Linker, NSP3 Targeting Ligand, Cycle, Fused Cycle, Spirocycle, Q, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 R 4 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 40 R 44 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 20 R 24 R 22 R 23 R 24 , R 26 , R 27 , R 28 , R 29 , R 30 , R 34 , R 32 , R 33 , R 34 , R 36 , and R 40 .
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.
  • the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention.
  • the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein, Linker, and NSP3 Targeting Ligand.
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc ).
  • the unsubstituted carbons may be deuterated.
  • the compound of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D 2 O, de-acetone, de-DMSO (dimethyl sulfoxide).
  • a solvate can be in a liquid or solid form.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group.
  • the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.
  • the alkyl contains from 1 to about 8 carbon atoms.
  • the alkyl is C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , or C 1 -C 6 .
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • C 1 - G> alkyl indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed.
  • C 1 -C 4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane.
  • the alkyl group is optionally substituted.
  • alkyl also encompasses cycloalkyl or carbocyclic groups.
  • cycloalkyl or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context.
  • alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.
  • alkyl is a C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyl, C 1 -C 6 alkyl, C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, or C 1 -C 2 alkyl.
  • alkyl has one carbon
  • alkyl has two carbons.
  • alkyl has three carbons.
  • alkyl has four carbons.
  • alkyl has five carbons. In one embodiment “alkyl” has six carbons.
  • alkyl include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • alkyl examples include: isopropyl, isobutyl, isopentyl, and isohexyl.
  • alkyl examples include: sec-butyl, sec-pentyl, and sec-hexyl.
  • alkyl examples include: tert-butyl, tert-pentyl, and tert-hexyl.
  • alkyl include: neopentyl, 3 -pentyl, and active pentyl.
  • alkyl is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • cycloalkyl is a Cs-C 8 cycloalkyl, C 3 -C 7 cycloalkyl, Cs-C 6 cycloalkyl, Cs-C 5 cycloalkyl, C 3 -C 4 cycloalkyl, Cx-Cxcycloalkyl, C 5 -C 8 cycloalkyl, or C 6 -C 8 cycloalkyl.
  • cycloalkyl has three carbons.
  • cycloalkyl has four carbons.
  • cycloalkyl has five carbons.
  • cycloalkyl has six carbons.
  • cycloalkyl has seven carbons.
  • cycloalkyl has eight carbons.
  • cycloalkyl has nine carbons.
  • cycloalkyl has ten carbons.
  • cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.
  • cycloalkyl include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring.
  • cycloalkyl is a “optionally substituted” with 1, 2, 3, or 4 substituents.
  • Alkenyl is a linear or branched aliphatic hydrocarbon groups having one or more carboncarbon double bonds that may occur at a stable point along the chain.
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted.
  • alkenyl also encompasses cycloalkyl or cycloalkyl groups possessing at least one point of unsaturation.
  • alkenyl is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain.
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • the alkynyl group is optionally substituted.
  • Alkynyl also encompasses cycloalkyl or cycloalkyl groups possessing at least one triple bond.
  • alkynyl is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • Alkylene is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6-carbon moiety, or an indicated number of carbon atoms, for example C 1 -C 2 alkylene, C 1 -C 3 alkylene, C 1 -C 4 alkylene, C 1 -C 5 alkylene, or C 1 -C 6 alkylene.
  • Alkenylene is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkenylene.
  • Alkynylene is a bivalent hydrocarbon having at least one carbon-carbon triple bond.
  • Alkynylenes for example, can be a 2 to 8 carbon moiety, a 2 to 6-carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkynylene.
  • Halo and “Halogen” refers independently to fluorine, chlorine, bromine or iodine.
  • “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and di chloropropyl.
  • Perhaloalkyl means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl.
  • haloalkyl is a C 1 -C 10 haloalkyl, C 1 -C 9 haloalkyl, C 1 -C 8 haloalkyl, C 1 - C 7 haloalkyl, C 1 -C 6 haloalkyl, C 1 -C 5 haloalkyl, C 1 -C 4 haloalkyl, C 1 -Cshaloalkyl, and C 1 - C 2 haloalkyl.
  • haloalkyl has one carbon
  • haloalkyl has one carbon and one halogen.
  • haloalkyl has one carbon and two halogens.
  • haloalkyl has one carbon and three halogens.
  • haloalkyl has two carbons.
  • haloalkyl has three carbons.
  • haloalkyl has four carbons.
  • haloalkyl has five carbons.
  • haloalkyl has six carbons.
  • haloalkyl include:
  • haloalkyl include:
  • haloalkyl include: an
  • haloalkyl include:
  • Chain indicates a linear chain to which ah other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule.
  • Haloalkoxy indicates a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Heterocycloalkyl is an alkyl group as described herein substituted with a heterocyclo group as described herein.
  • Arylalkyl is an alkyl group as described herein substituted with an aryl group as described herein.
  • arylalkyl include:
  • arylalkyl refers to a 2-carbon alkyl group substituted with an aryl group.
  • arylalkyl include:
  • arylalkyl refers to a 3 -carbon alkyl group substituted with an aryl group.
  • Heteroarylalkyl is an alkyl group as described herein substituted with a heteroaryl group as described herein.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g, bicyclic or tricyclic) 4n+2 aromatic ring system (e.g, having 6, ⁇ 0, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6 -14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1- naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms (“Ci4 aryl”; e.g., anthracyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • the one or more fused carbocyclyl or heterocycle groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described above.
  • the aryl group is an unsubstituted C 6 -14 aryl.
  • the aryl group is a substituted C 6 -i4 aryl.
  • An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.
  • aryl is a 6-carbon aromatic group (phenyl).
  • aryl is a 10-carbon aromatic group (napthyl).
  • aryl is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring.
  • aryl include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring.
  • aryl is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring.
  • aryl include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring.
  • aryl is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • heterocyclyl saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • Heterocyclic Moiety that is in the present invention and separately defined.
  • Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spirofused bicyclic ring systems). It does not include rings containing -O-O-.-O-S- or -S-S- portions.
  • Said “heterocycle” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.
  • substituents include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.
  • saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g.
  • pyrrolidinyl imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g. morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3 -dihydrobenzofl, 4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2, 3, 4- tetrahydro-isoquinolyl, 1 ,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7- trihydro-1, 2,4- triazolo[3,4- ⁇ ]
  • heterocyclyl also include moieties where heterocycle radicals are fused/condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms.
  • heterocycle radicals such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen
  • heterocycle refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.
  • heterocycle examples include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane.
  • heterocycle examples include pyrrolidine, 3 -pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine.
  • heterocycle examples include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3 -oxathiolane.
  • heterocycle examples include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.
  • heterocycle examples include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring.
  • group For example, group. However, group.
  • heterocycle also include:
  • heterocycle includes:
  • heterocycle includes:
  • Non-limiting examples of “heterocycle” also include: Non-limiting examples of “heterocycle” also include:
  • heterocycle includes:
  • heterocycle includes: In an alternative embodiment “heterocycle” is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • heteroaryl denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quartemized.
  • Examples include, but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 477-1,2,4-triazolyl, 1H-1 ,2,3-triazolyl, 277-1,2,3- triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen
  • heteroaryl is a 5 membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.
  • Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.
  • heteroaryl is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
  • nitrogen atoms i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl.
  • Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include:
  • heteroaryl is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.
  • heteroaryl groups that are bicyclic include: Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:
  • heteroaryl is a 10 membered bicyclic aromatic group containing 1 or
  • heteroaryl groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.
  • heteroaryl groups that are bicyclic include:
  • heteroaryl is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • bicycle refers to a ring system wherein two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl, and heteroaryl.
  • Non-limiting examples of bicycle groups include:
  • bivalent bicycle groups include:
  • “bicycle” is “optionally substituted” with 1, 2, 3, or 4 substituents.
  • the term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C 1 -C 10 alkyl, C 2 -C10 alkenyl, C 2 -C10 alkynyl, C 3 -C12 cycloalkyl, C 3 - C12 cycloalkenyl, C 1 -C12 heterocycloalkyl, C 3 -C12 heterocycloalkenyl, C 1 -C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C10 alkylamino, C 1 -C10 dialkylamino, arylamino, diarylamino, C 1 -C10 alkyl sulfonamino, arylsulfonamino, C 1 -C10 alkylimino, arylimino
  • any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C 2 -C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like,
  • “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, alkyl including C 1 -C 6 alkyl, alkenyl including C 2 -C 6 alkenyl, alkynyl including C 2 -C 6 alkynyl, -C 1 - C 6 alkoxy, alkanoyl including C 2 -C 6 alkanoyl, C 1 -C 6 alkylester, (mono- and di-C 1 - C6alkylamino)Co-C 2 alkyl, haloalkyl including C 1 -C 6 haloalkyl, hydoxyC 1 -C 6 alkyl, ester, carbamate, urea, sulfonamide, -C 1 -C6alkyl(heterocyclo), C 1 -C6alkyl(heteroaryl), -C 1
  • the suitable group on a “substituted” or “optional substituted” position may be monovalent, divalent, or trivalent such that it forms a stable molecule and meets the desired purpose of the invention.
  • a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.
  • a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.
  • a group described herein that can be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.
  • “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions.
  • "aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl.
  • Unsaturated aliphatic groups can be in a cis or trans configuration.
  • the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.
  • the aliphatic group contains from 1 to about 8 carbon atoms.
  • the aliphatic group is C 1 - C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 or C 1 -C 6 .
  • the specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species.
  • C 1 - G> aliphatic indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 -C 4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.
  • heteroaliphatic refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaliphatic is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety.
  • Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O- haloalkyl, etc.
  • a “dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
  • a “dosage form” can also include an implant, for example an optical implant.
  • an “effective amount” as used herein means an amount which provides a therapeutic or prophylactic benefit.
  • moduleating mediating a detectable increase or decrease in the level of a response in a patient compared with the level of a response in the patient in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated patient.
  • the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a patient, preferably, a human.
  • parenteral administration of a pharmaceutical composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), intrastemal injection, or infusion techniques.
  • peptide polypeptide
  • protein protein
  • a protein or peptide must contain at least two amino acids, and the maximum number of amino acids present within the protein or peptide’s sequence is typically comparable to up to that found in nature.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds.
  • polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others.
  • the polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.
  • a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e. palliative treatment) or to decrease a cause or effect of the disease or disorder (i.e. disease-modifying treatment).
  • antiviral activity refers to the activity demonstrated by a compound against a virus in various assays used in the field to evaluate antiviral activity, such as cytopathic effect (CPE) assays, plaque reduction assays, VSV-pseudotyped neutralization assays, and qPCR assays.
  • CPE cytopathic effect
  • the antiviral activity of compounds of the invention are measured using a CPE assay, and in particular, antiviral activity against SARS-CoV-2 is determined using a CPE assay measuring the protection of A549 +ACE2 cells, which are lung epithelial cells engineered to constitutively express human angiotensin-converting enzyme-2 (ACE2), after infection with a SARS-CoV-2 strain, such as SARS-CoV2, USA/WA-1/2020 strain.
  • a non-limiting example of a CPE assay includes the assay described in Yan et al.
  • compositions are compositions comprising at least one active agent, and at least one other substance, such as a carrier.
  • “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
  • “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2) n - COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • Lists of additional suitable salts may be found, e.g
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a “pharmaceutically acceptable carrier” means a carrier or excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a patient, typically a human.
  • an excipient is used that is acceptable for veterinary use.
  • a “patient” or “subject” is a human or non -human animal in need of treatment or prevention of any of the disorders as specifically described herein, for example that is modulated by a natural (wild-type) or modified (non-wild type) protein that can be degraded according to the present invention, resulting in a therapeutic effect.
  • the word patient or subject typically refers to a human patient or subject unless it is clear from the context or wording that, the disclosure is meant to include a non-human animal.
  • the patient is a human.
  • the patient or subject is a non-human animal in need of such therapy and responsive thereto.
  • a “therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a patient, typically a human patient, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself.
  • a “prodrug” is a version of the parent molecule that is metabolized or chemically converted to the parent molecule in vivo, for example in a mammal or a human.
  • Non-limiting examples of prodrugs include esters, amides, for example off a primary or secondary amine, carbonates, carbamates, phosphates, ketals, imines, oxazolidines, and thiazolidines.
  • a prodrug can be designed to release the parent molecule upon a change in pH (for example in the stomach or the intestine) or upon action of an enzyme (for example an esterase or amidase). For example, when the parent molecule is:
  • NSP3 Targeting Ligands for use in degraders of the present invention include: In certain embodiments the NSP3 Targeting Ligand is selected from:
  • the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from:
  • the NSP3 Targeting Ligand is selected from: In certain embodiments the NSP3 Targeting Ligand is selected from:
  • NSP3 Targeting Ligand is selected from:
  • NSP3 Targeting Ligand is selected from:
  • the NSP3 targeting ligand is selected from
  • R 1 is hydrogen
  • R 1 is alkyl
  • R 1 is alkenyl
  • R 1 is alkynyl. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is halogen, wherein the halogen is F. In certain embodiments, R 1 is halogen, wherein the halogen is Cl. In certain embodiments, R 1 is halogen, wherein the halogen is Br. In certain embodiments, R 1 is halogen, wherein the halogen is I.
  • R 2 is hydrogen. In certain embodiments, R 2 is hydrogen, wherein the hydrogen is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is alkyl. In certain embodiments, R 2 is alkyl, wherein the alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is haloalkyl. In certain embodiments, R 2 is haloalkyl, wherein the haloalkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is alkenyl. In certain embodiments, R 2 is alkenyl, wherein the alkenyl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is alkynyl. In certain embodiments, R 2 is alkynyl, wherein the alkynyl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is aryl. In certain embodiments, R 2 is aryl, wherein the aryl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is heteroaryl. In certain embodiments, R 2 is heteroaryl, wherein the heteroaryl is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is heterocycle. In certain embodiments, R 2 is heterocycle, wherein the heterocycle is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 2 is C(O)R 9 . In certain embodiments, R 2 is C(O)R 9 , wherein C(O)R 9 is substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .
  • R 3 is hydrogen
  • R 3 is alkyl
  • R 3 is alkenyl
  • R 3 is alkynyl.
  • R 3 is halogen. In certain embodiments, R 3 is halogen, wherein the halogen is F. In certain embodiments, R 3 is halogen, wherein the halogen is Cl. In certain embodiments, R 3 is halogen, wherein the halogen is Br. In certain embodiments, R 3 is halogen, wherein the halogen is I.
  • R 4 is hydrogen
  • R 4 is alkyl. In certain embodiments, R 4 is alkenyl.
  • R 4 is alkynyl.
  • R 4 is halogen. In certain embodiments, R 4 is halogen, wherein the halogen is F. In certain embodiments, R 4 is halogen, wherein the halogen is Cl. In certain embodiments, R 4 is halogen, wherein the halogen is Br. In certain embodiments, R 4 is halogen, wherein the halogen is I.
  • R 3 and R 4 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle. In certain embodiments, R 3 and R 4 together with the carbon to which they are bound form a 3 -membered spirocarbocycle. In certain embodiments, R 3 and R 4 together with the carbon to which they are bound form a 4-membered spirocarbocycle. In certain embodiments, R 3 and R 4 together with the carbon to which they are bound form a 5- membered spirocarbocycle. In certain embodiments, R 3 and R 4 together with the carbon to which they are bound form a 6-membered spirocarbocycle.
  • R 3 and R 4 together with the carbon to which they are bound form a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.
  • R 3 and R 4 together with the carbon to which they are bound form a 4-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.
  • R 3 and R 4 together with the carbon to which they are bound form a 5-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.
  • R 3 and R 4 together with the carbon to which they are bound form a 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group.
  • R 5 is alkyl
  • R 5 is haloalkyl
  • R 5 is alkenyl
  • R 5 is alkynyl.
  • R 5 is halogen. In certain embodiments, R 5 is halogen, wherein the halogen is F. In certain embodiments, R 5 is halogen, wherein the halogen is Cl. In certain embodiments, R 5 is halogen, wherein the halogen is Br. In certain embodiments, R 5 is halogen, wherein the halogen is I.
  • R 5 is heteroaryl. In certain embodiments, R 5 is aryl. In certain embodiments, R 5 is heterocycle.
  • R 5 is cyano
  • R 5 is -NR 7 R 8 . In certain embodiments, R 5 is -NR 7 C(O)R 9 . In certain embodiments, R 5 is -NR 7 C(S)R 9 . In certain embodiments, R 5 is -NR 7 C(O)R 9 . In certain embodiments, R 5 is -NR 7 S(O)2R 9 .
  • R 5 is -OR 7 '
  • R 5 is -SR 7 . In certain embodiments, R 5 is -S(O)2R 9 .
  • R 5 is -C(O)R 9 .
  • At least one R 5 is oxo.
  • one R 5 is oxo.
  • two R 5 ’s are oxo.
  • Non-limiting examples of R 15 and R 16 include:
  • the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula: In certain embodiments, the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is of Formula:
  • the compound of the present invention is selected from: In certain embodiments the compound of the present invention is selected from:
  • the compound of the present invention is selected from:
  • R 16 is which is optionally substituted with
  • R 16 is which is optionally substituted with
  • R 16 is which is optionally substituted with
  • R 16 is R 12 .
  • R 16 is which is optionally substituted with
  • R 17 is which is optionally substituted with
  • R is 12 which is optionally substituted with
  • R is 12 which is optionally substituted with
  • R is 12 which is optionally substituted with
  • R 18 is which is optionally substituted with
  • R 18 is which is optionally substituted with, 2, 3, or 4 substituents independently selected from R 5 .
  • R 18 is which is optionally substituted with, 2, 3, or 4 substituents independently selected from R 5 .
  • R 27 is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R 29 .
  • R 27 is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R 29 .
  • R 27 is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R 29 .
  • R 27 is which is optionally substituted with 1, 2,, or 4 substituents independently selected from R 29 .
  • R 28 is which is optionally substituted with 1, 2,
  • R 28 is which is optionally substituted with 1, 2,
  • each Y is independently selected from N, CH, or CR 5 , wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound.
  • each Y is independently selected from N, CH, or CR 5 , wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound.
  • Y is independently selected from N, CH, or CR 5 , wherein 0, 1, 2, 3, or 4 (as context allows) instances of Y are selected to be N and are selected to produce a stable ring as well known to those skilled in the art and that forms a pharmaceutically acceptable compound. Examples when present in a compound of the present invention include the following:
  • Examples when present in a compound of the present invention include:
  • a compound of Formula A is provided: or a pharmaceutically acceptable salt, A-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition; wherein:
  • Heterocyclic Moiety is selected from:
  • Q is CH 2 , NR 2 , O, or S;
  • X 3 , X 4 , X 5 , and X 6 are independently selected from N, CH, and CR 5 , wherein one of X 3 , X 4 , X 5 , and X 6 is a carbon atom that is attached to Linker;
  • R 1 , R 3 , R 4 , and R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen; or R 3 and R 4 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S, or an oxo group; or R 1 and R 6 are combine together to form a 1 or 2-carbon bridge; for example
  • each R 2 is selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, and -C(O)R 9 , each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;
  • each R 5 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , -C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 ,
  • R 16 is selected from: independently selected from R 5 ;
  • R 17 is selected from: independently selected from R 5 ;
  • R 18 is selected from: and each of which R 18 is optionally substituted with 1, 2, 3, or 4 substituents independently selected
  • Cycle is a fused aryl or heteroaryl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 and substituted with 1 R 12 substituent;
  • Spirocycle is a cycloalkyl, cycloalkene, or heterocycle group optionally substituted with 1,
  • R 12 is the attachment point to Linker
  • R 7 and R 8 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle; and C(O)R 14 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ; each R 9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -NR 7 R 8 , -OR 7 , and -SR 7 each of which is optionally substituted with 1, 2,
  • each R 10 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 11 R 13 , -OR 11 , -SR 11 , -C(O)R 14 , -C(S)R 14 , -S(O)R 14 , -S(O) 2 R 14 , -OC(O)R 14 , -OC(S)R 14 , -OS(O)R 14 , -OS(O) 2 R 14 , -NR 11 C(O)R 14 , -NR 11 C(S)R 14 , -NR 11 S(O)R 14 , -NR 11 S(O) 2 R 14 , -P(O)(R 14 ) 2 , -NR 11 P(O)(R 14 ) 2 , and -OP(O)(
  • R 11 and R 13 at each instance are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -C(O)R 14 , -C(S)R 14 , -S(O)R 14 ,
  • each R 14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 each of which except hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 15 ;
  • each R 15 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl) 2 ;
  • NSP3 Targeting Ligand is selected from:
  • y is 0 or 1
  • Fused Cycle is a fused aryl, heteroaryl, cycloalkyl, or heterocycle group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 ;
  • X 17 is selected from CR 33 R 34 , C(O), C(S), S(O), and S(O) 2 ; each x is independently 0, 1, 2, 3, or 4;
  • X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 15 are independently selected from N, CH, and CR 28 ;
  • each R 28 , R 29 , and R 30 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocycle, cyano, nitro, -NR 7 R 8 , -OR 7 , -SR 7 , -C(O)R 9 , - C(S)R 9 , -S(O)R 9 , -S(O) 2 R 9 , -OC(O)R 9 , -OC(S)R 9 , -OS(O)R 9 , -OS(O) 2 R 9 , -SC(O)R 9 , -OS(O) 2 R 9 , -NR 7 C(O)R 9 , -NR 7 C(S)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O)R 9 , -NR 7 S(O) 2
  • X 1 and X 2 are independently at each occurrence selected from bond, heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S;
  • R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of bivalent moieties selected from bond alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 26 )O-, -P(O)(OR 26 )-, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ;
  • R 26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic and heteroaliphatic; and
  • R 40 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl) 2 , -NHSO 2 (aliphatic, including alkyl), -N(aliphatic, including alkyljSChalkyl, -NHSChtaryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSChalkenyl, -N(alkyl)SO2alkenyl, -NHSChalkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl.
  • Ligand is selected from:
  • a compound of any one of embodiments 1-113 that has antiviral activity EC50 less than 1 pM is provided.
  • a pharmaceutical composition comprising an effective amount of a compound of any one of embodiments 1-114 and a pharmaceutically acceptable excipient is provided.
  • a method of treating a coronavirus comprising administering an effective amount of a compound of any one of embodiments 1-114 or a pharmaceutical composition of embodiment 115 is provided.
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from: y y s selected from: . 5 158
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from: In certain embodiments the Heterocyclic Moiety is selected from:
  • the Heterocyclic Moiety is selected from wherein Fused Cycle A, Fused Cycle B, and Fused Cycle C are independently selected from fused aryl, heteroaryl, cycloalkyl, and heterocycle each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 .
  • the Heterocyclic Moiety is selected from In certain embodiments Fused Cycle A is pyrrole.
  • Fused Cycle A is imidazole.
  • Fused Cycle A is pyrazole.
  • Fused Cycle A is pyrrolidine.
  • Fused Cycle A is pyrrolidone. In certain embodiments Fused Cycle B is phenyl.
  • Fused Cycle B is pyridine.
  • Fused Cycle C is phenyl
  • Fused Cycle C is pyridine.
  • Heterocyclic Moiety or Heterocyclic Moiety B is selected from In certain embodiments Heterocyclic Moiety B is selected from In certain embodiments the compound of the present invention is selected from:
  • Linker is included in the compounds of the present invention, such as described in Formula A.
  • Linker is a bond or a chemically stable bivalent group that covalently attaches the Heterocyclic Moiety to the selected NSP3 Targeting Ligand.
  • Linker can be any chemically stable group that attaches the Heterocyclic Moiety to the NSP3 Targeting Ligand.
  • Linker has a chain of
  • the chain has 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms of which one or more carbon atoms can be replaced by a heteroatom such as O, N, S, or P, as long as the resulting molecule has a stable shelf life for at least two months, three months, six months, or one year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable.
  • the chain has 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 contiguous atoms in the chain.
  • the chain may include 1 or more ethylene glycol units, and in some embodiments, may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more contiguous, partially contiguous, or non-contiguous ethylene glycol the Linker. In certain embodiments, the chain has at least 1, 2,
  • each branch has 10, 8, 6, 4, 3, 2, or 1 carbon.
  • the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and/or glycolic acid.
  • propylene glycol adds hydrophobicity, while propylene glycol adds hydrophilicity.
  • Lactic acid segments tend to have a longer half-life than glycolic acid segments.
  • Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity.
  • these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve the appropriate drug properties.
  • moieties such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve the appropriate drug properties.
  • the compound of the present invention has one or more exit vectors that appropriately orients the NSP3 Targeting Ligand and/or E3 ligase ligand (heterocyclic moiety) to improve properties of the compound for example to increase binding potency or ternary complex formation.
  • X 16 is an exit vector for the NSP3 Targeting Ligand.
  • a compound of the present invention has more than one exit vector.
  • X 1 or X 2 is an exit vector for the E3 ligase ligand.
  • the exit vector may make interactions with the protein it exits and/or may direct the linker portion and targeting ligand portion of the molecule at appropriate angles to allow formation of the ternary complex comprising the NSP3 Protein, compound of the present invention, and cereblon.
  • Linker is selected from wherein all variables are defined as above.
  • the linker includes In certain embodiments the linker includes
  • the linker includes or
  • the linker includes or
  • the linker includes In certain embodiments the linker includes
  • Linker includes:
  • Linker is selected from: In one embodiment X 1 is attached to the NSP3 Targeting Ligand. In another embodiment X 2 is attached to the NSP3 Targeting Ligand.
  • Non-limiting examples of moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include:
  • Additional non-limiting examples of moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include: Additional non-limiting examples of moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include: , Inadditionalembodiments,theLinkerisanoptionallysubstituted(poly)ethyleneglycol havingatleast1,atleast2,atleast3,atleast4,atleast5,atleast6,atleast7,atleast8,atleast9, atleast10,ethyleneglycolunits,oroptionallysubstitutedalkylgroupsinterspersedwithoptionally substituted,O,N,S,PorSiatoms.Incertainembodiments,Linkerisflanked,substituted,or interspersed with an aryl,phenyl, benzyl, alkyl,alkylene, or heterocycle group.
  • Linker maybeasymmetricorsymmetrical.Insomeembodiments,Linkerisa substitutedorunsubstitutedpolyethyleneglycolgroupranginginsizefromabout1toabout12 ethyleneglycolunits,between1andabout10ethyleneglycolunits,about2about6ethylene glycolunits,betweenabout2and5ethyleneglycolunits,betweenabout2and4ethyleneglycol units.Inanyoftheembodimentsofthecompoundsdescribedherein,Linkergroupmaybeany suitablemoietyasdescribedherein.
  • Linker isselectedfrom: -NR 61 (CH2)n1-(loweralkyl)-,-NR 61 (CH2)n1-(loweralkoxyl)-, -NR 61 (CH 2 ) n1 -(loweralkoxyl)-OCH 2 -,-NR 61 (CH 2 ) n1 -(loweralkoxyl)-(loweralkyl)-OCH 2 -, -NR 61 (CH 2 ) n1 -(cycloalkyl)-(loweralkyl)-OCH 2 -,-NR 61 (CH 2 ) n1 -(heterocycloalkyl)-, -NR 61 (CH2CH2O)n1-(loweralkyl)-O-CH2-,-NR 61 (CH2CH2O)n1-(heterocycloalkyl)-O-CH2-, -NR 61 (CH2CH2O)n1-(hetero
  • R 61 is H, methyl, or ethyl.
  • Linker is selected from: -N(R 61 )-(CH2) m1 -O(CH2) n2 -O(CH2) o1 -O(CH2) p1 -O(CH2) q1 -O(CH 2 ) r1 -OCH2-,
  • Linker is selected from:
  • Linker is selected from: , 10 , 15 , 198
  • Linker is selected from: , 199 d 5 , , 10 , 5 10
  • Linker is selected from: 5 , 210
  • Linker is selected from: , 10 211
  • Linker is selected from: 10 , 212
  • Linker is selected from: 5 , , , , and . In certain embodiments, Linker is selected from: , 10 In certain embodiments Linker is selected from: 15 , , , 213
  • Linker can be a 4-24 carbon atom linear chains, wherein one or more the carbon atoms in the linear chain can be replaced or substituted with oxygen, nitrogen, amide, fluorinated carbon, etc., such as the following: , 15 , , 214
  • Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties.
  • Linker may include contiguous, partially contiguous or non- 10 contiguous ethylene glycol unit groups ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.
  • Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 15 fluorine substituents.
  • Linker is perfluorinated.
  • Linker is a partially or fully fluorinated poly ether.
  • fluorinated Linker moieties include: , 20 216
  • Additional non-limiting examples of moieties of R 20 , R 21 , R 22 , R 23 , and R 24 include: 10 217
  • a compound of the invention such as a compound of Formula A, can be used in an effective amount to treat a host, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier to treat a coronavirus described herein.
  • the method comprises administering an effective amount of a 20 compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, i.e., a pharmaceutically acceptable composition, optionally in combination with another bioactive agent or combination of agents.
  • a compound of the present invention is used to treat a SARS-CoV- 2 variant.
  • a compound of the present invention is used to treat SARS-CoV- 25 2 alpha variant.
  • a compound of the present invention is used to treat a 218
  • SARS-CoV-2 beta variant In certain embodiments a compound of the present invention is used to treat a SARS-CoV-2 gamma variant. In certain embodiments a compound of the present invention is used to treat a SARS-CoV-2 delta variant. In certain embodiments a compound of the present invention is used to treat a SARS-C-V-2 omicron variant. 5 In certain embodiments a compound of the present invention is used to treat a coronavirus variant for example a SARS-CoV-2 variants selected from alpha, beta, gamma, delta, epsilon, eta, iota, kappa, mu, omicron, and zeta.
  • Non limiting examples of SARS-CoV-2 alpha variants include B.1.1.7 and Q.1-Q.8.
  • Non limiting examples of SARS-CoV-2 beta variants include B.1.351, B.1.351.2, and B.1.351.3.
  • Non limiting examples of SARS-CoV-2 gamma variants include P.1, 10 P.1.1, and P.1.2.
  • Non limiting examples of SARS-CoV-2 delta variants include B.1.617.2 and AY.1.
  • Non limiting examples of SARS-CoV-2 epsilon variants include B.1.427 and B.1.429.
  • Non limiting examples of SARS-CoV-2 eta variants include B.1.525.
  • Non limiting examples of SARS- CoV-2 iota variants include B.1.526.
  • Non limiting examples of SARS-CoV-2 kappa variants include B.1.617.1.
  • Non limiting examples of SARS-CoV-2 mu variants include B.1.621 and 15 B.1.621.1.
  • Non limiting examples of SARS-CoV-2 zeta variants include P.2. .
  • Non limiting examples of SARs-CoV2 omicron variants include B.1.1.529 and sub-lineage variants BA.1, BA.2, BA.2.12.1, BA.2.75, BA.3, BA.4, and BA.5.
  • a compound of the present invention is used to treat a coronavirus other than SARS-CoV-2.
  • coronaviruses include:, Severe Acute20 Respiratory Syndrome coronavirus (SARS-CoV), Bat SARS-like coronavirus WIV1 (Bat SL- CoV-WIVl), alpha coronaviruses 229E (HCoV-229E), New Haven coronavirus NL63 (HCoV- NL63), beta coronaviruses OC43 (HCoV-OC43), coronavirus HKIJ I (HCoV-HKU l ), and Middle East Respiratory Syndrome coronavirus (MERS-CoV).
  • SARS-CoV Severe Acute20 Respiratory Syndrome coronavirus
  • Bat SARS-like coronavirus WIV1 Bat SARS-like coronavirus WIV1
  • alpha coronaviruses 229E HoV-229E
  • New Haven coronavirus NL63 HCoV- NL63
  • beta coronaviruses OC43 HCoV-OC43
  • a compound of the present invention is used to treat a new 25 coronavirus that has not yet been discovered or has not infected an appreciable number of people.
  • a selected compound of the present invention can be administered as the neat chemical, but is often administered as a pharmaceutical composition, that includes an effective amount for a 30 host, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective 219
  • the pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent. 5
  • the pharmaceutical composition is in a dosage form that contains from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 800 mg, from about 1 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • Examples are dosage forms with at least about, or no more than, 0.001, 0.005, 0.010, 0.10, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt.
  • Compounds disclosed herein may be administered orally, topically, systemically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including 15 intravenous, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as a solid dosage form, liquid, an aerosol, a cream, a gel, a pill, an injection or infusion 20 solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration in an effective amount to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, 220
  • compositions/combinations can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the compound and usually at least about 5 10 wt.% of the compound.
  • Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound.
  • the LNP contains a cationic or ionizable limit. Examples include but are not limited to: U.S. Patent Publication Nos. 20060083780 and 20060240554; U.S. Pat. Nos.5,208,036; 5,264,618; 5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication 15 No. WO 96/10390, the disclosures of which are each herein incorporated by reference in their entirety for all purposes.
  • Formulations suitable for rectal administration are sometimes presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. 20 Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Formulations suitable for transdermal administration may be presented as discrete patches 25 adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and sometimes take the form of an optionally buffered aqueous solution of the active compound.
  • microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly 30 the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
  • Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
  • DPI dry powder inhalers
  • the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
  • nebulizers include jet 5 nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers.
  • Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. VII. GENERAL SYNTHESIS 10
  • the compounds described herein can be prepared by methods known by those skilled in the art.
  • the disclosed compounds can be made using the schemes below.
  • Compounds of the present invention with stereocenters may be drawn without stereochemistry for convenience.
  • One skilled in the art will recognize that pure enantiomers and 15 diastereomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following: i) physical separation of crystals – a technique whereby macroscopic crystals of the individual enantiomers are manually separated.
  • This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and 20 the crystals are visually distinct; ii) simultaneous crystallization – a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the enantiomer is a conglomerate in the solid state; iii) enzymatic resolutions – a technique whereby partial or complete separation of a 25 racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis – a synthetic technique whereby at least one step in the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; 30 v) chemical asymmetric synthesis – a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce 222
  • asymmetry i.e. chirality
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations – a technique whereby 10 diastereomers from the racemate quickly equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer of where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomers.
  • the desired enantiomer is 15 then released from the diastereomer; viii) kinetic resolutions – this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; 20 ix) enantiospecific synthesis from non-racemic precursors – a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography – a technique whereby the enantiomers of a racemate 25 are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including vial chiral HPLC).
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography – a technique whereby the racemate is volatilized and 30 enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; 223
  • the barrier may separate two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through; 10 xiv) simulated moving bed chromatography is used in one embodiment.
  • Step-3 15 To the stirred solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (4, 200 g, 419.85 mmol) in DMF (800 mL) was added 1,1'-carbonyldiimidazole (177.00 g, 1.09 mol) at 25- 35°C with observed exothermicity. Initial temperature 25°C was monitored with the final temperature of 35°C noted at 15 minutes. The reaction was stirred for 14 hours at room temperature. The reaction was charged into water (420 mL) at room temperature. Precipitation was 20 formed and the mixture was stirred for 3 hours.
  • Step-4 25 To a stirred solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (5, 108 g, 214.99 mmol) in DMF (1000 mL) was added sodium hydride (60% dispersion in mineral oil) (14.83 g, 644.96 mmol) portion-wise at 0-28°C. The reaction mixture was stirred for 1 hour, followed by dropwise addition of methyl iodide (stored over copper) (31.16 g, 214.99 mmol, 13.37 mL) over half an hour. The reaction mixture was diluted with ice cold water, and the resulting 30 solid was obtained, filtered, and dried over vacuum. The solid was extracted with ethyl acetate, then washed with brine, dried over sodium sulfate, and concentrated to dryness. The crude 226
  • Step-5 5 To a solution of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (6, 20 g, 38.73 mmol) in 1,4-dioxane (160 mL) and water (40 mL) was added sodium carbonate (12.32 g, 116.19 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (7, 15.57 g, 50.35 mmol).
  • the reaction was purged with nitrogen for 20 minutes, then charged with palladium (0) tetrakis(triphenylphosphine) (2.24 g, 1.94 mmol) and 10 heated to 90-100 °C for 5 hours.
  • the reaction was cooled to room temperature and filtered through a Celite bed and washed with EtOAc. The filtrate was distilled completely under vacuum at 45 °C.
  • the crude product was dissolved in EtOAc (15 V) and separated with water (10 V). The organic layer was washed with water (5 V), brine (5 V), then dried over anhydrous Na2SO4.
  • Step-6 To a solution of tert-butyl 4-[1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-2-oxo-benzimidazol-5-yl]- 20 3,6-dihydro-2H-pyridine-1-carboxylate (8, 40 g, 64.65 mmol) in methanol (1600 mL) was added 10% palladium on carbon, type 487, dry (12.00 g, 112.76 mmol) and nickel (12.00 g, 204.45 mmol). The reaction was heated at 60-65 °C under hydrogen atmosphere (10 kg) for 16 hours. The reaction mixture was then cooled to room temperature, filtered, and washed with DCM and MeOH.
  • Step-7 To a stirred solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5- yl]piperidine-1-carboxylate (9, 1.6 g, 3.62 mmol) in DCM (30 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (16.00 mL) at 26 °C . The resulting reaction mixture was stirred at 26 5 °C for 3 hours.
  • Step-8 10 To a stirred solution of 3-[3-methyl-2-oxo-5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (10, 1 g, 2.64 mmol) in DMF (10 mL) was added tert-butyl 2-bromoacetate (11, 617.83 mg, 3.17 mmol, 464.53 ⁇ L) at 26 °C and stirred for 10 minutes before N,N- diisopropylethylamine (2.73 g, 21.12 mmol, 3.68 mL) was added. The resulting reaction mixture was stirred at 26 °C for 1.5 hour.
  • Step-9 20 To a stirred solution of tert-butyl 2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 5-yl]-1-piperidyl]acetate (12, 1.0 g, 2.19 mmol) in DCM (34.00 mL) was added 4 M hydrogen chloride in 1,4-dioxane, 99% (40.00 mL) at 26 °C. The resulting reaction mixture was stirred at 26 °C for 20 hours.
  • Step 2 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1-10 (2,6-dibenzyloxy-3-pyridyl)-6-fluoro-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H- pyridine-1-carboxylate (3, 350 mg, 0.423 mmol) in anhydrous 1,4-dioxane (2 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (326.93 mg, 0.465 mmol) at ambient temperature.
  • reaction mixture was stirred at this temperature for 16 h under hydrogen atmosphere. After completion of the reaction, the reaction mixture was passed through a pad of 15 Celite and the Celite bed was washed with a mixture of 1:1 THF:DMF (200 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)-6-fluoro-3- methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (4, 200 mg, 0.402 mmol, 95% yield) as a grey solid.
  • Step 3 20 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate (4, 200.32 mg, 0.402 mmol) in anhydrous DCM (1.5 mL) was added 4M HCl in 1,4-dioxane (1.21 mL) at 0 °C. The reaction was stirred at ambient temperature for 2 h.
  • Step-2 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]piperidine-1-carboxylate20 (2, 200 mg, 433.70 ⁇ mol) in anhydrous DCM (2.5 mL) was added 4.0 M hydrochloric acid in 1,4- 233
  • Step-3 To a 25 mL round-bottom flask containing a well-stirred solution of 1-methyl-3-[3-methyl-2-oxo- 5-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (3, 160 mg, 403.18 ⁇ mol) in anhydrous DMF (2 mL) at 0 °C were added N,N-diisopropylethylamine (114.64 mg, 886.99 ⁇ mol, 10 154.50 ⁇ L) and tert-butyl bromoacetate (4, 94.37 mg, 483.81 ⁇ mol, 70.95 ⁇ L) under nitrogen atmosphere.
  • N,N-diisopropylethylamine 114.64 mg, 886.99 ⁇ mol, 10 154.50 ⁇ L
  • tert-butyl bromoacetate 94.37 mg, 483.81 ⁇ mol, 70.95 ⁇ L
  • Step-4 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 2-[4- [3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]-1-piperidyl]acetate (5, 20 160 mg, 299.22 ⁇ mol) in DCM (5 mL) was added hydrogen chloride (4 M solution in 1,4-dioxane, 5 mL, 20 mmol) under nitrogen atmosphere and the resulting solution was stirred at room temperature for 4 hours.
  • Step-2 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 4-(4,4- dimethoxybutyl)pyridine (3, 3.6 g, 17.88 mmol) in anhydrous MeOH (60 mL) and AcOH (0.2 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (3.84 g, 5.46 mmol) at 10 ambient temperature. The resulting mire was stirred at this temperature for 16 h under hydrogen atmosphere ( ⁇ 1 atm). After complete consumption of starting material, the reaction mixture was passed through a Celite pad and the Celite pad was washed with MeOH (150 mL).
  • Step-3 To a 250 mL sealed tube containing a well-stirred solution of 4-(4,4-dimethoxybutyl)piperidine (4, 795.26 mg, 3.91 mmol) and 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol- 2-one (5, 1.7 g, 3.26 mmol) in dry 1-4-dioxane (30 mL) was added cesium carbonate (2.65 g, 8.15 mmol) and reaction mixture was purged with nitrogen gas for 5 minutes.
  • RuPhos 20 (152.08 mg, 0.326 mmol) and RuPhos-Pd-G3 (272.59 mg, 0.326 mmol) were added and the reaction mixture was heated at 110 °C for 16 h.
  • reaction mixture was cooled to ambient temperature, filtered through a pad of Celite and Celite bed was washed with EtOAc (100 mL) and combined filtrate was concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (60-120 mesh; 50 g silica gel, 0-80% EtOAc in25 petroleum ether) to afford 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(4,4-dimethoxybutyl)-1-piperidyl]- 3-methyl-benzimidazol-2-one (6, 1.1 g, 1.64 mmol, 50% yield) as a brown gum.
  • Step-4 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 1-(2,6- 30 dibenzyloxy-3-pyridyl)-5-[4-(4,4-dimethoxybutyl)-1-piperidyl]-3-methyl-benzimidazol-2-one (6, 1.1 g, 1.64 mmol) in anhydrous 1,4-dioxane (35 mL) was added palladium hydroxide on carbon, 236
  • Step-5 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 3-[5-[4-(4,4- 10 dimethoxybutyl)-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (7, 140 mg, 0.262 mmol,) in anhydrous DCM (2.81 mL) was added 4M HCl in 1,4-dioxane (1.31 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h.
  • Step-2 To a 500 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl- 15 dimethyl-[5-(4-pyridyl)pentoxy]silane (3, 5 g, 15.92 mmol) in anhydrous MeOH (120 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (4 g, 5.70 mmol) and acetic acid (956.13 mg, 15.92 mmol, 0.911 mL) at ambient temperature. The reaction mixture was stirred at this temperature for 16 h under hydrogen gas (bladder ⁇ 1 atm pressure).
  • Step-3 To a 500 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl- 25 dimethyl-[5-(4-piperidyl)pentoxy]silane (4, 4.5 g, 15.60 mmol) in THF (80 mL) was added 239
  • Step-4 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-[5- [tert-butyl(dimethyl)silyl]oxypentyl]piperidine-1-carboxylate (5, 6.8 g, 13.92 mmol) in anhydrous THF (60 mL) was added TBAF (27.85 mL; 1M/THF) at 0 °C and stirring was continued at ambient 15 temperature for 3 h. After completion, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2 ⁇ 400 mL).
  • Step-5 To a 10 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-(5- hydroxypentyl)piperidine-1-carboxylate (6, 2 g, 6.48 mmol) in anhydrous DCM (20 mL) was added mixture of pyridinium chlorochromate (2.10 g, 9.72 mmol) and Celite (4 g) at 0 °C under 25 nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h.
  • Step-6 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-(5- oxopentyl)piperidine-1-carboxylate (7, 1.9 g, 6.2 mmol) in anhydrous MeOH (20 mL) were added 4-methylbenzenesulfonic acid; hydrate (235.85 mg, 1.24 mmol) and trimethyl orthoformate 5 (3.29 g, 31.00 mmol, 3.40 mL) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 2 h. After completion, the reaction mixture was poured into water (50 mL) and stirred for 5 minutes.
  • Step-7 15 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of benzyl 4-(5,5- dimethoxypentyl)piperidine-1-carboxylate (8, 2.0 g, 4.58 mmol) in anhydrous MeOH (40 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (2.0 g, 2.85 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 h under hydrogen atmosphere ( ⁇ 1 atm). After completion, the reaction mixture was passed through a Celite pad and 20 Celite bed was washed with MeOH (100 mL).
  • Step-8 To a 100 mL sealed tube containing a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy-3-25 pyridyl)-6-fluoro-3-methyl-benzimidazol-2-one (10, 920 mg, 1.34 mmol) and 4-(5,5- dimethoxypentyl)piperidine (9, 438.13 mg, 2.01 mmol) in dry 1,4-dioxane (30 mL) was added cesium carbonate (1.09 g, 3.36 mmol) and the reaction mixture was purged with nitrogen for 5 minutes.
  • Step-9 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 1-(2,6- dibenzyloxy-3-pyridyl)-5-[4-(5,5-dimethoxypentyl)-1-piperidyl]-6-fluoro-3-methyl- benzimidazol-2-one (11, 400 mg, 0.520 mmol) in anhydrous 1,4-dioxane (20 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (900 mg, 1.28 mmol) at ambient temperature. 10 The resulting mixture was stirred at this temperature for 16 h under hydrogen gas ( ⁇ 1 atm).
  • reaction mixture was passed through a pad of Celite and Celite bed was washed with 1,4-dioxane (200 mL) and combined filtrate was concentrated under reduced pressure.
  • the obtained crude was washed with MTBE (20 mL) and further purified by reverse phase C18 column chromatography (0.1% ammonium bicarbonate in water: ACN) to afford 3-[5-[4-(5,5- 15 dimethoxypentyl)-1-piperidyl]-6-fluoro-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (12, 60 mg, 0.111 mmol, 21% yield) as an off-white solid.
  • Step-2 To a 500 mL single-neck round-bottom flask containing a well-stirred solution of 5-fluoro-N- methyl-2-nitro-aniline (2, 8.5 g, 46.96 mmol) in DMF (250 mL) was added N,N-15 diisopropylethylamine (30.35 g, 234.81 mmol, 40.90 mL) followed by tert-butyl piperidine-4- 243
  • Step-3 10 To a stirred solution of tert-butyl 1-[3-(methylamino)-4-nitro-phenyl]piperidine-4-carboxylate (4, 8 g, 22.16 mmol) in THF (200 mL) was added 10% palladium on carbon (9.43 g, 8.86 mmol). The reaction mixture was stirred at rt for 16 h under H2 atmosphere. After consumption of the starting material, the reaction mixture was filtered through a pad of Celite, which was washed with THF:dioxane (300 mL).
  • Step-4 To a 1 L single-neck round-bottom flask containing a stirred solution of tert-butyl 1-[4-amino-3- (methylamino)phenyl]piperidine-4-carboxylate (5, 6.5 g, 19.85 mmol) in THF (400 mL) was 20 added di(imidazol-1-yl)methanone (6, 6.44 g, 39.71 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 ⁇ 400 mL).
  • Step-5 To a 500 mL three-neck round-bottom flask containing well stirred solution of tert-butyl 1-(3- 30 methyl-2-oxo-1H-benzimidazol-5-yl)piperidine-4-carboxylate (7, 2.5 g, 7.39 mmol) in anhydrous THF (100 mL) was added sodium hydride (60% dispersion in mineral oil, 4.14 g, 244
  • Step-6 10 To a 100 mL single-neck round-bottom flask containing well stirred solution of tert-butyl 1-[1- (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carboxylate (9, 500 mg, 1.10 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in dioxane (274.40 ⁇ L) at room temperature. The resulting mixture was stirred at room temperature for 1 h.
  • Example 12 Synthesis of 1-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5- yl]piperidine-4-carboxylic acid To a 50mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[1- 25 (2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carboxylate (1, 250 mg, 245
  • Step-2 To a 25 mL single-neck round-bottom flask containing well-stirred solution of tert-butyl 1-[3- 10 methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]piperidine-4-carboxylate (2, 100 mg, 219.04 ⁇ mol) in anhydrous DCM (2 mL) was added 4 M HCl in dioxane (1.10 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h.
  • Step-2 To a 50 mL sealed tube containing a well-stirred solution of 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-3-ethyl-benzimidazol-2-one (2, 720 mg, 1.28 mmol) and tert-butyl piperidine-4- carboxylate (3, 565.83 mg, 2.55 mmol) in anhydrous 1,4-dioxane (6 mL) was added cesium 247
  • reaction mixture was degassed with N 2 for 10 minutes.
  • RuPhos-Pd-G3 106.85 mg, 0.127 mmol was added and the resulting mixture was degassed with N2 for another 5 minutes.
  • the reaction mixture was stirred at 110 °C for 16 h. After completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed 5 was washed with EtOAc (150 mL).
  • Step-3 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[1- (2,6-dibenzyloxy-3-pyridyl)-3-ethyl-2-oxo-benzimidazol-5-yl]piperidine-4-carboxylate (4, 600 mg, 0.935 mmol) in anhydrous 1,4-dioxane (6 mL) was added palladium hydroxide on carbon, 20 wt.% 50% water (1.18 g, 1.68 mmol) at ambient temperature. The reaction mixture was stirred at 15 this temperature for 16 h under hydrogen atmosphere.
  • Step-4 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[1- (2,6-dioxo-3-piperidyl)-3-ethyl-2-oxo-benzimidazol-5-yl]piperidine-4-carboxylate (5, 500 mg, 0.964 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in 1,4-dioxane (2.41 mL) at 0 °C. The reaction mixture was stirred for 2 h at ambient temperature.
  • tert-butyl piperazine- 1-carboxylate (2, 3.68 g, 19.76 mmol) in anhydrous DMF (15 mL) was added at 0 °C and stirring 10 was continued at room temperature for 3 hours. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to get the crude compound. To this crude compound 1:1 mixture of MTBE and petroleum ether (50 mL) was added to get a solid that was filtered and dried 249
  • Step-2 5 To a 100 mL sealed-tube containing a well-stirred solution of tert-butyl 4-(2,5-difluoro-4-nitro- phenyl)piperazine-1-carboxylate (3, 4 g, 11.53 mmol) in 1,4-dioxane (30 mL) were added methylamine hydrochloride (1.17 g, 17.30 mmol) and N,N-diisopropylethylamine (4.47 g, 34.60 mmol, 6.03 mL) at room temperature. The reaction mixture was heated at 90 °C for 18 hours. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (250 mL).
  • Step-4 25 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- amino-2-fluoro-5-(methylamino)phenyl]piperazine-1-carboxylate (5, 2.8 g, 7.42 mmol) in THF (30 mL) was added 1,1'-carbonyldiimidazole (3.21 g, 22.27 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Afterwards, solvent was evaporated, and the residue was partitioned between water and DCM. The organic layer was 30 separated, and the aqueous layer was extracted with DCM (2 ⁇ 200 mL). The combined organic layers were washed with water and dried over sodium sulfate to get the crude material that was 250
  • Step-5 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-(6- fluoro-3-methyl-2-oxo-1H-benzimidazol-5-yl) piperazine-1-carboxylate (6, 500 mg, 1.36 mmol) in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 727.21 mg, 18.98 mmol) at 0 °C in three portions over 5 min interval and stirred at room temperature for 1 hr.
  • Step-6 20 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- (2,6-dioxo-3-piperidyl)-6-fluoro-3-methyl-2-oxo-benzimidazol-5-yl] piperazine-1-carboxylate (8, 450 mg, 955.61 ⁇ mol) in DCM (7 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 4.78 mL) at room temperature under nitrogen atmosphere. The resultant mixture was stirred at room temperature for 3 hours.
  • reaction mixture was stirred at this temperature for 16 h under hydrogen atmosphere ( ⁇ 1 atm). Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with mixture of 1:1 THF: DMF (50 mL). The filtrate was concentrated under reduced pressure to get tert-butyl N-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2- oxo-benzimidazol-5-yl]propyl]-N-methyl-carbamate (4, 35 mg, 0.081 mmol, 79% yield) as an off- 10 white solid.
  • Step-3 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl N-[3- [1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]-N-methyl-carbamate (4, 35.35 mg, 0.081 mmol) in DCM (0.5 mL) was added 4 M HCl in 1,4-dioxane (0.203 mL) at 0 °C. 15 After completion of the addition, the resulting mixture was stirred at ambient temperature for 2 h.
  • Step-1 To a 50 mL sealed tube containing a well-stirred solution of 4-bromo-1-(2,6-dibenzyloxy-3- pyridyl)-3-methyl-benzimidazol-2-one (1, 0.5 g, 0.803 mmol) in anhydrous acetonitrile (5 mL) were added hex-5-yn-1-ol (2, 157.75 mg, 1.61 mmol, 0.179 mL) and triethylamine (243.97 mg, 10 2.41 mmol, 0.336 mL).
  • reaction mixture was purged with nitrogen gas for 5 minutes, then added copper iodide (15.31 mg, 0.08 mmol) and dichloropalladium;triphenylphosphane (56.41 mg, 0.08 mmol).
  • the resulting reaction mixture was purged again with nitrogen gas for 2 minutes and then stirred at 90 °C for 10 h.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic phase was dried 15 over anhydrous Na2SO4 and filtered.
  • Step-2 To a 50 mL single-neck round-bottom flask containing a stirred solution of 1-(2,6-dibenzyloxy-3- pyridyl)-4-(6-hydroxyhex-1-ynyl)-3-methyl-benzimidazol-2-one (3, 0.42 g, 0.643 mmol) in 1,4- 254
  • Step-3 10 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of 3-[4-(6- hydroxyhexyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (4, 0.24 g, 0.66 mmol) in anhydrous DCM (10 mL) was added (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl) acetate (513.93 mg, 1.21 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 12 h.
  • Step-2 In a 250 mL single-neck round-bottom flask, a well-stirred solution of 2-(5-bromo-3-methyl-2- oxo-benzimidazol-1-yl)propanenitrile (3, 1 g, 3.57 mmol) in tetrahydrofuran (40 mL) was cooled to -78 °C.
  • Step-3 To a 250 ml single-neck round bottom flask containing a stirred solution of methyl 4-(5-bromo-3- methyl-2-oxo-benzimidazol-1-yl)-4-cyano-pentanoate (5, 4 g, 10.92 mmol) in THF (40 mL) and 20 water (20 mL) was added lithium hydroxide monohydrate (2.29 g, 54.61 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for 3 hr. After completion of the reaction, 30 ml of water was added and the reaction mixture was extracted with ethyl acetate (2 ⁇ 40 ml).
  • Step-4 To a 40 mL screw-capped vial containing a well-stirred solution of 4-(5-bromo-3-methyl-2-oxo- 30 benzimidazol-1-yl)-4-cyano-pentanoic acid (6, 3.0 g, 8.52 mmol) were added acetic acid (15.74 g, 262.03 mmol, 15 mL), sulfuric acid (835.48 mg, 8.52 mmol, 456.54 ⁇ L) at room temperature. The 257
  • the resulting reaction mixture 15 was stirred at 80 °C for 2 hr. The reaction mixture was then cooled to room temperature, water (30 ml) was added, and the mixture was extracted with ethyl acetate (2 ⁇ 40 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step-6 An oven dried 250 mL single-neck round-bottom flask was charged with tert-butyl 4-[3-methyl- 1-(3-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1- 25 carboxylate (9, 1.8 g, 3.73 mmol) in dioxane (40 mL). The contents were degassed with N 2 followed by the addition of palladium hydroxide on carbon, 20 wt.% 50% water (883.14 mg, 6.29 mmol). The resulting mixture was stirred at room temperature under hydrogen atmosphere (1kg pressure) for 16 h.
  • reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 50% 1,4-dioxane in ethyl acetate (500 mL). The filtrate30 was concentrated under reduced pressure to afford tert-butyl 4-[3-methyl-1-(3-methyl-2,6-dioxo- 258
  • Step-7 The enantiomers of tert-butyl 4-[3-methyl-1-(3-methyl-2,6-dioxo-3-piperidyl)-2-oxo- 5 benzimidazol-5-yl]piperidine-1-carboxylate (10, 500 mg, 1.05 mmol) was separated by chiral SFC following the method: YMC Cellulose-SA, Flowrate : 5 mL/minutes, Co-Solvent : 40%, Co- Solvent Name : IPA, Injected Volume : 7 ⁇ L, Temperature : 35 °C, Outlet Pressure: 100 bar.
  • Step-8 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- methyl-2-oxo-1-[(3R)-3-methyl-2,6-dioxo-3-piperidyl]benzimidazol-5-yl]piperidine-1-15 carboxylate (11, 101.01 mg, 0.219 mmol) in anhydrous DCM (3 mL) was added 4 N HCl in 1,4- dioxane (0.547 mL) at 0 °C. The resulting solution was stirred at ambient temperature for 1 h.
  • Step-2 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(3- hydroxy-4-nitro-phenyl) piperidine-4-carboxylate (3, 4.2 g, 12.77 mmol) in anhydrous 1,4- dioxane (50 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (4.48 g, 6.38 5 mmol) at ambient temperature. The resulting mixture was stirred at this temperature under hydrogen atmosphere ( ⁇ 1 atm) for 16 h. The reaction was monitored by UPLC.
  • Step-3 To a 100 mL single- neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(4- amino-3-hydroxy-phenyl) piperidine-4-carboxylate (4, 3.8 g, 11.57 mmol) in anhydrous THF (40 mL) was added carbonyldiimidazole (2.81 g, 17.35 mmol) at 25 °C under inert atmosphere. After 15 completion of the addition, the reaction mixture was stirred at the same temperature for 16 h by which time TLC indicated complete consumption of starting material.
  • Step-4 To a 500 mL three- neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(2- oxo-3H-1,3-benzoxazol-6-yl) piperidine-4-carboxylate (5, 2.5 g, 7.70 mmol) in anhydrous THF (15 mL) was added sodium hydride (4.31 g, 107.74 mmol, 60% dispersion in mineral oil) in 25 portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 1 h.
  • Step-5 To a 250 mL single-neck round-bottom flask containing a solution of tert-butyl 1-[3-(2,6-dioxo- 3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl] piperidine-4-carboxylate (7, 1.5 g, 3.49 mmol) in anhydrous DCM (20 mL) was added 4M HCl in dioxane (8.73 mL) at 0 °C. The reaction mixture was stirred at ambient temperature for 16 h and the reaction progress was monitored by LCMS.
  • Step-1 To a 250 mL single-neck round-bottom flask containing a well-stirred solution of 2-amino-6- bromo-phenol (1, 3 g, 15.96 mmol) in anhydrous THF (60 mL) was added 1,1'- carbonyldiimidazole (7.76 g, 47.87 mmol) at ambient temperature. The resulting mixture was 5 stirred at 80 °C for 2 h and monitored by UPLC. Upon completion of the reaction, THF was removed from the reaction mixture under reduced pressure.
  • Step-2 To a 500 mL three- neck round-bottom flask containing a well-stirred solution of 7-bromo-3H- 1,3-benzoxazol-2-one (2, 3.1 g, 14.48 mmol) in anhydrous THF (100 mL) was added sodium hydride (3.33 g, 86.91 mmol; 60% dispersion in mineral oil) at 0 °C. The resulting mixture was 15 stirred at 0 °C for 0.5 h.
  • Step-3 To a 50 mL sealed tube containing a well-stirred solution of 3-(7-bromo-2-oxo-1,3-benzoxazol-3- 25 yl) piperidine-2,6-dione (4, 0.5 g, 1.53 mmol) and hex-5-yn-1-ol (5, 450.86 mg, 4.59 mmol, 0.512 mL) in anhydrous acetonitrile (7 mL) was added TEA (619.81 mg, 6.13 mmol, 0.853 mL) at ambient temperature. The reaction mixture was purged with nitrogen gas for 10 minutes.
  • Step-4 To a 50 mL single- neck round-bottom flask containing a well-stirred solution of 3-[7-(6- hydroxyhex-1-ynyl)-2-oxo-1,3-benzoxazol-3-yl] piperidine-2,6-dione (6, 0.35 g, 0.899 mmol) in anhydrous 1,4-dioxane (4 mL) was added Palladium hydroxide on carbon, 20 wt.% 50 % water (315.87 mg, 0.449 mmol) at ambient temperature. The resulting reaction mixture was stirred for 6 10 h at ambient temperature under hydrogen atmosphere (1 atm).
  • Step-5 To a 100 mL single- neck round-bottom flask containing a well-stirred solution of 3-[7-(6- hydroxyhexyl)-2-oxo-1,3-benzoxazol-3-yl] piperidine-2,6-dione (7, 0.3 g, 0.743 mmol) in anhydrous DMF (4 mL) was added Dess-Martin Periodinane (472.73 mg, 1.11 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h.
  • Step-2 To a 2000 mL three-neck round bottom flask containing a well-stirred solution of methyl 6-bromo- 1-methyl-indazole-3-carboxylate (2, 13.14 g, 48.31 mmol) in THF (119.48 mL) was added DIBAL-H (1.2 M, 80.52 mL) at 0°C. The reaction was stirred at ambient temperature for 3 20 h and monitored by TLC and UPLC.
  • Methyl iodide (1.01 g, 7.13 mmol, 443.58 ⁇ L) was then added dropwise at -78°C. The resulting reaction mixture was stirred at -78°C for 20 25 min and the reaction progress was monitored by TLC and UPLC. The reaction mixture was then quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 ⁇ 200 mL).
  • Step-6 To a 250 mL single-neck round bottom flask containing a well stirred solution of 2-(6-bromo-1- methyl-indazol-3-yl)propanenitrile (7, 2.5 g, 8.73 mmol) in dioxane (36.51 mL) were added methyl acrylate (1.50 g, 17.45 mmol, 1.57 mL), benzyltrimethylammonium hydroxide, 40 wt. % (1.82 g, 4.36 mmol, 1.92 mL) at 0 °C. The resulting reaction mixture was stirred at room 10 temperature for 2 h.
  • Step-7 To a 20 mL pressure vial containing a well-stirred solution of methyl 4-(6-bromo-1-methyl- indazol-3-yl)-4-cyano-pentanoate (9, 2.4 g, 3.77 mmol) were added acetic acid (11.32 g, 188.46 mmol, 10.79 mL) and sulfuric acid (369.68 mg, 3.77 mmol, 202.01 ⁇ L) at room temperature. The reaction mixture was stirred at 110 °C for 3 h while monitoring by UPLC and TLC.
  • Step-8 To a 20 mL glass-vial containing a well-stirred solution of 3-(6-bromo-1-methyl-indazol-3-yl)-3- methyl-piperidine-2,6-dione (10, 0.6 g, 1.78 mmol) in anhydrous DMF (10.02 mL) was30 added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (11, 827.78 mg, 2.68 mmol) and cesium fluoride (542.20 mg, 3.57 mmol) at ambient 269
  • reaction mixture was purged with nitrogen gas for 10 minutes. Subsequently, Pd(dppf)Cl2 ⁇ DCM (291.50 mg, 0.356 mmol) was added and stirring was continued at 90 °C for 2 h. After completion of the reaction as shown by TLC, the reaction mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (350 mL).
  • Step-9 To a 25 mL single- neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- methyl-3-(3-methyl-2,6-dioxo-3-piperidyl) indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (12, 850 mg, 1.71 mmol) in anhydrous 1,4-dioxane (10 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (1.20 g, 1.71 mmol) at ambient temperature under nitrogen 15 atmosphere. The resulting mixture was stirred at ambient temperature under hydrogen atmosphere for 16 h.
  • Step-11 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-4- 5 (1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6-yl) piperidine-1-carboxylate (14, 85 mg, 0.192 mmol) in anhydrous DCM (2 mL) was added 4M HCl in 1,4-dioxane (0.48 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h.
  • Step-2 15 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]piperidine-4-carboxylate (3, 370 mg, 0.593 mmol) in anhydrous 1,4 dioxane (3 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (666.79 mg, 0.949 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h under hydrogen atmosphere.
  • reaction mixture was passed through a pad of Celite and the Celite bed was washed with 1,4-dioxane (150 mL). The combined filtrate was concentrated under reduced pressure to give tert-butyl 1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidine- 4-carboxylate (4, 280 mg, 0.590 mmol, 97% yield) as an off-white solid.
  • Step-3 To a 50 ml single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[3- (2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidine-4-carboxylate (4, 370 mg, 0.780 mmol) in anhydrous DCM (4 mL) was added 4M HCl in 1,4- dioxane (1.95 mL) at 0 °C. The reaction mixture was stirred for 2 h at ambient temperature. The reaction progress was monitored 30 by LCMS. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was washed with MTBE to afford 1-[3-(2,6-dioxo-3- 272
  • Step-2 The enantiomers (3) were separated by chiral SFC, Method details: Column Name: Chiral Pak AS- H, Co-Solvent: 40% and Co-Solvent Name: IPA; Outlet Pressure: 100 bar; Injected Volume: 0.007 ml, Temperature: 35 °C.
  • Step-3 10 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl (R)-1- (1-methyl-3-(3-methyl-2,6-dioxopiperidin-3-yl)-1H-indazol-6-yl) piperidine-4-carboxylate (4, 150 mg, 0.323 mmol) in anhydrous DCM (4 mL) was added 4N HCl in 1,4-dioxane (0.808 mL) at 0 °C. The resulting solution was stirred at ambient temperature for 16 h.
  • Step-1 To a solution of 3-(4-piperazin-1-ylanilino)piperidine-2,6-dione (1, 800 mg, 2.46 mmol, HCl salt) in DMF (5 mL) was added DIPEA (3.18 g, 24.63 mmol, 4.29 mL), 4-tert-butoxy-4-oxo- 10 butanoic acid (2, 514.85 mg, 2.96 mmol) and HATU (1.40 g, 3.69 mmol) at 25°C. The reaction mixture was allowed to stir at 25°C for 4 h. Upon completion of the reaction, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 ⁇ 100 mL).
  • Step-2 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[4- [4-[(2,6-dioxo-3-piperidyl)amino]phenyl]piperazin-1-yl]-4-oxo-butanoate (3, 700 mg, 1.57 20 mmol) in DCM (3 mL) was added TFA (5.92 g, 51.92 mmol, 4 mL) at 0°C and the reaction mixture was stirred at ambient temperature for 5 h. After completion of the reaction as indicated by UPLC, the reaction mixture was concentrated under reduced pressure and the residue was 275
  • RuPhos (532.03 mg, 1.14 mmol) and RuPhos-Pd-G3 (635.71 mg, 0.760 mmol) were added and stirred at 110 °C for 16 h.
  • the reaction 15 mixture was passed through a pad of Celite and the Celite bed was washed with EtOAc (100 mL).
  • Step-2 To a 50 mL single-neck round bottom flask containing a well-stirred solution of tert-butyl 1-(4- benzyloxyphenyl)piperidine-4-carboxylate (3, 1.6 g, 4.14 mmol) in 1:1 anhydrous MeOH/EtOAc (20 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (1.00 g, 1.43 mmol) at 5 ambient temperature. The resulting mixture was stirred at this temperature under hydrogen atmosphere ( ⁇ 1 atm) for 16 h and the reaction progress was monitored by UPLC. The reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (100 mL).
  • Step-3 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-(4- hydroxyphenyl)piperidine-4-carboxylate (4, 1 g, 3.32 mmol) in anhydrous DMF (10 mL) was 15 added sodium hydride (190.64 mg, 4.98 mmol, 60% dispersion in mineral oil) at 0 °C under nitrogen atmosphere and the resulting mixture was stirred for 15 minutes at 0 °C.
  • the reaction mixture was heated at 125 °C in an autoclave for 7 hours.
  • the reaction mixture was cooled to room temperature and poured into ice cold water (2000 ml) and stirred for15 30 minutes.
  • the solidified mass was filtered-off, washed with water, and dried well to afford 6- 278
  • Step-2 5 To the stirred solution of 6-bromo-1-methyl-indazol-3-amine (3, 50 g, 221.17 mmol) in hydrochloric acid (2 M, 500.00 mL, 1 mol) was added tetrabutylammonium bromide (7.13 g, 22.12 mmol) at room temperature. The reaction mixture was heated to 55 °C and acrylic acid (4, 23.91 g, 331.75 mmol, 22.77 mL) was added dropwise at this temperature. The reaction was heated to 100 °C for 12 hours. After the reaction was complete, the reaction mixture was 10 cooled to room temperature and diluted with ice cold water (1000 ml).
  • Step-3 To a stirred solution of 3-[(6-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (5, 160 g, 536.67 mmol) in acetic acid (1.07 kg, 17.76 mol, 1.02 L) was added sodium cyanate (46.67 g, 717.88 mmol). The reaction mixture was heated at 100 °C for 12 hours. Upon completion, the reaction was cooled to room temperature, filtered through a Büchner funnel and the filter cake was20 washed with water (2 ⁇ 500 mL).
  • Step-4 To a solution of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (6, 15 g,25 46.42 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (7, 18.66 g, 60.34 mmol) in 1,4-dioxane (150 mL) and water (30 mL) was added sodium acetate, anhydrous (11.42 g, 139.26 mmol) at room temperature.
  • reaction mixture was degassed with argon gas for 10 minutes and 1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (3.40 g, 4.64 mmol) was added. 30 The reaction mixture was degassed with argon for an additional 5 minutes before it was stirred at 90 °C for 16 hours. Subsequently, the reaction mixture was concentrated in vacuo to yield the 279
  • Step-5 A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (8, 3.6g, 8.46 mmol) in ethanol (30 ml) and DCM (10 ml) with a catalytic amount of glacial acetic acid (508.09 mg,8.46 mmol, 484.36 ⁇ L) was added to a Parr Shaker hydrogenator. Palladium on carbon, 10 wt.
  • Step-6 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-1-carboxylate (500 mg, 1.15 mmol) in anhydrous 1,4-dioxane (6 mL) was added 4.0 M hydrogen chloride solution in 1,4- 20 dioxane (2.87 mL, 11.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours.
  • the reaction mixture was cooled to 0 oC.
  • N,N-diisopropylethylamine (7.17 mL, 5.32 g, 41.25 mmol, 2.5 equiv.) and HATU (9.4 g, 24.8 10 mmol, 1.5 equiv.) were added to the reaction mixture and stirred for 16 hours while warming to room temperature.
  • the reaction mixture was diluted with sodium bicarbonate and extracted twice with ethyl acetate.
  • Step-2 Stirring at ambient temperature, crude tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-4-oxobutanoate (10 g) from previous step was dissolved in dicholoromethane (100 mL). Hydrogen chloride (4M solution in 1,4-dioxane, 41.2 281 mL, 165 mmol, 10 equiv.) was added, and the reaction mixture was stirred for 16 hours at ambient temperature.
  • Hydrogen chloride (4M solution in 1,4-dioxane, 41.2 281 mL, 165 mmol, 10 equiv.
  • Example 30 7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)- 7-oxoheptanoic acid 10 trahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)-7-oxoheptanoic acid was synthesized following the method described in the synthesis of 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)-4-oxobutanoic acid, using 4-(tert-butoxy)-4-oxoheptanoic acid as a building 15 block in Step-1.
  • Step-1 5 To a 20 mL glass-vial containing a well-stirred solution of 1-(6-bromo-5-fluoro-1-methyl-indazol- 3-yl)hexahydropyrimidine-2,4-dione (1, 250 mg, 0.710 mmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2, 329.71 mg, 1.07 mmol) in anhydrous DMF (2.5 mL) was added cesium fluoride (215.96 mg, 1.42 mmol) at ambient temperature.
  • cesium fluoride 215.96 mg, 1.42 mmol
  • reaction mixture was purged with nitrogen gas for 5 minutes. 10 Subsequently, Pd(dppf)Cl2.DCM (116.10 mg, 0.142 mmol) was added and stirring was continued at 90 °C for 16 h and the reaction was monitored by UPLC. Upon completion of the reaction, the reaction mixture was passed through a pad of Celite and Celite bed was washed with EtOAc (200 mL).
  • Step-2 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3-20 (2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate (3, 250 mg, 0.524 mmol) in anhydrous 1,4-dioxane (5 mL) was added Palladium hydroxide on carbon, 20 % wt. (294.85 mg, 0.419 mmol) at ambient temperature. The reaction mixture was stirred at this temperature under hydrogen atmosphere ( ⁇ 1 atm) for 16 h.
  • Step-3 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[3- 5 (2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]piperidine-1-carboxylate (4, 200 mg, 0.412 mmol) in anhydrous DCM (2 mL) was added 4 M HCl in 1,4-dioxane (1.24 mL) at 0 °C. After addition the contents were stirred at ambient temperature under nitrogen atmosphere for 2 h and monitored by UPLC.
  • Step-1 20 To a 50 mL sealed tube containing a well-stirred solution of 1-(6-bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (1, 500 mg, 1.55 mmol) in anhydrous 1,4-dioxane (10 mL) were added tert-butyl piperidine-4-carboxylate hydrochloride (2, 514.61 mg, 2.32 mmol) and cesium carbonate (1.26 g, 3.87 mmol) at ambient temperature.
  • the reaction mixture 284 20 To a 50 mL sealed tube containing a well-stirred solution of 1-(6-bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (1, 500 mg, 1.55 mmol) in anhydrous 1,4-dioxane (10 mL) were added tert-butyl piperidine-4-carbox
  • Step-2 10 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 1-[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]piperidine-4-carboxylate (3, 280 mg, 0.484 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in 1,4-dioxane (1.21 mL) at 0 °C under nitrogen atmosphere. The resulting solution was stirred at ambient temperature for 16 h and the reaction progress was monitored by UPLC-MS.
  • Step-3 To a solution of compound 3-[(7-bromo-1-methyl-indazol-3-yl)amino]propanoic acid (5, 18 g, 20 60.38 mmol) in AcOH (150 mL) was added sodium cyanate (7.85 g, 120.75 mmol, 4.15 mL) at room temperature and the mixture was stirred at 65 °C for 16 h. Then 4 M HCl (180.00 mL) was added at 65 °C and stirred at 65 °C for 4 h. After completion of the reaction, the reaction mixture 286
  • Step-4 To a 50 mL sealed tube containing a well-stirred solution of 1-(7-bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (6, 600 mg, 1.84 mmol) and hex-5-yn-1-ol (7, 360.81 mg, 3.68 mmol, 0.41 mL) in anhydrous acetonitrile (12 mL) was added triethylamine (744.02 mg, 7.35 mmol, 1.02 mL) at ambient temperature. The reaction mixture was degassed with N2 for 5 minutes.
  • Step-5 To a 25 mL single-neck round-bottom flask was added a well-stirred solution of 1-[7-(6- 20 hydroxyhex-1-ynyl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (8, 400 mg, 1.07 mmol) in anhydrous 1,4-dioxane (8 mL) at ambient temperature and the mixture was degassed with N2 for 5 minutes. Subsequently, Palladium hydroxide on carbon, 20% wt. (377.11 mg, 0.537 mmol) was added and the resulting reaction mixture was stirred at ambient temperature under hydrogen atmosphere ( ⁇ 1 atm) for 16 h.
  • Step-6 30 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 1-[7-(6- hydroxyhexyl)-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione (9, 150 mg, 0.430 287
  • Step-2 10 To a 50 mL single-neck round-bottom flask containing a solution of 1-1-(2,6-dibenzyloxy-3- pyridyl)-5-(5-hydroxypent-1-ynyl) benzo[cd]indol-2-one (3, 1 g, 1.76 mmol) in anhydrous 1,4- dioxane (6 mL) and DMF (4 mL) was added Palladium hydroxide on carbon, 20 wt.% 50% water (1.23 g, 1.76 mmol) at ambient temperature. Then the reaction mixture was purged with hydrogen gas and stirred under hydrogen atmosphere for 16 h at ambient temperature. The reaction progress 15 was monitored by UPLC.
  • the reaction mixture was filtered through a pad of Celite and the Celite bed was washed with 30% DMF in 1,4-dioxane solution. Then, the filtrate was concentrated under reduced pressure.
  • the obtained crude product was dissolved in anhydrous DMF (4 mL) and 1,4- dioxane (6 mL) and Palladium hydroxide on carbon, 20 wt.% 50% water (616.96 mg, 0.878 mmol, 20% purity) was added at ambient temperature. Then the reaction mixture was stirred under 20 hydrogen atmosphere for 16 h at this temperature. After 16 h, the reaction mixture was filtered through Celite bed, and Celite bed was washed with 30% DMF in 1,4-dioxane solution.
  • Step-3 To a 50 mL single-neck round-bottom flask containing a solution of 3-[5-(5-hydroxypentyl)-2- oxo-benzo[cd]indol-1-yl] piperidine-2,6-dione (4, 100 mg, 0.27 mmol) in anhydrous DMF (1 30 mL) was added Dess-Martin Periodinane (171.90 mg, 0.405 mmol) at ambient temperature. The reaction mixture was stirred for 3 h at ambient temperature. The reaction progress was monitored 289
  • Step-2 To a stirred solution of tert-butyl 4-indolin-5-yl-3,6-dihydro-2H-pyridine-1-carboxylate (3, 8 g, 15 26.63 mmol) in 1,4-dioxane (100 mL) was added palladium, 10% on carbon (4 g, 26.63 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under the pressure of hydrogen gas (bladder pressure) at room temperature for 16 h. After completion of the reaction, reaction mixture was diluted with MeOH (200 mL), filtered through Celite bed and the resulting filtrate was concentrated under reduced pressure to obtain crude.
  • MeOH 200 mL
  • Step-3 To a stirred solution of tert-butyl 4-indolin-5-yl-3,6-dihydro-2H-pyridine-1-carboxylate (4, 5 g,25 16.64 mmol) in DMF (50 mL) were added sodium bicarbonate (4.19 g, 49.93 mmol) and 3- bromopiperidine-2,6-dione (5, 4.79 g, 24.97 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure, dissolved in DCM (50 mL) and washed with water (2 ⁇ 50 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and 30 concentrated under reduced pressure to obtain crude.
  • the crude was purified by column chromatography (silica gel, 100-200 mesh), using 0-100% ethyl acetate in petroleum ether as 291
  • Step-4 Compound tert-butyl 4-[1-(2,6-dioxo-3-piperidyl)indolin-5-yl]piperidine-1-carboxylate (6, 1 g, 5 2.20 mmol) was purified by chiral SFC to separate ‘R' and 'S' isomers [Column: I Cellulose J, flow rate: 4 mL/min, elution: 80:20 (CO2:Co-solvent), Co-solvent: 0.2 % formic acid in acetonitrile/isopropanol].
  • Step-5 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[1- [(3R)-2,6-dioxo-3-piperidyl]indolin-5-yl]piperidine-1-carboxylate (7, 90 mg, 215.21 25 ⁇ mol) in anhydrous DCM (1.01 mL) was added 4 M HCl in 1,4-dioxane (1.08 mL) at 0 °C. The reaction was stirred at room temperature for 2 h.
  • Step-6 To a 25 ml round-bottom flask containing a solution of tert-butyl 4-[1-[(3S)-2,6-dioxo-3- piperidyl]indolin-5-yl]piperidine-1-carboxylate (8, 80 mg, 189.60 ⁇ mol) in DCM (0.8 mL) was added 4 M hydrogen chloride in 1,4-dioxane (529.06 ⁇ L) at 0°C. Then the reaction mixture was 5 stirred at room temperature for 1 h.
  • Step-2 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- ethynyl-1-piperidyl) methyl] piperidine-1-carboxylate (3, 5.0 g, 15.12 mmol) in anhydrous DCM (20 mL) was added 4M HCl in 1,4-dioxane (37.8 mL) at 0 °C. The resulting mixture was stirred at 5 ambient temperature for 1 h.
  • tert-butyl 4-fluoro-4-(hydroxymethyl) piperidine-1-carboxylate (1, 5 g, 21.43 mmol) in 15 anhydrous DCM (50 mL) was added at -78 °C and stirring was continued at -78 °C for 2 h. Then the resulting acid was quenched with triethylamine (10.84 g, 107.17 mmol, 14.94 mL) at -78 °C and the mixture was slowly warmed to ambient temperature and stirred for 30 minutes. Progress of the reaction was monitored by TLC. To this reaction mixture cold water (100 mL) was added and the aqueous layer was extracted with DCM (2 ⁇ 50 mL).
  • Step-2 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 4- ethynylpiperidine hydrochloride (3, 2.03 g, 13.86 mmol) and tert-butyl 4-fluoro-4-formyl- piperidine-1-carboxylate (2, 3.40 g, 13.86 mmol) in MeOH (50 mL) were added Sodium acetate, 5 anhydrous (3.41 g, 41.59 mmol) and Acetic acid (8.33 g, 138.64 mmol, 7.94 mL) and the reaction mixture was stirred at ambient temperature for 1 h.
  • Step-3 15 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- ethynyl-1-piperidyl) methyl]-4-fluoro-piperidine-1-carboxylate (4, 3.5 g, 7.20 mmol) in anhydrous dichloromethane (30 mL) was added 4N HCl/1,4-dioxane (3.60 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 2 h and monitored by UPLC.
  • Step-2 To a 20 mL glass-vial containing a well-stirred solution of 4-ethynylpiperidine hydrochloride (2, 3 g, 27.21 mmol) in EtOH (30 mL) was added tert-butyl 1-oxa-6-azaspiro [2.5] octane-6- 10 carboxylate (3, 5.8 g, 27.21 mmol) and the reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with ice-water, aqueous layer was extracted with EtOAc (3 ⁇ 150 mL).
  • Step-3 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- ethynyl-1-piperidyl)methyl]-4-hydroxy-piperidine-1-carboxylate (4, 8 g, 14.89 20 mmol) in anhydrous DCM (20 mL) was added 4M HCl in 1,4-dioxane (18.6 mL) at 0 °C. After completion of the addition, the resulting mixture was stirred at ambient temperature for 2 h.
  • tert-butyl 4-cyano-4-(hydroxymethyl) piperidine-1-carboxylate (1, 1.00 g, 4.16 mmol) in anhydrous DCM (20 mL) was added at -78 °C and stirring was continued at -78 °C for 4 h. Thereafter, the reaction was quenched with triethylamine (2.11 g, 20.81 mmol, 2.90 mL) at -78 °C and the mixture was slowly warmed to ambient temperature and stirred for 30 10 minutes and monitored by TLC. To the reaction mixture was added cold water (100 mL) and the aqueous phase was extracted with DCM (2 ⁇ 50 mL).
  • Step-2 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of 4- ethynylpiperidine (3, 230.69 mg, 2.10 mmol) and tert-butyl 4-cyano-4-formyl-piperidine-1- 20 carboxylate (2, 733.50 mg, 2.52 mmol) in THF (15 mL) were added acetic acid (1.26 g, 20.98 mmol, 1.20 mL), sodium acetate, anhydrous (430.32 mg, 5.25 mmol) and Titanium(IV) isopropoxide (1.19 g, 4.20 mmol, 1.25 mL) at ambient temperature.
  • Step-3 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- cyano-4-[(4-ethynyl-1-piperidyl)methyl]piperidine-1-carboxylate (4, 200 mg, 0.601 mmol) in anhydrous DCM (4 mL) was added 4 N HCl in 1,4-dioxane (1.50 mL) at ambient temperature 10 under nitrogen atmosphere. After completion of the addition, the resulting mixture was stirred at ambient temperature for 16 h.
  • Step-2 To a 20 mL screw-capped vial containing a well-stirred solution of 4-ethynylpiperidine (2, 700 5 mg, 6.35 mmol) in DMF (7.02 mL) was added triethylamine (1.61 g, 15.87 mmol, 2.21 mL) and ethyl 5-bromopentanoate (3, 1.99 g, 9.52 mmol) and the resulting suspension was heated at 70 °C for 3 hours. Afterwards, the reaction mixture was poured into water and extracted with DCM (2 ⁇ 100 mL).
  • Step-2 To a 100 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- ethynyl-3-hydroxy-piperidine-1-carboxylate (3, 500 mg, 1.93 mmol) in anhydrous DCM (15 mL) was added DAST (622.48 mg, 0.51 mmol, 0.51 mL) at 0 °C under nitrogen atmosphere. The 5 resulting mixture was stirred at ambient temperature for 4 h. After completion of the reaction as confirmed by LCMS, the reaction mixture was diluted with NaHCO3 (30 mL) and extracted with DCM (2 ⁇ 200 mL).
  • Step-3 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4- ethynyl-3-fluoro-piperidine-1-carboxylate (4, 200 mg, 0.862 mmol) in anhydrous DCM (2 mL) 15 was added 4 N HCl in 1,4-dioxane (2.16 mL) at 0 °C and the resulting mixture was stirred at ambient temperature for 2 h.
  • Step-2 To a 25 mL single-neck round-bottom flask containing a well-stirred solution of 4-ethynyl-4- fluoro-piperidine hydrochloride (2, 350 mg, 2.10 mmol) and tert-butyl 4-formylpiperidine-1- carboxylate (3, 536.51 mg, 2.52 mmol) in MeOH (10 mL) were added anhydrous Sodium acetate (343.92 mg, 4.19 mmol) and Acetic acid (1.26 g, 20.96 mmol, 1.20 mL) and the resulting reaction 10 mixture was stirred at ambient temperature for 1 h.
  • Step-3 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of tert-butyl 4-[(4- 20 ethynyl-4-fluoro-1-piperidyl)methyl]piperidine-1-carboxylate (4, 650 mg, 1.54 mmol) in anhydrous DCM (5 mL) was added 4 M HCl in dioxane (112.50 mg, 3.09 mmol) at room temperature. The contents were stirred at room temperature for 2 h. The reaction was monitored by UPLC.
  • Step-2 To a 100 mL two-neck round-bottom flask containing a well-stirred solution of 5- (bromotriphenyl-l5-phosphaneyl)pentanoic acid (3, 5.21 g, 11.76 mmol) in dry THF (60 mL), was added 1 M lithium bis(trimethylsilyl)amide solution in THF (23.51 mL) dropwise at 0 °C under 5 nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 1 h and then 4- [[tert-butyl(dimethyl)silyl]oxymethyl]cyclohexanone (950 mg, 3.92 mmol) in dry THF (10 mL) was added dropwise at 0 °C.
  • reaction mixture was stirred at ambient temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) at 0 °C 10 and extracted with EtOAc (3 ⁇ 100 mL).
  • Step-3 To a 100 mL two-neck round-bottom flask containing a well-stirred solution 5-(4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexylidene)pentanoic acid (4, 0.8 g, 2.45 mmol) in MeOH (20 mL) was added 2M (diazo methyl)trimethylsilane in hexane (5, 12.25 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 h. 20 Progress of the reaction was monitored by TLC and LCMS.
  • Step-4 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-(4- (((tert-butyldimethylsilyl)oxy)methyl)cyclohexylidene)pentanoate (6, 0.6 g, 1.76 mmol) in 1,4- 30 dioxane (10 mL) was added Palladium, 10% on carbon (625.93 mg, 0.528 mmol) and the resulting mixture was purged by bubbling hydrogen gas for 10 minutes. The mixture was then stirred under 303
  • Step-5 10 To a 50 mL two-neck round-bottom flask containing a well-stirred solution of methyl 5-(4-(((tert- butyldimethylsilyl)oxy)methyl)cyclohexyl)pentanoate (7, 0.5 g, 1.46 mmol) in THF (10 mL) was added 1M TBAF in THF (4.38 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS.
  • Step-6 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-(4- 25 (hydroxymethyl)cyclohexyl)pentanoate (8, 0.29 g, 1.27 mmol) in dry DCM (10 mL) was added (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl) acetate (1.08 g, 2.54 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 h. Progress of the reaction was monitored by TLC and LCMS.
  • reaction mixture was quenched with sodium thiosulfate solution (2 g in 15 mL) and sodium bicarbonate 30 solution (2 g in 15 mL) and the reaction mixture was stirred for 20 minutes at ambient temperature.
  • the aqueous phase was extracted with DCM (3 ⁇ 20 mL) and the organic phase was washed with 304
  • Step-7 To a 50 mL single-neck round-bottom flask containing a well-stirred solution of methyl 5-(4- formylcyclohexyl)pentanoate (9, 0.28 g, 1.06 mmol) in MeOH (5 mL) was added potassium carbonate, anhydrous, 99% (291.65 mg, 2.11 mmol). The reaction mixture was cooled to 0 °C, 10 before dimethyl (1-diazo-2-oxopropyl)phosphonate (10, 405.40 mg, 2.11 mmol, 0.506 mL) was added under nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 1 h.
  • reaction mixture was cooled to 0° C, diluted with water, and the solid precipitate was filtered.
  • the filtrate was extracted with ethyl acetate (2 ⁇ 150 mL). The combined organic layers and washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered.
  • Step-2 15 To a 250 mL sealed tube containing a well stirred solution of isopropyl 1-[1-(4-bromo-1- naphthyl)ethyl]piperidine-4-carboxylate (3, 5 g, 12.37 mmol), tert-butyl 4-ethynylpiperidine-1- carboxylate (4, 3.36 g, 16.08 mmol) in anhydrous acetonitrile (60 mL) was added cesium carbonate (10.07 g, 30.91 mmol) at room temperature.
  • reaction mixture was purged with nitrogen gas for 10 minutes before XPhos (589.50 mg, 1.24 mmol) and XPhos-Pd-G3 (524.00 mg, 20 618.29 ⁇ mol) were added.
  • the reaction was stirred at 90 °C for 5 hours.
  • the reaction mixture was filtered through a pad of Celite, the Celite bed was washed with ethyl acetate (500 mL).
  • Step-3 To a 250 mL single neck round bottom flask containing a stirred solution tert-butyl 4-[2-[4-[1-(4- isopropoxycarbonyl-1-piperidyl)ethyl]-1-naphthyl]ethynyl]piperidine-1-carboxylate (5, 4.08 g, 30 7.51 mmol) in methanol (40 mL) and THF (40 mL)and water (20 mL) was added lithium hydroxide monohydrate, 98% (3.15 g, 75.09 mmol) at ambient temperature and the resulting 307
  • Step-4 To a 100 mL round bottom flask containing a well-stirred solution of 1-[1-[4-[2-(1-tert- butoxycarbonyl-4-piperidyl)ethynyl]-1-naphthyl]ethyl]piperidine-4-carboxylic acid (6, 4 g, 7.51 10 mmol) and (3-fluorophenyl)methanamine (7, 940.19 mg, 7.51 mmol, 857.05 ⁇ L) in anhydrous DMF (40 mL) was added N,N-diisopropylethylamine (4.85 g, 37.56 mmol, 6.54 mL) at room temperature under nitrogen atmosphere.
  • Example 41 5 1-[1-[4-[2-[1-[7-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1- piperidyl]-7-oxo-heptanoyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 3) C ng the 10 corresponding intermediates.
  • Example 43 1-[1-[4-[2-[1-[6-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1- piperidyl]-6-oxo-hexanoyl]-4-piperidyl]ethynyl]-1-naphthyl]ethyl]-N-[(3- fluorophenyl)methyl]piperidine-4-carboxamide (Compound 5) 5 Co ing the corresponding intermediates.

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Abstract

La présente invention concerne des composés avantageux pour le traitement d'hôtes, y compris des êtres humains, infectés par un coronavirus, comprenant, mais sans y être limités, le SARS-CoV-2.
PCT/US2022/045889 2021-10-06 2022-10-06 Composés de dégradation de la protéine 3 non structurale de coronavirus WO2023059792A1 (fr)

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WO2017223452A1 (fr) * 2016-06-23 2017-12-28 Dana-Farber Cancer Institute, Inc. Dégradation de la protéine contenant un bromodomaine 9 (brd9) par conjugaison d'inhibiteurs de brd9 avec un ligand de la ligase e3 et procédés d'utilisation
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