WO2025174875A1 - Composés antibactériens - Google Patents

Composés antibactériens

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Publication number
WO2025174875A1
WO2025174875A1 PCT/US2025/015580 US2025015580W WO2025174875A1 WO 2025174875 A1 WO2025174875 A1 WO 2025174875A1 US 2025015580 W US2025015580 W US 2025015580W WO 2025174875 A1 WO2025174875 A1 WO 2025174875A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
solvate
pharmaceutically acceptable
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PCT/US2025/015580
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English (en)
Inventor
Junhua Fan
David Pifer MARTIN
David Lonergan
David T. Puerta
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Blacksmith Medicines Inc
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Blacksmith Medicines Inc
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Publication of WO2025174875A1 publication Critical patent/WO2025174875A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • heterocyclic compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting the growth of gram-negative bacteria.
  • the subject compounds and compositions are useful for the treatment of bacterial infection, such as pneumonia and the like.
  • compounds described herein are UDP- ⁇ 3-O-[(R)-3- hydroxymyristoyl] ⁇ -N-acetylglucosamine deacetylase (LpxC) modulator compounds.
  • the compounds described herein are UDP- ⁇ 3-O-[(R)-3-hydroxymyristoyl] ⁇ -N- acetylglucosamine deacetylase (LpxC) antagonists.
  • the compounds described herein are UDP- ⁇ 3-O-[(R)-3-hydroxymyristoyl] ⁇ -N-acetylglucosamine deacetylase (LpxC) inhibitors.
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 2a and R 2b are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl
  • L 1 is absent, -O, -N(R 9 ), -S, substituted or unsubstituted C 1 -C 6 alkyl, -O-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-O, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-N(R 9 ), -S-(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 1 -C 6 alkyl)-S;
  • R 9 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -O- (substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 2a and R 2b are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl;
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 2a and R 2b are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 is hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl
  • L 1 is absent, -O, -N(R 9 ), -S, substituted or unsubstituted C 1 -C 6 alkyl, -O-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-O, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-N(R 9 ), -S-(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 1 -C 6 alkyl)-S;
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -O- (substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • a compound described herein, or a pharmaceutically acceptable salt or solvate thereof is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.
  • the mammal is a human.
  • Metalloproteins influence a vast diversity of biological systems, biological processes, and diseases.
  • UDP- ⁇ 3-O-[(R)-3-hydroxymyristoyl] ⁇ -N-acetylglucosamine deacetylase (LpxC) is an essential enzyme involved in the first committed step in lipid A biosynthesis for gramnegative bacteria.
  • Lipid A is an essential component of the outer membrane of gram-negative bacteria.
  • LpxC is a zinc(II)-dependent metalloenzyme, with two histidines and an aspartic acid residue bound to the zinc(II) ion.
  • LpxC is highly conserved across strains of gram-negative bacteria, making LpxC an attractive target to treat gramnegative infections. To the contrary, LpxC is not a component of Gram-positive bacteria, such as Staphylococcus aureus.
  • Some embodiments provide a method of inhibiting UDP- ⁇ 3-O-[(R)-3-hydroxymyristoyl] ⁇ - N-acetylglucosamine deacetylase enzyme comprising contacting the enzyme with a compound of Formula (I) or (XI).
  • a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • the method of treating a gram-negative bacterial infection in a patient in need thereof comprises administering to the patient a compound of Formula (I) or (XI), a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • the method of treating a Pseudomonas aeruginosa infection in a patient in need thereof comprises administering to the patient the compound of Formula (I) or (XI), a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the gram-negative bacterial infection is pneumonia. In some embodiments, the gram-negative bacterial infection is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associate pneumonia (VAP), or a combination thereof. In some embodiments, the gram-negative bacterial infection is community-acquired pneumonia (CAP). In some embodiments, the gram-negative bacterial infection is health care-associated pneumonia (HCAP). In some embodiments, the gramnegative bacterial infection is hospital -acquired pneumonia (HAP). In some embodiments, the gramnegative bacterial infection is ventilator-associate pneumonia (VAP).
  • CAP community-acquired pneumonia
  • HCAP health care-associated pneumonia
  • HAP hospital -acquired pneumonia
  • the patient has been identified as having a lung disease.
  • the lung disease is a structural lung disease.
  • the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.
  • the patient has cystic fibrosis.
  • the patient has bronchiectasis.
  • the patient has emphysema.
  • the patient has chronic obstructive pulmonary disease (COPD).
  • the patient has chronic destroyed lung disease.
  • the administration is to treat an existing infection.
  • the administration is provided as prophylaxis.
  • the LpxC inhibitory compound as described herein is used for treating or preventing conditions caused by the bacterial production of endotoxin and, in particular, by gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxin.
  • the method of treating or preventing a condition caused by endotoxin or LPS in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • heterocyclic LpxC inhibitory compounds as described herein are useful in the treatment of conditions that are caused or exacerbated by the bacterial production of lipid A and LPS or endotoxin, such as chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB).
  • COPD chronic obstructive pulmonary disease
  • AECB acute exacerbations of chronic bronchitis
  • the method of treating or preventing a condition caused by endotoxin or LPS in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, wherein the condition caused by endotoxin or LPS is selected from chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB).
  • COPD chronic obstructive pulmonary disease
  • AECB acute exacerbations of chronic bronchitis
  • the compounds of the disclosure can be used for the treatment of a serious or chronic respiratory tract infection including serious lung and nosocomial infections such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kuyvera ascorbata, Kuyvera cryocrescense, Shigella sonnei, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, and Citrobacter freundi, Haemophilus influenzae, Kluyvera species, Legionella species, Moraxella catarrhalis, Enterobacter species, Acinetobacter species, Klebsiella
  • the infection is associated with a Pseudomonas species. In some embodiments, the infection is associated with Pseudomonas aeruginosa. In some embodiments, the compounds of the disclosure do not inhibit the growth of Gram-positive bacteria, such as Staphylococcus aureus. [0038] In some embodiments, the LpxC inhibitory compound as described herein is used in a method of preventing growth of a Pseudomonas species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa.
  • antibiotics have suboptimal concentrations in the lung leading to therapeutic failures for lung infections.
  • the heterocyclic LpxC inhibitory compound of Formula (I) or (XI) have optimal concentrations in the lung for treating or preventing a gram-negative bacterial infection in the lung.
  • the compounds are present in the lung in a therapeutically effective amount after administration.
  • a compound described herein, or a pharmaceutically acceptable salt or solvate thereof for use as therapeutically active substance.
  • a compound described herein, or a pharmaceutically acceptable salt or solvate thereof for use in treating or preventing a gram-negative bacterial infection.
  • the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.
  • the gram-negative bacterial infection is a respiratory infection.
  • the respiratory infection is pneumonia.
  • a compound described herein, or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for treating or preventing a gram-negative bacterial infection.
  • the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.
  • the gram-negative bacterial infection is a respiratory infection.
  • the respiratory infection is pneumonia.
  • heterocyclic LpxC inhibitory compounds and pharmaceutical compositions comprising said compounds.
  • the subject compounds and compositions are useful for inhibiting UDP- ⁇ 3-O-[(R)-3-hydroxymyristoyl] ⁇ -N-acetylglucosamine deacetylase (LpxC) and for the treatment of bacterial infection.
  • compounds of Formula (I) or (XI), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof are LTDP- ⁇ 3-O-[(R)-3-hydroxymyristoyl] ⁇ -N-acetylglucosamine deacetylase (LpxC) modulators.
  • the compounds of Formula (I) or (XI), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof are UDP- ⁇ 3-0- [(R)-3 -hydroxymyristoyl] ⁇ -N-acetylglucosamine deacetylase (LpxC) antagonists.
  • the compounds of Formula (I) or (XI), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof are UDP- ⁇ 3-O-[(R)- 3 -hydroxymyristoyl] ⁇ -N-acetyl glucosamine deacetylase (LpxC) inhibitors.
  • compounds of Formula (I) or (XI), or pharmaceutically acceptable salts or solvates thereof, described herein have increased solubility compared to corresponding compounds without a phosphate ester.
  • compounds of Formula (I) or (XI), or pharmaceutically acceptable salts or solvates thereof, described herein have increased bioavailability compared to corresponding compounds without a phosphate ester.
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • L 1 is absent, -O, -N(R 9 ), -S, substituted or unsubstituted C 1 -C 6 alkyl, -O-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-O, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-N(R 9 ), -S-(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 1 -C 6 alkyl)-S;
  • R 9 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl; R 7 is absent, substituted or unsubstituted C 3 -C 10 cycloalkyl or substituted or unsubstituted C 2 -
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -O- (substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • the compound of Formula (I) is a compound of Formula (la), (lb), (Ic), (II), (Ila), (III), (Illa), (IV), (IVa), (V), or (Va).
  • described herein is a pharmaceutically acceptable salt of a compound of Formula (I).
  • described herein is a compound of Formula (la):
  • R 2a and R 2b are each independently hydrogen.
  • R 4 is hydrogen, -CH 3 , or -CH 2 CH 3 . In some embodiments, R 4 is hydrogen.
  • L 1 -R 7 is absent and two R 6 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 - C 10 cycloalkyl. In some embodiments, L 1 -R 7 is absent and two R 6 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 2 -
  • R 7 is substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 2 -C 6 heterocycloalkyl, wherein heterocycloalkyl contains 0-2 N atoms or 0-2 O atoms in the ring.
  • R 7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide.
  • R 7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperazinyl.
  • R 7 is substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted azetidinyl. In some embodiments, R 7 is substituted or unsubstituted tetrahydrofuranyl or substituted or unsubstituted tetrahydropyranyl. In some embodiments, R 7 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, R 7 is substituted or unsubstituted cyclobutyl. In some embodiments, R 7 is substituted or unsubstituted tetrahydrofuranyl. In some embodiments, R 7 is substituted or unsubstituted tetrahydropyranyl. In some embodiments, R 7 is substituted or unsubstituted azetidinyl.
  • Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof is described herein.
  • described herein is a compound of Formula (IV): or a pharmaceutically acceptable salt or solvate thereof.
  • L a is absent or substituted or unsubstituted C 1 -C 6 alkyl)-; and each R 3 is independently hydrogen, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 ..
  • each R 5 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl; s is 0, 1, or 2; each R 6 is independently hydrogen, halogen, -CN, -OH, - OR a , -NR c R d , or substituted or unsubstituted C 1 -C 6 alkyl; and t is 0, 1, or 2.
  • each R 5 is independently hydrogen or halogen; s is 0, 1, or 2; each R 6 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl; and t is 0, 1, or 2.
  • each R 5 is independently hydrogen; and each R 6 is independently hydrogen, -F, -Cl, -CH 3 , -CH 2 CH 3 , or - CH(CH 3 ) 2 . In some embodiments, each R 5 is independently hydrogen; and each R 6 is independently hydrogen, -F, -Cl, or -CH 3 . In some embodiments, each R 5 is independently hydrogen; and each R 6 is independently hydrogen or -F. In some embodiments, each R 5 is independently hydrogen; and each R 6 is independently hydrogen.
  • each R 5 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 5 is independently hydrogen or halogen. In some embodiments, each R 5 is independently hydrogen. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.
  • each R 6 is independently hydrogen, halogen, -CN, -OH, -OR a , - NR c R d , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 6 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 6 is independently hydrogen, -F, -Cl, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In some embodiments, each R 6 is independently hydrogen. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.
  • L 1 is absent, -O-, -N(R 9 )-, -(substituted or unsubstituted Ci- Cealkyl)-, -O-(substituted or unsubstituted C 1 -C 6 alkyl)-, -(substituted or unsubstituted C 1 -C 6 alkyl)- O-, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl)-, or -(substituted or unsubstituted C 1 -C 6 alkyl)- N(R 9 )-; and R 9 is hydrogen or -CH 3 .
  • L 1 is absent, -O-, - N(H), -CH 2 -, -O-CH 2 - -CH 2 -O-, -N(H)-CH 2 -, or -CH 2 -N(H)-. In some embodiments, L 1 is absent, - O-, -O-CH 2 , or -CH 2 -O. In some embodiments, L 1 is absent, -N(H), -N(H)-CH 2 , or -CH 2 -N(H). In some embodiments, L 1 is absent. In some embodiments, L 1 is -O-. In some embodiments, L 1 is - N(H). In some embodiments, L 1 is -CH 2 -.
  • L 1 is -O-CH 2 - or-CH 2 -O-. In some embodiments, L 1 is -O-CH 2 -. In some embodiments, L 1 is -CH 2 -O-. In some embodiments, L 1 is a - N(H)-CH 2 - or -CH 2 -N(H)-.
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl;
  • R 11 is -
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl;
  • R 11 is -CN;
  • each R 10 is independently -OH; and n is i.
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 2a and R 2b are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl;
  • the compound of Formula (VI) is a compound of Formula (Via).
  • Ring A is heterocycloalkyl. In some embodiments, Ring A is heteroaryl.
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 9 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 7 is absent, substituted or unsubstituted C 3 -C 10 cycloalkyl or substituted or unsubstituted C 2 -
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -O- (substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • L a is absent, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; each R 3 is independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 2a and R 2b are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 is hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl
  • L 1 is absent, -O, -N(R 9 ), -S, substituted or unsubstituted C 1 -C 6 alkyl, -O-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-O, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-N(R 9 ), -S-(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 1 -C 6 alkyl)-S;
  • R 9 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 7 is absent, substituted or unsubstituted C 3 -C 10 cycloalkyl or substituted or unsubstituted C 2 -
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -O- (substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • the compound of Formula (XI) is a compound of Formula (Xia), (Xlb), (XIc), (XII), (Xna), (XIV), or (XlVa).
  • R 2a and R 2b are each independently hydrogen.
  • R 1 is substituted or unsubstituted C 1 -C 6 alkyl.
  • R 1 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R 1 is -CH 3 .
  • R 4 is hydrogen, -CH 3 , or -CH 2 CH 3 .
  • R 4 is hydrogen.
  • R 12 is hydrogen or halogen; and R 13 is hydrogen or halogen. In some embodiments, R 12 is hydrogen; and R 13 is hydrogen.
  • R 7 is substituted or unsubstituted Cs-Cgcycloalkyl or substituted or unsubstituted C 2 -C 6 heterocycloalkyl. In some embodiments, R 7 is substituted or unsubstituted monocyclic C 3 -C 6 cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl.
  • R 7 is substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted C 2 -C 6 heterocycloalkyl, wherein C 2 -C 6 heterocycloalkyl contains 0-2 N atoms or 0-2 O atoms in the ring.
  • R 7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, or substitituted or unsubstituted tetrahydrothiophene 1- oxide.
  • R 7 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperazinyl.
  • R 7 is substituted or unsubstituted cyclobutyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide. [00103] In some embodiments, R 7 is substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted azetidinyl.
  • R 7 is substituted or unsubstituted tetrahydrofuranyl or substituted or unsubstituted tetrahydropyranyl. In some embodiments, R 7 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, R 7 is substituted or unsubstituted tetrahydropyranyl. In some embodiments, R 7 is substituted or unsubstituted cyclobutyl.
  • L a is absent or substituted or unsubstituted C 1 -C 6 alkyl)-; and each R 3 is independently hydrogen, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 ..
  • each R 5 is independently hydrogen or halogen; s is 0, 1, or 2; each R 6 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl; and t is 0, 1, or 2.
  • each R 5 is independently hydrogen; and each R 6 is independently hydrogen, - F, -Cl, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • each R 5 is independently hydrogen; and each R 6 is independently hydrogen.
  • each R 5 is independently hydrogen; and each R 6 is independently hydrogen or -F.
  • each R 5 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 5 is independently hydrogen or halogen. In some embodiments, each R 5 is independently hydrogen. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.
  • each R 6 is independently hydrogen, halogen, -CN, -OH, -OR a , - NR c R d , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 6 is independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 6 is independently hydrogen, -F, -Cl, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In some embodiments, each R 6 is independently hydrogen, -F, or -Cl. In some embodiments, each R 6 is independently hydrogen or -F. In some embodiments, each R 6 is independently hydrogen. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.
  • L 1 is absent, -O-, -N(R 9 )-, -(substituted or unsubstituted Ci- Cealkyl)-, -O-(substituted or unsubstituted C 1 -C 6 alkyl)-, -(substituted or unsubstituted C 1 -C 6 alkyl)- O-, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl)-, or -(substituted or unsubstituted C 1 -C 6 alkyl)- N(R 9 )-; and R 9 is hydrogen or -CH 3 .
  • L 1 is absent, -O-, -N(H)-, -N(CH 3 )-, -CH 2 -, -O-CH 2 -, -CH 2 -O-, - N(H)-CH 2 -, -CH 2 -N(H)-, -N(CH 3 )-CH 2 -, or -CH 2 -N(CH 3 )-.
  • L 1 is absent, -O-, -N(H)-, -O-CH 2 -, -CH 2 -O-, -N(H)-CH 2 -, or -CH 2 -N(H)-.
  • L 1 is absent, -O-, or - N(H)-. In some embodiments, L 1 is absent, -O-, -O-CH 2 -, or-CIL-O-. In some embodiments, L 1 is absent, -N(H)-, -N(H)-CH 2 -, or -CH 2 -N(H)-. In some embodiments, L 1 is absent, -O-, -CH 2 -O-, or - N(H)-. In some embodiments, L 1 is absent. In some embodiments, L 1 is -O-. In some embodiments, L 1 is -N(H)-. In some embodiments, L 1 is -O-CH 2 - or-CIfc-O-. In some embodiments, L 1 is a -N(H)- CH 2 - or -CH 2 -N(H)-.
  • R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is
  • R 1 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 2a and R 2b are each independently hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 is hydrogen, halogen, or substituted or unsubstituted C 1 -C 6 alkyl
  • L 1 is absent, -O, -N(R 9 ), -S, substituted or unsubstituted C 1 -C 6 alkyl, -O-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-O, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -(substituted or unsubstituted C 1 -C 6 alkyl)-N(R 9 ), -S-(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 1 -C 6 alkyl)-S;
  • R 9 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl
  • R 7 is absent, substituted or unsubstituted C 3 -C 10 cycloalkyl or substituted or unsubstituted C 2 -
  • L 2 is substituted or unsubstituted C 1 -C 6 alkyl, -N(R 9 )-(substituted or unsubstituted C 1 -C 6 alkyl), -O- (substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted C 1 -C 6 heteroalkyl;
  • the compound is a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a diastereomer of a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of Table 2, or or solvate thereof.
  • prodrug is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7 9, 21 24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • the prodrug moeity comprises a phosphate group.
  • the phosphate ester compounds of Formula (I) or (XI), or pharmaceutically acceptable salts or solvates thereof, described herein function as prodrugs of the corresponding compounds without a phosphate ester (e.g., the corresponding free alcohol compounds).
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley -VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) or (XI) with an acid.
  • the compound of Formula (I) or (XI) i.e. free base form
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
  • Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2, 2-di chloroacetic acid; 2 -hydroxy ethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid
  • a compound of Formula (I) or (XI) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) or (XI) with a base.
  • the compound of Formula (I) or (XI) is acidic and is reacted with a base.
  • an acidic proton of the compound of Formula (I) or (XI) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • sites on the organic radicals (e.g., alkyl groups, aromatic rings) of compounds of Formula (I) or (XI) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 35 S, 18 F, 36 C1, 123 I, 124 1, 125 I, 131 1, 32 P and 33 P.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds of Formula (I) or (XI) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formula (I) or (XI) exists in the R configuration. In some embodiments, the compound of Formula (I) or (XI) exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E Delta-E
  • Z sixteen
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • compounds of Formula (I) or (XI) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.
  • stereoisomers are obtained by stereoselective synthesis.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • a “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic -acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • heterocyclic rings may exist in tautomeric forms.
  • the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form.
  • the alternative tautomeric forms are expressly included in this disclosure, such as, for example, the structures illustrated below.
  • benzimidazoles or imidazoles could exist in the following tautomeric forms:
  • Ci-C x includes C1-C2, C1-C3 . . . Ci-C x .
  • a group designated as “C 1 -C 6 ” indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, /.so-propyl, w-butyl, iso-butyl, secbutyl, and /-butyl.
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a Ci-C 10 alkyl.
  • an alkyl is a C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • an alkyl is methyl.
  • an “alkylene” group refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C 1 -C 6 alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like. In some embodiments, an alkylene is -CH 2 -.
  • alkoxy refers to a -O(alkyl) group, where alkyl is as defined herein.
  • alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • hydroxyalkyl refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl.
  • a hydroxyalkyl is a Ci-C4hydroxyalkyl.
  • Typical hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, - CH 2 CH 2 CH 2 CH 2 OH, and the like.
  • a hydroxyalkyl is -CH 2 OH or - CH 2 CH 2 OH.
  • a hydroxyalkyl is -CH 2 OH.
  • a hydroxyalkyl is -CH 2 CH 2 OH.
  • aminoalkyl refers to an alkyl in which one hydrogen atom is replaced by an amino.
  • aminoalkyl is a Ci-C4aminoalkyl.
  • Typical aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH2, -CH 2 CH 2 CH 2 CH 2 NH2, and the like.
  • an amino alkyl is -CH 2 NH2 or -CH 2 CH 2 NH2.
  • a hydroxyalkyl is -CH 2 NH2.
  • a hydroxyalkyl is -CH 2 CH 2 NH2.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl where one or two atoms are independently selected from O, NH, and S.
  • aromatic refers to a planar ring having a delocalized 7t-electron system containing 4n+2 it electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
  • pyridine e.g., pyridine
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • Carbocyclic refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • aryl is phenyl or a naphthyl.
  • an aryl is a phenyl.
  • an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl.
  • an aryl is a phenyl.
  • an aryl is a Ce-C 10 aryl.
  • an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbomyl and bicyclo [l.l.l]pentyl.
  • a cycloalkyl is a C 3 -C 6 cycloalkyl.
  • a cycloalkyl is a C3-C4cycloalkyl.
  • a cycloalkyl is a cyclopropyl.
  • a cycloalkyl is a cyclobutyl.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a C 1 -C 6 fluoroalkyl.
  • a fluoroalkyl is -CF3.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • non- aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyrany
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-l-yl (N-attached) or pyrrol- 3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both ⁇ -attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a Ci-Cyheteroaryl.
  • monocyclic heteroaryl is a Ci-Csheteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a Ce-Cgheteroaryl.
  • a “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl.
  • a heterocycloalkyl is a C 2 -C 10 heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C 10 heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8 -membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring.
  • a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , - CHF2, -CF 3 , -OCH 3 , -OCHF2, and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an antagonist.
  • a modulator is an inhibitor.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action.
  • these methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
  • topical and rectal administration include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
  • topical and rectal administration include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intra
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g., a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a coagent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • active ingredients e.g., a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a coagent
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • the heterocyclic LpxC inhibitory compound as described herein is administered as a pure chemical.
  • the heterocyclic LpxC inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • composition comprising at least one heterocyclic LpxC inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.
  • Some embodiments provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • the heterocyclic LpxC inhibitory compound as described by Formula (I) or (XI) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • composition comprising at least one heterocyclic LpxC inhibitory compound as described herein differ, depending upon the patient’s condition, that is, stage of the disease, general health status, age, and other factors.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • R 1 , R 2a , R 2b , R 4 , R 5 , R 6 , R 7 , L 1 , L a , s, and t are defined in any one of claims 1-43; and (2) removing PG to provide the compound of Formula (I).
  • the compound of Formula (A) is a compound of Formula (B):
  • R 1 , R 2a , R 2b , R 4 , R 5 , R 6 , R 7 , R 12 , R 13 , L 1 , L a , s, and t are defined herein;
  • the compound of Formula (X-A) is a compound of Formula (X-B):
  • the phosphorylating reagent is phosphoryl trichloride (POCI3).
  • the phosphorylating reagent is di-tert-butyl N,N-diisopropylphosphoramidite.
  • the phosphorylating reagent is a phosphite, phosphoramidite, or phosphorus oxyhalide.
  • the phosphorylating reagent is a phosphorus (III) reagent.
  • the phosphorylating reagent is a phosphorus (V) reagent.
  • PG is tetrahydropyranyl (THP).
  • PG is acetyl (Ac), benzoyl (Bz), benzyl (Bn), methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), pivaloyl (Piv), tert-butyl (tBu), tetrahydropyranyl (THP), trimethylsilyl (TMS), or tertbutyldimethylsilyl (TBS).
  • ACN or MeCN acetonitrile
  • aq aqueous
  • B2pin2 bis(pinacolato)diboron
  • DCM dichloromethane
  • DHP 3,4-dihydro-2H-pyran
  • DIAD diisopropyl azodicarboxylate
  • DMP Dess-Martin periodinane
  • DPPA diphenylphosphoryl azide
  • EtOAc ethyl acetate
  • g grams
  • h or hr(s) hour(s);
  • K2CO3 potassium carbonate
  • LDA lithium diisopropylamide
  • MeNCh nitromethane; mg: milligrams; min: minute; mL: milliliter; mmol: millimole;
  • MsCl methanesulfonyl (mesyl) chloride
  • NBS A-bromosuccinimide
  • Pet ether petroleum ether
  • PdCh(dppf) [l,r-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride;
  • PdCh(dtbpf) bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);
  • Pd(PPhs)4 palladium-tetrakis(triphenylphosphine);
  • PPTS pyridinium p-toluenesulfonate
  • p-TSA para-toluenesuflonic acid
  • TEA triethylamine (or EtsN);
  • TFA trifluoroacetic acid
  • THP tetrahydropyran
  • TsCl para-toluenesulfonyl (tosyl) chloride.
  • Step 2 [00220] To a solution of 3 (1.3 g, 1.89 mmol) in MeOH (20 mL), was added p-toluenesulfonic acid monohydrate (1.08 g, 5.67 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (50 mL), washed with 10% NaHCO3 solution (20 mL). The organic layer was dried over anhydrous ISfeSCL, filtered, and concentrated under reduced pressure.
  • Step l
  • Step l
  • Step 3 [00268] To a stirred solution of 4 (900 mg, 1.484 mmol) in DCM (15 mL), were added tetrakis(triphenylphosphine)palladium (0) (86 mg, 0.074 mmol) and pyrrolidine (0.123 mL, 1.484 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The obtained solid was triturated with EtOAc (20 mL) and dried under vacuum.
  • Step l
  • Step l
  • Step 4 [00309] To a stirred solution of 5-Isomer-2 (4 g, 14.65 mmol) in DCM (50 mL), were added 3,4- Dihydro-2H-pyran (4.02 mL, 43.9 mmol), pyridinium p-toluenesulfonate (PPTS) (0.368 g, 1.465 mmol) at room temperature and stirred for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with 5% EtOAc in hexanes (50 mL x 3).
  • PPTS pyridinium p-toluenesulfonate
  • Step l
  • Step l
  • Step 2 [00338] To a solution of 2 (50.0 g, 153 mmol) in DMF (330 mL), were added caesium carbonate (83 g, 254 mmol) and 4-bromophenol (3, 22 g, 127 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. Two more batches were performed with 22 g of 3. All three batches were mixed for work-up and purification. The reaction mixture was cooled to room temperature, quenched with ice-cold water (500 mL) and extracted with EtOAc (500 mL x 3).
  • Step l
  • Step l [00375] To a stirred solution of 1 (1.2 g, 1.475 mmol) in ACN (20 mL), were added pyridine (0.355 ml, 4.42 mmol) followed by phosphoryl trichloride (0.275 mL, 2.95 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at 25 °C for 30-40 min. To the reaction mixture, water (4 mL) was added and stirred for 30 min at 25 °C.
  • Step-1 & 2
  • Step l
  • the supernatant solvent was decanted and the resulting crude, thus obtained purified by reverse phase column chromatography (column: Redisep Gold, Cl 8 SiO2; 10 mM ammonium bicarbonate in water and ACN) to afford 250 mg of product.
  • the product was re-purified using RP-MPLC (column: Redisep Gold, Cl 8 SiO2; water and ACN) to afford Compound 55 as an off-white solid.
  • Step 15 [00580] To a stirred solution of 11 (1.5 g, 3.46 mmol) and boronate 17 (2.026 g, 5.19 mmol) in acetonitrile (15 mL) and water (5 mL), was added potassium carbonate (1.435 g, 10.38 mmol) and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.226 g, 0.346 mmol) was added and the reaction mixture heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL).
  • Step l [00596] To a stirred solution of 2 (2.0 g, 4.77 mmol) and 1 (3.02 g, 7.15 mmol) in a mixture of THF (50 mL) and water (5 mL), was added potassium phosphate tribasic (3.04 g, 14.31 mmol) and the reaction mixture purged with nitrogen for 5 min. Then, SPhos Pd G2 (0.344 g, 0.477 mmol) was added, and the reaction mixture stirred at 80 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL).

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Abstract

L'invention concerne des composés hétérocycliques et des compositions pharmaceutiques contenant lesdits composés qui sont utiles pour inhiber la croissance de bactéries à Gram négatif. Les composés et compositions de l'invention sont utiles pour le traitement d'infections bactériennes, telles que la pneumonie.
PCT/US2025/015580 2024-02-13 2025-02-12 Composés antibactériens Pending WO2025174875A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018216822A1 (fr) * 2017-05-25 2018-11-29 Taisho Pharmaceutical Co., Ltd. Nouveaux dérivés d'imidazole
WO2022173758A1 (fr) * 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2022173756A1 (fr) * 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2024036176A1 (fr) * 2022-08-10 2024-02-15 Blacksmith Medicines, Inc. Composés antibactériens
WO2024036170A1 (fr) * 2022-08-10 2024-02-15 Blacksmith Medicines, Inc. Composés antibactériens

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018216822A1 (fr) * 2017-05-25 2018-11-29 Taisho Pharmaceutical Co., Ltd. Nouveaux dérivés d'imidazole
WO2022173758A1 (fr) * 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2022173756A1 (fr) * 2021-02-11 2022-08-18 Forge Therapeutics, Inc. Composés antibactériens
WO2024036176A1 (fr) * 2022-08-10 2024-02-15 Blacksmith Medicines, Inc. Composés antibactériens
WO2024036170A1 (fr) * 2022-08-10 2024-02-15 Blacksmith Medicines, Inc. Composés antibactériens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAMADA, Y. ET AL.: "Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 23, 2020, pages 14805 - 14820, XP055942039, DOI: 10.1021/acs.jmedchem.0c01215 *

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