Antimicrobial compounds

Abstract

Provided herein are 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 treating bacterial infections, such as pneumonia.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 148,261, filed February 11, 2021, which is incorporated by reference in its entirety herein.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with Government support under IDSEP 160030 awarded by the United States Department of Health and Human Services. The Government has certain rights in this invention. [Background technology]

[0003] There is a need in the medical arts for effective treatments for diseases caused by bacterial infections. Summary of the Invention

[0004] Provided herein are heterocyclic compounds and pharmaceutical compositions comprising said compounds useful for inhibiting the growth of gram-negative bacteria. The subject compounds and compositions are useful for treating bacterial infections such as pneumonia. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulator compounds. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitors.

[0005] In one embodiment, a compound of formula (I):

[0006] [ka] or a pharma- ceutically acceptable salt or solvate thereof as described herein, 1 is C1-C4 alkyl, R 2a and R 2b are each independently hydrogen, halogen, or C1-C4 alkyl; R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 4 is hydrogen or C1-C4 alkyl; R 5 and R 6 are each independently hydrogen, halogen, or C1-C4 alkyl; R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; Alternatively, two R attached to the same nitrogen 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3; s is 1 or 2; and t is 1 or 2.

[0007] In some embodiments, the compound of formula (I) is a compound of formula (IIa):

[0008] [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein: R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 5 is hydrogen or fluoro; R 6 is hydrogen or fluoro; R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; Alternatively, two R attached to the same nitrogen 8together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0009] In some embodiments, the compound of formula (I) or (IIa) is a compound of formula (III):

[0010] [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein: R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 5 is hydrogen or fluoro; R 6 is hydrogen or fluoro; R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8, -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; Alternatively, two R attached to the same nitrogen 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0011] In some embodiments, the compound of formula (I) is a compound of formula (IV):

[0012] [ka] or a pharma- ceutically acceptable salt or solvate thereof; R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0013] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0014] Also described herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ocular administration.In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration.In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0015] In another aspect, provided herein is a method of treating or preventing a gram-negative bacterial infection in a patient, the method comprising administering to the patient a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In some embodiments, 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, provided herein is a gram-negative bacterial infection is community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or a combination thereof. In some embodiments, the patient is identified as suffering from a pulmonary disease. In some embodiments, the pulmonary disease is a structural pulmonary disease. In some embodiments, the pulmonary disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic depleted lung disease, or a combination thereof. In some embodiments, the administration is for treating an existing infection. In some embodiments, the administration is provided as a prophylactic method. In some embodiments, the compound or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition described herein is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.

[0016] In another aspect, provided herein is a method of inhibiting a UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase enzyme, the method comprising contacting the enzyme with a compound described herein.

[0017] In another aspect, provided herein is a method for treating a bacterial infection in a patient, the method comprising administering to the patient a composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0018] In any of the foregoing aspects, further embodiments are provided, wherein an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation, and / or (e) administered intranasally, or, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by eye drops, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0019] In any of the above aspects, further embodiments comprising a single administration of an effective amount of the compound include further embodiments in which the compound is administered to the mammal once a day, or the compound is administered to the mammal multiple times during the day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0020] In any of the embodiments disclosed herein, the mammal is a human.

[0021] Kits are provided that include packaging material and a compound of Formula (I) or a pharma- ceutically acceptable salt within the packaging material, and a label indicating that the compound or composition, or a pharma- ceutically acceptable salt, tautomer, pharma- ceutically acceptable N-oxide, pharma- ceutically active metabolite, pharma- ceutically acceptable prodrug, or pharma- ceutically acceptable solvate thereof, is used to modulate UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine] deacetylase (LpxC) or for the treatment, prevention, or amelioration of one or more symptoms of a disease or condition that would benefit from modulation of UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine] deacetylase (LpxC).

[0022] Other objectives, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, but it will be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0023] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] LpxC, lipid A, and gram-negative bacteria Metalloproteins affect a wide variety of biological systems, biological processes, and diseases. For example, UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine] deacetylase (LpxC) is an essential enzyme involved in the first critical step in lipid A biosynthesis in Gram-negative bacteria. Lipid A is an essential component of the Gram-negative bacterial outer membrane. LpxC is a zinc(II)-dependent metalloenzyme with two histidine and aspartic acid residues bound to a zinc(II) ion. The structure of LpxC shows that the zinc(II) ion is bound to two water molecules, both of which are involved in the mechanism of the enzyme. LpxC is highly conserved across strains of Gram-negative bacteria, making LpxC an attractive target for treating Gram-negative infections. Conversely, LpxC is not a component of Gram-positive bacteria such as Staphylococcus aureus.

[0025] In recent years, resistant and multidrug-resistant strains of bacteria have increased. Therefore, new antibiotics, especially those with new mechanisms of action, are needed. There remains a need for metalloprotein modulators of LpxC that are useful in the fields of therapy, diagnosis, and research.

[0026] Some embodiments provide a method of inhibiting a UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine] deacetylase enzyme, comprising contacting the enzyme with a compound of formula (I).

[0027] In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0028] How to use Disclosed herein is a method for treating a disease in which inhibition of bacterial growth is indicated. Such a disease includes a gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, a method for treating a gram-negative bacterial infection in a patient in need of treatment for the gram-negative bacterial infection comprises administering to the patient a pharmaceutical composition comprising a compound of formula (I), a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, a method for treating a Pseudomonas aeruginosa infection in a patient in need of treatment for the Pseudomonas aeruginosa infection comprises administering to the patient a pharmaceutical composition comprising a compound of formula (I), a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0029] In some embodiments, 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), healthcare-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associated 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 healthcare-associated pneumonia (HCAP). In some embodiments, the Gram-negative bacterial infection is hospital-acquired pneumonia (HAP). In some embodiments, the Gram-negative bacterial infection is ventilator-associated pneumonia (VAP).

[0030] In some embodiments, the patient has been identified as suffering from a pulmonary disease. In some embodiments, the pulmonary disease is a structural pulmonary disease. In some embodiments, the pulmonary disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic degenerative lung disease, or a combination thereof. In some embodiments, the patient has cystic fibrosis. In some embodiments, the patient has bronchiectasis. In some embodiments, the patient has emphysema. In some embodiments, the patient has chronic obstructive pulmonary disease (COPD). In some embodiments, the patient has chronic degenerative lung disease.

[0031] In some embodiments, the administration is to treat an existing infection.

[0032] In some embodiments, administration is provided as a prophylactic method.

[0033] In some embodiments, the LpxC inhibitor compounds described herein are used to treat or prevent conditions caused by bacterial production of endotoxins, particularly gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxins. In some embodiments, a method for treating or preventing a condition caused by endotoxins or LPS in a patient comprises administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another embodiment, the heterocyclic LpxC inhibitor compounds described herein are useful in treating conditions caused or exacerbated by bacterial production of lipid A and LPS or endotoxins, such as chronic obstructive pulmonary disease (COPD) and acute exacerbation of chronic bronchitis (AECB). In some embodiments, the method of treating or preventing an endotoxin- or LPS-induced condition in a patient comprises administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable excipient, wherein the endotoxin- or LPS-induced condition is selected from chronic obstructive pulmonary disease (COPD) and acute exacerbation of chronic bronchitis (AECB).

[0034] In other embodiments, the compounds of the disclosure are effective in treating severe or chronic respiratory tract infections, including severe pulmonary infections and hospital-acquired infections, such as Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kuyvera ascorbata, Kuyvera cryocrescense, Shigella sonnei, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and the like. 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 species, Burkholderia species, and Proteus species. Infections caused by Neisseria species, as well as other bacterial species, e.g., Neisseria species, Shigella speciesIn some embodiments, the compounds of the present disclosure may be used to treat infections caused by Salmonella species, Salmonella species, Helicobacler pylori, Vibrionaceae, and Bordetella species, as well as infections caused by Brucella species, Francisella tularensis, and / or Yersinia pestis. In some embodiments, the infection is associated with Pseudomonas spp. In some embodiments, the infection is associated with Pseudomonas aeruginosa. In some embodiments, the compounds of the present disclosure do not inhibit the growth of gram-positive bacteria, such as Staphylococcus aureus.

[0035] In some embodiments, the LpxC inhibitor compounds described herein are used in methods of preventing the growth of Pseudomonas. In some embodiments, the Pseudomonas is Pseudomonas aeruginosa.

[0036] In some instances, antibiotics have suboptimal concentrations in the lungs, which leads to therapeutic failure of lung infection. In some embodiments, the heterocyclic LpxC inhibitor compound of formula (I) has optimal concentrations in the lungs to treat or prevent Gram-negative bacterial infection in the lungs. In some embodiments, the compound is present in the lungs in a therapeutically effective amount after administration.

[0037] In some embodiments, disclosed herein are compounds described herein, or pharma- ceutically acceptable salts thereof, for use as therapeutically active substances.

[0038] In some embodiments, the present disclosure provides a compound as described herein or a pharma- ceutically acceptable salt thereof for use in treating or preventing gram-negative bacterial infection.In some embodiments, 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 respiratory infection is pneumonia.

[0039] In some embodiments, the present disclosure provides the use of the compound described herein or its pharma- ceutically acceptable salt for the preparation of a medicament for treating or preventing gram-negative bacterial infection.In some embodiments, 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 respiratory infection is pneumonia.

[0040] LpxC inhibitors In some embodiments, heterocyclic LpxC inhibitor compounds and pharmaceutical compositions comprising the compounds are provided herein. The subject compounds and compositions are useful for inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) and for treating bacterial infections.

[0041] In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine} deacetylase (LpxC) modulators. In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine} deacetylase (LpxC) antagonists. In some embodiments, the compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates, are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine} deacetylase (LpxC) inhibitors.

[0042] One aspect of the disclosure is a compound having the structure of formula (I):

[0043] [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, R 1 is C1-C4 alkyl, R 2a and R 2b are each independently hydrogen, halogen, or C1-C4 alkyl; R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 4 is hydrogen or C1-C4 alkyl; R 5 and R 6 are each independently hydrogen, halogen, or C1-C4 alkyl; R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; Alternatively, two R attached to the same nitrogen 8together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3; s is 1 or 2; and t is 1 or 2.

[0044] In some embodiments, R 1 is C1-C4 alkyl, R 2a and R 2b are each independently hydrogen, halogen, or C1-C4 alkyl; R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 4 is hydrogen or C1-C4 alkyl; R 5 and R 6 are each independently hydrogen, halogen, or C1-C4 alkyl; R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R8 )2, -NHCOR 8 , -NHSO2R 8 , C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 aminoalkyl; R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted with one or two groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3; Alternatively, two R attached to the same nitrogen 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3; s is 1 or 2; and t is 1 or 2.

[0045] In some embodiments, the compound of formula (I) is a compound of formula (Ia) or formula (Ib)

[0046] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0047] In some embodiments, the compound is a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof.

[0048] For any or all of the embodiments, the substituents are selected from among a subset of the listed alternatives. For example, in some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 1 is unsubstituted C1-C4 alkyl. In some embodiments, R 1 is C1-C2 alkyl. In some embodiments, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -C(CH3)3. 1 is -CH3 or -CH2CH3. In some embodiments, R 1 is -CH3.

[0049] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 2a and R 2b are each independently hydrogen, halogen, or unsubstituted C1-C4 alkyl. 2a and R 2b are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 2a and R 2b are each independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2.

[0050] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R2a is hydrogen. In some embodiments, R 2b is hydrogen. In some embodiments, R 2a and R 2b are hydrogen.

[0051] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 1 is -CH3, R 2a is hydrogen, and R 2b is hydrogen.

[0052] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 4 is hydrogen or unsubstituted C1-C4 alkyl. In some embodiments, R 4 is C1-C2 alkyl. In some embodiments, R 4 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH). 4 is hydrogen, -CH, or -CHCH. In some embodiments, R 4 is hydrogen or -CH3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3.

[0053] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 5 and R 6 are each independently hydrogen, halogen, or unsubstituted C1-C4 alkyl. 5 and R 6are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 5 and R 6 are each independently hydrogen, -F, -Cl, -CH, -CHCH, or -CH(CH). 5 and R 6 are each independently hydrogen, fluoro, chloro, or -CH3.

[0054] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 5 are each independently hydrogen, halogen, or unsubstituted C1-C4 alkyl. 5 are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 5 are each independently hydrogen, -F, -Cl, -CH, -CHCH, or -CH(CH). 5 are each independently hydrogen, fluoro, chloro, or -CH3.

[0055] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 6 are each independently hydrogen, halogen, or unsubstituted C1-C4 alkyl. 6 are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 6are each independently hydrogen, -F, -Cl, -CH, -CHCH, or -CH(CH). 6 are each independently hydrogen, fluoro, chloro, or -CH3.

[0056] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 5 are each independently hydrogen, -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3; and R 6 Each is hydrogen. In some embodiments, R 5 are each independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2, and R 6 Each is hydrogen. In some embodiments, R 5 are each independently hydrogen, fluoro, chloro, or -CH3, and R 6 are hydrogen.

[0057] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 5 are hydrogen, and R 6 are each independently hydrogen, -F, -Cl, -Br, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 5 are hydrogen, and R 6 are each independently hydrogen, -F, -Cl, -CH, -CHCH, or -CH(CH). 5 are hydrogen, and R 6 are each independently hydrogen, fluoro, chloro, or -CH3.

[0058] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 5 and R 6 are hydrogen.

[0059] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), s is 1. In some embodiments, s is 2.

[0060] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), t is 1. In some embodiments, t is 2.

[0061] In some embodiments of a compound of Formula (I), (Ia), or (Ib), s is 1 or 2 and t is 1. In some embodiments, s is 1 or 2 and t is 2. In some embodiments, s is 1 and t is 1. In some embodiments, s is 2 and t is 1.

[0062] In some embodiments of a compound of Formula (I), (Ia), or (Ib), t is 1 or 2 and s is 1. In some embodiments, t is 1 or 2 and s is 2. In some embodiments, t is 1 and s is 1. In some embodiments, t is 2 and s is 1.

[0063] In some embodiments of the compounds of Formula (I), (Ia), or (Ib), R 5 and R 6 are each independently hydrogen, fluoro, chloro, or -CH3, s is 1, and t is 1.

[0064] In some embodiments, the compound of formula (I) is a compound of formula (II):

[0065] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0066] In some embodiments, R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro.

[0067] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro, and R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; and 8are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted by 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0068] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro, and R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 aminoalkyl; and 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted by one, two, or three groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted by one or two groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen are each independently substituted by one, two, or three groups independently selected from 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0069] In some embodiments, the compound of formula (I) or (II) is a compound of formula (IIa) or formula (IIb)

[0070] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0071] In some embodiments, R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro.

[0072] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro, and R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; and 8are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted by 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0073] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro, and R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 aminoalkyl; and 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted by one, two, or three groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted by one or two groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen are each independently substituted by one, two, or three groups independently selected from 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0074] In some embodiments, the compound is a compound of formula (IIa) or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of formula (IIb) or a pharma- ceutically acceptable salt or solvate thereof.

[0075] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), R 5 is hydrogen. In some embodiments, R 5 is fluoro.

[0076] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), R 6 is hydrogen. In some embodiments, R 6 is fluoro.

[0077] In some embodiments of the compounds of Formula (II), (IIa), or (IIb), R 5 is hydrogen, and R 6 is hydrogen. In some embodiments, R 5 is fluoro, and R 6 is hydrogen. In some embodiments, R 5 is hydrogen, and R 6 is fluoro. In some embodiments, R 5 is fluoro, and R 6 is fluoro.

[0078] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (IIId)

[0079] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0080] In some embodiments, R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro.

[0081] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro, and R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , -CHCN, C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 aminoalkyl; and 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted by 1 or 2 groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen 8together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0082] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2, and R 5 is hydrogen or fluoro, and R 6 is hydrogen or fluoro, and R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C6 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-(C3-C6 cycloalkyl), -(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(C3-C6 cycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), or -(C1-C4 alkylene)-O-(4-6 membered heterocycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -CO2R 8 , -CON(R 8 )2, -CH2N(R 8 )2, -NHCOR 8 , -NHSO2R 8 , C1-C4 alkyl, C1-C4 hydroxyalkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 aminoalkyl; and 8are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted by one, two, or three groups independently selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, -SO2CH3, -C(=NH)NH2, phenyl, and monocyclic heteroaryl which is unsubstituted or substituted by one or two groups selected from -F, -CN, -OH, -NH2, -OMe, -N(CH3)2, -CO2H, -CONH2, and -SO2CH3, or two R attached to the same nitrogen are each independently substituted by one, two, or three groups independently selected from 8 together form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH2, -OMe, -CO2H, -CONH2, and -SO2CH3.

[0083] In some embodiments, the compound is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of formula (IIIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound of formula (IIId), or a pharma- ceutically acceptable salt or solvate thereof.

[0084] In some embodiments of the compounds of Formula (III), (IIIa), or (IIIb), R 5 is hydrogen. In some embodiments, R 5 is fluoro.

[0085] In some embodiments of the compounds of Formula (III), (IIIa), or (IIIb), R 6 is hydrogen. In some embodiments, R 6 is fluoro.

[0086] In some embodiments of the compounds of Formula (III), (IIIa), or (IIIb), R 5 is hydrogen, and R 6 is hydrogen. In some embodiments, R 5 is fluoro, and R 6 is hydrogen. In some embodiments, R 5 is hydrogen, and R 6 is fluoro. In some embodiments, R 5 is fluoro, and R 6 is fluoro.

[0087] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 3 is hydrogen.

[0088] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 3 is -(C1-C4 alkylene)-OH. In some embodiments, R 3 is -(C1-C2 alkylene)-OH. In some embodiments, R 3 is -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCHCHOH, -CH(CH)OH, -CHCH(CH)OH, -CH(CH)CHOH, -CHCH(CHCH)OH, or -CH(CHCH)CHOH. 3 is -CHOH, -CHCHOH, or -CH(CH)OH. In some embodiments, R 3 is -CHOH or -CHCHOH. In some embodiments, R 3 is -CHOH. In some embodiments, R 3 is -CH2CH2OH.

[0089] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 3 is -(C1-C4 alkylene)-NH2. In some embodiments, R 3 is -(C1-C2 alkylene)-NH2. In some embodiments, R 3 is -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, -CH(CH3)NH2, -CH2CH(CH3)NH2, -CH(CH3)CH2NH2, -CH2CH(CH2CH3)NH2, or -CH(CH2CH3)CH2NH2. In some embodiments, R 3 is -CHNH, -CHCHNH, or -CH(CH)NH. In some embodiments, R 3 is -CHNH or -CHCHNH. In some embodiments, R 3 is -CH2NH2.

[0090] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 3 is hydrogen or -(C1-C4 alkylene)-OH. In some embodiments, R 3 is hydrogen or -(C1-C2 alkylene)-OH. In some embodiments, R 3 is hydrogen, -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCHOH, -CHCHCHCHOH, -CH(CH)OH, -CHCH(CH)OH, -CH(CH)CHOH, -CHCH(CHCH)OH, or -CH(CHCH)CHOH. 3 is hydrogen, -CHOH, -CHCHOH, or -CH(CH)OH. In some embodiments, R 3is hydrogen, -CHOH, or -CHCHOH. In some embodiments, R 3 is hydrogen or -CHOH.

[0091] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 3 is hydrogen, -(C1-C2 alkylene)-OH, or -(C1-C2 alkylene)-NH2. In some embodiments, R 3 is hydrogen, -CHOH, -CHCHOH, or -CHNH. In some embodiments, R 3 is hydrogen, -CH2OH, or -CH2NH2.

[0092] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl). 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8, -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl. 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, NHSO2R 8 In some embodiments, R is substituted with one or two groups independently selected from -CHCN, -CH 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, and NHSO2R 8 and wherein the aryl group is substituted with one or two groups independently selected from:

[0093] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 8are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, where alkyl is unsubstituted or substituted with one or two groups independently selected from -CN, -OH, and oxadiazolyl. 8are each independently hydrogen or C1-C2 alkyl, wherein the C1-C2 alkyl is unsubstituted or substituted by one or two groups independently selected from -CN, -OH, and oxadiazolyl.

[0094] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0095] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8, -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; and 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5-membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0096] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, -NHSO2R 8 -CHCN; and -CHCN; 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, where alkyl is unsubstituted or substituted with one or two groups independently selected from -CN, -OH, and oxadiazolyl. 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, -NHSO2R 8 -CHCN; and -CHCN; 8 are each independently hydrogen or C1-C2 alkyl, wherein the C1-C2 alkyl is unsubstituted or substituted by one or two groups independently selected from -CN, -OH, and oxadiazolyl.

[0097] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7is C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 heteroalkyl, where the alkyl, alkoxy, or heteroalkyl is optionally substituted with 1, 2, or 3 groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2.

[0098] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C6 alkoxy. In some embodiments, R 7 is C1-C5 alkoxy. In some embodiments, R 7 is C3-C5 alkoxy.

[0099] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C6 alkoxy. In some embodiments, R 7 is C1-C6 alkoxy, where the alkoxy is unsubstituted or -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen or C1-C4 alkyl. 7 is C1-C6 alkoxy, and the alkoxy is -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen or C1-C4 alkyl. 7 is C1-C6 alkoxy, where the alkoxy is unsubstituted or -OR 8 and -N(R 8 )2; and R8 are each independently hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 7 is C1-C6 alkoxy, and the alkoxy is -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 7 is C1-C6 alkoxy, where the alkoxy is unsubstituted or -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen, -CH, -CHCH, or -CH(CH). In some embodiments, R 7 is C1-C6 alkoxy, and the alkoxy is -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen, -CH, -CHCH, or -CH(CH). In some embodiments, R 7 is a C1-C6 alkoxy, where the alkoxy is unsubstituted or substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is a C1-C6 alkoxy, wherein the alkoxy is substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. 7is a C1-C6 alkoxy, wherein the alkoxy is unsubstituted or substituted with one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is a C1-C6 alkoxy, wherein the alkoxy is substituted by one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2.

[0100] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C1-C5 alkoxy. In some embodiments, R 7 is C1-C5 alkoxy, where the alkoxy is unsubstituted or -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen or C1-C4 alkyl. 7 is a C1-C5 alkoxy, where the alkoxy is unsubstituted or substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is a C1-C5 alkoxy, wherein the alkoxy is substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. 7 is a C1-C5 alkoxy, wherein the alkoxy is unsubstituted or substituted with one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is a C1-C5 alkoxy, wherein the alkoxy is substituted with one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7is a C1-C5 alkoxy, wherein the alkoxy is substituted by one or two groups independently selected from -OH, -OCH3, and -NH2.

[0101] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C-C alkoxy. In some embodiments, R 7 is C3-C5 alkoxy, where the alkoxy is unsubstituted or -OR 8 and -N(R 8 )2; and R 8 are each independently hydrogen or C1-C4 alkyl. 7 is a C3-C5 alkoxy, where the alkoxy is unsubstituted or substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is a C3-C5 alkoxy, where the alkoxy is substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. 7 is a C3-C5 alkoxy, wherein the alkoxy is unsubstituted or substituted with one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is a C3-C5 alkoxy, wherein the alkoxy is substituted by one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2.

[0102] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7is C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl). 7 is C3-C4 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where cycloalkyl or heterocycloalkyl is unsubstituted or is -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7 is C3-C4 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where cycloalkyl or heterocycloalkyl is unsubstituted or is -OR 8 , -N(R 8 )2, -NHSO2R 8, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7 is C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where cycloalkyl or heterocycloalkyl is unsubstituted or -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, and monocyclic 5-membered heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7 is C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where cycloalkyl or heterocycloalkyl is unsubstituted or -OR 8 , -N(R 8 )2, -NHSO2R 8, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen or C1-C2 alkyl, which is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, and monocyclic 5-membered heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0103] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is -O-(C3-C6 cycloalkyl) or -O-(3- to 6-membered heterocycloalkyl), where the cycloalkyl or heterocycloalkyl is unsubstituted or -OR 8 , -N(R 8 )2, C1-C4 alkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is -O-(C3-C6 cycloalkyl) or -O-(3- to 6-membered heterocycloalkyl), where the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, -N(CH3)2, -CH3, and -CH2CH2OH. In some embodiments, R 7 is -O-(C3-C6 cycloalkyl) or -O-(3- to 6-membered heterocycloalkyl), where the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two groups independently selected from -OH, -OCH3, -NH2, -N(CH3)2, -CH3, and -CH2CH2OH.

[0104] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is -O-(C3-C6 cycloalkyl). In some embodiments, R 7 is -O-(C3-C6 cycloalkyl), where cycloalkyl is unsubstituted or -OR 8 , -N(R 8 )2, C1-C4 alkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is -O-(C3-C6 cycloalkyl), where cycloalkyl is unsubstituted or -OR 8 and -N(R 8 In some embodiments, R 7 is -O-(C3-C6 cycloalkyl), where cycloalkyl is unsubstituted or substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is -O-(C3-C6 cycloalkyl), where cycloalkyl is unsubstituted or substituted with one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is -O-(C3-C6 cycloalkyl), where cycloalkyl is unsubstituted or substituted with one or two groups independently selected from -OH and -NH2.

[0105] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is -O-(C3-C4 cycloalkyl), where cycloalkyl is unsubstituted or -OR 8 , -N(R 8)2, C1-C4 alkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is -O-(C3-C4 cycloalkyl), where cycloalkyl is unsubstituted or -OR 8 and -N(R 8 In some embodiments, R 7 is -O-(C3-C4 cycloalkyl), where cycloalkyl is unsubstituted or substituted with one, two, or three groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is -O-(C3-C4 cycloalkyl), where the cycloalkyl is substituted with one or two groups independently selected from -OH, -OCH3, -NH2, and -N(CH3)2. In some embodiments, R 7 is -O-(C3-C4 cycloalkyl), wherein the cycloalkyl is substituted by one or two groups independently selected from -OH and -NH2.

[0106] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is -O-(cyclopropyl), where cyclopropyl is unsubstituted or substituted with one or two groups independently selected from -OH and -NH. In some embodiments, R 7 is -O-(cyclopropyl), where cyclopropyl is substituted with one group selected from -OH and -NH. In some embodiments, R 7 is -O-(cyclopropyl), where cyclopropyl is substituted with one -OH group. 7 is -O-(cyclopropyl), where the cyclopropyl is substituted by one -NH2 group.

[0107] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is -O-(4-6 membered heterocycloalkyl). In some embodiments, R 7 is -O-(4-6 membered heterocycloalkyl), where heterocycloalkyl is unsubstituted or -OR 8 , -N(R 8 )2, C1-C4 alkyl, and C1-C4 hydroxyalkyl. In some embodiments, R 7 is -O-(4-6 membered heterocycloalkyl), where heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 groups independently selected from -OH, -OCH, -NH, -N(CH), and -CH. In some embodiments, R 7 is -O-(4-6 membered heterocycloalkyl), where the heterocycloalkyl is substituted with one or two groups independently selected from -OH, -OCH, -NH, -N(CH), -CHCN, -CH, and -CHCHOCH. 7 is -O-(4-6 membered heterocycloalkyl), where the heterocycloalkyl is substituted with one or two groups independently selected from -OH, -OCH, -NH, -N(CH), and -CH. In some embodiments, R 7 is -O-(4-6 membered heterocycloalkyl), wherein the heterocycloalkyl is substituted by one or two groups independently selected from -OH, -OCH3, -NH2, -N(CH3)2, and -CH3.

[0108] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R7 is -O-(tetrahydrofuranyl), which is unsubstituted or substituted with one or two groups independently selected from -OH, -OCH, -NH, -N(CH), and -CHCHOH. In some embodiments, R 7 is -O-(tetrahydrofuranyl), wherein the tetrahydrofuranyl is substituted by one group selected from -OH and -NH2.

[0109] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 is C-C cycloalkyl. In some embodiments, R 7 is C3-C4 cycloalkyl, cycloalkyl being -N(R 8 )2, -OR 8 , and -NHSO2R 8 and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7 is C3-C4 cycloalkyl, cycloalkyl being -N(R 8 )2, -OR 8 , and -NHSO2R 8 and R 8are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group. In some embodiments, R 7 is C3-C4 cycloalkyl, where cycloalkyl is -OH, -OMe, and -N(R 8 )2, and -NHSO2R 8 and R 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, where alkyl is unsubstituted or substituted with one or two groups independently selected from -CN, -OH, and oxadiazolyl. 7 is C3-C4 cycloalkyl, where cycloalkyl is -OH, -OMe, and -N(R 8 )2, and -NHSO2R 8 and R 8 are each independently hydrogen or C1-C2 alkyl, wherein the C1-C2 alkyl is unsubstituted or substituted with one or two groups independently selected from -CN, -OH, and oxadiazolyl. 7 is cyclobutyl, which has one -N(R 8 ) groups, and R 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C4 alkyl, where alkyl is unsubstituted or substituted with one or two groups independently selected from -CN, -OH, and oxadiazolyl. 7 is cyclobutyl, which has one -N(R 8 ) groups, and R 8are each independently hydrogen or C1-C2 alkyl, wherein the C1-C2 alkyl is unsubstituted or substituted by one or two groups independently selected from -CN, -OH, and oxadiazolyl.

[0110] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0111] [ka]

[0112] [ka] It is.

[0113] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0114] [ka]

[0115] [ka] It is.

[0116] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0117] [ka] It is.

[0118] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0119] [ka]

[0120] [ka] It is.

[0121] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0122] [ka] It is.

[0123] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIIa), (IIIb), (IIIc), or (IIId), R 7 teeth

[0124] [ka] It is.

[0125] In some embodiments of the compounds of formula (I), R 1 is -CH3, R 2a and R 2b are hydrogen, R 3is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 4 is hydrogen, R 5 and R 6 are hydrogen, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0126] In some embodiments of the compounds of formula (I), R 1 is -CH3, R 2a and R 2b are hydrogen, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 4 is hydrogen, R 5 and R 6 are hydrogen, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0127] In some embodiments of the compounds of formula (I), R 1 is -CH3, R 2a and R 2b are hydrogen, R 3 is hydrogen or -(C1-C4 alkylene)-OH, R 4 is hydrogen, R 5 and R 6 are hydrogen, R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5-membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0128] In some embodiments of the compounds of formula (I), R 1 is -CH3, R 2a and R 2b are hydrogen, R 3 is hydrogen or -(C1-C4 alkylene)-OH, R 4 is hydrogen, R 5 and R 6 are hydrogen, R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5-membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0129] In some embodiments of the compounds of formula (I), R 1 is -CH3, R 2a and R 2b are hydrogen, R 3 is hydrogen or -CHOH, R 4 is hydrogen, R 5 and R 6 are hydrogen, R 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R8 )2, -NHSO2R 8 -CHCN; and -CHCN; R 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, wherein alkyl is unsubstituted or substituted with one or two groups independently selected from -CN, -OH, and oxadiazolyl.

[0130] In some embodiments of the compounds of Formula (I), R 1 is -CH3, R 2a and R 2b are hydrogen, R 3 is hydrogen or -CHOH, R 4 is hydrogen, R 5 and R 6 are hydrogen, R 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, and -NHSO2R 8 and R 8 are each independently hydrogen or C1-C2 alkyl, wherein the C1-C2 alkyl is unsubstituted or substituted by one or two groups independently selected from -CN, -OH, and oxadiazolyl.

[0131] In some embodiments, the compound of formula (I) is a compound of formula (IV):

[0132] [ka] or a pharma- ceutically acceptable salt or solvate thereof. R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 methoxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0133] In some embodiments, R 3 is hydrogen, -(C1-C4 alkylene)-OH, or -(C1-C4 alkylene)-NH2; R 7is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0134] In some embodiments of the compound of formula (IV), R 3 is hydrogen or -(C1-C4 alkylene)-OH, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8, -CHCN, C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, C1-C4 hydroxyalkyl, and C1-C4 methoxyalkyl; and R 8 are each independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5-membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0135] In some embodiments of the compound of formula (IV), R 3 is hydrogen or -(C1-C4 alkylene)-OH, R 7 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C4 cycloalkyl, 4-6 membered heterocycloalkyl, -O-(C3-C4 cycloalkyl), -O-(4-6 membered heterocycloalkyl), -O-(C1-C4 alkylene)-(4-6 membered heterocycloalkyl), or -(C1-C4 alkylene)-O-(C3-C6 cycloalkyl), where alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 )2, -NHSO2R 8 , C1-C4 alkyl, -C(=O)-C1-C4 hydroxyalkyl, and C1-C4 hydroxyalkyl; and R 8are each independently hydrogen, C1-C4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5-membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

[0136] In some embodiments of the compound of formula (IV), R 3 is hydrogen or -CHOH, R 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, -NHSO2R 8 -CHCN; and -CHCN; R 8 are each independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C4 alkyl, wherein alkyl is unsubstituted or substituted with one or two groups selected from -CN, -OH, and oxadiazolyl.

[0137] In some embodiments of the compound of formula (IV), R 3 is hydrogen or -CHOH, R 7 is C1-C5 alkoxy, C3-C4 cycloalkyl, -O-(C3-C4 cycloalkyl), or -O-(4-6 membered heterocycloalkyl), where alkoxy, cycloalkyl, or heterocycloalkyl is -OH, -OMe, -N(R 8 )2, and -NHSO2R 8 and R 8are each independently hydrogen or C1-C2 alkyl, wherein the C1-C2 alkyl is unsubstituted or substituted by one or two groups selected from -CN, -OH, and oxadiazolyl.

[0138] In some embodiments of the compound of Formula (IV), R 7 teeth,

[0139] [ka]

[0140] [ka] It is.

[0141] In some embodiments of the compound of Formula (IV), R 7 teeth,

[0142] [ka]

[0143] [ka] It is.

[0144] In some embodiments of the compound of Formula (IV), R 7 teeth,

[0145] [ka] It is.

[0146] In some embodiments of the compound of Formula (IV), R 7 teeth,

[0147] [ka]

[0148] [ka] It is.

[0149] In some embodiments of the compound of Formula (IV), R 7 teeth,

[0150] [ka] It is.

[0151] In some embodiments of the compound of Formula (IV), R 7 teeth,

[0152] [ka] It is.

[0153] In some embodiments, the compounds described herein have the structure:

[0154] [ka] In the formula, R 3 and R 7 is as listed in Table 1.

[0155] In some embodiments, R 3 is hydrogen, CH2OH, or CH2NH2.

[0156] In some embodiments, R 7 teeth,

[0157] [ka]

[0158] [ka] It is.

[0159] In some embodiments, R 7 teeth,

[0160] [ka] It is.

[0161] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0162] Exemplary compounds described herein include those set forth in the table below.

[0163] [Table 1-1]

[0164] [Table 1-2]

[0165] [Table 1-3]

[0166] [Table 1-4]

[0167] [Table 1-5]

[0168] In some embodiments, the compound is a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound is a diastereomer of a compound of Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0169] The structures and names of the compounds in Table 1 can be found in Table 1a.

[0170] [Table 2-1]

[0171] [Table 2-2]

[0172] [Table 2-3]

[0173] [Table 2-4]

[0174] [Table 2-5]

[0175] [Table 2-6]

[0176] [Table 2-7]

[0177] [Table 2-8]

[0178] [Table 2-9]

[0179] [Table 2-10]

[0180] [Table 2-11]

[0181] [Table 2-12]

[0182] In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same type of activity are included within the scope of the present disclosure.In addition, the compounds described herein can exist not only in unsolvated form, but also in solvated form, including pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0183] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic at the concentrations or amounts used, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting adversely with any of the components of the composition in which it is contained.

[0184] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species and are rapidly soluble in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, and this ability can be manipulated as an aspect of delayed- and sustained-release behavior.Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for regulated passage across biological membranes.

[0185] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. 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, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic 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, glucoheptan-1,2-disulfonic acid, ethylhexanoic ... The acidic acids include sucrose, glycerol, glyceryl, stearate, sorbitol, sorbitolsulfonic ...

[0186] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0187] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with a base. In some embodiments, a compound of formula (I) is acidic and reacts with a base. In such a situation, the acidic proton of a compound of formula (I) is replaced with a metal ion, for example, lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein cooperate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0188] Reference to pharmaceutically acceptable salts should be understood to include solvent addition forms. In some embodiments, solvates include either stoichiometric or non-stoichiometric solvents and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0189] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharma- ceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds that have the same type of activity.

[0190] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of the compound of formula (I) is susceptible to various metabolic reactions. By incorporating an appropriate substituent on the organic radical, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0191] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0192] The compounds described herein include isotopically labeled compounds, which are identical to those detailed in the various formulas and structures presented herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33Isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as P. In one embodiment, the isotopically labeled compounds described herein, e.g. 3 H and 14 Compounds incorporating a radioactive isotope such as C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0193] In some embodiments, the compounds of formula (I) have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compounds of formula (I) exist in the R configuration. In some embodiments, the compounds of formula (I) exist in the S configuration. The compounds provided herein include all diastereomeric, individual enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0194] Individual stereoisomers can be obtained as desired by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by non-chiral or chiral chromatographic columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds of formula (I) 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. In some embodiments, resolution of the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or by chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0195] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in some circumstances, they are easier to administer than the parent drug. Prodrugs are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally or alternatively, the prodrug has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of the prodrug increases the effective water solubility. An example of a prodrug, without limitation, is a compound described herein that is administered as an ester ("prodrug"), but is subsequently metabolically hydrolyzed to yield the active entity. A further example of a prodrug is a short peptide (polyamino acid) that is bonded to an acid group, and the peptide is metabolized to reveal the active moiety. In certain embodiments, after in vivo administration, the prodrug is chemically converted to the biologically, pharma- ceutical, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharma- ceutical, or therapeutically active form of the compound.

[0196] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, the hydroxyl group of the compounds disclosed herein is used to form a prodrug, and the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, an ether, or the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, where the hydroxyl is metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0197] Prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to generate a compound of formula (I) as described herein) are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0198] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety, hi some embodiments, the prodrug moiety is as described above.

[0199] In additional or further embodiments, the compounds described herein, upon administration to an organism in need thereof, are metabolized to produce metabolites that are used to produce a desired effect, including a desired therapeutic effect.

[0200] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the sum of 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 can result in specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by either administration of the compound to a host and analysis of tissue samples from the host, or by in vitro incubation of the compound with hepatocytes and analysis of the resulting compounds.

[0201] In some cases, heterocycles can exist in tautomers. In such a situation, the structure of the compound is illustrated or named in one tautomer, but it is understood that it can be illustrated or named in alternative tautomers. Alternative tautomers are expressly included in the present disclosure, such as the structure illustrated below. For example, benzimidazole or imidazole can exist in the following tautomers:

[0202] [ka]

[0203] Preparation of compounds The compounds of formula (I) described herein are synthesized using standard synthetic techniques in combination with the methods described herein, or using methods known in the art.

[0204] Unless otherwise specified, conventional methods of mass spectrometry, NMR, and HPLC are employed.

[0205] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents or other reaction conditions.

[0206] In some embodiments, the compounds described herein are prepared as depicted in Scheme A.

[0207] [ka]

[0208] Organometallic coupling reactions such as Suzuki-Miyaura coupling between intermediate A and appropriate arylboronic acids or their esters or organotrifluoroborate (BF3K) B gave intermediate C. Removal of the protecting groups using an appropriate deprotection method produced the final compound D.

[0209] In some embodiments, the compounds described herein are prepared as depicted in Scheme B.

[0210] [ka]

[0211] Reaction of the ketone-containing intermediate E with a suitable amine (R'''-NH2) under suitable reductive amination conditions (such as treatment with a borohydride reagent, e.g., NaBH4, NaCNBH3, or NaB(OAc)3H) affords intermediate F. Removal of the protecting group using a suitable deprotection method affords the final compound G.

[0212] In some embodiments, the compounds are prepared as described in the Examples.

[0213] Specific Terms As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "a cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formulas, are used herein, all combinations and subcombinations of the ranges, and specific embodiments within the ranges, are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is an approximation within experimental variation (or within statistical experimental error), and thus the number or range of numbers may vary, in some cases, by 1% to 15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, embodiments such as, for example, any compositions of matter, compositions, methods, or processes described herein "consist of" or "consist essentially of" the described features.

[0214] Definitions of the following terms used in this application are provided below unless otherwise specified. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0215] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C6" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0216] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is branched or straight chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms (i.e., C1-C 10 alkyl). A number range such as "1-10" whenever it appears herein refers to each integer within the given range. For example, "1-10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" without a number range specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. In some embodiments, the alkyl is methyl.

[0217] An "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-.

[0218] An "alkoxy" group refers to an --O(alkyl) group, where alkyl is as defined herein.

[0219] The term "alkylamine" refers to -N(alkyl) x H y It refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0220] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced with hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like. In some embodiments, the hydroxyalkyl is -CH2OH or -CH2CH2OH. In some embodiments, the hydroxyalkyl is -CH2OH. In some embodiments, the hydroxyalkyl is CH2CH2OH.

[0221] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced with amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Exemplary aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like. In some embodiments, the aminoalkyl is -CH2NH2 or -CH2CH2NH2. In some embodiments, the hydroxyalkyl is -CH2NH2. In some embodiments, the hydroxyalkyl is -CH2CH2NH2.

[0222] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0223] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0224] The term "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 a combination thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkyl in which one or two atoms are independently selected from O, NH, and S.

[0225] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0226] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocycle from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom 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 aryl and cycloalkyl.

[0227] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is C6-C10 Depending on the structure, the aryl group may be a monoradical or a diradical (i.e., an arylene group).

[0228] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic radical, where each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is 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 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl.

[0229] The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0230] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with a fluorine atom. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is -CF3.

[0231] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings containing 1-4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3-10 atoms in its ring system, with the proviso that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3-10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5-10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of 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-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.Examples of 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, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are C-linked (or C-linked) or N-linked where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, e.g., pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0232] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of 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. In some embodiments, heteroaryls contain 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0233] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, 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. In one aspect, the heterocycloalkyl is a C2-C 10 In another embodiment, the heterocycloalkyl is a C4-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyl is monocyclic or bicyclic. In some embodiments, heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0234] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one embodiment, when a group described herein is a single bond, the referenced group is not present, thereby allowing for the formation of a bond between the remaining specified groups.

[0235] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0236] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0237] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is selected from the group consisting of halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR 21 , -CO2R 21 , -C(=O)N(R 21 )2, -N(R 21 )2, -NR 21 C(=O)R 22 , -SR 21 , -S(=O)R 22 , -SO2R 22 , and -SO2N(R 21 )2; and R is substituted with one or more R groups independently selected from the group consisting of 21 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 21 The groups, together with the N atom to which they are attached, form an N-containing heterocycle; R 22 are each independently selected from C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0238] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting deleterious effects on the health status of the subject being treated.

[0239] The term "modulate" as used herein means to interact with a target directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0240] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. The interaction includes, but is not limited to, that of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is an inhibitor.

[0241] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to enable delivery of a compound or composition to a 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 administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0242] Terms like "co-administration," as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include therapeutic regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same or different times.

[0243] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound being administered that relieves to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to clinically significantly reduce a disease symptom. An appropriate "effective" amount in an individual case is optionally determined using techniques such as dose escalation studies.

[0244] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, 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 sufficient to enhance the effect of another therapeutic agent in a desired system.

[0245] The term "pharmaceutical combination" as used herein refers to a product resulting from the mixing or combination of more than one active ingredient, and includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an auxiliary agent, both administered to a patient at the same time in the form of a single entity or dosage. The term "non-fixed combination" refers to the active ingredients, e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an auxiliary agent, both administered to a patient as separate entities, simultaneously, concurrently, or sequentially, without specific intervening time restrictions, where such administration provides the patient's body with effective levels of the two compounds. The latter term also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0246] The terms "article of manufacture" and "kit" are used synonymously.

[0247] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species, farm animals such as cows, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0248] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the progression or worsening of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a secondary condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0249] Pharmaceutical Compositions In certain embodiments, the heterocyclic LpxC inhibitor compounds described herein are administered as pure chemicals. In other embodiments, the heterocyclic LpxC inhibitor compounds described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0250] Provided herein is a pharmaceutical composition comprising at least one heterocyclic LpxC inhibitor compound described herein, or a stereoisomer, pharma-ceutically acceptable salt, or N-oxide thereof, together with one or more pharma-ceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and not deleterious to the recipient of the composition (i.e., the subject or patient).

[0251] Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0252] In certain embodiments, the heterocyclic LpxC inhibitor compounds as described by formula (I) are substantially pure, in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more of the steps of the synthetic process.

[0253] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0254] The dosage of the compositions comprising at least one heterocyclic LpxC inhibitor compound as described herein will vary depending on the patient's condition, i.e., stage of the disease, general health, age, and other factors.

[0255] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dosing and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome) or a reduction in the severity of symptoms. Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses vary depending on the patient's body type, weight, or blood volume.

[0256] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0257] Combination therapy In certain instances, it will be appropriate to administer at least one compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0258] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (including a treatment regimen) that also has a therapeutic effect.

[0259] In one particular embodiment, a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is co-administered with a second therapeutic agent, where the compound of formula (I), or a pharma- ceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall effect than administration of either therapeutic agent alone.

[0260] In any case, regardless of the disease, disorder, or condition being treated, the overall effect experienced by the patient is simply the additive of the two therapeutic agents or the patient experiences a synergistic effect.

[0261] With respect to the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0262] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms (e.g., as a single pill, or as two separate pills), by way of example only.

[0263] In conjunction with the combination therapy, the compound of formula (I) or its pharma- ceutically acceptable salt is administered before, during, or after the onset of disease or illness, and the timing of administering the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to disease or illness to prevent the onset of disease or illness. In another embodiment, the compounds and compositions are administered to subjects during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as feasible after the onset of disease or illness is detected or suspected, and for the period required for the treatment of the illness. In some embodiments, the period required for treatment varies, and the treatment period is adjusted to the specific needs of each subject.

[0264] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided only as illustrative of various embodiments and are not to be construed as limiting the invention in any way. EXAMPLES

[0265] As used above, and throughout the description of the present invention, unless otherwise specified, the following abbreviations shall be understood to have the following meanings: Abbreviations: ACN or MeCN: acetonitrile, aq: water-based, Boc or BOC: tert-butoxycarbonyl, DCM: dichloromethane, DIAD: diisopropyl azodicarboxylate; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide, DMP: Dess-Martin periodinane; DPPA: diphenylphosphoryl azide; Eq. or equiv: equivalent, EtOAc: ethyl acetate, g: grams, h or hr(s): time, HPLC: High Performance Liquid Chromatography; LC-MS, LC MS, or LCMS: liquid chromatography-mass spectrometry; LDA: lithium diisopropylamide; M: mole, MeOH: methanol, mg: milligram, min: minutes, mL: milliliter, mmol: millimolar, MsCl: methanesulfonyl (mesyl) chloride; MTBE: methyl tert-butyl ether; N: Normal, NBS: N-bromosuccinimide, NMR: nuclear magnetic resonance; Pet ether: Petroleum ether, PPTS: pyridinium p-toluenesulfonate; p-TSA: para-toluenesulfonic acid; rt: room temperature, SFC: Supercritical Fluid Chromatography; TEA: Triethylamine (or Et3N), TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran; TLC: thin layer chromatography; TsCl: para-toluenesulfonyl (tosyl) chloride.

[0266] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0267] I. Chemical synthesis Unless otherwise specified, reagents and solvents were used as obtained from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise specified. Spectra are given in ppm (δ) and coupling constants J are reported in Hertz. For proton spectra, the solvent peak was used as the reference peak.

[0268] Example 1: Preparation of 2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole (Int-5)

[0269] [ka]

[0270] Step 1: Pyridinium p-toluenesulfonate (0.408 g, 1.62 mmol) was added to a solution of ethyl (S)-(-)-lactate (Int-1, 50 g, 0.4232 mol) and 3,4-dihydro-2H-pyran (46.2 g, 0.549 mol) in DCM (566 mL, 11 v / w). The reaction mixture was stirred at room temperature for 4 h. After completion of the reaction monitored by TLC, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give pure Int-2 as a mixture of diastereomers as a colorless liquid. 1 H NMR data was in accordance with that reported in J. Org. Chem. 2009, 74, 8154. Yield: 80 g, 93%.

[0271] Step 2: To a solution of Int-2 (50 g, 0.2472 mol) in MeOH (750 mL, 15 v / w) cooled to 0° C., NaBH4 (37.40 g, 0.988 mol, 4 equiv.) was added in portions over 1 h. The reaction mixture was allowed to warm to room temperature over 3 h. After completion of the reaction monitored by TLC, the reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM (500 mL×3). The layers were separated and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica column chromatography (60-120 mesh, eluted with 30-50% EtOAc and petroleum ether) to give pure Int-3 as a colorless liquid. Yield: 25 g, 63%.

[0272] Step 3: To a solution of Int-3 (40 g, 0.2496 mol) in DCM (800 mL, 20 v / w) cooled to 0° C., Dess-Martin periodinane (158.8 g, 0.3744 mol) was added in portions over 30 min. The reaction mixture was allowed to warm to room temperature over 3 h. After completion of the reaction monitored by TLC, the reaction mixture was filtered through a bed of Celite and the bed was further washed with DCM (1000 mL). The filtrate was washed with saturated NaHCO3 solution followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure at 30° C. Some white solid was observed in the crude product. To remove this impurity, the crude product was dissolved in diethyl ether and washed with 10% NaOH solution (500 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude mass. Further formation of a white solid was observed so the crude mass was dissolved in diethyl ether (500 mL), filtered through a bed of celite and washed with diethyl ether (750 mL) to completely remove unwanted impurities. The filtrate was concentrated under reduced pressure at 30° C. to afford Int-4 as a mixture of diastereomers as a colorless liquid, which was used in the next step without further purification. 1 H NMR showed all the characteristic resonances reported in Org. Lett. 2009, 11, 1103. Yield: 39 g, 98%.

[0273] Step 4: To a solution of Int-4 (39 g, 246.5 mol) in MeOH (390 mL, 10 v / w) was added glyoxal (40% in water, 97.5 mL, 2.5 v / w). To the above mixture cooled to 10 °C, 28% aqueous ammonia solution (120 mL, 3 v / w) was added. The ice bath was removed and the temperature of the reaction mixture was allowed to reach room temperature for 4 h. After completion of the reaction monitored by TLC and LC-MS, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2 60-120 mesh, eluted with 80-100% EtOAc in petroleum ether) to give 2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole (Int-5) as a mixture of diastereomers as an off-white solid. Recorded in DMSO-d6. 1 H NMR and LCMS were in support of the structure. Recorded in CDCl3 1 For H NMR values, see WO2018216822A1. Yield: 27g, 56%. LC MS: 10 H 16 Calculated value of N2O2 is 196.25, measured value is 197.1 [M+H] + .

[0274] Example 2: Preparation of 1-(3-(4-iodophenyl)prop)-2-yn-1-yl)-2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole (Int-9)

[0275] [ka]

[0276] Step 1: To a stirred solution of 2,4-diiodobenzene (Int-6) (5 g, 15 mmol) in DMF (20 mL) was added propargyl alcohol (0.26 mL, 3 mmol) followed by Cul (5 mol%) and PdCl2(PPh3)2 (5 mol%). The reaction was heated at 50°C. Two equivalents of propargyl alcohol (0.26 ml x 2, 3 mmol) were added over the next 90 min and stirred for another 2 h with intervals of 45 min. The reaction mixture was quenched with ice-cold water (25 mL) and extracted with ethyl acetate (2 x 35 mL). The organic layer was further washed with brine, dried (MgSO4) and concentrated under vacuum to give the crude mixture. The compound was further purified on a silica gel column by eluting with hexane in ethyl acetate to give the desired compound Int-7 in about 52% yield.

[0277] Step 2: A solution of Int-7 (2 g, 7.6 mmol) in DCM (30 mL) was cooled to 0 °C. To this cooled solution, N-bromosuccinimide (8.1 mmol) and PPh3 (7.6 mmol) were added and stirred at 0 °C for 2 h. After the starting material was consumed, the reaction mixture was diluted with DCM, quenched by pouring into a cold saturated NaHCO3 solution, and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product Int-8. The compound was purified on a silica gel column by eluting with hexane in ethyl acetate to give the desired Int-8 (2.01 g, 84%) as a thick oil. LC MS: calculated for C9H8Brl was 322.97, not ionized.

[0278] Step 3: A solution of Int-5 (1 g, 5.1 mmol, see part II) in acetonitrile (5 mL) was added to a slurry of potassium carbonate (10 mmol) in acetonitrile (10 mL) and the reaction mixture was heated to 70 °C for 30 min. To the preheated reaction mixture, a solution of Int-8 (1.64 g, 5.1 mmol) in acetonitrile (5 mL) was added and heating was continued at 80 °C for 3 h. After the starting material was consumed, the reaction mixture was cooled to room temperature and quenched with saturated NH4Cl. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (230-400 mesh) by eluting with 1-2% methanol in DCM to give pure compound Int-9 (1.35 g, 78%). LC MS: C 19 H 23 Calculated value of IN2O2 is 438.31, Measured value: 439.2 [M+H] + .

[0279] Example 3: Preparation of (2S)-4-(4-bromophenyl)-2-(2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)but-3-yn-1-ol) (Int-15)

[0280] [ka]

[0281] Step 1: To a stirred solution of Int-10 (5 g, 0.0218 mol) in dry MeOH (50 mL) cooled to 0° C., dimethyl (1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent, 5.02 g, 0.0261 mol) was added dropwise and the reaction mixture was stirred at 0° C. for 5 min. Then, K2CO3 (6 g, 0.0436 mol) was added to the reaction mixture and stirred at 0° C. for 10 min. The ice-cold water bath was then removed and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with EtOAc (500 mL) and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) by eluting with 10-12% ethyl acetate in petroleum ether to give Int-11 (3.79 g, 77%). LC MS: 12 H 19 The calculated value for NO3 is 225.29, not ionized.

[0282] Step 2: To a stirred solution of Int-11 (3.79 g, 16.82 mmol) in dry toluene (40 mL), 1-bromo-4-iodobenzene (Int-12) (5.71 g, 20.18 mmol) and TEA (6.9 mL, 49.26 mmol) were added, the reaction mixture was degassed with nitrogen for 5 min, then bis(triphenylphosphine)palladium chloride (230 mg, 0.326 mmol) and CuI (187 mg, 0.985 mmol) were added and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with DCM (500 mL) and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) by eluting with 10-12% ethyl acetate in petroleum ether to give Int-13 (5.4 g, 84.5%). LC MS: 18 H 22 Calculated value of BrNO3 is 380.280, Found value: 282 [M-Boc+2] + .

[0283] Step 3: To a stirred solution of Int-13 (5.4 g, 0.0142 mol) in dry DCM (54 mL) cooled to 0° C., HCl (4N in dioxane, 18 mL) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was concentrated under reduced pressure to give the crude product as an off-white solid Int-14 (4.2 g). LC MS: 10 H 11 Calculated value for BrNO+ is 241.11, found value: 242 [M+2 for the free base].

[0284] Step 4: To a stirred solution of Int-14 (2 g, 0.0072 mol) in MeOH (20 mL), (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanal) (Int-4, 4.5 g, 0.021 mol), NHOAc (1.1 g, 0.0144 mol), and glyoxal (40% in H0, 1.6 mL, 0.0108 mol) were added at room temperature. The reaction mixture was stirred at 80° C. for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a crude residue (LCMS analysis showed about 46% desired product and 19% 2-unsubstituted imidazole). The crude residue was diluted with EtOAc (250 mL) and washed with water (100 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh) by eluting with 50-60% ethyl acetate in petroleum ether to give Int-15 (790 mg, 22.76%). LC-MS: 20 H 23 Calculated value for BrN2O2 is 419.230, Found value: 421 [M+2H] + .

[0285] Example 4 Preparation of tert-butyl ((2S)-4-(4-bromophenyl)-2-(2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)but-3-yn-1-yl)carbamate) (Int-21)

[0286] [ka]

[0287] Step 1: To a stirred solution of Int-14 (5.5 g, 22.91 mmol) in DCM (55 mL) was added Boc-anhydride (5.85 mL, 25.2 mmol) and triethylamine (9.37 mL, 68.7 mmol) at room temperature. The reaction mixture was stirred for 3 h. After complete consumption of the starting material, the reaction mixture was diluted with DCM (200 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 100-200 mesh size, 15-20% EtOAc in hexanes) to give Int-16 (5.0 g, 63.5%) as an off-white solid. LC-MS: C 15 H 18 Calculated value of BrNO3 is 340.22, Measured value: 284.0 [M-56] + and 286.0 [M-56+2] +

[0288] Step 2: To a stirred solution of Int-16 (5.0 g, 14.70 mmol) in THF (37 mL), phthalamide (2.378 g, 16.17 mmol) and triphenylphosphine (7.71 g, 29.4 mmol) were added and cooled to 0° C. DIAD (5.8 mL, 29.4 mmol) was slowly added to the reaction mixture and stirring was continued for 1 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude Int-17 (6.9 g (crude)), which was used in the next step without any purification. The sample showed contamination with PPH3O. LC-MS: C 23 H 21 Calculated value of BrN2O4 is 469.34, Measured value: 413.0 [M-56] + .

[0289] Step 3: To a stirred solution of Int-17 (6.9 g, 14.70 mmol) in DCM (70 mL) was added HCl (4 M in dioxane, 36.8 mL, 147 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The reaction was followed by TLC. After completion of the reaction, the solid formed was filtered under vacuum and washed with hexane to give Int-18 (4.5 g, 75%) as a white solid. LC-MS: C for ammonium ion. 18 H 14 Calculated value of BrN2O2 is 369, measured value: 369.0[M] + and 371.0[M+2] + .

[0290] Step 4: To a stirred solution of Int-18 (4.5 g, 11.09 mmol) in MeOH (45 mL) was added ammonium acetate (1.710 g, 22.19 mmol) and stirred at room temperature for 10 min. To this reaction mixture was added (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanal (7.02 g, 44.4 mmol) and stirring was continued for 10 min. Finally, glyoxal (40% aqueous solution, 1.916 mL, 16.64 mmol) was added. After stirring at room temperature for 10 min, the reaction mixture was heated at 80° C. for 2 h. After completion of the reaction, the volatiles were evaporated under reduced pressure. To the resulting residue was added water (100 mL) and extracted with 5% MeOH in DCM (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 230-400 mesh size, 80-90% EtOAc in hexanes) to give Int-19 (2.8 g, 46%) as a pale yellow gummy solid as a mixture of diastereoisomers seen in the LC profile without baseline separation. LC-MS: 28 H 26 Calculated value of BrN3O4 is 548.44, measured value: 548.0 [M] + ,550.0[M+2] + .

[0291] Step 5: To a stirred solution of Int-19 (2.8 g, 5.11 mmol) in MeOH (28 mL) was added methylamine (40% in water, 3.71 mL, 51.1 mmol) at room temperature. The pressure tube was sealed and heated at 85° C. for 2 h. After completion of the reaction, the reaction mixture was diluted with DCM (150 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Int-20 (2.0 g, 94%) as a pale yellow liquid. The crude was used in the next step without purification. LC-MS: C 20 H 24 Calculated value of BrN3O2 is 418.34, measured value: 418.2[M] + and 420.2[M+2] + .

[0292] Step 6: To a stirred solution of Int-20 (2.4 g, 5.74 mmol) in DCM (27 mL) was added triethylamine (2.347 mL, 17.21 mmol), Boc-anhydride (1.598 mL, 6.88 mmol) at room temperature. After stirring for 4 h, the reaction mixture was diluted with DCM (150 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2, 230-400 mesh size, 40% EtOAc in hexanes) to give Int-21 (1.0 g, 32%) as a brown gummy solid. LC-MS: C 25 H 32 Calculated value of BrN3O4 is 518.45, measured value: 518.0 [M] + , 520.0[M+2] + .

[0293] Example 5: Preparation of (3S)-5-(4-bromophenyl)-3-(2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)pent-4-yn-1-ol) (Int-109a)

[0294] [ka]

[0295] Step 1: To a stirred solution of D-homoserine (Int-100, 25.0 g, 210 mmol) in acetonitrile:water (1:1, 500 mL) was added NaOH (10.07 g, 252 mmol) at 0° C. After stirring at 25° C. for 1 h, Boc-anhydride (10.07 g, 252 mmol) was added to the reaction mixture. The reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene (200 mL) to give Int-101 as an off-white gummy solid, which was used in the next step without purification. Yield=50.0 g (crude product weight).

[0296] Step 2: To a stirred solution of Int-101 (50.0 g, 207 mmol) in DMF (300 mL) was added iodomethane (25.9 mL, 415 mmol) at 0° C. The reaction mixture was stirred for 3 h at 25° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give Int-102 as an off-white gummy solid. 1 H NMR showed the presence of DMF. This was used in the next step without further purification. Yield = 49.0 g (crude product weight).

[0297] Step 3: To a stirred solution of Int-102 (48.0 g, 206 mmol) in DMF (300 mL) was added imidazole (28.0 g, 412 mmol) and tert-butyldimethylsilyl chloride (46.5 g, 309 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL), washed with ice-cold water (200 mL x 2), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO2 100-200 mesh, 5-7% EtOAc in petroleum ether) to give Int-103 as a pale yellow liquid. Yield = 47.0 g (89%)

[0298] Step 4: To a stirred solution of Int-103 (20.0 g, 57.5 mmol) in dry toluene (200 mL) was added DIBAL-H (1.2 M in toluene, 71.9 mL, 86 mmol) at -78 °C. After stirring at -78 °C for 2 h, the reaction was quenched by addition of MeOH (100 mL). After stirring for 15 min, it was added 50% potassium sodium tartrate solution (150 mL) and stirred at room temperature for 1 h. It was extracted with EtOAc (300 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product Int-104 as a colorless liquid. The crude material was used in the next step without further purification. Yield = 13.8 g (76%).

[0299] Step 5: To a stirred solution of Int-104 (13.8 g, 43.5 mmol) in MeOH (140 mL) was added potassium carbonate (12.01 g, 87 mmol) followed by Bestmann Ohira reagent (11.92 mL, 15.26 g, 79.42 mmol) at 0 °C. After stirring for 10 min, the ice bath was removed and the reaction mixture was stirred at 25 °C for 1 h. The reaction was followed by TLC. The reaction mixture was concentrated under reduced pressure. The resulting residue was quenched with water (100 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh, 5% EtOAc in petroleum ether) to give Int-105 as a pale yellow liquid. Yield = 9.6 g (70%).

[0300] Step 6: To a stirred solution of Int-105 (9.5 g, 30.3 mmol) in toluene (100 mL) was added 4-bromo-1-iodobenzene (7, 10.29 g, 36.4 mmol), triethylamine (12.67 ml, 91 mmol), and copper(I) iodide (0.346 g, 1.818 mmol) at 25 °C and degassed with nitrogen for 15 min. To this reaction mixture was added bis(triphenylphosphine)palladium(II) chloride (0.425 g, 0.606 mmol) and stirred for 1 h. The reaction monitored by TLC (hexane: EtOAc 95:5) showed complete consumption of starting material. The reaction was quenched by adding water (200 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 100-200 mesh size, 7% EtOAc in hexanes) to give Int-106 as a brown liquid as a 60:40 mixture of two epimers. Yield = 11.03 g (77%) (before SFC, mixture of epimers). LC-MS: C 22 H 34 Calculated value of BrNO3Si: 468.507, Measured value: 412.0 [M-56] + and 414.0[M-56+2] + .

[0301] The isomers (11.03 g) were separated by SFC to give 106a (isomer 1) and 106b (isomer 2). Int-106a: Isomer 1: 3.0 g, single enantiomer with unknown stereochemistry. Int-106b: Isomer 2: 6.9 g, single enantiomer with unknown stereochemistry. Independently, both isomers (Int-106a and Int-106b) were used in the next step.

[0302] Step 7: To a stirred solution of Int-106a (3.0 g, 6.40 mmol) in DCM (30 mL) was added HCl (4.0 M in dioxane, 11.2 mL, 44.8 mmol) at 0° C. The reaction mixture was stirred for 6 h at 25° C. The reaction was monitored by TLC. After completion of the reaction, the solid formed was filtered under vacuum, washed with hexane and dried under vacuum to give Int-107a as an off-white solid. Yield=1.7 g (85%). LC-MS: Ammonium salt C 11 H 13 Calculated value of BrNO+ is 254.24, measured value: 254.0 [M] + and 256[M+2] + .

[0303] Step 8: To a stirred solution of Int-107a (1.7 g, 5.85 mmol) in MeOH (17 mL) was added ammonium acetate (0.902 g, 11.70 mmol) and stirred for 10 min. To this reaction mixture was added Int-108 (3.70 g, 23.40 mmol) and after stirring for 10 min, glyoxal (40% in water, 1.0 mL, 8.78 mmol) was added. After stirring for 10 min, the reaction mixture was heated at 80° C. for 2 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and extracted with DCM (150 mL×2). The combined organic layers were washed with ice-cold water (50 mL), followed by brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh, 5% methanol in DCM) to give Int-109a as a yellow gum. Yield = 1.5 g (58%). LC-MS: C 21 H 25 Calculated value of BrN2O3: 433.35, Measured value: 433.0 [M] + and 435.0[M+2] + .

[0304] Example 6: Preparation of 4-((4-bromophenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (Int-25a)

[0305] [ka]

[0306] Step 1: To a solution of (1,2-O-isopropylideneglycerol) (Int-22a, 1.0 g, 7.57 mmol) in DCM (10 mL) was added triethylamine (3.16 mL, 22.70 mmol), tosyl chloride (1.875 g, 9.84 mmol), and DMAP (92 mg, 0.757 mmol) at 0 °C. The reaction mixture was then stirred at 25 °C for 2 h. The reaction was monitored by TLC, which showed complete consumption of the starting material. The reaction was quenched by addition of saturated sodium bicarbonate solution and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh, 15% EtOAc in petroleum ether) to give Int-23a as a white solid. Yield: 1.5g (68%). LC-MS: C 13 H 18 Calculated value of O5S is 286.34, measured value: 287.1[M+1] + .

[0307] Step 2: To a solution of Int-23a (384 mg, 1.75 mmol) in DMF (5 mL) was added cesium carbonate (569 mg, 1.75 mmol) at 25 °C under nitrogen atmosphere and stirred for 20 min. To this reaction mixture was added Int-24 (500 mg, 1.75 mmol) and heated at 90 °C for 4 h. The reaction was monitored by TLC, which showed complete consumption of starting material. The reaction mixture was cooled to room temperature, quenched by addition of ice-cold water (30 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (600 mg) was purified by flash column chromatography (SiO2 230-400 mesh, 10% EtOAc in petroleum ether) to give Int-25a. Yield: 250 mg (29%). LC-MS: C 18 H 27 BO5 calculated value: 334.21, measured value: 335.2 [M+1] + (64% by LCMS).

[0308] A similar strategy was implemented to synthesize the (R) and (S) isomeric derivatives from the appropriate chiral starting materials to give Int-25b and Int-25c.

[0309] Example 7: Preparation of 5-((4-bromophenoxy)methyl)-2,2-dimethyl-1,3-dioxane (Int-28)

[0310] [ka]

[0311] Step 1: To a stirred solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (Int-26) (5.0 g, 34.2 mmol) in DCM (50 mL) was added triethylamine (9.53 mL, 68.4 mmol) and p-toluenesulfonyl chloride (7.17 g, 37.6 mmol) at 25 °C. After stirring for 16 h, the reaction mixture followed by TLC showed complete consumption of starting material. The reaction was quenched by addition of water (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2, 230-400 mesh, 8-10% EtOAc in hexanes) to give Int-27 as a pale yellow liquid. Yield: 8.0 g (78%). LCMS:C 14 H 20 O5S calculated value: 300.37, measured value: 301.2[M+1] + .

[0312] Step 2: To a stirred solution of Int-27 (8.0 g, 26.6 mmol) in DMF (80 mL) was added potassium carbonate (8.1 g, 58.6 mmol) and 4-bromophenol (Int-24) (5.07 g, 29.3 mmol) at 25 °C. The reaction mixture was then heated at 60 °C for 5 h. The reaction was followed by TLC, which showed complete consumption of the starting material. The reaction was quenched by adding water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (SiO2, 230-400 mesh, 8% EtOAc in hexanes) to give Int-28. Yield: 5.0 g (62%). LC MS: C 13 H 17 Calculated value of BrO3: 301.18, measured value: 301.2 [M] + and 303.2[M+2] + .

[0313] Example 8: Preparation of tert-butyl 4-(((4-bromophenyl)oxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (Int-31a)

[0314] [ka]

[0315] Step 1: To a stirred solution of Int-29a (2.5 g, 0.0108 mol) in DCM (50 mL) was added CBr4 (3.95 g, 0.012 mol) and stirred for 6 h. After 6 h, the reaction mixture was diluted with DCM (25 ml), washed with saturated NaHCO3 (15 mL), then saturated NaCl (15 mL), dried (Na2SO4) and concentrated in vacuo. The crude mixture was obtained as a yellow oil in 78% yield, which was used in the next step without further purification. LC MS: C 11 H 20 Calculated for BrNO3: 294.19; found: not observed.

[0316] Step 2: To a stirred solution of Int-30a (0.0064 mol) in dry THF (15 mL), NaH (60% dispersion in mineral oil) (0.0097 mol) was added portionwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Then, 4-bromophenol (Int-24) (0.0084 mol) was dissolved in THF and slowly added to the reaction mixture and stirred at 0° C. for 30 min. Then, the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution, diluted with EtOAc (500 mL), washed with ice-cold water (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh) by eluting with 6-10% ethyl acetate in petroleum ether to give the product Int-31a. Yield: 1.49 g (57.32%). LC-MS:C 17 H 24 Calculated value for BrNO4: 386.2; found value: not observed.

[0317] A similar strategy was implemented to synthesize the (R) and (S) isomeric derivatives from the appropriate chiral starting materials to give Int-31b and Int-31c.

[0318] Example 9: Preparation of tert-butyl ((1S,2S)-2-(4-iodophenoxy)cyclopropyl)carbamate (Int-37a)

[0319] [ka]

[0320] Step 1: To a stirred solution of 4-iodophenol (Int-32, 38 g, 172 mmol) in water (200 mL), NaOH (14.5 g, 362 mmol) and dibromoethane (162.2 g, 863 mmol) were added and the mixture was heated to 120 °C overnight. After completion of the reaction, the reaction mass was extracted with EtOAc (1000 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) by eluting with ethyl acetate in petroleum ether to give the pure product Int-33 as an off-white solid. Yield: 53 g (94%).

[0321] Step 2: To a stirred solution of Int-33 (67 g, 204 mmol) in THF (670 mL) was added t-BuOK (34.4 g, 307 mmol) and stirred at room temperature for 1 h. After completion of the reaction, the reaction mass was diluted with water and extracted with EtOAc (1000 mL×2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) by eluting with ethyl acetate in petroleum ether to give the pure product Int-34 as a colorless liquid. Yield: 49 g (97%).

[0322] Step 3: To a stirred solution of Int-34 (20 g, 81.3 mmol) in DCM (200 mL) and copper(II) acetylacetonate (2.12 g, 8.13 mmol), ethyl diazoacetate (50.27 g, 440 mmol) was added at a rate of 0.2 mL / min at 0 °C via syringe pump. After completion of addition, the reaction mixture was stirred at room temperature for 18 h. After completion of reaction, DCM was removed under reduced pressure. The residue was dissolved in EtOAc (500 mL) and washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (230-400 mesh) by eluting with 2-5% ethyl acetate in petroleum ether to give Int-35a (trans, non-polar) and Int-35b (cis, polar) as liquids. Yield: compound Int-35a-11.7 g (22%) and compound Int-35b-28 g (contaminated with ethyl diazoacetate).

[0323] Step 4: To a stirred solution of Int-35a (38 g, 114 mmol) in water (200 mL) and MeOH (200 mL), NaOH (22.8 g, 570 mmol) was added and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the aqueous layer was washed with EtOAc (500 mLx2), the aqueous layer was acidified with dilute hydrochloric acid and extracted with EtOAc (500 mLx2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude product Int-36a was used without further purification. Yield: 30 g (88%). LC MS: C 10 The calculated m / z value for H9IO3 is 304.08, and the measured value is 302.9[MH]+.

[0324] Step 5: To a stirred solution of Int-36a (30 g, 98.6 mmol) in dry t-BuOH (300 mL), TEA (15.1 mL, 108 mmol) and DPPA (29.9 g, 108 mmol) were added and the reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc (500 mL), washed with NaHCO3 and water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica gel (60-120 mesh and 230-400 mesh in 1:1 ratio) by eluting with 5-6% ethyl acetate in petroleum ether to give the pure product Int-37a as an off-white solid. Yield: 26.6 g (70%). LC MS: C 14 H 18 m / z calculated for INO3: 375.21, measured: 276 [M-100+H] + .

[0325] A similar strategy was carried out to prepare the cis derivative Int-35b from Int-37b.

[0326] Example 10: Preparation of (trans)-4-(4-bromophenoxy)tetrahydrofuran-3-ol (Int-39)

[0327] [ka]

[0328] Step 1: To a stirred solution of 4-bromophenol (Int-24) (4 g, 23.12 mmol) in 1,4-dioxane (40 mL), 3,6-dioxabicyclo[3.1.0]hexane (Int-38, 1.98 g, 23.12 mmol), Cs2CO3 (11.3 g, 34.68 mmol), and benzyltriethylammonium chloride (1.05 g, 4.62 mmol) were added at room temperature and the reaction mixture was heated at 120 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL), washed with saturated NaHCO3 solution (100 mL), water (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated with petroleum ether and dried to give Int-39. Yield: 5 g (84%). LC-MS: C 10 H 11 Calculated for BrO3 259.10, Found: No ionization was observed. The trans and cis isomers were separated to give Int-39a and Int-39b, respectively.

[0329] Example 11: Preparation of tert-butyl ((trans)-4-(4-bromophenoxy)tetrahydrofuran-3-yl)carbamate (Int-45)

[0330] [ka]

[0331] Step 1: To a stirred solution of 4-bromophenol (Int-24) (4 g, 23.12 mmol) in 1,4-dioxane (40 mL), 3,6-dioxabicyclo[3.1.0]hexane (Int-40, 1.98 g, 23.12 mmol), Cs2CO3 (11.3 g, 34.68 mmol), and benzyltriethylammonium chloride (1.05 g, 4.62 mmol) were added at room temperature and the reaction mixture was heated at 120 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL), washed with saturated NaHCO3 solution (100 mL), water (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated with petroleum ether and dried to give Int-41. Yield: 5 g (84%). LC-MS: C 10 H 11 Calculated for BrO3 259.10, Found: No ionization observed.

[0332] Step 2: To a stirred solution of Int-1 (0.600 g, 2.31 mmol) in DCM (6 mL) was added Et3N (0.5 mL, 3.47 mmol) and mesyl chloride (0.2 mL, 2.54 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mass was diluted with DCM (50 mL) and then washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mesylate Int-42 was used in the next step without further purification. Yield: 0.75 g (crude). LC-MS: C 11 H 13 Calculated mass for BrO5S was 337.18, observed mass: not ionized.

[0333] Step 3: To a stirred solution of mesylate (Int-42, 0.750 g, 2.22 mmol) in DMF (10 mL) was added sodium azide (0.433 g, 6.67 mmol) at room temperature and the reaction mixture was heated at 120° C. for 18 h. After completion of the reaction, the reaction mass was dissolved in water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL) and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product Int-43 was used in the next step without further purification. Yield: 0.600 g (crude).

[0334] Step 4: To a stirred solution of Int-43 (0.600 g, 2.11 mmol) in THF (9 mL) and water (3 mL) was added PPh3 (0.663 g, 2.53 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was acidified with 1.5 N HCl and extracted with EtOAc. The aqueous layer was basified with 10% NaOH solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product Int-44, which was used in the next step without further purification. Yield: 0.22 g (40%). LC-MS: C 10 H 12 Calculated value of BrNO2 is 258.12, Measured values: 258[M] and 260.0[M+2] + .

[0335] Step 5: To a stirred solution of Int-44 (0.220 g, 0.852 mmol) in dry DCM (3 mL), Et3N (0.35 mL, 2.55 mmol) and (Boc)2O (0.3 mL, 1.279 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (40 mL) and washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product Int-45, which was used in the next step without further purification. Yield: 0.250 g (crude).

[0336] Example 12: Preparation of (R)-1-(4-bromophenoxy)-3-methoxypropan-2-ol (Int-47)

[0337] [ka]

[0338] Step 1: To a stirred solution of 4-bromophenol (Int-24, 10.0 g, 57.80 mmol) in DMF (100 mL), K2CO3 (9.59 g, 69.40 mmol) and (R)-glycidyl tosylate (13.19 g, 57.8 mmol) were added at room temperature. The reaction mixture was stirred at 60 °C for 8 h. The reaction was monitored by TLC and after completion of the reaction, it was cooled to room temperature, quenched with water (200 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (SiO2, 100-200 mesh size, 20-30% EtOAc in hexane) to give Int-46 (10 g, 43.7 mmol, 76% yield) as a colorless oil. Yield = 10.0 g (76%). LC MS: calculated for C9H9BrO2 229.07, Found: no ionization observed.

[0339] Step 2: To a stirred solution of Int-46 (10.0 g, 43.70 mmol) in MeOH (100 mL) was added 25% sodium methoxide in MeOH (48.9 mL, 214.00 mmol) at 25° C. and the reaction mixture was stirred at 80° C. for 16 h. The reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, quenched with water (200 mL) and extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-47 as a colorless liquid. Yield: 10.0 g (88%). LC MS: C 10 H 13Calculated for BrO3 261.12, Found: No ionization observed.

[0340] Example 13: Preparation of (R)-1-(4-bromophenoxy)-3-methoxypropan-2-ol (Int-51)

[0341] [ka]

[0342] Step 1: To a stirred solution of Int-47 (9.0 g, 34.50 mmol) in DCM (135 mL), EtN (9.62 mL, 68.90 mmol) and mesyl chloride (3.20 mL, 41.40 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL×2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give Int-48 as a colorless liquid. The crude material was used in the next step without further purification. Yield: 9.0 g (77%). LC MS: C 11 H 15 Calculated for BrO5S: 339.20; Found: No ionization observed.

[0343] Step 2: To a stirred solution of Int-48 (3.0 g, 8.84 mmol) in DMF (30 mL) was added sodium azide (2.9 g, 44.20 mmol) at room temperature. The reaction mixture was heated at 80° C. for 5 h. After completion, the reaction was cooled to room temperature, quenched by addition of water (150 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give Int-49 as a colorless liquid. The crude product 6 was used in the next step without further purification. Yield: 2.50 g (99%). LC MS: C 10 H 12 Calculated value of BrN3O2: 286.13, Measured value: 258 (M-N2)+ and 260(M-N2+2) + and 180 (M-N2-Br) + A total of three batches were performed for step 2. The combined product was used in the next step.

[0344] Step 3: To a stirred solution of Int-49 (7.50 g, 26.20 mmol) in THF (75 mL) and water (37.5 mL) was added triphenylphosphine (8.25 g, 31.5 mmol) at 0° C. The reaction mixture was stirred for 24 h at 25° C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was acidified with 1.5 N HCl and extracted with EtOAc (30 mL×2). The aqueous layer was basified with 10% NaOH solution and extracted with 10% MeOH in DCM (100 mL×2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give Int-50. The crude product was taken on to the next step without further purification. Yield: 5 g (73%).

[0345] Step 4: To a stirred solution of Int-50 (5.0 g, 19.22 mmol) in DCM (75 mL) was added triethylamine (8.04 mL, 557.7 mmol) and Boc-anhydride (6.62 mL, 28.80 mmol) at 0° C. and the reaction mixture was stirred at 25° C. for 2 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give Int-51 as a pale yellow liquid. The crude product was used in the next step without further purification. Yield: 6.50 g (78%). LC MS: C 15 H 22 Calculated value of BrNO4: 360.25, Measured value: 260.2 [M-Boc] + and 262.2[M-Boc+2] + .

[0346] Example 14: Preparation of 6-(4-bromophenoxy)-2,2,3,3,10,10,11,11-octamethyl-4,9-dioxa-3,10-disiladodecane (Int-54)

[0347] [ka]

[0348] Step 1: To a stirred solution of 4-bromophenol (Int-24) (2.0 g, 11.56 mmol) in DMF (20 mL) was added cesium carbonate (5.65 g, 17.34 mmol) at 0° C. and stirred for 5 min. To this reaction mixture was added α-bromo-γ-butyrolactone (2.67 g, 16.18 mmol) at 0° C. and the reaction mixture was stirred for 24 h at 25° C. The reaction was monitored by TLC, which showed complete consumption of the starting material. The reaction was quenched by adding ice-cold water (100 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh size, 15-20% EtOAc in petroleum ether) to give Int-52 as a white solid. Yield = 2.1 g (71%). LC MS: C 10 Calculated for H9BrO3 257.08, Found: No ionization observed.

[0349] Step 2: To a stirred solution of Int-52 (2.1 g, 8.17 mmol) in a mixture of THF:MeOH (1:1, 40 mL) was added sodium borohydride (0.309 g, 8.17 mmol) in small portions at 0 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at 25 °C for 3 h. The reaction was followed by TLC, which showed complete consumption of the starting material. The reaction was quenched by addition of ice water (20 mL) and the volatiles were evaporated under reduced pressure. The resulting residue was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2, 230-400 mesh, 60% EtOAc in hexanes) to give Int-53 as a pale yellow liquid. Yield = 2.0 g (94%). LC MS: C10 H 13 Calculated for BrO3 261.12, Found: No ionization observed.

[0350] Step 3: To a stirred solution of Int-53 (2.0 g, 7.66 mmol) in DMF (20 mL) was added imidazole (1.56 g, 22.98 mmol), DMAP (0.19 g, 1.53 mmol), and TBDMS-Cl (2.89 g, 19.15 mmol) at 0 °C. After addition, the reaction was stirred for 16 h at 25 °C. The reaction was followed by TLC, which showed complete consumption of starting material. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with cold water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (SiO2 100-200 mesh size, 5% EtOAc in hexanes) to give Int-54 as a yellow liquid. Yield = 2.8 g (75%). LC-MS:C 22 H 41 Calculated for BrO3Si2 489.64; Found: No ionization observed.

[0351] Example 15: Preparation of 5-(4-bromophenoxy)pentane-1,4-diol (Int-57)

[0352] [ka]

[0353] Step 1: To a stirred solution of 4-bromophenol (Int-24) (11.56 mmol) in DMF (20 mL) was added potassium carbonate (17.34 mmol) at 0° C. and stirred for 5 min. To this reaction mixture was added 5-(bromomethyl)dihydrofuran-2(3H)-one (16.18 mmol) at 0° C. and the reaction mixture was stirred at 25° C. for 24 h. The reaction was monitored by TLC, which showed complete consumption of starting material. The reaction was quenched by adding ice-cold water (100 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh size, 15-20% EtOAc in petroleum ether) to give Int-55 as a white solid. Yield=65%. LC-MS:C 11 H 11 Calculated for BrO3 271.11, Found: No ionization observed.

[0354] Step 2: To a stirred solution of Int-55 (16.0 mmol) in methanol (50 mL) was added H2SO4 (7 mL) and heated at 60 °C for 2 h. The reaction was concentrated under vacuum. The reaction mixture was cooled, carefully poured into ice-cold water and basified with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh size, 50% EtOAc in petroleum ether) to give Int-56 as a white solid. Yield = 56%.

[0355] Step 3: To a stirred solution of Int-56 (7.00 mmol) in a mixture of THF:MeOH (8:2, 40 mL) was added lithium borohydride (7.00 mmol) in small portions at 0° C. under nitrogen atmosphere. The resulting reaction mixture was stirred at 25° C. for 3 h. The reaction was followed by TLC, which showed complete consumption of the starting material. The reaction was quenched by addition of ice water (20 mL) and the volatiles were evaporated under reduced pressure. The resulting residue was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2, 230-400 mesh, 60% EtOAc in hexanes) to give Int-57 as a pale yellow liquid. Yield=82%. LC MS: C 11 H 15 Calculated for BrO3 275.14, Found: No ionization observed.

[0356] Example 16: Preparation of 4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane (Int-59)

[0357] [ka]

[0358] A stirred solution of 1-(4-bromophenyl)-1,2-ethanediol (Int-58) (500 mg, 2.3 mmol) was dissolved in 15 mL of 2,2-dimethoxypropane. A catalytic amount of p-toluenesulfonic acid was added and the solution was stirred at 50° C. for 18 h. After adding 50 mL of toluene, the resulting mixture was washed with a saturated solution of NaHCO3. The organic phase was collected, dried over MgSO4 and the solvent was completely removed. This procedure gave the Int-59 compound, which was used without further purification. Yellow oil, yield 521 mg. Yield=88%. LC MS: C 11 H 13 Calculated BrO2 257.12, Found: No ionization observed.

[0359] Example 17: Preparation of 2-(3-(4-bromophenyl)azetidin-1-yl)-2-oxoethyl acetate (Int-61)

[0360] [ka]

[0361] To a stirred solution of Int-60 (500 mg, 2.00 mmol) in DCM (10 ml) was added triethylamine (0.700 ml, 2.5 equiv.) followed by acetoxyacetyl chloride (0.328 g, 2.41 mmol, 1.2 equiv.) and stirred for 45 min. TLC showed the reaction was complete. The reaction mixture was poured into water (15 mL) and extracted with DCM (2×25 mL). The combined organic layers were washed with 3M HCl solution (10 mL), saturated NaHCO3 (15 mL), saturated NaCl solution (25 mL), dried (Na2SO4) and concentrated to dryness. Crude Int-61 was isolated as a yellow oil in (95%) yield and was taken forward without further purification. LC MS: C 13 H 14 Calculated for BrNO3 312.0; Found: No ionization observed.

[0362] Example 18: Preparation of N-((trans)-3-(4-bromophenyl)cyclobutyl)methanesulfonamide (Int-63) and N-((1r,3r)-3-(4-bromophenyl)cyclobutyl)-2-cyanoacetamide) (Int-110)

[0363] [ka]

[0364] To a stirred solution of Int-62 (500 mg, 1.90 mmol) in DCM (15 ml) was added triethylamine (0.67 mL, 4.76 mmol, 2.5 equiv), followed by methylsulfonyl chloride (0.260 g, 2.28 mmol, 1.2 equiv) and stirred for 45 min. TLC showed the reaction was complete. The reaction mixture was poured into water (15 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with 3M HCl solution (10 mL), saturated NaHCO3 (15 mL), saturated NaCl solution (20 mL), dried (Na2SO4) and concentrated to dryness. The crude Int-63 was obtained in 90% yield as a yellow oil, which was carried forward without further purification.

[0365] To a stirred solution of Int-62 (500 mg, 1.90 mmol) in DCM (15 ml) was added triethylamine (0.67 mL, 4.76 mmol, 2.5 equiv.) followed by 2-cyanoacetyl chloride (0.300 g, 2.28 mmol, 1.2 equiv.) and stirred for 45 min. TLC showed the reaction was complete. The reaction mixture was poured into water (15 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with 3M HCl solution (10 mL), saturated NaHCO3 (15 mL), saturated NaCl solution (20 mL), dried (Na2SO4) and concentrated to dryness. The crude Int-110 was obtained in 90% yield as a yellow oil which was carried forward without further purification.

[0366] Example 19: Preparation of 4,4,5,5-tetramethyl-2-(4-(((3R,4S)-4-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-3-yl)methyl)phenyl)-1,3,2-dioxaborolane (Int-118)

[0367] [ka]

[0368] Step 1: To a solution of LiHMDS (1.0M in THF, 245 mL, 245 mmol) in THF (90 mL) was added (S)-4-hydroxydihydrofuran-2(3H)-one (Int-111, 10 g, 98 mmol) at −45° C. under nitrogen atmosphere and stirred for 30 min. To this reaction mixture was added a solution of 1-bromo-4-(bromomethyl)benzene (29.4 g, 118 mmol) in THF (90 mL) followed by 1,3-dimethyl-2-imidazolidinone (28.6 mL, 264 mmol) at −45° C. After stirring for 45 min at the same temperature, the reaction mixture was quenched by addition of saturated ammonium chloride solution (100 mL). It was extracted with EtOAc (400 ml×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material obtained was purified by flash column chromatography (SiO2 100-200 mesh, 45% EtOAc in hexanes) to give Int-112 as an off-white solid. Yield: 15 g (56%). LC MS: C 11 H 11 Calculated value of BrO3: 271.11, measured value: 271.0 [M] + and 273.0[M+2] + Absolute stereochemistry assignments are based on US Pat. No. 6,268,515.

[0369] Step 2: To a stirred solution of Int-112 (15 g, 55.3 mmol) in DCM (150 mL) was added imidazole (7.53 g, 111 mmol) followed by TBDPS-Cl (21.32 mL, 83 mmol) at 0 °C. The reaction mixture was stirred for 16 h at 25 °C. The reaction was quenched with water (150 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2 100-200 mesh, 5% EtOAc in hexanes) to give Int-113 as a colorless liquid. UPLC showed a purity of 68%. The product was taken on to the next step. Yield: 35 g (84%). LC MS: C 27 H29 Calculated value of BrO3Si: 509.51, Measured value: 526 [M+OH] + and 528[M+OH+2] + ,509.1[M] + and 511.1[M+2] + .

[0370] Step 3: To a stirred solution of Int-113 (35 g, 34.3 mmol) in DCM (30 mL) was added DIBAL-H (1.2 M in toluene, 48.7 mL, 58.4 mmol) at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -78 °C for 3 h. The reaction was quenched with NH4Cl solution (350 mL) and extracted with DCM (800 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2 100-200 mesh, 18% EtOAc in hexanes) to give Int-114 as a colorless gum. Yield: 17 g. LC MS: C 27 H 31 Calculated value of BrO3Si: 511.53, measured value: 510.9 [M] - .

[0371] Step 4: To a solution of Int-114 (17 g, 33.2 mmol) in DCM (200 mL) was added TFA (26.8 mL, 166 mmol) at 0 °C and the reaction mixture was stirred for 30 min. To this reaction mixture was added triethylsilane (5.12 mL, 66.5 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 6 h. After complete consumption of the starting material, the reaction was quenched with water (300 mL) and extracted with DCM (300 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 100-200 mesh, 11% EtOAc in hexanes) to give Int-115 as a colorless liquid. Yield: 10.1 g (61%).

[0372] Step 5: To a stirred solution of Int-115 (10.1 g, 20.38 mmol) in THF (100 mL) was added TBAF (1.0 M in THF, 30.6 mL, 30.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (250 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (SiO2 100-200 mesh, 60% EtOAc in hexanes) to give Int-116 as a white solid. Yield: 4.9 g (91%).

[0373] Step 6: To a stirred solution of Int-116 (4.8 g, 18.67 mmol) in dioxane (130 mL) was added KOAc (5.5 g, 56.0 mmol) and bis(pinacolato)diboron (7.11 g, 28.0 mmol) at 25 °C. The reaction mixture was degassed with nitrogen for 10 min. To this reaction mixture was added Pd(dppf)Cl2.DCM complex (1.52 g, 1.86 mmol) and stirred at 110 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), filtered through a celite bed, and the celite bed was washed with EtOAc (50 mL). Water (100 mL) was added to the filtrate and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (SiO2 230-400 mesh, 50% EtOAc in hexanes) to give Int-117 as a pale yellow liquid. Yield: 4.8 g (84%). LC MS: C 17 H 25 BO4 calculated value: 304.19, measured value: 305.4 [M+1] + .

[0374] Step 7: To a solution of Int-117 (5.1 g, 16.77 mmol) in DCM (120 mL) was added 3,4-dihydro-2H-pyran (2.3 mL, 25.1 mmol) and pyridinium p-toluenesulfonate (0.33 g, 1.34 mmol) at 0 °C. The reaction mixture was stirred for 16 h at 25 °C. The reaction was quenched with water (50 mL) and extracted with DCM (100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by flash column chromatography (SiO2 230-400 mesh, 15% EtOAc in hexanes) to give Int-118 as a colorless liquid. Yield: 4.4 g (66%).

[0375] Example 20: Preparation of (3R,4R)-1-(2-Methoxyethyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidin-3-ol (Int-121) and 2-((3R,4R)-3-hydroxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidin-1-yl)acetonitrile (Int-122)

[0376] [ka]

[0377] Step 1: To a stirred solution of 4-bromophenol (Int-24, 12 g, 69.4 mmol) in DMF (100 mL) was added 18-crown-6 (0.055 g, 0.208 mmol), cesium carbonate (27.1 g, 83 mmol) at room temperature. After 10 min, tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.28 g, 55.5 mmol) was added to the reaction mixture and stirred at 90° C. for 16 h. The reaction was quenched with ice water (200 mL) and the precipitate formed was filtered, washed with hexane, and dried under vacuum to give (rac)-Int-119 as a brown solid. LC-MS: C 15H 20 Calculated value of BrNO4: 358.23, Found value: 257.8 [M-Boc] + , 259.8[M-Boc+2] + , 301.8[M-56] + , 303.7[M-56+2] + .Yield: 18.0g (72%).

[0378] Step 2: To a stirred solution of (rac)-Int-119 (4.5 g, 11.30 mmol) in DCM (40 mL) was added HCl (4 M in dioxane, 10 mL, 11.72 mmol) at 0° C. The reaction mixture was stirred for 2 h at 25° C. Reaction progress monitored by TLC showed complete consumption of starting material (10% MeOH in DCM, SM stains purple, product stains yellow with ninhydrin). Volatiles were evaporated under reduced pressure and the resulting crude product was triturated with hexane (20 mL), filtered and dried under vacuum to give (rac)-Int-120 as a light brown solid. LC MS: C 10 H 13 Calculated value of BrNO2+ is 258.01, measured value: 258.0[M] + and 260.0[M+2] + Yield: 3.45g (99%).

[0379] Step 3a: To a stirred solution of (rac)-Int-120 (1.8 g, 6.11 mmol) in acetonitrile (20 mL) was added potassium carbonate (573 mg, 4.15 mmol) and 1-bromo-2-methoxyethane (0.636 mL, 6.72 mmol) at 0° C. The reaction mixture was heated at 60° C. for 7 h. The progress of the reaction was monitored by TLC. The volatiles were evaporated under reduced pressure, water (50 mL) was added and extracted with DCM (150 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (rac)-Int-121 as a brown liquid. LCMS: C 13 H 18 Calculated value of BrNO3: 316.2, measured value: 315.9 [M] + and 317.9[M+2] +.Yield: 1.2g (58%).

[0380] Following the same procedure as above to make the nitrile derivative using bromoacetonitrile on a 6.11 mmol scale afforded the desired (rac)-Int-122 as a brown liquid. Yield 1.3 g (62%). LCMS: C 12 H 13 Calculated value of BrN2O2: 296.15, measured value: 297.9 [M] + and 299.9[M+2] + .

[0381] Example 21: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Int-66)

[0382] [ka]

[0383] Step 1: To a stirred solution of Int-24 (2.0 g, 9.09 mmol) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (3.46 g, 13.64 mmol) and potassium acetate (2.2 g, 22.73 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 min. To this mixture was added Pd(dppf)Cl2 (665 mg, 0.91 mmol) and degassing continued for 2 min. The reaction mixture was then heated at 90 °C for 4 h. The reaction was monitored by TLC, which showed complete consumption of starting material. The reaction was filtered through a bed of Celite. The filtrate was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (2.5 g) was purified by flash column chromatography (SiO2 230-400 mesh, 5% EtOAc in petroleum ether) to give Int-66 as a white solid. Yield = 1.8 g (82%). LC-MS: 12 H 17 BO3 calculated value: 220.08, measured value: 218.9 [M-1] + .

[0384] The following compounds were prepared according to Example 21 using the appropriate starting materials: Int-80 was prepared from commercially available 4-bromophenylcyclobutanone (Int-64). Int-81 was prepared from commercially available (4-bromophenyl)methanol (Int-65).

[0385] [Table 3-1]

[0386] [Table 3-2]

[0387] Example 19: Preparation of tert-butyl(2-fluoroethyl)((1R,2R)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclopropyl)carbamate) (Int-82)

[0388] [ka]

[0389] To a stirred solution of Int-70a (0.5 g, 1.33 mmol) in dry DMF (5 mL) was added NaH (60% dispersion in mineral oil, 0.106 g, 2.66 mmol) at 0 °C. Then 1-bromo-2-fluoroethane (0.253 g, 1.99 mmol) was added and the reaction mixture was stirred at 0 °C-25 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution, diluted with EtOAc (50 mL), washed with ice-cold water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh) by eluting with 6-20% ethyl acetate in petroleum ether to give product Int-82. Yield: 0.4 g (71%). LC-MS: C 22 H 33BFNO5 calculated value: 421.32, measured value: 366.1 [M-56+1] + .

[0390] Example 20: Preparation of certain compounds of formula (I) by Suzuki reaction

[0391] [ka] Step 1: To a stirred solution of the appropriate aryl iodide (Int-9, Int-15, or Int-21) (0.45 mmol) in DMF (1 mL) was added the appropriate aryl boronic ester intermediate (see Example 18) (0.32 mmol), tribasic potassium phosphate (0.96 mmol), and water (0.5 mL) at room temperature. The reaction mixture was degassed with nitrogen gas for 5 minutes. To this reaction mixture was added PdCl2(dppf) (11.7 mg, 0.02 mmol) and degassing continued for 2 minutes. The reaction mixture was then subjected to microwave irradiation at 100° C. for 3 hours. After completion of the reaction, the inorganic solids were filtered through a celite pad. The filtrate was diluted with EtOAc (50 mL), washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude products were purified by flash column chromatography (SiO2 230-400 mesh, 3% MeOH in DCM) to afford intermediate compounds Int-83, Int-84, and Int-85.

[0392] Some of the compounds Int-83, Int-84, and Int-85 were deprotected to give the desired final compounds.

[0393] Step 2: To a stirred solution of Int-83, Int-84, and Int-85 compounds (0.219 mmol) in DCM (2 mL) was added 4.0 M HCl in dioxane (1 mL) at 0° C. The reaction mixture was then stirred at 25° C. for 2 h. The reaction was monitored by TLC, which showed complete consumption of starting material. The volatiles were evaporated under reduced pressure. The resulting crude product was purified by reverse phase preparative HPLC (10 mM ammonium bicarbonate in water and acetonitrile) to afford the desired specific compound of formula (I) as a white solid. The yields were in the range of 28-45%.

[0394] Step 2a: In some cases, alternative procedures were used to obtain the desired compounds. For example, to a stirred solution of Int-83 (200 mg, 0.267 mmol) in DCM (5 mL) was added trifluoroacetic acid (1.4 mL) dropwise at 0° C. After the addition was complete, the reaction mixture was stirred at 25° C. for 2 h. The reaction was followed by TLC. The volatiles were evaporated under reduced pressure. The resulting residue was basified with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by reverse phase preparative HPLC (10 mM ammonium bicarbonate buffer and acetonitrile) to obtain the specific compound of formula (I) as an off-white solid. Yield=13-40%.

[0395] The following compounds were prepared according to Example 20:

[0396] [Table 4]

[0397] For some compounds, final derivatization was performed before deprotection to give the desired final target, for example, hydrolysis of the acetyl protecting group was performed using NaOH in THF and water before deprotection.

[0398] Example 21: Preparation of Certain Compounds of Formula (I) by O-Alkylation of Intermediate Int-84

[0399] [ka]

[0400] Step 1: To a stirred solution of Int-84 (1.50 g, 6.58 mmol) in DMF (7 mL) was added K2CO3. The reaction mixture was stirred for 30 min. To this, the corresponding alkyl halide (6.58 mmol) was added and heated at 80 °C for 8 h. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography (SiO2 100-200 mesh size, 0-5% methanol in DCM) to give intermediate compounds Int-86a-c as solids. Yield 30-45%.

[0401] Step 2: To a stirred solution of Int-86a-c (0.2476 mmol) in dry DCM (2 mL) was added HCl (4 M in 1,4-dioxane, 2 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C to room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by using 0.1% HCOOH in HO and ACN to obtain the desired specific compound of formula (I) as an off-white semi-solid. The yields ranged from 23.5 to 50%.

[0402] The following compounds were prepared according to Example 21:

[0403] [Table 5]

[0404] Example 22: Preparation of Certain Compounds of Formula (I) by Reductive Amination Starting with Cyclobutanone Intermediate (Int-87 / 88)

[0405] [ka]

[0406] Step 1: Following the same procedure as step 1 of Example 20, Int-87 and Int-88 were prepared using Int-9 or Int-15 as appropriate along with Int-80.

[0407] Step 2: To a stirred solution of Int-87 (or Int-88) (60 mmol) in methanol (10 mL) was added the appropriate respective amine (R 2 NH2) was added (78 mmol, 1.3 equiv.) followed by dropwise addition of acetic acid. The reaction was stirred for 45 min. To this was added sodium cyanoborohydride (66 mol, 1.1 equiv.) and the reaction was stirred for 4 h. After 4 h, the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate (2×25 mL). The organic layer was washed with saturated NaCl (15 mL), dried over MgSO4 and concentrated to give the crude product of Int-89 (or Int-90). The yields were in the range of 75-90%. The reaction mixture was used in the next step without further purification.

[0408] Step 3: To a stirred solution of Int-89 (or Int-90) (50 mmol) in methanol (5 mL) was added 4 M HCl in dioxane (1.0 mL) at 0 °C for 30 min. The reaction was monitored by TLC, which showed complete consumption of the starting material. After completion of the reaction, the volatiles were evaporated under reduced pressure. The resulting crude product was purified by reverse phase preparative HPLC (10 mM ammonium bicarbonate buffer and acetonitrile) to obtain the desired specific compound of formula (I). The yields were in the range of 57-89%.

[0409] The following compounds were prepared according to Example 21:

[0410] [Table 6-1]

[0411] [Table 6-2]

[0412] Example 22:

[0413] [ka]

[0414] Step 1: To a stirred solution of Int-81 (3.0 g, 0.0128 mol) in DCM (25 mL), PPh3 (3.5 g, 0.0134 mol) was added followed by CBr4 (4.67 g, 0.0140 mol). The reaction mixture was stirred for 6 h. After 6 h, the reaction mixture was concentrated and purified on a silica gel column by eluting with 1-8% EtOAc in hexane to give the desired compound Int-91 as a thick yellow oil in about 85% yield. LC-MS: C 13 H 18 Calculated value for BBrO2 297.0, Found: No ionization (not observed).

[0415] Step 2: To a stirred solution of alcohol Int-29a (0.0064 mol) in dry THF (15 mL) was added NaH (60% dispersion in mineral oil) (0.0097 mol) in small portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Then (Int-91) (0.0084 mol) was dissolved in THF and slowly added to the reaction mixture and stirred at 0° C. for 30 min. Then the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution, diluted with EtOAc (500 mL), washed with ice-cold water (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product Int-92a was used directly in the next step without further workup. Yield: 1.49 g (57.32%). LC-MS: C 24 H 38 Calculated value for BNO6: 448.2; Found value: No ionization (not observed).

[0416] Following the same procedure, starting from tert-butyl ((1R,2R)-2-hydroxycyclopropyl)carbamate, Int-92b was obtained.

[0417] The following compounds were prepared according to Example 22 from the appropriate Int92a-b and Int-15 using a procedure similar to that in Example 20 to give the desired compounds as white solids in 28-32% yields.

[0418] [Table 7]

[0419] Example A-1: ​​Parenteral pharmaceutical composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a water-soluble salt of the compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. An appropriate buffer, together with an optional acid or base, is optionally added to adjust the pH. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0420] Example A-2: Oral Solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is added to water (along with an optional solubilizer, optional buffer, and taste masking excipient) to obtain a 20 mg / mL solution.

[0421] Example A-3: Oral Tablet Tablets are prepared by mixing 20-50% by weight of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate, or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0422] Example A-4: Oral Capsules To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is mixed with starch or other suitable powder mixture, and the mixture is incorporated into an oral dosage form, such as a hard gelatin capsule, suitable for oral administration.

[0423] In another embodiment, 10 to 500 mg of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, is placed into a size 4 capsule, or a size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

[0424] II. Biological Evaluation Example B-1: In vitro assays for screening compounds and metalloprotein modulators Bacterial susceptibility testing The minimum inhibitory concentration (MIC) was determined by the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Briefly, organism suspensions were diluted with 3 × 10 5 ~7×10 5 The final inoculum was adjusted to 100 colony forming units (CFU) / mL. Drug dilutions and inoculations were performed in sterile cation-adjusted Mueller-Hinton agar (Beckton Dickinson). In wells, an inoculum volume of 100 μL was mixed with 2 μL of DMSO along with 2-fold serial dilutions of drug. All inoculated microdilution trays were incubated for 18–24 h at 35 °C in ambient air. After incubation, the lowest concentration of drug that prevented visible growth (OD600nm < 0.05) was recorded as the MIC. The performance of the assay was monitored by the use of laboratory quality control strains and compounds with defined MIC spectra according to CLSI guidelines.

[0425] Exemplary in vitro assay data against select bacteria for compounds in embodiments of the present disclosure are provided in Table A. Compounds of the present disclosure do not inhibit Staphylococcus aureus.

[0426] [Table 8-1]

[0427] [Table 8-2]

[0428] LpxC binding assay IC against E. coli and P. aeruginosa LpxC 50 Values ​​are determined using the Rapid Fire MS assay previously described in J. Med. Chem. 2012, 55, 1662-1670.

[0429] Exemplary in vitro assay data against select bacteria for compounds in embodiments of the present disclosure are provided in Table B.

[0430] [Table 9]

[0431] The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein: R １ is C １ -C ４ is alkyl, R ２ａ and R ２ｂ are each independently hydrogen, halogen, or C １ -C ４ is alkyl, R ３ is hydrogen, -(C １ -C ４ alkylene)-OH, or -(C １ -C ４ (alkylene)-NH ２ and R ４ is hydrogen or C １ -C ４ is alkyl, R ５ and R ６ are each independently hydrogen, halogen, or C １ -C ４ is alkyl, R ７ is C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, 4-6 membered heterocycloalkyl, —O—(C ３ -C ６ cycloalkyl), -O-(4- to 6-membered heterocycloalkyl), -(C １ -C ４ alkylene)-(C ３ -C ６ Cycloalkyl), -(C １ -C ４ alkylene)-(4- to 6-membered heterocycloalkyl), —O—(C １ -C ４ alkylene)-(C ３ -C ６ cycloalkyl), -O-(C １ -C ４ alkylene)-(4- to 6-membered heterocycloalkyl), -(C １ -C ４ alkylene)-O-(C ３ -C ６ cycloalkyl), or -(C １ -C ４ alkylene)-O-(4- to 6-membered heterocycloalkyl), where the alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is -OR ８ , -N(R ８ ) ２ , -CO ２ R ８ , -CON(R ８ ) ２ , -CH ２ N (R ８ ) ２ , -NHCOR ８ , -NHSO ２ R ８ , -CH ２ C.N., C. １ -C ４ Alkyl, C １ -C ４ Hydroxyalkyl, -C(=O)-C １ -C ４ Hydroxyalkyl, C １ -C ４ Methoxyalkyl, and C １ -C ４ substituted by one, two, or three groups independently selected from aminoalkyl; R ８ are each independently hydrogen, C １ -C ４ Alkyl, -C(=O)-C １ -C ４ alkyl, or 4- to 6-membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or substituted with -F, -CN, -OH, -CH ２ OH, -NH ２ , -OMe, -N(CH ３ ) ２ , -CO ２ H, -CONH ２ , -SO ２ CH ３ , -C(=NH)NH ２ , phenyl, and unsubstituted or substituted with -F, -CN, -OH, -NH ２ , -OMe, -N(CH ３ ) ２ , -CO ２ H, -CONH ２ , and -SO ２ CH ３ and wherein the aryl is substituted by one, two, three, or four groups independently selected from: Alternatively, two R attached to the same nitrogen ８ are unsubstituted or -F, -CN, -OH, -NH ２ , -OMe, -CO ２ H, -CONH ２ , and -SO ２ CH ３ and forming a 4-6 membered heterocycloalkyl substituted by one, two or three groups independently selected from s is 1 or 2, and t is 1 or 2; A compound or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

2. R 1 is -CH 3 , R 2a is hydrogen; R 2b is hydrogen, and 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R4 is hydrogen.

3. Each R 5 is independently hydrogen, fluoro, chloro, or -CH 3 ; s is 1, Each R 6 is independently hydrogen, fluoro, chloro, or —CH 3 ; and 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein t is 1.

4. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R5 and R6 are each hydrogen.

5. Each R 5 is hydrogen, and 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each R 6 is independently hydrogen, fluoro, chloro, or -CH 3 .

6. The structure of formula (IIa) 【Chemistry 2】 or a pharma- ceutically acceptable salt, or solvate thereof, wherein: R 5 is hydrogen or fluoro; R 6 is hydrogen or fluoro, and 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R3 is hydrogen or -(C1-C4 alkylene)-OH.

7. The structure of formula (IIIa): 【Chemistry 3】 or a pharma- ceutically acceptable salt, or solvate thereof, wherein: R 5 is hydrogen or fluoro; R 6 is hydrogen or fluoro, and 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R3 is hydrogen or -(C1-C4 alkylene)-OH.

8. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R3 is hydrogen or -CH2OH.

9. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R3 is -CH2OH.

10. R 3 is hydrogen, -(C 1 -C 4 alkylene)-OH, or -(C 1 -C 4 alkylene)-NH 2 ; R 5 is hydrogen or fluoro; R 6 is hydrogen or fluoro; R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, —O—(C 3 -C 6 cycloalkyl), —O-(4- to 6-membered heterocycloalkyl), —(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkylene)-(4- to 6-membered heterocycloalkyl), —O—(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl), —O—(C 1 -C 4 alkylene)-(4- to 6-membered heterocycloalkyl), —(C 1 -C 4 alkylene)-O—(C 3 -C 6 cycloalkyl), or —(C 1 -C 4 alkylene)-O-(4-6 membered heterocycloalkyl), wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted by 1, 2, or 3 groups independently selected from -OR 8 , -N(R 8 ) 2 , -CO 2 R 8 , -CON(R 8 ) 2 , -CH 2 N(R 8 ) 2 , -NHCOR 8 , -NHSO 2 R 8 , -CH 2 CN, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -C(═O)-C 1 -C 4 hydroxyalkyl, C 1 -C 4 methoxyalkyl, and C 1 -C 4 aminoalkyl; and R 8 is each independently hydrogen, C 1 -C 4 alkyl, —C(═O)—C 1 -C 4 alkyl, or 4-6 membered heterocycloalkyl, where alkyl or heterocycloalkyl is unsubstituted or is selected from —F, —CN, —OH, —CH 2 OH, —NH 2 , —OMe, —N(CH 3 ) 2 , —CO 2 H, —CONH 2 , —SO 2 CH 3 , —C(═NH)NH 2 , phenyl, and is unsubstituted or selected from —F, —CN, —OH, —NH 2 , —OMe, —N(CH 3 ) 2 , —CO 2 H, —CONH 2 , and —SO 2 CH 3 . and wherein the aryl is substituted by one, two, three, or four groups independently selected from: Alternatively, two R 8 s attached to the same nitrogen are joined together to form a 4-6 membered heterocycloalkyl that is unsubstituted or substituted by 1, 2, or 3 groups independently selected from -F, -CN, -OH, -NH 2 , -OMe, -CO 2 H, -CONH 2 , and -SO 2 CH 3 , or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

11. R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 4 cycloalkyl, 4- to 6-membered heterocycloalkyl, -O-(C 3 -C 4 cycloalkyl), -O-(4- to 6-membered heterocycloalkyl), -O-(C 1 -C 4 alkylene)-(4- to 6-membered heterocycloalkyl), or -(C 1 -C 4 alkylene)-O-(C 3 -C 6 cycloalkyl), wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from -OR 8 , -N(R 8 ) 2 , -NHSO 2 R 8 , -CH 2 CN, C 1 -C 4 alkyl, -C(═O)-C 1 -C 4 hydroxyalkyl, C 1 substituted by one or two groups independently selected from -C 4 hydroxyalkyl, and C 1 -C 4 methoxyalkyl; and 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each R 8 is independently hydrogen, C 1 -C 4 alkyl, -C(=O)-C 1 -C 4 alkyl, or 4-6 membered heterocycloalkyl, wherein alkyl is unsubstituted or substituted by one, two, or three groups independently selected from -F, -CN, -OH, -CO 2 H, -C(=NH)NH 2 , and 5 membered monocyclic heteroaryl that is unsubstituted or substituted by one -CONH 2 group.

12. R 7 is cyclobutyl, which is substituted by one -N(R 8 ) 2 group, and 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each R8 is independently hydrogen, C1-C2 alkyl, or -C(=O)-C1-C2 alkyl, wherein alkyl is unsubstituted or substituted by one or two groups independently selected from -CN, -OH, and oxadiazolyl.

13. R 7 is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 2. The compound of claim 1, wherein:

14. The structure of formula (IV): 【Chemistry 5】 or a pharma- ceutically acceptable salt, or solvate thereof, wherein: R 3 is hydrogen, —(C 1 -C 4 alkylene)-OH, or —(C 1 -C 4 alkylene)-NH 2 ; R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, —O-(4- to 6-membered heterocycloalkyl), —O-(C 1 -C 4 alkylene)-(4- to 6-membered heterocycloalkyl), or —(C 1 -C 4 alkylene)-O-(C 3 -C 6 cycloalkyl), where the alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from —OR 8 , —N(R 8 ) 2 , —NHSO 2 R 8 , —CH 2 CN, C 1 -C 4 alkyl, —C(═O)-C 1 -C 4 hydroxyalkyl, C 1 -C 4 methoxyalkyl, and C 1 -C 4 substituted by one or two groups independently selected from hydroxyalkyl; and The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each R8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4- to 6-membered heterocycloalkyl, wherein alkyl or heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, or 4 groups independently selected from -F, -CN, -OH, -CH2OH, -CO2H, -C(=NH)NH2, and monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

15. R 3 is hydrogen or -(C 1 -C 4 alkylene)-OH; R 7 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 3 -C 4 cycloalkyl, 4- to 6-membered heterocycloalkyl, —O—(C 3 -C 4 cycloalkyl), —O—(4- to 6-membered heterocycloalkyl), —O—(C 1 -C 4 alkylene)-(4- to 6-membered heterocycloalkyl), or —(C 1 -C 4 alkylene)-O—(C 3 -C 6 cycloalkyl), where the alkyl, alkoxy, heteroalkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is selected from —OR 8 , —N(R 8 ) 2 , —NHSO 2 R 8 , —CH 2 CN, C 1 -C 4 alkyl, —C(═O)—C 1 -C 4 hydroxyalkyl, C 1 -C 4 substituted by one or two groups independently selected from hydroxyalkyl, and C 1 -C 4 methoxyalkyl; 15. The compound of claim 14, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each R8 is independently hydrogen, C1-C4 alkyl, -C(=O)-C1-C4 alkyl, or 4-6 membered heterocycloalkyl, wherein alkyl is unsubstituted or substituted with one, two, or three groups independently selected from -F, -CN, -OH, -CO2H, -C(=NH)NH2, and 5 membered monocyclic heteroaryl that is unsubstituted or substituted with one -CONH2 group.

16. 1: (2R)-4-(4'-(2-amino-3-hydroxypropoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((R)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 2: (R)-4-(4'-((S)-2-amino-3-hydroxypropoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 3: (2S)-4-(4'-(2-amino-3-methoxypropoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 4: (S)-4-(4'-((trans)-2-aminocyclopropoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 5: 1-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)ethane-1,2-diol, 6: (2S)-4-(4'-((2-amino-3-hydroxypropoxy)methyl)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 7: 2-amino-3-((4'-(3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propan-1-ol, 8: (S)-3-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)propane-1,2-diol, 9: (S)-4-(4'-(((trans)-2-aminocyclopropoxy)methyl)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 10: (trans)-4-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol, 11: 2-(((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)methyl)propane-1,3-diol, 12: (S)-4-(4'-((trans)-2-((2-fluoroethyl)amino)cyclopropoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 13: (2S)-4-(4'-((1,4-dioxan-2-yl)methoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 14: (S)-4-(4'-((R)-2-hydroxy-3-methoxypropoxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 15: (S)-4-(4'-(((trans)-4-aminotetrahydrofuran-3-yl)oxy)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 16: 3-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-2-methylpropane-1,2-diol, 17: 4-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)butane-1,2-diol, 18: (S)-3-((3-(4'-(3-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)propanenitrile, 19: (S)-2-((3-(4'-(3-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)ethan-1-ol, 20: (S)-1-(1-(3-(4'-(3-(oxetan-3-ylamino)cyclobutyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)-1H-imidazol-2-yl)ethan-1-ol, 21: (S)-2-hydroxy-1-(3-(4'-(3-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)azetidin-1-yl)ethan-1-one, 22: 2-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)butane-1,4-diol, 23: 5-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)pentane-1,4-diol, 24: (trans)-4-((4'-((S)-4-amino-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol, 25: (S)-2-((3-(4'-(3-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)acetimidamide, 26: (S)-(3-(4'-(3-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)glycine, 27: (S)-1-(1-(3-(4'-(3-((oxazol-4-ylmethyl)amino)cyclobutyl)-[1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)-1H-imidazol-2-yl)ethan-1-ol, 28: 2-((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)acetonitrile, 29: (S)-4-(4'-(3-(((1,2,4-oxadiazol-3-yl)methyl)amino)cyclobutyl)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 30: 3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutan-1-ol, 31: (S)-4-(4'-(3-((2,2-difluoroethyl)amino)cyclobutyl)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 32: 3-((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)propanenitrile, 33: 3-hydroxy-2-((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)propanenitrile, 34: (S)-4-(4'-(3-((2,2-difluoro-3-hydroxypropyl)amino)cyclobutyl)-[1,1'-biphenyl]-4-yl)-2-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-3-yn-1-ol, 35: 3-(((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)methyl)-1,2,4-oxadiazole-5-carboxamide, and 36: N-((1S,3r)-3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)methanesulfonamide, 37: 3-((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)-2-methylpropanoic acid, 38: (3R,4S)-4-((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)tetrahydrofuran-3-ol, 39: 3-((3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol, 40: 2-cyano-N-(3-(4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)cyclobutyl)acetamide, 41: (3S,4R)-4-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)methyl)tetrahydrofuran-3-ol, 42: (3R,4R)-4-((4'-(3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)prop-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol, 43: (3R,4R)-4-((4'-((R)-5-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)pent-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol, 44: (3R,4R)-4-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)-1-(2-methoxyethyl)pyrrolidin-3-ol, 45: 2-((3R,4R)-3-hydroxy-4-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)pyrrolidin-1-yl)acetonitrile, 46: (cis)-4-((4'-((S)-4-hydroxy-3-(2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)but-1-yn-1-yl)-[1,1'-biphenyl]-4-yl)oxy)tetrahydrofuran-3-ol, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof.

17. A pharmaceutical composition comprising the compound of claim 1, or a pharma- ceutically acceptable salt, or solvate thereof, and a pharma- ceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound according to claim 1, or a pharma- ceutically acceptable salt, or solvate thereof, for use as a therapeutically active substance, and a pharma- ceutically acceptable excipient.

19. Use of a compound according to claim 1 in the manufacture of a medicament for use in the treatment or prevention of a Gram-negative bacterial infection, wherein the Gram-negative bacterial infection is associated with Pseudomonas aeruginosa or is pneumonia.

20. The use described in claim 19, wherein the patient is identified as having a pulmonary disease, and the pulmonary disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic degenerative lung disease, or a combination thereof.

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