LPXC inhibitors and uses thereof

Abstract

Provided herein are LpxC inhibitor compounds, as well as pharmaceutical compositions comprising LpxC inhibitor compounds and methods of use thereof in the treatment of diseases that would benefit from treatment with an LpxC inhibitor, including Gram-negative bacterial infections, such as urinary tract infections.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 249,166, filed September 28, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] There is a need in the medical field for effective treatments for diseases caused by bacterial infections. Summary of the Invention

[0003] Provided herein are LpxC inhibitor compounds, as well as pharmaceutical compositions comprising the compounds and methods of use thereof in the treatment of diseases that would benefit from treatment with an LpxC inhibitor, including Gram-negative bacterial infections, such as urinary tract infections.

[0004] In one embodiment, the compound of formula (I)

[0005] [ka] or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, During the ceremony, P1 is -P(=O)(OR 1 )2, -(CR 3 R 4 )-OP(=O)(OR 1 )2, -S(=O)2OR 1 , -(CR 3 R 4 )-OS(=O)2OR 1 , -S(=O)2R 2 , -(CR 3 R 4 )-OS(=O)2R 2 , -C(=O)R 2 , -(CR 3 R 4 )-OC(=O)R 2 , -C(=O)OR2 , -(CR 3 R 4 )-OC(=O)OR 2 , -C(=O)-O-(CR 3 R 4 )-OC(=O)R 2 , -C(=O)NR 5 R 6 ,or

[0006] [ka] and Each R 1 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 2 is C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 5 and R 6 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocycloalkyl; Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0007] In some embodiments, the compound has formula (Ia):

[0008] [ka] or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0009] In some embodiments, the compound has formula (Ib):

[0010] [ka] or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0011] In some embodiments, P1 is -P(=O)(OR 1 )2, -CH2-OP(=O)(OR 1 )2, -S(=O)2OR 1 , -S(=O)2R 2 , -C(=O)OR 2 , -(CHR 4 )-OC(=O)OR 2 , -C(=O)-O-(CHR 4 )-OC(=O)R 2 , -C(=O)R 2 , -CH2-OC(=O)R 2 , -C(=O)NR 5 R 6 ,or

[0012] [ka] and Each R 1 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; R 2 is C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; R 4 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl, and R 5 and R 6 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C4 alkyl and 4- to 6-membered heterocycloalkyl.

[0013] In some embodiments, Each R 1 are independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2; R 2 is -CH3, -CH2CH3, -CH(CH3)2, or C(CH3)3, R 4 is hydrogen, -CH3, or phenyl, and R 5 and R 6 are each independently hydrogen, -CH3, or -CH2CH3; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C4 alkyl and 4- to 6-membered heterocycloalkyl.

[0014] In some embodiments, P1 is -P(=O)(OH)2, -CH2-OP(=O)(OH)2, -S(=O)2OH, -S(=O)2CH3, -C(=O)OCH2CH3, -(CH(CH3))-OC(=O)OCH(CH3)2, -(CH(CH3))-OC(=O)OCH2CH3, -C(=O)-O-(CH(phenyl))-OC(=O)C(CH3), -C(=O)C(CH3), -CH2-OC(=O)C(CH3), -C(=O)N(CH3), or

[0015] [ka] It is.

[0016] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound as described herein, or its pharma- ceutically acceptable salt, or pharma- ceutically acceptable solvate, and at least one pharma- ceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated for intravenous or oral administration to mammals.In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, or solution.

[0017] In another aspect, disclosed herein is a method of treating a gram-negative bacterial infection in a patient in need of such treatment, comprising administering to the patient a compound disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intraperitoneal infection, skin infection, and urinary tract infection. In some embodiments, the gram-negative bacterial infection is selected from chronic urinary tract infection, complicated urinary tract infection, cystitis, pyelonephritis, urethritis, recurrent urinary tract infection, bladder infection, urethral infection, and kidney infection. In some embodiments, the gram-negative bacterial infection is a chronic urinary tract infection. In some embodiments, the gram-negative bacterial infection is a complicated urinary tract infection. In some embodiments, the compound does not affect gram-positive bacteria.

[0018] In some embodiments, the compound disclosed herein, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate, is administered to the patient by IV injection or infusion.In other embodiments, the compound disclosed herein, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable solvate, is administered to the patient orally.

[0019] In some embodiments, administration is to treat an existing infection, hi other embodiments, administration is provided as a prophylaxis.

[0020] An article of manufacture is provided that includes packaging material, an LpxC inhibitory compound described herein, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, within the packaging material, and a label indicating that the compound, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate, or composition is used to modulate the activity of LpxC or for the treatment, prevention, or amelioration of one or more symptoms of a disease or condition that may benefit from modulation of LpxC activity.

[0021] 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 particular 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.

[0022] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 shows the mean final burden of E. coll UTI89 in urine, bladder, and kidneys at the end of the 96-hour urinary tract infection study. [Diagram 2] Figure 2 shows the mean final load of Klebsiella pneumoniae BAA-1705 in the urine, bladder, and kidneys at the end of the 96-hour urinary tract infection study.

[0024] Detailed Description of the Invention Provided herein are LpxC inhibitor compounds, as well as pharmaceutical compositions comprising the compounds, and methods of using the pharmaceutical compositions in treating diseases that may benefit from treatment with LpxC inhibitors, including gram-negative bacterial infections, such as urinary tract infections. In some embodiments, the compounds provided herein are prodrugs of compound A.

[0025] Compound A Compound A refers to (S)-l-(3-(5-hydroxy-6-oxo-l,6-dihydropyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile having the chemical structure shown below.

[0026] [ka]

[0027] Compound A, also known as (S)-l-(3-(5,6-dihydroxypyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile, is a tautomer of the above structure and has the chemical structure shown below.

[0028] [ka]

[0029] Compound A is a potent inhibitor of UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC). LpxC is an essential enzyme involved in the first critical step in the biosynthesis of lipid A in gram-negative bacteria. Lipid A is an essential component of the outer membrane of gram-negative bacteria. LpxC is highly conserved across strains of gram-negative bacteria, making it an attractive target for treating gram-negative infections.

[0030] Compound A is an LpxC inhibitor useful in the treatment methods described herein.Compound A is a potent inhibitor in gram-negative bacterial cell lines, exhibiting MIC values ​​of <1μg / mL against E.coli and K.pneumoniae cell lines.In addition, compound A does not inhibit gram-positive bacterial cell lines such as Staphylococcus aureus.

[0031] The preparation and use of Compound A has been previously described (see WO2020 / 061375, US2021 / 0221796, WO2021 / 195260, and US2021 / 0309651).

[0032] Prodrug The term "prodrug" is meant in some embodiments to refer to a compound that is converted to a biologically active compound under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharma- ceutically acceptable precursor of a biologically active compound. Prodrugs are typically inactive when administered to a subject, but are converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 79, 2124 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of active compounds described herein are prepared by modifying functional groups present in the active compound such that the modifications are cleaved either by routine manipulation or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate, phosphate, sulfonate, carbonate, and carbamate derivatives of alcohol or amine functional groups in the active compound.

[0033] In some embodiments, compound A

[0034] [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein the prodrug group is attached to a hydroxy or amino group of Compound A, and the prodrug moiety comprises a phosphate, sulfonate, sulfate, ester, carbonate, or carbamate group.

[0035] In some embodiments, the prodrug is attached to a hydroxy group of Compound A. In some embodiments, the prodrug is attached to an amino group of Compound A.

[0036] In some embodiments, the prodrug moiety comprises a phosphate group. In some embodiments, the prodrug moiety comprises a sulfonate group. In some embodiments, the prodrug moiety comprises a sulfate group. In some embodiments, the prodrug moiety comprises an ester group. In some embodiments, the prodrug moiety comprises a carbonate group. In some embodiments, the prodrug moiety comprises a carbamate group.

[0037] Although compound A is highly active in in vitro cell-based assays, in some instances, its low physiological solubility poses a challenge to its use in vivo. In some embodiments, the solubility of compound A is increased by using a prodrug of compound A. In some embodiments, a prodrug of compound A provided herein, e.g., a phosphate prodrug, has a 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or 10-fold or more increase in solubility compared to compound A under physiological conditions. In some embodiments, the solubility of compound A under physiological conditions, e.g., at pH 7.4, is <1 mg / mL. In some embodiments, the solubility of a prodrug of compound A provided herein, e.g., a phosphate prodrug, is >10 mg / mL under the same physiological conditions.

[0038] In another embodiment, the compound of formula (I)

[0039] [ka] or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof, During the ceremony, P1 is -P(=O)(OR 1 )2, -(CR 3 R 4 )-OP(=O)(OR 1 )2, -S(=O)2OR 1 , -(CR 3 R 4 )-OS(=O)2OR 1 , -S(=O)2R 2 , -(CR 3 R 4 )-OS(=O)2R 2 , -C(=O)R 2 , -(CR 3 R 4 )-OC(=O)R 2 , -C(=O)OR 2 , -(CR 3 R 4 )-OC(=O)OR 2 , -C(=O)-O-(CR 3 R 4 )-OC(=O)R 2 , -C(=O)NR 5 R 6 ,or

[0040] [ka] and Each R 1 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 2 is C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 3 and R4 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 5 and R 6 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one, two, or three substituents selected from the group consisting of C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocycloalkyl; Provided herein are compounds, or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0041] In some embodiments, the compound has formula (Ia):

[0042] [ka] or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0043] In some embodiments, the compound has formula (Ib):

[0044] [ka] or a pharma- ceutically acceptable salt, or a pharma- ceutically acceptable solvate thereof.

[0045] In any and all of the embodiments, the substituents are selected from among a subset of the alternatives listed. For example, in some embodiments, R 3is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. In some embodiments, R 3 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. 3 is hydrogen, -CH, or phenyl. In some embodiments, R 3 is hydrogen or C-C alkyl. In some embodiments, R 3 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 3 is hydrogen or -CH. In some embodiments, R 3 is hydrogen.

[0046] In some embodiments, R 4 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. In some embodiments, R 4 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. 4 is hydrogen, -CH, or phenyl. In some embodiments, R 4 is hydrogen or C-C alkyl. In some embodiments, R 4 is hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 4is hydrogen or -CH. In some embodiments, R 4 is hydrogen.

[0047] In some embodiments, R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. 3 and R 4 are each independently hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), -C(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. 3 and R 4 are each independently hydrogen, -CH, or phenyl. 3 and R 4 are each independently hydrogen or C1-C4 alkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 3 and R 4 are each independently hydrogen or -CH. In some embodiments, R 3 and R 4 are each hydrogen.

[0048] In some embodiments, each R 1 is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. In some embodiments, each R 1 is independently hydrogen or C-C alkyl. In some embodiments, each R 1is independently hydrogen, -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CHCH(CH), -CH(CH)(CHCH), or -C(CH). 1 is independently hydrogen, -CH, -CHCH, or -CH(CH). In some embodiments, each R 1 is hydrogen.

[0049] In some embodiments, R 2 is C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. In some embodiments, R 2 is C1-C4 alkyl. In some embodiments, R 2 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), or -C(CH3)3. 2 is -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3.

[0050] In some embodiments, P1 is -P(=O)(OR 1 )2 or -(CR 3 R 4 )-OP(=O)(OR 1 In some embodiments, P1 is -P(=O)(OR 1 )2 or -(CR 3 R 4 )-OP(=O)(OR 1 )2, and each R 1 are independently hydrogen or C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. In some embodiments, P1 is -P(=O)(OR 1 )2 or -CH2-OP(=O)(OR 1 )2, and each R 1is independently hydrogen, -CH, -CHCH, or -CH(CH). In some embodiments, P is -P(=O)(OH) or -CH-OP(=O)(OH).

[0051] In some embodiments, P1 is -P(=O)(OR 1 In some embodiments, P1 is -P(=O)(OR 1 )2, and each R 1 is independently hydrogen or C1-C4 alkyl. In some embodiments, P1 is -P(=O)(OR 1 )2, and each R 1 is independently hydrogen, -CH, -CHCH, or -CH(CH). In some embodiments, P is -P(=O)(OH).

[0052] In some embodiments, P1 is -(CR 3 R 4 )-OP(=O)(OR 1 In some embodiments, P1 is -(CR 3 R 4 )-OP(=O)(OR 1 )2, and each R 1 are independently hydrogen or C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. In some embodiments, P1 is -CH2-OP(=O)(OR 1 )2, and each R 1 is independently hydrogen, -CH, -CHCH, or -CH(CH). In some embodiments, P is -CH-OP(=O)(OH).

[0053] In some embodiments, P1 is -S(=O)2OR 1 or -(CR 3 R 4 )-OS(=O)2OR 1 In some embodiments, P1 is -S(=O)2OR1 or -(CR 3 R 4 )-OS(=O)2OR 1 and R 1 is hydrogen or C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. In some embodiments, P1 is -S(=O)2OR 1 In some embodiments, P1 is -(CR 3 R 4 )-OS(=O)2OR 1 In some embodiments, P1 is -S(=O)2OR 1 and R 1 is hydrogen, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, P1 is -S(=O)2OH.

[0054] In some embodiments, P1 is -S(=O)2R 2 or -(CR 3 R 4 )-OS(=O)2R 2 In some embodiments, P1 is -S(=O)2R 2 or -(CR 3 R 4 )-OS(=O)2R 2 and R 2 is C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. In some embodiments, P1 is -S(=O)2R 2 or -(CR 3 R 4 )-OS(=O)2R 2 and R 2 is C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. In some embodiments, P1 is -S(=O)2R 2In some embodiments, P1 is -(CR 3 R 4 )-OS(=O)2R 2 In some embodiments, P1 is -S(=O)2R 2 and R 2 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, P1 is -S(=O)2CH3.

[0055] In some embodiments, P1 is -C(=O)OR 2 , -(CR 3 R 4 )-OC(=O)OR 2 , or -C(=O)-O-(CR 3 R 4 )-OC(=O)R 2 In some embodiments, P1 is -C(=O)OR 2 , -(CR 3 R 4 )-OC(=O)OR 2 , or -C(=O)-O-(CR 3 R 4 )-OC(=O)R 2 and R 2 is C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. In some embodiments, P1 is -C(=O)OR 2 , -(CHR 4 )-OC(=O)OR 2 , or -C(=O)-O-(CHR 4 )-OC(=O)R 2 and R 2 is -CH3, -CH2CH3, or -CH(CH3)2, and R 4 is hydrogen, -CH, or phenyl. In some embodiments, P is -C(=O)OR 2 In some embodiments, P1 is -(CR 3 R 4 )-OC(=O)OR 2In some embodiments, P1 is -C(=O)-O-(CR 3 R 4 )-OC(=O)R 2 It is.

[0056] In some embodiments, P1 is -C(=O)R 2 or -(CR 3 R 4 )-OC(=O)R 2 In some embodiments, P1 is -C(=O)R 2 or -(CR 3 R 4 )-OC(=O)R 2 and R 2 is C1-C4 alkyl, and R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl. In some embodiments, P1 is -C(=O)R 2 or -CH2-OC(=O)R 2 and R 2 is -CH3, -CH2CH3, -CH(CH3)2, or C(CH3)3. In some embodiments, P1 is -C(=O)R 2 In some embodiments, P1 is -(CR 3 R 4 )-OC(=O)R 2 It is.

[0057] In some embodiments, P1 is -C(=O)NR 5 R 6 In some embodiments, R 5 and R 6 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. 5 and R 6 are each independently hydrogen or C1-C4 alkyl. In some embodiments, R 5 and R 6 are each independently hydrogen, -CH, or -CHCH. In some embodiments, R5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C4 alkyl and 4- to 6-membered heterocycloalkyl.

[0058] In some embodiments, P1 is

[0059] [ka] In some embodiments, P1 is

[0060] [ka] and R 1 is hydrogen or C1-C4 alkyl. In some embodiments, P1 is

[0061] [ka] and R 1 is hydrogen, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, P1 is

[0062] [ka] It is.

[0063] In some embodiments, P1 is -P(=O)(OR 1 )2, -CH2-OP(=O)(OR 1 )2, -S(=O)2OR 1 , -S(=O)2R 2 , -C(=O)OR 2 , -(CHR 4 )-OC(=O)OR 2 , -C(=O)-O-(CHR 4)-OC(=O)R 2 , -C(=O)R 2 , -CH2-OC(=O)R 2 , -C(=O)NR 5 R 6 ,or

[0064] [ka] Each R 1 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; R 2 is C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; R 4 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl, and R 5 and R 6 are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or phenyl; R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C4 alkyl and 4- to 6-membered heterocycloalkyl.

[0065] In some embodiments, Each R 1 are independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2; R 2 is -CH3, -CH2CH3, -CH(CH3)2, or C(CH3)3, R 4 is hydrogen, -CH3, or phenyl, and R 5 and R 6 are each independently hydrogen, -CH3, or -CH2CH3; or R5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl that is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C4 alkyl and 4- to 6-membered heterocycloalkyl.

[0066] In some embodiments, P1 is -P(=O)(OH)2, -CH2-OP(=O)(OH)2, -S(=O)2OH, -S(=O)2CH3, -C(=O)OCH2CH3, -(CH(CH3))-OC(=O)OCH(CH3)2, -(CH(CH3))-OC(=O)OCH2CH3, -C(=O)-O-(CH(phenyl))-OC(=O)C(CH3), -C(=O)C(CH3), -CH2-OC(=O)C(CH3), -C(=O)N(CH3), or

[0067] [ka] It is.

[0068] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of skill in the art to provide stable moieties and compounds.

[0069] Exemplary compounds of formula (I) include those set forth in Table 1 below.

[0070] [Table 1-1]

[0071] [Table 1-2]

[0072] In some embodiments, the compound is a pharma- ceutically acceptable salt of a compound of Table 1. In some embodiments, the compound is a pharma- ceutically acceptable solvate of a compound of Table 1.

[0073] definition Unless otherwise stated, the following terms used in this application have the definitions set forth below. Use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0074] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group includes 1-8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group includes 1-5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group includes 1-4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group includes 1-3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group includes 1-2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group includes 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group includes methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule by a single bond.

[0075] "Fluoroalkyl" refers to an alkyl group, as defined above, that is substituted with one or more fluoro radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0076] "Cycloalkyl" refers to a stable monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which contains no unsaturation and includes fused or bridged ring systems having from 3 to 15 carbon atoms. In certain embodiments, cycloalkyls contain from 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain from 3 to 6 carbon atoms. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls are attached to the remainder of the molecule by a single bond.

[0077] "Heterocycloalkyl" refers to a stable 3- to 18-membered ring containing 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur, free of unsaturation. Unless otherwise specified in the specification, a heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused, bridged, or spiro ring systems. The heteroatoms in a heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. In certain embodiments, a heterocycloalkyl contains 3-10 atoms in the ring. In other embodiments, a heterocycloalkyl contains 4-6 atoms in the ring. Examples of monocyclic heterocycloalkyl groups include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, tetrahydropyran, morpholine, thiomorpholine, dioxane, dithiane, azepane, oxepane, and homomorpholine. Heterocycloalkyls are attached to the remainder of the molecule through any atom of the ring, such as a carbon atom (C-linked heterocycloalkyl) or a nitrogen atom (N-linked heterocycloalkyl).

[0078] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, in which at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. In certain embodiments, the heteroaryl is a monocyclic heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In other embodiments, the heteroaryl is a 6-membered heteroaryl. Examples of monocyclic heteroaryls include, but are not limited to, pyrrole, furan, thiophene, imidazole, pyrazole, oxathiol, isoxathiol, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. The heteroaryl is attached to the remainder of the molecule through any atom of the ring.

[0079] 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.

[0080] 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.

[0081] 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, the interaction of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist.

[0082] 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. In some embodiments, the compounds and compositions described herein are administered intravenously.

[0083] The term "concomitant administration," as used herein, is meant to encompass the administration of selected therapeutic agents to a single patient, and is 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.

[0084] 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.

[0085] The terms "enhance" or "enhancing," as used herein, means 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.

[0086] 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, such as the LpxC inhibitory compounds disclosed herein, or their isotopes, tautomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates, being co-administered to a patient in the form of a single entity or dose. The term "non-fixed combination" refers to the active ingredients, such as the LpxC inhibitory compounds disclosed herein, or their isotopes, tautomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates, being administered to a patient simultaneously, concurrently, or sequentially as separate entities 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, such as the administration of three or more active ingredients.

[0087] The terms "article of manufacture" and "kit" are used synonymously.

[0088] 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, and the like; 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.

[0089] 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 of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0090] Further forms of the compound "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, i.e., it may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0091] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that is composed 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 a function of pH, allowing for selective dissolution in one or another part of the digestive tract, an ability that 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 controlled passage across biological membranes.

[0092] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. In some embodiments, a compound disclosed herein (i.e., in 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; These include tonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0093] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound disclosed herein with a base. In some embodiments, a compound disclosed herein is acidic and reacts with a base. Under such circumstances, the acidic proton of a compound disclosed herein is replaced with a metal ion, for example, a lithium ion, a sodium ion, a potassium ion, a magnesium ion, a calcium ion, or an 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, lysine, etc. 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, etc. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0094] It should be understood that references to pharma- ceutically acceptable salts include the solvent addition forms. In some embodiments, solvates contain either a stoichiometric or non-stoichiometric amount of solvent, and may be water-soluble.

[0095] During the process of crystallization using pharma- ceutically acceptable solvents such as ethanol and the like, 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.

[0096] "Tautomer" refers to a molecule that is capable of proton transfer from one atom of the molecule to another atom of the same molecule. In some instances, the heterocyclic LpxC inhibitory compounds disclosed herein exist in tautomers. The structure of the compound is illustrated in one tautomer for clarity. Alternative tautomers are expressly included in the present disclosure, such as, for example, the structure illustrated below.

[0097] [ka]

[0098] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of the compounds disclosed herein is vulnerable 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.

[0099] In another embodiment, the compounds described herein are labeled with isotopes (e.g., radioisotopes) or by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0100] 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 usually found in nature. Examples of isotopes that can be incorporated into the compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, phosphorus, etc., such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, 123I, 124I, 125I, 131I, 32P, and 33P. In one embodiment, the isotopically labeled compounds described herein, for example, compounds incorporating radioactive isotopes such as 3H and 14C, are useful for drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or altered metabolic pathways to reduce undesirable metabolites, or reduced dosage requirements.

[0101] In some embodiments, one or more hydrogen atoms on the compounds disclosed herein are replaced with deuterium. In some embodiments, the replacement with deuterium provides certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0102] In one aspect, the structure

[0103] [ka] or an isotope, tautomer, pharma- ceutically acceptable salt, solvate, or hydrate thereof is described. During the ceremony, each R is independently selected from hydrogen or deuterium, and P1 is as described herein, and each hydrogen atom can be optionally replaced with a deuterium atom.

[0104] In some embodiments, the compounds disclosed herein have one or more stereocenters, each of which is independently present in either the R or S configuration. For example, in some embodiments, when one stereocenter is present, the compounds disclosed herein are present in the R configuration. In other embodiments, when one stereocenter is present, the compounds disclosed herein are present in the S configuration. In some embodiments, when two stereocenters are present, the compounds disclosed herein are present in the RR configuration. In other embodiments, when two stereocenters are present, the compounds disclosed herein are present in the RS configuration. In other embodiments, when two stereocenters are present, the compounds disclosed herein are present in the SS configuration. In other embodiments, when two stereocenters are present, the compounds disclosed herein are present in the SR configuration.

[0105] The compounds presented herein include all diastereomeric forms, individual enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0106] Individual stereoisomers can be obtained, as appropriate, 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 an appropriate solvent or mixture of solvents. In certain embodiments, the compounds disclosed herein 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 enantiomer. In some embodiments, resolution of the individual enantiomers of the compounds disclosed herein is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers of the compounds disclosed herein are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of the stereoisomers disclosed herein is carried out by chromatography, or by separation of diastereomeric salts and separation by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0107] Separation of the individual enantiomers of a racemic mixture can be accomplished by the use of chiral supercritical fluid chromatography (SFC) or chiral high performance liquid chromatography (HPLC). In some embodiments, the enantiomers described herein are separated from each other by the use of chiral SFC or chiral HPLC. In some embodiments, compounds disclosed herein that contain one or more chiral centers (e.g., compounds disclosed herein, including trans-octahydro-1H-pyrido[3,4-b]morpholin-6-yl) are separated into individual enantiomers using chiral SFC or chiral HPLC. A variety of conditions and suitable columns are available.

[0108] Daicel polysaccharide chiral stationary phases (CSPs) are among the columns used for chiral SFC separations. In some embodiments, Daicel analytical immobilized and coated CHIRALPAK and CHIRALCEL HPLC columns can be used for SFC analysis.

[0109] In some embodiments, screening for suitability to use SFC columns is performed with four main stationary phases (CHIRALPAK IA, IB, IC, and ID) and four main coated columns (CHIRALPAK AD and AS, and CHIRALCEL OD and OJ) at various concentrations of organic modifier. A variety of column phases are available, including but not limited to OD and OJ, OX and OZ chlorinated phases, and a series of complementary cellulose-based CHIRALCEL phases including OA, OB, OC, OF, OG, and OK.

[0110] Non-limiting examples of chiral selectors contemplated for use in separating enantiomers include amylose tris(3,5-dimethylphenylcarbamate), cellulose tris(3,5-dimethylphenylcarbamate), cellulose tris(3,5-dichlorophenylcarbamate), amylose tris(3-chlorophenylcarbamate, amylose tris(3,5-dichlorophenylcarbamate), amylose tris(3-chloro,4-methylphenylcarbamate), amylose tris((S)-alpha-methylbenzylcarbamate), amylose tris(5-chloro-2-methylphenylcarbamate), cellulose tris(4-methylbenzoate), cellulose tris(4-chloro-3-methylphenylcarbamate), and cellulose tris(3-chloro-4-methylphenylcarbamate).

[0111] Non-limiting examples of chiral columns contemplated for use in the separation of enantiomers include CHIRALPAK IA SFC, CHIRALPAK AD-H SFC, CHIRALPAK IB SFC, CHIRALCEL OD-H SFC, CHIRALPAK IC SFC, CHIRALPAK ID SFC, CHIRALPAK IE SFC, CHIRALPAK IF SFC, CHIRALPAK AZ-H SFC, CHIRALPAK AS-H SFC, CHIRALPAK AY-H SFC, CHIRALCEL OJ-H SFC, CHIRALCEL OX-H SFC, and CHIRALCEL OZ-H SFC.

[0112] In further or additional 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.

[0113] 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 a compound 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 compound.

[0114] In certain embodiments, the LpxC inhibitory compounds as described herein are administered as pure chemicals. In other embodiments, the LpxC inhibitory compounds as 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)). (The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0115] Provided herein is a pharmaceutical composition comprising at least one LpxC inhibitory compound described herein, or a stereoisomer, pharma- ceutically acceptable salt, or solvate 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).

[0116] One embodiment provides a pharmaceutical composition comprising an LpxC inhibitory compound as described herein, or a pharma- ceutically acceptable salt, or solvate thereof, and at least one pharma- ceutically acceptable excipient.

[0117] In some embodiments, the pharmaceutical composition is in a dosage form for administration or administration by injection.In some embodiments, the pharmaceutical composition is in a dosage form for intravenous (IV) injection or infusion, or for intramuscular, subcutaneous, or intradermal injection.In some embodiments, the pharmaceutical composition is in a dosage form for IV injection or infusion.In some embodiments, the pharmaceutical composition is a solution.

[0118] In some embodiments, the pharmaceutical composition is in a dosage form for oral administration or administration. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a suspension, solution, syrup, or elixir. In some embodiments, the dosage form is a suspension. In some embodiments, the dosage form is a nanosuspension. In some embodiments, the dosage form is a solution. In other embodiments, the dosage form is a tablet or capsule.

[0119] In some embodiments, the at least one pharma- ceutically acceptable excipient is a co-solvent, an oil, a surfactant, a complexing agent, a solubilizing polymer, a P-gp modulator, a buffering agent, or a combination thereof.

[0120] In certain embodiments, the heterocyclic LpxC inhibitory compounds disclosed herein 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 during one or more of the steps of the synthetic process.

[0121] 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 administration 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.

[0122] 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 the biosynthesis of lipid A in Gram-negative bacteria. Lipid A is an essential component of the outer membrane of Gram-negative bacteria. 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.

[0123] 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.

[0124] One embodiment provides a method of inhibiting a UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine] deacetylase enzyme, comprising contacting the enzyme with an LpxC inhibitory compound disclosed herein.

[0125] Treatment Disclosed herein are methods of treating diseases in which inhibition of bacterial growth is indicated. Such diseases include gram-negative bacterial infections. In some embodiments, a method of treating a gram-negative bacterial infection in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising an LpxC inhibitory compound disclosed herein, or an isotopic variant, tautomer, prodrug, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intraperitoneal infection, skin infection, and urinary tract infection. In some embodiments, the gram-negative bacterial infection is a urinary tract infection (UTI), hospital-acquired / ventilator-associated pneumonia (HAP / VAP), or intraperitoneal infection (IAI). In some embodiments, the gram-negative bacterial infection is selected from a chronic urinary tract infection, a complicated urinary tract infection, cystitis, osteomyelonephritis, urethritis, recurrent urinary tract infection, a bladder infection, a urethra infection, and a kidney infection. In some embodiments, the compounds described herein are used to treat chronic urinary tract infections. In some embodiments, the compounds described herein are used to treat complicated urinary tract infections. In other embodiments, the compounds described herein are used to treat complicated intraperitoneal infections. In some embodiments, the compounds described herein are used to treat chronic intraperitoneal infections. In other embodiments, the compounds described herein are used to treat hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). In some embodiments, administration is to treat an existing infection. In some embodiments, administration is provided as prophylaxis.

[0126] In some embodiments, the LpxC inhibitory compounds described herein, or isotopic variants, tautomers, prodrugs, pharma- ceutically acceptable salts, solvates, or hydrates thereof, are used to treat diseases caused by bacterial production of endotoxins, particularly gram-negative bacteria and bacteria that use lipopolysaccharide (LPS) or LpxC in the biosynthesis of endotoxins. In some embodiments, a method for treating diseases caused by endotoxins or LPS in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising an LpxC inhibitory compound disclosed herein, or an isotopic variant, tautomer, prodrug, pharma- ceutically acceptable salts, solvates, or hydrates thereof, and a pharma- ceutically acceptable excipient. In another embodiment, the heterocyclic LpxC inhibitory compounds and formulations described herein are useful in treating diseases caused or exacerbated by bacterial production of lipid A and LPS or endotoxin, such as sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD), and acute exacerbation of chronic bronchitis (AECB). In some embodiments, a method of treating a disease caused by endotoxin or LPS in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising an LpxC inhibitory compound disclosed herein, or an isotopic variant, tautomer, prodrug, pharmacologic acceptable salt, solvate, or hydrate thereof, and a pharmacologic acceptable excipient, wherein the disease caused by endotoxin or LPS is selected from sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD), and acute exacerbation of chronic bronchitis (AECB).

[0127] In other embodiments, the LpxC inhibitory compounds described herein, or isotopic variants, tautomers, prodrugs, pharma- ceutically acceptable salts, solvates, or hydrates thereof, can be used to treat severe or chronic respiratory tract infections or complicated urinary tract infections, including severe pulmonary and hospital-acquired infections, which may be caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kluyvera ascorbata, Kluyvera cryocrescense, Shigella sonnei, Proteus mirabilis, Serratia marcescens, or other pathogenic bacteria. marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providencia sluarlii and Citrobacter freundii, Haemophilus influenzae, Kluyvera species, Legionella species, Moraxella catarrhalis, Enterobacter species species, Acinetobacter species, Klebsiella species, Burkholderia speciesspecies and Proteus species, as well as infections caused by Neisseria species, Shigella species, Salmonella species, Helicobacler pylori, Vibrionaceae, and Bordetella species, as well as infections caused by Brucella species, Francisella tularensis, and / or Yersinia pestis.

[0128] In one embodiment, a method of treating a Gram-negative bacterial infection in a patient in need of such treatment is provided, comprising administering to the patient a pharmaceutical composition comprising an LpxC inhibitory compound disclosed herein, or an isotopic variant, tautomer, prodrug, pharma- ceutically acceptable salt, solvate, or hydrate thereof, and at least one pharma-ceutically acceptable excipient.

[0129] One embodiment provides a method wherein the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, an intraperitoneal infection, a skin infection, and a urinary tract infection.

[0130] One embodiment provides a method, wherein the gram negative bacterial infection is selected from a chronic urinary tract infection, a complicated urinary tract infection, cystitis, pyelonephritis, urethritis, a recurrent urinary tract infection, a bladder infection, a urethral infection, and a kidney infection.

[0131] One embodiment provides a method wherein the gram-negative bacterial infection is a chronic urinary tract infection. One embodiment provides a method wherein the gram-negative bacterial infection is a complicated urinary tract infection. One embodiment provides a method wherein the administration is for treating an existing infection. One embodiment provides a method wherein the administration is provided as prophylaxis.

[0132] In some embodiments, the LpxC inhibitory compounds described herein, or isotopic variants, tautomers, prodrugs, pharma- ceutically acceptable salts, solvates, or hydrates thereof, are not active against Gram-positive bacteria. In some embodiments, the LpxC inhibitory compounds described herein, or isotopic variants, tautomers, prodrugs, pharma- ceutically acceptable salts, solvates, or hydrates thereof, are selected from the group consisting of Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Bacillus thuringiensis, Lactobacillus rhamnosus, Staphylococcus epidermidis, Bifidobacterium breve, Clostridium difficile, Clostridium sordellii, Peptostreptococcus anaerobius, Staphylococcus pyogenes, Staphylococcus aure ... anaerobius, Streptococcus pneumoniae, Corynebacterium jeikeium, Propionibacterium acnes, Listeria monocytogenes, and / or Nocardia cyriacigeorgica complex. Most gut bacteria are gram-positive, including C. difficile. Thus, in some embodiments, the lack of activity against gram-positive bacteria is beneficial. In some embodiments, the use of the LpxC inhibitory compounds described herein, or isotopic variants, tautomers, prodrugs, pharma- ceutically acceptable salts, solvates, or hydrates thereof, to treat gram-negative bacterial infections as described herein does not affect the gut microbiota, thus reducing the risk of secondary infections, for example, from C. difficile.

[0133] Combination therapy In some instances, Gram-negative bacteria are more resistant to many antibacterial and chemotherapeutic agents than Gram-positive bacteria due in part to their outer membrane, which acts as an efficient permeability barrier.

[0134] A survey of recently reported antibacterial agents of natural origin showed that, although they were active against gram-positive bacteria, over 90% lacked activity against E. coli. Young and Silver (J. Bacteriol. 173(12):3609-14 (1991)) demonstrated that envA1 strains with modified outer membranes were sensitive to a variety of large, hydrophobic antibacterial agents to which wild-type E. coli is resistant. Furthermore, Vaara et al. (Antimicrobial Agents and Chemotherapy 37(11):2255-2260 (1993)) have examined various outer membrane-deficient mutants of E. coli and S. typhimurium that exhibited higher sensitivity to a variety of antibacterial agents than the corresponding wild-type strains.

[0135] In some embodiments, the present invention provides a synergistic combination of an antibacterial agent and an LpxC inhibitory compound or pharmaceutical composition disclosed herein. In some embodiments, the LpxC inhibitory compound disclosed herein has both inherent antibacterial properties and the ability to improve the permeability of the outer membrane of Gram-negative bacteria to other antibacterial agents. In some embodiments, the antibacterial agent is selected from the group consisting of vancomycin, linezolid, azithromycin, imipenem, teicoplanin, daptomycin, clindamycin, rifampin, cefotaxime, gentamicin, novobiocin, and telavancin.

[0136] The use of such synergistic combinations of drugs can have many advantages over traditional single compound therapies, including reduced side effects of antibacterial agents due to lower doses used or shorter treatment times, more rapid cure of infections, reduced hospitalization, an increased spectrum of pathogens controlled, and a reduced incidence of antibiotic resistance.

[0137] Methods of Administration and Treatment Regimens In one embodiment, the LpxC inhibitory compounds disclosed herein, or isotopic variants, tautomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates thereof, are used to prepare a medicament for the treatment of a disease or condition in a mammal that would benefit from modulation of LpxC activity. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising the LpxC inhibitory compounds disclosed herein, or isotopic variants, tautomers, prodrugs, pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0138] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or illness in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or illness. Amounts effective for this use will depend on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0139] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0140] In general, however, dosages used in adult human treatment typically range from 0.01 mg to 2000 mg per day. In one embodiment, the desired dosage is suitably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more subdoses per day.

[0141] In one embodiment, a suitable daily dosage for the LpxC inhibitory compounds disclosed herein, or isotopic variants, tautomers, prodrugs, pharma- ceutically acceptable salts, solvates, or hydrates thereof, is about 0.01 mg / kg to about 50 mg / kg of body weight. In some embodiments, the amount of active ingredient in the daily dosage or dosage form will be less than or greater than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the physician's judgment.

[0142] In any of the foregoing aspects, an effective amount of an LpxC inhibitory compound disclosed herein, or an isotopic variant, tautomer, prodrug, pharma- ceutically acceptable salt, solvate, or hydrate thereof, is (a) administered systemically to the mammal; or (b) administered orally to the mammal.

[0143] In some embodiments, the LpxC inhibitory compound disclosed herein, or its isotopic variant, tautomer, prodrug, pharma- ceutically acceptable salt, solvate, or hydrate, is administered at a dose selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day.

[0144] Products and Kits In certain embodiments, kits and products are disclosed herein for use with one or more of the methods described herein.In some embodiments, the additional components of the kit include carriers, packages, or containers that are partitioned to receive one or more containers, such as vials, tubes, and each of the containers includes one of the separate elements used in the methods described herein.Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes.In one embodiment, the container is formed from various materials, such as glass or plastic.

[0145] The articles of manufacture provided herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and other packaging materials appropriate for the selected formulation and intended mode of use.

[0146] For example, the container comprises one or more of the compounds described herein. Such kits optionally include identifying markings or labels, or instructions for use in the methods described herein.

[0147] The kit typically includes a label listing the contents and / or instructions for use, and a package insert with instructions for use. A set of instructions is also usually included.

[0148] In one embodiment, the label is on or associated with the container. In one embodiment, the label is on the container if letters, numbers, or other indicia forming the label are affixed, molded, or engraved into the container itself. The label is associated with the container if it is present in a receptacle or carrier that holds the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents are to be used for a particular therapeutic application. The label also indicates how to use the contents, for example, in the methods described herein.

[0149] 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

[0150] I. Chemical synthesis Reagents and solvents were used as obtained from commercial suppliers unless otherwise specified. 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 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.

[0151] The following abbreviations and terms have the indicated meanings throughout: ACN = acetonitrile DCM = dichloromethane DMF = N,N-Dimethylformamide EtOAc = ethyl acetate g = grams h or hr = hours HPLC = High Pressure Liquid Chromatography LCMS = liquid chromatography-mass spectrometry m / z = mass-to-charge ratio mg = milligrams min=minutes mL = milliliters mmol = millimolar PBS = phosphate buffered saline RP-HPLC = Reversed Phase High Pressure Liquid Chromatography rt or RT = room temperature TFA = trifluoroacetic acid

[0152] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0153] Example 1: Preparation of (S)-1-(3-(5,6-dihydroxypyrimidin-4-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)azetidine-3-carbonitrile (Compound A) The preparation and use of Compound A has been previously described (see WO2020 / 061375, US2021 / 0221796, WO2021 / 195260, and US2021 / 0309651, each of which is incorporated by reference in its entirety). Example 2: Preparation of (S)-((4-(3-(3-cyanoazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)methyl dihydrogenphosphate (Compound 2)

[0154] [ka]

[0155] Step 1: To a stirred suspension of compound A (0.2 g, 0.392 mmol) in DMF (10 mL) was added potassium carbonate (0.054 g, 0.392 mmol) and di-tert-butyl(chloromethyl)phosphate (2-1, 0.508 g, 1.962 mmol) at 25° C. After stirring for 12 h, LCMS showed complete consumption of starting material and formation of mono- and di-alkylated products. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was triturated with diethyl ether. The precipitated solid was filtered through a Buchner funnel. The filtrate was further purified by column chromatography (SiO2 100-200 mesh; EtOAc and DCM) to give 2-2 (200 mg, 45%) as a gum. LCMS: C 48 H69 N5O 11 Calculated for P2: 954.05 (exact mass: 953.45); Measured: 953.9 [M+1] + .

[0156] Step 2: A solution of 2-2 (0.1 g, 0.105 mmol) in acetone (5 mL) and water (5 mL) was heated at 50° C. for 12 h. The reaction progress was monitored by LCMS. The volatiles were evaporated under reduced pressure and the crude product was purified by preparative HPLC (0.1% TFA in water buffer and acetonitrile) to give compound 2 (12.26 mg, 19%) as an off-white solid. LCMS: C 31 H 34 Calculated for N5O7P: 619.61; Found: 620.0 [M+1] + . Example 3: Preparation of (S)-4-(3-(3-cyanoazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-6-oxo-1,6-dihydropyrimidin-5-yl dihydrogen phosphate (Compound 1)

[0157] [ka]

[0158] To a solution of compound A (0.2 g, 0.392 mmol) in pyridine (8 mL) was added phosphoryl trichloride (0.093 mL, 0.995 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h. Acetonitrile (9.6 mL) was added to the reaction mixture and stirred at 25° C. for 2 h. The reaction was quenched with water (10 mL) and stirred at 25° C. for 16 h. The reaction mixture was concentrated. The resulting crude product was purified by reverse phase preparative HPLC (10 mM ammonium bicarbonate buffer and acetonitrile) to give compound 1 (45 mg, 19%) as a light pink solid. LC-MS: C 30 H 32 Calculated value for N5O6P: 589.59, Found value: 590.7[M+1] + . Example 4: Preparation of (S)-4-(3-(3-cyanoazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-6-oxo-1,6-dihydropyrimidin-5-yldimethylcarbamate (Compound 11)

[0159] [ka]

[0160] To a stirred suspension of compound A (0.25 g, 0.491 mmol) in THF (25 ml) was added pyridine (0.198 ml, 2.453 mmol), dimethylcarbamoyl chloride, 1-1 (0.079 g, 0.736 mmol), and 4-dimethylaminopyridine (5.99 mg, 0.049 mmol) and stirred at 25° C. for 12 h. The reaction mixture was filtered to remove unreacted starting material, the filtrate was concentrated under reduced pressure, and the crude product was purified using reverse phase preparative HPLC in 0.1% TFA / acetonitrile to give compound 11 as an off-white solid. Yield: 30 mg, (10% yield). LC-MS: C 33 H 36 Calculated for N6O4: 580.68, Found: 581.0 [M+H] + ;603(M+Na) + ;291 (M+2) 2+ / 2. Example 5: Preparation of (S)-4-(4-(3-(3-cyanoazetidin-1-yl)-2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propyl)-6-oxo-1,6-dihydropyrimidin-5-yl) 1-methyl 2,2-dimethylsuccinate (Compound 12)

[0161] [ka] Step 1: A solution of lithium diisopropylamide (2M in THF, 4.90 mL, 9.79 mmol) was diluted with tetrahydrofuran (15 mL) and the mixture was cooled to -78 °C. Methyl isobutyrate (12-1, 1 g, 9.79 mmol) was added dropwise, the mixture was stirred at -70 °C to -65 °C for 20 min, and tert-butyl 2-bromoacetate (12-2, 5.6 mL, 11.74 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 7 h. TLC indicated consumption of starting material. The reaction mixture was quenched with saturated NH4Cl(aq). The aqueous layer was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-(tert-butyl) 1-methyl 2,2-dimethylsuccinate (12-3, 1 g, 4.62 mmol, 47% yield) as a brown oil. The crude material was used as is in the next step. Step 2: A solution of 50% TFA (10.00 mL) in DCM (10 mL) was added to 4-(tert-butyl) 1-methyl 2,2-dimethylsuccinate (12-3, 1 g, 4.62 mmol) and stirred at room temperature for 4 h. TLC showed consumption of starting material. The reaction mixture was concentrated under reduced pressure to remove TFA and DCM. The reaction mixture was made basic with 10% sodium bicarbonate solution (30 mL) and washed with DCM. The aqueous layer was made acidic with 0.1 N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-methoxy-3,3-dimethyl-4-oxobutanoic acid (12-4, 0.7 g, 3.69 mmol, 80% yield) as a brown oil. The crude material was used directly in the next step. LC-MS: C7H 12 Calculated for O4: 160.17; Found: 161 [M+H] + and 143 [M-HO] + . Step 3: To a stirred solution of 4-methoxy-3,3-dimethyl-4-oxobutanoic acid (12-4, 0.100 g, 0.196 mmol), HATU (0.298 g, 0.785 mmol), N-ethyl-N-isopropylpropan-2-amine (0.101 g, 0.785 mmol) in DMF (2 mL), 4-(dimethylamino)pyridine (0.024 g, 0.196 mmol) in DMF (2 mL) was added and stirred at room temperature for 12 h. The reaction mixture was washed with water and extracted with ethyl acetate (2x20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give compound 12 (45 mg, 0.067 mmol, 34% yield) as a white solid. LC-MS:C 37 H 41 Calculated for N5O6: 651.76; Found: 652.2 [M+H] + ;510[M-Acyl group] + ;326.7[M+2] 2+ / 2.

[0162] Example 6: Thermal Solubility The solubility of the above compounds was evaluated in 100 mM potassium phosphate buffer, pH 7.4, after 24 hours at room temperature.

[0163] Accurately weighed K2HPO4 (2.79 g) and KH2PO4 (0.54 g) were dissolved in 90 mL of Milli-Q water and mixed well. The volume was adjusted to a maximum of 200 mL with the Milli-Q water and mixed well. The prepared phosphate buffer was stored at 2°C to 8°C and used within one month.

[0164] Approximately 30 mg of test compound was added to approximately 1 mL of potassium phosphate buffer, pH 7.4. If visual inspection revealed precipitation, no more compound was added. If visual inspection revealed a clear solution, additional compound was added until the solution was no longer clear.

[0165] The test compounds and control (caffeine) were further incubated for 24 hours at a temperature of 25°C on a thermomixer with a shaking speed of 1200 rpm. After incubation, the samples (200 μL) were transferred to a filtration plate with a plate attached at the bottom to collect the filtrate. The filtration plate was centrifuged at 4000 rpm for 2 minutes to collect the filtrate with the attached bottom plate. The filtrate was diluted based on the initial amount of compound added using filtered buffer. All samples were analyzed by HPLC-UV method against an 8-point calibration curve with concentrations ranging from 2.5 μg / mL to 1000 μg / mL.

[0166] [Table 2]

[0167] Compound 1 has a thermal solubility of 3 mg / mL or greater.

[0168] Compound 2 has a thermal solubility of 3 mg / mL or greater.

[0169] Compound A has a thermal solubility of less than 0.05 mg / mL.

[0170] Compound A, the hydrochloride salt, has a thermal solubility of less than 0.05 mg / mL.

[0171] Example 7: Kinetic Solubility The solubility of the compounds was evaluated in 10 mM phosphate buffered saline (PBS), pH 7, at final concentrations of 20, 40, and 50 mg / mL of the test compound.

[0172] In experiments with compound 1, clear solutions were obtained at concentrations of 20, 40, and 50 mg / mL after vortex mixing. All solutions remained soluble after storage at 4° C. for 20 hours.

[0173] In experiments with compound 2, milky suspensions were obtained at concentrations of 20, 40, and 50 mg / mL after vortex mixing. There was no change in appearance after 30 minutes of sonication in a 40°C water bath. A clear solution was observed after treatment with 1M HCL (final pH 4) and vortexing for 10 seconds. Addition of 1M NaOH (final pH 7) and vortexing for 10 seconds produced a clear solution.

[0174] Example 8: Pharmacokinetics (PK) Stock solutions of test compounds were prepared at 2.5 mg / mL or 5.0 mg / mL in 10 mM PBS. Male Sprague-Dawley (SD) rats (n=3 per group) or beagle dogs (n=3 per group) were administered test compounds IV or orally. For compounds administered IV, a 3-hour infusion was used. For compounds administered PO, a single bolus dose was used.

[0175] Whole blood samples were collected at 1, 3, 3.5, 4, 6, 8, and 24 hours after initiation of IV dosing (or after PO bolus dosing). All samples were collected in plasma K2-EDTA collection tubes, which were processed to separate plasma from red blood cells.

[0176] All plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) to quantify the test compounds and the active substance, Compound A. The lower limit of quantification (LLOQ) in rats and dogs was 1 ng / mL.

[0177] Administration of Compound 1 results in dose-dependent plasma exposure of Compound A after IV or PO administration, demonstrating its utility as a prodrug of Compound A. Although concentrations of the prodrug Compound 1 decline rapidly after administration (below 100 ng / mL after 4 hours in rats and 6 hours in dogs for all routes and doses tested), released Compound A shows systemic exposure after both oral and IV administration (Tables 2-3).

[0178] [Table 3]

[0179] [Table 4]

[0180] II. Biological Evaluation Example 9: Treatment of Urinary Tract Infections Compound A and its prodrugs disclosed herein were tested in an in vivo mouse model for urinary tract infection. Briefly, mice were infected with E. coli UTI 89 to cause UTI infection and treated with the compounds disclosed herein.

[0181] procedure Five days before infection, C3H / HeNR female mice were preconditioned with drinking water containing 5% glucose. Mice were stunned using parenteral anesthesia (ketamine / medetomidine) and then inoculated with 0.05 mL of a bacterial suspension of E. coli UTI 89 (1.2 × 10 9 CFU / mL (6.2 × 10 7 CFU / mouse) were administered transurethrally into the bladder to induce ascending UTI infection.

[0182] IV or PO treatment was started 24 hours after infection with 3mg, 10mg, 15mg / kg / dose IV Compound A; 3mg, 10mg, 15mg, 30mg / kg / dose IV Compound 1; 3mg and 10mg / kg / dose IV Compound 2; and 30mg / kg / dose oral Compound 1 or Compound 2 administered every 12 hours for 3 days (total of 6 doses). Ciprofloxacin was given at 10mg / kg / dose IV every 12 hours as a control. Compound A was formulated in 10% DMSO, 5% Cremophor, 85% SFI, and sterile phosphate buffered saline (PBS) formulations were used for the remaining compounds. Each group contained 5 mice each.

[0183] Urine, bladder, and kidneys were collected at 24 hours (pretreatment group only) and 96 hours post-infection and quantitatively cultured.

[0184] result Table 4 and Figure 1 summarize the results and show the mean final burden of E. coli UTI 89 in urine, bladder, and kidneys at the end of the study (96 h).

[0185] [Table 5]

[0186] Treatment with Compound A, Compound 1, and Compound 2 resulted in a statistically significant reduction in bacterial load in urine compared to vehicle-treated controls. There was no significant difference in efficacy between equivalent doses of Compound A, Compound 1, and Compound 2 administered IV.

[0187] Treatment with Compound A, Compound 1, and Compound 2 administered IV resulted in a reduction in bacterial load in the bladder compared to vehicle-treated controls.

[0188] Treatment with Compound A, Compound 1, and Compound 2 by IV administration resulted in a statistically significant reduction in bacterial load in the kidney compared to vehicle-treated controls.PO administration of Compound A, Compound 1, and Compound 2 was also effective.There was no significant difference in efficacy between equal doses of Compound A, Compound 1, and Compound 2 administered by IV administration.

[0189] K. pneumoniae BAA-1705 (MDR;MIC 90 The experiment was repeated using a different strain of K. pneumoniae (Table 5 and Figure 2) that was not associated with a higher BAA-1705 load than that of the control. Table 5 and Figure 2 summarize the results and show the mean final loads of K. pneumoniae BAA-1705 in the urine, bladder, and kidneys at the end of the study (96 h).

[0190] [Table 6]

[0191] Treatment with Compound A, Compound 1, and Compound 2 resulted in a statistically significant reduction in urinary bacterial load compared to vehicle-treated and ciprofloxacin controls (except for the experiment with 30 mg / kg IV Compound A).

[0192] Treatment with Compound A, Compound 1, and Compound 2 resulted in a statistically significant reduction in bacterial burden in the kidney compared to vehicle-treated and ciprofloxacin controls. Furthermore, treatment with Compound 1 resulted in bacterial burdens below the limit of detection for all routes of administration.

[0193] III. Pharmaceutical Compositions Example A-1 Parenteral Pharmaceutical Compositions To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-100 mg of a compound of formula (I), or a pharma- ceutically acceptable salt or a pharma-ceutically acceptable 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.

[0194] 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 or a pharma- ceutically acceptable solvate thereof, is added to water (along with an optional solubilizer, an optional buffer, and a taste masking excipient) to obtain a 20 mg / mL solution.

[0195] Example A-3 Oral tablets Tablets are prepared by mixing 20-50% by weight of a compound of formula (I), or a pharma- ceutically acceptable salt or pharma-ceutically acceptable solvate 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.

[0196] Example A-4 Oral Capsule To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, is mixed with starch or other suitable powder blend, and the mixture is incorporated into an oral dosage unit form, such as a hard gelatin capsule, suitable for oral administration.

[0197] 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.

[0198] 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. Formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, P 1 is -P(=O)(OR 1 ) 2 , -CH 2 -O-P(=O)(OR 1 ) 2 , -S(=O) 2 OR 1 , -S(=O) 2 R 2 , -C(=O)OR 2 , -(CHR 4 )-OC(=O)OR 2 , -C(=O)-O-(CHR 4 )-OC(=O)R 2 , -C(=O)R 2 , -CH 2 -O-C(=O)R 2 , -C(=O)NR 5 R 6 , or 【Chemistry 2】 and each R 1 is independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or phenyl; R 2 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or phenyl; R 4 is hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or phenyl; and R 5 and R 6 are each independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or phenyl; R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one or two substituents selected from the group consisting of C 1 -C 4 alkyl and 4- to 6-membered heterocycloalkyl; The compound, or a pharmaceutically acceptable salt or solvate thereof.

2. Formula (Ia) 【Chemistry 2】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or solvate thereof.

3. Formula (Ib) 【Chemistry 3】 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt or solvate thereof.

4. each R 1 is independently hydrogen or C 1 -C 4 alkyl; R 2 is C 1 -C 4 alkyl; R 5 and R 6 are each independently hydrogen or C 1 -C 4 alkyl; or 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, said 4- to 6-membered heterocycloalkyl being unsubstituted or substituted with one or two substituents selected from the group consisting of C 1 -C 4 alkyl and 4- to 6-membered heterocycloalkyl.

5. P 1 is -P(=O)(OR 1 ) 2 or -(CR 3 R 4 )-O-P(=O)(OR 1 ) 2 , each P 1 is independently hydrogen or C 1 -C 4 alkyl; and 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 and R 4 are each independently hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl.

6. P 1 is —P(═O)(OR 1 ) 2 or —CH 2 —O—P(═O)(OR 1 ) 2 , and 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 is independently hydrogen, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .

7. The compound according to claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein P 1 is —P(═O)(OH) 2 or —CH 2 —O—P(═O)(OH) 2 .

8. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein P 1 is —C(═O)NR 5 R 6 .

9. P 1 is 【Chemistry 4】 2. The compound of claim 1, wherein:

10. P 1 is -P(=O)(OH) 2 , -CH 2 -OP(=O)(OH) 2 , -S(=O) 2 OH, -S(=O) 2 CH 3 , -C(=O)OCH 2 CH 3 , -(CH(CH 3 )) -OC(=O)OCH(CH 3 ) 2 , -(CH(CH 3 )) -OC(=O)OCH 2 CH 3 , -C(=O)-O-(CH(phenyl)) -OC(=O)C(CH 3 ) 3 , -C(=O)C(CH 3 ) 3 , -CH 2 -O-C(=O)C(CH 3 ) 3 , -C(=O)N(CH 3 ) 2 , or 【Chemistry 6】 2. The compound of claim 1, wherein: 【Request 11】 【Chemical 7-1】 【Chemistry 7-2】 or a pharmaceutically acceptable salt or solvate thereof.

12. [Chemical 8] or a pharmaceutically acceptable salt or solvate thereof.

13. The compound comprising: 【Chemistry 9】 2. The compound of claim 1, wherein:

14. The compound comprising: 【Chemistry 10】 2. The compound of claim 1, wherein:

15. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

16. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a gram-negative bacterial infection.

17. The use of claim 16, wherein the gram-negative bacterial infection is selected from pneumonia, sepsis, cystic fibrosis, intra-abdominal infections, skin infections, and urinary tract infections.

18. The use of claim 16, wherein the gram-negative bacterial infection is selected from chronic urinary tract infections, complicated urinary tract infections, cystitis, pyelonephritis, urethritis, recurrent urinary tract infections, bladder infections, urethral infections, and kidney infections.

19. The use described in claim 16, wherein the gram-negative bacterial infection is a chronic urinary tract infection.

20. The use of claim 16, wherein the gram-negative bacterial infection is a complicated urinary tract infection.

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