WO2019232053A1 - Broad-spectrum carbapenems - Google Patents

Broad-spectrum carbapenems Download PDF

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Publication number
WO2019232053A1
WO2019232053A1 PCT/US2019/034402 US2019034402W WO2019232053A1 WO 2019232053 A1 WO2019232053 A1 WO 2019232053A1 US 2019034402 W US2019034402 W US 2019034402W WO 2019232053 A1 WO2019232053 A1 WO 2019232053A1
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WIPO (PCT)
Prior art keywords
optionally substituted
alkyl
compound
formula
alkenyl
Prior art date
Application number
PCT/US2019/034402
Other languages
French (fr)
Inventor
Christopher J. Burns
Guo-Hua Chu
Jodie HAMRICK
Steven A. Boyd
Stephen M. Condon
Original Assignee
VenatoRx Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by VenatoRx Pharmaceuticals, Inc. filed Critical VenatoRx Pharmaceuticals, Inc.
Priority to EP19810711.2A priority Critical patent/EP3802538A4/en
Priority to US17/057,594 priority patent/US20210188851A1/en
Priority to CN201980051027.4A priority patent/CN112513043A/en
Publication of WO2019232053A1 publication Critical patent/WO2019232053A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine

Definitions

  • Antibiotics are the most effective drugs for curing bacteria-related infectious diseases clinically. They are incredibly valuable therapeutic options that are currently losing efficacy due to the evolution and spread of drug resistance genes. A dramatic increase in the prevalence of infections caused by Multi Drug Resistant (MDR) Gram positive and Gram negative microorganisms is now occurring, both in the hospital and in the community. Carbapenem beta-lactams face two important issues with regard to their utility: (1) inactivity against MDR Gram positive bacteria (e.g.
  • MRSA methicillin- resistant Staphylococcus aureus
  • VRSA vancomycin-resistant Staphylococcus aureus
  • carbapenem compounds that provide significant antibacterial activity in vitro against a range of Gram positive and Gram negative bacteria.
  • heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 10 , -(CR 12 R 13 ) VI OR 10 , -CN, -N0 2 , halogen, -
  • heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and
  • R 1 is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • each R 3 is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -OR a ;
  • R 4 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl)(heteroaryl); each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkyny
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 10 , R 11 , R 20 , R 21 , R 30 , R 31 , R 40 , and R 41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl) ; or R 10 and R 11 , or R 20 and
  • each R 12 , R 13 , R 22 , R 23 , R 32 , R 33 , R 42 , and R 43 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 , R 24 , and R 44 are independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 15 , R 25 , R 35 , and R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • p 0-4;
  • vl, v2, v3, or v4 are independently 1-4;
  • wl, w2, w3, or w4 are independently 2-4;
  • y is 1-4;
  • z is 0-5.
  • R 1 is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • each R 6 is independently a basic substituent
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalky
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6
  • alkyl (C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • p 0-4;
  • v4 and v5 are independently 1-4;
  • w4 is 2-4;
  • y is 1-4;
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and a pharmaceutically acceptable excipient.
  • pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; a b-lactamase inhibitor; and a pharmaceutically acceptable excipient.
  • Described herein are methods of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound disclosed herein, or a
  • the bacterial infection is caused by gram-negative bacteria. In some embodiments, the bacterial infection is caused by gram-positive bacteria. In some embodiments, the bacterial infection is caused by multidrug-resistant (MDR) bacteria. In some embodiments, the bacterial infection is caused by carbapenem resistant Enterobacteriaceae (CRE).
  • MDR multidrug-resistant bacteria. In some embodiments, the bacterial infection is caused by carbapenem resistant Enterobacteriaceae (CRE).
  • MDR Multi Drug Resistant
  • MRSA methicillin resistant Staphylococcus aureus
  • PRP Penicillin-Resistant pneumococcus
  • ESBFs Extended Spectrum b-lactamase enzymes
  • MRSA and ESBF producing gram -negative bacteria frequently demonstrate cross-resistance to other antibiotic classes (e.g., aminoglycosides, quinolones) the choice for treatment of infections has diminished.
  • antibiotic classes e.g., aminoglycosides, quinolones
  • the spread of Class A/D (serine) and B (metallo) carbapenemases is now eroding efficacy of carbapenems, which is regarded as the most potent sub class of b-lactams.
  • Enterobacteriaceae and Pseudomonas aeruginosa would represent a major advance in the treatment of many nosocomial infections.
  • These novel carbapenems may also be paired with a proprietary pan- b-lactamase inhibitor to include even broader coverage of infections from carbapenem resistant Enterobacteriaceae (CRE).
  • CRE carbapenem resistant Enterobacteriaceae
  • These ultra-broad spectrum carbapenems would provide coverage that usually requires co-administration of two or even three antibacterials. This would provide a single product first-line empiric therapy for either gram-positive or negative pathogens, a polymicrobial mix, and/or anaerobes.
  • the present disclosure is directed to certain carbapenem compounds which are antibacterials active against the bacterial Penicillin Binding Proteins (PBPs).
  • PBPs Penicillin Binding Proteins
  • antibiotic refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism.
  • the phrase “inhibits the growth or proliferation” means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold.
  • examples antibiotics are those which can increase the generation time by at least about lO-fold or more (e.g., at least about lOO-fold or even indefinitely, as in total cell death).
  • an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent.
  • antibiotics suitable for use with respect to the present invention include penicillins, cephalosporins, and carbapenems.
  • b-lactam antibiotic refers to a compound with antibiotic properties that contains a b-lactam functionality.
  • Non-limiting examples of b-lactam antibiotics useful with respect to the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams.
  • b-lactamase denotes a protein capable of inactivating a b-lactam antibiotic.
  • the b-lactamase can be an enzyme which catalyzes the hydrolysis of the b-lactam ring of a b-lactam antibiotic.
  • microbial b-lactamases are microbial b-lactamases.
  • the b-lactamase may be, for example, a serine b-lactamase or a metallo ⁇ -lactamase.
  • Alkyl refers to a straight or branched chain hydrocarbon monoradical, which is fully saturated, having from one to about ten carbon atoms, or from one to six carbon atoms.
  • alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2 -methyl - 2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3 -butyl, 2,2-dimethyl- 1 -propyl, 2-methyl-l- pentyl, 3-methyl-l -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2 -pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, n-but
  • a numerical range such as“Ci-C 6 alkyl” or“Ci- 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated.
  • the alkyl is a Ci-Ci 0 alkyl, a Ci-C 9 alkyl, a Ci-C 8 alkyl, a Ci-C 7 alkyl, a Ci-C 6 alkyl, a Ci-C 5 alkyl, a Ci-C 4 alkyl, a Ci-C 3 alkyl, a Ci-C 2 alkyl, or a Ci alkyl.
  • an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or - N0 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as“C 2 -C 6 alkenyl” or“C 2-6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -N0 2 . In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, l,3-butadiynyl and the like.
  • a numerical range such as“C 2 -C 6 alkynyl” or“C 2-6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, - OMe, -NH 2 , or -N0 2 .
  • an alkynyl is optionally substituted with oxo, halogen, - CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to lO-membered aryl.
  • the aryl is a 6- membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -Ci 5 cycloalkyl), from three to ten carbon atoms (C 3 -Ci 0 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6- membered cycloalkyl.
  • the cycloalkyl is a 5 - to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2. l . l]hexane, bicyclo[2.2.
  • cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl.
  • the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl,
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the
  • heterocycloalkyl i.e. skeletal atoms of the heterocycloalkyl ring.
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
  • heterocycloalkyl heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heteroalkyl is optionally substituted with halogen.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -N0 2 .
  • “optional” or“optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted alkyl” means either“alkyl” or“substituted alkyl” as defined above.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), mono-substituted (e.g., - CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.).
  • an“effective amount” or“therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Treatment of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell.
  • treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.
  • treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a bacterial infection).
  • the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra abdominal infection, a skin infection or septicemia.
  • heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and
  • R 1 is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • R 2 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -Si(R c ) 3 ;
  • each R 3 is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -OR a ;
  • R 4 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl)(heteroaryl); each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkyny
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 10 , R 11 , R 20 , R 21 , R 30 , R 31 , R 40 , and R 41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl) ;
  • R 10 and R 11 , or R 20 and R 21 , or R 30 and R 31 , or R 40 and R 41 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R 12 , R 13 , R 22 , R 23 , R 32 , R 33 , R 42 , and R 43 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 , R 24 , and R 44 are independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl); each R 15 , R 25 , R 35 , and R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl;
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • n 0-2;
  • vl, v2, v3, and v4 are independently 1-4;
  • wl, w2, w3, and w4 are independently 2-4;
  • y is 1-4;
  • z is 0-5.
  • R 1 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), R 1 is methyl. In some embodiments of a compound of Formula (I), R 1 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (I), R 1 is C 2 -C 6 alkynyl.
  • R 2 is hydrogen. In some embodiments of a compound of Formula (I), R 2 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), R 2 is methyl. In some embodiments of a compound of Formula (I), R 2 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (I), R 2 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (I), R 2 is -Si(R c ) 3 .
  • each R 3 is hydrogen. In some embodiments of a compound of Formula (I), each R 3 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), each R 3 is independently hydrogen, Ci-C 6 alkyl, or OR a . In some embodiments of a compound of Formula (I), each R 3 is independently hydrogen, Ci-C 6 alkyl, or OH. In some embodiments of a compound of Formula (I), each R 3 is independently Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), one R 3 is methyl and the other R 3 is hydrogen. In some embodiments of a compound of Formula (I), each R 3 is independently hydrogen or C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (I), each R 3 is independently hydrogen or C 2 -C 6 alkynyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 10 , -(CR 12 R 13 ) VI OR 10 , -CN, -N0 2 , halogen, -
  • heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and
  • each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 40 , -(CR 42 R 43 ) v4 OR 40 , -CN, -N0 2 , -
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 10 , R 11 , R 20 , R 21 , R 30 , R 31 , R 40 , and R 41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl) ;
  • R 10 and R 11 , or R 20 and R 21 , or R 30 and R 31 , or R 40 and R 41 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R 12 , R 13 , R 22 , R 23 , R 32 , R 33 , R 42 , and R 43 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 14 , R 24 , and R 44 are independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6
  • alkyl (C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 15 , R 25 , R 35 , and R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • n 0-2;
  • n 0-2;
  • p 0-4;
  • z is 0-5.
  • a compound of Formula (I) or (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (Ia-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • n is 2 and m is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l) n is 2 and m is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l) n is 2 and m is 2.
  • n is 0 and m is 0 or n is 1 and m is 0.
  • z is 0-2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0 or 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 1-3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 1 or 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 2.
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl, -OR a , or -NR a R b .
  • each R 8 and R 9 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 8 and R 9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 8 and R 9 is independently hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 8 and R 9 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 8 and R 9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 8 and R 9 is independently hydrogen or halogen. In some
  • each R 8 and R 9 is hydrogen.
  • y is 1-3.
  • y is 1 or 2.
  • y is 1.
  • y is 2.
  • y is 3.
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl, -OR a , or -NR a R b .
  • each R 18 and R 11 is independently hydrogen, halogen, or Ci-C 6 alkyl.
  • each R 18 and R 19 is independently hydrogen or Ci-C 6 alkyl.
  • p is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 4.
  • each R 5 is independently hydrogen, halogen, optionally substituted C C 6 alkyl, -OR 40 , -(CR 42 R 43 ) v4 OR 40 , -CN, -N0 2 , or -NR 40 R 41 .
  • each R 5 is independently hydrogen, halogen, or Ci-C 6 alkyl.
  • each R 5 is hydrogen.
  • each R 5 is independently halogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 5 is independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 5 is optionally substituted methyl.
  • each R 5 is independently Ci-C 6 alkyl or Ci-C 6 hydroxyalkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 5 is independently methyl or -CH 2 OH.
  • Y is heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alky
  • Y is optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl.
  • Y is optionally substituted piperidinyl.
  • Y is optionally substituted pyrrolidinyl.
  • Y is optionally substituted piperazinyl.
  • Y is optionally substituted morpholinyl.
  • Y is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, halogen,
  • Y is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, halogen,
  • Y is unsubstituted piperidinyl, unsubstituted pyrrolidinyl, unsubstituted piperazinyl, or unsubstituted morpholinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted piperidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyrrolidinyl.
  • Y is unsubstituted piperazinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted morpholinyl.
  • Y is optionally substituted heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
  • Y is unsubstituted pyridyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyridazinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyrazinyl.
  • Y is optionally substituted pyridyl.
  • Y is pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl,
  • Y is -NR 30 R 31 .
  • Y is -NR 30 (CR 32 R 33 ) v3 B(OR 35 ) 2 .
  • R 10 , R 11 , R 20 , R 21 , R 30 , R 31 , R 40 , and R 41 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 10 , R 11 , R 20 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 21 , R 30 , R 31 , R 40 , and R 41 are independently selected from the group consisting of hydrogen or optionally substituted Ci-C 6 alkyl.
  • R 10 , R 11 , R 20 , R 21 , R 30 , R 31 , R 40 , and R 41 are hydrogen.
  • R 10 and R 11 , or R 20 and R 21 , or R 30 and R 31 , or R 40 and R 41 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 10 and R 11 , or R 20 and R 21 , or R 30 and R 31 , or R 40 and R 41 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 10 and R 11 , or R 20 and R 21 , or R 30 and R 31 , or R 40 and R 41 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • each R 12 , R 13 , R 22 , R 23 , R 32 , R 33 , R 42 , and R 43 is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • each R 12 , R 13 , R 22 , R 23 , R 32 , R 33 , R 42 , and R 43 is hydrogen or Ci-C 6 alkyl.
  • R , R , R , R , and R is hydrogen or halogen.
  • each R 12 , R 13 , R 22 , R 23 , R 32 , R 33 , R 42 , and R 43 is hydrogen or -NR a R b .
  • R 14 , R 24 , and R 44 are independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R 14 , R 24 , and R 44 are independently Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R 14 , R 24 , and R 44 are methyl.
  • each R 15 , R 25 , R 35 , and R 45 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 15 , R 25 , R 35 , and R 45 is hydrogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R 15 , R 25 , R 35 , and R 45 is Ci-C 6 alkyl.
  • two R 15 , or two R 25 , or two R 35 , or two R 45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • vl, v2, v3, and v4 are independently 1.
  • vl, v2, v3, and v4 are independently 2.
  • vl, v2, v3, and v4 are independently 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), vl, v2, v3, and v4 are independently 4.
  • wl, w2, w3, and w4 are independently 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), wl, w2, w3, and w4 are independently 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), wl, w2, w3, and w4 are independently 4.
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R a and R b are independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R a and R b are hydrogen.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R a and R b are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • each R c is
  • each R c is independently Ci-C 6 alkyl.
  • R 1 is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • each R 3 is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -OR a ;
  • R 4 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl)(heteroaryl); each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkyny
  • each R 6 is independently a basic substituent
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted - (Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl); or R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally
  • each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 1-2;
  • n 0-2;
  • p 0-4;
  • y is 1-4;
  • R 1 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), R 1 is methyl. In some embodiments of a compound of Formula (II), R 1 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (II), R 1 is C 2 -C 6 alkynyl.
  • R 2 is hydrogen. In some embodiments of a compound of Formula (II), R 2 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), R 2 is methyl. In some embodiments of a compound of Formula (II), R 2 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (II), R 2 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (II), R 2 is -Si(R c ) 3 .
  • each R 3 is hydrogen. In some embodiments of a compound of Formula (II), each R 3 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), each R 3 is independently hydrogen, Ci-C 6 alkyl, or OR a . In some embodiments of a compound of Formula (II), each R 3 is independently hydrogen, Ci-C 6 alkyl, or OH. In some embodiments of a compound of Formula (II), each R 3 is independently Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), one R 3 is methyl and the other R 3 is hydrogen.
  • each R 3 is independently hydrogen or C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (II), each R 3 is independently hydrogen or C 2 -C 6 alkynyl.
  • R 4 is hydrogen.
  • R 4 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), R 4 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (II), R 4 is C 2 - C 6 alkynyl. In some embodiments of a compound of Formula (II), R 4 is optionally substituted -(Ci-C 6 alkyl)(aryl). In some embodiments of a compound of Formula (II), R 4 is -(Ci-C 6 alkyl)(aryl) substituted with alkyl or -N0 2 .
  • each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 40 , -(CR 42 R 43 ) v4 OR 40 , -CN, -N0 2 , -
  • each R 6 is independently a basic substituent
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted - (Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl); each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl;
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 1-2;
  • n 0-2;
  • p 0-4;
  • v4 and v5 are independently 1-4;
  • w4 is 2-4;
  • z is 0-5.
  • a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (Ila-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • Ring A is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted pyridyl.
  • Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl, each optionally substituted with one, two, or three halogen, -CN, -OH, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, or -N0 2 .
  • Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl.
  • Ring A is phenyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ring A is cyclohexyl.
  • R 50 and R 51 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 50 and R 51 are independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 52 and R 53 are independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • R 52 and R 53 are independently selected from the group consisting of hydrogen, halogen, or optionally substituted Ci-C 6 alkyl.
  • R 54 is optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 54 is optionally substituted Ci-C 6 alkyl.
  • n is 1 and m is 0 or 1.
  • n is 2 and m is 0. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l) n is 2 and m is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l) n is 2 and m is 2.
  • L is -(CR 8 R 9 ) Z .
  • z is 0.
  • a compound of Formula (II), (Ila), or (Ila-l) z is not 0.
  • z is 1.
  • a compound of Formula (II), (Ila), or (Ila-l) z is 2.
  • a compound of Formula (II), (Ila), or (Ila-l) z is 3.
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -OR a , or -NR a R b .
  • each R 8 and R 9 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl.
  • each R 8 and R 9 are independently hydrogen, halogen, or Ci-C 6 alkyl.
  • each R 8 and R 9 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 8 and R 9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 8 and R 9 is independently hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 8 and R 9 is hydrogen.
  • y is 1-3.
  • y is 1 or 2.
  • y is 1.
  • y is 2.
  • each R 18 and R 19 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 18 and R 19 is independently hydrogen or methyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 18 and R 19 is independently hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 18 and R 19 is hydrogen.
  • each R 5 is independently halogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 5 is independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 5 is independently optionally substituted methyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 5 is independently Ci-C 6 alkyl or Ci-C 6 hydroxyalkyl.
  • each R 5 is independently methyl or -CH 2 OH.
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • each R 42 , R 43 , R 52 , and R 53 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52 , and R 53 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • each R 42. R 43. R 52. and R 53 is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • a compound of Formula (II), (Ila), or (Ila-) is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or halogen.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or -NR a R b .
  • R 44 and R 54 are independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 44 and R 54 are methyl.
  • R 45 is hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 45 is hydrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 45 is Ci-C 6 alkyl.
  • two R 45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • each R 6 is a basic substituent comprising at least one basic nitrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 6 is a basic substituent comprising one basic nitrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 6 is a basic substituent comprising one basic nitrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 4. [00110] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 6 is a basic substituent comprising at
  • each R 6 is a basic substituent comprising two basic nitrogens.
  • R 6 is -
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl); or R 60 and
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl).
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and -NR a R b . In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 6 is as defined above and each R 62 and R 63 is hydrogen.
  • R 6 is as defined above and each R 65 is independently hydrogen or optionally substituted Ci-C 6 alkyl; or two R 65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • R 6 is as defined above and two R 65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • R 6 is as defined above and v6 is 1-4. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 6 is as defined above and v6 is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R 6 is as defined above and v6 is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l),
  • R 6 is as defined above and v6 is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila- 1), R 6 is as defined above and v6 is 4.
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R a and R b are independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R a and R b are hydrogen.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • each R c is independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R c is independently Ci-C 6 alkyl.
  • R 2 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -Si(R c ) 3 ;
  • each R 3 is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -OR a ;
  • R 4 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl)(heteroaryl); each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkyny
  • each R 6 is independently a basic substituent
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted - (Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl; or two R 45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • n 0-2;
  • p 0-4;
  • v4 and v5 are independently 1-4;
  • w4 is 2-4;
  • y is 1-4;
  • z is 1-5.
  • R 1 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), R 1 is methyl. In some embodiments of a compound of Formula (III), R 1 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (III), R 1 is C 2 -C 6 alkynyl.
  • R 2 is hydrogen.
  • R 2 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), R 2 is methyl. In some embodiments of a compound of Formula (III), R 2 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (III), R 2 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (III), R 2 is -Si(R c ) 3 .
  • each R 3 is hydrogen. In some embodiments of a compound of Formula (III), each R 3 is independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), each R 3 is independently hydrogen, Ci-C 6 alkyl, or OR a . In some embodiments of a compound of Formula (III), each R 3 is independently hydrogen, Ci-C 6 alkyl, or OH. In some embodiments of a compound of Formula (III), each R 3 is independently Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), one R 3 is methyl and the other R 3 is hydrogen. In some embodiments of a compound of Formula (III), each R 3 is independently hydrogen or C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (III), each R 3 is independently hydrogen or C 2 -C 6 alkynyl.
  • R 4 is hydrogen. In some embodiments of a compound of Formula (III), R 4 is Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), R 4 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (III), R 4 is C 2 -C 6 alkynyl. In some embodiments of a compound of Formula (III), R 4 is optionally substituted -(Ci-C 6 alkyl)(aryl). In some embodiments of a compound of Formula (III), R 4 is -(Ci-C 6 alkyl)(aryl) substituted with alkyl or -N0 2 .
  • a compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (Ilia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 40 , -(CR 42 R 43 ) v4 OR 40 , -CN, -N0 2 , -
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl,
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted - (Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • n 0-2;
  • p 0-4;
  • v4 and v5 are independently 1-4; w4 is 2-4;
  • y is 1-4;
  • z is 1-5.
  • Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl, each optionally substituted with one, two, or three halogen, -CN, -OH, Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, or -N0 2 .
  • Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl.
  • Ring A is phenyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ring A is cyclohexyl.
  • R 50 and R 51 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 50 and R 51 are independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 52 and R 53 are independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • R 52 and R 53 are independently selected from the group consisting of hydrogen, halogen, or optionally substituted Ci-C 6 alkyl.
  • R 54 is optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 54 is optionally substituted Ci-C 6 alkyl.
  • n is 0 or 1 and m is 0 or 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 0 or 1.
  • n is 0 and m is 0.
  • n 1 and m is 0.
  • n is 1 and m is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), n is 1 and m is 2.
  • n 2 and m is 0.
  • n is 2 and m is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l) n is 2 and m is 2.
  • z is 5. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1-5. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1-4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1-3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1 or 2.
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl, -OR a , or - NR a R b .
  • each R 8 and R 9 is independently hydrogen, halogen, -CN, Ci-C 6 alkyl, Ci-C 6 haloalkyl, -OR a , or -NR a R b .
  • each R 8 and R 9 is independently hydrogen, halogen, Ci-C 6 alkyl, or Ci-C 6 haloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 8 and R 9 is independently hydrogen, halogen, or Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 8 and R 9 are independently hydrogen or Ci-C 6 alkyl.
  • each R 8 and R 9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 8 and R 9 is independently hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 8 and R 9 is hydrogen.
  • y is 1-3.
  • y is 1 or 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 4.
  • each R 18 and R 19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C 6 alkyl, -OR a , or -NR a R b .
  • each R 18 and R 11 is independently hydrogen, halogen, or Ci-C 6 alkyl.
  • each R 18 and R 19 is independently hydrogen or Ci-C 6 alkyl.
  • each R 18 and R 19 is independently hydrogen or methyl.
  • each R 18 and R 19 is independently hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 18 and R 19 is hydrogen.
  • p is 0. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 5 is
  • each R 5 is independently hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 5 is hydrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 5 is independently halogen or optionally substituted Ci-C 6 alkyl.
  • each R 5 is independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 5 is
  • each R 5 is independently Ci-C 6 alkyl or Ci-C 6 hydroxyalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 5 is independently methyl or -CH 2 OH.
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen or optionally substituted Ci-C 6 alkyl.
  • each R 40 , R 41 , R 50 , and R 51 is hydrogen.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • each R 42 , R 43 , R 52 , and R 53 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • each R . R . R . and R is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • each R , R , R . and R ' is hydrogen or Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or halogen.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or -NR a R b .
  • R 44 and R 54 are independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 44 and R 54 are methyl.
  • R 45 is hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 45 is hydrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 45 is Ci-C 6 alkyl.
  • two R 45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • q is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 4.
  • each R 6 is a basic substituent comprising at least one basic nitrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 6 is a basic substituent comprising one basic nitrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R 6 is a basic substituent comprising two basic nitrogens.
  • R 6 is -NR 60 R 61 .
  • R 6 is -
  • R 6 is - NR 60 (CR 62 R 63 ) V6 B(OR 65 ) 2 .
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl); or R
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
  • R 6 is as defined above and each R 60 and R 61 is hydrogen.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • a compound of Formula (III), (Ilia), or (Illa-l) is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and -NR a R b . In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and each R 62 and R 63 is hydrogen.
  • R 6 is as defined above and two R 65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • R 6 is as defined above and v6 is 1-4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and v6 is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
  • R 6 is as defined above and w6 is 2-4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and w6 is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
  • R 6 is as defined above and w6 is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R 6 is as defined above and w6 is 4.
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R a and R b are independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R a and R b are hydrogen.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R a and R b are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • each R c is independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R c is independently Ci-C 6 alkyl.
  • Ring A is cycloalkyl or heterocycloalkyl; each optionally substituted with one, two, or three
  • substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 50 , -
  • R 1 is optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • R 2 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -Si(R c ) 3 ;
  • each R 3 is independently hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or -OR a ;
  • R 4 is hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl)(heteroaryl); each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkyny
  • each R 6 is independently a basic substituent
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • p 0-4;
  • v4 and v5 are independently 1-4;
  • w4 is 2-4.
  • R 1 is methyl. In some embodiments of a compound of Formula (IV), R 1 is C 2 -C 6 alkenyl. In some embodiments of a compound of Formula (IV), R 1 is C 2 -C 6 alkynyl.
  • R 2 is hydrogen.
  • a compound of Formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (IVa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • Ring A is cycloalkyl or heterocycloalkyl; each optionally substituted with one, two, or three
  • each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -OR 40 , -(CR 42 R 43 ) v4 OR 40 , -CN, -N0 2 , -
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted - (Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -OR a , -NR a R b , optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • each R 44 and R 54 is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), or optionally substituted -(Ci-C 6 alkyl) (heteroaryl);
  • each R 45 is independently hydrogen or optionally substituted Ci-C 6 alkyl
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl; or R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl;
  • each R c is independently optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;
  • n 0-2;
  • n 0-2;
  • p 0-4;
  • w4 is 2-4.
  • a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (IVa-l) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
  • Ring A is cyclohexyl, piperidinyl, or morpholinyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ring A is cyclohexyl.
  • R 50 and R 51 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • R 50 and R 51 are independently selected from the group consisting of hydrogen and optionally substituted Ci-C 6 alkyl.
  • R 52 and R 53 are independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • R 52 and R 53 are independently selected from the group consisting of hydrogen, halogen, or optionally substituted Ci-C 6 alkyl.
  • R 54 is optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 54 is optionally substituted Ci-C 6 alkyl.
  • n is 0 or 1 and m is 0 or 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 0 or 1.
  • n is 0 and m is 0.
  • n is 0 and m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 0 and m is 2.
  • n 1 and m is 0.
  • n is 1 and m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 1 and m is 2.
  • n 2 and m is 0.
  • n is 2 and m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l) n is 2 and m is 2.
  • p is 0. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 4.
  • each R 5 is independently hydrogen, halogen, optionally substituted Ci-C 6 alkyl, -OR 40 , -(CR 42 R 43 ) v4 OR 40 , -CN, - N0 2 , or -NR 40 R 41 .
  • each R 5 is independently hydrogen or halogen.
  • each R 5 is hydrogen.
  • each R 5 is independently halogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R 5 is independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R 5 is
  • each R 5 is independently Ci-C 6 alkyl or Ci-C 6 hydroxyalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R 5 is independently methyl or -CH 2 OH.
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or C 2 -C 8 optionally substituted heterocycloalkyl.
  • each R 40 , R 41 , R 50 , and R 51 is independently selected from the group consisting of hydrogen or optionally substituted Ci-C 6 alkyl.
  • each R 40 , R 41 , R 50 , and R 51 is hydrogen.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 40 and R 41 , or R 50 and R 51 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • each R 42 , R 43 , R 52 , and R 53 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52 , and R 53 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52. and R 53 is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • R 42 , R 43 , R 52. and R 53 is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • each R , R , R . and R is hydrogen or Ci-C 6 alkyl.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or halogen.
  • each R 42 , R 43 , R 52 , and R 53 is hydrogen or -NR a R b .
  • R 44 and R 54 are independently optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 44 and R 54 are methyl.
  • R 45 is hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 45 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 45 is Ci-C 6 alkyl.
  • two R 45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • q is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), q is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), q is 3. In some embodiments of a compound of
  • each R 6 is a basic substituent comprising at least one basic nitrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R 6 is a basic substituent comprising one basic nitrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R 6 is a basic substituent comprising two basic nitrogens.
  • R 6 is -NR 60 R 61 .
  • R 6 is -
  • R 6 is - NR 60 (CR 62 R 63 ) V6 B(OR 65 ) 2 .
  • R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, C 2 -C 8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C 6 alkyl)(C 3 -C 8 cycloalkyl), optionally substituted -(Ci-C 6 alkyl)(C 2 -C 8 heterocycloalkyl), optionally substituted -(Ci-C 6 alkyl)(aryl), and optionally substituted -(Ci-C 6 alkyl) (heteroaryl).
  • each R 6 is as defined above and each R 60 and R 61 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l),
  • R 6 is as defined above and each R 60 and R 61 is hydrogen.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • a compound of Formula (IV), (IVa), or (IVa-l) is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R 6 is as defined above and R 60 and R 61 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen, halogen, -CN, -OR a , -NR a R b , or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen, halogen, -NR a R b , or Ci-C 6 alkyl.
  • R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and halogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and -NR a R b . In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and each R 62 and R 63 is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and each R 62 and R 63 is hydrogen.
  • R 6 is as defined above and each R 65 is independently hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and each R 65 is hydrogen.
  • R 6 is as defined above and each R 65 is independently hydrogen or optionally substituted Ci-C 6 alkyl; or two R 65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • R 6 is as defined above and two R 65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
  • R 6 is as defined above and w6 is 2-4. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and w6 is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa- 1), R 6 is as defined above and w6 is 3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R 6 is as defined above and w6 is 4.
  • R a and R b are independently hydrogen or optionally substituted Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R a and R b are independently hydrogen or Ci-C 6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R a and R b are hydrogen.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted C 2 -C 8 heterocycloalkyl.
  • R a and R b are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
  • R a and R b are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described 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, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of Formula (I), Formula (la), Formula (Ia-l), Formula (II), Formula (Ha), Formula (Ila-l), Formula (III), Formula (Ilia), Formula (Illa-l), or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 ⁇ 4, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 ⁇ 4 and carbon-l4, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, /. e.
  • the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate,
  • glycerophosphate glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate,
  • methanesulfonate methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1- napthalene sulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, f imaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanes
  • inorganic acids
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds of Formula (I), Formula (la), Formula (Ia-l), Formula (II), Formula (Ha), Formula (Ila-l), Formula (III), Formula (Ilia), Formula (Illa-l), solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a
  • salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C I-4 alkyl) 4 , and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of bacterial infections and processes for their preparation.
  • compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are synthesized using standard synthetic reactions known to those of skill in the art or using methods known in the art. The reactions can be employed in a linear sequence to provide the compounds or they may be used to synthesize fragments which are subsequently joined by the methods known in the art.
  • the starting material used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.
  • the products of the reactions are isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. In some embodiments, such materials are characterized using conventional means, including physical constants and spectral data.
  • compositions comprising a compound describe herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular
  • intranasal e.g., buccal
  • topical e.g., topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
  • compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.
  • compositions further comprise a preservative to prevent growth of microorganisms.
  • the antibiotic is administered by a route and in an amount commonly used, therefore, contemporaneously or sequentially with a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is optionally used.
  • the combination therapy also includes therapies in which the compound described herein, or a
  • the one or more antibiotics are beta-lactam antibiotics.
  • the beta-lactam antibiotic is a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, or combinations thereof.
  • Penicillins include, but are not limited to, amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathinebenzylpenicillin,
  • benzathinephenoxymethylpenicillin benzylpenicillin (G) carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, or any combinations thereof.
  • Penems include, but are not limited to, faropenem.
  • Carbapenems include, but are not limited to, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, or any combinations thereof.
  • Cephalosprins/cephamycins include, but are not limited to, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, ceftnenoxime, ceftnetazole, ceftninox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, ce
  • the beta-lactamase inhibitor is VNRX-5133, clavulanic acid, sulbactam, tazobactam, or any combinations thereof. In some embodiments, the beta-lactamase inhibitor is VNRX-5133.
  • non beta- lactam beta-lactamase inhibitor is avibactam, relebactam, or any combinations thereof.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes
  • compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and compositions thereof are administered in any suitable manner.
  • compositions can be administered orally, parenterally (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection), by inhalation, extracorporeally, topically (including transdermally, ophthalmically, vaginally, rectally, intranasally) or the like.
  • the bacterial infection is caused by gram-negative bacteria.
  • the bacterial infection is caused by multidrug-resistant (MDR) bacteria.
  • MDR multidrug-resistant bacteria.
  • CRE carbapenem resistant Enterobacteriaceae
  • the bacterial infection is caused by an aerobic bacteria.
  • the bacterial infection is caused by an anaerobic bacteria.
  • the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, a skin infection, or septicemia.
  • the bacterial infection is caused by a bacteria that include
  • Pseudomonas aeruginosa Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonasmaltophilia, Burkholderiacepacia,
  • Aeromonashydrophilia Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigelladysenteriae, Shigellaflexneri,
  • Klebsiellaoxytoca Serratiamarcescens, Francisellatularensis, Morganellamorganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,
  • Yersinia pestis Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilusinfluenzae, Haemophilusparainfluenzae, Haemophilushaemolyticus, Haemophilusparahaemolyticus, Haemophilusducreyi,
  • Pasteurellamultocida Pasteurellahaemolytica, Branhamellacatarrhalis, Helicobacter pylori,
  • Campylobacter fetus Campylobacter jejuni, Campylobacter coli, Borreliaburgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroidesfragilis,
  • Bacteroidesdistasonis Bacteroides 3452A homology group, Bacteroidesvulgatus, Bacteroidesovalus, Bacteroidesthetaiotaomicron, Bacteroidesuniformis, Bacteroideseggerthii, Bacteroidessplanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium
  • the infection that is treated is caused by a bacteria that includes Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonasmaltophilia, Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigelladysenteriae, Shigellaflexneri, Shigellasonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiellaoxytoca, Serratiamarcescens, Acinetobacter
  • Bacteroidesuniformis Bacteroideseggerthii, or Bacteroidessplanchnicus.
  • Also disclosed herein are methods for inhibiting bacterial growth comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a carbapenem derivative described herein.
  • the bacteria to be inhibited by administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are bacteria that are resistant to beta-lactam antibiotics.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to an experimental cell culture in vitro to prevent the growth of beta-lactam resistant bacteria.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a mammal, including a human to prevent the growth of beta-lactam resistant bacteria in vivo.
  • the method according to this embodiment comprises administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for a therapeutically effective period of time to a mammal, including a human.
  • the starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers (2001-2008).
  • the use of protective groups may be as described in methodology compendia such as Greene's Protective Groups in Organic Synthesis, Fourth Edition. John Wiley & Sons, Inc. 2006.
  • Certain compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are prepared from the corresponding functional-group-protected beta-lactams II by hydrogenation in the presence of a catalyst such as platinum on carbon, at a temperature between 0 °C and 10 °C, followed by purification of the crude products by flash chromatography on MCI GEL CHP20P.
  • a catalyst such as platinum on carbon
  • the functional -group -protected intermediates A may be prepared according to the route outlined in SCHEME 2. Pyrrolidine-thiols B were coupled with the carbonyl compounds C in the presence of a reducing reagent such as sodium triacetoxyborohydride to give the thiols D, which were condensed with the known and commercially available enol phosphate E in the presence of a base such as Hiinig’s base (DIEA, diisopropylethylamine). Pyrrolidine-thiols B, and the carbonyl compounds C may be obtained from commercial sources, prepared according to known methods in the literature, or prepared by a number of different reaction sequences.
  • a reducing reagent such as sodium triacetoxyborohydride
  • EXAMPLE 1 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- yl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate.
  • Step 2 Synthesis of tert-butyl (R)-3-(acetylthio)pyrrolidine-l-carboxylate.
  • Step 3 Synthesis of tert-butyl (R)-3-mercaptopyrrolidine-l-carboxylate.
  • Step 5 Synthesis of 4-nitrobenzyl 4-oxopiperidine-l-carboxylate.
  • Step 6 Synthesis of 4-nitrobenzyl (R)-4-(3-mercaptopyrrolidin-l-yl)piperidine-l-carboxylate.
  • Step 7 Synthesis of 4-nitrobenzyl (R)-4-(3-mercaptopyrrolidin-l-yl)piperidine-l-carboxylate 4- nitrobenzyl (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(l-(((4- nitrobenzyl)oxy)carbonyl)piperidin-4-yl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate.
  • Step 8 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- yl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of 4-nitrobenzyl (4-oxocyclohexyl)(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)propyl)carbamate.
  • Part iii The product from Part ii) (1.4 g, 2.78 mmol) was dissolved in acetone (60 mL), toluenesulfonic acid monohydrate (133 mg, 0.7 mmol) was added. The reaction mixture was stirred at rt for 60 h, concentrated in vacuo. The residue was dissolved in DCM, washed with saturated aqueous NaHC0 3 , dried over Na 2 S0 4 , concentrated in vacuo to give the crude product, which was used directly for the next step without further purification. ESI-MS m/z 461 (MH) + .
  • Step 2 Synthesis of (4R,5S,6S)-3-(((R)-l-(4-((3-boronopropyl)amino)cyclohexyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of l-(tert-butyl) 2-methyl (2S,4R)-4-(acetylthio)pyrrolidine-l,2-dicarboxylate.
  • Step 2 Synthesis of tert-butyl (2S,4R)-2-(hydroxymethyl)-4-mercaptopyrrolidine-l-carboxylate.
  • Step 3 Synthesis of ((2S,4R)-4-mercaptopyrrolidin-2-yl)methanol.
  • the above crude product (10 mmol) was dissolved in DCM (25 mL), and treated with TFA (25 mL) at 0 °C for 1 h, then concentrated and dried in vacuo, yielding the crude product as TFA salt, which was used directly for the next step without further purification.
  • Step 1 Synthesis of 4-nitrobenzyl 4-formylpiperidine-l-carboxylate.
  • EXAMPLE 8 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(((R)-pyrrolidin-2- yl)methyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 10 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(pyridin-3- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 12 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(piperidin-3- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 13 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(piperidin-2- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 14 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(((S)-pyrrolidin-2- yl)methyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 2 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((4-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 16 (4R,5S,6S)-3-(((R)-l-((4-fluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 2 Synthesis of (4R,5S,6S)-3-(((R)-l-((4-fluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 17 (4R,5S,6S)-3-(((R)-l-(((lr,4R)-4-(aminomethyl)cyclohexyl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 18 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((lr,4R)-4- ((methylamino)methyl)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
  • Step 1 Synthesis of ((lr,4r)-4-((methylamino)methyl)cyclohexyl)methanol.
  • Step 2 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((lr,4R)-4- ((methylamino)methyl)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
  • EXAMPLE 20 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(2-(piperazin-l- yl)ethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of 4-nitrobenzyl 4-(2-oxoethyl)piperazine-l-carboxylate.
  • EXAMPLE 22 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((ls,4S)-4- (methylamino)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
  • EXAMPLE 23 (4R,5S,6S)-3-(((R)-l-((lr,4R)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of 4-nitrobenzyl (4-oxocyclohexyl)carbamate.
  • Step 2 Synthesis of (4R,5S,6S)-3-(((R)-l-((ls,4S)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and (4R,5S,6S)-3-(((R)-l-((lr,4R)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4- methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
  • EXAMPLE 26 (4R,5S,6S)-3-(((R)-l-((l-(2-aminoethyl)piperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid,
  • EXAMPLE 27 (4R,5S,6S)-3-(((R)-l-(l-(2-aminoethyl)piperidin-4-yl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 28 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((2-methylpiperidin-4- yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of methyl 2-methylpiperidine-4-carboxylate.
  • Methyl 2 -chloro-6-methylisonicotinate (3.6g, 19.5 mmol) in TFA (60 mL) was hydrogenated in the presence of platinum oxide hydrate (660 mg) at 60 psi at rt for 3 days.
  • the reaction mixture was filtered, and the filtrate was concentrated to give the product as TFA salt, which was used directly for the next step without further purification.
  • Step 2 Synthesis of l-(tert-butyl) 4-methyl 2-methylpiperidine-l,4-dicarboxylate.
  • Step 3 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((2-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 29 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((6- ((methylamino)methyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic acid.
  • Step 1 Synthesis of methyl 6-(bromomethyl)nicotinate.
  • Step 4 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((6- ((methylamino)methyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic acid.
  • EXAMPLE 30 (4R,5S,6S)-3-(((3R)-l-((2-(aminomethyl)piperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of (3,4-bis(azidomethyl)phenyl)methanol.
  • Step 2 Synthesis of (3,4-bis(aminomethyl)phenyl)methanol.
  • Step 3 Synthesis of (4R,5S,6S)-3-(((R)-l-(3,4-bis(aminomethyl)benzyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of tert-butyl 3-(hydroxymethyl)-4-(methylsulfonyl)piperazine-l-carboxylate.
  • Step 2 Synthesis of 4-nitrobenzyl 3-(hydroxymethyl)-4-(methylsulfonyl)piperazine-l- carboxylate.
  • Step 3 Synthesis of 4-nitrobenzyl 3-formyl-4-(methylsulfonyl)piperazine-l-carboxylate.
  • Step 4 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((l- (methylsulfonyl)piperazin-2-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
  • EXAMPLE 33 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-methyl-l-(piperidin-4- ylmethyl)pyrrolidin-l-ium-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
  • Step 1 Synthesis of (3R)-3-(((4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-2-(((4- nitrobenzyl)oxy)carbonyl)-7-oxo-l-azabicyclo[3.2.0]hept-2-en-3-yl)thio)-l-methyl-l-((l-(((4- nitrobenzyl)oxy)carbonyl)piperidin-4-yl)methyl)pyrrolidin-l-ium iodide.
  • Step 2 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-methyl-l-(piperidin- 4-ylmethyl)pyrrolidin-l-ium-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
  • EXAMPLE 34 (4R,5S,6S)-3-(((3R)-l-(4-(l,2-diaminoethyl)benzyl)pyrrolidin-3-yl)thio)-6-((R)- l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of methyl 4-(amino(cyano)methyl)benzoate.
  • Step 2 Synthesis of (4-(l,2-diaminoethyl)phenyl)methanol.
  • Step 3 Synthesis of (4R,5S,6S)-3-(((3R)-l-(4-(l,2-diaminoethyl)benzyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • EXAMPLE 35 (4R,5S,6S)-3-(((R)-l-((l-carbamimidoylpiperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of tert-butyl (((tert-butoxycarbonyl)imino)(4-formylpiperidin-l- yl)methyl)carbamate.
  • Step 2 Synthesis of 4-nitrobenzyl (4R,5S,6S)-3-(((R)-l-((l-(N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
  • Step 4 Synthesis of (4R,5S,6S)-3-(((R)-l-((l-carbamimidoylpiperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 3 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(4- (methylamino)butyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of 8-amino-l,4-dioxaspiro[4.5]decane-8-carbonitrile.
  • Step 2 Synthesis of 4-nitrobenzyl ((8-amino- 1,4-dioxaspiro [4.5] decan-8-yl)methyl)carbam ate.
  • Step 3 Synthesis of 4-nitrobenzyl (l-(((((4-nitrobenzyl)oxy)carbonyl)amino)methyl)-4- oxocyclohexyl)carbamate.
  • Step 4 Synthesis of(4R,5S,6S)-3-(((R)-l-(4-amino-4-(aminomethyl)cyclohexyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of tert-butyl (R)-4-((3-mercaptopyrrolidin-l-yl)methyl)piperidine-l- carboxylate.
  • Step 2 Synthesis of (4R,5S,6S)-3-(((R)-l-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl) pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic 4-nitrobenzoic anhydride.
  • Step 4 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic 4- nitrobenzoic anhydride
  • EXAMPLE 40 (4R,5S,6S)-6-((R)-l-hydroxyethyl)-3-(((R)-l-((l-(2-hydroxyethyl) piperidin-4- yl)methyl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
  • Step 1 Synthesis of tert-butyl (R)-4-((3-(acetylthio)pyrrolidin-l-yl)methyl)piperidine-l- carboxylate.
  • Step 4 Synthesis of (R)-2-(4-((3-mercaptopyrrolidin-l-yl)methyl)piperidin-l-yl)ethan-l-ol
  • Step 5 Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-3-(((R)-l-((l-(2-hydroxyethyl)piperidin-
  • Step 1 Synthesis of S-(azetidin-3-yl) ethanethioate

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Abstract

The present disclosure provides broad-spectrum carbapenem derivatives and pharmaceutical compositions useful in the treatment of bacterial infections and methods for treating such infections using such derivatives and/or compositions.

Description

BROAD-SPECTRUM CARBAPENEMS
CROSS-REFERENCE
[001] This application claims the benefit of U. S. Provisional Application Serial No. 62/678,151 filed May 30, 2018 which is hereby incorporated by reference in its entirety.
STATEMENT AS TO FEDERAUUY SPONSORED RESEARCH
[002] This invention was made with government support under SBIR Grant number
R43AI120392 awarded by the National Institutes of Health (NIH) and SBIR Grant number
R44AI120392 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[003] Antibiotics are the most effective drugs for curing bacteria-related infectious diseases clinically. They are incredibly valuable therapeutic options that are currently losing efficacy due to the evolution and spread of drug resistance genes. A dramatic increase in the prevalence of infections caused by Multi Drug Resistant (MDR) Gram positive and Gram negative microorganisms is now occurring, both in the hospital and in the community. Carbapenem beta-lactams face two important issues with regard to their utility: (1) inactivity against MDR Gram positive bacteria (e.g. methicillin- resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA)), and (2) clinical failure due to spread of beta-lactamase -producing Gram negative Enterobacteriaceae and Pseudomonas aeruginosa. There is a growing consensus on the need for agents with activity against these MDR bacteria as first-line empiric treatment of many nosocomial infections, such as pneumonia, skin and soft tissue, intra-abdominal, and complicated urinary tract infections. These infections are caused by either Gram positive or negative pathogens, or a polymicrobial mix potentially including anaerobes. There is a significant need to develop a safe and bactericidal agent with the widest known spectrum of activity, including against MDR Gram-positives, Gram-negatives, and anaerobes, to treat empirically this wide range of infections.
SUMMARY OF THE INVENTION
[004] Described herein are carbapenem compounds that provide significant antibacterial activity in vitro against a range of Gram positive and Gram negative bacteria.
[005] Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000003_0001
Formula (I) wherein
Y is
(a) heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR10, -(CR12R13)VIOR10, -CN, -N02, halogen, -
Figure imgf000003_0002
(b) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and
pyrazinyl each optionally substituted with one, two, or three substituents each independently selected from optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR20, -(CR22R23)v2OR20, -CN, -N02, halogen, - S(=0)2R24, -(CR22R23)V2S(=0)2R24, -S(=O)2NR20R21, -(CR22R23)V2S(=O)2NR20R21, - C(=0)OR20, -(CR22R23)V2C(=0)0R2°, -C(=O)NR20R21, -C(=O)(CR22R23)V2NR20R21, - (CR22R23)V2C(=O)NR20R21, -NR20R21, -NR20(CR22R23)W2NR20R21, -NR20C(=NR21)NR20R21, - C(=NR20)NR20R21, -C(=NR20)R20, -N(R20)C(=NR21)R20, -(CR22R23)V2NR20R21, - (CR22R23)V2N(R20)C(=NR21)NR20R21, -(CR22R23)V2NR20(CR22R23)W2NR20R21, - NR21C(=NR21)NR20(CR22R23)W2NR20R21, -NR20(CR22R23)W2N(R20)C(=NR21)NR20R21, - (CR22R23)V2C(=NR21)NR20R21, -NR20(CR22R23)V2B(OR25)2, and -
(CR22R23)V2NR20(CR22R23)V2B(OR25)2; provided that at least one of the optional substituent is not -0(C3 alkenyl) when R4 is C3 alkenyl; or
Figure imgf000003_0003
NR31C(=NR31)NR30(CR32R33)W3NR30R31, -NR30(CR32R33)W3N(R30)C(=NR31)NR30R31, or - NR30(CR32R33)V3B(OR35)2 provided that z is not 0;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000004_0001
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R10, R11, R20, R21, R30, R31, R40, and R41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl) ; or R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R12, R13, R22, R23, R32, R33, R42, and R43 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R14, R24, and R44 are independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R15, R25, R35, and R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R15, or two R25, or two R35, or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
vl, v2, v3, or v4 are independently 1-4;
wl, w2, w3, or w4 are independently 2-4;
y is 1-4; and
z is 0-5.
[006] Also described herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000005_0001
Formula (III) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -(CR52R53)v5OR50, -CN, -N02, halogen, - S(=0)2R54, -(CR52R53)V5S(=0)2R54, -S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, - (CR52R53)V5C(=0)OR10, -C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000006_0001
each R6 is independently a basic substituent;
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb; each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6
alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally
substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4;
w4 is 2-4;
y is 1-4; and
z is 1-5.
[007] Disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and a pharmaceutically acceptable excipient. [008] Disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; a b-lactamase inhibitor; and a pharmaceutically acceptable excipient.
[009] Disclosed herein are methods of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[0010] Disclosed herein are methods of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with a b-lactamase inhibitor.
[0011] Described herein are methods of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
[0012] Described herein are methods of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound disclosed herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof in combination with a b-lactamase inhibitor.
[0013] In some embodiments, the bacterial infection is caused by gram-negative bacteria. In some embodiments, the bacterial infection is caused by gram-positive bacteria. In some embodiments, the bacterial infection is caused by multidrug-resistant (MDR) bacteria. In some embodiments, the bacterial infection is caused by carbapenem resistant Enterobacteriaceae (CRE).
INCORPORATION BY REFERENCE
[0014] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Decades of clinical use of antibiotics have led to a dramatic increase in the prevalence of infections caused by Multi Drug Resistant (MDR) bacteria. For gram-positive pathogens, methicillin resistant Staphylococcus aureus (MRSA) and Penicillin-Resistant pneumococcus (PRP) are increasingly prevalent. For gram- negatives, the extensive use of b-lactam antibiotics has pressured bacteria to develop several mechanisms of resistance, the most widely diffused and efficient of which is the production of Extended Spectrum b-lactamase enzymes (ESBFs) and Ambler Class C cephalosporinases. Because MRSA and ESBF producing gram -negative bacteria frequently demonstrate cross-resistance to other antibiotic classes (e.g., aminoglycosides, quinolones) the choice for treatment of infections has diminished. In addition, the spread of Class A/D (serine) and B (metallo) carbapenemases is now eroding efficacy of carbapenems, which is regarded as the most potent sub class of b-lactams.
[0016] Novel carbapenems with activity against MRSA, ESBL and Class C producing
Enterobacteriaceae , and Pseudomonas aeruginosa would represent a major advance in the treatment of many nosocomial infections. These novel carbapenems may also be paired with a proprietary pan- b-lactamase inhibitor to include even broader coverage of infections from carbapenem resistant Enterobacteriaceae (CRE). These ultra-broad spectrum carbapenems would provide coverage that usually requires co-administration of two or even three antibacterials. This would provide a single product first-line empiric therapy for either gram-positive or negative pathogens, a polymicrobial mix, and/or anaerobes. The present disclosure is directed to certain carbapenem compounds which are antibacterials active against the bacterial Penicillin Binding Proteins (PBPs). Some embodiments include compounds, compositions, pharmaceutical compositions, use and preparation thereof.
Definitions
[0017] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word“comprise” and variations thereof, such as,“comprises” and“comprising” are to be construed in an open, inclusive sense, that is, as“including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
[0018] Reference throughout this specification to“one embodiment” or“an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases“in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms“a,”“an,” and“the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term“or” is generally employed in its sense including“and/or” unless the content clearly dictates otherwise.
[0019] The term“antibiotic” refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism. The phrase “inhibits the growth or proliferation” means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold. Examples antibiotics are those which can increase the generation time by at least about lO-fold or more (e.g., at least about lOO-fold or even indefinitely, as in total cell death). As used in this disclosure, an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent.
Examples of antibiotics suitable for use with respect to the present invention include penicillins, cephalosporins, and carbapenems.
[0020] The term“b-lactam antibiotic” refers to a compound with antibiotic properties that contains a b-lactam functionality. Non-limiting examples of b-lactam antibiotics useful with respect to the invention include penicillins, cephalosporins, penems, carbapenems, and monobactams.
[0021] The term“b-lactamase” denotes a protein capable of inactivating a b-lactam antibiotic. The b-lactamase can be an enzyme which catalyzes the hydrolysis of the b-lactam ring of a b-lactam antibiotic. Of particular interest herein are microbial b-lactamases. The b-lactamase may be, for example, a serine b-lactamase or a metallo^-lactamase.
[0022] The terms below, as used herein, have the following meanings, unless indicated otherwise:
[0023] “Alkyl” refers to a straight or branched chain hydrocarbon monoradical, which is fully saturated, having from one to about ten carbon atoms, or from one to six carbon atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2 -methyl - 2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3 -butyl, 2,2-dimethyl- 1 -propyl, 2-methyl-l- pentyl, 3-methyl-l -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2 -pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as“Ci-C6 alkyl” or“Ci-6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Ci0 alkyl, a Ci-C9 alkyl, a Ci-C8 alkyl, a Ci-C7 alkyl, a Ci-C6 alkyl, a Ci-C5 alkyl, a Ci-C4 alkyl, a Ci-C3 alkyl, a Ci-C2 alkyl, or a Ci alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or - N02. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.
[0024] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1- propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, l,3-butadienyl and the like.
Whenever it appears herein, a numerical range such as“C2-C6 alkenyl” or“C2-6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, - CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.
[0025] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, l,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as“C2-C6 alkynyl” or“C2-6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, - OMe, -NH2, or -N02. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, - CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.
[0026] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
[0027] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
[0028] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to lO-membered aryl. In some embodiments, the aryl is a 6- membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the
hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
[0029] “Cycloalkyl” refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-Ci5 cycloalkyl), from three to ten carbon atoms (C3-Ci0 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6- membered cycloalkyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered cycloalkyl.
Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2. l . l]hexane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7, 7-dimethyl -bicyclo[2.2. l]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.
[0030] “Halo” or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0031] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like.
[0032] “Heterocycloalkyl” refers to a 3 - to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl,
decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, l,l-dioxo-thiomorpholinyl, l,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted,
heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the
heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,
heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
[0033] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
[0034] “Heteroaryl” refers to a 5 - to l4-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10- membered heteroaryl. In some embodiments, the heteroaryl is a 5 - to 6-membered heteroaryl.
Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, l-oxidopyridinyl, l-oxidopyrimidinyl, 1- oxidopyrazinyl, l-oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -N02. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
[0035] The term“optional” or“optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example,“optionally substituted alkyl” means either“alkyl” or“substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., - CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non -feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.
[0036] An“effective amount” or“therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
[0037] “Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition. In some embodiments, treatment also includes prophylactic treatment (e.g., administration of a composition described herein when an individual is suspected to be suffering from a bacterial infection).
Compounds
[0038] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, useful in the treatment of bacterial infections. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra abdominal infection, a skin infection or septicemia.
[0039] Described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000015_0001
Formula (I)
wherein
Y is
(a) heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR10, -(CR12R13)VIOR10, -CN, -N02, halogen, -
Figure imgf000016_0001
(b) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and
pyrazinyl each optionally substituted with one, two, or three substituents each independently selected from the group consisting of optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR20, -(CR22R23)v2OR20, -CN, -N02, halogen, -S(=0)2R24, -(CR22R23)v2S(=0)2R24, -S(=O)2NR20R21, -(CR22R23)v2S(=O)2NR20R21, - C(=0)OR20, -(CR22R23)V2C(=0)0R2°, -C(=O)NR20R21, -C(=O)(CR22R23)V2NR20R21, - (CR22R23)V2C(=O)NR20R21, -NR20R21, -NR20(CR22R23)W2NR20R21, -NR20C(=NR21)NR20R21, - C(=NR20)NR20R21, -C(=NR20)R20, -N(R20)C(=NR21)R20, -(CR22R23)V2NR20R21, - (CR22R23)V2N(R20)C(=NR21)NR20R21, -(CR22R23)V2NR20(CR22R23)W2NR20R21, - NR21C(=NR21)NR20(CR22R23)W2NR20R21, -NR20(CR22R23)W2N(R20)C(=NR21)NR20R21, - (CR22R23)V2C(=NR21)NR20R21, -NR20(CR22R23)V2B(OR25)2, and -
(CR22R23)V2NR20(CR22R23)V2B(OR25)2; provided that at least one of the optional substituent is not -0(C3 alkenyl) when R4 is C3 alkenyl; or
Figure imgf000016_0002
or - NR30(CR32R33)V3B(OR35)2 provided that z is not 0;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000017_0001
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R10, R11, R20, R21, R30, R31, R40, and R41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl) ;
or R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R12, R13, R22, R23, R32, R33, R42, and R43 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R14, R24, and R44 are independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl); each R15, R25, R35, and R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R15, or two R25, or two R35, or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
vl, v2, v3, and v4 are independently 1-4;
wl, w2, w3, and w4 are independently 2-4;
y is 1-4; and
z is 0-5.
[0040] In some embodiments of a compound of Formula (I), X is -S-. In some embodiments of a compound of Formula (I), X is -0-. In some embodiments of a compound of Formula (I), X is - S(=0)-. In some embodiments of a compound of Formula (I), X is -S(=0)2-. In some embodiments of a compound of Formula (I), X is -NR7-. In some embodiments of a compound of Formula (I), X is - NR7- and R7 is hydrogen.
[0041] In some embodiments of a compound of Formula (I), R1 is Ci-C6 alkyl. In some embodiments of a compound of Formula (I), R1 is methyl. In some embodiments of a compound of Formula (I), R1 is C2-C6 alkenyl. In some embodiments of a compound of Formula (I), R1 is C2-C6 alkynyl.
[0042] In some embodiments of a compound of Formula (I) R2 is hydrogen. In some embodiments of a compound of Formula (I), R2 is Ci-C6 alkyl. In some embodiments of a compound of Formula (I), R2 is methyl. In some embodiments of a compound of Formula (I), R2 is C2-C6 alkenyl. In some embodiments of a compound of Formula (I), R2 is C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R2 is -Si(Rc)3.
[0043] In some embodiments of a compound of Formula (I), each R3 is hydrogen. In some embodiments of a compound of Formula (I), each R3 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), each R3 is independently hydrogen, Ci-C6 alkyl, or ORa. In some embodiments of a compound of Formula (I), each R3 is independently hydrogen, Ci-C6 alkyl, or OH. In some embodiments of a compound of Formula (I), each R3 is independently Ci-C6 alkyl. In some embodiments of a compound of Formula (I), one R3 is methyl and the other R3 is hydrogen. In some embodiments of a compound of Formula (I), each R3 is independently hydrogen or C2-C6 alkenyl. In some embodiments of a compound of Formula (I), each R3 is independently hydrogen or C2-C6 alkynyl.
[0044] In some embodiments of a compound of Formula (I), R4 is hydrogen. In some embodiments of a compound of Formula (I), R4 is Ci-C6 alkyl. In some embodiments of a compound of Formula (I), R4 is C2-C6 alkenyl. In some embodiments of a compound of Formula (I), R4 is not C3 alkenyl. In some embodiments of a compound of Formula (I), R4 is C2-C6 alkynyl. In some embodiments of a compound of Formula (I), R4 is optionally substituted -(Ci-C6 alkyl)(aryl). In some embodiments of a compound of Formula (I), R4 is -(Ci-C6 alkyl)(aryl) substituted with alkyl or -N02.
[0045] In some embodiments a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000019_0001
Formula (la)
wherein
Y is
(a) heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR10, -(CR12R13)VIOR10, -CN, -N02, halogen, -
Figure imgf000019_0002
(b) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and
pyrazinyl each optionally substituted with one, two, or three substituents each independently selected from the group consisting of optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR20, -(CR22R23)v2OR20, -CN, -N02, halogen, -S(=0)2R24, -(CR22R23)v2S(=0)2R24, -S(=O)2NR20R21, -(CR22R23)v2S(=O)2NR20R21, - C(=0)OR20, -(CR22R23)V2C(=0)0R2°, -C(=O)NR20R21, -C(=O)(CR22R23)V2NR20R21, - (CR22R23)V2C(=O)NR20R21, -NR20R21, -NR20(CR22R23)W2NR20R21, -NR20C(=NR21)NR20R21, - C(=NR20)NR20R21, -C(=NR20)R20, -N(R20)C(=NR21)R20, -(CR22R23)V2NR20R21, - (CR22R23)V2N(R20)C(=NR21)NR20R21, -(CR22R23)V2NR20(CR22R23)W2NR20R21, - NR21C(=NR21)NR20(CR22R23)W2NR20R21, -NR20(CR22R23)W2N(R20)C(=NR21)NR20R21, - (CR22R23)V2C(=NR21)NR20R21, -NR20(CR22R23)V2B(OR25)2, and - (CR22R23)V2NR20(CR22R23)V2B(OR25)2; or
(c) -NR30R31, -NR30(CR32R33)W3NR30R31, -NR30C(=NR31)NR30R31, -C(=NR30)NR30R31, - C(=NR30)R30, -N(R30)C(=NR31)R30, -(CR32R33)V3NR30R31, -
NR31C(=NR31)NR30(CR32R33)W3NR30R31, -NR30(CR32R33)W3N(R30)C(=NR31)NR30R31, or - NR30(CR32R33)V3B(OR35)2 provided that z is not 0;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000020_0001
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R10, R11, R20, R21, R30, R31, R40, and R41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl) ;
or R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R12, R13, R22, R23, R32, R33, R42, and R43 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R14, R24, and R44 are independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6
alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R15, R25, R35, and R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R15, or two R25, or two R35, or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
vl, v2, v3, and v4 are independently 1-4;
wl, w2, w3, and w4 are independently 2-4; and
z is 0-5.
[0046] In some embodiments of a compound of Formula (I) or (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (Ia-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000021_0001
Formula (Ia-l).
[0047] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 or 2 and m is 0-2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 or 1 and m is 0 or 1.
[0048] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 and m is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 and m is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 and m is 2. [0049] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l) n is 1 and m is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 2.
[0050] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 2 and m is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l) n is 2 and m is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l) n is 2 and m is 2.
[0051] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 and m is 0 or n is 1 and m is 0.
[0052] In some embodiments of a compound of Formula (I), (la), or (Ia-l), L is -(CR8R9)Z. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is not 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0-5. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0- 4. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0-3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0-2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 0 or 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 1-3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 1 or 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 4. In some embodiments of a compound of Formula (I), (la), or (Ia-l), z is 5. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is independently hydrogen, halogen, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 aisre independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is independently hydrogen or halogen. In some
embodiments of a compound of Formula (I), (la), or (Ia-l), each R8 and R9 is hydrogen.
[0053] In some embodiments of a compound of Formula (I), (la), or (Ia-l), L is -(CR18R19)yC(=0)-. In some embodiments of a compound of Formula (I), (la), or (Ia-l), y is 1-3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), y is 1 or 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), y is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), y is 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), y is 3. In some
embodiments of a compound of Formula (I), (la), or (Ia-l), y is 4. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R18 and R11 is independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R18 and R19 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R18 and R19 is independently hydrogen or methyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R18 and R19 is independently hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R18 and R19 is hydrogen.
[0054] In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 0. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), p is 4. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is independently hydrogen, halogen, optionally substituted C C6 alkyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, or -NR40R41. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is hydrogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is independently halogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is optionally substituted methyl.
In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is independently Ci-C6 alkyl or Ci-C6 hydroxyalkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R5 is independently methyl or -CH2OH.In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR10, -(CR12R13)vlOR10, -CN, -N02, halogen, -S(=0)2R14, -
Figure imgf000023_0001
[0055] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl.
[0056] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl. In some embodiments of a compound of Formula (I), (la), or (Ia- 1), Y is optionally substituted piperidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted pyrrolidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted piperazinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted morpholinyl.
[0057] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, -(CR12R13)viNR10Rn, -C(=NR10)NR10Rn, -NR10C(=NR11)NR10R11, - C(=NR10)R10, -C(=O)NR10Rn, -C(=O)(CR12R13)vlNR10Rn, -(CR12R13)viC(=O)NR10Rn, _
(CR12R13)VIOR10, and -NR10(CR12R13)viB(OR15)2.In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl or piperidinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, -(CR12R13)viNR10Rn, -C(=NR10)NR10Rn, -NR10C(=NR11)NR10R11, - C(=NR10)R10, -C(=O)NR10Rn, -C(=O)(CR12R13)viNR10Rn, -(CR12R13)viC(=O)NR10Rn, _
(CR12R13)VIOR10, and -NR10(CR12R13)VIB(OR15)2.
[0058] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen,
C(=O)N
Figure imgf000024_0001
NR10(CR12R13)VIB(OR15)2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen,
C(=O)NR10Rn, -C(
Figure imgf000024_0002
[0059] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14,
Figure imgf000024_0003
[0060] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14,
Figure imgf000025_0001
[0061] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, -(CR12R13)vlNR10Rn, -C(=NR10)NR10R11 , and -NR10(CR12R13)vlB(OR15)2.
[0062] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl or piperidinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, - (CR12R13)vlNR10Rn, -C(=NR10)NR10Rn, and -(CR12R13)vlOR10.
[0063] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl or piperidinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, -
Figure imgf000025_0002
[0064] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl or piperidinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, - (CR12R13)vlNR10Rn, -C(=NR10)NR10Rn, and -NR10(CR12R13)vlB(OR15)2.
[0065] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyrrolidinyl or piperidinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R14, -NR10Rn, - (CR12R13)viNR10Rn, -C(=NR10)NR10Rn, and -(CR12R13)VIOR10.
[0066] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted piperidinyl, unsubstituted pyrrolidinyl, unsubstituted piperazinyl, or unsubstituted morpholinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted piperidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyrrolidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted piperazinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted morpholinyl.
[0067] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl each optionally substituted with one, two, or three substituents each independently selected from the group consisting of optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR20, -(CR22R23)v2OR20, -CN, -N02, halogen, -S(=0)2R24, -(CR22R23)v2S(=0)2R24, -
Figure imgf000026_0001
provided that at least one of the optional substituent is not -0(C3 alkenyl) when R4 is C3 alkenyl.
[0068] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
[0069] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyridyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyrimidinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyridazinyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is unsubstituted pyrazinyl.
[0070] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is optionally substituted pyridyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci-C6 alkyl, Ci-C6 haloalkyl,
Figure imgf000026_0003
[0071] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyridyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci- alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R24, -NR20R21, -(CR22R23)v2NR20R21, -
Figure imgf000026_0002
[0072] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is pyridyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of Ci- alkyl, Ci-C6 haloalkyl, halogen, -NR20R21, -(CR22R23)v2NR20R21, and -C(=NR20)NR20R21.
[0073] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is -NR30R31, - NR30(CR32R33)W3NR30R31, -NR30C(=NR31)NR30R31, -C(=NR30)NR30R31, -C(=NR30)R30, - N(R30)C(=NR31)R30, -(CR32R33)V3NR30R31, -NR31C(=NR31)NR30(CR32R33)W3NR30R31, - NR30(CR32R33)W3N(R30)C(=NR31)NR30R31, or -NR30(CR32R33)v3B(OR35)2; provided that z is not 0.
[0074] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is -NR30R31. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is -NR30C(=NR31)NR30R31, - C(=NR30)NR30R31, or -N(R30)C(=NR31)R30. In some embodiments of a compound of Formula (I), (la),
Figure imgf000027_0001
some embodiments of a compound of Formula (I), (la), or (Ia-l), Y is -NR30(CR32R33)v3B(OR35)2.
[0075] In some embodiments of a compound of Formula (I), (la), or (Ia-l), R10, R11, R20, R21, R30, R31, R40, and R41 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R10, R11, R20,
R21, R30, R31, R40, and R41 are independently selected from the group consisting of hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R10, R11, R20, R21, R30, R31, R40, and R41 are hydrogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[0076] In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R12, R13, R22, R23,
R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R12, R13, R22, R23, R32, R33, R42, and R43 is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R12, R13, R22, R23, R32, R33, R42, and R43 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R , R , R ,
R , R , R , R , and R is hydrogen or halogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R12, R13, R22, R23, R32, R33, R42, and R43 is hydrogen or -NRaRb.
[0077] In some embodiments of a compound of Formula (I), (la), or (Ia-l), R14, R24, and R44 are independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R14, R24, and R44 are independently Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), R14, R24, and R44 are methyl.
[0078] In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R15, R25, R35, and R45 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R15, R25, R35, and R45 is hydrogen. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each R15, R25, R35, and R45 is Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), two R15, or two R25, or two R35, or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester. [0079] In some embodiments of a compound of Formula (I), (la), or (Ia-l), vl, v2, v3, and v4 are independently 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), vl, v2, v3, and v4 are independently 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), vl, v2, v3, and v4 are independently 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), vl, v2, v3, and v4 are independently 4.
[0080] In some embodiments of a compound of Formula (I), (la), or (Ia-l), wl, w2, w3, and w4 are independently 2. In some embodiments of a compound of Formula (I), (la), or (Ia-l), wl, w2, w3, and w4 are independently 3. In some embodiments of a compound of Formula (I), (la), or (Ia-l), wl, w2, w3, and w4 are independently 4.
[0081] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Ra and Rb are independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Ra and Rb are hydrogen.
[0082] In some embodiments of a compound of Formula (I), (la), or (Ia-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (I), (la), or (Ia-l), Ra and Rb are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[0083] In some embodiments of a compound of Formula (I), (la), or (Ia-l), each Rc is
independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (I), (la), or (Ia-l), each Rc is independently Ci-C6 alkyl.
[0084] Also described herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000028_0001
Formula (II) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -(CR52R53)v5OR50, -CN, -N02, halogen, - S(=0)2R54, -(CR52R53)V5S(=0)2R54, -S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, - (CR52R53)V5C(=0)OR10, -C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000029_0001
each R6 is independently a basic substituent;
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl); or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 1-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4;
w4 is 2-4;
y is 1-4; and
z is 0-5.
[0085] In some embodiments of a compound of Formula (II), X is -S-. In some embodiments of a compound of Formula (II), X is -0-. In some embodiments of a compound of Formula (II), X is - S(=0)-. In some embodiments of a compound of Formula (II), X is -S(=0)2-. In some embodiments of a compound of Formula (II), X is -NR7-. In some embodiments of a compound of Formula (II), X is - NR7- and R7 is hydrogen.
[0086] In some embodiments of a compound of Formula (II), R1 is Ci-C6 alkyl. In some embodiments of a compound of Formula (II), R1 is methyl. In some embodiments of a compound of Formula (II), R1 is C2-C6 alkenyl. In some embodiments of a compound of Formula (II), R1 is C2-C6 alkynyl.
[0087] In some embodiments of a compound of Formula (II) R2 is hydrogen. In some embodiments of a compound of Formula (II), R2 is Ci-C6 alkyl. In some embodiments of a compound of Formula (II), R2 is methyl. In some embodiments of a compound of Formula (II), R2 is C2-C6 alkenyl. In some embodiments of a compound of Formula (II), R2 is C2-C6 alkynyl. In some embodiments of a compound of Formula (II), R2 is -Si(Rc)3.
[0088] In some embodiments of a compound of Formula (II), each R3 is hydrogen. In some embodiments of a compound of Formula (II), each R3 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), each R3 is independently hydrogen, Ci-C6 alkyl, or ORa. In some embodiments of a compound of Formula (II), each R3 is independently hydrogen, Ci-C6 alkyl, or OH. In some embodiments of a compound of Formula (II), each R3 is independently Ci-C6 alkyl. In some embodiments of a compound of Formula (II), one R3 is methyl and the other R3 is hydrogen. In some embodiments of a compound of Formula (II), each R3 is independently hydrogen or C2-C6 alkenyl. In some embodiments of a compound of Formula (II), each R3 is independently hydrogen or C2-C6 alkynyl.
[0089] In some embodiments of a compound of Formula (II), R4 is hydrogen. In some
embodiments of a compound of Formula (II), R4 is Ci-C6 alkyl. In some embodiments of a compound of Formula (II), R4 is C2-C6 alkenyl. In some embodiments of a compound of Formula (II), R4 is C2- C6 alkynyl. In some embodiments of a compound of Formula (II), R4 is optionally substituted -(Ci-C6 alkyl)(aryl). In some embodiments of a compound of Formula (II), R4 is -(Ci-C6 alkyl)(aryl) substituted with alkyl or -N02.
[0090] In some embodiments, a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000031_0001
Formula (Ila) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -(CR52R53)v5OR50, -CN, -N02, halogen, - S(=0)2R54, -(CR52R53)V5S(=0)2R54, -S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, - (CR52R53)V5C(=0)0R5°, -C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000032_0001
each R6 is independently a basic substituent;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl); each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 1-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4;
w4 is 2-4;
y is 1-4; and
z is 0-5.
[0091] In some embodiments, a compound of Formula (II) or (Ila), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (Ila-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000033_0001
Formula (Ila-l).
[0092] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ring A is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted pyridyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl, each optionally substituted with one, two, or three halogen, -CN, -OH, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, or -N02. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ring A is phenyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ring A is cyclohexyl.
[0093] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R50 and R51 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R50 and R51 are independently selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl.
[0094] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R52 and R53 are independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila- 1), R52 and R53 are independently selected from the group consisting of hydrogen, halogen, or optionally substituted Ci-C6 alkyl.
[0095] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R54 is optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R54 is optionally substituted Ci-C6 alkyl.
[0096] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 0 or 1.
[0097] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), n is 1 and m is 0. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l) n is 1 and m is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), n is 1 and m is 2.
[0098] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), n is 2 and m is 0. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l) n is 2 and m is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l) n is 2 and m is 2.
[0099] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), L is -(CR8R9)Z. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 0. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is not 0. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 4. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 5. In some embodiments of a compound of Formula (II), (Ha), or (Ila-l), z is 0-5. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 0-4. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 0-3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 0-2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 0 or 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 1 or 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), z is 1-3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is independently hydrogen, halogen, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 are independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is independently hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R8 and R9 is hydrogen.
[00100] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), L is - (CR18R19)yC(=0)-. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), y is 1-3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), y is 1 or 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), y is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), y is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), y is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), y is 4. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R18 and R19 is independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R18 and R19 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R18 and R19 is independently hydrogen or methyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R18 and R19 is independently hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R18 and R19 is hydrogen.
[00101] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), p is 0. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), p is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), p is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), p is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), p is 4.
[00102] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, -OR40, -(CR42R43)v4OR40, -CN, - N02, or -NR40R41. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently hydrogen or halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is hydrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently halogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently optionally substituted methyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently Ci-C6 alkyl or Ci-C6 hydroxyalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R5 is independently methyl or -CH2OH. [00103] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R40, R41, R50, and R51 is hydrogen.
[00104] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00105] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R42, R43, R52, and R53 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or
(Ila-l), each R 42. R 43. R 52. and R 53 is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-
1), each R 42 , R 43 , R 52 , and R 53 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R42, R43, R52, and R53 is hydrogen or halogen. In some
embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R 42 , R 43 , R 52 , and R 53 is hydrogen or -NRaRb.
[00106] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R44 and R54 are independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R44 and R54 are methyl.
[00107] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R45 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R45 is hydrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R45 is Ci-C6 alkyl.
[00108] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00109] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), q is 4. [00110] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is a basic substituent comprising at least one basic nitrogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is a basic substituent comprising one basic nitrogen. In some
embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is a basic substituent comprising two basic nitrogens.
[00111] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - C(=NR60)R60, -N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -C(=O)NR60R61, -C(=O)(CR62R63)V6NR60R61, -(CR62R63)v6 C(=O)NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, -(CR62R63)V6C(=NR61)NR60R61, -NR60(CR62R63)V6B(OR65)2, or -(CR62R63)V6NR60(CR62R63)V6B(OR65)2.
[00112] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, -(CR62R63)V6C(=NR61)NR60R61, -NR60(CR62R63)V6B(OR65)2, or -(CR62R63)V6NR60(CR62R63)V6B(OR65)2.
[00113] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, or -(CR62R63)v6C(=NR61)NR60R61.
[00114] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, or -(CR62R63)V6NR60R61.
[00115] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each R6 is independently -NR60R61, -C(=NR60)NR60R61, -(CR62R63)v6NR60R61, or -NR60(CR62R63)v6B(OR65)2.
[00116] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is -NR60R61.
[00117] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is -
(CR62R63)V6NR60R61.
[00118] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is - C(=NR60)NR60R61.
[00119] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is - NR60(CR62R63)V6B(OR65)2.
[00120] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl); or R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl). In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen and Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R60 and R61 is hydrogen.
[00121] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00122] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R62 and is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila- 1), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (II),
(Ila), or (Ila-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and halogen. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and -NRaRb. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R62 and R63 is hydrogen.
[00123] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl; or two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00124] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R65 is hydrogen.
[00125] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00126] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and v6 is 1-4. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and v6 is 1. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and v6 is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l),
R6 is as defined above and v6 is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila- 1), R6 is as defined above and v6 is 4.
[00127] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and w6 is 2-4. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and w6 is 2. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and w6 is 3. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and w6 is 4.
[00128] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ra and Rb are independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ra and Rb are hydrogen.
[00129] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), Ra and Rb are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00130] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each Rc is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), each Rc is independently Ci-C6 alkyl.
[00131] Also described herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000040_0001
Formula (III) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -(CR52R53)v5OR50, -CN, -N02, halogen, - S(=0)2R54, -(CR52R53)V5S(=0)2R54, -S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, - (CR52R53)V5C(=0)OR10, -C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000041_0001
each R6 is independently a basic substituent;
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl; or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4;
w4 is 2-4;
y is 1-4; and
z is 1-5.
[00132] In some embodiments of a compound of Formula (III), X is -S-. In some embodiments of a compound of Formula (III), X is -0-. In some embodiments of a compound of Formula (III), X is - S(=0)-. In some embodiments of a compound of Formula (III), X is -S(=0)2-. In some embodiments of a compound of Formula (III), X is -NR7-. In some embodiments of a compound of Formula (III), X is -NR7- and R7 is hydrogen.
[00133] In some embodiments of a compound of Formula (III), R1 is Ci-C6 alkyl. In some embodiments of a compound of Formula (III), R1 is methyl. In some embodiments of a compound of Formula (III), R1 is C2-C6 alkenyl. In some embodiments of a compound of Formula (III), R1 is C2-C6 alkynyl.
[00134] In some embodiments of a compound of Formula (III) R2 is hydrogen. In some
embodiments of a compound of Formula (III), R2 is Ci-C6 alkyl. In some embodiments of a compound of Formula (III), R2 is methyl. In some embodiments of a compound of Formula (III), R2 is C2-C6 alkenyl. In some embodiments of a compound of Formula (III), R2 is C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R2 is -Si(Rc)3.
[00135] In some embodiments of a compound of Formula (III), each R3 is hydrogen. In some embodiments of a compound of Formula (III), each R3 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), each R3 is independently hydrogen, Ci-C6 alkyl, or ORa. In some embodiments of a compound of Formula (III), each R3 is independently hydrogen, Ci-C6 alkyl, or OH. In some embodiments of a compound of Formula (III), each R3 is independently Ci-C6 alkyl. In some embodiments of a compound of Formula (III), one R3 is methyl and the other R3 is hydrogen. In some embodiments of a compound of Formula (III), each R3 is independently hydrogen or C2-C6 alkenyl. In some embodiments of a compound of Formula (III), each R3 is independently hydrogen or C2-C6 alkynyl.
[00136] In some embodiments of a compound of Formula (III), R4 is hydrogen. In some embodiments of a compound of Formula (III), R4 is Ci-C6 alkyl. In some embodiments of a compound of Formula (III), R4 is C2-C6 alkenyl. In some embodiments of a compound of Formula (III), R4 is C2-C6 alkynyl. In some embodiments of a compound of Formula (III), R4 is optionally substituted -(Ci-C6 alkyl)(aryl). In some embodiments of a compound of Formula (III), R4 is -(Ci-C6 alkyl)(aryl) substituted with alkyl or -N02.
[00137] In some embodiments, a compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (Ilia) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000043_0001
Formula (Ilia) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -(CR52R53)v5OR50, -CN, -N02, halogen, - S(=0)2R54, -(CR52R53)V5S(=0)2R54, -S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, - (CR52R53)V5C(=0)0R5°, -C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000043_0002
each R6 is independently a basic substituent; each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4; w4 is 2-4;
y is 1-4; and
z is 1-5.
[00138] In some embodiments, a compound of Formula (III) or (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (Illa-l) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000045_0001
Formula (Illa-l).
[00139] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ring A is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted pyridyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl, each optionally substituted with one, two, or three halogen, -CN, -OH, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, or -N02. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ring A is phenyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ring A is cyclohexyl.
[00140] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R50 and R51 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R50 and R51 are independently selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl.
[00141] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R52 and R53 are independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R52 and R53 are independently selected from the group consisting of hydrogen, halogen, or optionally substituted Ci-C6 alkyl.
[00142] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R54 is optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R54 is optionally substituted Ci-C6 alkyl. [00143] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 or 1 and m is 0 or 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 0 or 1.
[00144] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), n is 0 and m is 0.
In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l) n is 0 and m is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), n is 0 and m is 2.
[00145] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), n is 1 and m is 0.
In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l) n is 1 and m is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), n is 1 and m is 2.
[00146] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), n is 2 and m is 0.
In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l) n is 2 and m is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l) n is 2 and m is 2.
[00147] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), L is -(CR8R9)Z. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 5. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1-5. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1-4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1-3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), z is 1 or 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, -ORa, or - NRaRb. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is independently hydrogen, halogen, -CN, Ci-C6 alkyl, Ci-C6 haloalkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is independently hydrogen, halogen, Ci-C6 alkyl, or Ci-C6 haloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 are independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is independently hydrogen or methyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is independently hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R8 and R9 is hydrogen.
[00148] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), L is - (CR18R19)yC(=0)-. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 1-3.
In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 1 or 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), y is 4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, -ORa, or -NRaRb. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R18 and R11 is independently hydrogen, halogen, or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R18 and R19 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R18 and R19 is independently hydrogen or methyl.
In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R18 and R19 is independently hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R18 and R19 is hydrogen.
[00149] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 0. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), p is 4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is
independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, -OR40, -(CR42R43)v4OR40, -CN, - N02, or -NR40R41. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is independently hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is hydrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is independently halogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is
independently optionally substituted methyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is independently Ci-C6 alkyl or Ci-C6 hydroxyalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R5 is independently methyl or -CH2OH.
[00150] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R40, R41, R50, and R51 is hydrogen.
[00151] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00152] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R42, R43, R52, and R53 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R . R . R . and R is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or
42 43 52 53
(Illa-l), each R , R , R . and R ' is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R42, R43, R52, and R53 is hydrogen or halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R42, R43, R52, and R53 is hydrogen or -NRaRb.
[00153] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R44 and R54 are independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R44 and R54 are methyl.
[00154] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R45 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R45 is hydrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R45 is Ci-C6 alkyl.
[00155] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00156] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), q is 4.
[00157] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is a basic substituent comprising at least one basic nitrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is a basic substituent comprising one basic nitrogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is a basic substituent comprising two basic nitrogens.
[00158] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - C(=NR60)R60, -N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -C(=O)NR60R61, -C(=O)(CR62R63)V6NR60R61, -(CR62R63)v6 C(=O)NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, -(CR62R63)V6C(=NR61)NR60R61, -NR60(CR62R63)V6B(OR65)2, or -(CR62R63)V6NR60(CR62R63)V6B(OR65)2.
[00159] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, -
Figure imgf000049_0001
[00160] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, or -(CR62R63)v6C(=NR61)NR60R61; v6 is 1-4; and w6 is 2-4.
[00161] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, or -(CR62R63)V6NR60R61.
[00162] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each R6 is independently -NR60R61, -C(=NR60)NR60R61, -(CR62R63)v6NR60R61, or -NR60(CR62R63)v6B(OR65)2.
[00163] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is -NR60R61.
[00164] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is -
(CR62R63)V6NR60R61.
[00165] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is - C(=NR60)NR60R61.
[00166] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is - NR60(CR62R63)V6B(OR65)2.
[00167] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl); or R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl). In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen and Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
R6 is as defined above and each R60 and R61 is hydrogen.
[00168] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00169] In some embodiments of a compound of Formula (II), (Ila), or (Ila-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and halogen. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and -NRaRb. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R62 and R63 is hydrogen.
[00170] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl; or two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester. [00171] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and each R65 is hydrogen.
[00172] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00173] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and v6 is 1-4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and v6 is 1. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
R6 is as defined above and v6 is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and v6 is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and v6 is 4.
[00174] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and w6 is 2-4. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and w6 is 2. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l),
R6 is as defined above and w6 is 3. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), R6 is as defined above and w6 is 4.
[00175] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ra and Rb are independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ra and Rb are hydrogen.
[00176] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), Ra and Rb are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00177] In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each Rc is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (III), (Ilia), or (Illa-l), each Rc is independently Ci-C6 alkyl.
[00178] Also described herein are compounds of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000052_0001
Formula (IV)
wherein
Ring A is cycloalkyl or heterocycloalkyl; each optionally substituted with one, two, or three
substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -
Figure imgf000052_0002
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000052_0003
each R6 is independently a basic substituent;
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb; each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4; and
w4 is 2-4.
[00179] In some embodiments of a compound of Formula (IV), X is -S-. In some embodiments of a compound of Formula (IV), X is -0-. In some embodiments of a compound of Formula (IV), X is - S(=0)-. In some embodiments of a compound of Formula (IV), X is -S(=0)2-. In some embodiments of a compound of Formula (IV), X is -NR7-. In some embodiments of a compound of Formula (IV), X is -NR7- and R7 is hydrogen. [00180] In some embodiments of a compound of Formula (IV), R1 is Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), R1 is methyl. In some embodiments of a compound of Formula (IV), R1 is C2-C6 alkenyl. In some embodiments of a compound of Formula (IV), R1 is C2-C6 alkynyl.
[00181] In some embodiments of a compound of Formula (IV) R2 is hydrogen. In some
embodiments of a compound of Formula (IV), R2 is Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), R2 is methyl. In some embodiments of a compound of Formula (IV), R2 is C2-C6 alkenyl. In some embodiments of a compound of Formula (IV), R2 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R2 is -Si(Rc)3.
[00182] In some embodiments of a compound of Formula (IV), each R3 is hydrogen. In some embodiments of a compound of Formula (IV), each R3 is independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), each R3 is independently hydrogen, Ci-C6 alkyl, or ORa. In some embodiments of a compound of Formula (IV), each R3 is independently hydrogen, Ci-C6 alkyl, or OH. In some embodiments of a compound of Formula (IV), each R3 is independently Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), one R3 is methyl and the other R3 is hydrogen. In some embodiments of a compound of Formula (IV), each R3 is independently hydrogen or C2-C6 alkenyl. In some embodiments of a compound of Formula (IV), each R3 is independently hydrogen or C2-C6 alkynyl.
[00183] In some embodiments of a compound of Formula (IV), R4 is hydrogen. In some embodiments of a compound of Formula (IV), R4 is Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), R4 is C2-C6 alkenyl. In some embodiments of a compound of Formula (IV), R4 is C2-C6 alkynyl. In some embodiments of a compound of Formula (IV), R4 is optionally substituted -(Ci-C6 alkyl)(aryl). In some embodiments of a compound of Formula (IV), R4 is -(Ci-C6 alkyl)(aryl) substituted with alkyl or -N02.
[00184] In some embodiments, a compound of Formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (IVa) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000054_0001
Formula (IVa) wherein
Ring A is cycloalkyl or heterocycloalkyl; each optionally substituted with one, two, or three
substituents each independently selected from the group consisting of oxo optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, - (CR52R53)V5OR50, -CN, -N02, halogen, -S(=0)2R54, -(CR52R53)v5S(=0)2R54, -S(=O)2NR50R51, - (CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, -(CR52R53)V5C(=0)0R5°, -C(=O)NR50R51, and - (CR52R53)V5C(=O)NR50R51;
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000055_0001
each R6 is independently a basic substituent;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl; or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4; and
w4 is 2-4.
[00185] In some embodiments, a compound of Formula (IV) or (IVa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is of Formula (IVa-l) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000056_0001
Formula (IVa-l).
[00186] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ring A is optionally substituted cyclohexyl, optionally substituted piperidinyl, or optionally substituted morpholinyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ring A is cyclohexyl, piperidinyl, or morpholinyl,, each optionally substituted with one, two, or three halogen, - CN, -OH, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, or -N02. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ring A is cyclohexyl, piperidinyl, or morpholinyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ring A is cyclohexyl.
[00187] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R50 and R51 are independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R50 and R51 are independently selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl.
[00188] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R52 and R53 are independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R52 and R53 are independently selected from the group consisting of hydrogen, halogen, or optionally substituted Ci-C6 alkyl. [00189] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R54 is optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R54 is optionally substituted Ci-C6 alkyl.
[00190] In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 0 or 1 and m is 0 or 1. In some embodiments of a compound of Formula (I), (la), or (Ia-l), n is 1 and m is 0 or 1.
[00191] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 0 and m is 0.
In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l) n is 0 and m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 0 and m is 2.
[00192] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 1 and m is 0.
In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l) n is 1 and m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 1 and m is 2.
[00193] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), n is 2 and m is 0.
In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l) n is 2 and m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l) n is 2 and m is 2.
[00194] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 0. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), p is 4. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, -OR40, -(CR42R43)v4OR40, -CN, - N02, or -NR40R41. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is independently hydrogen or halogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is independently halogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is
independently optionally substituted methyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is independently Ci-C6 alkyl or Ci-C6 hydroxyalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R5 is independently methyl or -CH2OH.
[00195] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R40, R41, R50, and R51 is hydrogen. [00196] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine.
In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00197] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R42, R43, R52, and R53 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or
(IVa-l), each R 42 , R 43 , R 52. and R 53 is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or
42 43 52 53
(IVa-l), each R , R , R . and R is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R42, R43, R52, and R53 is hydrogen or halogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R42, R43, R52, and R53 is hydrogen or -NRaRb.
[00198] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R44 and R54 are independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R44 and R54 are methyl.
[00199] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R45 is hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R45 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R45 is Ci-C6 alkyl.
[00200] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00201] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), q is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), q is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), q is 3. In some embodiments of a compound of
Formula (IV), (IVa), or (IVa-l), q is 4.
[00202] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is a basic substituent comprising at least one basic nitrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is a basic substituent comprising one basic nitrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is a basic substituent comprising two basic nitrogens.
[00203] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - C(=NR60)R60, -N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -C(=O)NR60R61, -C(=O)(CR62R63)V6NR60R61,
Figure imgf000059_0001
[00204] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, -(CR62R63)V6C(=NR61)NR60R61, -NR60(CR62R63)V6B(OR65)2, or -(CR62R63)V6NR60(CR62R63)V6B(OR65)2.
[00205] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, -(CR62R63)V6N(R60)C(=NR61)NR60R61, - (CR62R63)V6NR60(CR62R63)W6NR60R61, -NR61C(=NR61)NR60(CR62R63)W6NR60R61, - NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, or -(CR62R63)v6C(=NR61)NR60R61.
[00206] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, -C(=NR60)NR60R61, - N(R60)C(=NR61)R60, or -(CR62R63)V6NR60R61.
[00207] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is independently -NR60R61, -C(=NR60)NR60R61, -(CR62R63)v6NR60R61, or -NR60(CR62R63)v6B(OR65)2.
[00208] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is -NR60R61.
[00209] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is -
(CR62R63)V6NR60R61.
[00210] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is - C(=NR60)NR60R61.
[00211] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is - NR60(CR62R63)V6B(OR65)2.
[00212] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl); or R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl). In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C3-C8 cycloalkyl, or C2-C8 optionally substituted heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen and optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each R6 is as defined above and each R60 and R61 is independently selected from the group consisting of hydrogen and Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l),
R6 is as defined above and each R60 and R61 is hydrogen.
[00213] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l),
R6 is as defined above and R60 and R61 are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00214] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, -NRaRb, or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and halogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and -NRaRb. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is independently selected from the group consisting of hydrogen and Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R62 and R63 is hydrogen.
[00215] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R65 is hydrogen.
[00216] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl; or two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00217] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester.
[00218] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and v6 is 1-4. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and v6 is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and v6 is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and v6 is 3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and v6 is 4.
[00219] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and w6 is 2-4. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and w6 is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa- 1), R6 is as defined above and w6 is 3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), R6 is as defined above and w6 is 4.
[00220] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ra and Rb are independently hydrogen or Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ra and Rb are hydrogen.
[00221] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted aziridine, azetidine, pyrrolidine, piperidine, morpholine, or piperazine. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), Ra and Rb are taken together with the nitrogen to which they are attached to form a pyrrolidine, piperidine, morpholine, or piperazine.
[00222] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each Rc is independently optionally substituted Ci-C6 alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-l), each Rc is independently Ci-C6 alkyl. [00223] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
[00224] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of:
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Further Forms of Compounds Disclosed Herein
Isomers/Stereoisomers
[00225] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described 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, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Labeled compounds
[00226] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of Formula (I), Formula (la), Formula (Ia-l), Formula (II), Formula (Ha), Formula (Ila-l), Formula (III), Formula (Ilia), Formula (Illa-l), or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H, ¾, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ¾ and carbon-l4, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, /. e. , 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof is prepared by any suitable method. [00227] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[00228] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00229] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of Formula (I), Formula (la), Formula (Ia-l), Formula (II), Formula (Ha), Formula (Ila-l), Formula (III), Formula (Ilia), Formula (Illa-l), or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
[00230] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate,
dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fiimarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate,
methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1- napthalene sulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.
[00231] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, f imaric acid, p- toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid, l,2-ethanedisulfonic acid, 2 -hydroxyethane sulfonic acid, benzenesulfonic acid, 2- naphthalene sulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds of Formula (I), Formula (la), Formula (Ia-l), Formula (II), Formula (Ha), Formula (Ila-l), Formula (III), Formula (Ilia), Formula (Illa-l), solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
[00232] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a
pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI-4 alkyl)4, and the like.
[00233] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.
Solvates
[00234] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00235] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers
[00236] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
Preparation of Compounds
[00237] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of bacterial infections and processes for their preparation. In some embodiments, compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are synthesized using standard synthetic reactions known to those of skill in the art or using methods known in the art. The reactions can be employed in a linear sequence to provide the compounds or they may be used to synthesize fragments which are subsequently joined by the methods known in the art. In some embodiments, the starting material used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Louis, Mo.). In some embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999); Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), all of which are incorporated by reference for such disclosures. In some embodiments, general methods for the preparation of compound as disclosed herein are derived from known reactions in the field, and the reactions are modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein.
[00238] In some embodiments, the products of the reactions are isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. In some embodiments, such materials are characterized using conventional means, including physical constants and spectral data. Pharmaceutical Compositions/Formulations
[00239] In another aspect, provided herein are pharmaceutical compositions comprising a compound describe herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.
[00240] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
[00241] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
[00242] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.
[00243] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[00244] Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.
[00245] Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof thereof. In some embodiments, the
pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms. Combination Treatment
[00246] Disclosed herein are combinations of compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof with one or more antibiotics for the treatment of bacterial infections. In some embodiments, the antibiotic is administered by a route and in an amount commonly used, therefore, contemporaneously or sequentially with a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. When a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is used contemporaneously with one or more antibiotics, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is optionally used. In some embodiments, the combination therapy also includes therapies in which the compound described herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof and one or more antibiotic are administered on different overlapping schedules. In some embodiments, when used in combination with one or more antibiotics, the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is used in lower doses than when each is used singly. [00247] In some embodiments, the one or more antibiotics are beta-lactam antibiotics. In certain embodiments, the beta-lactam antibiotic is a penicillin, a penem, a carbapenem, a cephalosporin, a cephamycin, a monobactam, or combinations thereof. Penicillins include, but are not limited to, amoxicillin, ampicillin, azidocillin, azlocillin, bacampicillin, benzathinebenzylpenicillin,
benzathinephenoxymethylpenicillin, benzylpenicillin (G), carbenicillin, carindacillin, clometocillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin, meticillin, mezlocillin, nafcillin, oxacillin, penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin, pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin, or any combinations thereof. Penems include, but are not limited to, faropenem. Carbapenems include, but are not limited to, biapenem, ertapenem, doripenem, imipenem, meropenem, panipenem, or any combinations thereof. Cephalosprins/cephamycins include, but are not limited to, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, ceftnenoxime, ceftnetazole, ceftninox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftarolinefosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef, loracarbef, or any combinations thereof. Monobactams include, but are not limited to, aztreonam, carumonam, nocardicin A, tigemonam, or any combinations thereof.
[00248] Also disclosed herein, are combination of compounds described herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof with one or more beta-lactamase inhibitors for the treatment of bacterial infections. In some embodiments, the beta-lactamase inhibitor is VNRX-5133, clavulanic acid, sulbactam, tazobactam, or any combinations thereof. In some embodiments, the beta-lactamase inhibitor is VNRX-5133.
[00249] Also disclosed herein, are combination of compounds described herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof with one or more non beta-lactam beta-lactamase inhibitors for the treatment of bacterial infections. In some embodiments, the non beta- lactam beta-lactamase inhibitor is avibactam, relebactam, or any combinations thereof.
Administration of Pharmaceutical Composition
[00250] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes
intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. [00251] In some embodiments, compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and compositions thereof are administered in any suitable manner.
The manner of administration can be chosen based on, for example, whether local or systemic treatment is desired, and on the area to be treated. For example, the compositions can be administered orally, parenterally (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection), by inhalation, extracorporeally, topically (including transdermally, ophthalmically, vaginally, rectally, intranasally) or the like.
[00252] Parenteral administration of the composition, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. A more recently revised approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained.
Assays for Antibacterial Activity
[00253] Assays for the inhibition of bacterial growth are well known in the art.
Methods
[00254] Disclosed herein are methods of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound described herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein are methods of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the bacterial infection is caused by gram-negative bacteria. In some embodiments, the bacterial infection is caused by multidrug-resistant (MDR) bacteria. In some embodiments, the bacterial infection is caused by carbapenem resistant Enterobacteriaceae (CRE). In some embodiments, the bacterial infection is caused by an aerobic bacteria. In some embodiments, the bacterial infection is caused by an anaerobic bacteria. In some embodiments, the bacterial infection is an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, a skin infection, or septicemia.
[00255] In some embodiments, the bacterial infection is caused by a bacteria that include
Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonasmaltophilia, Burkholderiacepacia,
Aeromonashydrophilia, Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigelladysenteriae, Shigellaflexneri,
Shigellasonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae,
Klebsiellaoxytoca, Serratiamarcescens, Francisellatularensis, Morganellamorganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,
Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilusinfluenzae, Haemophilusparainfluenzae, Haemophilushaemolyticus, Haemophilusparahaemolyticus, Haemophilusducreyi,
Pasteurellamultocida, Pasteurellahaemolytica, Branhamellacatarrhalis, Helicobacter pylori,
Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borreliaburgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroidesfragilis,
Bacteroidesdistasonis, Bacteroides 3452A homology group, Bacteroidesvulgatus, Bacteroidesovalus, Bacteroidesthetaiotaomicron, Bacteroidesuniformis, Bacteroideseggerthii, Bacteroidessplanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium
intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.
[00256] In some embodiments, the infection that is treated is caused by a bacteria that includes Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonasmaltophilia, Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigelladysenteriae, Shigellaflexneri, Shigellasonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiellaoxytoca, Serratiamarcescens, Acinetobacter
calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilusinfluenzae, Haemophilusparainfluenzae, Haemophilushaemolyticus, Haemophilusparahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroidesfragilis, Bacteroidesvulgatus, Bacteroidesovalus, Bacteroidesthetaiotaomicron,
Bacteroidesuniformis, Bacteroideseggerthii, or Bacteroidessplanchnicus.
[00257] Also disclosed herein are methods for inhibiting bacterial growth, such methods comprising contacting a bacterial cell culture, or a bacterially infected cell culture, tissue, or organism, with a carbapenem derivative described herein. Preferably, the bacteria to be inhibited by administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are bacteria that are resistant to beta-lactam antibiotics. The term“resistant” is well-understood by those of ordinary skill in the art (see, e g Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772 (1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30 1120-1126 (1995)).
[00258] These methods are useful for inhibiting bacterial growth in a variety of contexts. In certain embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to an experimental cell culture in vitro to prevent the growth of beta-lactam resistant bacteria. In certain some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a mammal, including a human to prevent the growth of beta-lactam resistant bacteria in vivo. The method according to this embodiment comprises administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof for a therapeutically effective period of time to a mammal, including a human.
EXAMPLES
General Examples for the Preparation of Compounds
[00259] The starting materials and intermediates for the compounds of this invention may be prepared by the application or adaptation of the methods described below, their obvious chemical equivalents, or, for example, as described in literature such as The Science of Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme publishers (2001-2008). The use of protective groups may be as described in methodology compendia such as Greene's Protective Groups in Organic Synthesis, Fourth Edition. John Wiley & Sons, Inc. 2006.
[00260] Certain compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof (SCHEME 1) are prepared from the corresponding functional-group-protected beta-lactams II by hydrogenation in the presence of a catalyst such as platinum on carbon, at a temperature between 0 °C and 10 °C, followed by purification of the crude products by flash chromatography on MCI GEL CHP20P.
Figure imgf000082_0001
SCHEME 1
[00261] The functional -group -protected intermediates A may be prepared according to the route outlined in SCHEME 2. Pyrrolidine-thiols B were coupled with the carbonyl compounds C in the presence of a reducing reagent such as sodium triacetoxyborohydride to give the thiols D, which were condensed with the known and commercially available enol phosphate E in the presence of a base such as Hiinig’s base (DIEA, diisopropylethylamine). Pyrrolidine-thiols B, and the carbonyl compounds C may be obtained from commercial sources, prepared according to known methods in the literature, or prepared by a number of different reaction sequences.
Figure imgf000083_0001
SCHEME 2
Synthetic Examples
[00262] The following preparations of compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and intermediates are given to enable those of skill in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as illustrative and representative thereof.
EXAMPLE 1: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- yl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000083_0002
Step 1: Synthesis of tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate.
Figure imgf000083_0003
[00263] To a solution of (S)-Boc-3-pyrrolidinol (8.42 g, 45 mmol) in DCM (150 mL) at 0 °C was added triethylamine (9.5 mL, 68.2 mmol) followed by methanesulfonyl chloride (4 mL, 50.8 mmol) The reaction mixture was stirred at 0 °C for 30 min, then warmed to rt for 30 min, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification.
Step 2: Synthesis of tert-butyl (R)-3-(acetylthio)pyrrolidine-l-carboxylate.
Figure imgf000083_0004
[00264] To a solution of the crude methylate in acetone (380 mL) was added potassium thioacetate (7.8 g, 68.3 mmol). The reaction mixture was refluxed for 20 h, cooled to rt, filtered, and the filtrate was concentrated. To the residue was added diethyl ether, washed with water, brine, dried over Na2S04, concentrated in vacuo, and purified by flash chromatography on silica gel (hexane -EtO Ac, 20: 1-2: 1) to afford the product, 9 g.
Step 3: Synthesis of tert-butyl (R)-3-mercaptopyrrolidine-l-carboxylate.
Boc
Figure imgf000084_0001
[00265] To a solution of the above product (9 g, 36.7 mmol) in methanol (60 mL) was added potassium carbonate (10.2 g, 73.9 mmol). The reaction mixture was stirred at 50 °C under Argon for 2 h, then cooled in ice-bath, acidified with 1 N HC1 to pH 4-5, extracted with diethyl ether. The organic extracts were combined, washed with water, brine, dried over Na2S04, and concentrated in vacuo to give the crude thiol, which was used directly for the next step without further purification.
Step 4: Synthesis of (R)-pyrrolidine-3-thiol.
Figure imgf000084_0002
[00266] The above crude product was dissolved in DCM (70 mL), treated with TFA (70 mL) at 0 °C for 1 h, and then concentrated in vacuo to give the crude product as a TFA salt, which was used directly for the next step without further purification.
Step 5: Synthesis of 4-nitrobenzyl 4-oxopiperidine-l-carboxylate.
Figure imgf000084_0003
[00267] To a solution of 4-piperidinone hydrochloride hydrate (4.59 g, 30 mmol) in dioxane (50 mL) and water (25 mL) was added sodium carbonate (6.36 g, 60 mmol) followed by 4-nitrobenzyl chloroformate (7.12 g, 33 mmol) at 0°C. The reaction mixture was stirred in ice-bath for 2 h, diluted with water, extracted with EtO Ac. The organic extracts were combined, dried over Na2S04, concentrated in vacuo. To the crude product was added hexane, then filtered, the solid was collected, washed with hexane, dried in vacuo to afford the product, 7.1 g. ESI-MS m/z 279 (MH)+.
Step 6: Synthesis of 4-nitrobenzyl (R)-4-(3-mercaptopyrrolidin-l-yl)piperidine-l-carboxylate.
Figure imgf000084_0004
[00268] To a solution of the above product (1.2 g, 4.29 mmol), (R) -pyrrolidine -3 -thiol from Step 4 (crude, 5.3 mmol) in l,2-dichloroethane (30 mL) was added sodium triacetoxyborohydride (1.37 g, 6.43 mmol). The reaction mixture was stirred at rt overnight, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (DCM-MeOH, 30: 1-5: 1) to afford the pure product, 400 mg. ESI-MS m/z 366 (MH)+. Step 7: Synthesis of 4-nitrobenzyl (R)-4-(3-mercaptopyrrolidin-l-yl)piperidine-l-carboxylate 4- nitrobenzyl (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(l-(((4- nitrobenzyl)oxy)carbonyl)piperidin-4-yl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylate.
Figure imgf000085_0001
[00269] To the above product (183 mg, 0.5 mmol), and 4-nitrobenzyl (4R,5R,6S)-3- ((diphenoxyphosphoryl)oxy)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- 2-carboxylate (327 mg, 0.55 mmol) was add dry acetonitrile (15 mL) under Argon at 0°C, followed by diisopropylethylamine (0.12 mL, 0.66 mmol). The reaction mixture was stirred in ice-bath for 8 h, kept in the refrigerator for 20 h, then concentrated. The residue was purified twice by flash chromatography on silica gel (EtOAc, then hexane-acetone, 1: 1-0: 100) to yield the product, 220 mg. ESI-MS m/z 710 (MH)+.
Step 8: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- yl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000085_0002
[00270] The above product (210 mg, 0.3 mmol) in THF (5 mL), iPrOH (5 mL), and phosphate buffer (pH 7, 10 mL) was hydrogenated in the presence of 5% Pt/C (130 mg) in ice-bath for 6 h. The reaction mixture was filtered through a pad of celite, washed with small amount of water and EtOAc. The aqueous layer was separated, washed with EtOAc, then purified by flash chromatography on MCI GEL CHP20P (0-10% aqueous THF) followed by lyophilized to yield the product, 40 mg. ESI-MS m/z 396 (MH)+.
EXAMPLE 2: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((S)-l-(piperidin-4- yl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000085_0003
[00271] By following the same reaction procedures as described in Example 1, except in Step 1 using (R)-Boc-3-pyrrolidinol instead of (S)-Boc-3-pyrrolidinol as starting material, the target compound was prepared. ESI-MS m/z 396 (MH)+. EXAMPLE 3: (4R,5S,6S)-3-(((R)-l-(4-((3-boronopropyl)amino)cyclohexyl)pyrrolidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000086_0001
Step 1: Synthesis of 4-nitrobenzyl (4-oxocyclohexyl)(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)propyl)carbamate.
Figure imgf000086_0002
[00272] Part i). 8 -Amino-l,4-dioxaspiro[4.5]decane (2.1 g, 13.4 mmol) was reacted with 3- bromopropylboronic acid pinacol ester (2.3 g, 9.24 mmol) in acetonitrile (50 mL) in the presence of K2C03 (2.07 g, 15 mmol) at reflux for 4 h, then cooled to rt, filtered, and the filtrate was concentrated in vacuo to afford the crude product, which was used directly for the next step without further purification.
[00273] Part ii). The crude product from Part i) was dissolved in DCM (100 mL), triethylamine (2.98 mL, 20.7 mmol) was added, followed by 4-nitrobenzyl chloroformate (3.19 g, 14.8 mmol). The reaction mixture was stirred at rt overnight, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane -EtO Ac, 20: 1-1: 1) to afford the product, 1.45 g. ESI-MS m/z 505 (MH)+.
[00274] Part iii). The product from Part ii) (1.4 g, 2.78 mmol) was dissolved in acetone (60 mL), toluenesulfonic acid monohydrate (133 mg, 0.7 mmol) was added. The reaction mixture was stirred at rt for 60 h, concentrated in vacuo. The residue was dissolved in DCM, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo to give the crude product, which was used directly for the next step without further purification. ESI-MS m/z 461 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-3-(((R)-l-(4-((3-boronopropyl)amino)cyclohexyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000086_0003
[00275] By following the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above ketone was converted to the target compound. ESI-MS m/z 496 (MH)+. EXAMPLE 4: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(piperidin-3- yl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000087_0001
[00276] By following the same reaction procedures as described in Example 1, except in Step 5 using 3-piperidinone hydrochloride hydrate instead of 4-piperidinone hydrochloride hydrate as starting material, the target compound was prepared. ESI-MS m/z 396 (MH)+.
EXAMPLE 5: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-3-(((3R,5S)-5-(hydroxymethyl)-l-(piperidin-4- yl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000087_0002
Step 1: Synthesis of l-(tert-butyl) 2-methyl (2S,4R)-4-(acetylthio)pyrrolidine-l,2-dicarboxylate.
Figure imgf000087_0003
Boc Boc
[00277] To a solution of Boc-cis-L-4-hydroxyproline methyl ester (2.45 g, 10 mmol) in THF (80 mL) was added triphenylphosphine (3.67 g, 14 mmol) followed by DIAD (2.7 mL, 14 mmol) at 0 °C under Argon. After 30 min, thioacetic acid (1.29 mL, 18 mmol) was added, and the reaction mixture was stirred between 0 - 10 °C for 3 h, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane -EtO Ac, 30: 1-2: 1) to afford the product, 3.02 g.
Step 2: Synthesis of tert-butyl (2S,4R)-2-(hydroxymethyl)-4-mercaptopyrrolidine-l-carboxylate.
Figure imgf000087_0004
[00278] To a solution of the above product (3.02 g, 10 mmol) in THF (100 mL) at -30 °C under Argon was added LiAlH4 (950 mg, 25 mmol). The reaction mixture was stirred between -30 - 0 °C for 2 h, quenched by careful addition of water, and 1 N HC1 to pH 3-4, extracted with EtO Ac. The combined organic extracts were washed with brine, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification.
Step 3: Synthesis of ((2S,4R)-4-mercaptopyrrolidin-2-yl)methanol.
Figure imgf000087_0005
[00279] The above crude product (10 mmol) was dissolved in DCM (25 mL), and treated with TFA (25 mL) at 0 °C for 1 h, then concentrated and dried in vacuo, yielding the crude product as TFA salt, which was used directly for the next step without further purification.
Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-3-(((3R,5S)-5-(hydroxymethyl)-l-
(piperidin-4-yl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000088_0001
[00280] By using the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above thiol was converted to the target compound. ESI-MS m/z 426 (MH)+.
EXAMPLE 6: (4R,5S,6S)-3-(((3R)-[l,3'-bipyrrolidin]-3-yl)thio)-6-((R)-l-hydroxyethyl)-4- methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid
Figure imgf000088_0002
[00281] By following the same reaction procedures as described in Example 1, except in Step 5 using 3-pyrrolidinone hydrochloride instead of 4-piperidinone hydrochloride hydrate as starting material, the target compound was prepared. ESI-MS m/z 382 (MH)+.
EXAMPLE 7: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000088_0003
Step 1: Synthesis of 4-nitrobenzyl 4-formylpiperidine-l-carboxylate.
Figure imgf000088_0004
[00282] Part i). By using the same reaction procedures as described in Step 5 of Example 1, 4- piperidinemethanol (2.07 g, 18 mmol) was converted to the PNZ carbamate, 5.2 g. ESI-MS m/z 295 (MH)+
[00283] Part ii). The product from Part i) (1.77 g, 6 mmol) was oxidized with PCC (2.59 g, 12 mmol) in DCM (60 mL) at rt for 5 h, diluted with diethyl ether, filtered through a Florisil column, the filtrate was concentrated to yield the crude aldehyde product, which was used directly for the next step without further purification. ESI-MS m/z 293 (MH)+. Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000089_0001
[00284] By using the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above aldehyde was converted to the target compound. ESI-MS m/z 410 (MH)+.
EXAMPLE 8: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(((R)-pyrrolidin-2- yl)methyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000089_0002
[00285] By using the same reaction procedures as described in above Example 7, except in Step 1 using (R)-prolinol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 396 (MH)+.
EXAMPLE 9: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(pyridin-4- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000089_0003
[00286] By using the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, 4- pyridinecarboxaldehyde was converted to the target compound. ESI-MS m/z 404 (MH)+.
EXAMPLE 10: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(pyridin-3- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000089_0004
[00287] By using the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, 3- pyridinecarboxaldehyde was converted to the target compound. ESI-MS m/z 404 (MH)+. EXAMPLE 11: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(2-(piperidin-4- yl)ethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000090_0001
[00288] By using the same reaction procedures as described in above Example 7, except in Step 1 using 4-piperidineethanol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 424 (MH)+.
EXAMPLE 12: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(piperidin-3- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000090_0002
[00289] By using the same reaction procedures as described in above Example 7, except in Step 1 using 3-piperidinemethanol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 410 (MH)+.
EXAMPLE 13: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(piperidin-2- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000090_0003
[00290] By using the same reaction procedures as described in above Example 7, except in Step 1 using 2-piperidinemethanol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 410 (MH)+.
EXAMPLE 14: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(((S)-pyrrolidin-2- yl)methyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000090_0004
[00291] By using the same reaction procedures as described in above Example 7, except in Step 1 using (S)-prolinol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 396 (MH)+. EXAMPLE 15: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((4-methylpiperidin-4- yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000091_0001
Step 1: Synthesis of (4-methylpiperidin-4-yl)methanol.
Figure imgf000091_0002
Boc H
[00292] l-Boc-4-(hydroxymethyl)-4-methylpiperidine (2.29 g, 10 mmol) in DCM (25 mL) was treated with TFA (25 mL) in ice-bath for 1 h, then concentrated in vacuo to yield the crude product as TFA salt, which was used directly for the next step without further purification.
Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((4-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000091_0003
[00293] By using the same reaction procedures as described in Example 7, the above product (4- methylpiperidin-4-yl)methanol was converted to the target compound. ESI-MS m/z 424 (MH)+.
EXAMPLE 16: (4R,5S,6S)-3-(((R)-l-((4-fluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000091_0004
Step 1: Synthesis of (4-fluoropiperidin-4-yl)methanol.
Figure imgf000091_0005
[00294] To ethyl N-Boc-4-fluoropiperidine-4-carboxylate (2.75 g, 10 mmol) in THF (100 mL) at - 30 °C under Argon was added LiAlH4 (760 mg, 20 mmol). The reaction mixture was stirred between - 30 - 0 °C for 2 h, quenched by careful addition of water, and 1 N HC1 to pH 3-4, extracted with EtOAc. The organic extracts were combined, washed with brine, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was treated with TFA (35 mL) in DCM (35 mL) in a similar manner as described in Step 1 of Example 15 to afford the crude product as TFA salt, which was used directly for the next step without further purification.
Step 2: Synthesis of (4R,5S,6S)-3-(((R)-l-((4-fluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000092_0001
[00295] By using the same reaction procedures as described in Example 7, the above product (4- fluoropiperidin-4-yl)methanol was converted to the target compound. ESI-MS m/z 428 (MH)+.
EXAMPLE 17: (4R,5S,6S)-3-(((R)-l-(((lr,4R)-4-(aminomethyl)cyclohexyl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000092_0002
[00296] By using the same reaction procedures as described in above Example 7, except in Step 1 using trans-4-[aminomethyl(cyclohexyl)]methanol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 438 (MH)+.
EXAMPLE 18: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((lr,4R)-4- ((methylamino)methyl)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
Figure imgf000092_0003
Step 1: Synthesis of ((lr,4r)-4-((methylamino)methyl)cyclohexyl)methanol.
Figure imgf000092_0004
[00297] Part i). To trans-4-[aminomethyl(cyclohexyl)]methanol (715 mg, 5 mmol) in DCM (30 mL) at 0 °C was added triethylamine (1.05 mL, 7.5 mmol) followed by methyl chloroformate (0.45 mL,
5.8 mmol). The reaction mixture was stirred in ice-bath for 45 min, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo to give the crude product.
[00298] Part ii). The product from Part i) was dissolved in THF (60 mL), added LiAlH4 (684 mg,
18 mmol). The reaction mixture was stirred at ~ 45 °C overnight, cooled in ice-bath, quenched with water (0.7 mL), 15% NaOH (0.7 mL), EtOAc (50 mL), and water (2 mL). The mixture was stirred at rt for 1 h, filtered through a pad of celite, the filtrate was concentrated, and dried in vacuo, yielding the crude product, which was used directly for the next step without further purification.
Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((lr,4R)-4- ((methylamino)methyl)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
Figure imgf000093_0001
[00299] By using the same reaction procedures as described in Example 7, the above product ((lR,4R)-4-((methylamino)methyl)cyclohexyl)methanol was converted to the target compound. ESI- MS m/z 452 (MH)+.
EXAMPLE 19: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(4- ((methylamino)methyl)benzyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
Figure imgf000093_0002
[00300] By using the same reaction procedures as described in Example 18, except in Step 1 using 4-aminomethylbenzyl alcohol instead of trans-4-[aminomethyl(cyclohexyl)]methanol as starting material, the target compound was prepared. ESI-MS m/z 446 (MH)+.
EXAMPLE 20: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(2-(piperazin-l- yl)ethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000093_0003
Step 1: Synthesis of 4-nitrobenzyl 4-(2-oxoethyl)piperazine-l-carboxylate.
Figure imgf000093_0004
[00301] Part i). By using the same reaction procedures as described in Step 5 of Example 1, 1- piperazineethanol (1.3 g, 10 mmol) was converted to the PNZ carbamate, 3.06 g. ESI-MS m/z 310 (MH)+.
[00302] Part ii). To oxalyl chloride (0.76 mL, 9 mmol) in DCM (20 mL) at -78 °C was added DMSO (1.28 mL, 18 mmol) under Argon. After 10 min, to the reaction mixture was added dropwise a solution of the product from Part i) (1.39 g, 4.5 mmol) in DCM (20 mL), and the reaction mixture was stirred for 1 h, then triethylamine (3.76 mL, 27 mmol) was added, the reaction was warmed to rt, quenched with water, extracted with DCM. The organic extracts were combined, washed with brine, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification. ESI-MS m/z 308 (MH)+
Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(2-(piperazin-l- yl)ethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000094_0001
[00303] By following the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above aldehyde was converted to the target compound. ESI-MS m/z 425 (MH)+.
EXAMPLE 21: Synthesis of(4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((lr,4R)-4- (methylamino)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
Figure imgf000094_0002
[00304] By using the same reaction procedures as described in Example 18, except in Step 1 using methyl trans-4-aminocyclohexane-carboxylate hydrochloride instead of trans-4- [aminomethyl(cyclohexyl)]methanol as starting material, the target compound was prepared. ESI-MS m/z 438 (MH)+.
EXAMPLE 22: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((ls,4S)-4- (methylamino)cyclohexyl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
Figure imgf000094_0003
[00305] By following the same reaction procedures as described in Example 18, except in Step 1 using methyl cis-4-aminocyclohexane-carboxylate hydrochloride instead of trans-4- [aminomethyl(cyclohexyl)]methanol as starting material, the target compound was prepared. ESI-MS m/z 438 (MH)+.
EXAMPLE 23: (4R,5S,6S)-3-(((R)-l-((lr,4R)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
Figure imgf000095_0001
EXAMPLE 24: (4R,5S,6S)-3-(((R)-l-((ls,4S)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
Figure imgf000095_0002
Step 1: Synthesis of 4-nitrobenzyl (4-oxocyclohexyl)carbamate.
Figure imgf000095_0003
[00306] Part i). By using the same reaction procedures as described in Step 5 of Example 1, 1,4- dioxaspiro[4.5]decan-8-amine hydrochloride (965 mg, 5 mmol) was converted to the PNZ carbamate, 1.66 g. ESI-MS m/z 337 (MH)+.
[00307] Part ii). The product from Part i) (1.66 g, 4.94 mmol) was dissolved in THF (60 mL), treated with 2 N HC1 (30 mL) at rt for overnight, extracted with DCM. The combined organic extracts were dried over Na2S04, concentrated in vacuo to yield the crude ketone product, which was used directly for the next step without further purification. ESI-MS m/z 293 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-3-(((R)-l-((ls,4S)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and (4R,5S,6S)-3-(((R)-l-((lr,4R)-4-aminocyclohexyl)pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4- methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
Figure imgf000095_0004
[00308] By using the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above ketone was converted to the target compounds, Example 23 and Example 24. ESI-MS m/z 410 (MH)+. EXAMPLE 25: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(l-(piperidin-4- yl)ethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000096_0001
[00309] By following the same reaction procedures as described in Example 1, except in Step 5 using l-(piperidin-4-yl)ethanone hydrochloride instead of 4-piperidinone hydrochloride hydrate as starting material, the target compound was prepared. ESI-MS m/z 424 (MH)+.
EXAMPLE 26: (4R,5S,6S)-3-(((R)-l-((l-(2-aminoethyl)piperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid,
Figure imgf000096_0002
[00310] By following the same reaction procedures as described in Example 20, except in Step 1 using (l-(2-aminoethyl)piperidin-4-yl)methanol instead of l-piperazineethanol as starting material, the target compound was prepared. ESI-MS m/z 453 (MH)+.
EXAMPLE 27: (4R,5S,6S)-3-(((R)-l-(l-(2-aminoethyl)piperidin-4-yl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000096_0003
[00311] By following the same reaction procedures as described in Example 20, except in Step 1 using l-(2-aminoethyl)piperidin-4-ol instead of 1 -piperazineethanol as starting material, the target compound was prepared. ESI-MS m/z 439 (MH)+.
EXAMPLE 28: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((2-methylpiperidin-4- yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000096_0004
Step 1: Synthesis of methyl 2-methylpiperidine-4-carboxylate.
Figure imgf000096_0005
[00312] Methyl 2 -chloro-6-methylisonicotinate (3.6g, 19.5 mmol) in TFA (60 mL) was hydrogenated in the presence of platinum oxide hydrate (660 mg) at 60 psi at rt for 3 days. The reaction mixture was filtered, and the filtrate was concentrated to give the product as TFA salt, which was used directly for the next step without further purification.
Step 2: Synthesis of l-(tert-butyl) 4-methyl 2-methylpiperidine-l,4-dicarboxylate.
Figure imgf000097_0001
[00313] The above product (19.5 mmol) was dissolved in DCM (200 mL), triethylamine was added, followed by di-tert-dicarbonate (6.54 g, 30 mmol). The reaction mixture was stirred at rt overnight, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane -EtO Ac, 50: 1-2: 1) to afford the pure product, 4.2 g.
Step 3: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((2-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000097_0002
[00314] By following the same reaction procedures as described in Example 16, the above product was converted to the target compound. ESI-MS m/z 424 (MH)+.
EXAMPLE 29: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((6- ((methylamino)methyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic acid.
Figure imgf000097_0003
Step 1: Synthesis of methyl 6-(bromomethyl)nicotinate.
Figure imgf000097_0004
[00315] Methyl 6-methylpyridine-3-carboxylate (3.02 g, 20 mmol) was reacted with N-bromo succinimide in the presence of AIBN (494 mg, 3 mmol) under Argon at reflux for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane -EtO Ac, 40: 1-3:2) to yield the bromide product, 2.29 g. ESI-MS m/z 230/232 (MH/MH+2)+. Step 2: Synthesis of (6-(bromomethyl)pyridin-3-yl)methanol.
Figure imgf000098_0001
[00316] To a solution of DIBAL (16 mL, 1.0 M in toluene, 16 mmol) in toluene (8 mL) was added dropwise a solution of the above product (1.38 g, 6 mmol) in toluene (15 mL) under Argon at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, quenched with 1 N HC1 to pH ~ 6-7, extracted with DCM. The organic extracts were combined, dried over Na2S04, concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (hexane -EtO Ac, 2: 1-0: 100) to afford the alcohol product, which was immediately used for the next step. ESI-MS m/z 202/204 (MH/MH+2)+. Step 3: Synthesis of (6-((methylamino)methyl)pyridin-3-yl)methanol.
Figure imgf000098_0002
[00317] The above product was immediately treated with methylamine (30 mL, 2.0 M in THF, 60 mmol) dissolved in DCM (200 mL) in the presence of NaHC03 (504 mg, 6 mmol) at rt overnight, then concentrated in vacuo to give the crude amine product, which was used directly for the next step without further purification. ESI-MS m/z 153 (MH)+.
Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((6- ((methylamino)methyl)pyridin-3-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic acid.
Figure imgf000098_0003
[00318] By following the same reaction procedures as described in Example 20, the above product was converted to the target compound. ESI-MS m/z 447 (MH)+.
EXAMPLE 30: (4R,5S,6S)-3-(((3R)-l-((2-(aminomethyl)piperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000098_0004
[00319] By following the same reaction procedures as described in Example 28, except in Step 1 using methyl 2-cyanoisonicotinate instead of methyl 2-chloro-6-methylisonicotinate as starting material, the target compound was prepared. ESI-MS m/z 439 (MH)+. EXAMPLE 31: (4R,5S,6S)-3-(((R)-l-(3,4-bis(aminomethyl)benzyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
Figure imgf000099_0001
Step 1: Synthesis of (3,4-bis(azidomethyl)phenyl)methanol.
Figure imgf000099_0002
[00320] Part i). By using the same reaction procedures as described in step 2 of Example 29, methyl 3,4-bis(bromomethyl)benzoate (1.94 g, 6 mmol) was converted to the crude alcohol, which was directly used for the next step without further purification. ESI-MS m/z 292/294 (MH/MH+2)+.
[00321] Part ii). The product from Part i) (6 mmol) was dissolved in DMF (60 mL), and treated with sodium azide (1.18 g, 18 mmol) at rt overnight, quenched with water, extracted with EtOAc- Et20 (1: 1). The organic extracts were combined, washed with water, brine, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane - EtOAc, 4: 1-1: 1) to afford the azide product, 1.3 g. ESI-MS m/z 219 (MH)+.
Step 2: Synthesis of (3,4-bis(aminomethyl)phenyl)methanol.
Figure imgf000099_0003
[00322] The above azide (1.3 g, 5.96 mmol) was dissolved in methanol (100 mL), and hydrogenated in the presence of 10% Pd/C (400 mg) at rt overnight, filtered through a pad of celite, and the filtrate was concentrated in vacuo to give the product, 990 mg. ESI-MS m/z 167 (MH)+.
Step 3: Synthesis of (4R,5S,6S)-3-(((R)-l-(3,4-bis(aminomethyl)benzyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000099_0004
[00323] By following the same reaction procedures as described in Example 7, the above product
(3,4-bis(aminomethyl)phenyl)methanol was converted to the target compound. ESI-MS m/z 461 (MH)+. EXAMPLE 32: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((l- (methylsulfonyl)piperazin-2-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
Figure imgf000100_0001
Step 1: Synthesis of tert-butyl 3-(hydroxymethyl)-4-(methylsulfonyl)piperazine-l-carboxylate.
Figure imgf000100_0002
[00324] Part i). To N-4-Boc-piperazine-2 -carboxylic acid methyl ester hydrochloride (4.2 g, 15 mmol) in DCM (200 mL) was added triethylamine (5.29 mL, 38 mmol), followed by methanesulfonyl chloride (1.38 mL, 18 mmol). The reaction mixture was stirred at rt for 18 h, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo to give the product.
[00325] Part ii). To the product from Part i) (15 mmol) in DCM (100 mL) at 0 °C under Argon was added dropwise DIBAL (45 mL, 1.0 M in DCM, 45 mmol). After 3 h, the reaction mixture was quenched with 2 N NaOH (50 mL), stirred for 30 min. The organic layer was separated, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane -EtO Ac, 4: 1-0: 100) to afford the product, 2.53 g.
Step 2: Synthesis of 4-nitrobenzyl 3-(hydroxymethyl)-4-(methylsulfonyl)piperazine-l- carboxylate.
Figure imgf000100_0003
[00326] Part i). To a solution of the product from Step 1 (2.5 g, 8.5 mmol) in DCM (25 mL) and methanol (50 mL) was added 4.0 M HC1 in dioxane (50 mL). The reaction mixture was stirred at rt for 2 h, then concentrated to give the crude product.
[00327] Part ii). By using the same reaction procedures as described in Step 5 of Example 1, this crude product was converted to the PNZ carbamate, 2.9 g. ESI-MS m/z 374 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl 3-formyl-4-(methylsulfonyl)piperazine-l-carboxylate.
Figure imgf000100_0004
[00328] To a solution of the product from Step 2 (1.38 g, 3.7 mmol) in DCM (90 mL) was added NaHC03 (960 mg, 11.4 mmol) followed by Dess-Martin periodinane (1.8 g, 4.26 mmol). The reaction mixture was stirred at rt for 1 h, quenched with saturated aqueous NaHC03 and saturated aqueous Na2S203, stirred for 30 min. The organic layer was separated, and the aqueous was extracted with DCM. The organic extracts were combined, dried over Na2S04, concentrated in vacuo to yield the aldehyde, which was used directly for the next step without further purification. ESI-MS m/z 372 (MH)+;
Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-((l- (methylsulfonyl)piperazin-2-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2- ene-2-carboxylic acid.
Figure imgf000101_0001
[00329] By using the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above aldehyde was converted to the target compound. ESI-MS m/z 489 (MH)+.
EXAMPLE 33: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-methyl-l-(piperidin-4- ylmethyl)pyrrolidin-l-ium-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Figure imgf000101_0002
Step 1: Synthesis of (3R)-3-(((4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-2-(((4- nitrobenzyl)oxy)carbonyl)-7-oxo-l-azabicyclo[3.2.0]hept-2-en-3-yl)thio)-l-methyl-l-((l-(((4- nitrobenzyl)oxy)carbonyl)piperidin-4-yl)methyl)pyrrolidin-l-ium iodide.
Figure imgf000101_0003
[00330] 4-Nitrobenzyl (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l-(((4- nitrobenzyl)oxy)carbonyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate (362 mg, 0.5 mmol), which was prepared as an intermediate for the synthesis of Example 7, was dissolved in acetone (5 mL) was allowed to react with excess methyl iodide (0.5 mL, 8 mmol) at rt for 19 h, then concentrated in vacuo to afford the quaternary ammonium salt, which was used directly for the next step without further purification. Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((3R)-l-methyl-l-(piperidin- 4-ylmethyl)pyrrolidin-l-ium-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Figure imgf000102_0001
COOPNB coo-
[00331] By using the same reaction procedures as described in Step 8 of Example 1, the above crude product was hydrogenated in the presence of 5% Pt/C to yield the target compound. ESI-MS m/z 424 (MH)+.
EXAMPLE 34: (4R,5S,6S)-3-(((3R)-l-(4-(l,2-diaminoethyl)benzyl)pyrrolidin-3-yl)thio)-6-((R)- l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000102_0002
Step 1: Synthesis of methyl 4-(amino(cyano)methyl)benzoate.
Figure imgf000102_0003
[00332] To a solution of methyl 4-formylbenzoate (3.28 g, 20 mmol) in THE (80 mL) was added LiHMDS (24 mL, 1.0 M in THE, 24 mmol) at -40 °C under Argon. The reaction mixture was stirred between -40 °C - rt for 4 h, then added acetone cyanohydrins (3.66 mL, 40 mmol). The reaction mixture was stirred at rt overnight, quenched with saturated aqueous NaHC03, extracted with EtOAc. The organic extracts were combined, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane -EtOAc, 2: 1-1:4) to afford the product, 2.5 g. ESI-MS m/z 191 (MH)+.
Step 2: Synthesis of (4-(l,2-diaminoethyl)phenyl)methanol.
Figure imgf000102_0004
[00333] To a solution of the above cyanohydrin product (1.9 g, 10 mmol) in DCM (12 mL) at - 10 °C under Argon was added dropwise DIBAL (70 mL, 1.0 M in DCM, 70 mmol). The reaction mixture was stirred between -10 - 0 °C for 3 h, quenched with 2 N NaOH (70 mL), more DCM (60 mL) was added. The resulting mixture was stirred at rt for 1 h, filtered, the filtrate was evaporated to remove DCM, yielding the crude product as an aqueous solution, which was used directly for the next step without further purification. ESI-MS m/z 167 (MH)+.
Step 3: Synthesis of (4R,5S,6S)-3-(((3R)-l-(4-(l,2-diaminoethyl)benzyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000103_0001
[00334] By following the same reaction procedures as described in Example 7, the above product (4-(l,2-diaminoethyl)phenyl)methanol was converted to the target compound. ESI-MS m/z 461 (MH)+.
EXAMPLE 35: (4R,5S,6S)-3-(((R)-l-((l-carbamimidoylpiperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000103_0002
Step 1: Synthesis of tert-butyl (((tert-butoxycarbonyl)imino)(4-formylpiperidin-l- yl)methyl)carbamate.
Figure imgf000103_0003
[00335] Part i). To a solution of 4-piperidinemethanol (2.07 g, 18 mmol) in DCM (150 mL) was added l,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (5.81 g, 20 mmol), thiethylamine (7.5 mL, 54 mmol), and HgCl2 (5.43 g, 20 mmol). The reaction mixture was stirred at rt overnight, filtered, the filtrate was washed with saturated aqueous NH4Cl, water and brine, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane- EtOAc, 10: 1-2: 1) to afford the product, 6.4 g.
Part ii). By using the same reaction procedures as described in Step 3 of Example 32, this alcohol was converted to the corresponding crude aldehyde, which was used directly for the next step without further purification.
Step 2: Synthesis of 4-nitrobenzyl (4R,5S,6S)-3-(((R)-l-((l-(N,N'-bis(tert- butoxycarbonyl)carbamimidoyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Figure imgf000104_0001
[00336] By following the same reaction procedures as described in Steps 6 and 7 of Example 1, the above aldehyde was converted to the target compound. ESI-MS m/z 787 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl (4R,5S,6S)-3-(((R)-l-((l-carbamimidoylpiperidin-4- yl)methyl)pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-
2-ene-2-carboxylate.
Figure imgf000104_0002
[00337] To a solution of the above product (472 mg, 0.6 mmol) in DCM (12 mL) was added triethylamine (1.0 mL, 7.2 mmol), followed by trimethylsilyl trifluoromethanesulfonate (0.66 mL, 3. 6 mmol) at 0 °C under Argon. After 5 min, the reaction mixture was allowed to warm to rt, and stirred for 39 h, quenched with methanol (2 mL) and phosphate buffer solution (pH 7), extracted with DCM. The organic extracts were combined, washed with brine, dried over Na2S04, concentrated in vacuo. The residue was then dissolved in THF (20 mL). To this solution at 0 °C was added water (5 mL), followed by a few drops of 1 N HC1 to adjust the pH to ~ 2. After 10 min, it was quenched with saturated aqueous NaHC03, extracted with EtOAc, and DCM. The organic extracts were combined, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification. ESI-MS m/z 587 (MH)+.
Step 4: Synthesis of (4R,5S,6S)-3-(((R)-l-((l-carbamimidoylpiperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000104_0003
[00338] By following the same reaction procedures as described in Step 8 of Example 1, the above crude product was hydrogenated in the presence of 5% Pt/C to yield the target compound, 45 mg. ESI-MS m/z 452 (MH)+.
EXAMPLE 36: (4R,5S,6S)-3-(((R)-l-(3-aminopropyl)pyrrolidin-3-yl)thio)-6-((R)-l- hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid.
Figure imgf000104_0004
[00339] By using the same reaction procedures as described in Step 5 of Example 1, 3-amino-l- propanol was converted to the corresponding PNZ carbamate, which was furtuer converted to target compound by following the same reaction procedures as described in Steps 3 and 4 of Example 32. ESI-MS m/z 370 (MH)+.
EXAMPLE 37: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(4-
(methylamino)butyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000105_0001
Step 1: Synthesis of ((4,4-diethoxy-N-methylbutan-l-amine.
i) CICOOMe;
Figure imgf000105_0002
[00340] By following the same reaction procedures as described in Step 1 of Example 18, 4,4- diethoxybutylamine (2.42 g, 15 mmol) was converted to the crude target compound, which was used directly for the next step without further purification..
Step 2: Synthesis of 4-nitrobenzyl methyl(4-oxobutyl)carbamate.
i) PNZCI;
Figure imgf000105_0003
[00341] Part i). By using the same reaction procedures as described in Step 5 of Example 1, the above crude product was converted to the PNZ carbamate, 4 g. ESI-MS m/z 355 (MH)+.
[00342] Part ii). The product from Part i) (2.62 g, 7.4 mmol) was dissolved in l,4-dioxane (30 mL), treated with 6 N HC1 (30 mL) at rt for 1 h, diluted with water, extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification. ESI-MS m/z 281 (MH)+.
Step 3: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(4- (methylamino)butyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000105_0004
[00343] By fiollowing the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, the above aldehyde was converted to the target compound. ESI-MS m/z 398 (MH)+. EXAMPLE 38: (4R,5S,6S)-3-(((R)-l-(4-amino-4-(aminomethyl)cyclohexyl)pyrrolidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000106_0001
Step 1: Synthesis of 8-amino-l,4-dioxaspiro[4.5]decane-8-carbonitrile.
Figure imgf000106_0004
[00344] To l,4-cyclohexandione monoethylene ketal (3.12 g, 20 mmol) in THF (40 mL) at -5 °C was added ammonia (7 N in MeOH, 11.5 mL, 80.5 mmol). The reaction mixture was stirred between - 5 - 10 °C for 1.5 h, then acetone cyanohydrins (3.66 mL, 40 mmol) was added. The reaction mixture was stirred at rt overnight, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane-EtOAc, 4: 1-0: 100) to afford the product, 1.6 g.
Step 2: Synthesis of 4-nitrobenzyl ((8-amino- 1,4-dioxaspiro [4.5] decan-8-yl)methyl)carbam ate.
Figure imgf000106_0002
[00345] Part i). By following the same reaction procedures as described in Step 2 of Example 34, the above product (1.6 g, 8.8 mmol) was reduced with DIBAL to give the crude diamine.
[00346] Part ii). By using the same reaction procedures as described in Step 5 of Example 1, the crude diamine was reacted with 4-nitrobenzyl chloroformate to afford the mono-PNZ carbamate product, 2.5 g. ESI-MS m/z 366 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl (l-(((((4-nitrobenzyl)oxy)carbonyl)amino)methyl)-4- oxocyclohexyl)carbamate.
Figure imgf000106_0003
[00347] Part i). To a DCM (40 mL) solution of the above product (730 mg, 2 mmol) was added diisopropylethylamine (0.53 mL, 3 mmol) followed by 4-nitrobenzyl chloroformate (648 mg, 3 mmol) and DMAP (49 mg, 0.4 mmol). The reaction mixture was stirred at rt for 3 h, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane-EtOAc, 2: 1-1:6) to afford the product, 1.08 g. ESI-MS m/z 545 (MH)+. [00348] Part ii). The product from Part i) was dissolved in THF (40 mL), treated with 2 N HC1 (20 mL) at rt overnight. The reaction mixture was extracted with DCM. The organic extracts were combined, dried over Na2S04, concentrated in vacuo to afford the ketone, which was used directly for the next step without further purification. ESI-MS m/z 501 (MH)+.
Step 4: Synthesis of(4R,5S,6S)-3-(((R)-l-(4-amino-4-(aminomethyl)cyclohexyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000107_0001
[00349] By using the same reaction procedures as described in step 6, 7 and 8 of Example 1, the above ketone was converted to the target compound. ESI-MS m/z 439 (MH)+.
EXAMPLE 39: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l-methyl piperidin-4-yl) methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000107_0002
Step 1: Synthesis of tert-butyl (R)-4-((3-mercaptopyrrolidin-l-yl)methyl)piperidine-l- carboxylate.
Figure imgf000107_0003
[00350] To a solution of tert-butyl 4-formylpiperidine-l-carboxylate (3.0 g, 14.1 mmol), (R)- pyrrolidine-3-thiol (crude, 14.1 mmol) in l,2-dichloroethane (30 mL) was added sodium
triacetoxyborohydride (5.98 g, 28.2 mmol). The reaction mixture was stirred at rt overnight, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (DCM-MeOH, 30: 1-10: 1) to afford the pure product, 3.2 g. ESI-MS m/z 301 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-3-(((R)-l-((l-(tert-butoxycarbonyl)piperidin-4-yl)methyl) pyrrolidin-3-yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic 4-nitrobenzoic anhydride.
Figure imgf000107_0004
[00351] To the above product (2 g, 6.56 mmol), and 4-nitrobenzyl (4R,5R,6S)-3-((diphenoxy phosphoryl)oxy)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (2.6 g, 4.37 mmol) was add dry acetonitrile (50 mL) under Argon at 0°C, followed by diisopropylethylamine (1.08 g, 8.74 mmol). The reaction mixture was stirred in ice-water bath for 12 h, then concentrated. The residue was purified twice by flash chromatography on silica gel
(EtOAc/MeOH=, 100: 1-10: 1) to yield the product, 3 g. ESI-MS m/z 645 (MH)+.
Step 3: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic 4-nitrobenzoic anhydride.
Figure imgf000108_0001
[00352] To a solution of the above product (3 g, 4.65 mmol) in DCM (100 mL) was added triethylamine (7.5 mL, 55.8 mmol), followed by trimethylsilyl trifluoromethane sulfonate (5.1 mL, 27.9 mmol) at 0 °C under Argon. After 5 min, the reaction mixture was allowed to warm to rt, and stirred for 19 h, quenched with methanol (4 mL) and phosphate buffer solution (pH 7), extracted with DCM. The organic extracts were combined, washed with brine, dried over Na2S04, concentrated in vacuo. The residue was then dissolved in THE (80 mL). To this solution at 0 °C was added water (20 mL), followed by a few drops of 1 N HCI to adjust to pH ~ 2. After 10 min, it was quenched with saturated aqueous NaHC03, extracted with EtOAc, and DCM. The organic extracts were combined, dried over Na2S04, concentrated in vacuo, yielding the crude product, which was used directly for the next step without further purification. ESI-MS m/z 545 (MH)+.
Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic 4- nitrobenzoic anhydride
Figure imgf000108_0002
[00353] To a solution of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2 -carboxylic 4-nitrobenzoic anhydride (1.0 g, 1.83 mmol), HCHO (148 mg, 2.0 mmol, 37% aqueous solution) was added sodium
triacetoxyborohydride (780 mg, 3.6 mmol). The reaction mixture was stirred at rt overnight, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on MCI-GEL (H20-THL, 100: 1-2: 1) to afford the pure product,
140 mg. ESI-MS m/z 559 (MH)+. Step 5: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l-methylpiperidin- 4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000109_0001
[00354] By following the same reaction procedures as described in Step 8 of Example 1, the above crude product was hydrogenated in the presence of 5% Pt/C to yield the target compound, 25 mg. ESI-MS m/z 424 (MH)+.
EXAMPLE 40: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-3-(((R)-l-((l-(2-hydroxyethyl) piperidin-4- yl)methyl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000109_0002
Step 1: Synthesis of tert-butyl (R)-4-((3-(acetylthio)pyrrolidin-l-yl)methyl)piperidine-l- carboxylate.
Figure imgf000109_0004
[00355] To a solution oftert-butyl 4-formylpiperidine-l-carboxylate (3.0 g, 14.1 mmol), (R)-S- (pyrrolidin-3-yl) ethanethioate hydrochloride (crude, 14.1 mmol) in 1 ,2-dichloroethane (30 mL) was added sodium triacetoxyborohydride (5.98 g, 28.2 mmol). The reaction mixture was stirred at rt overnight, washed with saturated aqueous NaHC03, dried over Na2S04, concentrated in vacuo. The residue was purified twice by flash chromatography on silica gel (DCM-MeOH, 30: 1-10: 1) to afford the pure product, 3.5 g. ESI-MS m/z 343 (MH)+.
Step 2: Synthesis of (R)-S-(l-(piperidin-4-ylmethyl)pyrrolidin-3-yl) ethanethioate
hydrochloride.
Figure imgf000109_0003
[00356] The above crude product was dissolved in dioxane saturated with HCl(g) (35 mL) at 0 °C, and was stirred for 1 h at rt, and then concentrated in vacuo to give the crude product as a HC1 salt, which was used directly for the next step without further purification. Step 3: Synthesis of (R)-S-(l-((l-(2-hydroxyethyl)piperidin-4-yl)methyl)pyrrolidin-3-yl) ethanethioate
Figure imgf000110_0001
[00357] To a solution of the above product (3 g, 10.7 mmol) in MeCN (60 mL) was added K2C03 (2.95 g, 21.4 mmol), followed by 2-bromoethan-l-ol (2.67 g, 21.4 mmol) at rt. The reaction mixture was allowed to warm to 80 °C, and stirred for 12 h, filtered through a pad of celite. The filtrate was concentrated under vacuum to give a yellow oil, 2.1 g, which was used directly for the next step without further purification. ESI-MS m/z 287 (MH)+.
Step 4: Synthesis of (R)-2-(4-((3-mercaptopyrrolidin-l-yl)methyl)piperidin-l-yl)ethan-l-ol
Figure imgf000110_0002
[00358] To a solution of the above product (2.1 g, 7.32 mmol) in methanol (60 mL) was added potassium carbonate (2.0 g, 14.63 mmol). The reaction mixture was stirred at 50 °C under Argon for 2 h, then cooled in ice -bath, acidified with 1 N HC1 to pH 4-5, extracted with EtOAc. The aqueous phase was lyophilized to afford the crude product, 1.6 g. ESI-MS m/z 245 (MH)+.
Step 5: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-3-(((R)-l-((l-(2-hydroxyethyl)piperidin-
4-yl)methyl)pyrrolidin-3-yl)thio)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000110_0003
[00359] By following the same reaction procedures as described in Steps 7 and 8 of Example 1, the above product was converted to the target compound. ESI-MS m/z 454 (MH)+.
EXAMPLE 41: (4R,5S,6S)-3-(((R)-l-((l-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)pyrrolidin-
3-yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000110_0004
[00360] By following the same reaction procedures as described in Steps 3, 4 and 5 of Example 40, utilizing 2-bromoacetamide in place of 2-bromoethan-l-ol in Step 2, the target compound was prepared. ESI-MS m/z 467 (MH)+. EXAMPLE 42: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-4- ylmethyl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000111_0001
Step 1: Synthesis of S-(azetidin-3-yl) ethanethioate
Figure imgf000111_0002
[00361] By following the same reaction procedures as described in Steps 1, 2 and 4 of Example 1, tert-butyl 3-hydroxyazetidine-l-carboxylate was converted to S-(azetidin-3-yl) ethanethioate, 10 g. ESI-MS m/z 132 (MH)+.
Step 2: Synthesis of 4-nitrobenzyl 4-formylpiperidine-l-carboxylate
Figure imgf000111_0003
[00362] By following the same reaction procedures as described in Steps 1 of Example 7, 4- piperidinemethanol was converted to the crude aldehyde product, 5 g. ESI-MS m/z 293 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl 4-((3-(acetylthio)azetidin-l-yl)methyl)piperidine-l- carboxylate
Figure imgf000111_0004
[00363] By following the same reaction procedures as described in Step 1 of Example 40, 4- nitrobenzyl 4-formylpiperidine-l-carboxylate (intermediate from Step 1 of Example 7) was reacted with the above product in the presence of sodium triacetoxyborohydride to yield the title compound. ESI-MS m/z 408 (MH)+.
Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-4- ylmethyl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000111_0005
[00364] By following the same reaction procedures as described in Steps 4 and 5 of Example 40, the above product was converted to the target compound. ESI-MS m/z 396 (MH)+.
EXAMPLE 43: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l- (piperidin-4-ylmethyl)piperidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000112_0001
Step 1: Synthesis of tert-butyl (R)-3-((methylsulfonyl)oxy)piperidine-l-carboxylate.
Figure imgf000112_0002
[00365] A mixture oftert-butyl (R)-3-hydroxypiperidine-l-carboxylate (5.15 g, 25 mmol) and Et3N (7.6 g, 77 mmol) in DCM (50 mL) was stirred at 0 °C, MsCl (5.8 g, 52 mmol) was added to solution in dropwise, keep stirred for 3 h. The solvent was washed by saturated aqueous NaHC03 (50 mL 2) then brine (50 mL), dried over Na2S04, purified by flash chromatography on silica gel (DCM: 100%) to afford product as yellow solid, 3.06 g. ESI-MS m/z 280 (MH)+.
Step 2: Synthesis of tert-butyl (R)-3-(acetylthio)piperidine-l-carboxylate.
Figure imgf000112_0003
[00366] A mixture oftert-butyl (R)-3-((methylsulfonyl)oxy)piperidine-l-carboxylate (3 g, 10.7 mmol) and KSAc (3.1 g, 26.8 mmol) was in DMF (30 mL) protected with N2. Warmed the solution to 100-105 °C for 4 h. Cooled the solution to r.t.. Saturated aqueous NaHC03 (200 mL) was added to solution, extracted by DCM (100 mL 2). dired over Na2S04, purified by flash chromatography on silica gel (PE/EA=90/l0) to afford product as brown oil, 900 mg. ESI-MS m/z 260 (MH)+.
Setp 3: Synthesis of (R)-S-(piperidin-3-yl) ethanethioate hydrochloride
Figure imgf000112_0004
[00367] To a mixture oftert-butyl (R)-3-(acetylthio)piperidine-l-carboxylate (900 mg, 3.4 mmol) in DCM (5 mL) at 0 °C was added HCl-EtOH (5 mL, 33%) dropwise, the reaction mixture was stirred for 10 min then warmed to r.t. for 1 h. The solvent was concentrated in vacuo at 40-50 °C, H20 (15 mL) was added to the residue, extracted with EtOAc (15 mL 2). The aqueous phase was lyophilized to yield the product as yellow oil. ESI-MS m/z 160 (MH)+.
Setp 4: Synthesis of 4-nitrobenzyl (R)-4-((3-mercaptopiperidin-l-yl)methyl)piperidine-l- carboxylate.
Figure imgf000112_0005
Ill [00368] To a solution of the above product (460 mg, 2.35 mmol) and 4-nitrobenzyl 4- formylpiperidine-l-carboxylate (intermediate from Step 1 of Example 7, 678 mg, 2.35 mmol) in DCE (10 mL) at r.t. was added Na(OAc)3BH (747.2 mg, 3.52 mmol) in portions. The reaction was stirred at rt overnight, then quenched with saturated aqueous NaHC03 (50 mL) the organic layer was separated, dried, concentrated, and the residue purified by preparative TLC (DCM/MeOH=l2/l) to afford product as colourless oil 264 mg. ESI-MS m/z 436 (MH)+.
Setp 5: Synthesis of 4-nitrobenzyl (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l-(((4- nitrobenzyl)oxy)carbonyl)piperidin-4-yl)methyl)piperidin-3-yl)thio)-7-oxo-l- azabicyclo [3.2.0] hept-2-ene-2-carboxylate.
Figure imgf000113_0001
[00369] To a mixture of the above product (240 mg, 0.6 mmol) and 4-nitrobenzyl (4R,5R,6S)-3- ((diphenoxyphosphoryl)oxy)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- 2-carboxylate (398 mg, 0.67 mmol) was in MeCN (20 mL) under nitrogen atmosphere was added DIPEA (102 mg, 0.79 mmol) the reaction mixture was stirred at 0 °C for 24 h, concentrated, purified by preparative TLC (DCM/MeOH=lO/l) to afford the title compound as yellow solid 190 mg. ESI- MS m/z 738 (MH)+.
Setp 6: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(piperidin-4- ylmethyl)piperidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000113_0002
[00370] By following the same reaction procedures as described in Step 8 of Example 1, the target compound was prepared. ESI-MS m/z 424 (MH)+.
EXAMPLE 44: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-4- ylmethyl)piperidin-4-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000113_0003
Step 1: Synthesis of A'-(piperidin-4-yl) ethanethioate
Figure imgf000113_0004
H
Boc TFA [00371] By following the same reaction procedures as described in Steps 1, 2 and 4 of Example 1, tert-butyl 4-hydroxypiperidine-l-carboxylate was converted to S-(piperidin-4-yl) ethanethioate as a TFA salt, 8 g. ESI-MS m/z 160 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-4- ylmethyl)piperidin-4-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000114_0001
[00372] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, using S-(piperidin-4-yl) ethanethioate in place of S-(azetidin-3-yl) ethanethioate as starting material, the target compound was prepared. ESI-MS m/z 424 (MH)+.
EXAMPLE 45: (4R,5S,6S)-3-(((3R)-l-((3-fluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000114_0002
Step 1: Synthesis of tert-butyl 3-fluoro-4-(hydroxymethyl)piperidine-l-carboxylate
Figure imgf000114_0003
Boc Boc
[00373] To a solution of l-(tert-butoxycarbonyl)-3-fluoropiperidine-4-carboxylic acid (1.95 g, 7.89 mmol) in THF (50 mL) was added BH3.THF (15.7 mL, 23.67 mmol). The reaction mixture was stirred at rt for 5 h. The resulting mixture was quenched by NaHC03 (aq), extracted with EtOAc, dried over Na2S04, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to afford a white solid, 1.7 g. ESI-MS m/z 234 (MH)+.
Step 2: Synthesis of (3-fluoropiperidin-4-yl)methanol hydrochloride
Figure imgf000114_0004
[00374] The above crude product was dissolved in dioxane saturated with HC1 (g) (35 mL) at 0 °C, and was stirred for 2 h at rt, and then concentrated in vacuo to give the crude product as a HC1 salt, which was used directly for the next step without further purification. Step 3: Synthesis of(4R,5S,6S)-3-(((3R)-l-((3-fluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000115_0001
[00375] By following the same reaction procedures as described in Steps 1 and 2 of Example 7, (3- fluoropiperidin-4-yl)methanol hydrochloride was converted to the target compound. ESI-MS m/z 428 (MH)+.
EXAMPLE 46: (4R,5S,6S)-3-(((3R)-l-((3,3-difluoropiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000115_0002
Step 1: Synthesis of (R)-pyrrolidine-3-thiol.
Figure imgf000115_0003
[00376] To a mixture oftert-butyl (R)-3-mercaptopyrrolidine-l-carboxylate (intermediate from Step 3 of Example 1, 2 g, 9.8 mmol) in DCM (20 mL) at 0 °C was added EtOH/HCl (1.25 M, 20 mL) dropwise. The reaction mixture was warmed to rt, stirred for 1 h, then concentrated in vacuo. Water (20 mL) was added to the residue, and the mixture was extracted with EtOAc (20 mL 2). then the aqueous was lyophilized to afford product as brown oil.
Step 2: Synthesis of 4-nitrobenzyl 3,3-difluoro-4-formylpiperidine-l-carboxylate.
Figure imgf000115_0004
[00377] By using the same reaction procedures as described in Step 1 of Example 7, the target compound was prepared from (3,3-difluoropiperidin-4-yl)methanol. ESI-MS m/z 329 (MH)+. Step 3: Synthesis of 4-nitrobenzyl 3,3-difluoro-4-(((R)-3-mercaptopyrrolidin-l- yl)methyl)piperidine-l-carboxylate.
Figure imgf000116_0001
[00378] By using the same reaction procedures as described in Step 6 of Example 1 using 4- nitrobenzyl 3,3-difluoro-4-formylpiperidine-l-carboxylate in place of 4-nitrobenzyl 4-oxopiperidine- l-carboxylate as starting material, the target compound was prepared. ESI-MS m/z 416 (MH)+.
Step 5: Synthesis of (4R,5S,6S)-3-(((3R)-l-((3,3-difluoropiperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000116_0002
[00379] By using the same reaction procedures as described in Step 5 and Step 6 of Example 43, the above product was converted to the target compound. ESI-MS m/z 446 (MH)+.
EXAMPLE 47: (4R,5S,6S)-3-(((R)-l-((l-glycylpiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000116_0003
Step 1: Synthesis of (((4-nitrobenzyl)oxy)carbonyl)glycine.
Figure imgf000116_0004
O2
[00380] To a solution of glycine (3 g, 40 mmol) in NaOH (aq, 2 mol/L, 20 mL) was added simultaneously from two dropping funnels under stirring NaOH (4 M in water, 10 mL) and a solution of 4-nitrobenzyl carbonochloridate (10.32 g, 48 mmol) in toluene over 10 min. The reaction mixture was stirred for 3 hrs at rt. The resulting mixture was extracted with EtOAc. The aqueous phase was acidified to pH 1 with HC1 (4 M in water), extracted with DCM. The organic layer was dried over Na2S04, evaporated under vacuum to afford a colorless oil, 8.6 g. ESI-MS m/z 253 (M-H). Step 2: Synthesis of 4-nitrobenzyl (2-(4-(hydroxymethyl)piperidin-l-yl)-2-oxoethyl)carbamate
Figure imgf000117_0001
[00381] To a solution of the above product in DCM (250 mL) was added HATU (12.8 g, 33.8 mmol) and DIPEA (13.1 g, 101.5 mmol), followed by piperidin-4-ylmethanol (3.88 g, 33.8 mmol). The reaction mixture was stirred at rt for 8 h. The resulting mixture was diluted with DCM, washed with water, dried over Na2S04, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to afford a yellow oil, 10 g. ESI-MS m/z 352 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl (2-(4-formylpiperidin-l-yl)-2-oxoethyl)carbamate
Figure imgf000117_0002
[00382] By following the same reaction procedures as described in Step 1 , Part (ii) of Example 7, the above alcohol was converted to the crude aldehyde product, 5 g. ESI-MS m/z 350 (MH)+.
Step 4: Synthesis of (4R,5S,6S)-3-(((R)-l-((l-glycylpiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000117_0003
[00383] By following the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, 4-nitrobenzyl (2-(4-(hydroxymethyl)piperidin-l-yl)-2-oxoethyl)carbamate was converted to the target compound. ESI-MS m/z 467 (MH)+.
EXAMPLE 48: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-((l- (methylglycyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
Figure imgf000117_0004
[00384] By following the same reaction procedures as described in Example 47, utilizing methylglycine instead of glycine as starting material, the target compound was prepared. ESI-MS m/z 481 (MH)+.
EXAMPLE 49: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((S)-morpholin-2- yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000118_0001
Step 1: Synthesis of 4-nitrobenzyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate
Figure imgf000118_0002
[00385] By using the same reaction procedures as described in Step 5 of Example 1, (S)-morpholin- 2-ylmethanol (700 mg, 4.56 mmol) was converted to the PNZ carbamate, 1.2 g. ESI-MS m/z 297 (MH)+.
Step 2: Synthesis of 4-nitrobenzyl (S)-2-formylmorpholine-4-carboxylate
Figure imgf000118_0003
[00386] To a solution of 4-nitrobenzyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate (1.0 g, 3.37 mmol) in DCM (30 mL) was added Dess-Martin reagent (2.86 g, 6.75 mmol). The reaction mixture was stirred at rt for 5 h. The resulting mixture was quenched by NaHC03 (aq), extracted with DCM, dried over Na2S04, and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (EA/PE=l: 10-1: 1) to afford a yellow solid, 850 mg. ESI-MS m/z 295 (MH)+.
Step 3: Synthesis of (S)-S-(pyrrolidin-3-yl) ethanethioate
Figure imgf000118_0004
Boc TFA
[00387] By following the same reaction procedures as described in Steps 1, 2 and 4 of Example 1, (S)-Boc-3-pyrrolidinol was converted to (S)-S-(pyrrolidin-3-yl) ethanethioate, 7.5 g. ESI-MS m/z 146 (MH)+. Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((S)-morpholin-2- yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
’■Q
Figure imgf000119_0004
[00388] By using the same reaction procedures as described in Step 2 and 3 of Example 42, 4- nitrobenzyl (S)-2-formylmorpholine-4-carboxylate and (S)-S-(pyrrolidin-3-yl) ethanethioate were converted to the target compound, ESI-MS m/z 412 (MH)+.
EXAMPLE 50: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-(((R)-l-(((R)-morpholin-2- yl)methyl)pyrrolidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000119_0001
[00389] By following the same reaction procedures as described in Example 49, utilizing (R)- morpholin-2-ylmethanol in place of (S)-morpholin-2-ylmethanol as starting material, the target compound was prepared. ESI-MS m/z 481 (MH)+.
EXAMPLE 51 : (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(((S)-pyrrolidin-3- yl)methyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000119_0002
[00390] By following the same reaction procedures as described in Example 46, except in Step 2 using (S)-pyrrolidin-3-ylmethanol place of (3,3-difluoropiperidin-4-yl)methanol as starting material, the target compound was prepared. ESI-MS m/z 396 (MH)+.
EXAMPLE 52: (4R,5S,6S)-3-(((R)-l-(((R)-l-carbamimidoylpyrrolidin-3-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000119_0003
[00391] By following the same reaction procedures as described in Example 35, except in Step 1 using (S)-pyrrolidin-3-ylmethanol instead of 4-piperidinemethanol as starting material, the target compound was prepared. ESI-MS m/z 438 (MH)+. EXAMPLE 53: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((R)-l-(((R)-pyrrolidin-3- yl)methyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000120_0001
[00392] By following the same reaction procedures as described in Example 51, using (R)- pyrrolidin-3-ylmethanol as starting material, the target compound was prepared. ESI-MS m/z 396 (MH)+.
EXAMPLE 54: (4R,5S,6S)-3-(((R)-l-(((S)-l-carbamimidoylpyrrolidin-3-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000120_0002
[00393] By following the same reaction procedures as described in Example 52, using (R)- pyrrolidin-3-ylmethanol as starting material, the target compound was prepared. ESI-MS m/z 438 (MH)+.
EXAMPLE 55: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-4- yl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000120_0003
Step 1: Synthesis of 4-nitrobenzyl 4-oxopiperidine-l-carboxylate
Figure imgf000120_0004
[00394] By using the same reaction procedures as described in Step 5 of Example 1, piperidin-4-one hydrochloride (3.9 g, 25.4 mmol) was converted to the PNZ carbamate, 7.3 g. ESI-MS m/z 279 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-4- yl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000120_0005
[00395] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl 4-(3-mercaptoazetidin-l-yl)piperidine-l-carboxylate was converted to the target compound. ESI-MS m/z 382 (MH)+.
EXAMPLE 56: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(2-(piperidin-4- yl)ethyl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000121_0001
[00396] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl 4-(2-oxoethyl)piperidine-l-carboxylate (intermediate of Example 11) was converted to the target compound. ESI-MS m/z 410 (MH)+.
EXAMPLE 57: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(piperidin-3- ylmethyl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000121_0002
[00397] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, piperidin-3-ylmethanol 4-nitrobenzyl 3-formylpiperidine-l-carboxylate (intermediate of Example 12) was converted to the target compound. ESI-MS m/z 396 (MH)+.
EXAMPLE 58: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(((R)-pyrrolidin-3- yl)methyl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000121_0003
[00398] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl (R)-3-formylpyrrolidine-l-carboxylate was converted to the target compound. ESI-MS m/z 382 (MH)+.
EXAMPLE 59: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-((l-(((S)-pyrrolidin-3- yl)methyl)azetidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000121_0004
[00399] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl (S)-3-formylpyrrolidine-l-carboxylate (intermediate of Example 51) was converted to the target compound. ESI-MS m/z 382 (MH)+.
EXAMPLE 60: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((R)-morpholin-2- yl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000122_0001
Step 1: Synthesis of 4-nitrobenzyl (R)-2-formylmorpholine-4-carboxylate
Figure imgf000122_0002
[00400] By following the same reaction procedures as described in Steps 1 and 2 of Example 49, utilizing (R)-morpholin-2-ylmethanol instead of (S)-morpholin-2-ylmethanol as starting material, 4- nitrobenzyl (R)-2-formylmorpholine-4-carboxylate was prepared. ESI-MS m/z 295 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((R)-morpholin-2- yl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000122_0003
[00401] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl (R)-2-formylmorpholine-4-carboxylate was converted to the target compound. ESI-MS m/z 398 (MH)+.
EXAMPLE 61: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((S)-morpholin-2- yl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000122_0004
[00402] By following the same reaction procedures as described in Steps 1 and 2 of Example 60, (S)-morpholin-2-ylmethanol as starting material, the target compound was prepared. ESI-MS m/z 398 (MH)+. EXAMPLE 62: (4R,5S,6S)-3-((l-(((lr,4R)-4-aminocyclohexyl)methyl)azetidin-3-yl)thio)-6-((R)- l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000123_0001
[00403] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl ((lr,4r)-4-formylcyclohexyl)carbamate (prepared from ((lr,4r)-4- aminocyclohexyl)methanol in a similar manner to 4-nitrobenzyl 4-formylpiperidine-l-carboxylate as described in Step 1 of Example 7) was converted to the target compound. ESI-MS m/z 410 (MH)+.
EXAMPLE 63: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l-(thiomorpholin-2- ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000123_0002
Step 1: Synthesis of 4-(((4-nitrobenzyl)oxy)carbonyl)thiomorpholine-2-carboxylic acid.
Figure imgf000123_0003
[00404] By following the same reaction procedures as described in Step 1 of Example 7, using thiomorpholine-2 -carboxylic acid hydrochloride in place of piperidin-4-ylmethanol as starting material, the target compound was prepared. ESI-MS m/z 327 (MH)+.
Step 2: Synthesis of 4-nitrobenzyl 2-(hydroxymethyl)thiomorpholine-4-carboxylate.
Figure imgf000123_0004
[00405] To a solution of 4-(((4-nitrobenzyl)oxy)carbonyl)thiomorpholine-2 -carboxylic acid (4.4 g, 13.48 mmol) in THF (10 mL) at 0 °C was added borane-THF (1 M, 40 mL) dropwise. The reaction mixture was stirred at 0 °C for 2 h, quenched with MeOH (10 mL), then concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc, 1: 1) to afford the title compound as yellow solid, 3.47 g. ESI-MS m/z 313 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl 2-formylthiomorpholine-4-carboxylate.
Figure imgf000123_0005
[00406] To a mixture of 4-nitrobenzyl 2-(hydroxymethyl)thiomorpholine-4-carboxylate (1.73 g, 5.5 mmol) and NaHC03 (1.4 g, 16.6 mmol) in DCM (50 mL) at rt was added Dess-Martin reagent (3.0 g, 7.2 mmol) in portions. The mixture was stirred at rt for 3 h, NaHC03 (saturated, 50 mL) was added, the organic layer was separated, washed with saturated Na2S03, dried over Na2S04, concentrationed and then purified by flash column chromatography on silica gel ((petroleum ether/EtOAc, 3:7) to afford the title compound as a colorless oil 1.051 g. ESI-MS m/z 311 (MH)+.
Step 4: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-3-(((3R)-l- (thiomorpholin-2-ylmethyl)pyrrolidin-3-yl)thio)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000124_0001
[00407] By using the same reaction procedures as described in Steps 3 and 4 of Example 46 using 4- nitrobenzyl 2-formylthiomorpholine-4-carboxylate instead of 4-nitrobenzyl 3,3-difluoro-4- formylpiperidine-l-carboxylate as starting material, the target compound was prepared. ESI-MS m/z 428 (MH)+.
EXAMPLE 64: (4R,5S,6S)-3-((l-(((ls,4S)-4-aminocyclohexyl)methyl)azetidin-3-yl)thio)-6-((R)- l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000124_0002
[00408] By following the same reaction procedures as described in Steps 2 and 3 of Example 42, 4- nitrobenzyl ((ls,4s)-4-formylcyclohexyl)carbamate (prepared from ((ls,4s)-4- aminocyclohexyl)methanol in a similar manner to 4-nitrobenzyl 4-formylpiperidine-l-carboxylate as described in Step 1 of Example 7) was converted to the target compound. ESI-MS m/z 410 (MH)+.
EXAMPLE 65: (4R,5S,6S)-3-(((3R)-l-((3,3-dimethylpiperidin-4-yl)methyl)pyrrolidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000124_0003
Step 1: Synthesis of 4-methyl l-(4-nitrobenzyl) 3,3-dimethylpiperidine-l,4-dicarboxylate
Figure imgf000124_0004
[00409] By using the same reaction procedures as described in Step 5 of Example 1, methyl 3,3- dimethylpiperidine-4-carboxylate hydrochloride (1.0 g, 4.8 mmol) instead of piperidin-4-one hydrochloride was converted to the PNZ carbamate, 1.48 g. ESI-MS m/z 351 (MH)+.
Step 2: Synthesis of 4-nitrobenzyl 4-(hydroxymethyl)-3,3-dimethylpiperidine-l-carboxylate
Figure imgf000125_0001
[00410] To a solution of 4-methyl l-(4-nitrobenzyl) 3,3-dimethylpiperidine-l,4-dicarboxylate (1.48 g, 4.2 mmol) in THF (15 mL) was added LiAlH4 (320 mg, 8.4 mmol) portionwise at 0 °C. The reaction mixture was stirred at rt for 6 h. The resulting mixture was quenched by NaOH (aq, 10%), filtered through a pad of celite. The filtrate was extracted with EtOAc, dried over Na2S04, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel
(EA/PE=l: 10-1: 1) to afford a yellow solid, 650 mg. ESI-MS m/z 323 (MH)+.
Step 3: Synthesis of (4R,5S,6S)-3-(((3R)-l-((3,3-dimethylpiperidin-4-yl)methyl)pyrrolidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000125_0002
[00411] By following the same reaction procedures as described in Steps 3 and 4 of Example 47, 4- nitrobenzyl 4-(hydroxymethyl)-3,3-dimethylpiperidine-l-carboxylate was converted to the target compound. ESI-MS m/z 438 (MH)+.
EXAMPLE 66: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((ls,4S)-4- (methylamino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid
Figure imgf000125_0003
Step 1: Synthesis of methyl (ls,4s)-4-(methylamino)cyclohexane-l-carboxylate
Figure imgf000125_0004
[00412] To a solution of methyl (ls,4s)-4-aminocyclohexane-l-carboxylate (2 g, 10 mmol) in MeCN (30 mL) was added K2C03 (2.85 g, 20 mmol), followed by Mel (1.61 g, 11 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 6 h. The resulting mixture was quenched by water, extracted with EtOAc, dried over Na2S04, and concentrated under vacuum to afford a white solid, 1.2 g. ESI-MS m/z 172 (MH)+.
Step 2: Synthesis of 4-nitrobenzyl ((ls,4s)-4-(hydroxymethyl)cyclohexyl)(methyl)carbamate
Figure imgf000126_0001
[00413] By following the same reaction procedures as described in Step 2 of Example 65, methyl (ls,4s)-4-(methylamino)cyclohexane-l-carboxylate was converted to 4-nitrobenzyl ((ls,4s)-4- (hydroxymethyl) cyclohexyl) (methyl)carbamate. ESI-MS m/z 323 (MH)+.
Step 3: Synthesis of 4-nitrobenzyl ((ls,4s)-4-formylcyclohexyl)(methyl)carbamate
Figure imgf000126_0002
[00414] By following the same reaction procedures as described in Steps 1, Part (ii) of Example 7, 4-nitrobenzyl ((ls,4s)-4-(hydroxymethyl) cyclohexyl)(methyl)carbamate was converted to the crude aldehyde product, 5 g. ESI-MS m/z 321 (MH)+.
Step 4: Synthesis of azetidine-3-thiol
Figure imgf000126_0003
"b I - NH TFA
Boc
[00415] By following the same reaction procedures as described in Steps 1, 2, 3 and 4 of Example 1, tert-butyl 3-hydroxyazetidine-l-carboxylate was converted to azetidine-3 -thiol, 7 g. ESI-MS m/z 90 (MH)+.
Step 5: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((ls,4S)-4- (methylamino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid
Figure imgf000126_0004
[00416] By following the same reaction procedures as described in Steps 6, 7 and 8 of Example 1, 4-nitrobenzyl ((ls,4s)-4-formylcyclohexyl)(methyl)carbamate and azetidine-3 -thiol were converted to the target compound, 12 mg. ESI-MS m/z 424 (MH)+. EXAMPLE 67: (4R,5S,6S)-3-((l-(((lr,4R)-4-guanidinocyclohexyl)methyl)azetidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000127_0001
Step 1: Synthesis of Carbamic acid, N-[(methylthio)[[(4- nitrophenylmethoxy)carbonyl]amino]methylene]-, (4-nitrophenyl)methyl ester.
Figure imgf000127_0002
[00417] A solution of methyl carbamimidothioate (10 g, 71.8 mmol) and NaOH (6.25N, 5.7 mL) in DCM (600 mL) was stirred at 0 °C for 10 min, NaOH (1N, 150 mL) and PNZ-C1 (31.7 g in DCM- (200 mL) were both added to the methyl carbamimidothioate solution dropwise, while maintaining pH=l 1. The reaction mixture was stirred at rt. for 24 h, the organic layer was separated, washed with brine, dried over Na2S04, and concentrated to afford the title compound as white solid, 27.49 g. ESI- MS m/z 449 (MH)+.
Step 2: Synthesis of carbamic acid, [[(4-hydroxymethyl)cyclohexyl]carbonimidoyl]bis-, bis(4- nitrophenylmethyl) ester.
Figure imgf000127_0003
[00418] To a mixture of (4-aminocyclohexyl)methanol hydrochloride hydrate (911.13 mg, 5.5 mmol) and the resulting product from Step 1 (2.24 g, 5 mmol), and Et3N (2.0 g, 20 mmol) in DCM (100 mL) at rt was added HgCl2 (1.5 g, 5.5 mmol) in portions, then the reaction mixture was stirred at rt overnight. The mixture was filtered, the filtrate was concentrated to a residue, which was purified by flash chromatography on silica gel (DCM/MeOH, 95/5) to afford the title compound as white solid, 2.437 g. ESI-MS m/z 530 (MH)+.
Step 3: Synthesis of carbamic acid, [[(4-formyl)cyclohexyl]carbonimidoyl]bis-, bis(4- nitrophenylmethyl) ester.
Figure imgf000127_0004
[00419] By using the same reaction procedures as described in Step 3 of Example 63, the target compound was prepared from the above product. ESI-MS m/z 528 (MH)+.
Step 4: Synthesis of carbamic acid, [[(4-(3-mercaptoazetidin-l-yl)cyclohexyl]carbonimidoyl]bis-, bis(4-nitrophenylmethyl) ester..
Figure imgf000128_0001
[00420] By using the same reaction procedures as described in Step 6 of Example 1, the target compound was prepared from the above aldehyde and azetidine-3-thiol. ESI-MS m/z 601 (MH)+.
Step 5: Synthesis of (4R,5S,6S)-3-((l-(((lr,4R)-4-guanidinocyclohexyl)methyl)azetidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000128_0002
[00421] By following the same reaction procedures as described in Steps 7 and 8 of Example 1, the above product was converted to the target compound. ESI-MS m/z 452 (MH)+.
EXAMPLE 68: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((lr,4R)-4- (methylamino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
Figure imgf000128_0003
Step 1: Synthesis of (4-(methylamino)cyclohexyl)methanol.
Figure imgf000128_0004
[00422] To a mixture of (4-aminocyclohexyl)methanol (6.62 g, 40 mmol) and K2C03 (11.04 g, 80 mmol) was in MeCN (60 mL) at 0 °C was added Mel (5.6 g, 40 mmol) dropwise, the reaction mixture was stirred at rt for 7 h, filtered, and the filtrate was concentrated to afford the crude title compound. ESI-MS m/z 144 (MH)+. Step 2: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((lr,4R)-4- (methylamino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid.
Figure imgf000129_0001
[00423] By following the same reaction procedures as described in Step 5 of Example 1, and Steps 3, 4, and 5 of Example 66, the above product was converted to the target compound. ESI-MS m/z 424 (MH)+.
EXAMPLE 69: (4R,5S,6S)-3-((l-(((lr,4R)-4-(ethylamino)cyclohexyl)methyl)azetidin-3-yl)thio)- 6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000129_0002
Step 1: Synthesis of methyl (lr,4r)-4-(ethylamino)cyclohexane-l-carboxylate
Figure imgf000129_0003
[00424] To a solution of methyl (lr,4r)-4-aminocyclohexane-l-carboxylate (3.2 g, 16.5 mmol) in DMF (30 mL) was added K2C03 6.8 g, 49.5 mmol) and KI (1.6 g, 9.9 mmol), followed by EtBr (2.2 g, 19.8 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 12 h. The resulting mixture was quenched by water, extracted with EtOAc, dried over Na2S04, and concentrated under vacuum to afford a yellow oil, 2.5 g. ESI-MS m/z 186 (MH)+.
Step 2: Synthesis of (4R,5S,6S)-3-((l-(((lr,4R)-4-(ethylamino)cyclohexyl)methyl)azetidin-3- yl)thio)-6-((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000129_0004
[00425] By following the same reaction procedures as described in Steps 2, 3, 4 and 5 of Example 66, methyl (lr,4r)-4-(ethylamino)cyclohexane-l-carboxylate was converted to the target compound,
20 mg. ESI-MS m/z 438 (MH)+.
EXAMPLE 70: (4R,5S,6S)-3-((l-(((ls,4S)-4-(ethylamino)cyclohexyl)methyl)azetidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000130_0001
[00426] By following the same reaction procedures as described in Steps 1 and 2 of Example 69, methyl (ls,4s)-4-aminocyclohexane-l-carboxylate was converted to the target compound, 15 mg. ESI-MS m/z 438 (MH)+.
EXAMPLE 71: (4R,5S,6S)-3-((l-(2-(l-carbamimidoylpiperidin-4-yl)ethyl)azetidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Figure imgf000130_0002
[00427] By using the same reaction procedures as described in Example 67 using 2-(piperidin-4- yl)ethan-l-ol instead of (4-aminocyclohexyl)methanol as starting material, the target compound was prepared. ESI-MS m/z 452 (MH)+.
EXAMPLE 72: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((lr,4R)-4-(l- methylguanidino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid
Figure imgf000130_0003
Step 1: Synthesis of methyl (lr,4r)-4-(methylamino)cyclohexane-l-carboxylate
Figure imgf000130_0004
[00428] By following the same reaction procedures as described in Step 1 of Example 66, methyl (lr,4r)-4-aminocyclohexane-l-carboxylate was converted to methyl (lr,4r)-4- (methylamino)cyclohexane-l-carboxylate, 4.2 g. ESI-MS m/z 172 (MH)+. Step 2: Synthesis of methyl (lr,4r)-4-((E)-l-methyl-2,3-bis(((4- nitrobenzyl)oxy)carbonyl)guanidino) cyclohexane-l-carboxylate
Figure imgf000131_0003
[00429] To a solution of methyl (lr,4r)-4-(methylamino)cyclohexane-l-carboxylate (3.88 g, 22.5 mmol) in DCM (150 mL) was added 2-methyl-2-thiopseudourea protected by PNZ ( 10.1 g, 22.5 mmol), thiethylamine (9.77 mL, 67.5 mmol), and HgCl2 (6.13 g, 24.7 mmol). The reaction mixture was stirred at rt overnight, filtered, the filtrate was washed with saturated aqueous NH4Cl, water and brine, dried over Na2S04, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE/EA= 10: 1-2: 1) to afford the product, 2.4 g. ESI-MS m/z 572 (MH)+.
Step 3: Synthesis of (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((lr,4R)-4-(l- methylguanidino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid
Figure imgf000131_0001
[00430] By following the same reaction procedures as described in Steps 2 (ii), 3, 4 and 5 of Example 66, methyl (lr,4r)-4-((E)-l-methyl-2,3-bis(((4-nitrobenzyl)oxy)carbonyl)guanidino) cyclohexane-l-carboxylate was converted to the target compound, 10 mg. ESI-MS m/z 466 (MH)+.
EXAMPLE 73: (4R,5S,6S)-3-((l-(((ls,4S)-4-guanidinocyclohexyl)methyl)azetidin-3-yl)thio)-6- ((R)-l-hydroxyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Figure imgf000131_0002
[00431] By following the same reaction procedures as described in Steps 2 and 3 of Example 72, methyl (ls,4s)-4-aminocyclohexane-l-carboxylate hydrochloride was converted to the target compound, 10 mg. ESI-MS m/z 452 (MH)+. EXAMPLE 74: (4R,5S,6S)-6-((R)-l-hydroxyethyl)-4-methyl-3-((l-(((ls,4S)-4-(l- methylguanidino)cyclohexyl)methyl)azetidin-3-yl)thio)-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid
Figure imgf000132_0001
[00432] By following the same reaction procedures as described in Steps 1, 2 and 3 of Example 72, methyl (ls,4s)-4-aminocyclohexane-l-carboxylate hydrochloride was converted to the target compound, 10 mg. ESI-MS m/z 466 (MH)+.
EXAMPLE Al: Parenteral Composition of a Compound described herein, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00433] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a compound of Formula (I), Formula (la), Formula (Ia-l), Formula (II), Formula (Ha), Formula (Ila-l), Formula (III), Formula (Ilia), Formula (Illa-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a water soluble pharmaceutically acceptable salt thereof, is dissolved in DMSO and then mixed with 10 mF of 0.9% sterile saline solution. The mixture is incorporated into a dosage unit suitable for administration by injection.
EXAMPLE A2: Oral Composition of a Compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[00434] To prepare a pharmaceutical composition for oral delivery, 400 mg of compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof and the following ingredients are mixed intimately and pressed into single scored tablets.
Tablet Formulation
Ingredient Quantity per tablet (mg)
compound 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
[00435] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Capsule Formulation
Ingredient Quantity per capsule (mg)
compound 200
lactose spray dried 148
magnesium stearate 2 Biological Examples
EXAMPLE Bl: In vitro Antibacterial Assays.
[00436] To determine the ability of test compounds to potentiate the inhibition of the growth of bacterial strains, classic cell-based broth microdilution MIC assays were employed. MIC assays are performed according to CLSI methods except where otherwise noted (CLSI, 2011 and CLSI, 2009). The reference strains S. aureus ATCC 29213 (methicillin sensitive), S. aureus ATCC 33591
(methicillin-resistant), E. coli ATCC 25922 (wild-type/QC strain), P. aeruginosa ATCC 27853 (wild- type/QC strain), and the clinical isolate P. aeruginosa PA 8 were used to determine the ability of the exemplary carbapenem compounds to inhibit bacterial growth. An expanded panel of methicillin resistance S. aureus (MRSA) and Pseudomonas was also used to determine the ability of exemplary carbapenem compounds to inhibit bacterial growth across a broader representation of those species.
To determine activity in MRSA and in addition to S. aureus ATCC 33591, S. aureus USA 300, USA 400 and USA 600, some of the most common clones found to cause human infection, were also used. To further gauge the impact on the carbapenem compounds due to various resistance mechanisms in Pseudomonas, the following strains were included: P. aeruginosa 35151 (hyper-permeable strain), P. aeruginosa AmexAB-OprM (an efflux pump knockout), and P. aeruginosa PA 3 (a clinical isolate of reduced carbapenem susceptibility). Briefly, cryo-preserved bacterial cultures of clinical strains are streaked for isolation on appropriate agar medium, in this case Mueller Hinton II agar. Following incubation to allow formation of colonies, these plates are sealed with parafilm and stored refrigerated for up to two weeks. For preparation of assay inocula and to ensure low variability, at least 5 colonies are picked from the agar plates with an inoculating loop and aseptically transferred to a culture tube containing 3 mL of Mueller-Hinton Broth (supplemented with divalent cations to required levels based on Manufacturers’ specification). The broth culture is grown for 3-5 hours at 37 °C with shaking at 200 rpm. Meanwhile, 2-fold serial dilutions of test compounds are conducted in a 96 well plate with a final volume of 75 pL per well at 2-fold the final desired concentration. After the dilution plates are set up the growing cultures are then diluted in a cuvette containing MH II broth and the optical density is measured at 600 nm. Inocula are diluted such that 75 pL of this culture in Mueller- Hinton Broth results in a starting bacterial concentration of 5 x 105 CFU/mL when added to the dilution plates. The plates are incubated 16-20 hours at 37 °C. The MIC is read visually as the lowest concentration well with no bacterial growth.
[00437] Representative results are shown in Tables 3, 4, and 5 where A represents an MIC >32 pg/mL, B represents an MIC between 8 and 32 pg/mL inclusive, C represents an MIC between 1 and 4 pg/mL inclusive, and D represents an MIC of <1 pg/mL. NT = Not Tested. Table 3: Inhibition of bacterial growth. Minimum Inhibitory Concentrations of Exemplary
Compounds.
Figure imgf000134_0001
Table 4. Inhibition of bacterial growth for methicillin-resistant S. aureus and E. coli strains.
Minimum Inhibitory Concentrations of exemplary compounds (MIC, in pg/mL).
Figure imgf000135_0001
Table 5. Inhibition of bacterial growth for P. aeruginosa strains. Minimum Inhibitory
Concentrations of exemplary compounds (MIC, in pg/mL).
Figure imgf000136_0001
[00438] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000138_0001
Formula (I) wherein
Y is
(a) heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR10, -(CR12R13)VIOR10, -CN, -N02, halogen, -S(=0)2R14, -(CR12R13)viS(=0)2R14, -S(=O)2NR10Rn, -
Figure imgf000138_0002
(b) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl each optionally substituted with one, two, or three substituents each independently selected from the group consisting of optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR20, - (CR22R23)V2OR20, -CN, -N02, halogen, -S(=0)2R24, -(CR22R23)v2S(=0)2R24, -
Figure imgf000138_0003
NR20(CR22R23)V2B(OR25)2, and -(CR22R23)v2NR20(CR22R23)v2B(OR25)2; provided that at least one of the optional substituent is not -0(C3 alkenyl) when R4 is C3 alkenyl; or
Figure imgf000139_0001
NR30(CR32R33)V3B(OR35)2 provided that z is not 0;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl);
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40,
Figure imgf000139_0002
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, -C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, -C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb; each R10, R11, R20, R21, R30, R31, R40, and R41 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl)(heteroaryl);
or R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the
nitrogen to which they are attached to form an optionally substituted C2-C8
heterocycloalkyl;
each R12, R13, R22, R23, R32, R33, R42, and R43 is independently selected from the group
consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R14, R24, and R44 are independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl);
each R15, R25, R35, and R45 is independently hydrogen or optionally substituted Ci-C6 alkyl; or two R15, or two R25, or two R35, or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an
optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
vl, v2, v3, or v4 are independently 1-4;
wl, w2, w3, or w4 are independently 2-4;
y is 1-4; and
z is 0-5.
The compound of claim 1, wherein X is -S-.
3. The compound of claims 1 or 2, wherein R1 is Ci-C6 alkyl.
4. The compound of any one of claims 1 to 3, wherein R2 is hydrogen.
5. The compound of any one of claims 1 to 4, wherein each R3 is independently hydrogen or Ci-Ce alkyl.
6 The compound of any one of claims 1 to 5, wherein R4 is hydrogen.
7. The compound of any one of claims 1 to 6, wherein the compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000141_0001
Formula (la)
wherein
Y is
(a) heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl, each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR10, -(CR12R13)VIOR10, -CN, -N02, halogen, -S(=0)2R14, -(CR12R13)viS(=0)2R14, -S(=O)2NR10Rn, -
Figure imgf000141_0002
(b) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl each optionally substituted with one, two, or three substituents each independently selected from the group consisting of optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR20, - (CR22R23)V2OR20, -CN, -N02, halogen, -S(=0)2R24, -(CR22R23)v2S(=0)2R24, -
Figure imgf000141_0003
Figure imgf000142_0001
NR30(CR32R33)V3B(OR35)2 provided that z is not 0;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40,
Figure imgf000142_0002
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, -C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, -C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R10, R11, R20, R21, R30, R31, R40, and R41 is independently selected from the group
consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl)(heteroaryl);
or R10 and R11, or R20 and R21, or R30 and R31, or R40 and R41 are taken together with the
nitrogen to which they are attached to form an optionally substituted C2-C8
heterocycloalkyl;
each R12, R13, R22, R23, R32, R33, R42, and R43 is independently selected from the group
consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R14, R24, and R44 are independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl);
each R15, R25, R35, and R45 is independently hydrogen or optionally substituted Ci-C6 alkyl; or two R15, or two R25, or two R35, or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an
optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
vl, v2, v3, or v4 are independently 1-4;
wl, w2, w3, or w4 are independently 2-4;
y is 1-4; and
z is 0-5.
8. The compound of any one of claims 1 to 7, wherein the compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (Ia-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000143_0001
Formula (Ia-l).
9. The compound of any one of claims 1 to 8, wherein Y is optionally substituted
heterocycloalkyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, and homopiperazinyl. 10 The compound of any one of claims 1 to 9, wherein Y is optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted piperazinyl.
11 The compound of any one of claims 1 to 10, wherein Y is pyrrolidinyl, piperidinyl,
piperazinyl, or morpholinyl, each optionally substituted with one, two, or three of Ci-C6 alkyl, Ci-Ce haloalkyl, halogen, -S(=0)2R14, -NR10Rn, -(CR12R13)viNR10Rn, -C(=NR10)NR10Rn, -
Figure imgf000144_0001
12 The compound of any one of claims 1 to 11, wherein R10 and R11 are independently hydrogen or Ci-C6 alkyl.
13. The compound of any one of claims 1 to 12, wherein each R12 and R13 are independently hydrogen or -NRaRb.
14. The compound of any one of claims 1 to 13, wherein R14 is Ci-C6 alkyl.
15. The compound of any one of claims 1 to 14, wherein each R15 is hydrogen.
16. The compound of any one of claims 1 to 11, wherein Y is unsubstituted piperidinyl.
17. The compound of any one of claims 1 to 11, wherein Y is unsubstituted pyrrolidinyl.
18. The compound of any one of claims 1 to 11, wherein Y is unsubstituted piperazinyl.
19. The compound of any one of claims 1 to 8, wherein Y is optionally substituted heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.
20 The compound of any one of claims 1 to 8 or 19, wherein Y is optionally substituted pyridyl.
21 The compound of any one of claims 1 to 8 or 19 or 20, wherein Y is pyridyl optionally
substituted with one, two, or three of Ci-C6 alkyl, Ci-C6 haloalkyl, halogen, -S(=0)2R24, -
Figure imgf000144_0002
22 The compound of any one of claims 1 to 8 or 19 to 21, wherein R20 and R21 are independently hydrogen or Ci-C6 alkyl.
23. The compound of any one of claims 1 to 8 or 19 to 22, wherein each R22 and R23 is
independently hydrogen or -NRaRb.
24. The compound of any one of claims 1 to 8 or 19 to 23, wherein R24 is Ci-C6 alkyl.
25. The compound of any one of claims 1 to 8 or 19 to 24, wherein each R25 is hydrogen.
26. The compound of any one of claims 1 to 8 or 19 to 21, wherein Y is unsubstituted pyridyl.
27. The compound of any one of claims 1 to 8, wherein Y is -NR30R31, -NR30(CR32R33)w3NR30R31, -C(=NR30)R30, -NR30C(=NR31)NR30R31, -C(=NR30)NR30R31, -N(R30)C(=NR31)R30, - (CR32R33)V3NR30R31, -NR31C(=NR31)NR30(CR32R33)W3NR30R31, -
NR30(CR32R33)W3N(R30)C(=NR31)NR30R31, or -NR30(CR32R33)v3B(OR35)2 provided that z is not 0
28. The compound of any one of claims 1 to 8 or 27, wherein Y is -NR30R31.
29. The compound of any one of claims 1 to 8 or 27 or 28, wherein R30 and R31 are independently hydrogen or Ci-C6 alkyl.
30. A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000145_0001
Formula (III) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, -(CR52R53)v5OR50, -CN, -N02, halogen, - S(=0)2R54, -(CR52R53)V5S(=0)2R54, -S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, - (CR52R53)V5C(=0)OR10, -C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
X is -0-, -S-, -S(=0)-, -S(=0)2-, or -NR7-;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
R1 is optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
R2 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -Si(Rc)3;
each R3 is independently hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or -ORa;
R4 is hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl); each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40, -CN, -N02, -
Figure imgf000146_0001
each R6 is independently a basic substituent;
R7 is hydrogen, optionally substituted Ci-C6 alkyl, -S(=0)2Rc, or -S(=0)2NRaRb;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl,
optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, - C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted - (Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl) (heteroaryl); each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4;
q is 1-4;
v4 and v5 are independently 1-4;
w4 is 2-4;
y is 1-4; and
z is 1-5.
31. The compound of claim 30, wherein X is -S-.
32. The compound of claim 30 or 31, wherein R1 is Ci-C6 alkyl.
33. The compound of any one of claims 30 to 32, wherein R2 is hydrogen.
34. The compound of any one of claims 30 to 33, wherein each R3 is independently hydrogen or Ci-C6 alkyl.
35. The compound of any one of claims 30 to 34, wherein R4 is hydrogen.
36. The compound of any one of claims 30 to 35, wherein the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000147_0001
Formula (Ilia) wherein
Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; each optionally substituted with one, two, or three substituents each independently selected from the group consisting of oxo (when Ring A is cycloalkyl or heterocycloalkyl), optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR50, - (CR52R53)V5OR5° _CN _NO2 halogen, -S(=0)2R54, -(CR52R53)v5S(=0)2R54, - S(=O)2NR50R51, -(CR52R53)V5S(=O)2NR50R51, -C(=0)OR50, -(CR52R53)V5C(=0)0R5°, - C(=O)NR50R51, and -(CR52R53)v5C(=O)NR50R51;
L is -(CR8R9)z- or -(CR18R19)yC(=0)-;
each R5 is independently hydrogen, halogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -OR40, -(CR42R43)v4OR40,
Figure imgf000148_0001
each R6 is independently a basic substituent;
each R8 and R9 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, -C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R18 and R19 is independently hydrogen, halogen, -CN, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, -ORa, -NRaRb, -C(=0)0Ra, -C(=0)NRaRb, -S(=0)2Rc, or -S(=0)2NRaRb;
each R40, R41, R50, and R51 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted -(Ci-C6 alkyl) (heteroaryl);
or R40 and R41, or R50 and R51 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R , R , R , and R is independently selected from the group consisting of hydrogen, halogen, -CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R44 and R54 is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), or optionally substituted -(Ci-C6 alkyl)(heteroaryl);
each R45 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R45 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
Ra and Rb are independently hydrogen or optionally substituted Ci-C6 alkyl;
or Ra and Rb are taken together with the nitrogen to which they are attached to form an
optionally substituted C2-C8 heterocycloalkyl;
each Rc is independently optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
n is 0-2;
m is 0-2;
p is 0-4
q is 1-4;
v4 and v5 are independently 1-4;
w4 is 2-4;
y is 1-4; and
z is 1-5.
37. The compound of any one of claims 30 to 36, wherein the compound of Formula (Ilia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (Illa-l), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
Figure imgf000149_0001
U Formula (Illa-l).
38. The compound of any one of claims 30 to 37, wherein Ring A is optionally substituted
phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted pyridyl.
39. The compound of any one of claims 30 to 38, wherein Ring A is phenyl, cyclohexyl, piperidinyl, morpholinyl, or pyridyl.
40. The compound of any one of claims 30 to 39, wherein:
each R6 is independently -NR60R61, -NR60(CR62R63)w6NR60R61, -NR60C(=NR61)NR60R61, - C(=NR60)NR60R61, -C(=NR60)R60, -N(R60)C(=NR61)R60, -(CR62R63)V6NR60R61, - C(=O)NR60R61, -C(=O)(CR62R63)V6NR60R61, -(CR62R63)v6 C(=O)NR60R61, - (CR62R63)V6N(R60)C(=NR61)NR60R61, -(CR62R63)V6NR60(CR62R63)W6NR60R61, - NR61C(=NR61)NR60(CR62R63)W6NR60R61, -NR60(CR62R63)W6N(R60)C(=NR61)NR60R61, - (CR62R63)V6C(=NR61)NR60R61, -NR60(CR62R63)V6B(OR65)2, or - (CR62R63)V6NR60(CR62R63)V6B(OR65)2;
each R60 and R61 is independently selected from the group consisting of hydrogen, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, C2-C8 optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -(Ci-C6 alkyl)(C3-C8 cycloalkyl), optionally substituted -(Ci-C6 alkyl)(C2-C8 heterocycloalkyl), optionally substituted -(Ci-C6 alkyl)(aryl), and optionally substituted - (Ci-C6 alkyl) (heteroaryl);
or R60 and R61 are taken together with the nitrogen to which they are attached to form an optionally substituted C2-C8 heterocycloalkyl;
each R62 and R63 is independently selected from the group consisting of hydrogen, halogen, - CN, -ORa, -NRaRb, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R65 is independently hydrogen or optionally substituted Ci-C6 alkyl;
or two R65 are taken together with the atoms to which there are attached to form a cyclic boronate ester;
v6 is 1-4; and
w6 is 2-4.
41. The compound of claim 40, wherein each R6 is independently -NR60R61, -C(=NR60)NR60R61, - (CR62R63)V6NR60R61, or -NR60(CR62R63)V6B(OR65)2.
42. The compound of claim 40 or 41, wherein each R60 and R61 is independently hydrogen or Ci-C6 alkyl.
43. The compound of any one of claims 40 to 42, wherein each R62 and R63 are independently hydrogen or -NRaRb.
44. The compound of any one of claims 40 to 43, wherein each R65 is hydrogen.
45. The compound of any one of claims 30 to 44, wherein q is 1.
46. The compound of any one of claims 30 to 44, wherein q is 2.
47. The compound of any one of claims 1 to 29, wherein n is 0 and m is 0.
48. The compound of any one of claims 1 to 46, wherein n is 1 and m is 0.
49. The compound of any one of claims 1 to 46, wherein n is 1 and m is 1.
50. The compound of any one of claims 1 to 49, wherein L is -(CR8R9)Z-.
51. The compound of any one of claims 1 to 50, wherein z is 1.
52. The compound of any one of claims 1 to 51, wherein each R8 and R9 is independently hydrogen or Ci-C6 alkyl.
53. The compound of any one of claims 1 to 52, wherein each R8 and R9 are hydrogen.
54. The compound of any one of claims 1 to 49, wherein L is -(CR18R19)yC(=0)-.
55. The compound of any one of claims 1 to 49 or 54, wherein y is 1 or 2.
56. The compound of any one of claims 1 to 49 or 54 or 55, wherein each R18 and R19 is independently hydrogen or Ci-C6 alkyl.
57. The compound of any one of claims 1 to 49 or 54 to 56, wherein each R18 and R19 are hydrogen.
58. The compound of any one of claims 1 to 57, wherein p is 0.
59. The compound of any one of claims 1 to 57, wherein p is 1.
60. The compound of any one of claims 1 to 57 or 59, wherein each R5 is independently optionally substituted Ci-C6 alkyl.
61. The compound of any one of claims 1 to 57 or 59 or 60, wherein each R5 is independently Ci-C6 alkyl or Ci-C6 hydroxyalkyl.
62. A compound selected from the group consisting of:
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 63. A compound selected from the group consisting of:
Figure imgf000155_0002
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
64. A pharmaceutical composition comprising a compound of any one of claims 1-63, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof and a pharmaceutically acceptable excipient.
65. A pharmaceutical composition comprising a compound of any one of claims 1-63, or a
pharmaceutically acceptable salt, solvate, or stereoisomer thereof; a b-lactamase inhibitor; and a pharmaceutically acceptable excipient.
66. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
67. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in combination with a b-lactamase inhibitor.
68. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 64.
69. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 65.
70. The method of any one of claims 66-69, wherein the bacterial infection is caused by gram negative bacteria.
71. The method of any one of claims 66-69, wherein the bacterial infection is caused by gram positive bacteria.
72. The method of any one of claims 66-69, wherein the bacterial infection is caused by
multidrug-resistant (MDR) bacteria.
73. The method of any one of claims 66-69, wherein the bacterial infection is cause by
carbapenem resistant Enterobacteriaceae (CRE).
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