WO2018129008A1 - Compounds and methods for treating bacterial infections - Google Patents
Compounds and methods for treating bacterial infections Download PDFInfo
- Publication number
- WO2018129008A1 WO2018129008A1 PCT/US2018/012137 US2018012137W WO2018129008A1 WO 2018129008 A1 WO2018129008 A1 WO 2018129008A1 US 2018012137 W US2018012137 W US 2018012137W WO 2018129008 A1 WO2018129008 A1 WO 2018129008A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- alkylnh
- compound
- heteroaryl
- optionally substituted
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 120
- 208000035143 Bacterial infection Diseases 0.000 title claims description 22
- 208000022362 bacterial infectious disease Diseases 0.000 title claims description 22
- 238000000034 method Methods 0.000 title claims description 21
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- 239000000203 mixture Substances 0.000 claims description 51
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- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 32
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- 239000001257 hydrogen Substances 0.000 claims description 21
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- 101710146026 Peptidoglycan D,D-transpeptidase FtsI Proteins 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
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- MTHKHSNWUJTOEY-UHFFFAOYSA-N tert-butyl [4-[N-[(2-methylpropan-2-yl)oxycarbonyl]-N'-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]carbamimidoyl]phenyl] carbonate Chemical compound C(OC1=CC=C(C=C1)\C(\NCCNC(=O)OC(C)(C)C)=N/C(=O)OC(C)(C)C)(OC(C)(C)C)=O MTHKHSNWUJTOEY-UHFFFAOYSA-N 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
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- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- 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
Definitions
- antibacterial compounds which are useful for, among other uses, the treatment of bacterial infections.
- Such com ounds are represented by Formula I,
- compositions comprising the compounds of Formula I.
- the disclosed compounds are designed to act as PBP3 inhibitors and show substantial in vitro and in vivo improvement over PBP2 inhibitor counterparts. See e.g., Table 2, which shows a direct comparison between a known PBP2 inhibitor and an exemplary compound of Formula I where the amino methyl group was replaced with a dimethyl amide group. Treatment of a murine model of P.
- FIG. 1 shows in vivo profiling for two P. aeruginosa PBP inhibitors, where panel a) is Example 6 and panel b) is a comparator compound.
- R 1 and FT 2 are each independently (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;
- R 3 and R 4 are each independently hydrogen, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl;
- R 6 is -OR A or -NR A R B ;
- R 7 is -OR C , -SR C , -NR D R E , -OCONR A R F , -OCOR G , -S(O)R H -S(O) 2 R H ,
- the (C 1 -C 6 )alkyl represented by R is optionally substituted with one or more groups selected from NH 2 , -NHCOO(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl) 3 , phenyl, monocyclic heteroaryl, monocyclic heterocyclyl,
- each R A is independently hydrogen or (C 1 -C 6 )alkyl;
- each R D is independently hydrogen, (C 1 -C 6 )alkyl, or -COO(C 1 -C 6 )alkyl;
- R B , R C , R E , R F , R G and R H are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, monocyclic heteroaryl, bicyclic fused heteroaryl, or monocyclic heterocyclyl, wherein:
- -(C 1 -C 6 )alkylNH(C NH)NH 2 , COOH, -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , -CONR A R I -SO 2 NR A R A , -COO(C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylCONR A R I ;
- the (C 1 -C 6 )alkyl represented by R B , R C , R E , R F , R G and R H is optionally substituted with one or more groups selected from NH 2 ,
- -(C 1 -C 6 )alkylNH(C NH)NH 2, COOH, -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , -CONR A R I -SO 2 NR A R A , -COO(C 1 -C 6 )alkyl, and -(C 1 -C 6 )alkylCONR A R I ; and R 1 is hydrogen, (C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylNH 2 .
- a hyphen designates the point of attachment of that group to the variable to which it is defined.
- -(C 1 -C 6 )alkylCONR A R I means that the point of attachment for this group occurs on the (C 1 -C 6 )alkyl.
- alkyl used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, and the like, means saturated straight-chain or branched monovalent
- an alkyl group typically has 1-6 carbon atoms, i.e., (C 1 -C 6 )alkyl.
- a "(C 1 -C 6 )alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
- haloalkyl includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.
- Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
- (C 1 -C 4 )alkoxy includes methoxy, ethoxy, proproxy, and butoxy.
- aralkoxy or “aryloxy alkyl” refers to an aromatic carbocyclic ring system having, unless otherwise specified, a total of 6 to 10 ring members.
- aryl may be used
- aryl ring refers to an aromatic ring system which includes, but is not limited to, phenyl (abbreviated as “Ph”), naphthyl and the like. It will be understood that when specified, optional substituents on an aryl group may be present on any substitutable position and, include, e.g., the position at which the aryl is attached.
- heteroaryl used alone or as part of a larger moiety as in
- heteroarylalkyl refers to a 5- to 12- membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. Nitrogen atoms in an heteraryl may be quaternized e.g., as in 1-methylpyridin- l-ium (see e.g., compounds 32, 48, and the like).
- heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic".
- a heteroaryl group may be mono- or bi-cyclic.
- Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc.
- Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings.
- Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl,
- pyrrolopyridinyl pyrrolopyrimidinyl
- pyrrolopyridinyl pyrrolopyrimidinyl
- thienopyridinyl thienopyrimidinyl
- indolizinyl purinyl, naphthyridinyl, and pteridinyl.
- optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.
- heterocyclyl means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- heterocycle means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
- monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and
- Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.
- Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
- Enantiomer means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more
- a hyphen ("-") at the beginning or end of a recited group designates the point at which a recited group is attached to a defined group.
- -SO 2 -(C 1 -C3)alkyl-(C 2 -C6)cycloalkyl means that the group is attached via the sulfonyl.
- Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.
- Gaometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z
- the compounds of the herein may be prepared as individual enantiomers by either enantio-specific synthesis or resolved from an enantiomerically enriched mixture.
- Conventional resolution techniques include forming the salt of a free base of each isomer of an enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each enantiomer of an enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the enantiomers of an enantiomeric pair using an optically pure acid, amine or alcohol (followed by
- the stereochemistry of a disclosed compound is named or depicted by structure
- the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers.
- Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers.
- the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure.
- Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
- stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
- a disclosed compound is named or depicted by structure without indicating the stereochemistry and e.g. , the compound has more than one chiral center (e.g., at least two chiral centers), it is to be understood that the name or structure encompasses one stereoisomer free of other stereoisomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s).
- the name or structure may encompass one stereoisomer free of other diastereomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).
- the compounds of the herein may be present in the form of pharmaceutically acceptable salts.
- the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
- Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
- subject and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
- companion animals e.g., dogs, cats, and the like
- farm animals e.g., cows, pigs, horses, sheep, goats and the like
- laboratory animals e.g., rats, mice, guinea pigs and the like.
- the subject is a human in need of treatment.
- inhibitor includes a decrease in the baseline activity of a biological activity or process.
- treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
- treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
- treatment may be administered in the absence of symptoms.
- treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
- the term "effective amount” or “therapeutically effective amount” includes an amount of the compound of Formula I that will elicit a biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a bacterial DNA gyrase or a bacterial infection, amelioration of symptoms of a bacterial infection, or the slowing or delaying of progression of a bacterial infection.
- the language "effective amount” includes the amount of a compound of Formula I, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate a bacterial infection or inhibit bacterial DNA gyrase, and/or reduce or inhibit the bacterial growth, replication or bacterial load of a bacteria in a subject.
- compositions of this disclosure refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, organic or inorganic carriers, excipients or diluents suitable for pharmaceutical applications.
- R 1 and R 2 in Formula I are each independently (C 1 - C 6 )alkyl; and R is (C 1 -C 6 )alkyl, wherein the remaining variables are as described above for Formula I.
- each R C in Formula I is independently phenyl, monocyclic heterocyclyl, monocyclic heteroaryl, or (C 1 -C 6 )alkyl, wherein:
- R is hydrogen or (C 1 -C 6 )alkyl optionally substituted with one or more groups selected from NH 2 , -NHCOO(C 1 -C 6 )alkyl, -N((C 1 -C 6 )alkyl) 3 , phenyl,
- the compound of Formula I is of the Formula Ila or Ilb:
- the compound of Formula I is of the Formula IIla or Illb:
- the compound of Formula I is of the Formula IVa or IVb:
- the compound of Formula I is of the Formula Va or Vb:
- the compound of Formula I is of the Formula VI:
- R D in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or VI is hydrogen or -COO(C 1 -C 6 )alkyl;
- R E is -(C 1 -C 6 )alkylNH 2 or
- R F is -(C 1 -C 6 )alkylNH 2 ;
- Vb or VI is selected from
- the compound of Formula I is of the Formula Vila or Vllb:
- the compound of Formula I is of the Formula Villa or VIIIb:
- the compound of Formula I is of the Formula IXa or IXb:
- the compound of Formula I is of the Formula Xa or Xb:
- R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is phenyl or a monocyclic nitrogen containing heteroaryl optionally substituted with (C 1 -C 6 )alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment.
- R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is phenyl or pyridinyl optionally substituted with (C 1 -C 6 )alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment.
- R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is hydrogen, a 5- or 6- membered monocyclic nitrogen containing heteroaryl, a 9-membered fused bicyclic nitrogen containing heteroaryl, -(C 1 - C 6 )alkylNH 2 , -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , or (C 1 -C 6 )alkyl substituted with a 5- or 6- membered nitrogen containing heteroaryl, wherein each of said heteroaryl are optionally substituted with one or more -NH 2 , (C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylN((C 1 -C 6 )alkyl) 3 , wherein the remaining variables are as described above for Formula I or the second or eight
- IXa, IXb, Xa, or Xb is hydrogen, pyridinyl, pyrazolyl, indazolyl, -(C 1 -C 6 )alkylNH 2 , or (C 1 - C 6 )alkyl substituted with pyridinyl or pyrazolyl, wherein each of said pyridinyl and pyrazolyl are optionally substituted with one or more -NH 2 , (C 1 -C 6 )alkyl, or -(C 1 -C 6 )alkylN((C 1 - C 6 )alkyl)3, wherein the remaining variables are as described above for Formula I or the second or eighteenth embodiment.
- R 6 in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is selected from
- Gram-negative bacteria include, but are not limited, to Haemophilus influenzae, Acinetobacter baumannii,
- Burkholderia spp. Citrobacter spp., Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa, Klebsiella spp., Stenotrophomonas maltophila, Francisella tularensis, Yersinia spp., Salmonella spp., Shigella spp., Legionella spp. and Neisseria gonorrhoeae.
- Atypical bacteria include, but are not limited to, Mycoplasma pneumoniae, Chlamydophila
- the bacteria are resistant to one or more antibacterials other than the compounds of Formula I described herein.
- the language “resistance” and “antibacterial resistance” refers to bacteria that are able to survive exposure to one or more antibacterials.
- the compounds described herein can be used to treat bacterial infections caused by Gram-negative bacteria or resistant Gram-negative bacteria.
- the compounds described herein can be used to treat bacterial infections caused by Pseudomonas Aeruginosa, Acinetobacter Baumannii, or Enter obacteriaceae, as well as antibacterial- resistant forms.
- the compounds described herein can be used to treat bacterial infections caused by Pseudomonas Aeruginosa, as well as antibacterial-resistant forms.
- resistance mechanisms in Gram- negative bacteria include, but are not limited to, extended- spectrum ⁇ -lactamase expression, metallo- ⁇ -lactamase expression, carbapenemase expression, DNA gyrase mutation, porin mutation, efflux system
- the bacterial infection treated by the present compounds is caused by a Gram-negative bacteria.
- the bacterial infection treated by the present compounds is caused by P. aeruginosa, A. baumannii, E. coli, or K. pneumoniae and other Enterobacteriaceae.
- the bacterial infection treated by the present compounds is caused by P. aeruginosa.
- the bacterial infection treated by the present compounds is caused by an antibacterial-resistant Gram-negative bacteria.
- the bacterial infection treated by the present compounds is caused by an antibacterial-resistant strain of P. aeruginosa.
- Bacterial infections treated by the present compounds include, but are not limited to, respiratory (e.g., pneumonia), blood stream (e.g., bacteremia), heart (e.g., endocarditis), CNS (e.g., meningitis, brain abscess), ear (e.g., otitis externa), eye (e.g., bacterial keratitis, endophthalmitis), GI tract (diarrhea, enteritis, enterocolitis), urinary tract, skin,
- respiratory e.g., pneumonia
- blood stream e.g., bacteremia
- CNS e.g., meningitis, brain abscess
- ear e.g., otitis externa
- eye e.g., bacterial keratitis, endophthalmitis
- GI tract diarrhea, enteritis, enterocolitis
- the compounds described herein inhibit penicillin binding protein 3 (PBP3).
- PBP3 penicillin binding protein 3
- the present disclosure provides a method of inhibiting PBP3, comprising administering to a subject in need thereof one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
- the compounds described herein inhibit penicillin binding protein 1 (e.g., PBPla and/or PBPlb).
- PBPla penicillin binding protein 1
- PBPlb penicillin binding protein 1
- the present disclosure provides a method of inhibiting PBP1, comprising administering to a subject in need thereof one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
- the compounds described herein are not specific inhibitors of penicillin binding protein 2 (PBP2).
- compositions comprising a compound described herein; and a pharmaceutically acceptable carrier. These compositions can be used to treat one or more of the bacterial infections described above, as well as inhibit PBP3.
- compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- Liquid dosage forms, injectable preparations, solid dispersion forms, and dosage forms for topical or transdermal administration of a compound are included herein.
- the amount of provided compounds that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration. [0062] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound in the composition will also depend upon the particular compound in the composition.
- Tert-butyl 3,5-dioxopiperidine-l-carboxylate can be purchased from commercial sources (for example PharmaBlock) or synthesized following the procedure described in Blake, James F. et al., WO2012118850.
- nBuli (285.87mL, 457.38mmol) was added to an ice bath cooled solution of diisopropylamine (64.11mL, 457.38mmol) in THF (466.74mL) and stirred for 20 minutes then further cooled to -78°C and this was added (via cannula) to a solution of tert- butyl 3-(benzyloxymethyl)-l-methyl-4-oxo-5,7-dihydropyrazolo[3,4-c]pyridine-6- carboxylate (48.54g, 130.68mmol) and PMDTA (95.49mL, 457.38mmol) in THF
- 2,2,2- trifluoroacetaldehyde (44 mL, 20.00 equiv) was then slowly added. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting oil was re-dissolved in DCM and washed with saturated solution of sodium bicarbonate. The resulting mixture was washed with brine. The mixture was dried over sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum.
- DIPEA 10-allyloxy-3- (benzyloxymethyl)-5-methyl-9-oxo-4,5,8, 10-tetrazatricyclo ]undeca-2(6),3-diene- 7-carboxylic acid (5.61g, 14.08mmol), dimethylamine hydrochloride (2296.32mg,
- DIPEA (0.07mL, 0.4000mmol) was added to a solution of 10-allyloxy-7- (dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8,10-tetrazatricyclo undeca-2(6),3- diene-3 -carboxylic acid (70. mg, 0.2000mmol), l-Methyl-lH-pyrazol-4-amine (38.92mg, 0.4000mmol) and HATU (83.81mg, 0.2200mmol) in DMF (lmL) and the reaction was stirred for 20min. LCMS shows reaction is complete.
- Tubes that had the desired product mass were combined and lyophilized together to give 77mg beige solid which was purified on Sepabeads SP20SS (0-10%ACN/Water), then lyophilized to give [7- (dimethylcarbamoyl)-5-methyl-3-[(l-methylpyrazol-4-yl)carbamoyl]-9-oxo-4,5,8,10- tetrazatricyclo undeca-2(6),3-dien-10-yl] hydrogen sulfate (47mg, O. lOmmol,
- TEA (2.07mL, 14.88mmol) was added to a mixture of Ethyl 4- hydroxybenzenecarboximidoate hydrochloride (1.5g, 7.44mmol) and Tert-butyl-N- 2(aminoethyl)carbamate (1.43g, 8.93mmol) in DMF (lOmL) and the reaction stirred at RT. After 2 hours the reaction was complete and used as is in next step assuming 100% yield. (ES, m/z): 297 [M+1] .
- Peak A the first to elute, retention time 5.6 minutes, in the chiral preparative separation conditions described for Int-30, was pooled and solvent removed under reduced pressure to give the chiral product Int-32 (4S,8R)-5-(benzyloxy)-N,N, l-trimethyl-6-oxo- 4,5,6,8-tetrahydro- lH-4,7-methanopyrazolo[3,4-e] [l,3]diazepine-8-carboxamide (525mg, 32%) with an as a white solid.
- the %ee was checked using the analytical SCF described for Int-30 and the chiral purity of Int-32, retention time 1.98 minutes, was >99.9%.
- mice Female CD-I mice from Charles River Laboratories and were allowed to acclimate for 5 days prior to start of study. Animals were housed 5 per cage with free access to food and water. To induce a transcient state of neutropenia mice received two doses of cyclophosphamide on days -4 and -1 with 150 mg/kg and 100 mg/kg delivered
- P. aeruginosa strain ARC 6347 (AmpC+, PoxB+) was prepared for infection from an overnight plate culture. A portion of the plate was resuspended in sterile saline and adjusted to an OD of 0.1 at 625 nm. The adjusted bacterial suspension was further diluted to target an infecting inoculum of 5.0xl0 5 CFU/mouse. Plate counts of the inoculum was performed to confirm inoculum concentration. Mice were infected with 100 uL of the prepared bacterial inoculum into both the left and right thigh muscles.
- mice were dosed with either test article, positive control antibiotic (levofloxacin), or vehicle.
- Mice receiving Example 6 and Comparator 1 or vehicle were dosed subcutaneous at 10 mL/kg for 8 doses spaced 3 hours apart.
- Animals receiving levofloxacin were dosed with a single dose of 160 mg/kg at two hours post infection.
- mice Three animals were dosed per group / concentration. One group of three mice were euthanized at initiation of therapy (T-Rx) and CFUs determined. All remaining mice were euthanized at 26 hours post infection. Both thighs were aseptically removed, weighed, homogenized to a uniform consistency, serially diluted and plated on bacterial growth media. The CFUs were enumerated after overnight incubation.
- aeruginosa were measured using the BOCILLIN FL penicillin fluorescence anisotropy assay method ⁇ Anal. Biochem. 463, 15-22 (2014)).
- the BOCILLIN FL (Thermo-Fisher Scientific, Waltham, MA) concentration was 30 nM in each case.
- the PBP concentrations were 60 nM for P. aeruginosa PBPla and PBP3, and 300 nM for P. aeruginosa PBP2.
- the assay buffer was 0.1 M sodium phosphate with 0.01% Triton X-100.
- the pH was 7.0 for all the PBPs with the exception of P. aeruginosa PBP2, for which the pH was 6.2. Serial 2-fold dilutions of compounds were employed, with concentrations ranging from 328 to 0.02 ⁇ for the P. aeruginosa PBPs.
- MIC minimal inhibitory concentration
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Abstract
Provided herein are antibacterial compounds represented by Formula I, or a pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are as defined herein. Also provided are pharmaceutical compositions comprising the compounds of Formula I.
Description
COMPOUNDS AND METHODS FOR TREATING BACTERIAL INFECTIONS
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 62/442182, filed January 4, 2017, the entire contents of which are incorporated herein by reference.
BACKGROUND
[0002] According to the Center for Disease Control and Prevention (CDC) an estimated 51,000 healthcare-associated P. aeruginosa infections occur each year in the United States alone with more than 6,000 (13%) of these infections being derived from multi-drug resistant strains. This has led to, on average, about 400 deaths per year. The European Center for Disease Control and Prevention has even higher values with an estimate in 2009 of approximately 800,000 extra hospital days and 10,000 extra deaths caused by resistant P. aeruginosa strains. Currently the multi-drug resistant rate is about 20% for P. aeruginosa and is expected to rise to about 30% by the year 2040.
[0003] Present treatments against P. aeruginosa include β-lactam antibiotics. Although some β-lactam antibiotics show promise in vitro, most, if not all, are plagued by high resistance in clinical settings. Due to the continued resistance and estimated increase for infection, the development of new antibacterials, particular those which confer little or no resistance, is an important medical need.
SUMMARY
[0004] Provided herein are antibacterial compounds which are useful for, among other uses, the treatment of bacterial infections. Such com ounds are represented by Formula I,
or a pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein. Also provided are pharmaceutical compositions comprising the compounds of Formula I.
[0005] The disclosed compounds are designed to act as PBP3 inhibitors and show substantial in vitro and in vivo improvement over PBP2 inhibitor counterparts. See e.g., Table 2, which shows a direct comparison between a known PBP2 inhibitor and an exemplary compound of Formula I where the amino methyl group was replaced with a dimethyl amide group. Treatment of a murine model of P. aeruginosa lung infection with this replacement compound led to more than a 2 Log(CFU/g) reduction in bacterial burden with an exposure of 70% Time above the MIC, whereas the free amino PBP2 known inhibitor counterpart was not active in vivo (did not achieve stasis in this study even with exposures of 100% Time above the MIC) (FIG. 1). Selective inhibition of PBP2 (which is not the primary mode of action of the disclosed compounds) was found to correlate with a high frequency of resistance, severe inoculum effect and low bactericidal activity (high MBC/MIC ratio) all of which are liabilities for antibiotic drugs (Table 2).
BRIEF DESCRIPTION OF THE FIGURES
[0006] FIG. 1 shows in vivo profiling for two P. aeruginosa PBP inhibitors, where panel a) is Example 6 and panel b) is a comparator compound.
DETAILED DESCRIPTION
1. General Description of Compounds
[0007] In certain embodiments the present disclosure provides a compound of Formula I:
or a pharmaceutically acceptable salts thereof, wherein
R 1 and FT 2 are each independently (C1-C6)alkyl or halo(C1-C6)alkyl;
R3 and R4 are each independently hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl;
R5 is hydrogen, -COR6, -NHCOR6, -CH2R7, or -CH=CHR8;
R6 is -ORA or -NRARB;
R7 is -ORC, -SRC, -NRDRE, -OCONRARF, -OCORG, -S(O)RH -S(O)2RH,
-NHC(O)NRARF, phenyl, monocyclic heteroaryl or (C1-C6)alkyl; and
R is phenyl or monocyclic heteroaryl, wherein:
the phenyl represented by R7 and R8 is optionally substituted with one or more groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, -OSO2OH, -COO(C1-C6)alkyl, -CONRARF, -(C1-C6)alkylNH2, and -(C1-C6)alkylOH; the monocylic heteroaryl represented by R7 and R8 is optionally substituted with one or more groups selected from C=0, (C1-C6)alkyl, (C1- C6)haloalkyl, -OSO2OH, -COO(C1-C6)alkyl, -CONRARF, -(C1-C6)alkylNH2, and -(C1-C6)alkylOH;
the (C1-C6)alkyl represented by R is optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, monocyclic heteroaryl, monocyclic heterocyclyl,
NH2, -NH(C=NH)NH2, -CONRARF, and -COR1, wherein the phenyl, monocyclic heteroaryl, and monocyclic heterocyclyl in the substituted (C1- C6)alkyl represented by R7 are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2
-(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARF, -SO2NRARA, -COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARF; each RA is independently hydrogen or (C1-C6)alkyl;
each RD is independently hydrogen, (C1-C6)alkyl, or -COO(C1-C6)alkyl;
R B , RC, R E , R F, R G and RH are each independently hydrogen, (C1-C6)alkyl, phenyl, monocyclic heteroaryl, bicyclic fused heteroaryl, or monocyclic heterocyclyl, wherein:
the phenyl represented by R B , R C , R E , R F , R G and RH is optionally substituted with one or more groups selected from NH2, -(C=NH)NH2i -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, or -(C1-C6)alkylCONRARI; the monocyclic heteroaryl, the bicyclic heteroaryl, and the monocyclic heterocyclyl represented by R B , R C , R E , R F , R G and RH are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3,
-CONRARI, -SO2NRARA, COO(C1-C6)alkyl, -(C1-C6)alkylCONRARI;
the (C1-C6)alkyl represented by RB, RC, RE, RF, RG and RH is optionally substituted with one or more groups selected from NH2,
-NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, monocyclic heteroaryl, monocyclic heterocyclyl, NH2, -NH(C=NH)NH2, -CONRARI and -COR1, wherein the phenyl, monocyclic heteroaryl, and monocyclic heterocyclyl in the substituted (C1-C6)alkyl represented by RC are each independently and optionally substituted with one or more groups selected from NH2,
-(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARI; and R1 is hydrogen, (C1-C6)alkyl, or -(C1-C6)alkylNH2.
2. Definitions
[0008] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -(C1-C6)alkylCONRARI means that the point of attachment for this group occurs on the (C1-C6)alkyl.
[0009] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, CI), bromine (bromo, Br), and iodine (iodo, I).
[0010] The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "haloalkyl", and the like, means saturated straight-chain or branched monovalent
hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e., (C1-C6)alkyl. As used herein, a "(C1-C6)alkyl" group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
[0011] The term "haloalkyl" includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.
[0012] "Alkoxy" means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, proproxy, and butoxy.
[0013] The term "aryl" used alone or as part of a larger moiety as in "aralkyl",
"aralkoxy", or "aryloxy alkyl", refers to an aromatic carbocyclic ring system having, unless otherwise specified, a total of 6 to 10 ring members. The term "aryl" may be used
interchangeably with the term "aryl ring", "aryl group", "aryl moiety," or "aryl radical". In
certain embodiments, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl (abbreviated as "Ph"), naphthyl and the like. It will be understood that when specified, optional substituents on an aryl group may be present on any substitutable position and, include, e.g., the position at which the aryl is attached.
[0014] The term "heteroaryl" used alone or as part of a larger moiety as in
"heteroarylalkyl", "heteroarylalkoxy", or "heteroarylaminoalkyl", refers to a 5- to 12- membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. Nitrogen atoms in an heteraryl may be quaternized e.g., as in 1-methylpyridin- l-ium (see e.g., compounds 32, 48, and the like). The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl,
pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached.
[0015] The term "heterocyclyl" means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be mono- or bicyclic. Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and
tetrahydropyrimidinyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group
may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.
[0016] Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
"Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more
asymmetrically substituted carbon atoms. The symbol "*" in a structural formula represents the presence of a chiral carbon center. "R" and "S" represent the configuration of substituents around one or more chiral carbon atoms. Thus, "R*" and "S*" denote the relative configurations of substituents around one or more chiral carbon atoms.
[0017] As used herein, a hyphen ("-") at the beginning or end of a recited group designates the point at which a recited group is attached to a defined group. For example, -SO2-(C1-C3)alkyl-(C2-C6)cycloalkyl means that the group is attached via the sulfonyl.
[0018] "Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.
[0019] "Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z
(substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. When a disclosed compound is named or depicted by structure without indicating a particular geometric isomer form, it is to be understood that the name or structure encompasses one geometric isomer free of other geometric isomers, mixtures of geometric isomers, or mixtures of all geometric isomers.
[0020] The compounds of the herein may be prepared as individual enantiomers by either enantio-specific synthesis or resolved from an enantiomerically enriched mixture.
Conventional resolution techniques include forming the salt of a free base of each isomer of an enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each enantiomer of an
enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the enantiomers of an enantiomeric pair using an optically pure acid, amine or alcohol (followed by
chromatographic separation and removal of the chiral auxiliary), or resolving an enantiomeric mixture of either a starting material or a final product using various well known
chromatographic methods.
[0021] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
[0022] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
[0023] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer.
[0024] When a disclosed compound is named or depicted by structure without indicating the stereochemistry and e.g. , the compound has more than one chiral center (e.g., at least two chiral centers), it is to be understood that the name or structure encompasses one stereoisomer free of other stereoisomers, mixtures of stereoisomers, or mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s). For example, the name or structure may encompass one stereoisomer free of other diastereomers, mixtures of
stereoisomers, or mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).
[0025] The compounds of the herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
[0026] The terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.
[0027] The term "inhibit," "inhibition" or "inhibiting" includes a decrease in the baseline activity of a biological activity or process.
[0028] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
[0029] The term "effective amount" or "therapeutically effective amount" includes an amount of the compound of Formula I that will elicit a biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a bacterial DNA gyrase or a bacterial infection, amelioration of symptoms of a bacterial infection, or the slowing or delaying of progression of a bacterial infection. In some embodiments, the language "effective amount" includes the amount of a compound of Formula I, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate a bacterial infection or inhibit bacterial DNA gyrase, and/or reduce or inhibit the bacterial growth, replication or bacterial load of a bacteria in a subject.
[0030] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may
be used in the compositions of this disclosure include, but are not limited to, organic or inorganic carriers, excipients or diluents suitable for pharmaceutical applications.
3. Description of Exemplary Compounds
[0031] In a first embodiment the present disclosure provides a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.
[0032] In a second embodiment, R 1 and R 2 in Formula I are each independently (C1- C6)alkyl; and R is (C1-C6)alkyl, wherein the remaining variables are as described above for Formula I.
[0033] In a third embodiment, each RC in Formula I is independently phenyl, monocyclic heterocyclyl, monocyclic heteroaryl, or (C1-C6)alkyl, wherein:
p
the (C1-C6)alkyl represented by RC is substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, monocyclic heteroaryl, monocyclic heterocyclyl, -NH(C=NH)NH2, -CONRARF, or -CORG, wherein the phenyl, monocyclic heteroaryl, and monocyclic heterocyclyl in the substituted (C1-C6)alkyl
p
represented by RC are each independently and optionally substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI
-SO2NRARA, -COO(C1-C6)alkyl, and -(C1-C6)alkylCONRV
p the phenyl, monocyclic heterocyclyl, monocyclic heteroaryl represented by RC are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI;
R is (C1-C6)alkyl optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, heteroaryl, -NH(C=NH)NH2,
-CONRA RF , or -COR I , wherein the phenyl and heteroaryl for R E are each independently optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI, or RE is heteroaryl optionally substituted with (C1-C6)alkyl or halo(C1-C6)alkyl;
R is hydrogen or (C1-C6)alkyl optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl,
heteroaryl, -NH(C=NH)NH2, -CONRARI and -COR1, wherein the phenyl and heteroaryl for R are each optionally and independently substituted with one or more groups selected from NH2,
-(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARF, -SO2NRARA, -COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI;
R is heterocyclyl optionally substituted with -(C=NH)NH2; and
R is (C1-C6)alkyl optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, heteroaryl, -NH(C=NH)NH2,
-CONRARI, or -COR1, wherein the phenyl and heteroaryl for RH are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2 -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH,
-(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI, wherein the remaining variables are as described above for Formula I or the second embodiment.
[0034] In a fourth embodiment, R in Formula I is a monocyclic heteroaryl, bicyclic fused heteroaryl, or (C1-C6)alkyl, each of which are independently optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, heteroaryl, -NH(C=NH)NH2, -CONRA RF, or -COR1, wherein the phenyl and heteroaryl for the optional substituents present on the monocyclic heteroaryl, bicyclic fused heteroaryl, and (C1-C6)alkyl represented by R are each independently optionally substituted with one or more groups selected from NH2, -(C=NH)NH2 -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI
-SO2NRARA, COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARI, wherein the remaining variables are as described above for Formula I or the second or third embodiment.
[0035] In a fifth embodiment the compound of Formula I is of the Formula Ila or Ilb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second, third, or fourth embodiment.
[0036] In a sixth embodiment, the compound of Formula I is of the Formula IIla or Illb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second, third, or fourth embodiment.
[0037] In a seventh embodiment, the compound of Formula I is of the Formula IVa or IVb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second, third, or fourth embodiment.
[0038] In an eighth embodiment, the compound of Formula I is of the Formula Va or Vb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second, third, or fourth embodiment.
[0039] In a ninth embodiment, the compound of Formula I is of the Formula VI:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second, third, or fourth embodiment.
[0040] In a tenth embodiment, R7 in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or
VI is -ORC, -SRC, -NRDRE, -OCONRARF, -OCORG, -S(O)RH -S(O)2RH, -NHC(O)NRARF, monocyclic heteroaryl, or (C1-C6)alkyl, wherein: the monocyclic heteroaryl represented by R is optionally substituted with one or more groups selected from C=0, -OSO2OH, -COO(C1- C6)alkyl, -CONRARF, -(C1-C6)alkylNH2, and -(C1-C6)alkylOH; and the (C1-C6)alkyl represented by R is substituted with NH2 or a monocyclic heteroaryl optionally substituted with one or more (C1-C6)alkyl or halo(C1-C6)alkyl; each RC is independently phenyl, monocyclic heterocyclyl, monocyclic heteroaryl, or (C1-C6)alkyl, wherein: each of said phenyl, heterocyclyl, and heteroaryl for RC are optionally substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1- C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3,
-CONRARI -SO2NRARA, COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARI; and the (C1- C6)alkyl for RC is substituted with one or more groups selected from phenyl, NH2,
-NH(C=NH)NH2, -CONRARI and -COR1, wherein the remaining variables are as described above for Formula I or the second, third, or fourth embodiment. Alternativley, R in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or VI is -ORC, -SRC, -NRDRE, -OCONRARF, -OCORG, -S(O)RH -S(O)2RH, -NHC(O)NRARF, pyridinyl, or triazolyl, or (C1-C6)alkyl, wherein: the pyridinyl or triazolyl represented by R is optionally substituted with one or more groups selected from C=0, OSO2OH, -COO(C1-C6)alkyl, -CONRARI
-(C1-C6)alkylNH2, and -(C1-C6)alkylOH; and the (CrC^alkyl represented by R7 is substituted with one or more NH2 or pyridinyl;each RC is independently phenyl, pyrrolidinyl, azetidinyl, pyridinyl, pyrazolyl or (C1-C6)alkyl, wherein: the (C1-C6)alkyl represented by RC is substituted with one or more phenyl, NH2, -NH(C=NH)NH2, -CONRA RF, or -COR1; and each of said pyrrolidinyl, azetidinyl, pyridinyl, or pyrazolyl for RC are optionally substituted with one or more NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI
-SO2NRARA, COO(C1-C6)alkyl, or -(C1-C6)alkylCONRARI, wherein the remaining variables are as described above for Formula I or the second, third, or fourth embodiment.
[0041] In an eleventh embodiment, RC in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or VI is independently phenyl optionally substituted with 1 or 2 groups selected from - (C=NH)NH2, -(C=NH)NH(piperidinyl), -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, COOH, -CONRARI and -SO2NRARA; pyrrolidinyl optionally substituted with -CONRV; azetidinyl optionally substituted with 1 or 2 -(C=NH)NH2; pyridinyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -COO(C1-C6)alkyl, and COOH; pyrazolyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, and -(C1-C6)alkylN((C1-C6)alkyl)3; or (C1-C6)alkyl substituted with 1 or 2 groups selected from phenyl, NH2, -NH(C=NH)NH2, -CONRA RF, and -COR1, wherein the remaining variables are as described above for Formula I or the second, third, fourth, or tenth embodiment. Alternatively, RC in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or VI is independently phenyl optionally substituted with -(C=NH)NH2, -(C=NH)NH(piperidinyl), -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, COOH, -CONH(C1-C6)alkylNH2, -CONH2, and SO2NH2; pyrrolidinyl optionally substituted with -CON((C1-C6)alkyl)2; azetidinyl optionally substituted with -(C=NH)NH2; pyridinyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -COO(C1-C6)alkyl, and COOH; pyrazolyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, and -(C1-C6)alkylN((C1-C6)alkyl)3; or
-(C1-C6)alkylphenyl, -(C1-C6)alkylNH(C=NH)NH2, -(C1-C6)alkylNH2,
-(C1-C6)alkylNH2CON((C1-C6)alkyl)2, -(C1-C6)alkylNH2CO(piperzinyl),
-(C1-C6)alkylCONH(C1-C6)alkylNH2, or
-(C1-C6)alkylCON[((C1-C6)alkyl)((C1-C6)alkylNH2)], wherein the remaining variables are as described above for Formula I or the second, third, fourth, or tenth embodiment.
[0042] In a twelfth embodiment, RD in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va, Vb or VI is hydrogen or -COO(C1-C6)alkyl; RE is -(C1-C6)alkylNH2 or
-(C1-C6)alkylNHC(O)0(C1-C6)alkyl; RF is -(C1-C6)alkylNH2; RG is piperazinyl optionally substituted with -(C=NH)NH2; and RH is -(C1-C6)alkyl(C=NH)NH2, wherein the remaining variables are as described above for Formula I or the second, third, fourth, tenth, or eleventh, embodiment.
[0043] In a thirteenth embodiment, R7 in Formula I, Ila, Ilb, IIla, Illb, IVa, IVb, Va,
Vb or VI is selected from
remaining variables are as described above for Formula I or the second, third, fourth, tenth, eleventh, or twelfth embodiment.
[0044] In a fourteenth embodiment, the compound of Formula I is of the Formula Vila or Vllb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second embodiment.
[0045] In a fifteenth embodiment, the compound of Formula I is of the Formula Villa or VIIIb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second embodiment.
[0046] In a sixteenth embodiment, the compound of Formula I is of the Formula IXa or IXb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second embodiment.
[0047] In a seventeenth embodiment, the compound of Formula I is of the Formula Xa or Xb:
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I or the second embodiment.
[0048] In an eighteenth embodiment, R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is phenyl or a monocyclic nitrogen containing heteroaryl optionally substituted with (C1-C6)alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is phenyl or pyridinyl optionally substituted with (C1-C6)alkyl, wherein the remaining variables are as described above for Formula I or the second embodiment.
[0049] In a nineteenth embodiment, R in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is hydrogen, a 5- or 6- membered monocyclic nitrogen containing heteroaryl, a 9-membered fused bicyclic nitrogen containing heteroaryl, -(C1- C6)alkylNH2, -(C1-C6)alkylN((C1-C6)alkyl)3, or (C1-C6)alkyl substituted with a 5- or 6- membered nitrogen containing heteroaryl, wherein each of said heteroaryl are optionally substituted with one or more -NH2, (C1-C6)alkyl, or -(C1-C6)alkylN((C1-C6)alkyl)3, wherein the remaining variables are as described above for Formula I or the second or eighteenth
embodiment. Alternatively, R in the compound of Formula I, Vila, Vllb, Villa, Vlllb,
IXa, IXb, Xa, or Xb is hydrogen, pyridinyl, pyrazolyl, indazolyl, -(C1-C6)alkylNH2, or (C1- C6)alkyl substituted with pyridinyl or pyrazolyl, wherein each of said pyridinyl and pyrazolyl are optionally substituted with one or more -NH2, (C1-C6)alkyl, or -(C1-C6)alkylN((C1- C6)alkyl)3, wherein the remaining variables are as described above for Formula I or the second or eighteenth embodiment.
[0050] In a twentieth embodiment, R6 in the compound of Formula I, Vila, Vllb, Villa, Vlllb, IXa, IXb, Xa, or Xb is selected from
Formula I or the second, eighteenth, or nineteenth embodiment.
[0051] Specific examples of compounds are provided in the EXEMPLIFICATION. Pharmaceutically acceptable salts as well as the neutral forms of these compounds are included herein.
4. Uses, Formulation and Administration
[0052] The compounds described herein can be used to treat bacterial infections caused by one or more species of Gram-negative, or atypical bacteria. Gram-negative bacteria include, but are not limited, to Haemophilus influenzae, Acinetobacter baumannii,
Burkholderia spp. Citrobacter spp., Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa, Klebsiella spp., Stenotrophomonas maltophila, Francisella tularensis, Yersinia spp., Salmonella spp., Shigella spp., Legionella spp. and Neisseria gonorrhoeae. Atypical bacteria include, but are not limited to, Mycoplasma pneumoniae, Chlamydophila
pneumoniae, and Legionella pneumophila.
[0053] In some aspects, the bacteria are resistant to one or more antibacterials other than the compounds of Formula I described herein. The language "resistance" and "antibacterial resistance" refers to bacteria that are able to survive exposure to one or more antibacterials. In one aspect, the compounds described herein can be used to treat bacterial infections caused by Gram-negative bacteria or resistant Gram-negative bacteria. In yet a further aspect, the compounds described herein can be used to treat bacterial infections caused by Pseudomonas Aeruginosa, Acinetobacter Baumannii, or Enter obacteriaceae, as well as antibacterial- resistant forms. In yet a further aspect, the compounds described herein can be used to treat bacterial infections caused by Pseudomonas Aeruginosa, as well as antibacterial-resistant forms. For example, resistance mechanisms in Gram- negative bacteria include, but are not limited to, extended- spectrum β-lactamase expression, metallo-β-lactamase expression, carbapenemase expression, DNA gyrase mutation, porin mutation, efflux system
overexpression, lipopolysaccharide modification, and 16S rRNA methylase expression.
[0054] In one aspect, the bacterial infection treated by the present compounds is caused by a Gram-negative bacteria. In another aspect, the bacterial infection treated by the present compounds is caused by P. aeruginosa, A. baumannii, E. coli, or K. pneumoniae and other Enterobacteriaceae. In a further aspect, the bacterial infection treated by the present
compounds is caused by P. aeruginosa. In another aspect, the bacterial infection treated by the present compounds is caused by an antibacterial-resistant Gram-negative bacteria. In yet another aspect, the bacterial infection treated by the present compounds is caused by an antibacterial-resistant strain of P. aeruginosa.
[0055] Bacterial infections treated by the present compounds include, but are not limited to, respiratory (e.g., pneumonia), blood stream (e.g., bacteremia), heart (e.g., endocarditis), CNS (e.g., meningitis, brain abscess), ear (e.g., otitis externa), eye (e.g., bacterial keratitis, endophthalmitis), GI tract (diarrhea, enteritis, enterocolitis), urinary tract, skin,
intraabdominal, nosocomial and wound/burn infections.
[0056] In one aspect, the compounds described herein inhibit penicillin binding protein 3 (PBP3). Thus, in one aspect, the present disclosure provides a method of inhibiting PBP3, comprising administering to a subject in need thereof one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
[0057] In another aspect, the compounds described herein inhibit penicillin binding protein 1 (e.g., PBPla and/or PBPlb). Thus, in one aspect, the present disclosure provides a method of inhibiting PBP1, comprising administering to a subject in need thereof one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.
[0058] In yet another aspect, the compounds described herein are not specific inhibitors of penicillin binding protein 2 (PBP2).
[0059] According to other aspect, the present disclosure provides pharmaceutically acceptable compositions comprising a compound described herein; and a pharmaceutically acceptable carrier. These compositions can be used to treat one or more of the bacterial infections described above, as well as inhibit PBP3.
[0060] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Liquid dosage forms, injectable preparations, solid dispersion forms, and dosage forms for topical or transdermal administration of a compound are included herein.
[0061] The amount of provided compounds that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.
[0062] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound in the composition will also depend upon the particular compound in the composition.
EXEMPLIFICATION
[0063] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds herein, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
Scheme 1
Int-1
[0064] Tert-butyl 3,5-dioxopiperidine-l-carboxylate can be purchased from commercial sources (for example PharmaBlock) or synthesized following the procedure described in Blake, James F. et al., WO2012118850.
Int-2
[0065] Into a 10-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 3,5-dioxopiperidine-l-carboxylate (300 g, 1408.45 mmol, 1.00 equiv), AcOH (3900 mL), Water (900 mL), then 4-methylbenzene-l-sulfonohydrazide (261.97 g, 1408.45 mmol, 1.00 equiv) in AcOH (1950 mL), water (1950 mL) was added at 0°C. The resulting solution was stirred for 48 hs at 25°C. After the reaction is done, the solids were filtered (AcOH- Water filtrate has some product in it but mostly side product), rinsed with minimum amount of water then solid-cake was taken into ~5000-6000mL EtOAc and stirred until all the chunks are in a nice suspension and filtered again to collect white solid
(-70% yield), EtOAc filtrate was then washed with sat. NaHC03 and then brine, dried over Na2S04, filtered and evaporated to give product (-10% yield) more yellow solid containing about 10% side product by NMR. This was purified via flash chromatography using
EtOAc/Hexanes. This resulted in 403 g (75%) of tert-butyl 5-[(4- methylphenyl)hydrazinesulfonyl]-3-oxo- l,2,3,6-tetrahydropyridine-l-carboxylate as a white solid. (ES, m/z): 382[M+1] .
Int-3
[0066] Into a 10-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 5-[(4-methylphenyl)hydrazinesulfonyl]-3-oxo- l,2,3,6- tetrahydropyridine-1 -carboxylate (340 g, 891.3 mmol, 1.00 equiv), N,N-dimethylformamide (3000 mL), 2-(benzyloxy)acetaldehyde (133.86 g, 891.4 mmol, 1.00 equiv), AcOH (45.51 g, 757.9 mmol, 0.85 equiv), TEA (180.3 g, 1781.8 mmol, 2.00 equiv). The resulting solution was stirred for 2 hs at 90°C in an oil bath. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 177.2 g (85%) of tert-butyl 3-[(benzyloxy)methyl]-4-oxo- lH,4H,5H,6H,7H- pyrazolo[3,4-c]pyridine-6-carboxylate as yellow oil. (ES, m/z): 358[M+1] .
Int-4
[0067] Into a 10-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 3-[(benzyloxy)methyl]-4-oxo-lH,4H,5H,6H,7H-pyrazolo[3,4- c]pyridine-6-carboxylate (118 g, 330.16 mmol, 1.00 equiv) in MeCN (6500 mL), then potassium carbonate (54.73 g, 395.99 mmol, 1.20 equiv) was added, then cooled to 0°C, dimethyl sulfate (41.64 g, 330.13 mmol, 1.00 equiv) was added dropwise at 0°C. The resulting solution was stirred for 12 h at room temperature. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with ethyl acetate and brine. The organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/hexane (1 : 10). This resulted in 37 g (30%) of tert-butyl 3- [(benzyloxy)methyl]- l-methyl-4-oxo- lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6- carboxylate as brown oil. (ES, m/z): 372[M+1] ; 1H NMR (300 MHz, DMSO) δ 1.422 (s, 9H), 3.818 (m, 3H), 4.011 (s, 2H), 4.532 (s, 2H), 7.244-7.364 (m, 5H).
Int-5
[0068] In a 3-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, nBuli (285.87mL, 457.38mmol) was added to an ice bath cooled solution of diisopropylamine (64.11mL, 457.38mmol) in THF (466.74mL) and stirred for 20 minutes then further cooled to -78°C and this was added (via cannula) to a solution of tert- butyl 3-(benzyloxymethyl)-l-methyl-4-oxo-5,7-dihydropyrazolo[3,4-c]pyridine-6- carboxylate (48.54g, 130.68mmol) and PMDTA (95.49mL, 457.38mmol) in THF
(466.74mL) which was also cooled to -78°C. After 20 minutes stirring the deep red/brown anion observed, excess CO2 was vigorously bubbled into the reaction and the color faded to a light yellow over 30 minutes (use wide needle to avoid clogging). The CO2 line was removed and the reaction kept cold. After 20 minutes the dry ice/acetone bath was removed and reaction was stirred for 30-40 min (temp reached -12°C) then very slowly and carefully quenched with 900ml 10% aqueous HC1 (pH=l). NOTE: significant CO2 gassing off from dissolved gas, also you will need to carefully warm to around 0°C to avoid ice forming during slow HC1 addition. The mixture was stirred 20 minutes while letting warm to RT to decompose any bis-carboxylated material into the desired product. Then extracted 2x with EtOAc. The combined organics were washed with brine, dried over MgS04 and solvent removed under reduced pressure. The dried solids were dissolved in Et20 and washed 3X with IN NaOH, LCMS indicates all product was removed from the organic layer. The combined aqueous layer was cooled in ice bath and made pH=l by adding first 300mL 10%HC1 then concentrated HC1 and the product was extracted 3X with EtOAc. The combined EtOAc layers were washed with brine, dried over MgS04 to give the product as a dark tan foam on rotary evaporator which became a brown solid under high vacuum (color may vary from beige to brown depending on whether a foam- like or glass-like material is being obtained under vacuum) to give 3-(benzyloxymethyl)-6-tert-butoxycarbonyl-l-methyl- 4-oxo-5,7-dihydropyrazolo[3,4-c]pyridine-7-carboxylic acid (32.7g,78.71mmol, 60.23% yield). (ES, m/z): 416[M+1].
Int-6
[0069] Into a 50-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-[(benzyloxy)methyl]-6-[(tert-butoxy)carbonyl]-l- methyl-4-oxo-lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (31.5 g, 75.82 mmol, 1.00 equiv) in N,N-dimethylformamide (25 mL), then K2C03 (10.5 g, 75.97 mmol, 1.00 equiv) and Me2S04 (10.6 g, 1.10 equiv) were added. The resulting solution was stirred for 2 h at 25°C. The resulting solution was diluted with EtOAc. The resulting mixture was
washed with brine twice. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1 : 1). This resulted in 26.1 g (80%) of 6-tert-butyl 7-methyl 3- [(benzyloxy)methyl]- l-methyl-4-oxo- lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7- dicarboxylate as yellow oil. (ES, m/z): 430[M+1].
Int-7
[0070] Into a 500-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-tert-butyl 7-methyl 3-[(benzyloxy)methyl]-l-methyl-4- oxo- lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7-dicarboxylate (20.5 g, 47.73 mmol, 1.00 equiv), in methanol (180 mL), cooled to -50°C. NaBH4 (800 mg, 21.15 mmol, 0.45 equiv) was then added in small portions at -50°C. The resulting solution was stirred for 20 min at - 50°C. The resulting solution was stirred for an additional 1.5 h at room temperature. The resulting solution was diluted with EtOAc. The resulting mixture was washed with aqueous solution of citric acid and sat sodium bicarbonate. The resulting mixture was washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 19.6 g (95%) of 6-tert-butyl 7-methyl 3-[(benzyloxy)methyl]-4-hydroxy-l- methyl- lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7-dicarboxylate as a colorless foam. (ES, m/z): 432[M+1] .
Int-8
[0071] Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-tert-butyl 7-methyl 3 -[(benzyloxy)methyl]-4-hydroxy- l -methyl - lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7-dicarboxylate (25.5 g, 59.10 mmol, 1.00 equiv), 2-(prop-2-en-l-yloxy)hydrazine-l-thione (13.9 g, 118.20 mmol, 2.00 equiv), PPh3 (46.5 g, 177.28 mmol, 3.00 equiv), in tetrahydrofuran (790 mL), then cooled to 0°C, and then DIAD (35.9 g, 177.54 mmol, 3.00 equiv) was added dropwise at 0°C. The resulting solution was stirred for 12 h at room temperature. The reaction mixture was filtered and washed with ether. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 31.7 g (80%) of 6-tert-butyl 7-methyl 3 -[(benzyloxy)methyl]-l -methyl - 4- [N- [( 1 E)-prop- 1 -en- 1 -yloxy] (4-nitrobenzene)sulfonamido] - 1 H,4H,5H,6H,7H-pyrazolo [3 ,4- c]pyridine-6,7-dicarboxylate as a yellow oil. (ES, m/z): 672[M+1] .
Int-9
[0072] Into a 250-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-tert-butyl 7-methyl 3-[(benzyloxy)methyl]-l-methyl-4- [N- [( 1 E)-prop- 1 -en- 1 -yloxy] (4-nitrobenzene)sulfonamido] - 1 H,4H,5H,6H,7H-pyrazolo [3 ,4-
c]pyridine-6,7-dicarboxylate (23 g, 34.24 mmol, 1.00 equiv) and 2-sulfanylacetic acid (6.348 g, 68.91 mmol, 2.00 equiv) in N,N-dimethylformamide (172 ml), then LiOH (3.312 g, 138.30 mmol, 4.00 equiv) was added. The resulting solution was stirred for 30 min at room
temperature. The resulting solution was diluted with EtOAc. The resulting mixture was washed with water. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with Petroleum Ether/EtOAc (3: 1). This resulted in 10.9 g (65%) of 6-tert-butyl 7-methyl 3-[(benzyloxy)methyl]- l-methyl-4- [[(lE)-prop- l-en- l-yloxy]amino]-lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7- dicarboxylate as yellow oil. (ES, m/z): 487[M+1].
Int-10
[0073] Into a 15-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-tert-butyl 7-methyl 3-[(benzyloxy)methyl]- l-methyl-4-[[(lE)-prop- l-en- l-yloxy]amino]- lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7-dicarboxylate (14.3 g, 29.39 mmol, 1.00 equiv) in dichloromethane (200 mL), then cooled to 0°C. 2,2,2- trifluoroacetaldehyde (44 mL, 20.00 equiv) was then slowly added. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The resulting oil was re-dissolved in DCM and washed with saturated solution of sodium bicarbonate. The resulting mixture was washed with brine. The mixture was dried over sodium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 12 g (crude) of methyl 3-[(benzyloxy)methyl]- l-methyl-4-[[(lE)- prop- l-en-l-yloxy]amino]-lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-7-carboxylate as a yellow oil. (ES, m/z): 387[M+1] .
Int-11
[0074] Into a 5-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-tert-butyl 7-methyl 3-[(benzyloxy)methyl]-l-methyl-4-[[(lE)-prop-l- en-l-yloxy]amino]- lH,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-6,7-dicarboxylate (7.3 g, 15.00 mmol, 1.00 equiv) and DIEA (12.2 g, 94.40 mmol, 5.00 equiv) in dichloromethane (1900 mL, 1.00 equiv), then cooled to 0°C, and then a solution of triphosgene (2.3 g, 7.75 mmol, 0.40 equiv) in MeCN (170 mL, 1.00 equiv) was added dropwise at the rate of 0.08ml/min at 0 oC for 8 hours. The resulting solution was allowed to warm to room temperature while stirring for an additional 12 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM. The resulting mixture was washed with brine. The mixture was dried over sodium sulfate. This resulted in 5.8 g (94%) of methyl (lR,7S)-3-[(benzyloxy)methyl]- 5-methyl-9-oxo-10-(prop-2-en- l-yloxy)-4,5,8,10-tetraazatricyclo undeca-
2(6),3-diene-7-carboxylate as a yellow oil. (ES, m/z): 413[M+1] ; IH-NMR 3.12 (d, IH), 3.39 (d, IH), 3.70 (s, 3H), 3.78 (s, 3H), 4.2-4.3 (m, 2H), 4.5 (s, 2H), 4.6 (s, 2H), 5.20 (s, IH), 5.21 (q, 2H), 5.52(s, IH), 5.59-5.79 (m, IH), 7.30-7.37 (m, 5H).
Int-12
[0075] IN LiOH (14.55mL, 14.55mmol) was added dropwise over lOmin into an ice-bath cooled solution of methyl 10-allyloxy-3-(benzyloxymethyl)-5-methyl-9-oxo-4,5,8,10- tetrazatricyclo
undeca-2(6),3-diene-7-carboxylate (6.g, 14.55mmol) in THF (137.7mL) and Water (13.7mL). The reaction was stirred at 0°C for 20min. The reaction in ice bath was then added dropwise IN HCl (21.82mL, 21.82mmol) to pH=3. The mixture was diluted with EtOAc and washed with water, and then with brine. The organic layer was then dried over Na2S04, filtered and concentrated to give 10-allyloxy-3-(benzyloxymethyl)-5- methyl-9-oxo-4,5,8, 10-tetrazatricyclo undeca-2(6),3-diene-7-carboxylic acid
(5.611g, 14.083mmol, 96.81% yield) as a light beige foam. (ES, m/z): 399.3 [M+l], IH-NMR (300 MHz, DMSO-d6): δ 3.10 (d, IH); 3.39 (dd, IH); 3.70 (s, 3H); 4.27 (m, 2H); 4.44 (s, 2H); 4.51 (s, 2H); 4.65 (d, IH); 5.19 (m, IH); 5.29 (m, IH); 5.34 (s, IH); 5.84 (m, IH); 7.33 (m, 5H); 13.67 (s, IH).
Int-13
[0076] DIPEA (7.36mL, 42.24mmol) was added to a solution of 10-allyloxy-3- (benzyloxymethyl)-5-methyl-9-oxo-4,5,8, 10-tetrazatricyclo
]undeca-2(6),3-diene- 7-carboxylic acid (5.61g, 14.08mmol), dimethylamine hydrochloride (2296.32mg,
28.16mmol) and HATU (5889.41mg, 15.49mmol) in DMF (61.22mL) at OoC and the reaction was stirred for 20min. Reaction was then diluted with EtOAc. The organic layer was washed 4X with brine, dried over Na2S04 and solvent was removed. The material was chromatographed on silica eluting with 80-100% EtOAc/Hexanes. The combined purified fractions were removed of solvent and the material placed under high vacuum to give the product 10-allyloxy-3-(benzyloxymethyl)-N,N,5-trimethyl-9-oxo-4,5,8, 10- tetrazatricyclo undeca-2(6),3-diene-7-carboxamide (5.04g, l 1.84mmol, 84.1%
yield) as a light beige glassy solid. (ES, m/z): 426.4 [M+l], IH-NMR (300 MHz, DMSO-d6): δ 2.92 (s, 3H); 3.04 (d, IH); 3.25 (s, 3H); 3.32 (dd, IH); 3.52 (s, 3H); 4.27 (m, 2H); 4.44 (d, 2H); 4.51 (s, 2H); 4.65 (d, IH); 5.19 (d, IH); 5.29 (d, IH); 5.60 (s, IH); 5.84 (m, IH); 7.35 (m, 5H)
Int-14
[0077] 1M solution of BC13 in DCM (18.13mL, 18.13mmol) was slowly added to an ice bath cooled solution of 10-allyloxy-3-(benzyloxymethyl)-N,N,5-trimethyl-9-oxo-4,5,8, 10-
tetrazatricyclo undeca-2(6),3-diene-7-carboxamide (5.04g, 11.83mmol) in DCM
(138.3mL) and the reaction kept cold for lh. The material precipitated out from the reaction over time. The reaction in the ice bath was added solid NaHC03 (11.93g, 142mmol) pH still ~1, followed by methanol (7.19mL, 177.5 lmmol). The material was then sonicated for a few minutes. The mixture was stirred at RT for 90minutes then the salts were filtered off. The filtrate was removed of solvent. The material was chromatographed on silica eluting from 50 to 100% acetone/DCM. The combined purified fractions were removed of solvent and the material placed under high vacuum to give the product 10-allyloxy-3-(hydroxymethyl)- N,N,5-trimethyl-9-oxo-4,5,8,10-tetrazatricyclo
undeca-2(6),3-diene-7- carboxamide (3.215g, 9.59mmol, 81.0% yield) as a white solid. (ES, m/z): 336.3 [M+1], 1H- NMR (300 MHz, DMSO-d6): δ 2.92 (s, 3H); 3.04 (d, IH); 3.25 (s, 3H); 3.32 (dd, IH); 3.49 (s, 3H); 4.38 (m, 4H); 4.75 (d, IH); 4.95 (t, IH); 5.26 (d, IH); 5.33 (d, IH); 5.57 (s, IH); 5.95 (m, IH)
Int-15
[0078] To a suspension of periodic acid (1840.36mg, 9.59mmol) in wet MeCN (25mL) (0.75% water by volume) at room temperature was added chromium(VI) oxide (8.63mg, 0.0900mmol). The mixture was stirred until complete dissolution was achieved. To a solution of 10-allyloxy-3-(hydroxymethyl)-N,N,5-trimethyl-9-oxo-4,5,8,10- tetrazatricyclo undeca-2(6),3-diene-7-carboxamide (1072mg, 3.2mmol) in wet
MeCN (25mL) (0.75% water by volume) at 0°C was added dropwise the previously formed oxidizing solution. Let stir overnight. The reaction mixture was then evaporated, added cone, citric acid and then extracted 8x with DCM. The organics were dried over sodium sulfate, filtered and concentrated to afford 10-allyloxy-7-(dimethylcarbamoyl)-5-methyl-9-oxo- 4,5,8,10-tetrazatricyclo undeca-2(6) ,3 -diene-3 -carboxylic acid (914mg,2.62mmol,
81.8% yield) as an off-white solid. (ES, m/z): 350.2 [M+1], IH-NMR (300 MHz, DMSO-d6): δ 2.92 (s, 3H); 3.04 (d, IH); 3.25 (s, 3H); 3.32 (dd, IH); 3.63 (s, 3H); 4.36 (d, 2H); 4.98 (d, IH); 5.26 (m, IH); 5.33 (m, IH); 5.68 (s, IH); 5.92 (m, IH); 12.77 (s, IH)
Int-16
[0079] DIPEA (0.07mL, 0.4000mmol) was added to a solution of 10-allyloxy-7- (dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8,10-tetrazatricyclo
undeca-2(6),3- diene-3 -carboxylic acid (70. mg, 0.2000mmol), l-Methyl-lH-pyrazol-4-amine (38.92mg, 0.4000mmol) and HATU (83.81mg, 0.2200mmol) in DMF (lmL) and the reaction was stirred for 20min. LCMS shows reaction is complete. The reaction was added EtOAc, washed 4X with brine, dried over Na2S04, filtered and solvent removed. The material was
chromatographed on silica gel column (15-100%Acetone/DCM) to give 10-allyloxy- N7,N7,5-trimethyl-N3-(l-methylpyrazol-4-yl)-9-oxo-4,5,8,10- tetrazatricyclo
undeca-2(6),3-diene-3,7-dicarboxamide (74mg,0.17mmol, 86.2% yield) as a white solid. (ES, m/z): 429.3 [M+l], 1H-NMR (300 MHz, DMSO-d6): δ 2.94 (s, 3H); 3.04 (d, IH); 3.28 (s, 3H); 3.44 (dd, IH); 3.67 (s, 3H); 4.09 (s, 6H); 5.25 (d, IH); 5.71 (s, IH); 8.65 (s, 2H); 10.81 (s, IH)
Int-17
[0080] A mixture of 10-allyloxy-N7,N7,5-trimethyl-N3-(l-methylpyrazol-4-yl)-9-oxo- 4,5,8,10-tetrazatricyclo[ undeca-2(6),3-diene-3,7-dicarboxamide (85.mg,
0.2000mmol) 1,3-dimethylbarbituric acid (61.95mg, 0.4000mmol) and Pd(PPh3)4 (22.93mg, 0.0200mmol) in Methanol (2mL) was stirred at RT for 4h. The solvent was removed and material was purified via flash chromatography (40g, 20-100% Acetone/DCM) to give 10- hydroxy-N7,N7,5-trimethyl-N3-(l-methylpyrazol-4-yl)-9-oxo-4,5,8,10- tetrazatricyclo
undeca-2(6),3-diene-3,7-dicarboxamide (70mg, 0.18mmol, 90.8% yield) as an orange oil. Crude was used in the next step. (ES, m/z): 389.2 [M+l]
Int-18
[0081] To 10-hydroxy-N7,N7,5-trimethyl-N3-(l-methylpyrazol-4-yl)-9-oxo-4,5,8,10- tetrazatricyclo
undeca-2(6),3-diene-3,7-dicarboxamide (70. mg, 0.1800mmol) was added Pyridine (2mL) and pyridin-l-ium-1- sulfonate (286.86mg, 1.8mmol) then stirred for 6h. Pyridine was evaporated and the residue kept under high-vacuum for 4h then water was added then tetrabutylammonium sulfate (0.4 ImL, 0.1800mmol) and extracted with DCM. DCM was evaporated to obtain [7-(dimethylcarbamoyl)-5-methyl-3-[(l-methylpyrazol-4- yl)carbamoyl]-9-oxo-4,5,8,10-tetrazatricyclo
undeca-2(6),3-dien-10-yl] hydrogen sulfate (pyridine- 1-ium salt by LCMS) as a yellow film. The crude was used in the next step. (ES, m/z): 469.2 [M+l]
Example 1
[0082] Dowex 50WX8, 100-200 mesh (10.5g, 1458.7mmol) was conditioned by stirring for 3 hours in 2N NaOH (25mL, 50mmol). The resin was then loaded into a cartridge and washed with water until the pH was < 7. It was then washed with (1/1) acetone/water (30mL), followed by water (30 mL). Crude from previous step was taken up in water/acetone. The pale yellow solution was loaded on the resin and washed through with water. Tubes that had the desired product mass were combined and lyophilized together to give 77mg beige solid which was purified on Sepabeads SP20SS (0-10%ACN/Water), then lyophilized to give [7-
(dimethylcarbamoyl)-5-methyl-3-[(l-methylpyrazol-4-yl)carbamoyl]-9-oxo-4,5,8,10- tetrazatricyclo undeca-2(6),3-dien-10-yl] hydrogen sulfate (47mg, O. lOmmol,
55.7% yield over 3 steps) as a white fluffy solid. (ES, m/z): 469.3 [M+l]; 1H-NMR (300 MHz, DMSO-d6): δ 2.94 (s, 3H); 3.04 (d, IH); 3.28 (s, 3H); 3.43 (dd, IH); 3.65 (s, 3H); 3.79 (s, 3H); 5.21 (d, IH); 5.70 (s, IH); 7.60 (s, IH); 8.02 (s, 2H); 9.98 (s, IH)
Example 2
[0083] To a solution of [7-(dimethylcarbamoyl)-5-methyl-3-[(l-methylpyrazol-4- yl)carbamoyl]-9-oxo-4,5,8,10-tetrazatricyclo[
undeca-2(6),3-dien-10-yl] hydrogen sulfate (14mg, 0.028mmol) in DMF (0.9mL) at -78°C was added trimethyloxonium tetrafluoroborate (8.4mg, 0.06mmol) then the reaction was warmed to RT and stirred at RT for lh. This was repeated several times until all the starting material was gone by LCMS. Then added 2mL pH=7 buffer, loaded onto Sepabeads SP20SS column and eluted with 0- 16%ACN/Water to give [7-(dimethylcarbamoyl)-3-[(l,2-dimethylpyrazol-2-ium-4- yl)carbamoyl]-5-methyl-9-oxo-4,5,8,10-tetrazatricyclo
undeca-2(6),3-dien-10-yl] sulfate (5.9 mg, 0.012mmol, 40.7% yield) as a white solid. (ES, m/z): 483.4 [M]; 1H-NMR (300 MHz, DMSO-d6): δ 2.94 (s, 3H); 3.04 (d, IH); 3.28 (s, 3H); 3.44 (dd, IH); 3.67 (s, 3H); 4.09 (s, 6H); 5.25 (d, IH); 5.71 (s, IH); 8.65 (s, 2H); 10.81 (s, IH).
Scheme 2
lnt-19 lnt-20 lnt-21
lnt-14 lnt-22 lnt-23
Example 3
lnt-24
Int-19
[0084] TEA (2.07mL, 14.88mmol) was added to a mixture of Ethyl 4- hydroxybenzenecarboximidoate hydrochloride (1.5g, 7.44mmol) and Tert-butyl-N- 2(aminoethyl)carbamate (1.43g, 8.93mmol) in DMF (lOmL) and the reaction stirred at RT. After 2 hours the reaction was complete and used as is in next step assuming 100% yield. (ES, m/z): 297 [M+1] .
Int-20
[0085] To the crude reaction of Int- 19 was added Boc20 (4.04g, 18.53mmol) and TEA (3.09mL, 22.23mmol) and the reaction was stirred overnight. Solvent was evaporated and the material placed under high vacuum. The material was dissolved in EtOAc and washed 5X brine, 4X 5% Citric acid, 2X NaHC03, IX Brine, dried over Na2S04 and the solvent removed. The material was chromatographed on 80g silica eluting 100% Hexanes to 100% EtOAc and the combined purified fractions were evaporated to give Int-20 as a beige solid, (ES, m/z): 479 [M+1] ; 1H-NMR (300 MHz, DMSO-d6): δ 1.20 (s, 9H), 1.40 (s, 9H), 1.50 (s, 9H), 3.11-3.17 (M, 2H), 3.24-3.30 (m, 2H), 6.88-6.91 (m, 1H), 7.24-7.29 (m, 2H), 7.40-7.45 (m, 2H), 7.76 (br. S, 1H).
Int-21
[0086] LiOH (1.15mL, 1.15mmol) was added to a solution of [4-[(E)-N'-tert- butoxycarbonyl-N-[2-(tert-butoxycarbonylamino)ethyl]carbamimidoyl]phenyl] tert-butyl carbonate (500mg, 1.04mmol) in THF (4mL), MeOH (4mL) and Water (lmL) and the reaction was stirred overnight at room temperature. To the reaction was added some additional LiOH (1.15mL, 1.15mmol) and the mixture stirred for 1 extra hour. The solvent was removed and the material partitioned between 5% citric acid and EtOAc. The material formed a precipitate in EtOAc and was filtered off and placed under high vac overnight. (ES, m/z): 379 [M+1] ; 1H-NMR (300 MHz, DMSO-d6): δ 1.22 (s, 9H), 1.38 (s, 9H), 3.08-3.14 (m, 2H), 3.20-3.26 (m2H), 6.72-6.77 (mlH), 6.87-6.90 (m2H), 7.20-7.25 (m2H), 7.49 (br. S, 1H).
Int-22
[0087] Tert-butyl (NE)-N-[[2-(tert-butoxycarbonylamino)ethylamino]-(4- hydroxyphenyl)methylene]carbamate (84.86mg, 0.2200mmol) was added to a solution of PPh3 (58.66mg, 0.2200mmol) and DIAD (0.04mL, 0.1800mmol) in THF (2mL) and stirred for lOmin. To this mixture was added 10-allyloxy-3-(hydroxymethyl)-N,N,5-trimethyl-9- oxo-4,5,8,10-tetrazatricyclo[6.2.1.0A2,6]undeca-2(6),3-diene-7-carboxamide (50. mg, 0.1500mmol) and reaction was stirred at RT. After 1 hour the reaction was removed of solvent and chromatographed on 20g silica eluting EtOAc to 10%MeOH/EtOAc and the
combined purified fractions removed of solvent to give the product tert-butyl (NE)-N-[[4- [[10-allyloxy-7-(dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8, 10- tetrazatricyclo
undeca-2(6),3-dien-3-yl]methoxy]phenyl]-[2-(tert- butoxycarbonylamino)ethylamino]methylene]carbamate (80mg, O. l lmmol, 77.0% yield) as a clear glassy solid. (ES, m/z): 697[M+1]
Int-23
[0088] Pd(PPh3)4 (26.5mg, 0.02mmol) was added to a solution of tert-butyl (NE)-N-[[4- [[10-allyloxy-7-(dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8, 10- tetrazatricyclo ]undeca-2(6),3-dien-3-yl]methoxy]phenyl]-[2-(tert-
butoxycarbonylamino)ethylamino]methylene]carbamate (80mg, O. l lmmol) and 1,3- Dimethylbarbituric acid (35.85mg, 0.23mmol) in Methanol (2mL). After 2hrs, the solvent was removed and the crude Int-23 used as is in the next step.
Int-24
[0089] Pyridine (2mL) and S03.pyridine (182.74mg, 1.15mmol) were added to the crude Int 23 and the mixture was stirred at RT for 3 hours. The reaction was removed of solvent and material dissolved in DCM, precipitate was filtered off and the filtrate was removed of solvent. The material was dissolved in DCM, filtered again and the solvent removed to give 84mg crude product tert-butyl (NE)-N-[[2-(tert-butoxycarbonylamino)ethylamino]-[4-[[7- (dimethylcarbamoyl)-5-methyl-9-oxo- 10-sulfooxy-4,5,8,10- tetrazatricyclo undeca-2(6),3-dien-3-yl]methoxy]phenyl]methylene]carbamate as
an orange solid which was used as is in the next step. (ES, m/z): 737[M+1]
Example 3
[0090] TFA (2mL, 0.1 lmmol) was added to solution of crude tert-butyl (NE)-N-[[2-(tert- butoxycarbonylamino)ethylamino]-[4-[[7-(dimethylcarbamoyl)-5-methyl-9-oxo-10-sulfooxy- 4,5,8,10-tetrazatricyclo
undeca-2(6),3-dien-3- yl]methoxy]phenyl]methylene]carbamate (Int 24, 84 mg) in DCM (2mL) and the reaction was stirred at RT. After 1 hour the solvent was removed and the material placed under high vacuum. The crude gum was dissolved in 4mL pH7 buffer and was purified over 2 runs on a 20g Interchim RPAQ C18 column eluting with water to 30%ACN over 15min. The clean fractions combined and removed of solvent then dissolved in 50%ACN/water and lyophilized to give the product [3-[[4-[N-(2-aminoethyl)carbamimidoyl]phenoxy]methyl]-7- (dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8,10-tetrazatricyclo
undeca-2(6),3- dien-10-yl] hydrogen sulfate (17mg, 0.028mmol, 25% over 3 steps) as a white powder. (ES,
m/z): 537[M+1] ; 1H NMR (300MHz, DMSO-J6) δ 2.93 (s, 3H), 3.00-3.10 (m, 3H), 3.27 (s, 3H), 3.41 (dd, IH, J=2.7, 11.7Hz), 3.55 (s, 3H), 4.88 (d, IH, J=2.7Hz), 5.11 (s, 2H), 5.63 (s, IH), 7.34 (d, 2H, J=9.0Hz), 7.78 (d, 2H, J=9.0), 8.13 (br. s, 5H).
Scheme 3
lnt-25
[0091] 10-allyloxy-7 -(dimethylcarbamoyl)-5-methyl-9-oxo-4,5 , 8,10- tetrazatricyclo undeca-2(6),3-diene-3-carboxylic acid (Int-15, 30mg, 0.09mmol),
triethylamine (0.06mL, 0.43mmol) and diphenylphosphoryl azide (0.05mL, 0.21mmol) in Toluene (lmL) and THF (0.7mL) were subjected to 3 cycles of vacuum/Nitrogen flush and stirred at RT until all starting material was converted to the acylazide by LCMS (warmed to 50°C for lh for completion) then cooled to RT and added n-boc-ethanolamine (0.07mL, 0.43mmol) and stirred for lh at RT then heated at 85oC for 8h. Volatiles were evaporated and crude was purified via flash chromatography (40g silica gel column, 0- 100%Acetone/DCM) to give 2-(tert-butoxycarbonylamino)ethyl N-[10-allyloxy-7- (dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8,10-tetrazatricyclo
undeca-2(6),3- dien-3-yl]carbamate (27mg, 0.05mmol, 61.9% yield) as a yellow sticky oil. (ES, m/z): 508.3 [M+l]
Int-26
[0092] Methanol (2mL) was added to a mixture of 2-(tert-butoxycarbonylamino)ethyl N- [10-allyloxy-7-(dimethylcarbamoyl)-5-methyl-9-oxo-4,5,8,10- tetrazatricyclo undeca-2(6),3-dien-3-yl]carbamate (90mg, 0.1800mmol), 1,3-
dimethylbarbituric acid (55.38mg, 0.35mmol) and Pd(PPh3)4 (20.5mg, 0.02mmol) and the reaction was stirred at RT for 4h. The solvent was removed and material was purified via flash chromatography (40g, 0-100% Acetone/DCM) to give 2-(tert-
butoxycarbonylamino)ethyl N-[7-(dimethylcarbamoyl)- 10-hydroxy-5-methyl-9-oxo-4,5,8, 10- tetrazatricyclo
undeca-2(6),3-dien-3-yl]carbamate (49mg, 0.105mmol, 59.1% yield) as an orange oil. (ES, m/z): 468.3 [M+l].
Int-27
[0093] 2-(tert-butoxycarbonylamino)ethyl N-[7-(dimethylcarbamoyl)- 10-hydroxy-5- methyl-9-oxo-4,5,8, 10-tetrazatricyclo
]undeca-2(6),3-dien-3-yl]carbamate (47.63mg, O. lmmol) was added Pyridine (2mL) and pyridin-l-ium-1- sulfonate (162.16mg, 1.02mmol) then stirred overnight. Evaporated Pyridine, kept under high vacuum for 4h then purified on a combined column of C18 gold (5g) and RPAQ column (5g, interchim) to give [3-[2-(tert-butoxycarbonylamino)ethoxycarbonylamino]-7-(dimethylcarbamoyl)-5-methyl-9- oxo-4,5,8, 10-tetrazatricyclo
undeca-2(6),3-dien- 10-yl] sulfate;pyridin- 1-ium (25mg, 0.04mmol, 39.16% yield). (ES, m/z): 548.2 [M+l].
Example 4
[0094] [3-[2-(tert-butoxycarbonylamino)ethoxycarbonylamino]-7-(dimethylcarbamoyl)- 5-methyl-9-oxo-4,5,8,10-tetrazatricyclo undeca-2(6),3-dien- 10-yl]
sulfate;pyridin- 1-ium (25.mg, 0.04mmol) was dissolved in DCM (lmL) at OoC then TFA (2mL, 0.04mmol) was added. The reaction was then stirred for 3 hours. The solvent was removed. The material was dissolved in pH 7 phosphate buffer (~3mL) and purified on Sepabeads SP20SS (0-15% water/ACN), and corresponding fractions were lyophilized to give 2-aminoethyl N-[7-(dimethylcarbamoyl)-5-methyl-9-oxo-10-sulfooxy-4,5,8,10- tetrazatricyclo
undeca-2(6),3-dien-3-yl]carbamate (17mg, 0.04mmol, 90.5% yield) as a white solid. (ES, m/z): 448.1 [M+l]; 1H-NMR (300 MHz, DMSO-d6): δ 2.93 (s, 3H); 3.06 (m, 3H); 3.26 (s, 3H); 3.36 (dd, IH); 3.45 (m, 2H); 4.19 (s, 3H); 5.01 (d, IH); 5.57 (s, lH); 7.18 (s, 2H); 9.46 (s, IH).
lnt-29
[0095] A hydrogen balloon (excess mmol) was fitted atop a mixture of (trans racemic)-5- (benzyloxy)-N,N, l-trimethyl-6-oxo-4,5,6,8-tetrahydro- lH-4,7-methanopyrazolo[3,4-e] [l,3] diazepine-8-carboxamide (223mg, 0.63mmol) (lnt-28, which was prepared following a procedure similar to Aszodi, J. et al. WO2002100860) and Pd/C 10%(50mg, 0.05mmol) in methanol (lOmL) and mixture stirred at RT. After lhr, the catalyst was filtered off and the filtrate removed of solvent under reduced pressure and placed under high vacuum to give the product lnt-29 (trans racemic)-5-hydroxy-N,N,l-trimethyl-6-oxo-4,5,6,8-tetrahydro-lH-4,7- methanopyrazolo[3,4-e] [l,3]diazepine-8-carboxamide (155mg,0.58mmol, 93% yield) as a white solid. (ES, m/z): 266[M+1] ; 1H NMR (300MHz, DMSO-d6) δ 2.92 (s, 3H), 3.01 (d, IH, J=10.8 Hz), 3.26 (s, 3H), 3.34 (dd, IH, J=3.0, 10.8 Hz), 3.54 (s, 3H), 4.36 (d, IH, J=2.4 Hz), 5.54 (s, IH), 7.38 (s, IH), 9.61 (s, IH).
Example 5
[0096] S03 Pyridine (279.mg, 1.75mmol) was added to a solution of (trans racemic)-5- hydroxy-N,N,l-trimethyl-6-oxo-4,5,6,8-tetrahydro-lH-4,7-methanopyrazolo[3,4- e][l,3]diazepine-8-carboxamide (155mg, 0.58mmol) in pyridine (3mL) and reaction stirred at RT. After 2hrs, additional SO3 Pyridine (279mg, 1.75mmol) was added. After a total of 3 hours of stirring, the reaction was removed of solvent under reduced pressure and material was placed under high vacuum. The material was triturated with DCM, the precipitate filtered off and the filtrate was removed of solvent. This crude material was dissolved in water and placed in an 80g Dowex 50WX8, 100-200 mesh resin column which had been conditioned with 6N NaOH and flushed with water until pH was neutral. The compound was eluted from the resin with water and the combined fractions were lyophilized. The material was dissolved in water and applied to a 3.5x14cm Sepabead HP20SS (Supelco 13618-U) column conditioned to water per manufacturer's instructions and column eluted via gravity flow with a step gradient of 150mL water, 150mL l%ACN/water and 150ml 2%ACN/water collecting lOmL fractions. The combined fractions were filtered and lyophilized to give (trans racemic)- 8-(dimethylcarbamoyl)-l-methyl-6-oxo-4,8-dihydro-lH-4,7-methanopyrazolo[3,4- e][l,3]diazepin-5(6H)-yl hydrogen sulfate sodium salt (97mg, 48%) as a white solid. (ES, m/z): 346[M+1] [Retain time: 1.32 min]; 1H NMR (300MHz, DMSO-d6) δ 2.93 (s, 3H), 3.04 (d, 1H, J=11.4Hz), 3.27 (s, 3H), 3.37 (dd, 1H J=2.7, 10.8Hz), 3.54 (s, 3H), 4.69(d, 1H, J=2.4Hz), 5.60 (s, 1H), 7.35 (s, 1H).
Int-30
[0097] Chiral separation of 1.6g (trans racemic)-5-(benzyloxy)-N,N,l-trimethyl-6-oxo- 4,5,6,8-tetrahydro-lH-4,7-methanopyrazolo[3,4-e][l,3]diazepine-8-carboxamide, Int-28, prepared according to Aszodi, J. et al. WO2002100860 was performed on Berger II preparative SFC with a Chiralpak ID 21.2x250mm, 5μΜ, column eluting isocratic
30%MeOH/CO2, 10 minute run with stacked injections at 5mL/min flow rate, a column temperature of 40°C, and collecting at 210nm. The solvent from Peak B, the second peak in the elution order, retention time 7.5minutes, was pooled and removed under reduced pressure to give the chiral product Int-30 (4R,8S)-5-(benzyloxy)-N,N,l-trimethyl-6-oxo-4,5,6,8- tetrahydro-lH-4,7-methanopyrazolo[3,4-e][l,3]diazepine-8-carboxamide (601mg, 37%) as a white solid. The %ee was checked on Berger analytical SCF with a Chiralpak ID
4.6x 100mm, 5μΜ, column eluting gradient CO2 to 25%MeOH/CO2 over 5 minutes, at 5mL/min flow rate, a column temperature of 40°C, and monitoring at 210nm. The chiral purity of Int-30, analytical retention time 2.62minutes, was 97.2%ee.
Int-32
[0098] Peak A, the first to elute, retention time 5.6 minutes, in the chiral preparative separation conditions described for Int-30, was pooled and solvent removed under reduced pressure to give the chiral product Int-32 (4S,8R)-5-(benzyloxy)-N,N, l-trimethyl-6-oxo- 4,5,6,8-tetrahydro- lH-4,7-methanopyrazolo[3,4-e] [l,3]diazepine-8-carboxamide (525mg, 32%) with an as a white solid. The %ee was checked using the analytical SCF described for Int-30 and the chiral purity of Int-32, retention time 1.98 minutes, was >99.9%.
Example 6
[0099] Chiral Int-30 was progressed as described for Int-29 to make Int-31 and this progressed as described for Example 5 to give the chiral product Example 6 (4R,8S)-8- (dimethylcarbamoyl)-l-methyl-6-oxo-4,8-dihydro-lH-4,7-methanopyrazolo[3,4- e] [l,3]diazepin-5(6H)-yl hydrogen sulfate sodium salt (140mg, 26%) as a white solid. (ES, m/z): 346[M+1] ; 1H NMR (300MHz, DMSO-d6) δ 2.93 (s, 3H), 3.04 (d, 1H, J=l l . lHz), 3.27 (s, 3H), 3.37 (dd, 1H, J=3.0, 11.1Hz), 3.54 (s, 3H), 4.69(d, 1H, J=2.7Hz), 5.59 (s, 1H), 7.35 (s, 1H).
Example 7
[00100] Chiral Int-32 was progressed as described for Int-29 to make Int-33 and this progressed as described for Example 5 to give the chiral product Example 7 (4S,8R)-8- (dimethylcarbamoyl)-l-methyl-6-oxo-4,8-dihydro-lH-4,7-methanopyrazolo[3,4- e] [l,3]diazepin-5(6H)-yl hydrogen sulfate sodium salt, (222mg, 43%) as a white solid. (ES, m/z): 346[M+1] ; 1H NMR (300MHz, DMSO-d6) δ 2.93 (s, 3H), 3.04 (d, 1H, J=l 1.1 Hz), 3.27 (s, 3H), 3.36 (dd, 1H, J=3.0, 11.1Hz), 3.54 (s, 3H), 4.69(d, 1H, J=2.7Hz), 5.59 (s, 1H), 7.35 (s, 1H).
Analytical data for Additional Examples
[00101] All compounds below in Table 1 were synthesized according to schemes 1-3 or similar reactions easily known to a person skilled in the art. All compounds were isolated as trans racemic. Chiral enantiomers can be obtained following the procedure described in scheme 4.
[00102] In vitro profiling of a PBP2 inhibitor (Comparator 1) versus a PBP3 inhibitor (Example 6) demonstrated that, despite resulting in a low MIC against P. aeruginosa, the selective inhibition of PBP2 correlates with a high frequency of resistance, severe inoculum effect and low bactericidal activity (high MBC/MIC ratio) all of which are liabilities for antibiotic drugs. These phenotypes, which were determined according to standard methods (Method M26A, CLSI (2015); Pope, et al. (2008) Antimicrob. Agents Chemother. 52: 1209), were not observed for the PBP3 inhibitor Example 6. It is well-established in the field that PBP2 inhibition results in spherical cells while PBP3 inhibition results in filamentous cells (Nonejuie, et al. (2013) PNAS 110: 16169). The PBP3 mode of action of Example 6 was therefore confirmed using microscopy. Log-phase cultures of P. aeruginosa (PAOl) were exposed to the indicated amount of the compound of interest and incubated at 35°C with shaking for 3 hours, then visualized with light microscopy at 600X. The mechanism of action of the claimed compounds was therefore designed to be PBP3 -mediated. Data is shown below in Table 2.
Table 2
In Vivo Profiling for P. aeruginosa PBP Inhibitors
[00103] In vivo efficacy of Comparator 1 and Example 6 was evaluated against a P. aeruginosa clinical isolate (ARC6347, AmpC+, PoxB+) in a neutropenic murine thigh model. See FIG. la and lb. The PBP2 compound (Comparator 1, chiral) was not active (did not achieve stasis in this study even with exposures of 100% Time above the MIC) while the PBP3 compound (Example 6, chiral) showed robust efficacy (more than 2 Log(CFU/g) reduction with an exposure of 70% Time abobve the MIC). This is surprisingly, particularly since the structural difference between Example 6 and Comparator 1 is the replacement of an amino methyl group by a dimethylamide group.
[00104] Female CD-I mice from Charles River Laboratories and were allowed to acclimate for 5 days prior to start of study. Animals were housed 5 per cage with free access to food and water. To induce a transcient state of neutropenia mice received two doses of cyclophosphamide on days -4 and -1 with 150 mg/kg and 100 mg/kg delivered
intraperitoneally, respectively. All procedures were performed to corporate animal welfare policy with IACUC procedures and guidelines as well as OLAW standards. P. aeruginosa strain ARC 6347 (AmpC+, PoxB+) was prepared for infection from an overnight plate culture. A portion of the plate was resuspended in sterile saline and adjusted to an OD of 0.1 at 625 nm. The adjusted bacterial suspension was further diluted to target an infecting inoculum of 5.0xl05 CFU/mouse. Plate counts of the inoculum was performed to confirm inoculum concentration. Mice were infected with 100 uL of the prepared bacterial inoculum into both the left and right thigh muscles. Beginning at two hours post infection mice were dosed with either test article, positive control antibiotic (levofloxacin), or vehicle. Mice receiving Example 6 and Comparator 1 or vehicle were dosed subcutaneous at 10 mL/kg for 8 doses spaced 3 hours apart. Animals receiving levofloxacin were dosed with a single dose of 160 mg/kg at two hours post infection.
[00105] Three animals were dosed per group / concentration. One group of three mice were euthanized at initiation of therapy (T-Rx) and CFUs determined. All remaining mice were euthanized at 26 hours post infection. Both thighs were aseptically removed, weighed,
homogenized to a uniform consistency, serially diluted and plated on bacterial growth media. The CFUs were enumerated after overnight incubation.
Measurement of Acylation Rate Constants for P. aeruginosa PBPla, PBP2 and PBP3.
[00106] Second-order acylation rate constants with PBPla, PBP2 and PBP3 from P.
aeruginosa were measured using the BOCILLIN FL penicillin fluorescence anisotropy assay method {Anal. Biochem. 463, 15-22 (2014)). The BOCILLIN FL (Thermo-Fisher Scientific, Waltham, MA) concentration was 30 nM in each case. The PBP concentrations were 60 nM for P. aeruginosa PBPla and PBP3, and 300 nM for P. aeruginosa PBP2. The assay buffer was 0.1 M sodium phosphate with 0.01% Triton X-100. The pH was 7.0 for all the PBPs with the exception of P. aeruginosa PBP2, for which the pH was 6.2. Serial 2-fold dilutions of compounds were employed, with concentrations ranging from 328 to 0.02 μΜ for the P. aeruginosa PBPs.
[00107] As seen in Table 3, an improvement in PBP3 acylation was achieved by installing a dimethylamide group at the position corresponding to R 1 R 2 in Formula I (Example 5), while the primary amide analog (Comparator 2) and even the monomethyl amide analog (Comparator 3) showed low PBP3 acylation rates.
Table 3
MIC against Gram-negative clinical isolates
[00108] The minimal inhibitory concentration (MIC) values against each organism and compounds were determined using the Clinical and Laboratory Standards Institute guidelines (CLSI) broth microdilution methodology (CLSI M07-A10).
Table 4
[00109] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.
Claims
Listing of Claims: 1. A compound of the Formula:
or a pharmaceutically acceptable salt thereof, wherein
R 1 and FT 2 are each independently (C1-C6)alkyl or halo(C1-C6)alkyl;
R3 and R4 are each independently hydrogen, (C1-C6)alkyl or halo(C1-C6)alkyl;
R5 is hydrogen, -COR6, -NHCOR6, -CH2R7, or -CH=CHR8;
R6 is -ORA or -NRARB;
R7 is -ORC, -SRC, -NRDRE, -OCONRARF, -OCORG, -S(O)RH -S(O)2RH,
-NHC(O)NRARF, phenyl, monocyclic heteroaryl or (C1-C6)alkyl; and
R is phenyl or monocyclic heteroaryl, wherein:
the phenyl represented by R 7 and R8 is optionally substituted with or more groups selected from (C1-C6)alkyl, (C1-C6)haloalkyl, -OSO2OH, -COO(C1-C6)alkyl, -CONRARF, -(C1-C6)alkylNH2, and -(C1-C6)alkylOH; the monocylic heteroaryl represented by R 7 and R8 is optionally substituted with one or more groups selected from C=0, (C1-C6)alkyl, (C1-C6)haloalkyl, -OSO2OH, -COO(C1-C6)alkyl, -CONRARF, -(C1-C6)alkylNH2, and -(C1-C6)alkylOH;
the (C1-C6)alkyl represented by R is optionally substituted with o more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, monocyclic heteroaryl, monocyclic heterocyclyl, NH2, -NH(C=NH)NH2, -CONRARF, and -COR1, wherein the phenyl, monocyclic heteroaryl, and monocyclic heterocyclyl in the substituted (C1-C6)alkyl represented by R are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARF, -SO2NRARA, -COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARF
each RA is independently hydrogen or (C1-C6)alkyl;
each RD is independently hydrogen, (C1-C6)alkyl, or -COO(C1-C6)alkyl;
RB , RC, RE , RF, R G and RH are each independently hydrogen, (C1-C6)alkyl, phenyl, yclic heteroaryl, bicyclic fused heteroaryl, or monocyclic heterocyclyl, wherein:
the phenyl represented by R B , R C , R E , R F , R G and RH is optionally substituted with one or more groups selected from NH2, -(C=NH)NH2 -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1
C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, or -(C1-C6)alkylCONRARI;
the monocyclic heteroaryl, the bicyclic heteroaryl, and the monocyclic heterocyclyl represented by R B , R C , R E , R F , R G and RH are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, COO(C1-C6)alkyl, -(C1-C6)alkylCONRARI;
the (C1-C6)alkyl represented by RB, RC, RE, RF, RG and RH is optionally substituted with one or more groups selected from NH2,
-NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, monocyclic heteroaryl, monocyclic heterocyclyl, NH2, -NH(C=NH)NH2, -CONRARI and -COR1, wherein the phenyl, monocyclic heteroaryl, and monocyclic heterocyclyl in the substituted (C1-C6)alkyl represented by RC are each independently and optionally substituted with one or more groups selected from NH2,
-(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARI; and R1 is hydrogen, (C1-C6)alkyl, or -(C1-C6)alkylNH2.
2. The compound of Claim 1, wherein R 1 and R 2 are each independently (C1-C6)alkyl; is (C1-C6)alkyl.
3. The compound of Claim 1 or 2, wherein
each RC is independently phenyl, monocyclic heterocyclyl, monocyclic heteroaryl, or (C1-C6)alkyl, wherein:
the (C1-C6)alkyl represented by RC is substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, monocyclic heteroaryl, monocyclic heterocyclyl, -NH(C=NH)NH2, -CONRARF, or -CORG, wherein the phenyl, monocyclic heteroaryl, and monocyclic heterocyclyl in the substituted (C1-C6)alkyl
p
represented by RC are each independently and optionally substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and -(C1-C6)alkylCONRV
p the phenyl, monocyclic heterocyclyl, monocyclic heteroaryl represented by RC are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI;
RE is (C1-C6)alkyl optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, heteroaryl, -NH(C=NH)NH2,
-CONRA RF , or -CORI , wherein the phenyl and heteroaryl for RE are each independently optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI, or RE is heteroaryl optionally substituted with (C1-C6)alkyl or halo(C1-C6)alkyl;
R is hydrogen or (C1-C6)alkyl optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl,
heteroaryl, -NH(C=NH)NH2, -CONRA RF
, and -COR1, wherein the phenyl and heteroaryl for R are each optionally and independently substituted with one or more groups selected from NH2,
-(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, - (C1-C6)alkylN((C1-C6)alkyl)3, -CONRARF, -SO2NRARA, -COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRV;
RG is heterocyclyl optionally substituted with -(C=NH)NH2; and
RH is (C1-C6)alkyl optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, heteroaryl, -NH(C=NH)NH2,
-CONRARI, or -COR1, wherein the phenyl and heteroaryl for RH are each optionally and independently substituted with one or more groups selected from NH2, -(C=NH)NH2
-(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH,
-(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, -COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI.
4. The compound of any one of Claims 1 to 3, wherein
R is a monocyclic heteroaryl, bicyclic fused heteroaryl, or (C1-C6)alkyl, each of which are independently optionally substituted with one or more groups selected from NH2, -NHCOO(C1-C6)alkyl, -N((C1-C6)alkyl)3, phenyl, heteroaryl, -NH(C=NH)NH2,
-CONRARI, or -COR1, wherein the phenyl and heteroaryl for the optional substituents present on the monocyclic heteroaryl, bicyclic fused heteroaryl, and (C1-C6)alkyl represented by R are each independently optionally substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, COO(C1-C6)alkyl, and
-(C1-C6)alkylCONRARI.
5. The compound of any one of Claims 1 to 4, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
6. The compound of any one of Claims 1 to 5, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
7. The compound of any one of Claims 1 to 6, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
8. The compound of any one of Claims 1 to 7, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
9. The compound of any one of Claims 1 to 8, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
10. The compound of any one of Claims 1 to 9, wherein
R7 is -ORC, -SRC, -NRDRE, -OCONRARF, -OCORG, -S(O)RH -S(O)2RH, -NHC(O)NRARF, monocyclic heteroaryl, or (C1-C6)alkyl, wherein:
the monocyclic heteroaryl represented by R is optionally substituted with one or more groups selected from C=0, -OSO2OH, -COO(C1-C6)alkyl, -CONRARF, -(C1-C6)alkylNH2, and -(C1-C6)alkylOH; and
the (C1-C6)alkyl represented by R is substituted with NH2 or a monocyclic heteroaryl optionally substituted with one or more (C1-C6)alkyl or halo(C1-C6)alkyl;
each RC is independently phenyl, monocyclic heterocyclyl, monocyclic heteroaryl, or (C1-C6)alkyl, wherein:
each of said phenyl, heterocyclyl, and heteroaryl for RC are optionally substituted with one or more groups selected from NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2,
-(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, COO(C1-C6)alkyl, and -(C1-C6)alkylCONRARI; and the (C1-C6)alkyl for RC is substituted with one or more groups selected from phenyl, NH2, -NH(C=NH)NH2, -CONRARI and -COR1.
11. The compound of any one of Claims 1 to 10, wherein
R7 is -ORC, -SRC, -NRDRE, -OCONRARF, -OCORG, -S(O)RH -S(O)2RH,
-NHC(O)NRARF, pyridinyl, or triazolyl, or (C1-C6)alkyl, wherein:
the pyridinyl or triazolyl represented by R is optionally substituted with one or more groups selected from C=0, OSO2OH, -COO(C1-C6)alkyl,
-CONRARI -(C1-C6)alkylNH2, and -(C1-C6)alkylOH; and
the (C1-C6)alkyl represented by R is substituted with one or more NH2 or pyridinyl;
each RC is independently phenyl, pyrrolidinyl, azetidinyl, pyridinyl, pyrazolyl or (C1- C6)alkyl, wherein:
the (C1-C6)alkyl represented by RC is substituted with one or more phenyl, NH2, -NH(C=NH)NH2, -CONRARI or -COR1; and
each of said pyrrolidinyl, azetidinyl, pyridinyl, or pyrazolyl for RC are optionally substituted with one or more NH2, -(C=NH)NH2, -(C=NH)NH(monocyclic
heterocyclyl), (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylNH2, -(C=NH)NH(C1- C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, COOH, -(C1-C6)alkylN((C1-C6)alkyl)3, -CONRARI -SO2NRARA, COO(C1-C6)alkyl, or -(C1-C6)alkylCONRARI.
12. The compound of any one of Claims 1 to 11, wherein each RC is independently
phenyl optionally substituted with 1 or 2 groups selected from -(C=NH)NH2,
-(C=NH)NH(piperidinyl), -(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, COOH,
-CONRARI and -SO2NRARA;
pyrrolidinyl optionally substituted with -CONRARI;
azetidinyl optionally substituted with 1 or 2 -(C=NH)NH2;
pyridinyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -COO(C1-C6)alkyl, and COOH;
pyrazolyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, and -(C1-C6)alkylN((C1-C6)alkyl)3; or
(C1-C6)alkyl substituted with 1 or 2 groups selected from phenyl,
NH2, -NH(C=NH)NH2, -CONRARI and -COR1.
13. The compound of any one of Claims 1 to 12, wherein each RC is independently
phenyl optionally substituted with -(C=NH)NH2, -(C=NH)NH(piperidinyl),
-(C1-C6)alkylNH2, -(C=NH)NH(C1-C6)alkylNH2, COOH, -CONH(C1-C6)alkylNH2, -CONH2, and SO2NH2;
pyrrolidinyl optionally substituted with -CON((C1-C6)alkyl)2;
azetidinyl optionally substituted with -(C=NH)NH2;
pyridinyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -COO(C1-C6)alkyl, and COOH;
pyrazolyl optionally substituted with 1 or 2 groups selected from (C1-C6)alkyl, -(C1-C6)alkylNH2, -(C1-C6)alkylNH(C=NH)NH2, and -(C1-C6)alkylN((C1-C6)alkyl)3; or
-(C1-C6)alkylphenyl, -(C1-C6)alkylNH(C=NH)NH2, -(C1-C6)alkylNH2,
-(C1-C6)alkylNH2CON((C1-C6)alkyl)2, -(C1-C6)alkylNH2CO(piperzinyl),
-(C1-C6)alkylCONH(C1-C6)alkylNH2, or -(C1-C6)alkylCON[((C1-C6)alkyl)((C1- C6)alkylNH2)].
14. The compound of any one of Claims 1 to 13, wherein
RD is hydrogen or -COO(C1-C6)alkyl;
RE is -(C1-C6)alkylNH2 or -(C1-C6)alkylNHC(O)0(C1-C6)alkyl;
RF is -(C1-C6)alkylNH2;
RG is piperazinyl optionally substituted with -(C=NH)NH2; and RH is -(C1-C6)alkyl(C=NH)NH2.
15. The compound of any one of Claims 1 to 14, wherein R7 is selected from
The compound of Claim 1 or 2, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
17. The compound of any one of Claims 1, 2, and 16, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
18. The compound of any one of Claims 1, 2, 16, and 17, wherein the compound is of the Formula:
pharmaceutically acceptable salt thereof.
19. The compound of any one of Claims 1, 2, and 16 to 18, wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
20. The compound of any one of Claims 1, 2, and 16 to 19, wherein R is phenyl or a monocyclic nitrogen containing heteroaryl optionally substituted with (C1-C6)alkyl.
21. The compound of any one of Claims 1, 2, and 16 to 20, wherein R is phenyl or pyridinyl optionally substituted with (C1-C6)alkyl.
22. The compound of any one of Claims 1, 2, and 16 to 21, wherein R is hydrogen, a 5- or 6- membered monocyclic nitrogen containing heteroaryl, a 9-membered fused bicyclic nitrogen containing heteroaryl, -(C1-C6)alkylNH2, -(C1-C6)alkylN((C1-C6)alkyl)3, or (C1- C6)alkyl substituted with a 5- or 6-membered nitrogen containing heteroaryl, wherein each of said heteroaryl are optionally substituted with one or more -NH2, (C1-C6)alkyl, or -(C1- C6)alkylN((C1-C6)alkyl)3.
23. The compound of any one of Claims 1, 2, and 16 to 22, wherein R is hydrogen, pyridinyl, pyrazolyl, indazolyl, -(C1-C6)alkylNH2, or (C1-C6)alkyl substituted with pyridinyl or pyrazolyl, wherein each of said pyridinyl and pyrazolyl are optionally substituted with one or more -NH2, (C1-C6)alkyl, or -(C1-C6)alkylN((C1-C6)alkyl)3.
24. The compound of any one of Claims 1, 2, and 16 to 23, wherein R6 is selected from
25. A compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
26. A method of treating a bacterial infection in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, or the composition of Claim 25.
27. The method of Claim 26, wherein the bacterial infection is caused by a Gram-negative bacteria.
28. The method of Claim 26 or 27, wherein the bacterial infection is caused by P.
aeruginosa, A. baumannii, E. coli, or K. pneumoniae and other Enterobacteriaceae.
29. The method of any one of Claims 26 to 28, wherein the bacterial infection is caused by P. aeruginosa.
30. A method of inhibiting penicillin binding protein 3 in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, or the composition of Claim 25.
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| US11905286B2 (en) | 2018-08-09 | 2024-02-20 | Antabio Sas | Diazabicyclooctanones as inhibitors of serine beta-lactamases |
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