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  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/333—Radicals substituted by oxygen or sulfur atoms
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  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to the field of medical technology, and relates to a compound as an antibiotic, a pharmaceutically acceptable salt thereof, an ester, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof, a process for preparing the compound, and the like
• Pharmaceutical compositions of the compounds; the invention also relates to the use of said compounds for the treatment and/or prophylaxis of infectious diseases, in particular for the treatment and/or prophylaxis of infectious diseases caused by Gram-negative bacteria.
• Lipid A is a membrane-bound region of the outer membrane lipopolysaccharide (LPS) of Gram-negative bacteria (such as Pseudomonas aeruginosa and Acinetobacter baumannii), which protects bacteria against external factors (such as antibiotics).
• LPS membrane lipopolysaccharide
• UDP-3-O-(R-hydroxytetradecanoyl)-N-acetylglucosamine deacetylase is a zinc metalloenzyme that catalyzes the second biosynthesis of lipid A in Gram-negative bacteria.
• the step is an enzyme necessary for the survival of Gram-negative bacteria, and therefore, by inhibiting LpxC, the growth of bacteria can be inhibited, thereby exerting an effect on diseases caused by Gram-negative bacteria.
• LpxC inhibitors such as CHIR-090 are disclosed in WO2004062601 A2 and the like, and some LpxC inhibitors such as ACHN-975 are also disclosed in WO2008154642 A2.
• a series of LpxC inhibitors are also disclosed in the patent WO2011132712 A1, etc., wherein the structure of some LpxC inhibitors is as follows:
• a compound of the invention which is a compound which is an inhibitor of UDP-3-O-(R-hydroxytetradecanoyl)-N-acetylglucosamine deacetylase (LpxC).
• the present invention provides a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, an ester, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof:
• R 1 is selected from -(CH 2 ) 0-4 C(R 1a , R 1b )(CH 2 ) 0-4 OR 3 , -(CH 2 ) 0-4 C(O)NR 4 R 5 , -(CH 2 ) 0-4 C(R 1a , R 1b )NR 4 R 5 , -(CH 2 ) 0-4 C(R 1a ,R 1b )(CH 2 ) 0-4 S(O) 0-2 R 6 And -(CH 2 ) 0-4 C(R 1a ,R 1b )(CH 2 ) 0-4 SC(O)R 7 ,
• R 1a , R 1b , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, C 1-6 alkyl and OH;
• R 1 ' is selected from the group consisting of hydrogen and C 1-6 alkyl
• a 1 , A 2 , and A 3 are each independently selected from CH and a hetero atom;
• X and Y are each independently selected from the group consisting of a benzene ring group, a 3-8 member unsaturated heterocyclic group, an alkenyl group, an alkynyl group, and
• B is absent or represents -(C 1-8alkyl )-, wherein the 0-2 carbon atoms of the -(C 1-8alkyl )- are optionally replaced by O or NR 8 ,
• C is selected from C 1-6 alkyl, -OR 9 , -NR 9 R 9' , phenyl and 3-8 membered saturated and/or unsaturated heterocyclic group,
• R 8 , R 9 and R 9 ' are each independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group and a C 3-6 cycloalkyl group;
• n 0, 1, 2 or 3.
• R 1 is selected from -(CH 2 ) 0-4 C(R 1a , R 1b )(CH 2 ) 0-4 OR 3 , -(CH 2 ) 0-4 C(O)NR 4 R 5 and -(CH 2 ) 0-4 C(R 1a , R 1b )NR 4 R 5 , wherein R 1a , R 1b , R 3 , R 4 , R 5 are each independently selected from H, C 1-4 alkyl and OH;
• R 1 ' is selected from the group consisting of hydrogen and C 1-6 alkyl
• a 1 , A 2 , and A 3 are each independently selected from CH and a hetero atom;
• X and Y are each independently selected from a benzene ring group, a 5-8 member unsaturated heterocyclic group, an alkenyl group, an alkynyl group, and
• B is absent or represents -(C 1-8alkyl )-, wherein the 0-2 carbon atoms of the -(C 1-8alkyl )- are optionally replaced by O or NR 8 ,
• C is selected from C 1-6 alkyl, -OR 9 , -NR 9 R 9' , phenyl and 3-8 membered saturated and/or unsaturated heterocyclic group,
• R 8 , R 9 and R 9 ' are each independently selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group and a C 3-6 cycloalkyl group;
• n 0, 1, or 2.
• R 1 is selected from -C(R 1a , R 1b )OR 3 and -C(O)NR 4 R 5 , wherein R 1a , R 1b , R 3 , R 4 and R 5 are each independently selected from a hydrogen atom, Methyl and hydroxy;
• R 1 ' is selected from the group consisting of hydrogen and C 1-4 alkyl
• a 1 , A 2 , and A 3 are each independently selected from CH and N;
• X, Y are each independently selected from the group consisting of a benzene ring group, a 5-6 membered unsaturated heterocyclic group, an alkenyl group, an alkynyl group, and
• C is selected from -OR 9 and -NR 9 R 9' ,
• R 9 and R 9 ' are each independently selected from a hydrogen atom, a methyl group, an ethyl group and an isopropyl group;
• n 0, 1, or 2.
• R 1 is selected from -C(R 1a , R 1b )OR 3 and -C(O)NR 4 R 5 , wherein R 1a , R 1b , R 3 , R 4 and R 5 are each independently selected from a hydrogen atom, Methyl and hydroxy;
• R 1 ' is selected from the group consisting of hydrogen and C 1-4 alkyl
• a 1 , A 2 , and A 3 are each independently selected from CH and N;
• X and Y are each independently selected from the group consisting of a benzene ring group, a pyrrole ring group, an imidazole ring group, a pyrazole ring group, a 1,2,3-triazole ring group, and a 1,2,4-triazo group.
• R 2 is (CH 2 ) 1-4 OH
• n 0, 1, or 2.
• R 1 is selected from the group consisting of -C(H,CH 3 )OH and -C(O)NHCH 3 ;
• R 1 ' is selected from the group consisting of hydrogen, methyl and ethyl
• a 1 , A 2 , and A 3 are each independently selected from CH and N;
• X and Y are each independently selected from the group consisting of a benzene ring group, a pyrrole ring group, an imidazole ring group, a pyrazole ring group, a 1,2,3-triazole ring group, and a 1,2,4-triazo group.
• R 2 is -CH 2 OH
• m 0 or 1.
• W represents -(C 0-8 alkyl optionally substituted by a substituent)-C(O)-N(R 1 ' )-(C 1-8 alkyl optionally substituted by R 1 )-C (O)-N(H)-OH;
• R 1 is each independently selected from C 1-8 alkyl optionally substituted by a substituent, -(C 0-8 alkyl optionally substituted by a substituent) C(O)NR 4 R 5 , - (optional) C 0-8 alkyl)S(O) 1-2 R 3 substituted by a substituent and -(C 0-8 alkyl optionally substituted by a substituent) S(O) 1-2 NR 4 R 5 , Wherein R 3 , R 4 and R 5 are each independently selected from a hydrogen atom, a halogen atom, a C 1-8 alkyl group optionally substituted by a substituent, a C 2-8 alkenyl group optionally substituted by a substituent, and a C 2-8 alkynyl group substituted with a substituent;
• R 1 ' is selected from a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a C 1-8 alkyl group optionally substituted by a substituent, a C 2-8 alkenyl group optionally substituted by a substituent, and optionally substituted with a substituent.
• a C 2-8 alkynyl group, or R 1 ' is bonded to a carbon atom on a C 0-8 alkyl group optionally substituted with a substituent in the W group, together with the N, C(O) group to form 5-6 Metacyclic heterocyclic group;
• a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each independently selected from CR a R a , NR c , O and S;
• P 1 , P 2 , P 3 , P 4 and P 5 are each independently selected from CR a R a , NR c , O and S;
• n an integer of 0-4;
• R 2 is independently represented
• Each occurrence of B independently represents a bond or independently selected from C 1- wherein at least one carbon atom is replaced by at least one of S, O and NR c and/or optionally substituted with a substituent.
• An alkyl group, optionally at least one carbon atom is replaced by at least one of S, O and NR c and/or a C 2-8 alkenyl group optionally substituted with a substituent and optionally at least one carbon atom is S, At least one of O and NR c is substituted for and/or optionally substituted with a C 2-8 alkynyl group;
• Each occurrence of C independently represents a hydrogen atom, a cyano group, a decyl group, a halogen atom, a carboxyl group, a nitro group, a C 1-8 alkyl group optionally substituted by a substituent, and a C 1-8 alkane optionally substituted with a substituent.
• R a or each absent, or each occurrence is independently selected from a hydrogen atom, a cyano group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -OR c , -NR c R c , -N(OH) R c , -C(O)R d , -C(O)OR c , -C(O)NR c R c , -OC(O)NR c R c , -NR c C(O)OR c ,- NR c C(O)R d , -S(O) 1-2 -NR c R c , -S(O) 1-2 R d , -NR c S(O) 1-2 R d , -S( O) 1-2 -OR c, optionally substituted C 1-8 alkyl group substituted by, - (optionally substituted C 1-8 alkyl group substitute
• R c is either absent or, each occurrence, independently selected from a hydrogen atom, a halogen atom, a carboxyl group, -C(O)R d , -C(O)OR b , -C(O)NR b R b , -S(O) 1-2 -NR b R b , -S(O) 1-2 R d , -S(O) 1-2 -OR b , C 1- optionally substituted by a substituent 8 alkyl, - (C 1-8 alkyl optionally substituted by a substituent) OR b , - (C 1-8 alkyl optionally substituted by a substituent) NR b R b , optionally substituted by a substituent C 2-8 alkenyl group, C 2-8 alkynyl group optionally substituted by a substituent, 3-12 membered cycloalkyl group optionally substituted by a substituent, 3-12 membered heterocyclic
• R b is independently selected from a hydrogen atom, a halogen atom, a carboxyl group, a sulfonic acid group, a C 1-8 alkyl group optionally substituted by a substituent, and a C 1-8 optionally substituted by a substituent.
• Each occurrence of R d is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, an amino group, a C 1-8 alkylamino group optionally substituted with a substituent, (optionally substituted) a substituted C 1-8 alkyl) 2 amino group, a sulfonic acid group, a C 1-8 alkyl group optionally substituted by a substituent, a C 1-8 alkoxy group optionally substituted with a substituent, optionally substituted a substituted C 1-8 alkylsulfonyl group, a C 1-8 alkylsulfinyl group optionally substituted by a substituent, a 3-12 membered cycloalkyl group optionally substituted by a substituent, optionally substituted with a substituent a 3-12 membered heterocyclic group, a 6-14 membered aryl
• substituents in the "optionally substituted by a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, a carboxyl group, a cyano group, a nitro group, an amino group, a halogen atom, a sulfonic acid group, a C 1-8 alkyl group, a C 1 group.
• the five-membered ring (the ring labeled with P in the general formula (II), which is denoted by the same symbol hereinafter) and the six-membered ring (the ring labeled with A in the general formula (II), which are denoted by the same symbols hereinafter) Representing a double bond optionally present in the ring;
• R 1 represents a C 1-8 alkyl group substituted by a substituent, and wherein the substituent has a hydroxyl group, wherein each carbon atom of the C 1-8 alkyl group carries at least one hydrogen;
• R 1 represents a C 1-8 alkyl group substituted by a substituent, and when the substituent contains a hydroxyl group, the five-membered ring does not represent an imidazole ring group;
• R 1 represents a C 1-8 alkyl group substituted with a substituent, and the substituent contains an amino group, a C 1-8 alkylamino group or a (C 1-8 alkyl) 2 amino group, at least one of X and Y represents any a 6-14 membered aromatic group substituted with a substituent;
• m is not 0;
• the five-membered ring contains one N atom, the five-membered ring is bonded to X through a non-N atom;
• R 1 represents -(C 0-8 alkyl optionally substituted by a substituent) C(O)NR 4 R 5 , neither X nor Y is a bond, and a five-membered ring represents a furan ring group, and m Not 0.
• a compound represented by the formula (II) a pharmaceutically acceptable salt, an ester thereof, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof thereof. It is a compound represented by the following formula (V) or formula (VI):
• Z represents a C 1-8 alkyl group optionally substituted by R 1 , Represents a single or double key.
• the P ring in the formula (II) is a heteroaryl ring.
• in the ring A of the formula (II) Indicates that there is at least one double bond in the ring.
• a in the formula (II) is a benzene ring or a heteroaryl ring.
• W represents (C 0-8 alkyl optionally substituted by a substituent)
• the R 1 in the formula (II) is each independently selected from a C 1-8 alkyl group optionally substituted with a substituent, -(CH 2 ) 0-4 C ( R 1a , R 1b )(CH 2 ) 0-4 OR 3 , -(CH 2 ) 0-4 C(R 1a , R 1b )(CH 2 ) 0-4 NR 3 R 3 , -(CH 2 ) 0 -4 C(O)NR 4 R 5 and -(CH 2 ) 0-4 S(O) 1-2 R 3 .
• R 1 in the formula (II) is each independently selected from C 1-4 alkyl optionally substituted by a substituent, - (C 1- optionally substituted by a substituent) 4- alkyl)OR 3 , -(C 1-4 alkyl optionally substituted by a substituent) NR 4 R 5 and -(C 0-4 alkyl optionally substituted by a substituent) C(O)NR 4 R 5 and -(C 1-4 alkyl optionally substituted by a substituent) S(O) 1-2 R 3 .
• R 1 in formula (II) is each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hydroxymethyl Base, hydroxyethyl, hydroxypropyl, isohydroxypropyl, hydroxybutyl, hydroxy-sec-butyl, hydroxy-tert-butyl, aminomethyl, aminoethyl, aminopropyl, isoaminopropyl, aminobutyl, Amino sec-butyl, amino-tert-butyl, -(CH 2 ) 0-4 C(O)NH 2 and -(CH 2 ) 0-4 S(O) 2 C 1-4 alkyl.
• R 1a and R 1b in the formula (II) are each independently selected from a hydrogen atom, an amino group, a hydroxyl group, and a C 1-8 alkyl group optionally substituted with a substituent.
• R 1a and R 1b in the formula (II) are each independently selected from the group consisting of a hydrogen atom, an amino group, a hydroxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group and a tert-butyl group. base.
• R 3 , R 4 and R 5 in the formula (II) are each independently selected from a hydrogen atom and a C 1-8 alkyl group optionally substituted with a substituent.
• R 3 , R 4 and R 5 in the formula (II) are each independently selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group and a t-butyl group. .
• R 1 ' in the formula (II) is selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen atom, and a C 1-8 alkyl group.
• R 1 ' in the formula (II) is bonded to a carbon atom on a C 0-8 alkyl group which is optionally substituted by a substituent in the W group, and N, C ( The O) groups together form a 5-6 membered unsaturated heterocyclic group.
• R 1 ' in the formula (II) is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, and a t-butyl group.
• R 1 ' in the formula (II) is bonded to a carbon atom on a C 0-8 alkyl group which is optionally substituted by a substituent in the W group, and N, C ( The O) groups together form a 6-membered unsaturated heterocyclic group.
• the group in which the A ring of the formula (II) is bonded to the W group is a C atom.
• the A ring of the formula (II) is selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring.
• X and Y are each independently selected from a bond, a benzene ring group optionally substituted with a substituent, and a pyrrole ring group optionally substituted with a substituent.
• a group optionally a pyrazole ring group substituted with a substituent, a 1,2,3-triazole ring group optionally substituted with a substituent, and 1,2,4-triazo optionally substituted with a substituent
• X and Y in the formula (II) are not simultaneously a 6-14 membered aromatic group optionally substituted with a substituent. It is preferred that X and Y in the formula (II) are not simultaneously a benzene ring group which is optionally substituted with a substituent.
• neither X nor Y represents a bond.
• At least one of P 1 , P 2 , P 3 , P 4 and P 5 is a group selected from the group consisting of NR c , O and S.
• the P ring in the formula (II) is selected from the group consisting of a pyrroline ring group, a pyrrolidine ring group, an imidazoline ring group, an imidazolidine group, and a pyrazoline ring group.
• the P ring of formula (II) is selected from the group consisting of a furan group, a pyrrole group, a pyrazole group, a triazole group, and a thiophene group.
• each occurrence of B in the formula (II) is independently selected from a bond, a C 1-8 alkyl group optionally substituted with a substituent, and at least one carbon atom is O. And a C 1-8 alkyl group substituted with at least one of NR c and optionally substituted with a substituent.
• each occurrence of C in the formula (II) independently represents a hydrogen atom, a C 1-8 alkyl group optionally substituted with a substituent, -OR c , -NR c R c , a 3-10 membered cycloalkyl group optionally substituted by a substituent, a 3-10 membered heterocyclic group optionally substituted by a substituent, a 5-10 membered heteroaryl group optionally substituted with a substituent, and optionally A 6-10 membered aryl group substituted with a substituent.
• each occurrence of C in the formula (II) is independently selected from a hydrogen atom, a C 1-4 alkyl group optionally substituted by a substituent, -OR c , -NR c R c , a 3-8 membered cycloalkyl group optionally substituted by a substituent, a 3-8 membered heterocyclic group optionally substituted by a substituent, a 5-6 membered heteroaryl group optionally substituted by a substituent, and A 6-10 membered aryl group substituted with a substituent is selected.
• C in the formula (II) may be the following group optionally substituted with a substituent:
• Q is a group selected from the group consisting of CR a R a , NR c , O and S.
• n in the formula (II) is 0, 1, 2 or 3.
• R 1 in the formula (II) represents -(C 0-8 alkyl group optionally substituted by a substituent) C(O)NR 4 R 5 , both X and Y All indicate -(C ⁇ C)-, P represents a furan ring group, and m is not zero.
• R 1 in the formula (II) represents a C 1-8 alkyl group substituted with a substituent, and the substituent contains an amino group, a C 1-8 alkylamino group or (C 1- In the case of an 8- alkyl) 2 amino group, at least one of X and Y represents a 6-14 membered aromatic group optionally substituted with a substituent, and the P ring represents a pyrazole ring group.
• the P ring does not represent an imidazole ring group.
• R a in the general formula (II) is either absent or is each independently selected from a hydrogen atom, a cyano group, a decyl group, a halogen atom, a carboxyl group, and a nitrate.
• R a in the formula (II) is either absent or, each occurrence, independently selected from a hydrogen atom, a halogen atom, a carboxyl group, a nitro group, a hydroxyl group, an amino group.
• R c in formula (II) is either absent or, at each occurrence, each independently selected from a hydrogen atom, a halogen atom, a carboxyl group, optionally substituted with a substituent C 1-4 alkyl, - (optionally substituted with C 1-4 alkyl) OR b, - (optionally substituted with C 1-4 alkyl) NR b R b, optionally substituted with a substituted C 2-4 alkenyl group, a C 2-4 alkynyl group optionally substituted by a substituent, a 3-10 membered cycloalkyl group optionally substituted by a substituent, 3-10 optionally substituted with a substituent a heterocyclic group, a 6-10 membered aryl group optionally substituted by a substituent, and a 5-10 membered heteroaryl group optionally substituted by a substituent, or a case where two R c are bonded to the same atom, two R Together with
• R c in the formula (II) is either absent or, at each occurrence, independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group.
• R b in the formula (II) is each independently selected from a hydrogen atom, a halogen atom, a carboxyl group, a sulfonic acid group, and optionally a C substituted by a substituent.
• a 1-4 alkyl group, a C 1-4 alkylsulfonyl group optionally substituted with a substituent a 3-10 membered cycloalkyl group optionally substituted by a substituent, a 3-10 membered heterocyclic ring optionally substituted with a substituent a 6-10 membered aryl group optionally substituted with a substituent and a 5-10 membered heteroaryl group optionally substituted with a substituent.
• R b in the formula (II) is each independently selected from a hydrogen atom, a halogen atom, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group. a butyl group, a sec-butyl group, a tert-butyl group, a 3-6 membered cycloalkyl group optionally substituted by a substituent, a 3-6 membered heterocyclic group optionally substituted by a substituent, or a 6 optionally substituted by a substituent a 10-membered aryl group and a 5-6 membered heteroaryl group optionally substituted with a substituent.
• R d in the formula (II) is each independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, an amino group, and optionally Substituent substituted C 1-4 alkylamino group, (optionally substituted C 1-4 alkyl) 2 amino group, sulfonic acid group, C 1-4 alkyl group optionally substituted by a substituent, optionally a C 1-4 alkoxy group substituted with a substituent, a C 1-4 alkylsulfonyl group optionally substituted with a substituent, a 3-10 membered cycloalkyl group optionally substituted with a substituent, optionally substituted with a substituent A 3-10 membered heterocyclic group, a 6-10 membered aryl group optionally substituted with a substituent, and a 5-10 membered heteroaryl group optionally substituted
• R d in the formula (II) is each independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, an amino group, a sulfonic acid group, a methyl group, and a Base, propyl, isopropyl, butyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy a 3-6 membered cycloalkyl group optionally substituted by a substituent, a 3-6 membered heterocyclic group optionally substituted by a substituent, a 6-10 membered aryl group optionally substituted with a substituent, and optionally a substituent Substituted 5-6 membered heteroaryl.
• the substituents in the "optionally substituted with a substituent" are each independently selected from the group consisting of a hydroxyl group, a thiol group, a carboxyl group, a cyano group, a nitro group, an amino group, a halogen atom, and a sulfonic acid group.
• the substituents in the "optionally substituted with a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, a carboxyl group, a cyano group, a nitro group, an amino group, a halogen atom, a sulfonic acid group, and an Base, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, isohydroxypropyl, hydroxybutyl, hydroxy sec-butyl, hydroxy Tert-butyl, aminomethyl, aminoethyl, aminopropyl, isoaminopropyl, aminobutyl, amino sec-butyl, amino-tert-butyl, methoxy, ethoxy, propoxy, isopropoxy , butoxy, sec-butoxy, tert-butoxy,
• the compound of the present invention is an inhibitor compound of UDP-3-O-(R-hydroxytetradecanoyl)-N-acetylglucosamine deacetylase (LpxC).
• LpxC UDP-3-O-(R-hydroxytetradecanoyl)-N-acetylglucosamine deacetylase
• a compound of the present invention a pharmaceutically acceptable salt, an ester thereof, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof thereof has good activity against Gram-negative bacteria;
• C ab group (a and b represent an integer of 0 or more, a ⁇ b) means that a "group” has ab carbon atoms, for example, a C 1-4 alkyl group, that is, a carbon atom.
• the alkyl group, C 1-4 alkoxy C 1-4 alkyl group means a group in which an alkoxy group having 1 to 4 carbon atoms is bonded to an alkyl group having 1 to 4 carbon atoms.
• the subscript of C is 0, it means that the C 0 group is not present.
• a alkyl NH 2 " when a is 0, it means "-NH 2 ".
• (group) ab " (a and b represent an integer of 0 or more, a ⁇ b) means that there are ab "group", and when the subscript is 0, it means that the group does not exist, for example -S(O) 0-2 indicates that 0, 1, and 2 oxygen atoms can be bonded to S, that is, -S-, -S(O)-, -S(O) 2 -.
• -(CH 2 ) 0-2 OH represents -OH, -CH 2 OH, -(CH 2 ) 2 OH.
• C(R 1a , R 1b ) means that R 1a and R 1b are each bonded to a carbon atom.
• -C(H,CH 3 )OH means that the H atom and -CH 3 are each bonded to a carbon atom, that is, Group.
• base and “group” mean a monovalent group or a divalent or higher group which conforms to a valence as required, for example, "cycloalkyl (also expressed as a cycloalkyl group) includes removal from a cycloalkane.
• a monovalent group obtained by one hydrogen atom also includes a divalent or higher group obtained by removing two or more hydrogen atoms from the same carbon atom of a cycloalkane or two or more different carbon atoms.
• halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
• a fluorine atom, a chlorine atom and a bromine atom are preferred.
• halo means that one or more hydrogens on any carbon atom of the substituent may be substituted by one or more of the same or different halogen atoms, and may be monohalogenated or polyhalogenated. The substitution may be a perhalogenation, that is, a position in which all of the groups in the halogen atom can be substituted.
• C 1-8 alkyl group as used in the present invention means a linear or branched monovalent derived from the removal of one or more hydrogen atoms from a linear or branched alkane having 1-8 carbon atoms or as needed.
• a divalent or higher alkyl group for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methyl can be cited.
• C 1-8 alkyl group may be a C 1-6 alkyl group, a C 1-4 alkyl group, or a C 1-3 alkyl group.
• C 1-6 alkyl group as used in the present invention means the above-mentioned example having 1 to 6 carbon atoms
• C 1-4 alkyl group means the above-mentioned example having 1 to 4 carbon atoms
• C 1- 3 alkyl means the above example containing 1-3 carbon atoms.
• C 2-8 alkenyl group as used in the present invention means a monovalent value derived from the removal of one or more hydrogen atoms from a linear or branched olefin having 2 to 8 carbon atoms containing at least one carbon-carbon double bond or as needed. A divalent or higher olefin group.
• a vinyl group for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 1,3-butadien-1-yl group, a 1-penten-3-yl group, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl , 1-hexen-3-yl, 1,4-hexadien-1-yl.
• the "C 2-8 alkenyl group” contains a carbon-carbon double bond.
• " C2-4" alkenyl means the above examples containing from 2 to 4 carbon atoms.
• C 2-8 alkynyl group as used in the present invention means a monovalent or based derivative derived by removing one or more hydrogen atoms from a linear or branched alkyne having 2 to 8 carbon atoms containing at least one carbon-carbon triple bond. A divalent or higher alkyne group is required.
• the "C 2-8 alkynyl group” contains a carbon-carbon triple bond.
• the "C 2-4 alkynyl group” means the above examples containing 2 to 4 carbon atoms.
• C 1-8 alkoxy represents a previously defined “C 1-8 alkyl” through an oxygen atom to the parent moiety is connected, i.e., "C 1-8 alkyl -O-"
• the group may, for example, be a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a t-butoxy group, a n-pentyloxy group, a neopentyloxy group and a n-hexyloxy group. Oxyl and the like.
• the "C 1-4 alkoxy group” means the above-mentioned example having 1 to 4 carbon atoms, that is, a "C 1-4 alkyl-O-" group.
• C 1-8 alkyl C 1-8 alkoxy means the above-mentioned "C 1-8 alkyl group” .
• a group obtained by bonding an alkyl group to a corresponding group such as a "C 1-8 alkoxy group", an "amino group", an “ester group”, an “aminocarbonyl group” or a "halogen atom”.
• the expression of the group containing "C 1-4 alkyl group” means a group obtained by bonding the above-mentioned “C 1-4 alkyl group” of the present invention to a corresponding group.
• containing "C 1-8 alkoxy”, “C 1-4 alkoxy” denote groups of the present invention, the above-described "C 1-8 alkoxy", “C 1-4 alkoxy a group obtained by bonding with a corresponding group.
• the cyclic group may be a monocyclic system or a polycyclic system.
• two or more rings are connected by a bridge ring, a spiral ring, and a ring.
• the bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
• the spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other.
• the parallel ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (ie, sharing one bond).
• the "3-12 membered cycloalkyl group” as used in the present invention means a saturated cyclic alkane group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring-forming carbon atoms, which may It is a monovalent group, and may be a divalent or higher group as needed. It may be a single ring system or a polycyclic system.
• the "3-12 membered cycloalkyl group” of the present invention may be a 3-12 membered cycloalkyl group, a 3-10 membered cycloalkyl group, a 3-8 membered cycloalkyl group, or a 3-6 membered cycloalkyl group.
• cycloalkyl group of the present invention examples include, but are not limited to, cyclopropyl group, cyclobutylalkyl group, cyclopentyl group, cyclohexane group, cycloheptyl group, cyclooctyl group, cyclopentane-1,3- Diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, norbornyl, adamantyl; from bicyclo [3.1.1] heptane, bicyclo [2.2.1] a monovalent group derived from heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane or a divalent or higher a monovalent group or a divalent or higher group derived by removing one hydrogen atom or two or more hydrogen atom
• the "3-12 membered heterocyclic ring" means that at least one selected from the group consisting of O, S, and N is contained in the ring (may be 1-5, 1-4, 1-3, 1-2)
• One or one) group acts as a non-aromatic cyclic hydrocarbon of a ring-forming atom, provided that the ring of the group does not contain two adjacent O or S atoms. It may be a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring-forming atoms. There may optionally be at least one double bond in the ring to form an unsaturated heterocyclic group.
• the ring-forming atom may be optionally oxo, that is, C, S as a ring-forming atom may form a C(O), S(O), S(O) 2 group.
• the heterocyclic ring of the present invention may be a single ring system or a polycyclic system.
• heterocyclic ring examples include ethylene oxide, thietane, oxetane, 1,2-dioxetane, thietane, aziridine, 1,2- Diazetanidine, azetidin, 1,2-diazacyclobutene, pyrroline (4,5-dihydropyrrole, 2,5-dihydropyrrole), pyrrolidine, imidazoline (4,5-dihydroimidazole), imidazolidine, pyrazoline (4,5-dihydropyrazole), pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, Dihydropyridine, dihydropyridazine, dioxane, thiophene ring, sulfurized cyclopentane, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, 2-pyridone,
• Monocyclic heterocycle Monocyclic heterocycle; indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo[d]oxazole-2(3H)-one, tetrahydrogen
• a fused heterocyclic ring such as benzothiophene.
• a hetero ring obtained by replacing at least one ring carbon atom of the spiro ring and the bridged ring exemplified in the above examples of the cycloalkyl group with a hetero atom selected from O, S, and N may be mentioned.
• the "3-12 membered heterocyclic group (heterocyclic group)" as used in the present invention means a monovalent or divalent derivative obtained by removing one or more hydrogen atoms from any of the ring-forming atoms of the above "3-12 membered heterocyclic ring". A group above the price.
• the "3-12 membered heterocyclic group” of the present invention may be a 3-10 membered heterocyclic group, a 3-8 membered heterocyclic group, a 3-6 membered heterocyclic group or a 5-6 membered heterocyclic group.
• the "6-14 membered aryl (aromatic group)" as used in the present invention means a monovalent group having 6 to 14 ring-forming carbon atoms derived from an aromatic carbocyclic hydrocarbon or a divalent ring as needed.
• the above groups are, for example, a phenyl group, a naphthyl group, a phenanthryl group or a fluorenyl group
• the 6-10 member aryl group is, for example, a phenyl group or a naphthyl group. When it is a divalent group, a phenylene group, a naphthylene group, etc. are mentioned.
• the "5-14 membered heteroaryl (heteroaryl group)" as used in the present invention means at least one selected from the group consisting of O, S, and N (may be 1-5, 1-4, 1-3 , 1-2 or 1) a hetero atom as an aromatic monovalent or a divalent or higher cyclic hydrocarbon group as required, provided that the ring of the group does not contain two adjacent O Or S atom. It may be a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 membered heteroaryl ring group. Further, in the heteroaryl group of the present invention, the ring-forming atom may be optionally substituted by oxo without affecting the aromaticity, that is, C, S as a ring-forming atom may form C(O), S(O).
• the heteroaryl ring group of the present invention may be a monocyclic system or a polycyclic system. Specific examples thereof include pyrrolyl, pyrazinyl, pyrazolyl, indolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazole (1, 2, 3-thiadiazole, 1,3,4-thiadiazole), oxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4- a monocyclic heteroaryl ring group such as an oxadiazolyl group; and an iso
• At least one carbon atom is S, O, and NR c in at least one group of alternate C 1-8 alkyl
• C 1-8 alkyl is at least one carbon atom is selected from S
• At least one of O and NR c is substituted, for example, a group in which two groups of O and NR c are substituted for a C 8 alkyl group may be a C 2 alkyl-OC 2 alkyl-NR c -C 2 alkyl group. -.
• the atoms in the present invention include all isotopes of atoms.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• Carbon isotopes include 13 C and 14 C.
• Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using the appropriate isotopically labeled reagents in place of the non-labeled reagents originally employed.
• hetero atom means an atom selected from the group consisting of S, O and N.
• the five-membered ring and the six-membered ring Represents a double bond optionally present in the ring which may be present in one, two or three, limited to the maximum number of double bonds that may be present in the ring.
• a double bond optionally present in the ring which may be present in one, two or three, limited to the maximum number of double bonds that may be present in the ring.
• substituent in the present invention, “optionally substituted with a substituent” means that it may be unsubstituted or substituted. In the case of substitution, it may be a 1 substituent, a 2 substitution, a 3 substitution, a 4 substitution, a 5 substitution, a 6 substitution, a 7 substitution, an 8 substitution or a further number of substitutions. In the case of being polysubstituted (substituted with two or more substituents), the respective substituents may be the same or different.
• a “pharmaceutically acceptable salt” of a compound of the invention refers to a base or acid addition salt of a compound of the invention with a pharmaceutically acceptable, non-toxic base or acid, including organic acid salts, inorganic acid salts, Organic base salt, inorganic base salt.
• Organic acid salts include formates, acetates, propionates, besylate, benzoates, p-toluenesulfonates, 2,3-dihydroxysuccinates, camphorsulfonates, citric acid Salt, methanesulfonate, ethanesulfonate, propanesulfonate, fumarate, gluconate, glutamate, isethionate, lactate, maleate, malate , mandelic acid salt, mucic acid salt, pamoate, pantothenate, succinate, tartrate, etc., particularly preferably benzoate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, Citrate, maleate, fumarate, tartrate.
• the inorganic acid salt includes a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a phosphate, a nitrate, etc., and particularly preferably a hydrochloride, a hydrobromide, a sulfate, or a phosphate.
• the organic base salt includes an amine salt including a salt formed with primary, secondary and tertiary amines, a cyclic amine and an alkali ion exchange resin, and may be selected from salts formed with the following organic bases: for example, arginine, betaine, caffeine, gallium Base, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethyl Piperidine, meglumine, glucosamine, histidine, seabamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, guanidine, cocoa Base, triethylamine, trimethylamine, tripropylamine and tromethamine.
• organic bases for example, arginine, betaine, caffeine, gallium Base, N
• Inorganic alkali salts include salts with ammonia, alkali metals, alkaline earth metals, such as ammonium salts, and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, copper salts,
• the ferrous salt, the manganese salt, and the divalent manganese salt are particularly preferably an ammonium salt and a sodium salt, a potassium salt, a calcium salt or a magnesium salt.
• a "pharmaceutically acceptable ester" of a compound of the invention refers to an in vivo hydrolyzed ester of a compound of the invention and includes an ester which readily decomposes in the human body leaving the parent compound or a salt thereof.
• Suitable ester groups include, for example, ester groups derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acids, alkenoic acids, cyclic alkanoic acids and alkanoic acids, wherein each alkyl or alkenyl moiety is preferred. It has 6 or less carbon atoms.
• Representative examples of specific esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, and ethyl succinate.
• a "prodrug" of a compound of the invention refers to a compound that undergoes chemical conversion by metabolic or chemical processes after administration to a subject to produce a compound of the invention and/or a salt and/or solvate thereof.
• Any compound that is converted in vivo to provide a bioactive agent i.e., a compound of the invention
• a prodrug within the scope and spirit of the invention.
• a compound containing a carboxyl group can form a physiologically hydrolyzable ester which is prepared by hydrolysis in vivo to produce the compound of the present invention itself.
• Such prodrugs are preferably administered orally, since hydrolysis occurs in many cases primarily under the influence of digestive enzymes.
• ester itself is active or hydrolyzed in the blood
• parenteral administration can be used.
• prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems, ACS Sessions Series (ACSSymposium Series) Volume 14"; "Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987", both references cited The way is incorporated herein.
• the compounds of the invention in free form can be converted to the corresponding compounds in the form of a salt, and vice versa.
• the compounds of the invention in free form or in salt form and/or solvate form can be converted to the corresponding compound in free form or in the form of a salt in an unsolvated form; and vice versa.
• Some of the compounds of the present invention contain one or more asymmetric centers and thus exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. .
• the compounds of the invention have asymmetric centers, each of which will independently produce two optical isomers, the scope of the invention including all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound.
• the invention includes all stereoisomeric forms of these compounds.
• the invention includes both cis isomers and trans isomers. These stereoisomers are of the "R" or "S" configuration depending on the configuration of the substituents around the chiral element.
• R and S as used herein are those defined in the following: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
• Single stereoisomers of the compounds of the invention can be prepared synthetically from commercially available starting materials comprising asymmetric or chiral centers, or by preparing racemic mixtures and then resolved by methods well known to those skilled in the art. . These resolution methods can be exemplified by the following: (1) linking a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and optionally from an auxiliary.
• optically pure product is released as described below: Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) A mixture of optical antipodes is directly separated on a chiral column, or (3) a fractional recrystallization method.
• a compound of a geometric isomer of a carbon-carbon double bond and a carbon-nitrogen double bond is included in the compound of the present invention.
• the substituents around the carbon-carbon or carbon-nitrogen double bond are referred to as the Z or E configuration, and the substituents around the cycloalkyl or heterocycle are referred to as the cis or trans configuration. All geometric isomeric forms of the compounds of the invention and mixtures thereof are included within the scope of the invention.
• the "solvate” of the compound of the present invention means a molecular complex comprising a compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, and examples of the solvent include water and ethanol.
• the solvent is water, it may also be referred to as "hydrate”.
• the structures described herein also include compounds in which one or more isotopically enriched atoms are present.
• compounds having the structure of the present invention but including replacement of hydrogen by hydrazine or hydrazine or carbon by enrichment of 13 C or 14 C carbon are within the scope of the invention.
• the compounds of the present invention exhibit antibacterial activity, for example, exhibiting antibacterial activity against bacteria such as Gram-positive bacteria, Gram-negative bacteria, and the like.
• the compound of the present invention specifically exerts antibacterial action against bacteria such as Gram-positive bacteria or Gram-negative bacteria, has the ability to inhibit proliferation or bactericidal action, and has the ability to inhibit the growth of bacteria, and simultaneously kill some bacteria and reduce the number thereof. .
• Gram-positive bacteria examples include Staphylococcus (S. aureus, Staphylococcus epidermidis, etc.), Streptococcus (S. pyogenes, Group B streptococci, pneumococcus, etc.), Enterococcus (feces) Enterococcus faecalis, Enterococcus faecium, etc.
• the Gram-negative bacteria may, for example, be Pseudomonas (Pseudomonas aeruginosa, etc.), Coliforms (coliforms, etc.), Klebsiella (Klebsiella pneumoniae, Klebsiella oxytoca) Etc.), Haemophilus (influenza, parainfluenza, etc.), Bordetella (pertussis, bronchial septicemia, etc.), Serratia (Serratia marcescens, etc.) ), Proteus mirabilis (Proteus mirabilis, etc.), Enterobacter (Enterobacter cloacae), Campylobacter (Campylobacter jejuni, etc.), Citrobacter, Vibrio Genus (Vibrio cholerae, Vibrio cholerae, etc.), Morganella (Morganella morganii, etc.), Salmonella (S.
• Bacteroides Bacteroides (Bacteroides fragilis) (Bacteroides fragilis), etc., Neisseria (Neisseria gonorrhoeae, Cerebrospinal Inflammatory bacteria, etc., Moraxella (Moraxella catarrhalis, etc.), Chlamydia (Chlamydia trachomatis, Chlamydiapsittaci, etc.) and Helicobacter (Helicobacter pylori, etc.).
• composition comprising a compound of the invention.
• composition comprising a compound of the invention and one or more pharmaceutical excipients is provided.
• the compound of the present invention can be combined with one or two or more kinds of pharmaceutically acceptable excipients to prepare any pharmaceutical preparation.
• a pharmaceutically acceptable excipient a pharmaceutically acceptable carrier, an excipient, a diluent, and the like can be used.
• carrier excipient and diluent, water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol and the like are included.
• excipient or diluent additives such as a thickener, a binder, a disintegrant, a pH adjuster, a dissolving agent and the like which are generally used are mixed as needed, and can be formulated into tablets by a conventional formulation technique.
• Oral or non-oral medications such as agents, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, and skin patches.
• the invention also provides the use of a compound of the invention, a pharmaceutical composition comprising a compound of the invention, for the treatment and/or prevention of an infectious disease.
• a method of inhibiting deacetylase (LpxC) in Gram-negative bacteria, thereby affecting bacterial growth comprising administering a compound of the invention to a patient in need of such inhibition.
• LpxC deacetylase
• a method of inhibiting LpxC, thereby modulating the toxicity of a bacterial infection comprising administering a compound of the invention to a patient in need of such inhibition.
• the compound is about 50 LpxC inhibitors MIC values less than or equal to 16 ⁇ g / mL. In other such embodiments, MIC 50 value is less than or equal 8 ⁇ g / mL, less than or equal to 4 ⁇ g / mL, less than or equal to 2 ⁇ g / mL, less than or equal to 1 ⁇ g / mL, or less than or equal to 0.5 ⁇ g/mL.
• a method of treating and/or preventing a subject comprises administering to the subject an effective antibacterial amount of a compound of the invention or a pharmaceutical composition of the invention.
• the subject is a mammal. In some embodiments, the subject is a human.
• a method of administering a compound of the invention to a fermented or non-fermented Gram-negative bacterium is provided.
• the Gram-negative bacterium is selected from the group consisting of Pseudomonas aeruginosa and Stenotrophomonas. Maltophila), Burkholderiacepacia, Alcaligenesxylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus, and Neisseria ) species.
• the invention provides a Gram-negative bacterium, for example selected from an organism, such as Serratia marcescens, Proteus, Klebsiella ), Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, and Edward A method of administering an inhibitory amount of a compound of the invention to Enterobacteriaceae in Edwardsiella and Escherichia coli.
• Another embodiment of the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the invention and at least one other pharmaceutically active ingredient.
• a pharmaceutical composition comprising a compound of the invention and at least one other pharmaceutically active ingredient for the treatment and/or prevention of an infectious disease.
• the pharmaceutically active ingredient is an antibacterial agent (hereinafter also referred to as a second antibacterial agent) other than the compound of the present invention.
• the pharmaceutically active ingredient is a non-antibacterial agent other than the compound of the invention.
• the compounds of the invention increase the sensitivity of Gram-negative bacteria to a wide variety of existing antimicrobial agents.
• antimicrobial agents include, but are not limited to, erythromycin, rifampicin, nalidixic acid, carbenicillin, bacitracin, cycloserine, fosfomycin, vancomycin, piperacillin, amikacin, cyclopropane Sand star, polymyxin, ceftazidime and imipenem.
• a further aspect of the invention is the use of an LpxC inhibitor for the treatment of infections, especially bacterial infections.
• the treatment of a bacterial infection with a compound of the invention may be a primary infection or a co-infection caused by a bacterial species and one or more additional infectious agents selected from the group consisting of bacteria, viruses, parasites, and fungi.
• treating and/or preventing refers to reversing, alleviating, inhibiting or arresting a disease/condition, one or more symptoms of the disease or condition.
• the compounds of the present invention can be used for the treatment and/or prevention of diseases caused by bacteria (especially Gram-negative bacteria) and LpxC-producing bacteria in the biosynthesis of lipopolysaccharide (LPS) or endotoxin, producing endotoxin/ Symptoms / conditions.
• bacteria especially Gram-negative bacteria
• LpxC-producing bacteria in the biosynthesis of lipopolysaccharide (LPS) or endotoxin, producing endotoxin/ Symptoms / conditions.
• the compounds of the invention are useful in diseases/symptoms/conditions caused by the production of lipid A and LPS or endotoxin by bacteria, for example, for the treatment and/or prevention of sepsis, septic shock, systemic inflammation, local inflammation, chronic obstruction Acute lung disease (COPD) and acute exacerbation of chronic bronchitis (AECB).
• the treatment comprises administering a compound of the invention, a pharmaceutical composition of the invention or a compound of the invention, optionally in combination with other pharmaceutically active ingredients, wherein the other pharmaceutically active ingredient is a second antibacterial or non-antibacterial agent.
• preferred non-antibacterial agents include endotoxin receptor-binding antibodies, endotoxin - Anti-endotoxin and tyrosine kinase inhibitors that bind antibodies, anti-CD14-binding protein antibodies, anti-lipopolysaccharide-binding protein antibodies.
• the compounds of the invention may also be administered by inhalation with non-antibacterial agents.
• non-antibacterial agents in the above treatments include anti-inflammatory steroids, non-steroidal anti-inflammatory agents, bronchodilators, mucolytics, anti-asthma therapeutics, and pulmonary surfactants.
• the non-antibacterial agent may be selected from the group consisting of albuterol, albuterol, budesonide, beclomethasone, dexamethasone, nedocromil, beclomethasone, fluticasone, flunisolide, triamcinolone, ibuprofen, rofe Saxib, naproxen, celecoxib, nedocromil, ipratropium, oxycin, pyrbuterol, salmeterol, bronchiodilators, mucolytics, calfactant, bellacontan, Poractant alfa, surfaxin and pulmozyme (also known as alpha chain enzyme).
• beclomethasone dexamethasone
• nedocromil beclomethasone
• fluticasone flunisolide
• triamcinolone ibuprofen
• rofe Saxib naproxen
• celecoxib celecoxib
• the compounds of the invention may be used alone or in combination with a second antibacterial and/or non-antibacterial agent to treat and/or prevent acute or chronic respiratory infections, including acute lung and nosocomial infections, such as the gastroenterology.
• Enterobacteraerogenes Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis , Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter calcoaceticus, xylose Infections caused by Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providencia stuartii, and Citrobacter freundi, common lung infections such as influenza bloodthirsty Haemophilus Influenzae, Legionella s Pecies), Moraxella catarr
• the use of the compounds of the invention may render the Gram-negative bacteria susceptible to the effects of the second antibacterial agent when used to treat and/or prevent a disease caused by Gram-negative bacteria.
• the second antimicrobial agent includes, but is not limited to, selected from the group consisting of:
• macrolides or ketolides such as erythromycin, azithromycin, erythromycin, and telithromycin
• ⁇ -lactam includes penicillin, cephalosporin, and carbapenems such as carbapenem, imipenem, and meropenem;
• monomycin such as penicillin, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, melo Xilin, piperacillin, azlocillin, temocillin, cefotaxime, cefpirin, cefradine, ceftazidime, cefazolin, cefmenudene, cefuroxime, cephalexin, cefprozil, cefaclor, chlorine Cephalosporin, cefoxitin, cefmetazole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cephalosporin Pyridoxine and Anqunan;
• quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, Fleroxacin, gepafloxacin, sparfloxacin, trovafloxacin, clinfloxacin, gatifloxacin, moxifloxacin, sitafloxacin, ganefloxacin, gemifloxacin and pazufloxacin;
• antibacterial sulfa drugs and antibacterial sulfonamides including p-aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and N-nonanoyl sulfonamide;
• aminoglycosides such as streptomycin, neomycin, kanamycin, paromomycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, west Somi Star, Dibekacin and Isepamicin;
• tetracyclines such as tetracycline, chlortetracycline, dimecycline, minocycline, oxytetracycline, metacycline and doxycycline;
• rifamycin such as rifampicin (also known as rifampicin), rifapentine, rifabutin, benzoxazine rifampicin and rifaximin;
• Lincosamides such as lincomycin and clindamycin
• glycopeptides such as vancomycin and teicoplanin
• chain-positivemycins such as quinupristin and dafolopin
• the second antibacterial agent can be administered in combination with a compound of the invention administered prior to, concurrently with, or subsequent to administration of the compound of the invention.
• the administration route is the same, and the compound of the present invention can be formulated into the same dosage form as the second antibacterial agent.
• An example of a dosage form containing a compound of the invention and a second antibacterial agent is a tablet or capsule.
• the compounds of the invention may also be used alone or in combination with a second antibacterial agent for administration by inhalation.
• a preferred second antibacterial agent is selected from the group consisting of tobramycin, gentamicin, antrexam, ciprofloxacin, polymyxin B, fentanin, azithromycin, and polymyxin E.
• composition of the present invention can be formulated into any of clinically or pharmaceutically acceptable dosage forms, preferably oral preparations and injections.
• the compounds of the present invention can be formulated into any pharmaceutically acceptable dosage form which is administered orally, parenterally (intravenously, intramuscularly, subcutaneously or rectally), topically, etc., to a mammal, such as a human.
• the compound of the present invention can be formulated into an injection, including a sterile solution type, an emulsion type, a dispersion type or a suspension for intramuscular injection, intravenous injection, intravenous drip, subcutaneous injection or the like.
• the injection can be produced by a conventional method in the existing pharmaceutical field, and an optional aqueous solvent or a nonaqueous solvent can be used.
• aqueous solvent is water for injection, sodium chloride solution or other suitable aqueous solution
• non-aqueous solvent is vegetable oil, for example, soybean oil for injection, and other aqueous solutions of ethanol, propylene glycol, polyethylene glycol, etc. Wait.
• suitable additives such as osmotic pressure regulator, pH adjuster, solubilizer, filler, antioxidant, bacteriostatic agent, emulsifier, suspending Agents, etc.
• Commonly used osmotic pressure adjusting agents include sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol, etc., preferably sodium chloride or glucose; commonly used pH adjusting agents include acetic acid - sodium acetate, lactic acid, hydrazine Acid-sodium citrate, sodium bicarbonate-sodium carbonate, etc.; commonly used solubilizing agents include polysorbate 80, propylene glycol, lecithin, polyoxyethylene castor oil, cyclodextrin, etc.; commonly used fillers include lactose, mannitol , sorbitol, dextran, etc.; commonly used antioxidants are sodium sulfite, sodium bisulfite, sodium metabisulfite, etc.; commonly used bacteriostatic agents are phenol, cresol, chlorobutanol and the like.
• the pharmaceutical composition may also be formulated in a conventional form for rectal or topical administration, including suppositories, ointments, creams, patches, powders, sprays, inhalants, and the like.
• the compound of the present invention can be formulated into a conventional solid preparation such as a tablet, a capsule, a pill, a granule, etc. by a conventional method; or an oral liquid preparation such as an oral solution or an oral mixture.
• the tablets are mainly oral tablets, and include tablets, sublingual tablets, oral patches, chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, sustained release tablets, controlled release tablets and enteric coated tablets.
• Capsules can be classified into hard capsules, soft capsules, sustained release capsules, controlled release capsules and enteric capsules according to their dissolution and release characteristics. Pills include dropping pills, sugar pills, pellets, and the like.
• Granules can be divided into soluble particles, suspended particles, effervescent particles, enteric particles, sustained release particles and controlled release particles.
• a suitable filler, binder, disintegrant, lubricant or the like may be added.
• Commonly used fillers include starch, powdered sugar, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, etc.
• commonly used binders include sodium carboxymethyl cellulose, PVP -K30, hydroxypropyl cellulose, starch syrup, methyl cellulose, ethyl cellulose, hypromellose, gelatinized starch, etc.
• commonly used disintegrating agents include dry starch, crospovidone, cross-linked carboxylate Methylcellulose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, etc.
• commonly used lubricants include magnesium stearate, talc, sodium lauryl sulfate, micronized silica gel, and the like.
• the pharmaceutical composition of the present invention contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.1 to 500 mg, preferably 0.1 to 200 mg, more preferably 1 to 100 mg. For example, it is 0.5 mg, 1 mg, 3 mg, 5 mg, 10 mg, 15 mg.
• the pharmaceutical composition (e.g., pharmaceutical preparation) of the present invention may be in unit dosage form, and the unit dose contains 0.01 to 1000 mg, preferably 0.1 to 500 mg, preferably 0.1 to 200 mg, more preferably 1 to 100 mg, of the compound of the present invention.
• the invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prevention of an infectious disease.
• the compound of the present invention can be administered to an adult patient in the above-mentioned dosage form, and administered in a total amount of 0.001 to 1500 mg/day, preferably 0.01 to 1000 mg/day, more preferably 0.1 to 800 mg/day, once or divided into several times a day. It is particularly preferably 1-600 mg/day, for example 250 mg/day, 400 mg/day, 500 mg/day, 600 mg/day.
• the dose of the compound of the present invention can be appropriately increased or decreased depending on the type of the disease to be treated, the age, body weight, symptoms, and the like of the patient.
• the compound of the invention as an antibiotic, exhibits good antibacterial activity, good biostability, and particularly has good antibacterial activity against Gram-negative bacteria, and can be used for treating and/or preventing various diseases caused by Gram-negative bacteria. disease.
• Test strains The following clinical isolates were purchased at public institutions.
• Test sample imipenem, ceftazidime: commercial product, the following experiments were carried out according to the content of active ingredients in each commercial product;
• the experimental results show that the compound of the present invention has excellent antibacterial activity against the test strain.
• the compounds of the invention have superior antibacterial activity to the control compound or to the control compound. Therefore, the compounds of the invention have good clinical application potential.
• Test compound The compound of the present invention is prepared according to the method of the preparation example;
• Test strains Escherichia coli carrying the mcr-1 gene and the quality control strain Escherichia coli ATCC25922 isolated from animals were provided by South China Agricultural University.
• the MIC value of the test drug against polymyxin-resistant mcr-1 positive Escherichia coli was determined by agar dilution method in CLSI.
• Preparation of drug-containing agar plates prepare the highest concentration of drug solution, and dilute the drug solution with the highest concentration of each compound. Take 1 mL of each dilution gradient (20 ⁇ drug working solution) and add 19mL 45°C to 50° CMH. Agar, immediately mix the agar and the drug solution to prepare a drug-containing agar plate at a final concentration of 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.06 ⁇ g / mL, and solidify for use; A growth control group was also set.
• Preparation and culture of inoculum After reconstituting the strain at -80 °C, the turbidity is adjusted to reach or exceed 0.5# McPherson unit; 96-well plate is used as the inoculating tank, and the bacterial solution is diluted with sodium chloride injection. The amount of bacteria inoculated on the agar was 10 4 CFU/dot.
• the multi-point inoculation device was used to inoculate the bacterial liquid onto the surface of the labeled drug-containing agar. After the water of the inoculation site was completely absorbed by the agar, the plate was placed in a constant temperature incubator at 37 ° C for 16-20 hours.
• the compounds 5 and 6 of the present invention have good in vitro antibacterial activity against the polymyxin E-resistant mcr-1 positive enterobacteria, and the MIC 50 values are 0.125 ⁇ g/mL and 0.5, respectively.
• Gg/mL, MIC 90 values of 0.5 ⁇ g/mL and 1 ⁇ g/mL, respectively, are superior to the marketed drugs ampicillin, cefotaxime, gentamicin, ciprofloxacin, tetracycline, imipenem and compound Xinnuo Ming ( ⁇ 4 is resistant). This indicates that the compounds of the invention have good clinical application potential compared to existing compounds.
• Test article The compound of the present invention was prepared according to the method of Preparation Example; Compound C was prepared by referring to WO2008154642 A2.
• the minimum inhibitory concentration (MIC) of the compound against the strain was determined by reference to the steps of the 2018 American Institute of Clinical Laboratory Standards (CLSI) agar dilution method.
• Preparation of drug-containing plates (1) The highest concentration of the drug solution was prepared, and the highest concentration of the compound was 160 ⁇ g/mL. (2) The drug solution with the highest concentration of each compound was subjected to double dilution, a total of 10 concentration gradients, 2 mL of the drug solution of each dilution gradient, and 18 mL of MH agar solution which was autoclaved at 121 ° C and cooled to about 50 ° C. , mix, stand still after cooling, it is a drug-containing plate, and mark it. The final concentrations of the compounds were 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 ⁇ g/mL.
• Preparation and inoculation of inoculum fresh single colonies were selected, diluted with 0.9% sodium chloride injection and adjusted to 0.5# Mai's turbidity, and then diluted 10 times with 0.9% sodium chloride injection, then automatically connected with multiple points. Inoculate the bacteria on the labeled drug-containing plate.
• the compound 6 of the present invention has excellent in vitro antibacterial activity against Pseudomonas aeruginosa, and the MIC 50 value and the MIC 90 value are 0.5 ⁇ g/mL and 1 ⁇ g/mL, respectively; whereas, the compound C is on the patina
• the in vitro antibacterial activity of Pseudomonas was poor, with MIC 50 and MIC 90 values of 4 ⁇ g/mL and >16 ⁇ g/mL, respectively.
• the compounds of the present invention have superior antibacterial activity against Pseudomonas aeruginosa than Compound C.
• the compounds of the invention are self-made and are dissolved in a suitable vehicle.
• Rat blood collection fixed animals, the tail was heated in a water bath 10 minutes before each time point, and about 200 ⁇ l of blood was collected through the tail vein, and the blood was collected and placed in an anticoagulant tube containing sodium heparin. Blood samples were centrifuged at 8000 rpm for 6 min at 4 ° C to obtain plasma samples, which must be prepared within 30 min after blood collection. Store in a -80 ° C freezer before plasma testing.
• the concentration of the test substance was output using AB's Analyst 1.6.1.
• Microsoft Excel calculates the mean, standard deviation, coefficient of variation and other parameters (Analyst 1.6.1 direct output is not calculated), PK parameters are calculated using Pharsight Phoenix 6.1 software.
• Methyl p-bromomethylbenzoate 50 g, 0.22 mol
• triethyl phosphite 73 g, 0.45 mol
• nitrogen gas was cooled down to room temperature, concentrated and decompressed to remove most of the remaining triethyl phosphite, and 100 mL of toluene was added to continue concentration.
• the mixture was concentrated three times to dryness to obtain 68 g of light yellow oil (weight greater than the theoretical amount). Used directly in the next step.
• Furan formaldehyde (150 g, 1.56 mol) was added to a 5.0 L three-necked flask, and 900 mL of ethanol was added thereto, and the mixture was cooled to 10 ° C or less in an ice water bath, and a solution of sodium hydroxide (40 g, 1.0 mol) dissolved in 1.8 L of purified water was added dropwise.
• an aqueous acetaldehyde solution 400 g, 3.6 mol, 40% aqueous solution was added dropwise, and the temperature of the system was maintained at about 0 ° C during the dropwise addition, and the addition was completed in about 5 hours.
• the crude intermediate 1-3 (270 mg) was dissolved in 3 mL of methanol, 1 mL of 50% aqueous hydroxylamine solution was added, and the mixture was stirred for 40 hours.
• the work-up system was poured into water, suction filtered, and the filter cake was washed with water and dried to give the compound 79 mg.
• Methyl p-bromomethylbenzoate 60 g, 0.26 mol, 1.0 eq.
• triethyl phosphite 87 g, 0.52 mol, 2.0 eq.
• the TLC was monitored until the starting material 1 disappeared.
• the nitrogen gas was cooled down to room temperature, and most of the remaining triethyl phosphite was removed by concentration under reduced pressure.
• Toluene (100 mL) was added to continue to concentrate, and the mixture was concentrated three times to dryness to afford 78 g of pale yellow oil.
• One step reaction 60 g, 0.26 mol, 1.0 eq.
• triethyl phosphite 87 g, 0.52 mol, 2.0 eq.
• the starting materials 3-5 (185 g, 1.49 mol, 1.0 eq.) were dissolved in 560 mL of dry acetonitrile under nitrogen, and then powdered sodium hydroxide (56 g, 0.196 mol, 1.05 eq.) was added and cooled in a water bath.
• 3-Bromopropene (450 g, 3.74 mol, 2.5 eq.) was added dropwise to the system, and the addition was completed, and the reaction was stirred at room temperature.
• the crude intermediate 3-11 (270 mg) was dissolved in 1.5 mL of methanol, and 1 mL of a 50% aqueous solution of hydroxylamine was added, and the mixture was stirred for 24 hours.
• the post-treatment system was poured into water, filtered, filtered, washed with water and dried to give 145 mg of Compound 3.
• Methyl 4-((trimethylsilyl)ethynyl)benzoate (31.5 g, 135.6 mmol) was dissolved in methanol (450 mL), K 2 CO 3 (37.5 g, 271.5 mmol) was added and the mixture was stirred for 2 hours. After drying, 450 mL of ethyl acetate and 450 mL of water were added, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
• Methyl 4-ethynylbenzoate (21.75 g, 135.79 mmol) was dissolved in 500 mL of acetone, silver nitrate (2.176 g, 12.81 mmol) was added, and after stirring for 40 min, NBS (26.90 g, 151.16 mmol) was added, After stirring for 2 hours, it was filtered, and the filtrate was evaporated to dryness and crystallised from isopropyl alcohol to give 26.75 g of white solid.
• Methyl 4-(bromoethynyl)benzoate (26.75 g, 111.89 mmol) was dissolved in 200 mL of methanol and 20 mL of water, NaOH (8.96 g, 224 mmol) was added, and the reaction was stirred for 2 hours, and 350 mL of water was added, with 1 N of diluted hydrochloric acid. The pH was adjusted to 6, and 18.92 g of a white solid was obtained by filtration, yield: 75%.
• the compound 6 was synthesized using methyl (2S,3R)-2-(4-(bromoethynyl)benzoylamino)-3-hydroxybutanoate.
• the compound 7 was synthesized using methyl 2-(4-(bromoethynyl)benzoylamino)-3-hydroxybutanoate.
• Compounds 6, 8-10 are stereoisomers of Compound 7, and their 1 H-NMR data were substantially the same, and no significant difference was observed.
• Mobile phase A Accurately measure 0.8 mL of trifluoroacetic acid, and mix it in 1000 mL of water to obtain.
• Mobile phase B Accurately measure 0.5 mL of trifluoroacetic acid, and mix it in 1000 mL of methanol to obtain.
• Test solution Take appropriate amounts of compound 6, compound 9 and compound 10, accurately weigh, add methanol to dissolve and make a solution containing about 0.5 mg per 1 mL as the test solution.
• the product of the above step was dissolved in 8 mL of anhydrous methanol, and 3 mL of a 50% aqueous solution of hydroxylamine was added thereto, and the mixture was reacted at room temperature for 3 hours, and the liquid phase was directly purified to obtain a total of 20 mg of the compound 16 in a yield of 16.6%.
• the intermediate 21-2 (150 mg, 0.403 mmol) was dissolved in 4 mL of methanol, and 2 mL of a 50% aqueous solution of hydroxylamine was added, and the mixture was stirred for 40 hours.
• the work-up system was poured into water, suction filtered, and the filter cake was washed with water and dried to give 74 mg of Compound 30.
• Methyl 4-((trimethylsilyl)ethynyl)benzoate (2.10 g, 9.04 mmol) was dissolved in methanol (30 mL), K 2 CO 3 (2.50 g, 18.1 mmol), and the mixture was stirred for 2 hours. After drying, 30 mL of ethyl acetate and 30 mL of water were added, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
• Methyl 1-methylpyrrole-2-carboxylate (3.0 g, 21.6 mmol) and NBS (3.84 g, 21.6 mmol) were dissolved in 40 mL of dichloromethane and reacted in the dark for 12 hours.
• (Petroleic ether) obtained 2.21 g of product with a yield of 46.8%.
• the 5-ethynyl-1-methyl -1H- pyrrole-2-carboxylate (1.05g, 6.43mmol) was dissolved in 20mL anhydrous THF, at 0 °C was slowly added LiAlH 4 (0.367g, 9.66mmol) reaction Stir at room temperature for 7 hours, cool to 0 ° C, add ethyl acetate until no more bubbles are formed in the reaction mixture, add 2 mL of water, suction filtration, extract the filtrate with ethyl acetate, wash with 20 mL of water, use anhydrous sulfuric acid for organic phase
• the solid obtained in the previous step was dissolved in 10 mL of methanol, and 8 mL of 50% aqueous hydroxylamine solution and lithium hydroxide monohydrate (0.032 g, 0.762 mmol) were added, and the mixture was stirred for 3 hours, and a white solid was precipitated, filtered, and filtered cake with methanol and water. Washing separately gave 0.096 g of a white solid in a two-step yield: 20.4%.
• Methyl (2S,3R)-2-(4-((4-(1H-pyrazol-5-yl)phenyl)ethynyl)benzamide)-3-hydroxybutanoate (0.12g, 0.297 Methyl acetate was dissolved in 10 mL of methanol, and 8 mL of 50% aqueous hydroxylamine solution and lithium hydroxide monohydrate (0.008 g, 0.19 mmol) were added, and the mixture was stirred at room temperature for 3 hours, and then dried, and passed through a silica gel column to obtain 0.056 g of compound 37. Yield: 46.5 %.
• PE: EA 1:2
• Compound 46 was synthesized by reference to Example 39.
• Compound 47 was synthesized by reference to Example 39.
• Compound 48 was synthesized by reference to Example 39.
• the present invention provides an antibacterial agent which, as an LpxC inhibitor, exhibits excellent antibacterial activity against bacteria, particularly against Gram. Further, the compound of the present invention is excellent in metabolic stability in vivo.

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