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NZ620447B2 - Quinolone compound - Google Patents
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NZ620447B2 - Quinolone compound - Google Patents

Quinolone compound Download PDF

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Publication number
NZ620447B2
NZ620447B2 NZ620447A NZ62044712A NZ620447B2 NZ 620447 B2 NZ620447 B2 NZ 620447B2 NZ 620447 A NZ620447 A NZ 620447A NZ 62044712 A NZ62044712 A NZ 62044712A NZ 620447 B2 NZ620447 B2 NZ 620447B2
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NZ
New Zealand
Prior art keywords
group
optionally substituted
alkyl
compound
salt
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NZ620447A
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NZ620447A (en
Inventor
Mamuti Abudusaimi
Jayfei Cheng
Hisashi Miyamoto
Daisuke Oka
Jiangqin Sun
Fangguo Ye
Jay Fei Cheng
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Otsuka Pharmaceutical Co Ltd
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Priority claimed from PCT/CN2012/080753 external-priority patent/WO2013029548A1/en
Publication of NZ620447A publication Critical patent/NZ620447A/en
Publication of NZ620447B2 publication Critical patent/NZ620447B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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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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    • C07D401/02—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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    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
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    • C07D401/14—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 three or more hetero 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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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
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The present disclosure provides a compound represented by the formula (I) wherein X is a hydrogen atom or a fluorine atom; R is a hydrogen atom or alkyl; R1 is (1) cyclopropyl optionally substituted by to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen atoms; R2 is alkyl, alkoxy, haloalkoxy, a halogen atom, cyano, etc.; and R3 is 7-oxo-7,8-dihydro-1,8-naphthyridinyl, 3-pyridyl, etc., or a salt thereof. The compound of the present disclosure has excellent antimicrobial activity against Clostridium difficile and is useful for the prevention or treatment of intestinal infection such as Clostridium difficile- associated diarrhea. xy, haloalkoxy, a halogen atom, cyano, etc.; and R3 is 7-oxo-7,8-dihydro-1,8-naphthyridinyl, 3-pyridyl, etc., or a salt thereof. The compound of the present disclosure has excellent antimicrobial activity against Clostridium difficile and is useful for the prevention or treatment of intestinal infection such as Clostridium difficile- associated diarrhea.

Description

DESCRIPTION ONE COMPOUND Technical Field The present invention relates to quinolone compounds and pharmaceutical use thereof.
Background Art Clostridium difficile infection is associated with consumption of antibiotics which disrupt the normal microbial flora of the gut, allowing Clostridium difficile to establish itself and produce disease. Currently, only vancomycin or metronidazole is recommended for treatment and many patients suffer from relapse on infection t Opin. Ther. Patents (2010) 20(10), pp. 1389-1399). 214 A1 bes use of ozenoxacin for Clostridium difficile .
Some quinolone compounds useful as antibacterial agents are disclosed in JP1-319463 A, WO99/51588, WO99/03465, JP3-66301 B and WO99/07682.
Summary of Invention The object of the present invention is to provide a novel quinolone nd which has excellent antimicrobial activity, ularly excellent antimicrobial activity t Clostridium difficile. Another object of the present invention is to provide a pharmaceutical composition containing said quinolone compound, which is useful for the prevention or treatment of various ious diseases ing antibiotics-associated diarrhea (AAD) such as Clostridium difficile-associated diarrhea (CDAD). A further object of the present invention is to provide a method for preventing or treating a bacterial infection including AAD such as CDAD, which comprises administering said quinolone compound to a human or an .
The objects of the invention should be read (Followed by page 1a) ctively with the object of also providing the public with a useful alternative.
The present invention provides a quinolone compound, a (Followed by page 2) WO 29548 pharmaceutical composition comprising said nd, I) use or said compound, and a method for preventing or treating a bacterial ion, as described in Items 1 to 27 below.
Item 1. A compound represented by the formula (") O O ‘ (I) R3 T R2 R1 wherein X is a hydrogen atom or a fluorine atom; Q is a hydrogen atom or al<y;; ?’ is (l) cyclopropyl optionally substituted by l to 3 halogen atoms or (2) phenyl optionally substituted by l to 3 halogen atoms; R? is a en atom; alkyl optionally substituted by l or 2 substituents selected from the group consisting o: a halogen atom and yl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro; amiro; formy'; alkenyl or alkynyl; or R? and R? are bonded to form a 5- or 6-membered ring optionally substituted by alkyl; R3 is (l) a fused heterocyclic group of the formula wherein ===== represents a single bond or a double bond, Xlis C(Rb or N, Q4 is a hydrogen atom or alkyl, and Q5 is (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) ritro, (e) rydroxy, (t) a'kyl optionally substituted by l to 3 halogen atoms, (g) alkenyl or alkynyl, (h) aryl, or (i) alkoxy optionally substituted by l to 3 halogen atoms, when X1 is C(Ré), R4 and R5 are optionally bonded to form a 5- or 6—membered ring optionally substituted by oxo, said fused heterocyclic group is optionally substituted by l or 2 substituents selected jrom the group consisting o; a halogen atom, cyano, nitro, hydroxy and alkyl, (2) a gr0ip 03 the jormJla 2\N/\k— (C) N/ V wherein X2 is C(R?) or N, and R5, R7 and R3 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) nitro, (e) amino, (5) alkyl optional'y substituted by l to 3 substituents ed jrom the group consisting o: a n atom, alkoxy and amino, (9) a keny , (h) a kyny', (i) aryl, (j) formyl or CH=N—OH, (k) carboxy, (l) carbamoyl, (m) a 5- to LO-membered aromatic cyclic group optionally tuted by alkyl, or (n) alkenyloxy, (3) a group o: the jormula X/B \ S \ I or | /N A; (D) \N X (E) wherein X3 and X4 are N, or X3 is N ard X4 is CR”, wherein R” is hydrogen atom, amino, hydroxy, alkyl ally substituted by l to 3 substituents selected from the group consisting 0: alkoxy and dimethylamino OI mercap':o, OI X3 is CH and X4 is N, R’ is a hydrogen atom or alkyl optionally substituted by l to 3 subsuiuuents selected from the group consisting o; substiuuued hydroxyl and amino, and R5 is as defired above, (4) a group o: the jormula WO 29548 R6 R6 H N aU«N \ (1%S , \N/ / wherein ------ represents a single bond or a double bond and R5 is as defined above, (5) 3-pyridyl optionally substituted by l or 2 substituents selected from the group consisting I] (a) a halogen atom, (b) cyano, (c) nitro, (d) hydroxy, (e) amino, (5) alkyl optional'y substituted by l to 3 substituents selected jrom ,he group consisting o: a halogen atom, alkylamino, dialkylamino and hydroxy, (g) alkeny', a'kynyl (h) aryl, (i) cyc'oa'kyl, (j) alkoxy, (k) alkylamino, (l) dialkylamino, (m) phenylamino optionally substituted by 1 to 3 n atoms, (n) a cyclic amino group ally substitu':ed by alkoxycarbonyl, (o) formyl, (p) carbamoyl optionally substituted by alkyl ally substituted by hydroxy, and (q) a 5- to lO-membered aromatic heterocyclic group optionally tuted by alkyl, (6) 4—pyridyl optionally tuoed by a halogen atom, (7) 5—pyrimidinyl optional'y substituted by l or 2 substituents selected from the group consisting 0: amino, alkylamino, lamino and carboxy, (8) 2—indoly', 3—indolyl, 5—indo'yl, 6—indolyl, benzofuranyl, benzothiophenyl, benzoxazo'y' or benzothiazolyl, each optionally substituted by l or 2 substituents selected from the group consisting o; (a) a halogen atom, cyano, nitro, hydroxy, alkyl optionally substituted by l to 3 tuents selected jrom the group consisting 0: amino, alkoxycarbonylamino, alkylamino and dialkylamino, a'koxy, formyl, carboxy, and amino optionally substituted by l or 2 substituents selected jrom the group consisting o; (i) alkoxycarbonyl, (ii) arbony' optionally substituted by a substituent selected from the I) group consisting o; (A) cycloalkyloxy optionally substituted by l to 3 alkyl, (3) alkylamino, (C) dialkylamino, (D) a cyclic amino group optionally substituted by alkoxycarbonyl, and (E) a halogen atom, (iii) phenylcarbonyl ally substituted by l to 3 tuents selected from the I] group consisting 0; alkyl and alkoxy, (iv) lkylcarbonyl, (v) a 5- to lO-membered aromatic heterocycly'carbonyl group optionally substituted by alkyl optionally substituted by l to 3 halogen atoms, (vi) benzylcarbony' optionally substituted by l to 3 substituents selected from the group consisting o; a halogen atom and alkoxy, (vii) arylsul‘onyl optionally tuted by alkoxy, (viii) cycloa'kylalkylsul‘onyl optionally substituted by l to 3 substituents selected from the group consisting 0: alkyl and oxo, (ix) a 5- to lO-membered aromatic heterocycly'sul‘onyl group optionally substituted by l :o 3 alkyl, and (x) —C(=N—CN)—SR9 wherein R9 is alkyl, (9) a group o: the jormula / Y1 Y2 \ Yzé |&\\ ‘ or I l \ R24 ‘\\ vv yi\\‘\\ Y4 Y4 VV (F) (G) wherein one 0: Y1, Y2, Y3 and Y4 is N or N+(—O'), and the ing three are each C(R25), C(R2% and C(RZU, W is o, 5, NH or N(R”) QB is a en atom or alkyl, and 'RM, R%, R26 and R27 are each independently, (a) a hydrogen atom, (b) cyano, or (c) nitro, (10) a group o: the jormula N4R21km or t N N (H) T (J) wherein Q” is a hydrogen atom or hydroxy, and 'R” is a hydrogen atom or alkyl, (11) a group 03 the jormula x7/ \ | | _ X8 2 \\N X5 IL‘I O whereir X5 is C(Rll) or N, x6 is C 2, C(=O), o, s, 502 or N(R12), X7 is C R13), C(=O) or MR”), x8 is c R”) or c<=o>, R”, R12 and R14 are each independently, (a) a hydrogen atom or (b) alkyl, and RH, R13 and R15 are each independently, (a) a hydrogen atom, (b) a halogen atom, c) cyano, (d) nitro, (e) amino, (f) mino, (g) dialkylamino, (h) alkyl optionally substituted by hydroxy, or (i) alkenyl, when X5 is C(Qn), R10 and R11 are optionally bonded to form a 5- or 6-membered ring optionally substituted by alkyl or oxo, and when X6 is N(?”) and X7 is CH(RB), R12 and R13 are ally bonded to form a 5- or 6-membered ring, (12) a group 03 the jormula / \ (L) 8 wherein. l 6 .
R is (a) a hydrogen atom, (b) alkyl optional ly substituted by l to 3 substituents selected from ,he group ting o:: cyano, alkylamino and dialkylamino, C ) alkenyl optionally substituted by carboxy, (d) formyl, (e) carboxy, (f) carbamoyl I (g) —C(RN)=N—OH wherein R17 is a hydrogen atom, cyano or hydroxy, (h) a 5- to LO-membered ic heterocyclic group optionally substituted by alkyl, alkoxycarbonyl, carboxy or , or (i) cyano, (13) a group o: the jormula (WOW (M) wherein R18 is a hydrogen atom or alkyl optionally substituted by l to 3 substituents selected from the group consisting o: a halogen atom and phenyl, n is O or 1, R”, R20 and R33 are each independently, (a) a hydrogen atom, (b) a n atom, (c) cyano, (d) alkyl optional ly substituted by l to 3 substituents selected from ,he I) group consisting o: (i) a halogen atom, (ii) cyano, (iii) hydroxy, (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group optionally substituted by alkyl, (e) alkoxy, (f) amino ally substituted by l or 2 substituents selected jrom ,he group consisting of (i) alkylcarbonyl ally substituted by a cyclic amino group, (ii) ulfonyl, (iii) carbamoyl, (iv) alkyl, cycloalkyl or cycloalkylalkyl, and (v) 5- to lO-membered saturated heterocyclic group, (g) carboxy, (h) carbonyl, (i) carbamoyl optionally substituted by a'ky' optionally substituted by amino, alkylamino, 'amino or alkoxycarbonylamino, (j) formyl, (k) a 5- to LO-membered aromatic heterocyclic group optionally substituted by alkyl, (l) —CH=N—OR21 wherein R21 is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino, (m) nitro, (n) a 5- to LO-membered saturated heterocyclic group optionally substituted by amino, (o) phenyl, or (p) —NHC(SMe)=CHCN, (14) a group 03 the jormula R wherein R30 is (a) a en atom, (b) a halogen atom, (c) cyano, (d) alkyl optionally substituted by l to 3 substituents ed from the group consisting o: a halogen atom ard hydroxy, (e) a'keny', ('2) a' kyny' , (g) aLkoxy, (h) formyl, (i) —CH=N—OH, or (j) carbamoyl, (L5) naphthyL or isochromenyl, (L6) quinoly' or isoquino'yl, or their oxide derivatives, (L7) a group o: the "ormu'a / boa (18) a group o: the jormula U is O or S, and R31 is (a) a hydrogen atom, (b) a haLogen atom, (c) alkyL optionally substituted by l to 3 halogen atoms, (d) carboxy, (e) nitro, (f) cyano, or (g) amir 0/ (19) a group o. the jormula R32 is (a) a halogen atom, (b) phenyl, OI (C) a group o__ the jormula H H O N N \ | \ or (20) a group o. the _formula \ I— 1 0 R35 wherein R34 and R35 are each independently, (a) a hydrogen atom, or (b) aminoalkyl, or R34 and R35 are bonded to form a 6-membered ring optionally tuted by amino or oxo, (21) a group o_ the jormula wherein R36 is (a) a hydrogen atom, (b) a halogen atom, (c) nitro, or (d) thienyl, or (22) a group or the jormula of, oofi Cf F30Ij/ \ o N or H , “0/ or a salt thereo:.
Item 1A. The compound 0: item 1, wherein X is a hydrogen atom or a fluorine atom; Q is a hydrogen atom or al<yl; ?’ is (l) cyclopropyl optionally substituted by l to 3 n atoms or (2) phenyl optionally substituted by l to 3 halogen atoms; Q2 is alkyl, alkoxy, haloalkoxy, a chlorine atom or cyano; or Q: and R? are bonded to form a 5- or 6-membered ring optionally ststituted by alkyl; ard Q3 is (l) a fused cyclic group or the jormula wherein ------ represents a single bond or a double bond, wo 2013/029548 X1 is C(Ré) or N, 34 is a hydrogen atom or alkyl, and Q5 is (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) ritro, (e) rydroxy, (t) a'kyl optionally substituted by l to 3 halogen atoms, (g) l or alkynyl, (h) aryl, or (i) alkoxy optionally substituted by l to 3 halogen atoms, when X1 is C(Ré), R4 and R5 are optionally bonded to form a 5- or 6—membered ring optionally substituted by oxo, said fused heterocyclic group is optionally substituted by l or 2 tuents ed jrom the group consisting o; a halogen atom, cyano, nitro, hydroxy and alkyl, (2) a groap o: the jormJla R74</X2\N/\k)— (C) N/ A; n X2 is C(R?) or N, and R5, R7 and R3 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) nitro, (e) amino, (5) alkyl optional'y substituted by l to 3 substituents selected jrom the group consisting o: a halogen atom, alkoxy and amino, (9) a'keny' , (h) a'kyny' , (i) aryl, (j) formyl or CH=N—OH, (k) carboxy, (l) carbamoyl, or (m) a 5- to bered aromatic heterocyclic group optionally substituted by alkyl, (3) a group o: the jormula X3 \ S \ \N X (D) \N X (E) wherein X3 and X4 are N, or X3 is N and X4 is CR”, n R” is a hydrogen atom, amino, hydroxy, alkyl or mercapto, or X3 is CH and X4 is N, R’ is a hydrogen atom or alkyl optionally substituted by l to 3 subsuiuuents selected from the group consisting o; substiuuued hydroxy and amino, and R5 is as defired above, (4) a group o: the jormula WO 29548 wherein ------ represents a single bond or a double bond and R5 is as defined above, (5) 3-pyridyl optionally substituted by l or 2 substituents selected from the I) group consisting o; a halogen atom, cyano, nitro, hydroxy, amino, alkyl optional'y substituted by l to 3 substituents selected jrom ,he group ting o: a halogen atom, alkylamino, dialkylamino and hydroxy, l or alkynyl, aryl, cyc'oa'kyl, alkoxy, alkylamino, dialkylamino, amino ally substituted by l to 3 halogen atoms, a cyclic amino group optionally substituted by alkoxycarbonyl, formyl, carbamoyl optionally substituted by alkyl optionally substituted by y, and a 5- to lO-membered aromatic heterocyclic group optionally substituted by alkyl, 4—pyridyl optionally subsoituoed by a halogen atom, -pyrimidiny1 optional'y substituted by l or 2 substituents selected from the group consisting 0: amino, alkylamino, dialkylamino and carboxy, 2—indoly', 3—indolyl, 5—indo'yl, 6—indolyl, uranyl, hiophenyl, benzoxazo'y' or benzothiazolyl, each optionally substituted by l or 2 substituents selected from the group consisting o; (a) a halogen atom, cyano, nitro, hydroxy, alkyl optionally substituted by l to 3 substituents selected jrom the group consisting 0: amino, alkoxycarbonylamino, alkylamino and dialkylamino, formyl, carboxy, and amino optionally substituted by l or 2 substituents selected jrom the group consisting o; (i) carbonyl, (ii) alkylcarbony' optionally substituted by a substituent selected from the I) group consisting o; (A) cycloalkyloxy optionally substituted by l to 3 alkyl, (3) alkylamino, (C) dialkylamino, (D) a cyclic amino group optionally substituted by alkoxycarbonyl, and (E) a halogen atom, (iii) phenylcarbonyl optionally substituted by l to 3 substituents selected from the I] group ting 0; alkyl and alkoxy, (iv) cycloalkylcarbonyl, (v) a 5- to lO-membered ic heterocycly'carbonyl group optionally substituted by alkyl optionally substituted by l to 3 halogen atoms, (vi) benzylcarbony' optionally substituted by l to 3 substituents selected from the group consisting o; a halogen atom and alkoxy, (vii) arylsul‘onyl optionally tuted by alkoxy, (viii) cycloa'kylalkylsul‘onyl optionally tuted by l to 3 substituents selected from the group ting 0: alkyl and oxo, (ix) a 5- to lO-membered aromatic heterocycly'sul‘onyl group optionally substituted by l :o 3 alkyl, and (x) —C(=N—CN)—SR9 wherein R9 is alkyl, (9) a group o: the jormula / Y1 Y2 \ Yzé |&\\ ‘ or I l \ R24 \ w Y\\ Y4 Y4 W (F) (G) wherein one 0: Y1, Y2, Y3 and Y4 is N or N+(—O'), and the remaining three are each C(R25), C(R2% and C(RZU, W is o, s or N(R23) QB is a hydrogen atom or alkyl, and 'RM, R%, R26 and R27 are each independently, (a) a hydrogen atom, (b) cyano, or (c) nitro, (10) a group o: the a N4 R21km/ N or t N N (H) T (J) wherein Q” is a hydrogen atom or hydroxy, and 'R” is a hydrogen atom or alkyl, (11) a group 03 the jormula x7/ \ | | _ X8 2 \\N X5 FL] 0 whereir X5 is C(Rll) or N, x6 is C 2, C(=O), o, s, 502 or N(R12), X7 is C R13), C(=O) or MR”), x8 is c R”) or c<=o>, R”, R12 and R14 are each independently, (a) a hydrogen atom or (b) alkyl, and RH, R13 and R15 are each independently, (a) a hydrogen atom, (b) a halogen atom, c) cyano, (d) nitro, (e) amino, (f) mino, (g) dialkylamino, (h) alkyl optionally tuted by hydroxy, or (i) alkenyl, when X5 is C(Qn), R10 and R11 are optionally bonded to form a 5- or 6-membered ring optionally substituted by alkyl or oxo, and when X6 is N(?”) and X7 is CH(RB), R12 and R13 are optionally bonded to form a 5- or 6-membered ring, (12) a group 03 the jormula / \ (L) S wherein. l 6 .
R is (a) a hydrogen atom, (b) alkyl ally tuted by l to 3 substituents selected jrom ,he group consisting o: cyano, alkylamino and dialkylamino, c) alkenyl optionally substituted by carboxy, (d) formyl, (e) carboxy, (f) oyl, (g) —C(RN)=N—OH wherein R17 is a hydrogen atom, cyano or hydroxy, (h) a 5- to LO-membered aromatic heterocyclic group optionally tuted by alkyl, alkoxycarbonyl, carboxy or phenyl, or (i) cyano, (13) a group o: the jormula \/§/ r’ \\ R180_: (M) wherein R18 is a hydrogen atom or alkyl optionally substituted by l to 3 substituents selected from the group consisting o: a halogen atom and phenyl, and R19 and R20 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) alkyl optionally substituted by l to 3 substituents selected jrom ,he group consisting o; (i) a halogen atom, (ii) cyano, (iii) y, (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group optionally substituted by alkyl, (D alkoxy, A Ii) v amino optionally substituted by l or 2 substituents selected jrom ,he group consisting o; (i) arbonyl optionally substituted by a cyclic amino group, (ii) alkylsulfonyl, (iii) carbamoyl, and (iv) alkyl or cycloalkyl, alkoxycarbonyl, carbamoyl ally substituted by a'ky' optionally substituted by amino, alkylamino, dia'ky'amino or alkoxycarbonylamino, formyl, a 5- to lO-membered aromatic heterocyclic group op:iona"y subsoiouoed by a'ky', —CH=N—OR21 wherein R21 is a hydrogen atom or alkyl op:iona"y subsoiouoed by a'ky'amino or dialkylamino, or (m) nitro, (14) a group or the jormula wherein R30 is (a) a hydrogen atom, (b) a halogen atom, (C) cyano, (d) alkyl ally substituted by l to 3 substituents selected from the group consisting o: a halogen atom and hydroxy, (e) a'keny', (f) a kyny', (g) aLkoxy, (h) formyl, or (i) —CH=N—OH, (I5) naphthyI or omenyl, or (I6) quinoly' or isoquinolyl, or oxide derivative thereor,I] or a salt thereo:.
Item 2. The compound of iIem l or 1A, wherein X is a fluorine atom, or a salt thereo:.
Item 3. The compound 0: item 1 or 1A, wherein R3 is a fused heterocyclic group of the formula | T R4 ( > R4 (B> wherein ------ X1 , and R4 are as defined in item ’, and said fused heterocycIic group is optionally substituted by l or 2 substituents seIected from the group consisting o: a hangen atom, cyano, nitro, hydroxy and alkyl, or a salt thereor.
Item 4. The compound 0: item 1 or 1A, wherein R3 is a group of the formula X2\ X2\ / N/j/\ N \ 0 r R7 / N/ /\/ N/ / R6 R6 wherein X2, R6 and R7 are as d in item 1, or a salt thereor.
Item 5. The nd 0: item 1 or 1A, wherein R3 is a group of the formula 2012/080753 X//X3 \ S \ ‘ or | /N A; (D) \N X (E) wherein X3, X4, R6 and R’ are as de‘ined in item 1, or a salt thereor.
Item 6. The compound 0: item 1 or 1A, wherein R3 is a group or Lhe jormula 2012/080753 wherein —————— and R5 are as de‘ined in item 1, or a salt thereo:.
Item 7. The compound 0: item 1 or lA, wherein R3 is a group o“ the Iormula HZN N wherein R22 is (a) a n atom, (b) cyano, (c) nitro, (d) a'kyl optional'y substituted by l to 3 substituents selected Irom the group consisting o: a halogen atom, alkylamino, dialkylamino and hydroxy, (e) alkenyl or alkynyl, ('2) ary' I (g) cyc loalkyl, (h) alkoxy, (i) formyl, or (j) carbamoyl optionally substituted by alkyl optionally substi'tuted by hydroxy, or a salt thereor.
Item 8. The compound ’ 0" item or 1A, wherein Q3 is 5- pyrimidinyl subs'tituted by l or 2 substituents seIected Irom the group consisting 0: amino, alky:_amino, Iamino and carboxy, or a salt thereo:.
Item 9. The compound 0: item 1 or 1A, wherein R3 is 2— indolyI optionally tu'ted by l or 2 substituents selected from the group consisting 0; (a) a halogen atom, (b) cyano, (c) nitro, (d) hydroxy, WO 29548 (e) alkyl optionally substituted by l to 3 substituents selected jrom the group consisting 0: amino, alkoxycarbonylamino, alkylamino and dialkylamino, a'koxy, formyl, carboxy, and amino optionally tuted by l or 2 substituents selected jrom the group consisting o; (i) alkoxycarbonyl, (ii) alky'carbony' optionally substituted by a substituent ed from the I) group consisting o; (A) cycloalkyloxy optionally substituted by l to 3 alkyl, (3) alkylamino, (C) dialkylamino, (D) a cyclic amino group optionally substituted by carbonyl, and (E) a halogen atom, (iii) pheny'carbonyl optionally substituted by l to 3 substituents ed jrom the I] group consisting 0; alkyl and alkoxy, (iv) cycloalkylcarbonyl, (v) a 5- to lO-membered aromatic heterocyclylcarbonyl group optionally tuted by alkyl optionally substituted by l to 3 halogen atoms, (vi) benzylcarbonyl optionally substituted by l to 3 substituents selected from the group consisting o; a n atom and alkoxy, (vii) arylsul‘onyl optionally substituted by alkoxy, (viii) cycloa'kyla'ky'su'tonyl optionally substituted by l to 3 substituents selected from the group consisting 0' a'ky' and oxo, (ix) a 5- to lO-membered aromatic heterocyclylsul‘onyl group optionally substituted by l to 3 alkyl, and (x) CN)—SR9 wherein R9 is alkyl, or a salt thereo:.
Item 10. The compound 0: item 1 or lA, wherein R3 is a group O“ the Iormula / Y1 Y2 Yzé I ‘ \ \ O r I l R24 \3\ w Y\\ Y4 W (F) Y4 (G) n Y1, Y2, Y3, Y4, W and R24 are as de‘ined in item 1, or a salt thereo:.
Item ll. The compound of item 1 or lA, wherein R3 is a group oI the Iormula N//\/ \ N K | or k \N N (H) T (J) wherein R28 and R29 are as de‘ined in item 1, or a salt thereof Item 12. The compound 0: item 1 or lA, wherein R3 is a group O“ the Iormula X6 X6 T” \ T” \ | | X8 / or X8 / \N x5 \N x5 $10 $10 wherein X5, X3 )5, X8 and R10 are as de‘ined in item 1, or a salt thereo:.
Item 13. The compound 0: item 1 or 1A, n R3 is a group or the jormula R168 8 wherein R is (a) alkyl optionally substituted by l to 3 substituents selected jrom ,he group consisting o: cyano, alkylamino and dialkylamino, (b) alkenyl optionally substituted by y, (c) formyl, (d) carboxy, (e) carbamoyl, (f) —C(RN)=N—OH wherein R17 is a hydrogen atom, cyano or hydroxy, (g) a 5- to LO-membered aromatic heterocyclic group ally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or (h) cyano, or a salt thereo;.I) Item 14. The compound 0: item 1 or 1A, wherein R3 is a group or the jormula R1921 R18ao wherein ?i% is alkyl, and 'Rwa is (a) a halogen atom, (b) cyano, (c) alkyl optionally tuted by l to 3 substituents selected from the I] group consisting o; (i) a halogen atom, (ii) cyano, (iii) hydroxy, (iv) amino, (v) alkylamino, (vi) dia'ky'amino, and (vii) a cyclic amino group optionally substituted by alkyl, alkoxy, amino optionally substituted by l or 2 substituents selected from the group consisting o; (i) alkylcarbonyl optionally substituted by a cyclic amino group, (ii) alkylsulfonyl, (iii) oyl, and (iv) alkyl or cycloalkyl, carboxy, alkoxycarbonyl, carbamoy' optiona'ly substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, formyl, a 5- to LO-membered aromatic heterocyclic group optiona"y substituted by a'ky', —CH=N—OR21 wherein R21 is a hydrogen atom or alkyl optiona"y substituted by mino or dialkylamino, or (l) nitro, or a salt thereo:.
Item 15. The nd 0: item 1 or 1A, n R3 is a group or the jormula W0 2013/029548 wherein R30 is as d in item 1, or a salt thereo:.
Item 16. The compound 0: item 1 or lA, wherein R3 is naphthyI or isochromenyl, or a salt thereo:.
Item 17. The compound 0: item 1 or lA, wherein R3 is quinoly' or isoquinolyl, or oxide derivative thereo:, or a salt thereo:.
Item 18. The compound 0: item 1 or lA, wherein R is a hydrogen atom, or a salt thereo:.
Item 19. The compound 0: item 1 or lA, wherein R1 is cyclopropyl, 2—‘luorocyclopropyl or ‘luorophenyl, or a salt thereo:.
Item 20. The compound 0: item 1 or lA, wherein R2 is methyl, methoxy or a chlorine atom, or a salt thereo:.
Item 21. A pharmaceutical composition comprising a compourd 0: item 1 or 1A or a salt thereo: and a pharmaceutically able carrier.
Item 22. An antimicrobial agent comprising I) a nd or item 1 or 1A or a salt thereo:.
Item 23. A compound 0: item 1 or 1A or a salt thereo or use as a medicament.
Item 24. A compound 0: item 1 or 1A or a salt thereo or use as an antimicrobial agert.
Item 25. A compound 0: item 1 or 1A or a salt :hereo Oi” use in the tior or treatment 0: a ial in:fection.
Item 26. Use 0: acmwo and o: item 1 or 1A or a salt :hereo "or the manu ac cure 0.- a medicament for preventing or :reatirg a bacterial ion.
Item 27. A method for preventing or treating a bacterial infection which comprises administering an e "ective amount 0; a compound 0: item 1 or 1A or a salt : to a human or an animal The compound oI the "ormula (W or a salt thereo: (herei ter sometimes to be abbreviated as nd CD) has excellen, c ,erial activity against various gram positive and gram negative bacteria, and is use ul "or the prevention or treatment 0" various in fectious diseases induced by various bacteria in human, other animals and fish and is also useful as an external antimicrobial or disin ecoant agent for medical instruments or the like.
Erie-I) Description 0; Drawings Fig. l is a graph showing the results oI ,he anima:_S administered with compound 2—18 in Experimenta l Example 2.
Fig. 2 is a graph showing the results oI ,he anima:_S administered with vancomycin in mental Example 2.
Detailed Description of tre Invention Specific examples 0: groups in the formula are as follows.
Examp' es 0" "halogen atom" include fluorine atom, chlorine atom, bromire atom, and iodine atom.
Examp' GSO __ "alkyl" and "alkyl" moiety in "alkylamino", "dia'ky'amino", "alkylcarbonyl", "cycloalkyla'kylsul‘onyl", "cyc'oa'kylalkyl ", a'ky'" and "alkylsu'jonyl" include straight or branched C14 a" ky' such as methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, pentyl, ethylpropyl, isopentyl, neopentyl, tert-pentyl, hexyl, 1,2,2- trimethylpropyl, methylbutyl, 2-ethylbutyl, isohexyl, 3- methylpentyl, etc. ?xamples o " yl" include straight or branched ng alkeny; such as vinyl, enyl, 2—propenyl, l-butenyl, 2— butenyl, 3-butenyl, l—methyl—2—propenyl, 2—pentenyl, 2—hexenyl, etc. ?xamp'es O' "a- kynyl" include straight or branched ng alkyny; sucr as ethyr yl, 2-propynyl, 2-butynyl, 3-butynyl, 1— methyl—2—propynyl, 2—pentynyl, 2—hexynyl, etc. ?xamp'es o "a- koxy" and "alkoxy" moiety in "haloalkoxy", "alkoxycarbonyl " and "alkoxycarbonylamino" include straight or branched Cyfi alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, 3-methylpentyloxy, etc. ?xamples O" "haloalkoxy" include straight or branched C14 alkoxy substituted by l to 3 halogen atoms. Examples thereo; include fluoromethoxy, difluoromethoxy, tri methoxy, chloromethoxy, dichloromethoxy, :richloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2, 2,2-tri:fluoroethoxy, 2- chloroethoxy, 3, 3,3—trtT uoropropoxy, 2—chloropropoxy, 3_ chloropropoxy, 3 propoxy, 4,4,4-tri:fluorobutoxy, 2_ chlorobutoxy, 4_ chlorobutoxy, 4—bromobutoxy, 5,5,5- tri '5' uoropentyloxy, 5—chloropentyloxy, 6, 6,6-trifluorohexyloxy, rohexyloxy , etc. rable es thereo: include di fluoromethoxy. ?xamples O" "alkenyloxy" include s:raight or branched C2fi al {enyloxy such C s vinyloxy, l—propenyloxy, 2—propenyloxy, l— loxy, 2—butenyloxy, 3-butenyloxy, l—methyl—Z—propenyloxy, 2—pentenyloxy, 2 —hexenyloxy, etc. ?xamples O" "ah-ry‘l H and "ah-FY moiety in "arylsulfony e C644 (preferably C640) ary; such as phenyl, y; (e.g., l—naphthyl, 2—naphthyl), etc. Preferable es thereo;I) include phenyl. ?xamples O" "5- to lO-membered aromatic heterocyclic group" and "5- to lO-membered aromatic heterocyc'yl" moiety in "5- to lO-membered aromatic heterocycly' carbonyl group" and "5- :o LO-membered aromatic heterocyclylsul-fonyl group" include 5- :o LO-membered (pre:ferably 5- or 6-membered) aromatic heterocyclic group containing 1 to 4 (preferably 1 to 3, more preferably 1 or 2) heueroauoms selected from a nitrogen atom, an oxygen atom and a sulfur a,om4 Sixamples thereO" include furyl, thienyl, yl, lyl, inidazolyl, tri azolyl (e.g., l,7,3-triazoly', l ,?,4—triazolyl), :etrazolyl, isoxazolyl, oxazolyl, furazanyl, azolyl, :hiazolyl, l (e.g., 2- pyridyl, 3-pyridyl, 4-pyridyl), zinyl, pyrimidinyl, pyrazinyl, benzo:furanyl, isobenzofuranyl, benzo[b]thiophenyl, benzo[c]thiophenyl, indolyl, isoindolyl, indoliziny', indazolyl, benzimidazo'y', benzo:riazo'y', benzoxazolyl, l,2- benzisoxazo'y', benzo:hiazo'y', nzisothiazoly', puriny', quinoly', isoquinolyl, quinolizinyl, cinnoliny', quinazoliny', a:_inyl, phthalazinyl, naphthyridinyI_, pteridinyl, etc.
Preferable examp:_es thereo: include pyrro' yl, imidazo'yl, oxazoly', triazo'y' (e.g., 1,7,3-triazoly' ,l ,?,4—triazolyl), tetrazo' yl, pyridy' (e.g., 2-pyridyl, 3—pyridyl, 4—pyridyl), benzimidazolyl, etc. ?xamples O" "alkylamino" inclee Cyfi alkylamino such as amino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, tert-pentylamino, hexylamino, etc. ?xamples O" "dialkylamino" include di(Cyfi alkyl)amino such as ylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert- butyl)amino, dipentylamino, di(tert-pentyl)amino, dihexylamino, ethylmethylamino, etc. ?xamples 0'' "aminoalkyl" include Cyfi alkyl such as aminomethyl I 2—aminoethyl , 3—aminopropyl, 4-aminobutyl, 5- aminopentyl I 6-aminohexyl I etc. es 0'' "cycloalkyl" and "cycloalkyl" moiety in "cyc'oa'ky'oxy", "cycloalkylcarbonyl H I "cycloal<ylalkyl" and "cyc'oa'ky' alkylsul-Conyl" e Cyg cyc'oalky' such as cyc'opropy' I cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornanyl (e.g., 2—norbornanyl), etc. ?xamples 0'' alkylalkyl" include Cyg lkyl—Cpg alkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl I cycloheptylmethyl, ctylmethyl, norbornanylmethyl (e.g., norbornan—2— ylmethyl), etc. ?xamples 0'- "cyclic amino group" includes a 4- to 7- membered (pre:ferably 5- or 6-membered) cyclic amino group containing one r itrogen atom and optionally further containing one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. esE thereo: e l—azetidinyl, l_ pyrro'idinyl, l—i midazolidinyl, l—pyrazolidinyl, piperidino, l— zinyl, morpholino, thiomorpholino, l—azepanyl, 1,4— oxazepan—4—yl, etc. Preferable examples thereo:: include 1- pyrrol 1' di nyl , piperi di no, l—piperazinyl, morpholino, thiomorpholino, etc. ?xamples 0'' "alkoxycarbonyl" include Cyfi alkoxy-carbonyl wherein the alkoxy moiety is Cpfi alkoxy. Examples thereo: include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, ter' butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, G'ZC . ?xamples 0'' "alkoxycarbonylamino" include Cyfi alkoxy- carbonylamino wherein the alkoxy moiety is Cyfi alkoxy. Examples : include methoxycarbonylamino, ethoxycarbonylamiro, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, sec- W0 2013/029548 butoxycarbonylamino, tert-butoxycarbony:_amino, pentyloxycarbonylamino, hexyloxycarbony:_amino, etc. ?xamples 0'' "alkylcarbonyl" include Cyfi alkyl-carbonyl wherein the alkyl moiety is Cyfi alky'. ?xamples thereo:: include acetyl, ethy— yl, propylcarbony', isopropylcarbonyl, buty' carbony' I isobutylcarbonyl, sec-butylcarbonyl, tert— buty' carbony' I pentylcarbonyl, hexylcarbonyl, etc. ?xamples 0'' "cycloa:_kyloxy" include Cyg cycloalkyloxy such as cyclopropyloxy, t tyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, etc. ?xamples 0'' "cycloa' bonyl" include C}8 cycloalkyl— carbonyl such as ropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, etc. es 0' "5- to lO-membered ic heterocyc' ylcarbonyl group" include a 5- :o lO-membered (pre':erab' y 5- or 6-membered) aromatic heterocyclylcarbonyl group wherein :he heterocyclyl moie':y con':ains l to 4 (pre:ferably l to 3, more pre':erably l or 7) he ,eroa ,oms selected from a ni:rogen atom, an oxygen atom and a suljur a som. IExamples O: the he':erocyclyl moiety are same as the examples 0:f tte 5- to lO-membered aromatic heterocyc:_ic group mentioned above.
Preferable examples 0: "5_ to LO-membered aromatic cyclylcarbonyl group" include lcarbonyl (e.g., 2— pyridyI_carbonyl, 3-pyridylcarbonyl, 4—pyridy'carbony' ). ?xamples 0'' "arylsul-:onyl" include C644 (preferably Calm arylsu' _Cony' such as phenylsul:fonyl, y' sul-:ony' (e.g., l_ naphthy'sul 'Eonyl , 7—naphthylsu' ‘onyl), etc. Preferable es thereO' inc" ude phenylsul:fonyl. ?xamples 0'' "cycloalkylalkylsul-Conyl" include Cyg cyc' oa' ky' —C,_6 al ky— yl such as cyclopropylmethylsulfonyl, cyclobutylme:hy' su' _Cony' I cyc:_openuylme uhy' su' ‘ony' cyclohexylmethy' su' _Cony' I cyc:_ohep ,ylmeuhy'su' ‘ony' cyclooctylmethy' su' _Cony' I norbornany' me' hy' su'fiony' norbornan—2—ylmethy' sul"onyl), etc. ?xamples O" "5- to lO-membered aromatic heterocyc'ylsulfonyl group" include a 5- to lO-membered (preferab'y 5- or 6-membered) aromatic heterocyclylsulfonyl group wherein the heterocyclyl moiety contains 1 to 4 (preferably 1 to 3, more preferably 1 or 7) heteroauoms selected from a ni':rogen atom, an oxygen atom and a sulfur auomd IExamples O: the heterocyclyl moiety are same as the examples of tre 5- to LO-membered aromatic heterocyclic group mentioned above.
Preferable examples 0: "5- to LO-membered aromatic heterocyclylsul-:onyl group" include imidazolylsulfonyl. ?xamples 0' sulfonyl" include CL% alkylsulfonyl n the a'ky' moiety is Cyfi alky'. 'ixamples thereo: include methylsu'fony', ethylsu"onyl, sulfony', py'sulfony' , buty'sulfonyl, isobutylsu'fonyl, sec- buty'su'fony', tert—butylsu'fonyl, pentylsulfonyl, hexy'su'fony', etc. es O" "cyclopropyl optionally ststituted by l to 3 halogen atoms" include cyclopropy' optional'y substituted by l fluorine atom such as cyclopropyl, 7—- uorocyclopropyl, etc. ?xamples O" "phenyl optionally ststituted by l to 3 halogen atoms" e phenyl substituted by two fluorine atoms such as 2,4—di:fluorophenyl, etc. ?xamples O" "5- to lO-membered saturated cyclic group" include a 5- to bered (preferably 5- or 6-membered) saturated heterocyclic group containing 1 to 4 (preferably 1 to 3, ’ more preferabl y or 7) heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom” les thereo: include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, etc. ?xamples O" "6—membered ring optionally substituted by amino or oxo" formed by R34 and R% include a 6-membered ring optiona"y containing one nitrogen atom, and said ring is optiona"y substituted by amino or oxo. IExamples thereo: e cyclohexene and opyridine, each optionally substituted by amino or oxo. ?xamples O" "5- or 6-membered ring optionally substituted by a'kyl" formed by R? and R? include a 5- or 6-membered (preferably 6—membered) ring containing one nitrogen atom and op:iona"y further containing one oxygen atom, and said ring is op:iona"y substituted by alkyl. Rreferably, R? and R? are op:iona"y bonded to form —O—CH2—C{(CH3)— wherein the oxygen atom is bonded to the phenyl ring of tte quinolone ring as shown below. 0 O R3 N ?xamples of "5- or ered ring optionally substituted by oxo" formed by RA and R5 include a 5- or 6-membered (preferably 6—membered) ring containing one en atom and op:iona"y r containing one oxygen atom, and said ring is op:iona"y substituted by oxo. Preferably, R4 and R5 are op:iona"y bonded to form -CH2-O-(C=O)- wherein the carbonyl is bonded to the phenyl ring 0: the quinolone ring as shown below. / \ ko o ?xamples O" "5- or 6-membered ring optionally substituted by alkyl or oxo" formed by R10 and R11 e a 5- or ered (preferably 5—membered) ring containing 2 or 3 nitrogen atoms, and said ring is optionally tuted by alkyl or oxo.
Preferably, R10 and R11 are optiorally bonded to form -(C=O)-NH-, —C(Rfl)=N— or —N=N— wherein R31 is a hydrogen atom or alkyl, and the nitrogen atom is bonded to the phenyl ring of the fused ring, as shown below.
X6 /X6 /X6 x7/ \ x7 X\\8 /// X\\8 ///' X\\8 /// N N l\ NH N N————N 0 R31 ?xamples of "5- or 6-membered ring" formed by R12 and RE include a 5- or 6-membered (preferably 6-membered) ring containing one nitrogen atom” Preferably, R12 and R13 are optionally bonded to form -(CHfl4- as shown below. \\\\ \\ 6/’J T X X is a hydrogen atom or a fluorine atom, preferably, a fluorine atom.
R is a hydrogen atom or al<yl, preferably, a en atom.
R? is (1) cyclopropyl optionally substituted by l to 3 halogen atoms or (2) phenyl optionally substituted by l to 3 n atoms, preferably, cyclopropyl, 7—fluorocyclopropyl or 2,4—difluorophenyl.
R? is a en atom; alkyl optionally tuted by l or 2 substituents selected from the group consisting o; a halogen atom and hydroxyl; alkoxy; haloalkoxy; a halogen atom; cyano; cyclopropyl; nitro; amino; formyl; alkenyl or a'kynyl, preferably, alkyl, a'koxy, ha'oa'koxy, a chlorine atom or cyano, more preferab'y, Cyfi a'ky', Cyfi alkoxy, Cyfi alkoxy substituted by L to 3 halogen atoms, a chlorine atom or cyano, still more preferably, methyl, methoxy or a chlorine atom. ?xamples o a "used heterocyclic group of the formula (A) or (3) include a fused heterocyclic group of Lre formula / / o N X1 o N X1 o N R4 , R4 0 r R4 n X1 and R4 are as defined above, and said fused cyclic group is optionally substituted by l or 2 substituents selected from the group consisting o: a n atom, cyano, nitro, hydroxy and alkyl.
Preferable examples 0 a "used heterocyclic group of the formu'a (A) or (3) include a fused heterocyclic group o: the formu'a WO 29548 wherein R4 and R5 are as d above, and said :JSGd heterocyclic group is optionally substituted by l or 2 substituents selected from the group consisting o: a halogen atom, cyano, nitro, hydroxy and alkyl.
Other preferable examples 0" I) a "used cyclic groap o; ,he formula (A) or (3) include a fused heterocyclic group of the formula / \ // or o N X1 whrein X1 and R4 are as defined above, and said fused heterocyclic group is optionally substituted by l or 2 substituents selected from the group consisting o: a halogen atom, cyano, nitro, hydroxy and alkyl. ?xamples of a group of the formula (C) include I) a group or the formula X2\ \ X2\ \ R7% N/j/ N o r R7% N/// /></ N¢‘;l\\\é?// R6 R6 wherein X2, R6 and R7 are as defined above.
Preferable examples 0: a group of the formula (C) include a group of the formula R7%/ g R? NW , 41M , WAQ/AN \ N\N \ or R74<N/1 n R5, R7 and R3 are as defined above.
In the above formulas, R5, R7 and R3 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) nitro, (e) amino, (f) alkyl optional'y substituted by l to 3 substituents selected from ,he group consisting o: a n atom and amino, (g) a keny , (h) a kyny', (i) aryl, (j) formyl, (k) carboxy, (l) carbamoyl, or (m) a 5- to lO-membered aromatic heterocyclic group (e.g., pyridyl, triazolyl) optionally substituted by alkyl. ?xamp1es O" a group or the formula (3) OI CL-lJ ) include a group o_ the jormula \ \ N X or N H R6 wherein 6 R is as defined above. R6 is rably a hydrogen atom, a halogen atom, nitro or amino.
Pre ‘erab'y, R3 is 3—pyridyl optionally substituted by l or 2 substituents selected jrom ,he I) group consisting o; a n atom, cyano, nitro, hydroxy, amino, alkyl optional'y substituted by l to 3 substituents ed jrom ,he group consisting o: a halogen atom, alkylamino, dialkylamino and hydroxy, alkenyl, aryl, cycloalkyl, alkoxy, mino, dialkylamino, phenylamino optionally substituted by l to 3 halogen atoms, (n) a cyclic amino group (e.g., l—piperazinyl, morpholino) optionally substituted by alkoxycarbonyl, (o) formyl, (p) carbamoy--I and (q) a 5- to bered aromatic heterocyclic group (e.g., triazolyl) optionally substituted by alkyl.
More pre:ferably, R3 is a group or the jormula H2N wherein R22 is (a) a halogen atom, (b) cyano, (c) nitro, (d) a'kyl optional'y substituted by l to 3 substituents selected jrom ,he group consisting o: a halogen atom, mino, dialkylamino and y, (e) alkenyl, (5) ary', (g) cycloalkyl, (h) alkoxy, (i) formyl, OI (j) carbamoyl. ferably, R22 is (a) cyano, (b) nitro, (c) aryl, (d) , OI (e) carbamoyl. ?referably, a3 is 5—pyrimidinyl substituted by 1 or 2 substi':uents selec ,ed from the group consisting 0: amino, 2012/080753 alkylamino and dialkylamino. ?referably, R3 is lyl, 3—indolyl, 5—indolyl or 6- indolyl, each optionally substituted by l or 2 substituents selected from the group ting o; (a) a halogen atom, (b) cyano, (c) nitro, (d) hydroxy, (e) alkyl optionally tuted by l to 3 substituents selected from the group consisting 0: amino, alkoxycarbonylamino, mino and dialkylamino, (5) a'koxy, (g) formyl, (h) carboxy, and (j) amino optionally substituted by l or 2 substituents selected jrom ,he group consisting o; (i) alkoxycarbonyl, (ii) alkylcarbony' optionally substituted by a substituent selected from the group consisting o; (A) cycloalkyloxy optionally substituted by l to 3 alkyl, (3) alkylamino, (C) dialkylamino, (D) a cyclic amino group (e.g., morpholino, l— piperazinyl) optionally substituted by alkoxycarbonyl, and (E) a halogen atom, (iii) phenylcarbonyl optionally substituted by l to 3 tuents selected from the group consisting or alkyl and alkoxy, (iv) cycloalkylcarbonyl, (v) a 5- to lO-membered aromatic heterocyclylcarbonyl group (e.g, pyridylcarbonyl) optionally substituted by alkyl optionally tuted by l to 3 halogen atoms, (vi) benzylcarbonyl optionally substituted by l to 3 substituents selected from the group consisting o; a halogen atom and alkoxy, (vii) arylsul‘onyl optionally substituted by alkoxy, (viii) 'kylalkylsu'jonyl optionally tuted by l to 3 substituents selecoed jrom the group consisting O" alky' and oxo (e.g., rsulfonyl), (ix) a 5- :o lO-membered aromatic heterocyc'ylsul‘onyl group (e.g., imidazoly'sul‘onyl) optionally substituted by l to 3 alkyl, and (x) —C(=N—CN)—SR9 wherein R9 is alkyl.
More pre:ferably, R3 is 7—irdoly' optionally substituted by l 2 substituents selected jrom ,he I) or group consisting o; a halogen atom, cyano, nitro, hydroxy, alkyl optional ly tuted by l to 3 substituents selected jrom ,he group consisting 0: amino, alkoxycarbonylamino, alkylamino and dialkylamino, a'koxy, formyl, carboxy, and amino optional ly substituted by l or 2 substituents selected jrom ,he group consisting o; (i) carbonyl, (ii) alkylcarbony' optionally substituted by a substituent selected from the I) group consisting o; (A) cycloalkyloxy optionally substituted by l to 3 alkyl, (3) alkylamino, (C) dialkylamino, 2012/080753 (D) a cyclic amino group (e.g., morpholino, l— piperazinyl) optionally substituted by alkoxycarbonyl, and (E) a halogen atom, (iii) phenylcarbonyl optionally substituted by l to 3 substituents selected from the I) group consisting 0; alkyl and , (iv) cycloalkylcarbonyl, (v) a 5- to lO-membered aromatic heterocyclylcarbonyl group (e.g, pyridylcarbonyl) optionally substituted by alkyl optionally subsoiouted by L :o 3 halogen atoms, (vi) benzylcarbonyl optionally substituted by l to 3 subsoiouents selected from the group ting o; a halogen atom and alkoxy, (vii) arylsul‘onyl optionally substituted by alkoxy, (viii) cycloa'kylalkylsul‘onyl optionally substituted by l to 3 substituents selected from the group consisting 0: alkyl and oxo (e.g., camphorsulfonyl), (ix) a 5- :o lO-membered aromatic heterocyc'ylsul‘onyl group (e.g., imidazoly'sul‘onyl) optionally substituted by l to 3 alkyl, and (x) CN)—SR9 wherein R9 is alkyl. es O" a group or the jormula (F) or (G) include a group o_ the jormula R25 R25 R24 R24 R26 R26 | \ / | \ R23 7 r R23 R25 R24 R25 R25 N N/ / / l \ | \ \ \ l R26 N R26 N\ R27 \N N R23 , R23 \ R27 , R23 I \ or R24 R27 \N+ N l \R23 wherein ?B is a hydrogen atom or alkyl, and 'RM, R%, R26 and R27 are each ndently, (a) a hydrogen atom, (b) cyano, or (c) nitro. ?xamples O" a group of the formula (K) include I] a group o; the formula X6 X6 )|(7/ \ )|(7/ \ I I X8 / or X8 / \N x5 \N x5 $10 $10 wherein X5, X3 )5, X8 and R’0 are as defined above.
Preferable examples 0: a group of the formula (K) include a group o: the jormula R1310 R13 s R13 O N % O N 0 T R10 R11 7 R10 R11 7 R10 R11 7 O 0 R12 R14 R14 O N 0 T O N O 7 T 7 T , R10 R11 R10 R10 R11 R13 0 R13 R13 R15 N Wm o R15 T N R10 R11 7 R10 R11 7 R10 , IL O O R13 R13 3 R13:£\\S/ R15 N R15 N R15 N: ’ ’ ; R10 R11 R10 R11 R10 R11 R1310 O N R10 R11 wherein R10, R11, R12, R13 RM and R15 , are as defined above.
When R10 and R11 are bonded to form a 5— or 6-membered ring optionally substituted by alkyl or oxo, pre':erab' e es 0; a group 0. the formula (K) include a group o. the jormula O O O N N |\ NH I —N or N—N 0 R31 wherein R31 is a hydrogen atom or alkyl.
When R12 and R13 are bonded to form a 5- or 6-membered ring, preferable examples 0: a group or the jormula (K) include a group or the jormula O N More preferable examples 0: a group or the jormula (K) e a group or the jormula R138 0 R158 N R108 R118 whrein R10a is (a) a hydrogen atom or (b) alkyl, and Rma, R13a and R15a are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) nitro, (e) amino, (f) alkylamino, (g) dialkylamino, (h) alkyl optionally substituted by hydroxy, or (i) l, ‘5 R10a and R11a are optional ly bonded to form a 5- or ered ring optionally substitu':ed by alkyl or oxo, provided that Rum, Rfla, R13a and R15a are not simultaneously en atom.
Preferably, R3 is a group or the jormula / \ wherein R16 is (a) a hydrogen atom, (b) alkyl optional ly substituted by l to 3 substituents selected jrom ,he group ting o:: cyano, alkylamino and dialkylamino, C ) alkenyl optionally substituted by carboxy, (d) formyl, (e) carboxy, (f) carbamoyl, (g) —C(RN)=N—OH wherein R17 is a hydrogen atom, cyano or hydroxy, or (h) a 5- to lO-membered aromatic heterocyclic group (e.g., tetrazolyl, pyrrolyl, oxazolyl, benzimidazolyl , triazoly') optionally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl.
More preferably, R3 is a group or the jormula (a) alkyl optionally tuted by l to 3 substituents selected jrom ,he group ting o: cyano, alkylamino and dialkylamino, (b) l optionally substituted by carboxy, C) formyl, (d) carboxy, (e) carbamoyl, (f) —C(RN)=N—OH wherein R17 is a hydrogen atom, cyano or hydroxy, or (g) a 5- to lO-membered aromatic heterocyclic group (e.g., tetrazolyl, pyrrolyl, oxazolyl, benzimidazolyl, triazoly') optionally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl.
Preferably, R3 is a group or the jormula wherein R18 is alkyl ally substituted by l to 3 substituents selected from the group consisting o: a halogen atom and phenyl, and R19 and R20 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) alkyl optionally substituted by l to 3 tuents selected jrom ,he I) group consisting o; (i) a halogen atom, (ii) cyano, (iii) hydroxy, (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group (e.g., l—piperazinyl) optionally substituted by alkyl, (D alkoxy, 01 A H) v amino optionally substituted by l or 2 substituents selected jrom ,he group consisting o; (i) alkylcarbonyl optiona'ly substituted by a cyclic amino group (e.g., morpholino), (ii) alkylsulfonyl, and (iii) carbamoyl, (g) carboxy, (h) alkoxycarbonyl, (i) carbamoyl ally substituted by a'ky' optionally substituted by amino, alkylamino, dia'ky'amino or alkoxycarbonylamino, (j) formyl, (k) a 5- to lO-membered ic heterocyclic group (e.g., oxazolyl, benzimidazolyl), OI (l) —CH=N—OR21 wherein R21 is a en atom or alkyl optionally substituted by alkylamino or dialkylamino.
More preferably, R3 is a group o: the jormula R1921 R18ao wherein 'nga is alkyl, and ?i% is (a) a halogen atom, (b) cyano, (c) alkyl optionally substituted by l to 3 substituents ed from the I) group consisting o; (i) a n atom, (ii) cyano, (iii) hydroxy, (iv) amino, 2012/080753 (v) alkylamino, (vi) dia'ky'amino, and (vii) a cyclic amino group (e.g., l—piperazinyl) ally substituted by alkyl, alkoxy, amino optionally substituted by l or 2 substituents selected from the group consisting o; (i) alkylcarbonyl optionally substituted by a cyclic amino group (e.g., morpholino), (ii) alkylsulfonyl, and (iii) carbamoyl, carboxy, alkoxycarbonyl, carbamoyl optionally substituted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, formyl, a 5- to bered aromatic heterocyclic group (e.g., oxazolyl, benzimidazolyl), or —CH=N—OR21 n R21 is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino.
Preferable examples 0: compound (I) are as described below.
[Compound I-l] A compound or the "ormula (") n Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; or Q? and R? are optionally bonded to form —O—CH2—CH(CH3)— wherein the oxygen atom is bonded to the prenyl ring 0: the quinolone ring; and R3 is a fused heterocyclic group or the jormula 2012/080753 wherein X1 is C(RS) or N, Q4 is a hydrogen atom or Cyfi alkyl, and Q5 is (a) a hydrogen atom, (b) a halogen atom, c) cyano, (d) nitro, (e) hydroxy, (f) C1% alkyl ally substituted by l to 3 halogen atoms, (9) C2_6 alkynyl I (h) C644 aryl, or (i) C1% alkoxy optionally substituted by l to 3 halogen atoms, when X1 is C(Ré), R4 and R5 are optionally bonded to form -CH2- O-(C=O)- wherein the carbonyl is bonded to the phenyl ring 0; the quinolone ring, said fused heterocyclic group is optionally subStituted by l or 2 subStituents selec ,ed jrom the group consiSting o; a halogen atom, cyano, ni:ro, hydroxy and Cyfi alkyl, or a salt thereo:.
[Compound 2—2] A nd or the "ormula (") wherein Q is a hydrogen atom; Q1 is cyclopropyl, 7— tluorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., ), C1% alkoxy (e.g., methoxy) or a chlorine atom; or Q? and R? are optionally bonded to form —O—CH2—CH(CH3)— wherein the oxygen atom is bonded to the prenyl ring 0: the quinolone ring; and R3 is a group o. the formula / fi/ / N \ or R, N/ X N/ / R6 R6 wherein X2 is C(R?) or N, and R5, R7 and R3 are each independently, (a) a hydrogen atom, (b) a halogen atom, c) cyano, (d) nitro, (e) amino, (f) Cyfi alkyl optional ly tuted by l to 3 substituents selecued jrom ,he I] group consisting o; a halogen atom and amino, (9) C26 a keny' I (h) C2_6 a'kyny' I (i) C644 eryl, (j) ‘ormy', (k) carboxy, (l) carbamoyl, OI (m) a 5- to LO-membered aromatic heterocyclic group (e.g., pyridyl, lyl) optionally substituted by C1_6 aJ_<yl, or a salt thereo:.
[Compound 2—3] A compound or the "ormula (") wherein Q is a hydrogen atom; Q1 is cyclopropyl, 7— filuorocyclopropy' or 7,4-di filuorophenyl; 'R2 is c1_6 alkyl (e.g., methyl), c1_6 a:_koxy (e.g., y) or a chlorine atom; and R3 is a group or the jormula /X3 \ S \ X< l or \ l N /\/ N /\/ H R6 R6 wherein X3 and X4 are N, or X3 is N and X4 is CH, or is CE and X4 is N, and R5 is a hydrogen atom, a halogen atom, nitro or amino, or a salt thereo:.
[Compound 2—4] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., y) or a chlorine atom; and R3 is a group or the jormula \ \ \ I HI | / | M N/ I N/ I M N/ ' / l <N \ l NY \ \ N / N N/ , N N/ , , H H / CU /\N\ \N/ / or a salt thereo:.
[Compound 2—5] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; or Q? and R? are optionally bonded to form —O—CH2—CH(CH3)— wherein the oxygen atom is bonded to the ptenyl ring 0: the one ring; and Q3 is a group or the jormula H2N N wherein R22 is (a) a halogen atom, (b) cyano, (c) nitro, (d) Cyfi alkyl optionally substituted by l to 3 substituents selecoed jrom ,he group consisting o; a n atom, Cyfi alkylamino, di(Cy6 alkyl)amino and hydroxy, (e) C2_6 a; kenyl, (If) C6—l4 53$le (9) Cyg cycloalkyl, (h) Cyfi alkoxy, (i) ‘ormy', or (j) carbamoyl, or a salt thereo:.
[Compound 2—6] A nd or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; or Q? and R? are ally bonded to form —O—CH2—CH(CH3)— wherein the oxygen atom is bonded to the prenyl ring 0: the quinolone ring; and R3 is a group or the jormula H2N N wherein R22 is cyano, nitro, C6—l4 aryl, formyl, or carbamoyl, [Compound 2-7] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; and Q3 is 5—pyrimidinyl ttted by l or 2 tuents selected from the group consisting 0: amino, Cyfi alkylamino and di(Cp6 alkyl)amino, or a salt :.
[Compound 2-8] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; and R3 is 7—ir dolyl optionally substituted by l or 2 substituents se lected from the group consisting o; a halogen atom, cyano, nitro, hydroxy, Cyfi alkyl optionally substituted by l to 3 substituents selecued jrom ,he I] group consisting 0; amino, Cyfi alkoxy—carbonylamino, Cyfi alkylamino and di(Cyfi amino, Cyfi alkoxy, WO 29548 (g) formyl, (h) carboxy, and (j) amino optional ly substituted by l or 2 substituents selected _rom the group consisting o; (i) C1% -carbonyl, (ii) C1% alkyl—carbony' optionally substituted by a tuent selected irom the group ting o; (A) C}8 cycloalkyloxy optionally substituted by 1 t0 3 C1_6 a; kyl, (:3) c1_6 alkyl amino, (C) di(C1_6 a; kyl)amino, (D) a cyclic amino group (e.g., morpholino, l— piperazinyl) optionally substituted by Cpg alkoxy-carbonyl, and (E) a n atom, (iii) carbonyl optionally substituted by l to 3 substituents selected from the group consisting I] Cyfi alkyl and Cyfi alkoxy, (iv) C3_8 Cycloalkyl—carbonyl, (v) a 5- t o LO-membered aromatic heterocyclylcarbonyl group (e.g., pyridylcarbonyl) optionally substi':uted by Cyfi alkyl optionally substituted by l to 3 halogen atoms, (vi) benzylcarbonyl optionally substituted by l to 3 substituents selected from the group consisting o; a halogen atom and C1% alkoxy, (vii) ng4 arylsul-Conyl optionally substituted by Cyg alkoxy, (viii) Cyg cycloalkyl-Cpfi alkylsul‘onyl optionally substituted by l to 3 tuents selected from the group consisting o: C1% alkyl and oxo (e.g., camphorsulfonyl), (ix) a 5- to lO-membered aromatic heterocyc'ylsul‘onyl group (e.g., imidazoly' sul‘onyl) optionally substituted by l to 3 W0 2013/029548 C14 alkyl, and (x) —C(=N—CN)—SR9 wherein R9 is cm alkyl, or a salt thereo:.
[Compound 2-9] A compound or the a (") wherein Q is a hydrogen atom; Q? is ropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; and R3 is a group or the jormula R25 R25 R24 R24 R26 R26 | \ / | \ R23 7 r R23 R25 R24 R25 R25 N 26 // R l l R24 \\‘\ \ R26 N R26 “K R27 \\\N N \R23 ' R23 R27 ' \R23 / \ or I R24 (If \Rn wherein 'RB is a hydrogen atom or C1% alkyl, and QM, R%, R26 and R27 are each independently, (a) a hydrogen atom, (b) cyano, or (c) nitro, or a salt thereo:.
[Compound Z—lO] A compound or the a (") wherein Q is a hydrogen atom; Q1 is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; a2 is c1_6 alkyl (e.g., methyl), ch6 a:_koxy (e.g., methoxy) ora chlorine atom; and R3 is a group or the jormula N’/\/’ N t I \ or t wherein Q28 is a hydrogen atom or hydroxy, and 'Q” is a hydrogen atom or C1% alkyl, or a salt thereo:.
[Compound Z—ll] A compound or the "ormula (") wherein Q is a hydrogen atom; Q1 is ropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q? is C1% alkyl (e.g., methyl), C1% y (e.g., methoxy) ora chlorine atom; and Q3 is a group or the jormula 0 T R10 R10 R10 R11 7 0 R12 \N O N O¢7i\\T \ O T , R10 R1 R10 R11 R13 o R13 R13 o R15 N R1mN R15 T N R10 R R11 R10 , O O R13 IL S \S/ R15 N N R15 N: ; R10 R R11 R10 R11 R10 R11 wherein R”, R12 and R14 are each independently, (a) a hydrogen atom or (b) Cyfi alkyl, and Rn, R13 and R15 are each independently, a hydrogen atom, a halogen atom, (c) cyano, nitro, WO 29548 (e) amino, (f) Cyfi alkylamino, (g) di(Cyfi alkyl)amino, (h) Cyfi a'ky' optionally substituted by hydroxy, or (i) Cgfi alkenyl, or R10 and R11 are optionally bonded to form —(C=O)—NH—, —C(Rfl)=N— or —N=N— wherein R31 is a hydrogen atom or Clm alkyl, and the nitrogen atom is bonded to the phenyl ring or the jused ring, R12 and Q” are optionally bonded to form -(CHfl4-, or a salt thereo:. und 2—12] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), Clm alkoxy (e.g., methoxy) or a chlorine atom; and R3 is a group or the jormula R138 0 R158 N R108 R118 whrein R10a is (a) a hydrogen atom or (b) Cyfi alkyl, and Rma, R13a and R15a are each ndently, (a) a hydrogen atom, (b) a halogen atom, c) cyano, (d) nitro, (e) amino, (f) C14 alkylamino, (g) di(Cyfi alkyl)amino, (h) Cyfi a'ky' optionally tuted by hydroxy, or (i) Cgfi alkenyl, and ed that Rum, Rfla, R13a and R15a are not simultaneously hydrogen atom, or a salt :hereo:.
[Compound 2—13] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; and Q3 is a group or the jormula O O O N N |\ NH ' N or N--N 0 R31 wherein QM is a hydrogen atom or Clfi alkyl, or a salt thereo;.
[Compound 2—14] A compound or the "ormula (") wherein Q is a hydrogen atom; Q? is ropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; and R3 is a group or the jormula n 16a R is (a) Cyfi alkyl optional'"y substituted by l to 3 substituents se;ec ,ed jrom ,he I) group consisting o; cyano, Cyfi alkylamino and di(Cyfi alkyl)amino, (b) Cz% alkenyl optionally substituted by carboxy, (C) ‘ormy', (d) y, (e) carbamoyl, (f) —C(RN)=N—OH wherein R17 is a hydrogen atom, cyano or hydroxy, or (g) a 5- to lO-membered aromatic heterocyclic group (e.g., tetrazolyl, pyrroryl, oxazolyl, benzimidazolyl, triazolyl) ally substituted by C1% al<yl, C1% alkoxy-carbonyl, y or phenyl, or a salt thereof.
[Compound 2—15] A compound 0: the "ormula (") wherein Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), Clm alkoxy (e.g., methoxy) or a chlorine atom; and R3 is a group o: the jormula R1921 R18ao wherein 'nga is c1_6 alkyl, and 'Rwa is (a) a n atom, (b) cyano, (c) Clm alkyl optionally substituted by l to 3 substituents selecued jrom ,he group consisting of (i) a halogen atom, (ii) cyano, 2012/080753 (iii) hydroxy, (iv) amino, (v) Cyfi alkylamino, (vi) di(Cpfi alkyl)amino, and (vii) a cyclic amino group (e.g., L—piperazinyl) optionally substituted by Cyfi alkyl, C14 alkoxy, amino optionally substituted by l or 2 substituents ed from the group consisting o; (i) C14 a'kyl—carbonyl optionally tuted by a cyclic amino group (e.g., morpholino), (ii) Cyfi alkylsulfonyl, and (iii) carbamoyl, carboxy, C1% alkoxy-carbonyl, carbamoy' optional'y substituted by Cyfi alkyl optionally substituted by amino, C1% alkylamino, di(Cpfi alkyl)amino or C1% alkoxy—carbonylamino, formyl, a 5- to LO-membered ic heterocyclic group (e.g., oxazolyl, benzimidazolyl), or —CH=N—OR21 wherein R21 is a hydrogen atom or Cpg alkyl optionally substituted by Cyfi alkylamino or di(Cyfi alkyl)amino, or a salt thereof.
[Compound 2—16] A compound 0: the "ormula (") n Q is a hydrogen atom; Q? is cyclopropyl, 7—‘luorocyclopropy' or 7,4—di‘luorophenyl; Q2 is Cyfi alkyl (e.g., methyl), C1% alkoxy (e.g., methoxy) or a chlorine atom; and Q3 is a group or the jormula VV()2013/02954s R30 is (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) Cyfi alkyl optionally s Jbstituted by l to 3 substituents selected from the I) group ting o; a halogen atom and hydroxy, (e) C2% a'keny', (f) Cfifi a kyny', (g) Cbfi aikoxy, (h) ‘ormy', or (i) —CH=N-OH, or a salt thereo:. ?xamples o sal,s o the compound ol the "ormula (") include pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts o: the compound ol the jormula (I) are conventional non-toxic salts and e, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example , an a" ka'i metal salt (e.g., sodium salt, potassium salt, etc.) , an a" ka'ine earth metal salt (e.g., calcium salt, magnesium sal t, etc. ), an ammonium salt; a salt with an c base, for example, an organic amine salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, :riethanolamine salt, dicyclohexylamine salt, ibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hloride, hydrobromide, sulfate, hydrogensulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.). nd (I ) can be produced, for example, by a method according to the following reaction schemes.
Reaction Scheme I o o o o o x X X OH a OR32 b OR32 —> —> | I F I F I F oR33 R2 R2 R2 (1) (2) (3) O 0 o o OR32 d OR32 _> _> | F NH I ' I}! R2 R1 R2 R1 R1-NH2 (4) (5) wherein X, R? and R? are as de:fined above, R32 is alkyl and R33 is alkyl.
Step a nd (1) can be converted to acid halide by ng compound (1) with a halogenating agent in the presence or absence 0: a solvent. The solvent includes aromatic hydrocarbons such as benzene, e and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; ethers such as dioxane, tetrahydrofuran and diethyl ether; N,N— ylformamide ( DMF); dimethyl sul foxide ( DMSO); and the like. Tte halogenating agent may be a ny conventional halogenating agents which can convert hydroxy in carboxy group into a halogen atom, and includes, for example, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, and the like.
The amounts 0: compound (1) and the nating agent are not particularly limited, but, in case 0: using no solvent, the WO 29548 halogenating agent is usually used in a large excess amount, and in case 0: using a solvent, the halogenating agent is usually used in an amount 0‘ at "east 1 mo'e, preterably 7 to 4 moles, per 1 mole of compound (l). The on temperature and the reaCtion period 0: time are nOt particularly limited, but the reaCtion is usually carried out at a temperature 0 "rom room temperature to about ’00°C ‘or about 30 minutes to about 6 hours.
The obtained acid halide is reacted with magnesium salt I] malonic acid monoalkyl ester to give compoand (2). Magnesium sa't O" malonic acid monoalkyl ester can be prepared in situ from potassium salt 0: malonic acid monoal<yl ester such as potassium ethyl malonate in the presence 0: magnesium chloride and a basic nd such as triethylamine. The reaction can be d out in a suitable solvent. The solvent used in the on may be any conventional solvents unless they give any undesirable e "ect on the reaction, and includes, for example, esters such as ethyl acetate; ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; alcohols such as methanol, ethanol and isopropanol; aromatic arbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as n—hexane, heptane, cyclohexane and ligroin; amines such as pyridine and N,N—dimethylaniline; halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride; c polar solvents such as DMF, DMSO and hexamethylphosphoric triamide (HM?A); and a mixture 0: these solvents. The reaction is usually carried out at a temperature 0 ”rom about 0°C to about 150°C, preterably ‘rom about 0°C to about 120°C, for about 0.5 to about 20 hours. ?otassium salt 0: malonic acid monoalkyl ester is usually used in an amount 0: at least 1 mole, ably 1 to 7 moles, per 1 mole of compound (1). Magnesium chloride and the basic compound are usually used in an amount or at least 1 mole, preterably l to 7 mo'es, per 1 mole 0: compound (1).
Step b Compound (3) can be prepared by reacting compound (2) with trialky' oroho"orma,e such as hyl ormate and triethy' oroho"orma,e in acetic anhydride. Tre reaction is Jsually carried out at a temperature 0 ”rom about 0°C to about 200°C, preterably ‘rom about 0°C to aboat 150°C, for about 0.5 to about 20 hours. yl ortho‘ormate is y used in an amount 0: at least 1 mole, ably to 10 moles, per 1 mole of compound (2).
Step c Compound (4) can be prepared by reacting compound (3) with compound (6).
The reaction between compound (3) and compound (6) can be carried out in a suitable solvent. The t employed in the reaction may be any conventional solvents unless they give any undesirable e "ect on the reaction, and includes, for e, alcohols such as methanol, ethanol and propanol; ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aromatic arbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as n-hexane, heptane, cyclohexane and ligroin; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; c polar solvents such as DMF, DMSO and HMPA; and the like. The reaction is y carried out at a temperature 0 ”rom about 0°C to about 150°C, preterably ‘rom room temperature to about 100°C, :or about 0.l to about l5 hours. Compound (6) is usually used in an least ’ amount 0: at mole, preterably 1 to 7 moles, per 1 mole 0: compound (3).
Step d Compound (5) can be prepared by cyclization 0: compound (4).
The cyclization of compound (4) can be carried out in a suitable solvent in the presence 0: a basic compound. The solvent employed in the reaction may be any conventional solvents unless they give any undesirable e "ect on the reaction, and includes, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, monoglyme and diglyme; aliphatic hydrocarbons such as n-hexane, heptane and ligroin; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; aprotic polar solvents such as DMF, DMSO and HM?A; and the like. The basic compourd employed in the reaCtion includes inorganic bases such as metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, pOtassium hydroxide, sodium carbonate and potassium ate, metal alcoholates such as sodium methylate and sodium te, organic bases such as l,8-diazabicyclo[5.4.0]undec ene (DBU), yltrimethylammonium hydroxide and tetrathylammonium hydroxide, and the li<e. The reaction is usually carried out at a temperature 0 "rom about 0°C to about 200°C, ably ‘rom room temperature to about 150°C, for about 0.5 to about l5 hours. The basic compound is usually used in an amount 0 a, "east 1 mole, preterably 1 to 7 moles, per 1 mole o: the compound (4).
Reaction Scheme R3_B/ o o O O ‘o o o x 0R32 OH (7) 0R32 3 | _b> | + | R3 R3 or I N N N I R2 R1 R2 R1 OH R2 R1 R3—B’ (5) (la) (lb) (8 ) wherein X, R3 If, R? and R32 are as defined above.
Step a nd (Ia) can be prepared by reaCting compound (5) and compound (7) or compound (8) in an inert solvent or without using any solvents, in the presence or absence 0: a basic compound, in the presence 0: a palladium catalyst.
Txamples O“ inert solvents include water; ethers such as dioxane, tetrahydrofuran, l ether, l,2-dimethoxyethane, diethylene glycol dimethyl ether and ethylene glycol dimethyl ether; ic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol and isopropanol; ketones such as e and methyl e:hyl ketone; and aprotic polar :s such as DMF DMSO, HM?A and acetonitrile.
, These inert solven:s can be used singly or in ations 0: two or more .
The palladium catalyst used in the reaction is no: particularly limi':ed, but include, for example, tetraval palladium catalys:s such as sodium hexachloropa:_ladate(ZV) tetrahydrate and potassium loropa:_ladate(ZV); divalent pa' 'adium catalysts such as palladium( ) chloride, pa"adium( ) bromide, palladium( ) acetate, palladium( ) acetonate, dichlorobis(benzonitrile)palladium( ), dichlorobis(acetonitrile)palladium( ), dichlorobis(triphenylphosphine)pal' adium( ), dichlorotetramine pa' ( ), dichloro(cycloocta-i_,5-diene)palladium( ), pa' ( ) tri-:luoroacetate, and l,l'— bis(diphenylphosphino):ferrocene dich' oropalladium( romethane complex (Pd(dppf)Cl2.CH2Cl2); zerovalent palladium catalysts chh as :ris(dibenzyl_ideneace':one)dipa' 'adium(0), :ris(dibenzyl_ideneace:one)dipa' 'adium(0) chloro:form complex and ,elrakis(triphenylphosphine)pa' 'adium(0), etc. These palladium catalysts are used singly or in ations 0: two or more.
In the reaC':ion, the amount 0: the palladium catalyst is not ularly limited, bat is typically in the range from 0.00000l to 70 mo' es in terms o: palladium relative to 1 mole o; compound (5). The amount 0: the palladium cata lyst is preferably in the range from 0.0001 to 5 moles in terms 0'' palladium relative to 1 mole o: compound (5).
This reaction advantageously proceeds in the presence 0: a suitable ligand. Txamples 0'- ligands o: the palladium catalyst include, for example, 2,2'—bis(diphenylphosphino)—l,l'— binaphthy' ( _% NAP) , tri-o-tolylphosphine, bis(diphenylphosphino)ferrocene, triphenylphosphine, tri-t- butylphosphine and 4,5-bis(diphenylphosphino)—9,9— dimethylxanthene hos). These ligands are used singly or in combinations 0: two or more.
The proportion ol ,he palladium catalyst and ligand is not particularly limited” Tte amount 0: the ligand is about 0.1 to about 100 moles per 1 mo'e O" the palladium catalyst, and preferably about 0.5 to about 15 moles per 1 mole o: the palladium catalyst.
Various known inorganic and organic bases can be used as basic compounds.
Inorganic bases include, for example, alkali metal ides such as sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; alkali metal carbonates such as sodium carbonate, ium carbonate, cesium carbonate and lithium carbonate; alkali metal hydrogen carbonates chh as lithium hydrogen carbonate, sodium hydrogen carbonate and pOtassium hydrogen carbonate; alkali metals such as sodium and ium; phosphates such as sodium phosphate and pOtassium phosphate; amides such as sodium amide; and alkali metal es such as sodium hydride and potassium hydride.
Organic bases include, for e, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t- butoxide, potassium methoxide, potassium ethoxide and potassium t-butoxide, and amines such as triethylamine, tripropylamine, pyridine, quinoline, dine, imidazole, N— ethyldiisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, l,5-diazabicyclo[4.3.0]non— -ene (DQN), l,8-diazabicyclo[5.4.0]undecene (DBU), 1,4— diazabicyclo[2.2.2]octane (DABCO), etc.
Such basic compounds can be used singly or in combinations 0: two or more. More preferable basic compounds used in the reaction include alkali metal carbonates such as sodium ate, potassium carbonate, cesium carbonate and lithium carbonate.
The basic compoand is y used in an amount 0: 0.5 to 10 moles per 1 mole 0: nd (5), and preferably 0.5 to 6 moles per 1 mole 0: compound (5).
Compound (7) or compound (8) is usually used in an amount o a, "east 1 mole per 1 mole 0‘ nd (5), and preferably about l to about 5 moles per 1 mole 0: compound (5).
The on can be conducted under normal pressure, under inert gas atmosphere including nitrogen, argon, etc., or under increased pressure.
The reaction ds usually from room temperature to about 200°C, and preterably ‘rom room temperature to about 150°C, and is usually completed in about 1 to about 30 hours. The reaCtion is also achieved by heating at about 100°C to about 200°C for about 5 minutes to abOLt 1 hour using a microwave reaCtor.
Step b Compound (Ib) can be ed by hydrolysis of compound (Ia).
The hydrolysis 0: compound (Ia) can be carried out under the conditions of conventional hydrolysis, tor example, in the presence 0: a basic compound such as sodium hydroxide, potassium ide, barium hydroxide or potassium carbonate; a mineral acid such as sulfuric acid, hydrochloric acid or nitric acid; or an organic acid such as acetic acid or an aromatic sulfonic acid, in a solvent including water, alcohols such as methanol, ethanol and isopropanol; s such as acetone and methyl ethyl ketone; ethers such as dioxane and ethylene glycol diethyl ether; acetic acid; or a mixture thereo:. The reaction is usually carried out at a temperature 0 "rom room temperature to about 200°C, preterably ‘rom room temperature to about 150°C, :or about 0.1 to about 30 hours.
Qeaction Scheme ?reparation of boronate and boronic acid 0‘ ,o a ,0 b ,OH R3—z + IB—B\ —> R3-B\ R3—z —> R3-B\ o o o OH (9) (10) (7) (9) (8) wherein Q? is as defined above, and Z is a e atom or an iodine atom.
Step a Compound (7) can be prepared by reaCting compound (9) with bis(pinacolato)diboron (10) in an inert solvent in the presence 0: a palladium catalyst and a basic compound.
Txamples O“ inert solvents and palladium catalyst are same as those described in Step a in Reaction Scheme The basic compound employed in the reaction includes potassiJm acetate, triethylamine, N—methylmorpholin, sodium carbonate, pOtassium carbonate, cesium carbonate, lithium carbonate, pOtassium phosphate and sodium hydrogen carbonate.
In the reaCtion, the amount 0: the palladium catalyst is not particularly limited, bjfi is typically in the range from 0.00000l to 70 mo'es in terms of palladium relative to 1 mole o; compound (9). The amount 0: the ium catalyst is preferably in the range from 0.0001 to 5 moles in terms 0" palladium relative to 1 mole 0: compound (9).
The basic compoand is usually used in an amount of 0.5 to moles per 1 mole of compound (9), and ably 0.5 to 6 moles per 1 mole 0: compound (9). 3is(pinacolato)diboron (10) is usually used in an amount o a, "east l mole per l mole of compound (9), and preferably about L to about 5 moles per 1 mole 0: compound (9).
The reaction can be ted under normal pressure, under inert gas atmosphere including en, argon, etc., or under increased re.
The reaction proceeds usually from room temperature to about 200°C, and preferably from room temperature to about 150°C, WO 29548 and is usually completed in about 1 to about 30 hours.
Step b Compound (8) can be prepared by reacting compound (9) with trialkyl borate such as trimethyl borate, triethyl borate, tri(isopropyl) borate and butyl) borate in an inert solvent in the presence 0: n—butyllithium or lithium ropylamide.
Txamples O“ inert solvents are same as those described in Step a in Reaction Scheme The trialkyl borate is usually used in an amoun, ol at least l mo'e per l mo'e of compound (9), and preferab'y about 1 to about 5 moles per ’ mo'e 0" compound (9). n—Qutyllithium or lithiJm diisopropylamide is usually used in an amount ’ 0: at least mo'e per l mo'e 0" compound (9), and preferably about 1 to about 5 moles per mo'e 0" compound (9).
The reaction is usually carried ou, a, a temperature or from about -70°C to about 0°C for about 0.1 to about l5 hours.
Compound (") O" the present ion can easily be converted into a salt thereof by treating with a pharmaceutically acceptable acid or base. The acid includes inorganic acids such as hydrochloric acid, ic acid, phosphoric acid and hydrobromic acid and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, ic acid, citric acid, benzoic acid, lactic acid, methanesulfonic acid and propionic acid” The base includes sodium hydroxide, pOtassium hydroxide, calcium hydroxide, sodium carbonate, pOtassium hydrogen carbonate, and the like.
The nd thus obtained can easily be ed and purified by conventional methods, such as, for example, extraction with solvents, dilution method, tallization, column chromatography and preparative thin layer chromatography.
Compound (I) shows an excellent antimicrobial activity against mycoplasma, Pseudomonas aeruginosa, anaerobic bacteria, resistant cells t various antimicrobials, clinically WO 29548 2012/080753 isolated bacteria, and gram negative and gram positive bacteria such as Clostridium ile, Fnterococcus is and Staphylococcus pyogenes and hence is useful as an antimicrobial agent jor the treatment ol es induced by these microorganisms. Compound (I) also shows low toxicity and less side e "ects and is cha racteristic in good absorbability and in sustained activity.
Since compound (2 ) shows an excellent antimicrobial activity against Clostridium difficile, it is use ul "or the prevention or ent ol intestinal injections including antibiotics-associated diarrhea (AAD) such as Clostridium difficile-associated ea (CDAD).
The compounds 0: the present invention are usually used in the ‘orm O" a usual pharmaceutical preparation. The pharmaceutical preparation can be prepared in admixture with conventional pharmaceutically acceptable diluents or carriers, such as ‘il'ers, bulking agents, binding agents, wetting agents, disintegrators, surjacoants and ating agents. The pharmaceutical preparat ion includes various preparations le jor treatment ol the diseases, for example, tablets, pills, powders, solutions, stpensions, emulsions, granules, capsules, itories, injections such as solutions and suspensions, and the like. In the preparation 0‘ tablets, there may be used any conventional carriers, ‘or example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starches, calcium carbonate, kaolin, crystalline ose and silicate, binding agents such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and po'yvinylpyrro'idone, egrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl su'tate, stearic monoglyceride, starches and lactose, disintegration inhibitors such as white sugar, stearin, cacao butter and hydrogenated oils, absorption ers such as nary ammonium salts and sodium lauryl sulfate, wetting agents such as glycerin and starches, adsorbents such as starches, lactose, kaolin, ite and colloidal silicates, lubricants such as purified ,alc, stearates, boric acid powder and polyethylene glycol, and the like. Tte tablets may also be coated with tional coating agents, for example, may be in the form 0" a sugar coated tablet, a gelatin-coated tablets, an enteric coating ,able,, a film coating tablet, or a double or multiple layers ,ab'e,. "r the preparation of pills, there may be used conventiona' carriers, including excipients such as glucose, lactose, es, cacao butter, hydrogenated vegetable oils, kaolin and talc, binding agents such as gum arabic powder, anth powder, gelatin and ethanol, disintegrators such as laminaran and agar, and the like. In the preparation 0; suppositories, there may be used conventional carriers, such as, for example, polyethylene glycol, cacao buooer, higher alcohols, higher alcohol , gelatin and ynthesized glycerides.
In the preparation 0: injeCtions, the solutions, emulsions or suspensions of the compounds are sterilized and are preferably made isotonic with the body liquid” These solutions, enulsions and suspensions are prepared by admixing the active compound with a conventional diluent, such as water, aqueous lactic acid solution, ethyl a'coho', propylene glycol, lated isostearyl ', po'yoxylated isostearyl alcohol or polyoxyethylene sorbitan fatty acid esters. The preparations may also be incorporated with sodium chloride, glucose or glycerin in an amount su ”icient to make them isotonic with the body liquid” The preparatiors may also be incorporated with conventional lizers, bu""ering agents, anesthetizing , and further, with coloring agents, vatives, perfumes, avors, sweetening agents, and other medicaments. The preparations in the form 0" a paste, cream or gel may be prepared by using as a diluent such as white petrolatum, 2012/080753 para 1n, glycer in, cellulose derivatives, polyethylene glycol, silicone, bentonite, or the like. When the compound of the active ingredient itates in the injection, an acid such as, for example, methanesul‘onic acid, propionic acid, hloric aci d, succinic acid or lactic acid may be added to the injection as required to preserve the injection in a stable solution.
Compound (I ) may be contained in any amount in the preparations, and are usually contained in an amount 0 "rom 1 to 70% by weight based on the whole weight 0: the preparations.
The pharmaceutical preparations 0: the t invention can be stered in any methods. Suitable method :OI administration may be selected in accordance with the prepara,ion jorm , age and sex of patients, severity of the diseases, and the like. For instance, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered in oral route. In case 0: injection, it is administered intravenously in a single form or er with an auxiliary liquid such as glucose or amino solution. The injections may also be administered in in':ramuscular, intracutaneous, subcutaneous, or eritoneal route. Suppositories are administered in intrarectal route.
The dosage 0: the pharmaceutical preparations of the present invention may vary according to administratior methods, age and sex of patients, severi oy o_ ,he diseases, and the like, usually in the range o: about 0 .l to preterab' yinthe range 0: about O. to about 50 mg, 0: compound (W ’ per kg body weight of the patient per day. The ation is usually administered by dividing in'to 2 to 4 times per day.
The present ion is illustrated by the following Txamples, mental Examples and Preparation Txamples. "t is to be anderstood that the present invention is not limited to these Txamples, Txperimental Txamples or Preparation Txamples and various changes and modi:fications can be made without departing from the scope and spirit 0: the present invention.
Examples General Scheme ". Synthesis 0: intermediates 0 O O O O F F F OH a OEt b OEt _. _. | I F I F | F OEt R2 R2 Reaction reagents and ions: a. KOZCCHZCOZEt, MgCIZ, Et3N, 80°C; b. HC(EtO)3, 150°C; 0. Cyclopropylamine; d. K2003, DMSO, 100°C In our work, Suzuki ng was employed as key on to construct our final produc:s. For the coupling, the corresponding iodo—intermediates could be prepared through well—known methods that were wildly used to synthesis 0; quinolones before (General Scheme 2).
Example 1: Synthesis I) 0' "ntermediate 5a (R? = Me) l.l. Compound 2: A mixture of compound 1 (2 g, 6.71 mmol) and thionyl chloride (9.8 mL) was refluxed for 3 hr, and then concentrated to give acid chloride. To the residue was added dry EtOAc (10 mL) and then the e was concentrated.
A mixture of potassium ethyl malonate (1.6 g, 9.40 mmol) and MgC12 (1.91 g, 20.13 mmol) in dry EtOAc was stirred for 30 min below 50°C. To the mixture was added 3:3N (2.83 mL, 20.13 mmol) below 50°C. Then, the mixture was refluxed for 1 hr. To the e was added dropwise a solution of the acid chloride in dry EtOAc (10 mL) at 50-70°C and then the mixture was refluxed for 1.5 hr. Water (30 mL) and 5 N HCl (30 mL) were added to the reaction mixture under ice-cooling. The EtOAc solution was washed with water, dried and concentrated to give compound 2 as a yellow oil, which was used in the next step without purification. 1.2. Compound 3: A mixture 0: compound 2 (11 g, 29.88 mmol), triethyl orthoformate (7.47 mL, 44.82 mmol) and acetic anhydride (6.77 mL, 71.72 mmol) was heated at 150°C for 1 hr, and then concentrated to give compound 3, which was used in the next step without purification. 1.3. Compound 4: To compound 3 (obtained above) were added EtOi (50 mL) and cyclopropylamine (2.48 mL, 35.86 mmol). The mixture was stirred for 30 min and concentrated to give compound 4, which was used in the next step without purification. 1.4. Intermediate 5a: Compound 4 (obtained above) was dissolved in dry DMSO (100 mL). KxXh (16.52 g, 119.53 mmol) was added to the solution. The reaction mixture was stirred at 100°C for 1 hr. When TLC /dipropyl ether=1/1) indicated the reaction was completed, the e was cooled to room ature, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to give a yellow solid which was recrystallized from ?tOAc. ediate 5a was obtained as a white solid in 75% overall yield. 1H NMR (400 MHz, 3 SO) 5 8.60 (s, 11), 7.70 (d, J'= 7.8 2, 1 ), 4.29 — 4.14 (m, 3 ), 2.96 (s, 3H), 1.28 (t, J": 7.1 2, 3 ), 1.14 (q, J'= 7.0 2, 2H), 0.87 - 0.76 (m, 2H).
The following compounds were synthesized according to General Scheme 2. le 2: "ntermedi ate 5b (R2 = OMe): 1H NMR (400 MHZ, DMSO) 8 8.51 (s, 1H), 7.69 (d, J: 7.7 Hz, 1H), 4.23 (dd, J: 11.0, 6.9 Hz, 2H), 4.03 (s, 1H), 3.80 (s, 3H), 1.28 (t, J: 7.0 Hz, 3H), 1.09 (d, J: 6.2 Hz, 2H), 0.97 (m, 2H).
W0 2013/029548 Example 3: Intermediate 5c (R2 = 01): 1H NMR (400 MHZ, DMSO) 8 8.61 (s, 1H), 7.81 (d, J'= 7.6 Hz, 1H), 4.23 (m, 3H), 1.28 (t, J'= 7.1 Hz, 34), 1.21 — 1.08 (dd, J'= 7.1, 2.2 Hz, 2H), 0.99 — 0.92 (m, 2H).
Example 4: ediate 5d: 1H NMR (400 MHZ, CDC13) 5 8.59 — 8.51 (d, J'= 3.1 Hz, 1H), 8.03 — 7.92 (d, J'= 7.5 Hz, 1H), 4.98 — 4.73 (dddd, J'= 62.9, 6.3, 4.9, 3.4 Hz, 14), 4.44 — 4.34 (q, J'= 7.1 Hz, 2 ), 3.91 — 3.83 (dt, J'= 8.6, 5.4 Hz, 1H), 2.95 — 2.88 (s, 3 ), 1.59 — 1.48 (m, 1H), 1.45 — 1.38 (t, J'= 7.1 Hz, 3H), 1.35 — 1.18 (m, 1H).
Example 5: Intermediate 5e: 1H NMR (400 MHZ, CDC13) 5 8.51 — 8.43 (d, J'= 2.0 Hz, 1H), 7.94 — 7.86 (d, J'= 7.6 Hz, 1H), 4.90 — 4.65 (dddd, J'= 62.7, 6.0, 5.1, 3.3 z, 14), 4.37 — 4.28 (q, J'= 7.1 Hz, 2H), 3.80 — 3.76 (s, 3 ), 3.75 — 3.69 (dt, J'= 8.7, 5.5 Hz, 1H), 1.61 — 1.47 (m, 2H), 1.46 — 1.30 (m, 4H) Example 6: Intermediate 5f: 14 NMR (400 MHz, DMSO) 8 8.65 (s, 1H), 7.48 (d, J'= 8.16 Hz, 11), 4.79 (q, J'= 6.65 Hz, 1H), 4.62 (dd, J'= 1.82, 11.36 Hz, 1H), 4.44 (dd, J'= 2.20, 11.36 z, 1 ), 4.23 (qd, J'= 2.95, 7.09 Hz, 2H), 1.40 (d, J'= 6.65 z, 3 ), 1.28 (t, J'= 7.09 Hz, 3H). 0 o o o F F OEt OEt I N I N OMeZ: o\¢/K‘ Fv5e H General Scheme Preparation 0‘ boronate and boronic acid O o a o OH \ b I / R3—z + 3 RLZ RLS —> R -B\ —————> /B—B\ \ O o o OH Z=Br,| Z=Br,| Reaction reagents and conditions: a. Pd(dppf)C|2.CH2C|2 (5% mol), KOAc, dioxane, 80°C; b. nBuLi (or LDA), B(OiPr)3, THF General Scheme outlined the preparation 0" required c acids and boronates. They are readily prepared h general methods.
Example 7 Synthesis of boronic acid 7 Br I Reaction reagents and conditions: a. 1) NaH, THF, rt; 2) nBuLi, B(OiPr)3, -70°C to 0°C 7. l Boronic acid 7: To a on 0: compound 6 (10 g, 44.44 mmol) in dry tetrahydrofuran (350 mL) was added sodium hydride (2 g, 66.66 mmol, 80% dispersion) at 0°C. After the mixture was stirred at room temperature for 30 min, the mixture was cooled below -60°C in a dry ice/a cetone bath, and n— butyllithium (70 mL, 112 mmol, 1.6 M in hexane) was added over min. The mixture was kept stirring for another 30 min, then triisopropyl borate (40 mL, L77 mmol) was added se. The reaction e was stirred for 10 min, and :hen warmed to 0°C slowly in an ice bath. HCl (5 N) was added to the mixture to adjust pH = 3—4, and the mixture was stirred for 20 min. Aq.
NaOH was added to the mixture to adjust pi = L0. After jiltraoion, the organic layer was separated. The s layer was 6X":racted with a mixture of ethyl aceCate/THF (4/1; 2 x L20 mL) andIEtOAc (100 mL). Tte aqueous layer was adjusted to pH 5—6 with HCl. The precipitate thus formed was collected 2012/080753 by filtration and dried to give c acid 7 (3.5 g, 41%) as a white solid. e 8 Synthesis 0: boronate 10 NC NC Br / / NC 5’; —> —> / \o H MINm2 H NIJ2 U H2N N 8 9 10 8.1 Compound 9: 2—Aminonicotinonitri1e 8 (100 g, 0.839 mol) was dissolved in HOAc (800 mL). To the solution was added NaQCO3 (88.97 g, 0.839 mol). Then, 3r2 (46.4 mL, 0.923 mol) was added dropwise. The reaction mixture was stirred at room temperature for 50 min. To tre mixture was added water (600 mL). The mixture was cooled to about 5°C. The precipitate thus formed was collected by filtration and dried to give compound 9 (207 g, 96%). 8.2 Boronate 10: nd 9 (50 g, 0.224 mol), bis(pinacolato)diboron (85.6 g, 0.337 mol), KOAc (44.1 g, 0.449 mol) and Pd(dppf)Clg.CHfiflg (2.77 g, 3.4 mmol) were d into a flask. Dioxane (400 mL) was added. The reaction mixture was stirred at 100°C for 2 hr under Ar. When LC-MS indicaoed Lha, the reaction was completed, the mixture was cooled to room temperature. The mixture was "1'tered through diatomite, concentrated, diluted with I] a mixture 0; ethyl acetate and hexane in 3/1 ratio (1000 mL), filtered through silica gel (300-400 mesh), concentrated, crystallized and dried to give boronate 10 (32 g, 66%) as a white solid.
Example 9 Synthesis of boronate 13 N/ N’ I | 2) \ \ N / \O H2N H2N | CI CI H2N 11 12 13 9.1 Compound 12: 3-Chloropyridin—2-amine (100 g, 0.778 mol) was dissolved in acetic acid (1200 mL). To the solution was added Na2C03 (82.4 g, 0.778 Hol). Then, 3r2 (39.1 mL, 0.856 mmol) was added dropwise. After addition, the reaction mixture was stirred at room temperatJre for 30 min. To the mixture was added water (800 mL). The mixture was cooled to about 5°C.
The resulting solid was collected by filtration and dried to give nd 12 (147 g, 91%) as a white solid. 9.2 Boronate 13: Compound 12 (4 g, 17.2 mmo1), bis(pinacolato)diboron (4.79 g, 18.8 mmol), KOAc (3.37 g, 34.2 mmol) and Pd(dppf)C12.CH2C12 (0.210 g, 0.25 mmol) were charged into a flask. Dioxane (80 mL) was added. The mixture was stirred at 85°C for 2 hr under Ar. When LC-MS indicated that the reaction was completed, the mixture was cooled to room temperature. The e was filtered through diatomite and concentrated. The residue was diluted with ethyl acetate and hexane (3/1, 100 mL), filtered through silica gel (300-400 mesh), trated and crystallized by ne to give boronate 13 (3.4 g, 78%) as a white solid.
General Scheme 14 15 Reaction reagents and conditions: a. Pd(dppf)C|2.CHZC|2(5% mol), K2003, dioxane, 80°C; b. NaOH, EtOH Example 10 Synthesis 0: compound 1-2 .1 Compound 16: Intermediate 5a (30 g, 65 mmol), boronic acid 7 (17 g, 7 1.6 mmol) and K2CO3 (27, 195 mmol) were charged into a f'ask. Dioxane (600 mL) and wa:er (60 mL) were added.
The so 1ution was deoxygenated with N2 for 15 min.
Pd (dppf) C12 . CH2C12 (2.8 g, 3.24 mmol) was added to the mixture.
The reaction mixture was stirred at 85°C overnight. When the reaction was completed, the reaction mixture was cooled to room temperature. The itate was filtered, dissolved in water, filtered, triturated with ELOH, filtered and dried to give compound 16 (16 g, 57%) as an o""—whi1e solid. The ed compound was pure enough for Jse.
The organic filtrate was concentrated. To the e were added water, dichloromethane and EtOAc. The precipitate thus formed was collected by filtration and ved in HCl (5 N). A ”Ler ”filtration to remove Pd e, the filtrate was basified with aq. NaOH (pH 7—8). The precipitate was collected by filtration and dried to give compound 16 (3 g, 11%) as an o" "—white solid. .2 Compound 1-2: Compound 16 (33 g, 76.1 mmol) was suspended in EtOi (300 mL). Ag. NaOH (4 N, 100 mL) was added to the suspension, and the mixture was stirred at 60°C for 2 hr. 200 mi 0' ?tOH was evaporated und r r duc d pr ssur To the residue was added HCl (5 N) to adjust p 1 = 4. Tte resulting precipitate was filtered, triturated with EtOH, filtered and dried to give compound 1- 2 (30 g, 97% ) as ano "—white solid. m.p. > 300°C. NMR (400 MHZ, DMSO) 5 14.64 (SI 1H), 12.39 (S, 1H), 8.92 (s, :4), 8.58 (8, 1H), 8.28 (s, 1H), 8.01 (m, 2H), 6.67 (d, J: 9.4 Hz, 1H), 4.42 (s, 1H), 2.68 (s, 3H), 1.27 (d, J 6.4 Hz, 2H), 1.12 — ;.03 (m, 2H). 13C NMR (101 MHZ, DMSO) 8 '76.92, '65.?5, , '58.16, ’55.72, '52.71, ’50.92, , '39.29, '38.79, '37.62, ’33.70, '33. 52, ’31.80, 127.47, 127.38, 123.75, '23.42, ’3.89, 108 .05, 107.81, 107.29, 41.29, 20.64, 20. 62, 10.62. HPLC-MS m/z 406 (MH+).
Anal. Ca' cd :01” C22H16FN3O42 C, 65. 18, H, 3.98, N, 10.37. Found: c, 63.50, H, 4.00, N, 9.91.
Example 11 Synthesis 0: compound 2-18 / 3‘0 11.1 Compound 17: Boronate 10 (14 g, 56.1 mmol), ediate 5a (20 g, 46.7 mmol), Cs2CO3 (15.22 g, 46.7 mmol) and ?d(dppf)C12A}bC12 (0.98 g, 1.2 mmol) were charged into a flask.
Dioxane (500 mL) and water (5 mL) were added. The mixture was stirred at 110°C overnight under Ar. The mixture was cooled to room ature. The mixture was filtered, and the solid was washed with dioxane and ethyl acetate. The solid was dissolved in hot CHflflg (1200 mL), and the on was filtered through diatomite. The operation was ed twice. The organic layers were combined and concentrated. To the residue was added ethyl acetate (200 mL). The solid was collected by filtration, washed with ethyl e (60 mL) and dried to give compound 17 (17.6 g, 90%) as a white solid. 11.2 Compound 2-18: Compound 17 (43 g, 0.101 mol) was dissolved in THF and EtOH (1/1, 500 mL). To the solution was added NaOH (60 mL, 4 W). The mixture was stirred at room temperauure for 2 hr. HCl (63 mL, 4 N) was added to acidify the mixture (pH = 3—4). The solid was collected by filtrauion, washed with EtOH (100 mL) and dried to give compound 2-18 (35.7 g, 99%) as a white solid. m.p. > 300°C. 1H NMR (400 M 2, DMSO) 5 14.65 (s, 1H), 8.89 (s, 1H), 8.32 — 8.23 (m, 1H), 8.08 (d, J": 2.09 HZ, 11), 7.94 (d, J'= 8.87 Hz, 1H), 7.28 (s, 2 ), 4.40 (tt, J'= 3.74, 7.17 Hz, 1H), 2.67 (s, 3H), 1.31 — 1.19 (m, 2H), 1.10 — 0.99 (m, 2H). 13C NMR (101 MHZ, DMSO) 5 176.95, '76.92, , '59.60, '58.?9, '55.86, 154.07, 152.67, 143.59, ’39.32, ’33.39, ’33.?2, ’31.73, ’27.13, ’27.05, 116.93, ’16.52, ’07.96, ’07.71, ’07.?7, 89.15, 41.32, 20.64, 20.62, 10.65. S m/z 379 (MH+). Anal. Calcd for CgfithNHh: C, 63.49, H, 4.00, N, 14.81. Found: C, 62.04, H, 4.20, N, 13.97. e 12 Synthesis 0: compound 3-11 o o g F \ I M g9 13 58‘ 3-11 12.1 Compound 18: Boronate 13 (20 g, 75.4 mmol), intermediate 5a (24.1 g, 58.03 mmol), Cs2C03 (26.5 g, 81.2 mmol) and ?d(dppf)C12.CH2C12 (1.42 g, 1.7 mmol) were charged into a flask. e (400 mL) and water (4 mL) were added. The mixture was stirred at 100°C overnight under Ar. The mixture was cooled to room temperature. The mixture was filtered, and the solid was washed with dioxane and ethyl acetate. The solid was dissolved in hot CHflflg (1200 mL), and the solution was filtered through diatomite. The operation was repeated twice. The organic layers were combined and concentrated. To the residue was added ethyl acetate (200 mL). The solid was collected by filtration, washed with ethyl acetate (60 mL) and dried to give compound 18 (21 g, 85%) as a white solid. 12.2 Compound 19: Compound 18 (39 g, 91.91 mmol) was dissolved in THF and EtOH (1/1, 600 mL). To the mixture was added NaOH (4 N, 60 mL). The e was stirred at room temperature for 2 hr. HCl (4 N, 62 mL) was added to acidify the on (pH 3-4). The solid was ted by filtration, washed with EtOH (100 mL) and dried to give compound 19 (34 g, 98%) as a white solid. 12.3 Compound 3-11: Chloroacetaldehyde (40% in water, 80 mL) was added to a solution 0: compound 19 (34 g, 91.9 mmol) in EtOH (600 mL). The mixture was refltxed for 3 hr. When LC—MS ted that the reaction was comp1eted, the mixture was cooled to 5°C and filtered. The solid was dried to give compound 3—11 (21 g). The mo:her 1iquid was basified (pH=7—8) with aq. NaOl. The precipitate was ted by filtration, washed with EtOH and dried to give compound 3-11 (11.5 g) as a white solid. In total, 32.5 g of nd 3-11 was obtained in 93% yield” m.p.: 307 — 311°C. 1H NMR (400 MHZ, DMSO) 8 14.53 (s, 1H), 8.98 — 8.84 (m, 24), 8.28 (d, 0': 1.16 Hz, 1H), 7.98 (d, 0': 8.83 Hz, 1H), 7.90 (d, 0': 0.89 Hz, 1H), 7.77 (s, 1H), 4.43 (tt, 0': 3.70, 7.10 Hz, 1H), 3.50 — 3.36 (m, 1H), 2.72 (s, 3H), 1.26 (d, 0': 6.80 Hz, 2H), 1.07 (a, 0': 18.24 Hz, 2H). l3C WM? (101 MHZ, DMSO) 5 176.91, 176.88, 165.23, 158.22, 155.77, 152.84, 139.98, '39.17, , '32.44, 132.15, 131.98, '3 .54, 127.86, 127.78, 127.38, ‘20.72, ’18.97, 116.37, ’O8.15, ’07.91, ‘07.37, 41.38, 20.54, 20.52, 10.72.
PLC—MS: m/Z 412 (MH+). Anal. Calcd for CgfihBClFNfih: c, 61.25, , 3.67, N, 10.20. Found: c, 58.59, H, 3.86, N, 9.76.
Compounds listed in the following Tables were synthesized according to General Scheme o._n_I $8 $8 £8 $8 $8 I 32 hrs; NN+ 8+ o++ +N+ 8+ 8+ .3 1,638.9? .3 .3 .NI £3 2: .NI 1, .3 l, .fm .3 £3 8w wow 8w 3 .NI .fm 3 .3 5w .3 .3 +3 .NI .: £3 5.: l, 3 l, .3 Sb 5.: 83 a: 5.: 3 .fm .3 .A_._+ .3 .3 ++.m u .3 fl, .3 .3 £3 I .3 w mg N3 N++ £3 .3 83 5.: .fm .3 .NI $3 5w .3 .N_._ 5.: .3 +3 .NI woe .: £3 83 £3 .3 3 ms 5.: £3 3 $3 .3 :3 5.: 5.: 5.: .fm .3 fl, 1, .3 .3 £3 .3 8.3 I .3 l, .N_._ 2+ .3 .3 .fm I .N_._ 3+3 .3 .3 8.3 .3 +.m .fm 3+3 .NI I 8.3 +5 +3 +m+ .3 2: 2.3 N+.N3 S3 own S .3 I «:22 5.: $3 fl, £3 w: 1, £3 .fm fl, $3 .fm .fm 5.: 5.: .3 .3 8.3 .3 + .3 .3 3:13 £3 .3 .3 .3 .3 .3 £3 8.3 .NI +33 #3 I .3 5.: .NI 3.3 .NI 3w N+.m N: $3 83 8.3 Now 8w NN3 ON .N_._ 8.3 3 n .fm 5+ n n .fm 1, £3 n n 8320 5.: n £3 5.: u 832a 1, 3 I .3 .3 .3 .fm 632a .3 .3 .3 5w .N_._ 632a .3 +N.@ l, 5w 8+ 6320 .3 6320 w .3 gm 83 +N+ +.© 9% .NI_>_ 5.: .NI_>_ 33 .3 >_ .NI_>_ .fm 83 5.: £3 5.: 5.: fl, £3 5.: .3 £3 .N_.__>_ £3 gm .N_.__>_ .3 £3 .3 83 .3 .3 .fm .3 .N_._ 83 .3 83 .3 83 +3 .NI 83 5.: no.3 83 .3 .NI .NI 8+ «:22 wow 3 «:22 mg N3 «:22 53 to, I 8.3 «:22 wow «:22 3 .N_._ «:22 3 I T: £3 .3 .fm u T: 5.: T: £3 Em I T: 5.: .m+© T: 1, 3 I33 T: w m++ E E95296 38585 E95296 E95296 E 220 22 220 22 6 I H Y/ V/\z_ o mm \2_ zI zI \ \ o 2E 0 0 mm .58 338 .02 3-3 N3 3 +3 3 5 WO 29548 .3 .I. I I .IN I 8.3 .I. .NI w .... I .3 .3 u .3 u .IN I w w 83 m... m... .m. .3 .IN I No.
.NI .NI .NI 3.. 8.3 Ed 0.3 .3 .3 .I. .IN .33 83 .NI .3 .I. mm. m... .IN .I. .Im .3 w .I.. 3. .3 .I. .I. E... .NI .I. $3 3 .I. mo. .3 .NI .3 .3 .I. u l, .Im .3 .3 .3 .I. ON. .3 .I. .3 1,638+..I. .3 .IN .3 3 mg mom .3... .3 $3 .3 .3 mm. mg .3 .3 .3 .3 I mm... 1, .3 .NI .NI I I .I. 5.. fl, .I. mom .3 I 8.. .3 .3 I .3 wow. .3 o: E. mm. .I. .3 I .I. .I. .3 I .I. N... 3 .3 .I. 8.1I. 3.. .3 I .I. 8.. .I. :10, .3 .I. .3 .3 fl, mm. om... 8.. .I. .3 .I. 8... .I. .Im fl, .3 Na... .3 .3 .3 .3 mmm. .IN .I. $3. .NI .3 8... .3 8.. .I. .I. .I. .NI .I. 5.. .3 x: mm.
.I. m... 8.... .NI 3... .NI .3 .I. .3 3 .I. .I. Ed .I. 8.3 .NI mm. .Im .3 .I. .3 I u 5. .3 .IN .I. .3 .I.
.I. u .3 .I. .3 am... I .I. 8.... .NI .3... .3 mm... w 8.... .3 .3 .Im .NI .3 .NI u 3.113 .2 .3 .3 E... .3 w mm... 8.... .NI 8....
.N. 3.. gm n w... .3 n 2 2 .3 .I. n 8.. n n n .. w... $3 o: n m... 1, fl, Ed fl, .Im I u .I. .0320 8.. 69.5 69.5 .NI u .IN .3 .03 w w .I. .3 .3 .I. .I. .3 .3 I 33.. 69.5 .3 .NI .0320 .I. 69.5 69.5 I .3 .NI_>_ 8.. .3 .NI .NI_>_ u .NI_>_ m... .I. 3.3 .NI_>_ 8.. 0.. .NI_>_ 8.3 8.. 3.0, 3.. 8.3 w m: .NI_>_ .3 fl, .NI_>_ .2 .I. .3 N... .I. .I. m: .I. 83 u .I.
.NI w .IN 83 .I. .Iv 83 .3 .E I 83 .I. .I. .3 83 .3911I. .I. .3 .NI 83 .NI .IN 83 .IN .NI 322 .3 .3 .3 «:22 .3 I .3 322 I om...
E .Iv «:22 .NI .3 vm. «:22 3 .NI 322 3 .NI .3 «:22 .3 .10, I. fl, 8.3 $3 I. 8.3 2... 8.. I. .I. 3..
I R. .3 I. u t; .Im I. fl, 3 I. fl, Ia mo. I. 5.. .o. 38529.0 38529.0 38529.0 I. 38529.0 350529.0 .EI 22 22 I u w .3 .3 .3 w mg 2.11;: .3 5.: 3.3 .3 w .Ev .3 .3 1, AT: 5.: $3 .3 AT: .fm m3 .N_._ .fm 83 .3 2.w 8.3 SN 8.3 2.w .NI 3.w .N_._ .fm max .NI .3 AT: 5.: g AT: 3% .NI 5.: .fm 5.: .fm 5.: 3 5.: m: .3 m3 u 5.: 3 .3 Ow .3 u .fm w 3 .3 AT: .3 .3 .3 338.113 .NI .3 l, .3 w N3 .fm EN .3 w .fm fl, 5w .3 fl, N3 .3 .3 .3 .3 N3 gm 83 .NI 3% 3mm .3 5w 5.: .3 .3 5.: t; 2.w .3 AT: mm: 5.: 5.: 3% u 5.: :3 5.: SN 2.3 .3 9: w .3 33 2.3 8w AT: .3 5.: 3.3 5.: .3 AT: .3 .3 .3 5.: .fm .3 AT: .3 fl, .3 AT: .fm 52 .fm m: .3 AT: .fm .N_._ .fm .3 .N_._ 8.3 22 .3 .3 £3 3% 2.3 3.3 3w .NI .3 2.2 .N_._ 5.: 5w .NI .3 AT: .3 in .3 83 83 .fm 5.: 3 E 2 83 3 5.: u gm AT: 3.3 5.: AT: 5.: m3 5.: u .N_._ 5.: u 34°, .3 fl, w AT: AT: .3 l, .3 w .3 .3 .3 E w .3 .3 .3 3.3 AT: .3 .3 .3 .fm N53 AT: 8.3 .NI .3 .3 $3 .3 83 8.3 gm .sz 1, .3 5.: .NI Ex .3 3.3 Now .3 2.3 w: 2.3 .3 n 3.3 32.113 3 2; mm: n 5.: n n .fm 3.3 AT: n n n 3 gm n 632a .fm 6320 632a fl, 6320 6320 AT: AT: fix N: .3 5.: AT: fl, .3 .3 .NI .3 .fm .3 26 6320 .NI .fm 8320 .N_._ 5.: 6320 .3 5.: .3 .3 .NI_>_ EN .N_.__>_ m: .NI .3 2 .NI_>_ 2: .N_._ SN .N_.__>_ wok :5 fl, .fm .N_.__>_ AT: .N_.__>_ 3 03 .N_._ .fm .fm fl, 3: >_ g 3 AT: .fm 1, .N_.__>_ .3 S .fm 5.: as 83 83 83 .3 .3 83 .NI .: 83 .3 .fm 83 .3 no.3 83 AT: u .3 .N_._ fl, .NI .NI 1, w .fm «:22 .3 .NI m: «:22 as .3 .fm «:22 m3 3 .N_._ «:22 83 8.3 «:22 «:22 23 :5 .3 «:22 max .3 .fm «:22 .3 .3 u mm T: wow I T: w m3 .3 T: fl, 1m T: .fm .fm T: u .me .fm T: AT: #3 T: 5.: SE .3 T: H wmx no.3 385296 385296 385296 385296 385296 385296 385296 385296 .3 3 .3 I .f: .3 u .3 .f: 3.: .3 1, .fm .3 .f: .3 .f: .3 own w .f: 8: wow fl, com .3 83 .3 Ba .N_._ .fm 53 .3 .NI SN .3 Ba .NI 3:1: own .NI .f: .f: .3 .f: .f: mm: .f: NON .sz .f: m: a: .NI .f: 3 .f: o: .f: 3 3 .f: .3 .3 .3 m? .3 5.: .3 .f: .3 .3 u u u u .3 .f: .3 w .f: .3 w o; .3 w o; 3% .f: a: m3 3w .3 3.: .3 .N_._ mg fl, 3.: .NI .3 83 .N_._ 3% .3 5w .3 I I .f: .NI .f: .f: I E .sz 5.: m: 5.: NS .3 5.: 3 8: 5.: m: 5.: 3: 5.: 3: 2 mm: .3 fl, .N_._ .3 u .f: .3 w .3 .3 .3 .f: #3 .3 .fm .3 1, .f: N321: .3 .f: N321: 3.8 fl, £9 mad NE: .fm mm: .fm .3 3 .3 .N_._ .3 5.: m2: .3 8.: .3 .NI 8.: .3 .3 .3 .NI :2 ox .3 mm: .f: I .3 mm: om: m: fl, m: 5 of 5 .f: .3 E .f: N3 .f: gm N©.N 5.: .f: .f: .f: .f: .3 .f: .3 .f: .f: .f: .f: .3 .3 2% .3 .3 .3 .3 .3 .f: .fm .3 .f: .3 .f: .3 .f: .fm mm: mm: 8.: E: .N_._ .3 .N_._ 8.: .3 E: 8.: .NI 1, .NI .3 3.: .NI .f: m: .3 NM: m: 38 m: .3 m: 3 3 63 m n o: n n n 8.: n n u u u 6320 fl, .N_._ u .f: w o: .f: 5.: w N3 w .f: .3 E 632a .3511: .3 .3 .3 .3 .3 6320 .f: 6320 .f: 8320 .NI 6320 .3 .fm 6320 1,635.9? 6320 w .f: .N_.__>_ 3: 1, .3 8.: .3 3 .3 a: 8.: .sz 8.: .AIN 3: .3 .3 .sz .NI_>_ 3: .N_.__>_ .N_.__>_ .NI .N_.__>_ .NI .NI .f: .f: 93 .N_.__>_ >_ .N_.__>_ .fm 3m fl, 86 .f: #3 .f: 3 .3 .f: .23 83 N: .3 83 .fm 83 83 .3 83 83 83 .NI 3.1:: .N_._ .f: .N_._ 1, 83 .f: .fm .N_._ .fm .NI fl, 8.: .NI fl, 8.: «:22 mm .f: 8.: «:22 .3 .3 «:22 Ow .N_._ «:22 3 .3 .fm «:22 wow .NI .3 «:22 1w .3 «:22 3 .3 .fm «:22 3 .3 .fm _._F 1, .N_._ .fm :3 gm ow u IF _._r 1, _._r w 03 .3 _._r .f: mm 2.: 1, u _._r N3 u _._F w a: .3 _._F w a: .3 385296 385296 385296 385296 385296 385296 385296 385296 .IIll22 I 86 .3 6.: .3 .66. 8; .66. 6 0: .66. N66 I 63 I .3 AT: .3 .fm :6 .3 AT: max $6 86 86 .3 .fm 86 N6 w: 86 6.: 66.6 .fm N: .66. .NI 666 6.: u AT: I I .66. 6.: ”6 u .66. 6 3216 AT: 6.6 .fm 6 AT: .66. .3 .3 at .3 EN 666 S f6 .3 6.: .AIN .3 .3 $6 .3 .3 .3 .3 $6 66.6 5.6 u 66 .N_._ N66 ”6 63 36 u 63 63 N66 No.6 $6 I 86 $6 6.: 6 AT: 3 ”6 56 56 u .fm 6 I .3 .: I I .3 6: 5.: .N_._ .66. 6 66.6 6.: 6.6 No.6 AT: .3 AT: 62 .3 $6 mom .N_._ AT: 8.15.6: 56 $6 63 .3 E S f6 .3 I .3 .66. 3 I mm; .3 I 66.: u u AT: 3.: N: 2.2 .66. 63 AT: AT: AT: mom 6 .33 6 .3 03 Se .fm 86 66 I 3 E6 $6 .fm 63 .66. .3 .3 .3 6.6 mg 666 u 6.: 6.: .fm 6.: 6.: u .3 AT: $66 6 .3 m6 62 AT: 66.6 I 6 ”6 ”6 8.66 86 .3 6.: I .3 .3 63 .3 .3 86 63 .3 .3 EN .61 I 6: AT: I .3 .2 I .66 63 63 a; wow a: wow 62 0.: 86 66.1.6.6: AT: :6 86 u .fm .66. 8.66 I N666 .fm 6 66.6 266383612 I S66 I 6.: AT: 6.6 n mm; 6 n 6.: n AT: .66. AT: .N_._ .3 6 6320 06 .3 I 6320 8320 832g 63 N3 .3 6.: 66 ”6 $6 .23 .61 m: .66. 86 66.6 u .66. 3 N: AT: 6 6: .6; 666 I .fm 380 $6 .3 0.: .N6 >_ 6.: .3 .fm I mm: .N_.__>_ .N_.__>_ .3 .N_._ 63 u 63 ”6 6.: 66.N u 6:2 86 6:2 m: 6 .N_._ 6 ”6 ”6 .66. 26 $6 863 AT: E 863 863 .3 86 63 .fm .3 .3 .3 6.: N: 863 .N_._ .fm 863 No.6 863 I u I 666 I .3 6 a; «:22 63 .3 E N66 26 66.6 26 86 ”6 «:22 ta «:22 .fm «:22 .666 .fm «:22 63 62 3 «:22 I I T: OS .3 T: ”6 SN T: AT: AT: .3 T: AT: u .3 T: AT: I mad f6 T: mg AT: 666 .fm mm; 385296 385296 385296 385296 385296 385296 33 #2 .3 I #2 .3 I I 33 a: .3 83 am .fm 5.: .fm 8.2.: .fm New 3; and mg u 3% .fm EN £3 .NI 2% .NI I .23 mg .3 .fm .3 I I I 5.: .fm .NI .3 N. .fm .3 2 mod .3 .3 mg 5.: .3 AT: N. .3 3 3: 8.3 tic, .NI .3 Ed .3 8.2 u 3m :3 u 3.2 w #2 .fm I .3 8.3 .3 I w mg 5.: 3 .23 5.: I RN 8.2.: .fm .3 wme Now 1, m; .3 .fm I .NI I .NI mg .NI 3.113336 .NI kw .3 I I I £2 fix .N_._ .3 5.: m; .N_._ 8d £2 3.3 3 5.: .N_._ 2: I I ow I .fm m; #2 83 2.1.: ©.N o.“ mm: I 3 11353 .3 8% .sz I .2 .N_._ #3 u AT: mom u fl, 8.3 .2 NM; £3 83 .3 u .3 w w u 8.1.: .3 w .3 fl, .AIN .3 .NI #2 .3 5.2.: Now .3 #2 .m. 5.: .fm .3 .3 £3 u 8.2 .3 .3 .NI .3 3: .3 2.3 w .3 5.3 3 .3 Ed 8.3 3 2.3 .3 I AT: I u .NI .NI mg .3 5.: m3 $2 g $3 Ex .NI I 3.3 u I w .3 333 u 33 :3 I I w I I .NI I 8N .fm wow E3 Ow I Nd .3 3 .33 5.: .fm 3.3 w 8.3 3.0 I I 2.3 .fm u 2.2 u 30:13 3.15 I 8.3 .3 2.3 8.2 mod 2 u .3 .3 .fm w 2+ w w N3 .3 n 3: fl, .NI n .fm n .3 .3 EN n .3 n .3 n 828 N: 83 5.: EN .fm 8.2% .3 632a I .3 omx .fm $2 I mm: .3 .N_._ 33?: 3.w .NI 8.0 .NI u .sz .fm 632a .AIN 632a I .3 8320 .fm w; I 3 632a 3:13 .30: Ed 8022 wow I I w E g .NI_>_ 83 .3 I .3 >_ 5.: .3 23 u Ed .fm .N_.__>_ .3 .NI .NI_>_ .NI_>_ AT: a: 1, .NI_>_ .NI_>_ u w 8.3 .3 am mm 83 .N_._ 8N 3.w £3 and £3 .3 I .3 max SN .3 5.: .3 .3 .NI .fm I I 83 8N 83 I 5.: 83 1, Na mg 83 8.3 owe 3 AT: 83 2x o: AT: .3 Sm .3 .3 NM: .3 «:22 .3 u 3.0, wow .3 m; I «:22 I I I I u .3 .3 I w «:22 mg .fm «:22 «:22 3: «:22 32.2 .AIN «:22 w I m2 .fm 8.3 _.: I .23 T: 340, 03w .3 .fm T: m: 8.3 5.: T: I 2: T: .3 .NI mg .3 T: wow 3“: I 385296 385226 385296 385226 385226 385226 385226 $003 mg .NI u w EN a; .NI .AIm .NI I u mg OS .AIm I .NI I .AI. m; w I o.© 33 w .AI. ow .3 I .AI. .3 3 .3 I.“ .AI. 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T: 3m T: od 8.3 T: 5.: .3 T: 5.: $8 nxém 8? .I NS :10, I 8g 83 .3 w 83 .3 AT: 5.: .fm .AT: mg .: m: .N_._ I .3 .56; .NI I .fm 23 .N_._ ow S; g .NI AT: 5.: fl, u , 5.: 3 w .3 .3 .3 .3 .NI .N_._ fl, mg EN ohm 51,383 o; 3 .3 .: I AT: 5.: N; .3 1:” N: .: .N_._ w u I .3 .3 .3 AT: w .3 mm $4 8.: N3 N3 63 1, .3 t; .30, AT: 5.: 5.: .3 2.2 8g I .3 I om: .3 .3 we; I 8.3 o: :1; 5.: 5: 3.2 5.: .AT: .N_._ n 5.: n .N_._ .fm n 832a .3 1m .NI mg .3 RN .sz 6320 1, 632a n 51,3240, 3 w I .Ev .3 :5 .NI_>_ 5.: $.33 .N_.__>_ 8x .NI_>_ .fm {w 83 .N_._ $3 83 5.: .NI 83 w I ow 3 .3 8.21;: 322 .fm $22 .3 1, fl, 322 86 NS 3: IV .3 .3 _._r m: .3 IF I .fm u WO 29548 o._n_I .28. .28 32 I23 3:0, .8 .3 .NI w .NI .3 mg .3 9% .3 .3 w .3 .3 .3 of 3 vm. ..w m: .AI. mo. .AI. .AI. kw mm. mm: .AI. l, 1, .AIm .AI. .AIN .3 .AIN .3 .3 .AI. .AIN .3 .3 .AIm .AIN .NI .3 33 .NI .3 3: 3% .NI 23 0: .3 23 3 3.. 3.
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.AI. .AIm .AI. .AIm .AI. .AIm .AI. .AI. .AI. .AI. .AIN .3 .AI. .AI. .AIm .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 .3 23 N: w: .3 .NI .3 E... 8w 8.3 31. 05.. EN E... o: 5... 0:. 3.. SM. 3 05.. .3 n .AI. n .AI. n .AI. n n .AI. n .AI. .AIN n fl, n .AI. 632a .AIN .3 632a .3 .AIN 6320 .NI .NI .3 632a 632a 632a .NI 6320 .3 .AIN .3 3 8320 mm... .3 .3 .3 .383 ..m 3m 03 .3 .3 .NI_2 u .AI. .NI_2 .NI_2 w l, .AI. .NI_2 8.. 1, .AI. .AI. .NI_2 .NI_2 .NI_2 5.0 .3 .3 .3 .AI. .NI_2 .AI. 83 .3 83 .3 .AIm 83 .3 83 .3 83 max 83 8x vm. 83 .3 .AIN 83 .3 «:22 RN «:22 m: .NI «:22 SN «:22 NS «:22 «:22 «:22 83 .NI .AI. BF .AIN .AI. 3. .AI. .AIm .AI. 3 «:22 I. I. u I. .AIN I. I. .3 .AIN I. .3 .3 I. .AI. n I. .AI. 22 0 E _>_ u v9 em I 2an .58 338 .02 E N-“ WO 29548 8.3 .3 8.3 EN .N2 8.3 3 .N_._ .3 u w .fm AT: .fm .NI l, .3 .N_._ u l, .3 3 .3 5.: 8.3 8 8 8.3 8.3 3 w 5.: 5.: .NI .NI .N_._ .fm l, .3 .3 l, .3 .3 .3 .fm No.8 v.8 8.8 0.8 fl, 3.3 5.: l, 8.3 .3 3+ .3 AT: u fl, .3 .3 N; .N_._ o: SN .N_._ w 1, .fm .3 3 8.8 5.: SN .3 .3 .3 .3 8.3 .3 m: .: 5.: 5.: 83 3 1, 5.: .AIN .3 8.3 AT: .3 .3 AT: 5.: l, .N_._ .3 8.8 53 8.3 5.: 5.: .3 .fm .3 $8 .3 .3 .3 3: 8.0 .3 .3 AT: .23 .fm 33 8.8 .23 3.1.3 .3 .sz .3 3.8 3.3 38 8.3 .fm a; 3.3 .3 .3 .3 8.8 .3 .sz .NI 8.3 .: .fm 5.: fl, 5.: .fm N; .3 5.: .fm 8.8 8N 3 EN AT: m3. .3 .3 .3 .fm .3 .3 5.: .fm .3 $8 8.8 .3 fl, .3 .3 8.3 E3 3.3 .3 .3 3.3 $3 AT: 5.: 5.: 32.113 .3 3-8.3 .3 8w I .3 .: 88 3.3 5.: 3.8 m3 .fm .3 .3 8.8 .3 2.3 .3 8.8 .23 N: 8.3 .: 5.: 5.: .3 .AIN AT: .23 5.: .3 .3 5.: 5.: $3 3.1.3 N: AT: AT: 5.: .3 5.: .23 .3 .3 .3 8.3 .3 .3 .3 .3 N37 .3 m: 8.3 .3 I .23 .3 .3 :10, .3 .3 8.3 o: 8.3 3: 8.3 3w .: 2.3 2.: .fm 8.3 3: 8.3 .3 mg .3 8.3 8.3 5.: 58 SN n 5.: n .fm n 5.: n .N_._ .3 n .3 .fm n 83 n EN n 23:13 n .3 n .23 6320 .3 8.3 8320 .N_._ 8.2113 638 .3 6320 8.3 8.3 6320 .3 638 .AIN 638 5.: 638 .3 .3 v.8 .fm mg 6320 N: I .: .fm 3: x: 6320 .3 5m .N_.3 5.: .N_.3 fl, .N_3 .3 .3 .: .N_.3 t; .3 .3 .3 .N_.3 5.: .N_3 8.3 .N_3 a: .N_3 5.: 8.3 .N_.3 .N_.3 5.: 83 .NI 83 5.: 3: .3 .3 8 3.3 83 .3 83 m: EN 83 83 .fm .fm 83 5.: .fm 83 .fm 83 83 .3 ~32 ~32 .fm .fm ~32 SN ~32 5.: .fm ~32 SN ~32 .N_._ .3 ~32 .3 .3 ~32 RN fl, .N_._ ~32 .szd ~32 m; _.: .3 .fm .N_._ 5.: u _.: .3 T: _.: .3 .N_._ _.: 5.: .fm T: 3w 8.3 T: SN 8.3 T: 5.: 3 _.: w _.: 5.: WO 29548 .323 .sz AT: N: .3 I mg #3 n .fm 632a .3 .NI_>_ 5.: 83 .53 ~32 m; Ir 5.: WO 29548 Table 8-1 --MS<MH) __5236 lap—_————— ————_—— 8-27 F 353.34 398.34 387.79 368.36 432.24 353.34 378.35 385.36 383.37 446.27 383.37 403.35 368.36 381.35 377.37 381.4 379.38 367.37 397.36 411.38 380.41 8-48 nitro—3— Me 470.41 dimethylamino WO 29548 Table 8-2 0 o MSMW) WO 29548 WO 29548 WO 29548 Table 9 MS(MH+) WO 29548 WO 29548 Experimental Txample ’ In Vitro Antibacterial ty All compounds were dissolved in dimethyl sulfoxide (DMSO, Merck, purity >99.9%) to achieve final 1 mg/ml desired concentrations.
MZCs (minimum tory concentrations) were determined by the broth microdilution technique with 96—well microdilution plates. The antimicrobials were tested using the following M'‘C ranges: 0.008 to 8 ug/ml. The plates were filled with 100 pl Ol reinforced clostridial medium (Oxoid; Unipath Ltd., 3asingstoke, United Kingdom) per well containing the final antibiotic concentrations. The plates were thawed and preircubated for 3 hours in an anaerobic chamber (Thermal, USA) ning an atmosphere of 80% Ng, l5% C02, and 5% {2. The bacterial a were prepared by suspending growth from 48 hours cultures in reinforced clostridial l The final inoculum was approximately 1.0 x 105—6 CFU/well. The plates were ted :OI 48 hours at 37°C in the anaerobic chamber. The MIC was defined as the lowest antibiotic concentration that inhibited visible growth. Ciprofloxacin, vancomycin and metronidazole were used as a positive control. The results are shown in Table 10.
Table l0: M"C 0‘ example compounds against C. ile (Mg/mL) 'OO C.difficile C.difficile C.difficile C.difficile pound ATCC43255 ATCC700057 ATCC70092 IQCC23903 2 l 8 2 4 6 l 4 2 4 9 I|3 £0 008 0 032 0.0l6-0.032 0.032 0.016-0.063 l-2 0 032 0 125 0.032-0.125 0.125 0.063-0.25 U) | 2 |_\ 0. 0; 6-0 032 0.0l6-0.063 0.016-0.063 0.032-0.063 N | 3 00 0 0L6 0 032 0.0l6-0.032 0.032-0.063 0.016-0.032 3-30 0.032 0 063 0.l25 0.063-0.l25 0.063-0.25 Experimental Example 2 In Vivo Antibacterial ._‘,— _. "icacy Tn Vivo e "icacy was evaluated in a hamster intestinal injection ,reatment model. Male Golden Syrian rs were purchased from Charles River Laboratories (Kingston, NY, USA) and were about 6 wee<s 0: age, with weights ranging from 80 to 100 g at the start or the study; The animals were housed individually in ‘iltered polycarbonate shoe-box style cages equipped with water bottles, and Harlan Teklab Global Diet 20l6 was available ad m via food hoppers. The hamsters were pre-treated with clindamycin (l mg/kg, p.o.) and ycin (50 mg/kg, p.o.), formulated in arabic gum, at Day 0. At Day 7, each hamster was inoculated via oral gavage with 0.5 mL 0: a suspension of C. difficile ATCC 43255 (105 CFU/body, p.o.). To prepare this inoculum, C. difficile was grown in GAM agar (Japan) for 5 days at 37°C, and the bacteria were harvested by centrifugation, rinsed twice with arabic gum, resuspended in arabic gum and the exaCt bacteria density was determined using the dilution plate count method. Oral dosing 0: compounds, pulverized and formulated in arabic gum was commenced the 'o'lowing day (Day 8). Treatmerts were administered once a day for 5 consecutive days at specified doses (10, 2, and 0.4 mg/kg), with five hamsters per group. Controls were included an uninfected group and an ed but untreated group, and vancomycin was used as positive control. The hamsters were observed daily to record clinical signs (duration, time o; onset, time 0: recovery or death), and animals in a lethargic, clearly moribund state were ized. A necropsy was per:formed on animals that were either :oand dead or were euthanized at the end 0: the study (37 days). The results are shown in Fig. l and Fig. 2.
Preparation Txample l An injection preparation is prepared "rom the following components. ents Amount nd 1-2 200 mg Glucose 250 mg Distilled water for injection q.s.
Total 5 ml Compound 1—2 and glucose are dissolved in led water for injection, and the on is added to a 5 ml ampoule, which is purged with nitrogen gas and then subjected to sterilization at 121°C for 15 minutes to give an injection preparation. ?reparation Txample 2 Film coated s are prepared from the following components.
Components Amount Compound 2-18 100 g Avicel(registered trademark) 40 g Corn starch 30 g Magnesium stearate 2 g TC-5(registered trademark) 10 g Polyethylene glycol 6000 3 g Castor oil 40 g Ethanol 40 g Compound 2—18, Avicel (registered trademark of microcrystalline cellulose, manufactured by Asahi Kasei Corporation, Japan), corn starch and magnesiJm stearate are mixed and kneaded, and the e is tabletted using a conventional pounder (R 10 mm) for sugar coating (manufactured by Kikusui Seisakusho Ltd., Japan). The tablets thus obtained are coated with a film g agent consisting of TC—5 (registered trademark O" hydroxypropyl methylcellulose, manufactured by Shin-Etsu Chemical Co., Ltd., Japan), polyethylene glycol 6000, castor oil and ethanol to give :ilm coated table ts.
Preparation Example 3 An ointment is ed from the following components.
Components Amount Compound 3-11 2 g ?urified n 5 g Bleached x 5 g White petrolatum 88 g Total 100 g Bleached beeswax is made liquid by heating, and thereto are added compound 3—11, purified lanolin and white petrolatum, and the mixture is heated until it becomes liquid.
The e is stirred until it is solidified to give an ointment.

Claims (39)

1. A compound ented by the formula (I) 5 wherein X is a fluorine atom; R is a en atom or alkyl; R1 is (1) cyclopropyl optionally substituted by 1 to 3 halogen atoms or (2) phenyl optionally substituted by 1 to 3 halogen 10 atoms; R2 is alkyl optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom and hydroxyl; alkoxy; haloalkoxy; a ne atom; cyano; cyclopropyl; nitro; amino; formyl; alkenyl or alkynyl; or 15 R1 and R2 are bonded to form a 5- or 6-membered ring optionally substituted by alkyl; R3 is (1) a fused heterocyclic group of the formula 20 wherein represents a single bond or a double bond, X1 is C(R5) or N, R4 is a hydrogen atom or alkyl, and R5 is (a) a hydrogen atom, 25 (b) a halogen atom, (c) cyano, (d) nitro, (e) hydroxy, (f) alkyl optionally substituted by 1 to 3 halogen atoms, 5 (g) alkenyl or alkynyl, (h) aryl, or (i) alkoxy optionally substituted by 1 to 3 halogen atoms, when X1 is C(R5), R4 and R5 are optionally bonded to form a 5- 10 or 6-membered ring optionally substituted by oxo, said fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group ting of a halogen atom, cyano, nitro, hydroxy and alkyl, (2) a group of the formula R7 (C) 15 R6 wherein X2 is C(R8) or N, and R6, R7 and R8 are each independently, (a) a en atom, 20 (b) a halogen atom, (c) cyano, (d) nitro, (e) amino, (f) alkyl optionally substituted by 1 to 3 tuents 25 selected from the group consisting of a halogen atom, alkoxy and amino, (g) alkenyl, (h) alkynyl, (i) aryl, 30 (j) formyl or CH=N-OH, (k) carboxy, (l) carbamoyl, (m) a 5- to 10-membered aromatic cyclic group optionally substituted by alkyl, or (n) alkenyloxy, (3) a group of the formula wherein X3 and X4 are N, or X3 is N and X4 is CR”, wherein R” is hydrogen atom, amino, hydroxy, alkyl optionally substituted by 1 to 3 substituents 10 selected from the group consisting of alkoxy and dimethylamino or mercapto, or X3 is CH and X4 is N, R’ is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of 15 tuted hydroxyl and amino, and R6 is as defined above, (4) a group of the formula N , , , H N N N H N N N , , N N H N , H O O N , , N N , , N , O O S , N , N , H H R6 R6 H N O N N , N or represents a single bond or a double bond and R6 is as defined above, (5) 3-pyridyl optionally substituted by 1 or 2 substituents selected from the group consisting of (a) a halogen atom, 5 (b) cyano, (c) nitro, (d) hydroxy, (e) amino, (f) alkyl optionally substituted by 1 to 3 tuents 10 selected from the group consisting of a halogen atom, mino, dialkylamino and hydroxy, (g) l, alkynyl (h) aryl, (i) cycloalkyl, 15 (j) alkoxy, (k) alkylamino, (l) dialkylamino, (m) phenylamino optionally substituted by 1 to 3 n atoms, 20 (n) a cyclic amino group optionally substituted by alkoxycarbonyl, (o) formyl, (p) carbamoyl optionally substituted by alkyl optionally substituted by hydroxy, and 25 (q) a 5- to 10-membered aromatic heterocyclic group optionally substituted by alkyl, (6) 4-pyridyl optionally substituted by a n atom, (7) 5-pyrimidinyl optionally substituted by 1 or 2 substituents selected from the group consisting of amino, 30 alkylamino, dialkylamino and carboxy, (8) 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl or benzothiazolyl, each optionally substituted by 1 or 2 tuents selected from the group ting of 35 (a) a halogen atom, (b) cyano, (c) nitro, (d) y, (e) alkyl optionally substituted by 1 to 3 substituents 5 selected from the group consisting of amino, alkoxycarbonylamino, alkylamino and dialkylamino, (f) alkoxy, (g) formyl, (h) carboxy, and 10 (j) amino optionally substituted by 1 or 2 substituents selected from the group consisting of (i) carbonyl, (ii) alkylcarbonyl optionally substituted by a substituent selected from the group consisting of 15 (A) cycloalkyloxy ally substituted by 1 to 3 alkyl, (B) alkylamino, (C) dialkylamino, (D) a cyclic amino group optionally substituted 20 by alkoxycarbonyl, and (E) a n atom, (iii) phenylcarbonyl optionally tuted by 1 to 3 substituents selected from the group consisting of alkyl and alkoxy, 25 (iv) cycloalkylcarbonyl, (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group optionally substituted by alkyl optionally substituted by 1 to 3 halogen atoms, 30 (vi) benzylcarbonyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and alkoxy, (vii) arylsulfonyl optionally substituted by alkoxy, (viii) cycloalkylalkylsulfonyl ally 35 substituted by 1 to 3 substituents selected from the group ting of alkyl and oxo, (ix) a 5- to 10-membered aromatic heterocyclylsulfonyl group optionally tuted by 1 to 3 alkyl, and 5 (x) –C(=N-CN)-SR9 wherein R9 is alkyl, (9) a group of the formula wherein one of Y1, Y2, Y3 and Y4 is N or N+(-O-), and the remaining three 10 are each C(R25), C(R26) and C(R27), W is O, S, NH or N(R23) R23 is a hydrogen atom or alkyl, and R24, R25, R26 and R27 are each independently, (a) a hydrogen atom, 15 (b) cyano, or (c) nitro, (10) a group of the formula N N N N N N H (H) (J) wherein 20 R28 is a hydrogen atom or hydroxy, and R29 is a hydrogen atom or alkyl, (11) a group of the formula N X5 wherein X5 is C(R11) or N, X6 is CH2, C(=O), O, S, SO2 or N(R12), 5 X7 is CH(R13), C(=O) or , X8 is CH(R15) or C(=O), R10, R12 and R14 are each independently, (a) a hydrogen atom or (b) alkyl, and 10 R11, R13 and R15 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) nitro, 15 (e) amino, (f) alkylamino, (g) dialkylamino, (h) alkyl optionally substituted by hydroxy, or (i) alkenyl, 20 when X5 is C(R11), R10 and R11 are optionally bonded to form a 5- or 6-membered ring optionally substituted by alkyl or oxo, and when X6 is N(R12) and X7 is ), R12 and R13 are optionally bonded to form a 5- or 6-membered ring, (12) a group of the formula 25 S wherein R16 is (a) a hydrogen atom, (b) alkyl optionally substituted by 1 to 3 substituents selected from the group ting of cyano, alkylamino and dialkylamino, (c) alkenyl optionally substituted by carboxy, 5 (d) formyl, (e) carboxy, (f) carbamoyl, (g) –C(R17)=N-OH wherein R17 is a hydrogen atom, cyano or hydroxy, 10 (h) a 5- to bered aromatic heterocyclic group optionally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or (i) cyano, (13) a group of the formula wherein R18 is a hydrogen atom or alkyl optionally substituted by 1 to 3 substituents ed from the group consisting of a halogen atom and phenyl, 20 n is 0 or 1, R19, R20 and R33 are each independently, (a) a hydrogen atom, (b) a halogen atom, (c) cyano, 25 (d) alkyl optionally tuted by 1 to 3 substituents selected from the group consisting of (i) a halogen atom, (ii) cyano, (iii) hydroxy, 30 (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group optionally substituted by alkyl, (e) alkoxy, 5 (f) amino optionally substituted by 1 or 2 substituents selected from the group consisting of (i) alkylcarbonyl optionally substituted by a cyclic amino group, (ii) alkylsulfonyl, 10 (iii) carbamoyl, (iv) alkyl, cycloalkyl or cycloalkylalkyl, and (v) 5- to 10-membered saturated heterocyclic group, (g) carboxy, (h) alkoxycarbonyl, 15 (i) carbamoyl optionally tuted by alkyl optionally substituted by amino, alkylamino, dialkylamino or carbonylamino, (j) formyl, (k) a 5- to 10-membered aromatic heterocyclic group 20 optionally tuted by alkyl, (l) –CH=N-OR21 wherein R21 is a hydrogen atom or alkyl optionally substituted by mino or dialkylamino, (m) nitro, 25 (n) a 5- to 10-membered saturated heterocyclic group optionally tuted by amino, (o) phenyl, or (p) –NHC(SMe)=CHCN, (14) a group of the formula 30 R30 wherein R30 is (a) a hydrogen atom, (b) a halogen atom, (c) cyano, (d) alkyl optionally substituted by 1 to 3 substituents 5 selected from the group consisting of a halogen atom and y, (e) alkenyl, (f) alkynyl, (g) alkoxy, 10 (h) , (i) –CH=N-OH, or (j) carbamoyl, (15) naphthyl or isochromenyl, (16) quinolyl or isoquinolyl, or their oxide derivatives, 15 (17) a group of the formula (18) a group of the formula wherein 20 U is O or S, and R31 is (a) a hydrogen atom, (b) a halogen atom, (c) alkyl optionally substituted by 1 to 3 halogen atoms, 25 (d) carboxy, (e) nitro, (f) cyano, or (g) amino, (19) a group of the a wherein 5 R32 is (a) a halogen atom, (b) phenyl, or (c) a group of the formula (20) a group of the formula 10 R35 wherein R34 and R35 are each independently, (a) a hydrogen atom, or (b) aminoalkyl, 15 or R34 and R35 are bonded to form a 6-membered ring optionally substituted by amino or oxo, (21) a group of the formula 20 wherein R36 is (a) a hydrogen atom, (b) a n atom, (c) nitro, or (d) thienyl, or (22) a group of the formula 5 , or a salt thereof, providing that, when R1 and R2 are bonded to form a 6- membered ring substituted by alkyl, R3 is not 4-pyridyl, quinolyl or nolyl.
2. The compound of claim 1, wherein R3 is a fused heterocyclic group of the formula wherein , X1 and R4 are as defined in claim 1, and said 15 fused heterocyclic group is optionally substituted by 1 or 2 substituents selected from the group consisting of a halogen atom, cyano, nitro, hydroxy and alkyl, or a salt thereof.
3. The compound of claim 1, wherein R3 is a group of the 20 formula X2 X2 N N R7 or R7 N N R6 R6 wherein X2, R6 and R7 are as defined in claim 1, or a salt thereof. 5
4. The compound of claim 1, wherein R3 is a group of the formula wherein X3, X4, R6 and R’ are as d in claim 1, or a salt thereof.
5. The compound of claim 1, wherein R3 is a group of the formula N , , , H N N N H N N N , N N , , H H H O O N , , N N , , N , O O S , N , N , H H R6 R6 or N N , wherein and R6 are as d in claim 1, or a salt thereof.
6. The compound of claim 1, wherein R3 is a group of the formula H2N N 5 wherein R22 is (a) a halogen atom, (b) cyano, (c) nitro, (d) alkyl optionally substituted by 1 to 3 substituents 10 selected from the group consisting of a halogen atom, alkylamino, dialkylamino and y, (e) alkenyl, alkynyl, (f) aryl, (g) cycloalkyl, 15 (h) alkoxy, (i) formyl, or (j) carbamoyl optionally substituted by alkyl optionally substituted by hydroxyl, or a salt thereof.
7. The compound of claim 1, wherein R3 is midinyl substituted by 1 or 2 substituents ed from the group consisting of amino, alkylamino, dialkylamino and y, or a salt thereof.
8. The compound of claim 1, wherein R3 is 2-indolyl optionally substituted by 1 or 2 substituents selected from the group consisting of (a) a halogen atom, 30 (b) cyano, (c) nitro, (d) hydroxy, (e) alkyl optionally substituted by 1 to 3 substituents ed from the group consisting of amino, alkoxycarbonylamino, alkylamino and dialkylamino, (f) alkoxy, 5 (g) , (h) carboxy, or (j) amino optionally substituted by 1 or 2 substituents selected from the group consisting of (i) alkoxycarbonyl, 10 (ii) alkylcarbonyl optionally tuted by a substituent ed from the group consisting of (A) cycloalkyloxy optionally substituted by 1 to 3 alkyl, (B) alkylamino, 15 (C) dialkylamino, (D) a cyclic amino group optionally substituted by alkoxycarbonyl, and (E) a halogen atom, (iii) phenylcarbonyl optionally substituted by 1 to 20 3 substituents selected from the group consisting of alkyl and alkoxy, (iv) cycloalkylcarbonyl, (v) a 5- to 10-membered aromatic heterocyclylcarbonyl group optionally tuted by 25 alkyl optionally substituted by 1 to 3 halogen atoms, (vi) benzylcarbonyl optionally tuted by 1 to 3 substituents selected from the group consisting of a halogen atom and alkoxy, 30 (vii) arylsulfonyl optionally substituted by alkoxy, (viii) cycloalkylalkylsulfonyl optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl and oxo, (ix) a 5- to 10-membered aromatic 35 heterocyclylsulfonyl group optionally substituted by 1 to 3 alkyl, and (x) –C(=N-CN)-SR9 wherein R9 is alkyl, or a salt thereof. 5
9. The compound of claim 1, wherein R3 is a group of the formula wherein Y1, Y2, Y3, Y4, W and R24 are as defined in claim 1, or a salt thereof.
10. The compound of claim 1, wherein R3 is a group of the N N N N N N H (H) (J) wherein R28 and R29 are as d in claim 1, or a salt 15 thereof.
11. The compound of claim 1, wherein R3 is a group of the formula X6 X6 X7 X7 X8 or X8 N X5 N X5 R10 R10 20 wherein X5, X6, X7, X8 and R10 are as defined in claim 1, or a salt thereof.
12. The compound of claim 1, wherein R3 is a group of the formula R16a 5 S wherein R16a is (a) alkyl optionally substituted by 1 to 3 substituents ed from the group consisting of cyano, alkylamino and dialkylamino, 10 (b) alkenyl optionally substituted by carboxy, (c) formyl, (d) carboxy, (e) carbamoyl, (f) –C(R17)=N-OH wherein R17 is a hydrogen atom, cyano or 15 hydroxy, (g) a 5- to 10-membered aromatic heterocyclic group ally substituted by alkyl, alkoxycarbonyl, carboxy or phenyl, or (h) cyano, 20 or a salt thereof.
13. The compound of claim 1, n R3 is a group of the formula R19a R18aO 25 n R18a is alkyl, and R19a is (a) a halogen atom, (b) cyano, (c) alkyl optionally substituted by 1 to 3 substituents selected from the group consisting of (i) a halogen atom, (ii) cyano, (iii) hydroxy, 5 (iv) amino, (v) alkylamino, (vi) dialkylamino, and (vii) a cyclic amino group optionally substituted by alkyl, 10 (d) alkoxy, (e) amino ally tuted by 1 or 2 substituents selected from the group consisting of (i) alkylcarbonyl optionally substituted by a cyclic amino group, 15 (ii) alkylsulfonyl, (iii) carbamoyl, and (iv) alkyl or cycloalkyl, (f) y, (g) alkoxycarbonyl, 20 (h) carbamoyl optionally tuted by alkyl optionally substituted by amino, alkylamino, dialkylamino or alkoxycarbonylamino, (i) formyl, (j) a 5- to 10-membered aromatic heterocyclic group 25 optionally substituted by alkyl, (k) –CH=N-OR21 wherein R21 is a hydrogen atom or alkyl optionally substituted by alkylamino or dialkylamino, or (l) nitro, 30 or a salt thereof.
14. The compound of claim 1, wherein R3 is a group of the formula wherein R30 is as defined in claim 1, or a salt thereof.
15. The compound of claim 1, wherein R3 is naphthyl or 5 isochromenyl, or a salt thereof.
16. The compound of claim 1, wherein R3 is quinolyl or isoquinolyl, or their oxide derivatives, or a salt thereof. 10
17. The compound of claim 1, wherein R is a hydrogen atom, or a salt thereof.
18. The compound of claim 1, wherein R1 is ropyl, 2- fluorocyclopropyl or 2,4-difluorophenyl, or a salt thereof.
19. The compound of claim 1, wherein R2 is methyl, methoxy or a chlorine atom, or a salt f.
20. The compound of claim 1, which is a compound represented 20 by the formula O O H2N N , or a salt thereof.
21. The nd of claim 1, which is a compound represented 25 by the formula O O N N H2N N , or a salt thereof.
22. The compound of claim 1, which is a compound represented 5 by the formula O O H , or a salt thereof.
23. The compound of claim 1, which is a compound ented 10 by the formula O O N N N N or a salt thereof.
24. The compound of claim 1, which is a compound represented 15 by the formula O O N N N Me Cl , or a salt thereof.
25. The compound of claim 1, which is a compound represented by the formula O O H2N N F , or a salt thereof. 5
26. The compound of claim 1, which is a compound represented by the formula O O O N N H , or a salt thereof. 10
27. The compound of claim 1, which is a compound represented by the formula O O N N N Cl , or a salt thereof. 15
28. The compound of claim 1, which is a compound represented by the a O O H2N N F , or a salt thereof.
29. The compound of claim 1, which is a nd represented by the formula O O N N N Cl , or a salt thereof.
30. A pharmaceutical composition comprising a compound of any one of claims 1 to 29 or a salt thereof and a ceutically acceptable carrier. 10
31. An antimicrobial agent comprising a compound of any one of claims 1 to 29 or a salt thereof.
32. A compound of any one of claims 1 to 29 or a salt thereof for use as a medicament.
33. A compound of any one of claims 1 to 29 or a salt thereof for use as an antimicrobial agent.
34. A compound of any one of claims 1 to 29 or a salt thereof 20 for use in the prevention or treatment of a bacterial infection.
35. Use of a nd of any one of claims 1 to 29 or a salt thereof for the manufacture of a medicament for preventing or treating a bacterial infection.
36. A compound of claim 1, substantially as herein described with reference to any one of the accompanying examples and/or figures. 30
37. The ceutical ition of claim 30, substantially as herein described with reference to any one of the accompanying examples and/or figures.
38. The antimicrobial agent of claim 31, substantially as herein described with reference to any one of the accompanying examples 5 and/or figures.
39. The use of claim 35, substantially as herein described with nce to any one of the accompanying examples and/or figures.
NZ620447A 2011-08-31 2012-08-30 Quinolone compound NZ620447B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CNPCT/CN2011/001477 2011-08-31
CN2011001477 2011-08-31
CN2012001044 2012-08-06
CNPCT/CN2012/001044 2012-08-06
PCT/CN2012/080753 WO2013029548A1 (en) 2011-08-31 2012-08-30 Quinolone compound

Publications (2)

Publication Number Publication Date
NZ620447A NZ620447A (en) 2016-02-26
NZ620447B2 true NZ620447B2 (en) 2016-05-27

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