WO2005049602A1 - Quinolone antibacterial agents - Google Patents

Quinolone antibacterial agents Download PDF

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Publication number
WO2005049602A1
WO2005049602A1 PCT/IB2004/003666 IB2004003666W WO2005049602A1 WO 2005049602 A1 WO2005049602 A1 WO 2005049602A1 IB 2004003666 W IB2004003666 W IB 2004003666W WO 2005049602 A1 WO2005049602 A1 WO 2005049602A1
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Prior art keywords
methyl
cyclopropyl
oxo
dihydro
carboxylic acid
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PCT/IB2004/003666
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French (fr)
Inventor
Edmund Lee Ellsworth
Clarke Bentley Taylor
Sean Timothy Murphy
Mark Ryan Rauckhorst
Jeremy Tyson Starr
Kim Marie Hutchings
Chris Limberakis
Denton Wade Hoyer
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Warner-Lambert Company Llc
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Publication of WO2005049602A1 publication Critical patent/WO2005049602A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds bearing a quinolone core structure which exhibit antibacterial activity, methods for their preparation, as well as pharmaceutically acceptable compositions comprising such compounds.
  • Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections pose an increasing burden for health care systems worldwide. As a result, alternative and improved agents are needed for the treatment of bacterial infections, particularly for the treatment of infections caused by resistant strains of bacteria.
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Rj is (Ci-Qdalkyl, halo(C 1 -C 6 )alky], (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl;
  • R 2 is OH
  • R 2e and R 2e' are each independently H or (C 1 -C 6 )alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X] and Y] are each independently NH or O;
  • R 3 , R 4 , and R 5 are each independently H, OH, halo, NRyR z , wherein R y and R 2 are each independently H or (Q- C 6 )alkyl,
  • R ⁇ and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C 1 -C 6 )alkyl; and
  • R' ( R", R'", and R"" are each independently H, (Q-Q alkyl, -OCQ-QOalkyl, haloCd-C ⁇ alkyl, aryl,or heteroaryl;
  • R' is not -O(C 1 -C 6 )alkyl, and wherein "- ⁇ " indicates the point of attachment;
  • R c and R d are each independently H, (C 1 -C 6 )alkylnitrile
  • R 2a R2a' — (CR 2a R2a')g-0 QR 2b f wherein g is an integer from to 10j Q is as defined above, and R 2a and R 2a > are each independently H or (C 1 -C 6 )alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R 2 is ( -C ⁇ alkyl, aryl, or heteroaryl,
  • TMTM indicates the point of attachment
  • p is 0 or 1
  • R 2c is H
  • R2a, R2b, and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C ⁇ -
  • R 2 d and R 2e are each independently H, (Ci-C ⁇ alkyl, or (C3-
  • R 2f and R 2 f are each independently H, (C ⁇ -Cg)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R 2g is (C 1 -C 6 )alkyl,
  • R e and R f are each independently H, C C ⁇ alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R g and R h are each independently H, alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.;
  • R j and R k are each independently H, (C 1 -C 6 )alkyl, haloalkyl, (d-C 6 )alkyl-
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Rj is (CrQ alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl;
  • R 2 is OH
  • R 2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR 2c R2d, wherein R 2c and R 2c j are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, or
  • TMTM indicates the point of attachment
  • 2a is as defined above
  • R 2e and R 2e - are each independently H or (d-C 6 )alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring
  • e is an integer of from 1 to 10
  • p is an integer of from 2 to 10
  • Xi and Yi are each independently NH or O
  • R 3 , R 4 , and R 5 are each independently H, halo
  • R y and R z are each independently H or ( - ) alkyl, ( -Q alkyl, halo(C C 6 )alkyl, O(C 1 -C 6 )alkyl, O(C r C 6 )haloalkyl, nitrile;
  • Ri and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C C 6 )alkyl; and
  • z is O, 1, or 2;
  • R' is H
  • R c is H, (C 1 -C 6 )alkylnitrile
  • R 2b is (C 1 -C 6 )alkyl, aryl, or heteroaryl
  • R2a 5 R2b > and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C!- C6»2, or NR 2d R 2e , wherein R 2d and R 2e are each independently H, (C ⁇ -C6)alkyl, or (C3-
  • R 2 f and R 2 f are each independently H, (Cj-C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a
  • R 2g is
  • R e and Rf are each independently H, -C ⁇ alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a
  • R g and Rh are each independently H, C t -C ⁇ alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Ri is (CrC 6 )alkyl, halo(C 1 -C 6 )alkyl,
  • R 2 is OH, OBF 2
  • R 2a is as defined above, n is an integer of from 2 to 10
  • Y is OH or NR 2c R 2 d, wherein R 2c and R 2 d are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C6)cycloalkyl, or
  • R 2e and R 2e - are each independently H or ( -C ⁇ alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X 1 and Y] are each independently NH or O;
  • R 3 , R , and R 5 are each independently H, halo,
  • R y and R z are each independently H or ( -C ⁇ ) alkyl
  • R x and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C ⁇ -C 6 )al yl; and
  • z is O, l, or 2;
  • R' is H
  • R a and R b are each independently H, (C 1 -C 6 )alkyl, ( -C ⁇ alkoxy, haloC -
  • Rc is H
  • R 2c is H
  • R2 a> 2 b> and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C ⁇ -
  • R 2d and R 2e are each independently H, (C ⁇ -C6)alkyl, or (C3-
  • R 2 f and R 2f are each independently H, (C ⁇ -C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2 g is
  • R e and R f are each independently H, Ci-C 6 alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R g and R h are each independently H, -C ⁇ alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R j and R k are each independently H, (C ⁇ -C6)alkyl, haloalkyl, (C 1 -C 6 )alkyl-
  • the invention is also directed to a compound of formula IV:
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • R t is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl;
  • R 2 is OH, OBF 2
  • R 2e and R 2e - are each independently H or (C 1 -C 6 )alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X ⁇ and
  • Y] are each independently NH or O;
  • R 3 , R 4 , and R 5 are each independently H, halo,
  • R y and R z are each independently H or ( - C 6 )alkyl
  • Ri and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (d-C ⁇ alkyl; and
  • z 0, 1, or 2;
  • R a and R b are each independently H, ( -C ⁇ alkyl, (C 1 -C 6 )alkoxy, haloC - C 6 )alkyl, halo, or R a and R b taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
  • R' is H, halo
  • R c and R d are each independently H
  • R 2b is (C 1 -C 6 )alkyl, aryl, or heteroaryl
  • TM ⁇ indicates the point of attachment
  • p is 0 or 1
  • R 2c is H, (C 1 -C 6 )alkyl
  • R 2a , R 2b , and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C ⁇ -
  • R 2d and R 2e are each independently H, (C; ⁇ -C(j)alkyl, or (C3-
  • R 2g is
  • R e and R f are each independently H, C C 6 alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a
  • X is N or C, provided that when X is N, R 5 is absent at that position;
  • Rj is (Q-Q alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, heterocyclic, aryl, heteroaryl; and CH 2 (C 3 -C 6 )cycloalkyl; R 2 is OH,
  • OCd-C ⁇ alkyl O(C 3 -C 6 )cycloalkyl, O 0-(CHR 2a ) m -0 Q R 2b 5 wherein m is an integer from 1 to 10, Q is O or NH or N(C 1 -C 6 )alkyl or is absent, and R 2a is H or (C 1 -C 6 )alkyl and R 2b is aryl, or heteroaryl, 0-(CHR 2a ) n -Y ⁇ wherein R 2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR 2o R 2 d, wherein R c and R 2 d are each independently H, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, or NR 2a , wherein R 2a is as defined above,
  • R 2e and R 2e > are each independently H or ( -C ⁇ alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X ⁇ and Yi are each independently NH or O;
  • R 3 , R_ ⁇ , and R 5 are each independently H, halo,
  • R y and R z are each independently H or ( - C 6 )alkyl, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, O(C ⁇ -C 6 )haloalkyl, nitrile; R ⁇ and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- pr 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO 2 , or NR X , wherein R x is H or (C 1 -C 6 )alkyl; and
  • q is 0, 1, 2, or 3 and z is 0, 1, or 2;
  • R b is H, ( -C ⁇ alkyl, haloCd-C ⁇ alkyl, halo, or R a and R b taken together with the carbon to which they are attached form a 3,4,5 or 6- membered substituted or unsubstituted ring;
  • R', R", R'", and R" are each independently H, (d-C 6 ) alkyl, -O(C C 6 )alkyl, haloCQ-C f alkyl, aryl, or heteroaryl;
  • R c and R d are each independently H, (C 1 -C 6 )alkylnitrile
  • R 2b is (C ⁇ -C 6 )alkyl, aryl, or heteroaryl
  • R 2c is H, (C ⁇ -C 6 )alkyl, O(C ⁇ -C 6 )alkyl, (C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
  • R 2a , R 2b , and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH) 2 , OPO(O(C!-
  • R 2d and R 2e are each independently H, (C ⁇ -C6)alkyl, or (C3-
  • R 2f and R 2f are each independently H, (C ⁇ -C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R 2g is
  • R e and R f are each independently H, Q-C ⁇ alkyl, haloalkyl, halo, or R e and
  • R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R g and R h are each independently H, CrC 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R g and R h are each independently H, CrC 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring
  • R g and R h are each independently H, CrC 6 alkyl, haloalky
  • R j and R are each independently H, (Q-C ⁇ alkyl, haloalkyl, (C 1 -C 6 )alkyl-
  • a pharmaceutical formulation comprising a compound of one of formula I, ⁇ , HI, IV, V, or VI admixed with a pharmaceutically acceptable diluent, carrier, or excipient.
  • What is also provided is a method of treating a bacterial infection in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula I, ⁇ , HI, IV, V, or VI.
  • alkyl refers to a linear or branched hydrocarbon of from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • the alkyl group can also be substituted with one or more of the substituents selected from lower (C ⁇ -C( ) )alkoxy, (Cj-C ⁇ thioalkoxy, halogen, aryl, heteroaryl, oxo, thio, -OH, -SH, -F, -CF ,- OCF 3 , -NO 2 , -CO 2 H, -CO 2 (C ⁇ -C 6 )alkyl, or — O,
  • (C 3 -C 6 )cycloalkyl means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Where possible, the cycloalkyl group may contain double bonds, for example, 3-cyclohexen-l-yl.
  • the cycloalkyl ring may be unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, for yl, carboxyl, -CO2(Ci -C ⁇ alkyl, -CO(C ⁇ -C6)alkyl, aryl, heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein, or as indicated above for alkyl.
  • substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, for yl, carboxyl, -CO2(Ci -C ⁇ alkyl, -CO(C ⁇ -C6)alkyl, aryl, heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein, or as indicated above for alkyl.
  • substituted cycloalkyl groups include fluorocycl
  • halo includes chlorine, fluorine, bromine, and iodine.
  • haloalkyl means a (Cj-C ⁇ lkyl group substituted with one or more halo.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, and being unsubstituted or substituted with one or more of the substituent groups recited above for alkyl groups including, halogen, nitro, cyano
  • Examples include, but are not limited to phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxy ⁇ henyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3- chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 5- chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthreny
  • heteroaryl means an aromatic cyclic or polycyclic ring system having from 1 to 4 heteroatoms selected from N, O, and S.
  • Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5- 1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2- pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-
  • heteroaryl groups may be unsubstituted or substituted by 1 to 3 substituents selected from those described above for alkyl, alkenyl, and alkynyl, for example, cyanothienyl and formylpyrrolyl.
  • Preferred aromatic fused heterocyclic rings of from 8 to 10 atoms include but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • Heteroaryl also includes 2- and 3- aminomethylfuran, 2- and 3- aminomethylthiophene and the like.
  • heterocyclic means a monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring systems.
  • Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S, and preferably from 3 to 7 member atoms, in the ring.
  • Bicyclic heterocyclics contain from about 5 to about 17 ring atoms, preferably from 5 to 12 ring atoms.
  • Bicyclic heterocyclic rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein the substituents are those described above for the alkyl and cycloalkyl groups.
  • Typical substituted cyclic ethers include propyleneoxide, phenyloxirane (styrene oxide), cis-2-butene-oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofuran, 2,6-dimethyl- 1,4-dioxane, and the like.
  • Heterocycles containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-l-yl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro- l,3-dithiol-2-yl, and hexahydrothiophen-4-yl and substituted groups such as aminomethyl thiophene.
  • heterocycles include dihydro- oxathiol-4-yl, dihydro-lH-isoindole, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro- oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene.
  • protecting groups may have been used to allow synthetic manipulation of one functional group in the presence of other functional groups.
  • the appropriate use and choice of protecting groups is well-known by one skilled in the art. It is also to be understood that such groups not only serve to protect chemically reactive sites, but also to enhance solubility or otherwise change physical properties.
  • a good general reference for protecting group preparation and deprotection is Greene, Theodora, Protective Groups in Organic Synthesis; Wiley: New York, USA, 1991 and later editions.
  • invention compounds characterized by the presence of a protecting group as disclosed and described in Greene are also to be considered invention compounds.
  • ⁇ When a bond is represented by a line such as " ⁇ " this is meant to represent that the bond is the point of attachment between two molecular subunits.
  • patient means all mammals, including humans. Other examples of patients include cows, dogs, cats, goats, sheep, pigs, and rabbits.
  • a “therapeutically effective amount” is an amount of a compound of the present invention that, when administered to a patient, provides the desired effect; i.e., lessening in the severity of the symptoms associated with .a bacterial infection. It will be appreciated by those skilled in the art that compounds of the invention having one or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, geometric, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity or cytotoxicity using the standard tests described herein, or using other similar tests which are well known in the art. Certain compounds of the invention are also useful as intermediates for preparing other compounds of the invention. Thus, a compound wherein R 2 is BF 2 , can be hydrolyzed to form another compound of the invention wherein R 2 is H.
  • pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S.M. et. al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19).
  • the acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine,
  • N-methylgluc amine N-methylgluc amine
  • procaine see, for example, Berge S.M., supra., 1977.
  • the base addition salts of said acidic compounds are prepared by contacting the free acid orm with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • a “prodrug” is an inactive derivative of a drug molecule that requires a chemical or an enzymatic biotransformation in order to release the active parent drug in the body.
  • a specific value for X is C or N.
  • a specific value for R] is (C ⁇ -
  • a specifc value for R 3 is H or NH .
  • a specific value for R is H or halo.
  • a specific value for R5 is halo, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoro ethoxy, or trifluoromethoxy when X is C.
  • a specific value for X is C or N.
  • a specific value for ⁇ is cyclopropyl or fluorocyclopropyl.
  • a specific value for R 3 is H or NH 2 .
  • a specific value for R 4 is H or F.
  • a specific value for X is C or N.
  • a specific value for R 5 is halo, methyl, or methoxy.
  • R l3 R 3 , and R5 are as provided in the following structures, wherein R 2 is OH, OBF 2 , or O(C ⁇ -C 6 )alkyl,
  • A is or 2. Specifically, z is 0, 1, 2, when q is 2 or 3; alternatively, z is 1 or 2 when q is 0, 1, 2, or 3.
  • R', R", R'", and R"" each independently can be H, (Q- C 6 )alkyl, -O(C 1 -C 6 )alkyl, halo(C 1 -Ce)alkyl, aryl,or heteroaryl. More specifically, R', R", R 1 ", and R”" are each independently H, fluoro, methyl, ethyl, flouromethyl, fluoroethyl, phenyl, benzyl, or methoxy.
  • B is R f R e R - R W
  • R' is not -O(C ⁇ -C 6 )alkyl.
  • R c and R each independently can be H, (C 1 -C 6 )alkylnitrile,
  • R c and R each independently are H, methyl, or ethyl.
  • R e and R f each independently can be H, -C ⁇ alkyl, haloalkyl, halo, or R e and R f taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, R e and R f each independently are H, methyl, or ethyl.
  • R g and Rh each independently can be H, Ci-C 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, R g and R h each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl, carboxyethyl, or O )
  • R j and R k each independently can be H, ( -C ⁇ alkyl, haloalkyl, (d-C 6 )alkyl-NR c R d , (C 1 -C 6 )alkyl-OR c , aryl, heteroaryl, heterocycle,
  • R d O (C-i -C 6 )alkyl Z— R d ⁇ wherein z is 0 or j ⁇ or Rj and Rk tB ⁇ sa together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, Rj and R k each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl,
  • B can or
  • B can have any of the following structures:
  • R is CH 2 CH 2 CN.
  • R is CH 2 CN.
  • R is CH 2 CH 2 CN. Also given the description of A and B, encompasses any of the following structures r
  • R c is H or (C 1 -C 6 )alkyl and R is CH 2 CN.
  • compounds of the present invention are characterized by a quinolone core, covalently bound to a C-7 sidechain , 0 r .
  • the invention compounds can be prepared via coupling of a suitably C-7 substituted quinolone core, wherein X 2 is halo, triflate, or a similar reactive group known to the skilled artisan, and an appropriately substituted azetidine, pyrollidine, piperidine.
  • the first part describes the synthesis of the requisite quinolone core precursors.
  • the second part describes the synthesis of the requisite C-7 sidechain precursors.
  • 3-(l- tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-l-carboxylic acid tert-butyl ester was prepared from 3-formyl-pyrrolidine-l -carboxylic acid tert-butyl ester by the addition of lithiated isopropylcyanide to the intermediate a- amidoalkyl sulfone.
  • the compound was prepared as provided in WO 96/39407.
  • cyclopenta[c]pyrrol-3a-ylmethyl)-carbamic acid tert-butyl ester Alternatively, if the reduction of the ester moiety in 2-benzyl-hexahydro- cyclopenta[c]pyrrole-3a-carboxylic acid methyl ester is stopped at the aldehyde oxidation state (for example, by employing DIBALH as the reducinig agent), a reductive amination using ammonium formate or a primary alkyl amine such as methyl or ethyl amine can be employed to provide the aminated product. Reductive amination conditions and reagents are readily known to the skilled artisan.
  • Coupling of the sidechain precursor to the quinolone core precursor to provide the compounds of the present invention or precursors to compounds of the present invetnion can occur from either the core precursor as the free acid, alkyl ester, or borate ester, as depicted in Scheme II.
  • a molar excess of the side chain precursor is combined with the quinolone core in a polar solvent such as acetonitrile.
  • a molar excess of an amine base such as triethylamine is added, and the reaction mixture is heated to about 80 °C.
  • the reaction mixtures becomps homogenous.
  • the mixture is heated for sufficient time to drive the raction to completion, typically from about 3 to about 12 hours.
  • the mixture is then worked up according to procedures widely uused by the skilled artisan to provide a compound of the invention.
  • the quinolone core, sidechain, and triethylamine are combined in a solvent such as acetonitrile.
  • the resulting reaction mixture is heated to 80 °C and stirred for 12 hours, is heated to about 80 °C.
  • the reaction mixtures becomes homogenous.
  • the mixture is heated for sufficient time to drive the raction to completion, typically from about 3 to about 12 hours.
  • the mixture is then worked up according to procedures widely uused by the skilled artisan to provide a compound of the invention.
  • the requisite borate ester is typically prepared from the free acid upon reaction with BF 3 according to conditions available to the skilled artisan.
  • the borate ester is typically combined with the side chain in a solvent such as acetonitrile and treated with an amine base such as triethylamine.
  • a solvent such as acetonitrile
  • an amine base such as triethylamine.
  • the resulting reaction mixture is typically stirred at room temperature for sufficient time to drive the reaction to completion, typically from about 24 to about 96 hours.
  • the mixture is then worked up according to procedures widely used by the skilled artisan (i.e., deprotection of the borate ester in ethanol in the presence of triethylamine) to provide a compound of the invention.
  • Coupling of the sidechain precursors to the quinolone core precursors may give rise to invention compounds.
  • post-coupling transformations may be necessary to give rise to invention compounds.
  • Typical post-coupling transformation include deprotection of protected amines to provide invention compounds of formula TJ, as depicted in Scheme IH. Deprotection, as well as reaction with acrylonitrile or the like, gives rise to invention compounds of formulas III and IV.
  • the present invention also provides pharmaceutical compositions which comprise a bioactive invention compound or a salt such or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.
  • the compositions include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in mammals including humans.
  • the compounds, such as antibiotic compounds, also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other bioactive agents such as antibiotics. Such methods are known in the art and are not described in detail herein.
  • the composition can be formulated for administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parenteral.
  • the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also.contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present, for example, from about 1% up to about 98% of the formulation. For example, they may form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods will known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain, for example, from about 0.1% by weight, e.g., from about 10-60% by weight, of the active material, depending on the method of administration.
  • each unit will contain, for example, from about 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will range, for example, from about 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to 50 mg/kg per day.
  • the dosage is, for example, from about 5 to 20 mg/kg per day.
  • the invention compounds can be screened to identify bioactive molecules with different biological activities using methods available in the art.
  • the bioactive molecules for example, can possess activity against a cellular target, including but not limited to enzymes and receptors, or a microorganism.
  • a target cellular ligand or microorganism is one that is known or believed to be of importance in the etiology or progression of a disease.
  • diseases states for which compounds can be screened for biological activity include, but are not limited to, inflammation, infection, hypertension, central nervous system disorders, and cardiovascular disorders.
  • the invention provides methods of treating or preventing a bacterial infection in a subject, such as a human or other animal subject, comprising administering an effective amount of an invention compound as disclosed herein to the subject.
  • an "infectious disorder” is any disorder characterized by the presence of a microbial infection, such as bacterial infections.
  • infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • the compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically.
  • Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration.
  • the specific dosage of antimicrobial to be administered, as well as the duration of treatment, may be adjusted as needed.
  • the compounds of the invention may be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms.
  • Gram positive and Gram negative aerobic and anaerobic bacteria including Staphylococci, for example S. aureus; Enterococci, for example E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.
  • Other examples include Mycobacteria, for example M. tuberculosis; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example M. pneumoniae.
  • the ability of a compound of the invention to inhibit bacterial growth, demonstrate in vivo activity, and enhanced pharmacokinetics are, demonstrated using pharmacological models that are well known to the art, for example, using models such as the tests described below.
  • Test A Antibacterial Assays
  • the compounds of the present invention were tested against an assortment of Gram-negative and Gram-positive organisms using standard microtitration techniques (Cohen et. al., Antimicrob., 1985;28:766; Heifetz, et. al., Antimicrob., 1974;6:124). The results of the evaluation are shown in Tables IA and B.
  • N-(l-Benzhydryl-3-ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide (3.67 g) was hydrogenated (Pd/C in 100 mL MeOH) with one equivalent of HCl overnight to give 2.40 g, (100 % yield) of the title compound which was used without purification.
  • Ammonium acetate (6.00 g, 77.8 mmol) was added to a mixture of 1-(1- benzhydryl-azetidin-3-yl)-propan-l-one (2.59 g, 9.27 mmol) and 4 angstrom molecular sieves (2.60 g) in methanol (80 mL). The mixture was cooled to 0 °C, and sodium cyanoborohydride (1.17 g, 18.5 mmol) was added in several portions.
  • NN-Dibenzylacrylamide (79.5 g, 0.317 mol) and ⁇ -(methoxymethyl)- ⁇ - (trimethylsilylmethyl)- ⁇ -methylbenzylmine (103 g, 0.412 mol) were dissolved in CH 2 C1 2 (1500 mL) and cooled to 0 °C.
  • Trifluoroacetic acid solution 1.0 M in CH 2 C1 2 , 27 mL was added over a period of 20 minutes and the resulting reaction mixture was stirred at room temperature overnight. The mixture was washed with aqueous NaHCO 3 , brine, dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography (heptane-EtOAc-Et 3 N/10:2:0.1) to furnish 97.7 g of the title compound (77% yield) as a mixture of two diasteromers.
  • EtMgBr ethylmagnesium bromide
  • EtMgBr (3.0 M in ether, 150 mL, 0.450 mol) was added followed by the rapid addition of Ti(OzPr) 4 (54.6 g, 55.6 mL, 0.192 mol) in THF (150 mL). The resulting mixture was stirred at room temperature for 1.0 hour before it was quenched with aqueous ammonium chloride (3000 mL) and water (800 mL). The mixture was filtered through Celite, rinsed with ether. The organic layer was separated. The aqueous layer was made basic (pH ⁇ 8.5) with aqueous NaOH and extracted with ether.
  • the phthalimide (5.00g, 14.9 mmol) was taken up in isopropyl alcohol and charged with hydrazine hydrate (7.04g, 149 mmol). The resulting solution was heated to 60 °C. After 1 hour a colorless precipitate had formed. The reaction was diluted with isopropyl alcohol and filtered. The filter cake was washed with isopropyl alcohol and the combined filtrates were concentrated to give an off white oily solid.
  • reaction was then quenched with saturated aqueous ammonium chloride (NE C1) and extracted twice with CH 2 C1 2 .
  • the organic phase was washed with saturated aqueous NaHCO 3 , then dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Diastereomer B (2.1 g) was separated by chiral HPLC using a ChiralPak AD column eluted with a methanol/ethanol gradient to give 0.87 g of isomer Bl (41%) and 0.53 g of isomer B2 (25%).
  • the solid was further purified via preparatory high performance liquid reverse phase chromatography eluting with a gradient of water (0.1% formic acid): acetonitrile (0.1% formic acid) (95:5 to 50:50) to afford a yellow residue.
  • the residue was dissolved in a minimum amount of water and lyophilized to deliver 19 mg (20%) of the title compound as a yellow solid.
  • the compound was approximately 75% parent and 25% formate salt by 1H NMR.
  • LC/MS (APCI) 427.2; HPLC purity 100%.
  • the invention compound, lactose, and com starch (for mix) are blended to uniformity.
  • the corn starch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human from one to four times a day for treatment of pathogenic bacterial infections.
  • Sorbitol Solution (70 % N.F.) 40 mL
  • the sorbitol solution is added to 40 mL of distilled water, and the invention compound is dissolved therein.
  • the saccharin, sodium benzoate, flavor, and dye are added and dissolved.
  • the volume is adjusted to 100 mL with distilled water.
  • Each milliliter of syrup contains 4 mg of invention compound.

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Abstract

Compounds of formula (I) wherein A is formula (II), formula (III) or formula (IV), and B is formula (V), formula (VI), or formula (VII), can be used in a variety of applications including use as antibacterial agents.

Description

QUINO ONE ANTIBACTERIAL AGENTS
FIELD OF THE INVENTION The invention relates to compounds bearing a quinolone core structure which exhibit antibacterial activity, methods for their preparation, as well as pharmaceutically acceptable compositions comprising such compounds.
BACKGROUND OF THE INVENTION Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. The morbidity, mortality, and financial costs of such infections pose an increasing burden for health care systems worldwide. As a result, alternative and improved agents are needed for the treatment of bacterial infections, particularly for the treatment of infections caused by resistant strains of bacteria.
SUMMARY OF THE INVENTION These and other needs are met by the present invention, which is directed to a compound of formula I:
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, provided that when X is N, R5 is absent at that position;
Rj is (Ci-Qdalkyl, halo(C1-C6)alky], (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, heterocyclic, aryl, heteroaryl; and CH2(C3-C6)cycloalkyl;
R2 is OH,
OBF2
O(C C6)alkyl, O(C3-C6)cycloalkyl,
0 0-(CHR2a)m-0 QR2b 5 wherein m is an integer from 1 to 10, Q is O or NH or N(C1-C6)alkyl or is absent, and R2a is H or (CrC6)alkyl and R2b is (C1-C6)alkyl, aryl, or heteroaryl, O— (CHR2a)n— Y s wherein R2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2d are each independently H, (C1-C6)alkyl, or (C3-C6)cycloalkyl, or NR a, wherein R2 is as defined above,
Figure imgf000003_0001
, wherein " ~ " indicates the point of attachment, 2a is as defined above, R2e and R2e' are each independently H or (C1-C6)alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X] and Y] are each independently NH or O;
R3, R4, and R5 are each independently H, OH, halo, NRyRz, wherein Ry and R2 are each independently H or (Q- C6)alkyl,
(C C6)alkyl, halo(Cι-C6)alkyl, O(C1-C6)alkyl,
O(Cι- )haloalkyl, nitrile;
R} and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO2, or NRX, wherein Rx is H or (C1-C6)alkyl; and
, wherein z is 0, 1, or 2
Figure imgf000004_0001
Ra and R are each independently H, (C1-C6)alkyl, (C1-C6)alkoxy, halo(Cr C6)alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form C=O, C=NO(C1-C6)alkyl, or a 3,4,5 or 6-membered substituted or unsubstituted ring;
R'( R", R'", and R"" are each independently H, (Q-Q alkyl, -OCQ-QOalkyl, haloCd-C^alkyl, aryl,or heteroaryl;
and B is
Figure imgf000005_0001
provided that when B is
Figure imgf000005_0003
i inn
Figure imgf000005_0002
n orr , R' is not -O(C1-C6)alkyl, and wherein "-^ " indicates the point of attachment;
Rc and Rd are each independently H, (C1-C6)alkylnitrile;
Figure imgf000005_0004
o
— P-0(C C6)alkyl 0(CrC6)alkyl
(C,-C6)a]kyl, (C3-C6)cycloalkyl, heteroaryl, SO2-(Cι-C6)alkyl,
SO2-aryl, SO2-heteroaryl,
O
— (CR2aR2a')g-0 QR2b f wherein g is an integer from to 10j Q is as defined above, and R2a and R2a> are each independently H or (C1-C6)alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R2 is ( -C^alkyl, aryl, or heteroaryl,
O O
(CR2aR2a.)g-0-P-(OH)2 or (CR2aR2a.)g-0-P-(0(C C6)alkyl)2 wherein R2a and R2a-are as defined above,
Figure imgf000006_0001
, wherein " ™™ " indicates the point of attachment, p is 0 or 1, and R2c is H,
(Ci-Ctøalkyl, O(C1-C6)alkyl,
(C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
O -(CHR2a)h-C-LQR2b of -(CHR2a)j-Y ^ fhβ[ώ
R2a, R2b, and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH)2, OPO(O(Cχ-
C ))2, or NR2dR2e, wherein R2d and R2e are each independently H, (Ci-Cβ alkyl, or (C3-
C7)cycloalkyl,
Figure imgf000006_0002
, wherein q is 0 or 1 , R2f and R2f are each independently H, (Cι-Cg)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2g is (C1-C6)alkyl,
(C3-C7)cycloalkyl, aryl, or heterocyclo, or heteroaryl;
Re and Rf are each independently H, C Cβ alkyl, haloalkyl, halo, or Re and Rf taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
Rg and Rh are each independently H,
Figure imgf000007_0001
alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.; and
Rj and Rk are each independently H, (C1-C6)alkyl, haloalkyl, (d-C6)alkyl-
NRcRd, ( -C^alkyl-ORc, aryl, heteroaryl, heterocycle,
O (C^ -C6)alkyl Z— Rd ? wher n z is O or NRC, or Rj and Rk taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.
What is' also provided is a compound of formula II:
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, provided that when X is N, R5 is absent at that position; Rj is (CrQ alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, heterocyclic, aryl, heteroaryl; and CH2(C3-C6)cycloalkyl;
R2 is OH,
OBF2
O(C1-C6)alkyl,
O(C3-C6)cycloalkyl,
O 0-(CHR2a)m-0 QR2b 5 wherein m is an integer from 1 to 10, Q is O or NH or N(C1-C6)alkyl or is absent, and R2a is H or
(C1-C6)alkyl and R2b is (C1-C6)alkyl, aryl, or heteroaryl, O— (CHR2a)n— Y 5 herein R2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2cj are each independently H, (C1-C6)alkyl, or (C3-C6)cycloalkyl, or
NR2a, wherein R2a is as defined above,
Figure imgf000008_0001
ι wherein " ™™ " indicates the point of attachment, 2a is as defined above, R2e and R2e- are each independently H or (d-C6)alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and Xi and Yi are each independently NH or O; R3, R4, and R5 are each independently H, halo,
NRyRz, wherein Ry and Rz are each independently H or ( - ) alkyl, ( -Q alkyl, halo(C C6)alkyl, O(C1-C6)alkyl, O(CrC6)haloalkyl, nitrile;
Ri and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO2, or NRX, wherein Rx is H or (C C6)alkyl; and
z is O, 1, or 2;
R' is H,
( -Ce^lkyl, halo(C1-C6)alkyl, aryl, or heteroaryl;
Ra and Rb are each independently H, (Cι-C6)alkyl, (C1-C6)alkoxy, haloCC}- C6)alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form C=O, C=NO(C1-C6)alkyl, or a 3,4,5 or 6-membered substituted or unsubstituted ring;
Rc is H, (C1-C6)alkylnitrile; O
II
— P-OH OH ,
0 — P-0(C C6)alkyl 0(C C6)alkyl
( -Q alkyl, (C3-C6)cycloalkyl, heteroaryl,
SO2-(C1-C6)alkyl,
SO2-aryl, SO2-heteroaryl,
O — (CR2aR2a.)g-0 QR2b ^ wherein g is an integer from 1 to 10, Q is as defined above, and R a and R2a- are each independently
H or (C1-C6)alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R2b is (C1-C6)alkyl, aryl, or heteroaryl,
O O (CR2aR2a)g-0-P-(OH)2 or (CR2aR2a.)g-0-P-(0(C C6)alkyl)2 j wherein R2a and R2a-are as defined above,
Figure imgf000010_0001
, wherein " wι " indicates the point of attachment, p is 0 or 1, and R2c is H, (Cι-C6)alkyl,
O(Cι-C6)alkyl, (C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or o
-(CHR2a)h-θJL.QR2b or -(cH 2a)j- j Wherein
R2a5 R2b> and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH)2, OPO(O(C!- C6»2, or NR2dR2e, wherein R2d and R2e are each independently H, (Cι-C6)alkyl, or (C3-
C7)cycloalkyl,
Figure imgf000011_0001
, wherein q is 0 or l, R2f and R2f are each independently H, (Cj-C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a
3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2g is
(Cι -C6)alkyl,
(C3-C7)cycloalkyl, aryl, or heterocyclo, or heteroaryl;
Re and Rf are each independently H, -Cδ alkyl, haloalkyl, halo, or Re and Rf taken together with the carbon to which they are attached form a
3,4,5 or 6-membered substituted or unsubstituted ring; and
Rg and Rh are each independently H, Ct-Cβ alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.
What is also provided is a compound which is:
Figure imgf000012_0001
-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000012_0002
-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methyl-4- oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000012_0003
-{3-[(2-Cyano-ethyl)-methyl-amino]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000012_0004
-{3-[(2-Cyano-ethyl)-methyl-amino]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000013_0001
7-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl-4-oxo-l,4- dihydro-quinoline-3-carboxylic acid;
Figure imgf000013_0002
- { 3 - [(2-Cyano-ethyl)-methyl-amino] -pyrrolidin- 1 -yl } - 1 -cyclopropyl-8-methoxy- 4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000013_0003
- { 3- [(2-Cyano-ethyl)-methyl-amino] -pyrrolidin- 1 -yl } - 1 -cyclopropyl-8-methyl-4- oxo-1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000013_0004
9-[3-(2-Cyano-ethylamino)-cyclopentyl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro- 6H-l-oxa-3a-aza-phenalene-5-carboxylic acid; or
Figure imgf000014_0001
-{3-[(2-Cyano-ethyl)-methyl-amino]-cyclopentyl}-8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid.
What is also provided is a compound of formula III:
Figure imgf000014_0002
or a pharmaceutically acceptable salt thereof, wherein:
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, provided that when X is N, R5 is absent at that position;
Ri is (CrC6)alkyl, halo(C1-C6)alkyl,
(C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, heterocyclic, aryl, heteroaryl; and
CH2(C3-C6)cycloalkyl;
R2 is OH, OBF2
.O(CrC6)alkyl,
O(C3-C6)cycloalkyl,
O 0-(CHR2a)m-0 QR2 ^ wherein m is an integer from 1 to 10, Q is O or NH or N(C1-C6)alkyl or is absent, and R2a is H or
(C1-C6)alkyl and R2b is (Cι-C6)alkyl, aryl, br heteroaryl, 0-(CHR2a)n— Y ? wherein R2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2d are each independently H, (C1-C6)alkyl, or (C3-C6)cycloalkyl, or
NR2a, wherein R a is as defined above,
Figure imgf000015_0001
, wherein " ΛΛΛΛ " indicates the point of attachment, 2a is as defined above, R2e and R2e- are each independently H or ( -C^alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X1 and Y] are each independently NH or O;
R3, R , and R5 are each independently H, halo,
NRyRz, wherein Ry and Rz are each independently H or ( -Cβ) alkyl,
( -Cejalkyl, halo(C1-C6)alkyl,
OCd-C^alkyl,
O(C C6)haloalkyl, nitrile; Rx and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO2, or NRX, wherein Rx is H or (Cι-C6)al yl; and
z is O, l, or 2;
R' is H,
(CrC alkyl, -OC -Q alkyl, halo(Ci-C6)alkyl, aryl,or heteroaryl;
Ra and Rb are each independently H, (C1-C6)alkyl, ( -C^alkoxy, haloC -
C6)alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form C=O, C=NO(C C6)alkyl, or a 3,4,5 or 6-membered substituted or unsubstituted ring;
Rc is H,
(C1-C6)alkylnitrile;
O — P-OH
I
OH
O — P-0(C C6)alkyl 0(CrC6)alkyl
(C1-C6)alkyl, (C3-C6)cycloalkyl, heteroaryl, SO2-(Cι-C6)alkyl,
SO2-aryl, SO2-heteroaryl, 0 — (CR2aR2a')g-0 QR2b ^ wherein g is an integer from 1 to 10, Q is as defined above, and R2a and R2a- are each independently H or (C1-C6)alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R2b is (Cι-C6)alkyl, aryl, or heteroaryl,
O O
(CR2aR2a')g-0-P-(OH)2 or (CR2aR2a.)g-0-P-(0(C1-C6)alkyl)2j wherein R2a and R2a-are as defined above,
Figure imgf000017_0001
, wherein " ~«~ " indicates the point of attachment, p is 0 or 1, and
R2c is H,
(Cι-C6)alkyl,
O(Cι-C6)al yl,
(C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
O — (CHRzΛ-O-N-QRa, or —(CHR2a)j-Y , wherein
R2a> 2b> and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH)2, OPO(O(Cχ-
Cg))2, or NR2dR2e, wherein R2d and R2e are each independently H, (Cχ-C6)alkyl, or (C3-
C7)cycloalkyl,
Figure imgf000018_0001
, wherein q is 0 or 1, R2f and R2f are each independently H, (Cχ-C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2g is
(Ci-C^alkyl, (C3-C7)cycloalkyl, aryl, or heterocyclo, or heteroaryl;
Re and Rf are each independently H, Ci-C6 alkyl, haloalkyl, halo, or Re and Rf taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
Rg and Rh are each independently H, -Cβ alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring; and
Rj and Rk are each independently H, (Cι-C6)alkyl, haloalkyl, (C1-C6)alkyl-
NRcRd, (C1-C6)alkyl-ORc, aryl, heteroaryl, heterocycle,
O (C C6)alkyl— Z— Rd j wherein z is O or NRC, or Rj and Rk taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.
What is also provided is a compound which is
Figure imgf000019_0001
-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3 -carboxylic acid;
Figure imgf000019_0002
-{3R-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000019_0003
-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000019_0004
-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-pyrrolidin-l-yl)-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000020_0001
-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-pyrrolidin-l-yl)-l-cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000020_0002
- { 3-[ 1 -(2-Cyano-ethylamino)-ethyl]-pyrrolidin- 1 -yl } - 1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000020_0003
- { 3-[ 1 -(2-Cyano-ethylamino)-ethyl]-pyrrolidin- 1 -yl } - 1 -cyclopropyl-6-fluoro-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000020_0004
-(3-{l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000021_0001
-(3 - { 1 - [(2-Cyano-ethyl)-methyl-amino] -ethyl } -pyrrolidin- 1 -yl)- 1 -cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000021_0002
- { 3 - [(2-Cyano- 1 -methyl -ethyl amino)-methyl] -pyrrolidin- 1 -yl } - 1 -cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000021_0003
-{3-[(2-Cyano-l-methyl-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000021_0004
- { 3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l -yl } - 1 -cyclopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000022_0001
- { 3- [(2-Cyano-ethylamino)-methyl] -3 -methyl-pyrrolidin- 1 -yl } - 1 -cyclopropyl-6- fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000022_0002
7-(3-{ [(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000022_0003
7-(3-{ [(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000022_0004
7- { 3 -[ 1 -(2-Cyano-ethylamino)-cyclopropyl] -pyrrolidin- 1 -yl }- 1 -cyclopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000023_0001
7- { 3-[ 1 -(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin-l -yl } - 1 -cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000023_0002
7-(3- { 1 - [(2-Cyano-ethyl)-methyl-amino] -cyclopropyl } -pyrrolidin- 1 -yl)- 1 - cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000023_0003
7-(3-{ l- [(2-Cyano-ethyl)-methyl-amino] -cyclopropyl } -pyrrolidin- 1 -yl)- 1 - cycloρropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000023_0004
7- { 3-[2-Acetylamino- 1 -(2-cyano-ethylamino)-ethyl]-pyrrolidin- 1 -yl } - 1- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000024_0001
7-{3-[2-Acetylamino-l-(2-cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000024_0002
-(3-{2-Acetylarmno-l-[(2-cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000024_0003
-(3-{2-Acetylamino-l-[(2-cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000024_0004
7-{3-[(2-Cyano-ethylarnino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-8-methoxy- 4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000025_0001
-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-8-methyl-4- oxo-1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000025_0002
-(3- { [(2-Cyano-ethyl)-methyl-amino]-methyl } -pyrrolidin- 1 -yl)- 1 -cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000025_0003
-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-pyrrolidin-l-yl)-l-cyclopropyl-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000025_0004
-{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l-cyclopropyl-8-methoxy- 4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000026_0001
- { 3-[ 1 -(2-Cyano-ethylamino)-ethyl] -pyrrolidin- 1 -yl } - 1 -cyclopropyl-8-methyl-4- oxo-l,4-dihydro-quinoline-3Tcarboxylic acid;
Figure imgf000026_0002
-(3- { 1 -[(2-Cyano-ethyl)-methyl-amino]-ethyl } -pyrrolidin- 1 -yl)- l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000026_0003
-(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l-cyclopropyl-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000026_0004
-{3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l-yl}-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000027_0001
-{3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l-yl}-l-cyclopropyl-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000027_0002
7-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000027_0003
7-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000027_0004
7-{ 3-[ 1 -(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin- 1 -yl } - 1 -cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000028_0001
-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin-l-yl}-l-cyclopropyl-8- methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000028_0002
7-(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-cyclopropyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000028_0003
7-{3-[2-Acetylamino-l-(2-cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000028_0004
7-{3-[2-Acetylamino-l-(2-cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000029_0001
-(3- { 2- Acetylamino- 1 - [(2-cyano-ethyl)-methyl-amino] -ethyl } -pyrrolidin- 1 -yl)- 1 - cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000029_0002
-(3- { 2- Acetylamino- 1 - [(2-cyano-ethyl)-methyl-amino] -ethyl } -pyrrolidin- 1 -yl)- 1 - cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000029_0003
-[l-(2-Cyano-ethylamino)-5-aza-spiro[2.4]hept-5-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000029_0004
-[l-(2-Cyano-ethylamino)-5-aza-spiro[2.4]hept-5-yl]-l-cyclopropyl-6-fluoro-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000030_0001
-{ 3- [ l .(2-Cyano-ethylamino)-propyl]-azetidin- 1 -yl } -1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000030_0002
-{3-[l-(2-Cyano-ethylamino)-propyl]-azetidin-l-yl}-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000030_0003
-(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-propyl}-azetidin-l-yl)-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000030_0004
-(3- { 1 -[(2-Cyano-ethyl)-methyl-amino]-propyl } -azetidin- 1 -yl)-l -cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000031_0001
7-{3-[l-(2-Cyano-ethylamino)-cyc]opropyl]-azetidin-l-yl}-l-cycIopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000031_0002
7-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000031_0003
7-(3-{l-[(2-Cyano-ethyl)-methyl-amino]-cyclopropyl}-azetidin-l-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000031_0004
7-(3-{l-[(2-Cyano-ethyl)-methyl-amino -cyclopropyl}-azetidin-l-yl)-l- cyclopropyl-6-fluoro-8-methyI-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000032_0001
7-(3-{ l-[(2-Cyano-ethyl)-ethyl-amino]-cyclopropyl}-pyrrolidin-l-yl)-l- cycloρropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000032_0002
7-(3-{ l-[(2-Cyano-ethyl)-ethyl-amino]-cyclopropyl}-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000032_0003
-(3-{2-Acetylarnino-l-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000032_0004
-(3-{2-Acetylamino-l-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000033_0001
S odium; 7- { 3- [ 1 -(2-cyano-ethylamino)-propyl] -azetidin- 1 -yl } - 1 -cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylate.;
Figure imgf000033_0002
Sodium; 7-{ 3-[(2-cyano-ethylamino)-methyl]-3-methyl-azetidin-l-yl }-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylate;
Figure imgf000033_0003
7- { 3-[ 1 -(2-Cyano-ethylamino)-cyclopropyl]-azetidin- 1 -yl } - l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000033_0004
7-{3-[(2-Cyano-ethylamino)-methyl]-3-ethyl-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000034_0001
7-{3-[(2-Cyano-ethylamino)-methyl]-3-ethyl-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000034_0002
-{ 3-[(2-Cyano-ethylamino)-methyl]-cyclopentyl } -8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid; or
Figure imgf000034_0003
-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-cyclopentyl)-8-fluoro-3-methyl- 6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid.
The invention is also directed to a compound of formula IV:
Figure imgf000034_0004
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, provided that when X is N, R5 is absent at that position;
Rt is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, heterocyclic, aryl, heteroaryl; and CH2(C3-C6)cycloalkyl;
R2 is OH, OBF2
OCQ-Ce^lkyl, O(C3-C6)cycloalkyl,
O 0-(CHR2a)m-0 QR2b 5 wherein m is an integer from 1 to 10, Q is O or NH or N(CrC6)alkyl or is absent, and R2a is H or (C!-C6)alkyl and R2b is (d-C6)alkyl, aryl, or heteroaryl,
O— (CHR2a)n— Y s wherein R2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2d are each independently H, (C1-C6)alkyl, or (C3-C6)cycloalkyl, or NR2a, wherein R2a is as defined above,
Figure imgf000035_0001
wherein " •wu " indicates the point of attachment, 2a is as defined above, R2e and R2e- are each independently H or (C1-C6)alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and Xι and
Y] are each independently NH or O;
R3, R4, and R5 are each independently H, halo,
NRyRz, wherein Ry and Rz are each independently H or ( - C6)alkyl,
(C C6)alkyl, halo(C1-C6)alkyl,
O(C1-C6)alkyl, O(C1-C6)haloalkyl, nitrile;
Ri and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO2, or NRX, wherein Rx is H or (d-C^alkyl; and
z is 0, 1, or 2;
Ra and Rb are each independently H, ( -C^alkyl, (C1-C6)alkoxy, haloC - C6)alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
R' is H, halo,
( -CeOalkyl, O(C1-C6)alkyl halo(C1-C6)alkyl, aryl,or heteroaryl;
Rc and Rd are each independently H,
(C1-C6)alkylnitrile; O II
— P-OH OH ,
O — P-0(C C6)alkyl 0(CrC6)alkyl
(C1-C6)alkyl, (C3-C6)cycloalkyl, heteroaryl,
SOHCx-C^alkyl,
SO2-aryl, SO2-heteroaryl,
O — (CR2aR2a')g-0 QR2b f wherein g is an integer from 1 to 10, Q is as defined above, and R2a and R2a> are each independently
H or (C1-C6)alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R2b is (C1-C6)alkyl, aryl, or heteroaryl,
O O (CR2aR2a)g-0-P-(OH)2 or (CR2aR2a')g-0-P-(0(C C6)alkyl)2 wherein R2a and R2a'are as defined above,
Figure imgf000037_0001
, wherein " ™ΛΛ " indicates the point of attachment, p is 0 or 1, and R2c is H, (C1-C6)alkyl,
O(Cι-C6)alkyl,
(C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or 0 -(CHR2a)h-θJL-QR2b or — (CHR2a)j-Y wherein
R2a, R2b, and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH)2, OPO(O(Cι-
Cg))2, or NR2dR2e, wherein R2d and R2e are each independently H, (C;χ-C(j)alkyl, or (C3-
C7)cycloalkyl,
Figure imgf000038_0001
independently H, (Cχ-C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a
3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2g is
Figure imgf000038_0002
(C3-C7)cycloalkyl, aryl, or heterocyclo, or heteroaryl; and
Re and Rf are each independently H, C C6 alkyl, haloalkyl, halo, or Re and Rf taken together with the carbon to which they are attached form a
3,4,5 or 6-membered substituted or unsubstituted ring.
What is also provided is a compound which is:
Figure imgf000038_0003
9-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid;
Figure imgf000039_0001
9-[3-(R)-(2-Cyano-l-(S)-methylamino-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-(S)- methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid
Figure imgf000039_0002
- [3 -( 1 - Amino-2-cyano-ethyl)-pyrrolidin- 1 -yl]- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydro-quinoline-3-carboxylic acid;
Figure imgf000039_0003
- [3-( 1- Amino-2-cyano-ethyl)-pyrrolidin- 1 -yl]- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydro-[l,8]naphthyridine-3-carboxylic acid;
Figure imgf000039_0004
7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000040_0001
-[3-(l -Amino-2-cyano-ethyl)-pyrrolidin- 1 -yl]- 1 -cyclopropyl-6-fluoro-8-methyl- 4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000040_0002
-[3-(l-Amino-2-cyano-ethyl)-ρyrrolidin-l-yl]-l-cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000040_0003
7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl-4-oxo-
1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000040_0004
5-Amino-7-[3-(l-amino-2-cyano-ethyl)-ρyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-quinoIine-3-carboxylic acid;
Figure imgf000041_0001
-Amino-7-[3-(l-amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl- 4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000041_0002
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000041_0003
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrroli in-l-yl]-l-cycloρropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000041_0004
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000042_0001
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000042_0002
5-Amino-7-[3-(l-amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l- cycloρropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000042_0003
5-Amino-7-[3-(l-amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000042_0004
-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4- dihydro-quinoline-3-carboxylic acid;
Figure imgf000043_0001
-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4- oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000043_0002
-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6-oxo- 2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid;
Figure imgf000043_0003
-[3(R)-(2-Cyano- 1 (S)-methylamino-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6- oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid;
Figure imgf000043_0004
-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4- oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid;
Figure imgf000044_0001
- [3-(2-Cyano- l-methylamino-ethyl)-pyrrolidin- 1 -yl]- 1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000044_0002
7-[3(R)-(2-Cyano-l(S)-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000044_0003
-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000044_0004
-[3-(2-Cyano- 1 -methylamino-ethyl)-pyrrolidin- 1 -yl]- 1 -cyclopropyl-8-methoxy- 4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000045_0001
7-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl-4- oxo-1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000045_0002
5- Amino-7- [3-(2-cyano- 1 -methylamino-ethyl)-pyrrolidin- 1 -yl] - 1 -cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000045_0003
5-Amino-7-[3-(2-cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000045_0004
7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000046_0001
7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000046_0002
7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000046_0003
7- [3 -(2-Cy ano-2,2-dimethyl- 1 -methyl amino-ethyl)-pyrrolidin- 1 -yl] - 1 - cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000046_0004
5-Amino-7-[3-(2-cyano-2,2-dimethyl- 1 -methylamino-ethyl)-pyrrolidin- 1 -yl]- 1 - cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; or
Figure imgf000047_0001
-Amino-7-[3-(2-cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid.
What is also provided is a compound of formula V or VI
Figure imgf000047_0002
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, provided that when X is N, R5 is absent at that position;
Rj is (Q-Q alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, heterocyclic, aryl, heteroaryl; and CH2(C3-C6)cycloalkyl; R2 is OH,
OBF2
OCd-C^alkyl, O(C3-C6)cycloalkyl, O 0-(CHR2a)m-0 QR2b 5 wherein m is an integer from 1 to 10, Q is O or NH or N(C1-C6)alkyl or is absent, and R2a is H or (C1-C6)alkyl and R2b is
Figure imgf000048_0001
aryl, or heteroaryl, 0-(CHR2a)n-Y } wherein R2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR2oR2d, wherein R c and R2d are each independently H, (C1-C6)alkyl, or (C3-C6)cycloalkyl, or NR2a, wherein R2a is as defined above,
Figure imgf000048_0002
, wherein " ~ " indicates the point of attachment, 2a is as defined above, R2e and R2e> are each independently H or ( -C^alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and X\ and Yi are each independently NH or O;
R3, R_<, and R5 are each independently H, halo,
NRyRz, wherein Ry and Rz are each independently H or ( - C6)alkyl, (C1-C6)alkyl, halo(C1-C6)alkyl, O(C1-C6)alkyl, O(Cι-C6)haloalkyl, nitrile; Rι and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- pr 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO2, or NRX, wherein Rx is H or (C1-C6)alkyl; and
q is 0, 1, 2, or 3 and z is 0, 1, or 2;
Rb is H, ( -C^alkyl, haloCd-C^alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form a 3,4,5 or 6- membered substituted or unsubstituted ring;
R', R", R'", and R"" are each independently H, (d-C6) alkyl, -O(C C6)alkyl, haloCQ-Cf alkyl, aryl, or heteroaryl;
B is
Figure imgf000049_0001
provided that when B is
Figure imgf000050_0001
R' is not O(CrC6)alkyl, and wherein ",WΛΛ " indicates the point of attachment, and
Rc and Rd are each independently H, (C1-C6)alkylnitrile;
O II
— P-OH OH
O — P-0(CrC6)alkyl 0(C C6)alkyl
(C1-C6)alkyl, (C3-C6)cycloalkyl, heteroaryl,
SO2-(C1-C6)alkyl,
SO2-aryl, SO2-heteroaryl,
O — (CR2aR2a.)g-0 QR2b 5 wherein g is an integer from 1 to 10, Q is as defined above, and R a and R2a> are each independently
H or (Cϊ-C6)alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R2b is (Cι-C6)alkyl, aryl, or heteroaryl,
O . 0 (CR2aR2a)g-0-P-(OH)2 of (CR2aR2a')g-0-P-(0(C1-C6)alkyl)25 wherein R2a and R2a>are as defined above, O
x ' , wherein " ■«« " indicates the point of attachment, p is 0 or 1, and R2c is H, (Cι-C6)alkyl, O(Cι-C6)alkyl, (C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
O — (CHRaah-O-U-QRzb or ~ <CHR2a)j-Y , wherein
R2a, R2b, and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH)2, OPO(O(C!-
C6))2, or NR2dR2e, wherein R2d and R2e are each independently H, (Cχ-C6)alkyl, or (C3-
C7)cycloalkyl,
Figure imgf000051_0001
, wherein q is 0 or 1 , R2f and R2f are each independently H, (Cχ-C6)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2g is
(Cι-C6)alkyl, (C3-C7)cycloalkyl, aryl, or heterocyclo, or heteroaryl;
Re and Rf are each independently H, Q-Cδ alkyl, haloalkyl, halo, or Re and
Rf taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring; Rg and Rh are each independently H, CrC6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring; and
Rj and R are each independently H, (Q-C^alkyl, haloalkyl, (C1-C6)alkyl-
NRcRd, (C1-C6)alkyl-ORc, aryl, heteroaryl, heterocycle,
O (Ci -C6)alkyi 2— Rd ^ wherein z is O or NRC, or Rj and Rk taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.
What is also provided is a compound which is
Figure imgf000052_0001
-[4-(2-Cyano-ethylamino)-hexahydro-cycloρenta[c]pyrrol-2-yl]-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000052_0002
-[4-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000052_0003
_[4_(2-Cyano-ethylarnino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000053_0001
-[4-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000053_0002
7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000053_0003
7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cycloproρyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000053_0004
7- [4-( 1 - Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl] - 1 - cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000054_0001
7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000054_0002
-[3a-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl- 6-fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000054_0003
-[3a-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl- 6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000054_0004
-[3a-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl- 8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000055_0001
-[3a-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl- 8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000055_0002
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000055_0003
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
Figure imgf000055_0004
7-[3a-( 1 - Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl] - 1 - cyclopropyl-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; or
Figure imgf000056_0001
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid.
What is also provided is a pharmaceutical formulation comprising a compound of one of formula I, π, HI, IV, V, or VI admixed with a pharmaceutically acceptable diluent, carrier, or excipient.
What is also provided is a method of treating a bacterial infection in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of formula I, π, HI, IV, V, or VI.
DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to presently preferred compositions or embodiments and methods of the invention, which constitute the best modes of practicing the invention presently known to the inventors.
The term "alkyl" as used herein refers to a linear or branched hydrocarbon of from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents selected from lower (Cχ-C())alkoxy, (Cj-C^thioalkoxy, halogen, aryl, heteroaryl, oxo, thio, -OH, -SH, -F, -CF ,- OCF3, -NO2, -CO2H, -CO2(Cι -C6)alkyl, or — O,
— o >
The term "(C3-C6)cycloalkyl" means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Where possible, the cycloalkyl group may contain double bonds, for example, 3-cyclohexen-l-yl. The cycloalkyl ring may be unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, for yl, carboxyl, -CO2(Ci -C^alkyl, -CO(Cχ-C6)alkyl, aryl, heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein, or as indicated above for alkyl. Examples of substituted cycloalkyl groups include fluorocyclopropyl.
The term "halo" includes chlorine, fluorine, bromine, and iodine.
The term "haloalkyl" means a (Cj-Cβ^lkyl group substituted with one or more halo.
The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, and being unsubstituted or substituted with one or more of the substituent groups recited above for alkyl groups including, halogen, nitro, cyano
-OH, -SH, -F, -CF3, -OCF3, — O -CO2H, -CO2Cι-C6 alkyl, or - SO2alkyl.
Examples include, but are not limited to phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxyρhenyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3- chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 5- chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and 4'-bromobiphenyl.
The term "heteroaryl" means an aromatic cyclic or polycyclic ring system having from 1 to 4 heteroatoms selected from N, O, and S. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5- 1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2- pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl. The heteroaryl groups may be unsubstituted or substituted by 1 to 3 substituents selected from those described above for alkyl, alkenyl, and alkynyl, for example, cyanothienyl and formylpyrrolyl. Preferred aromatic fused heterocyclic rings of from 8 to 10 atoms include but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7- benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl. Heteroaryl also includes 2- and 3- aminomethylfuran, 2- and 3- aminomethylthiophene and the like.. The term "heterocyclic" means a monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring systems. Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S, and preferably from 3 to 7 member atoms, in the ring. Bicyclic heterocyclics contain from about 5 to about 17 ring atoms, preferably from 5 to 12 ring atoms. Bicyclic heterocyclic rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein the substituents are those described above for the alkyl and cycloalkyl groups. Typical substituted cyclic ethers include propyleneoxide, phenyloxirane (styrene oxide), cis-2-butene-oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofuran, 2,6-dimethyl- 1,4-dioxane, and the like. Heterocycles containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-l-yl, and the like. Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro- l,3-dithiol-2-yl, and hexahydrothiophen-4-yl and substituted groups such as aminomethyl thiophene. Other commonly employed heterocycles include dihydro- oxathiol-4-yl, dihydro-lH-isoindole, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro- oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene.
In some cases, to prepare the compounds of the invention disclosed herein, protecting groups may have been used to allow synthetic manipulation of one functional group in the presence of other functional groups. The appropriate use and choice of protecting groups is well-known by one skilled in the art. It is also to be understood that such groups not only serve to protect chemically reactive sites, but also to enhance solubility or otherwise change physical properties. A good general reference for protecting group preparation and deprotection is Greene, Theodora, Protective Groups in Organic Synthesis; Wiley: New York, USA, 1991 and later editions. Thus, it is to be further understood that invention compounds characterized by the presence of a protecting group as disclosed and described in Greene are also to be considered invention compounds.
When a bond is represented by a symbol such as " " this is meant to represent that the bond may be absent or present provided that the resultant compound is stable and of satisfactory valency.
When a bond is represented by a line such as " ^^ " this is meant to represent that the bond is the point of attachment between two molecular subunits. The term "patient" means all mammals, including humans. Other examples of patients include cows, dogs, cats, goats, sheep, pigs, and rabbits.
A "therapeutically effective amount" is an amount of a compound of the present invention that, when administered to a patient, provides the desired effect; i.e., lessening in the severity of the symptoms associated with .a bacterial infection. It will be appreciated by those skilled in the art that compounds of the invention having one or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, geometric, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity or cytotoxicity using the standard tests described herein, or using other similar tests which are well known in the art. Certain compounds of the invention are also useful as intermediates for preparing other compounds of the invention. Thus, a compound wherein R2 is BF2, can be hydrolyzed to form another compound of the invention wherein R2 is H.
Some of the compounds of Formula I are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention. Thus, pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S.M. et. al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977;66:1-19). The acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine,
N-methylgluc amine, and procaine (see, for example, Berge S.M., supra., 1977).
The base addition salts of said acidic compounds are prepared by contacting the free acid orm with a sufficient amount of the desired base to produce the salt in the conventional manner.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
A "prodrug" is an inactive derivative of a drug molecule that requires a chemical or an enzymatic biotransformation in order to release the active parent drug in the body.
Specific and preferred values for the compounds of the present invention are listed below for radicals, substituents, and ranges are for illustration purposes only, and they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
Unless otherwise stated or defined, abbreviations used herein conform to the style sheet of American Chemical Society journals.
Thus, we turn now to a compound of formula I, which has the structure:
Figure imgf000061_0001
A specific value for X is C or N. A specific value for R] is (C\-
Ce)cycloalkyl and halo(C1-C6)cycloalkyl, aryl, or heteroaryl. A specifc value for R3 is H or NH . A specific value for R is H or halo. A specific value for R5 is halo, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoro ethoxy, or trifluoromethoxy when X is C. In another embodiment of a compound of formula I, a specific value for X is C or N. A specific value for ι is cyclopropyl or fluorocyclopropyl. A specific value for R3 is H or NH2. A specific value for R4 is H or F. A specific value for X is C or N. A specific value for R5 is halo, methyl, or methoxy.
In another embodiment of a compound of formula I, Rl3 R3, and R5 are as provided in the following structures, wherein R2 is OH, OBF2, or O(Cι-C6)alkyl,
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
As indicated previously, in compounds of the invention, A is
Figure imgf000064_0002
Figure imgf000064_0003
or 2. Specifically, z is 0, 1, 2, when q is 2 or 3; alternatively, z is 1 or 2 when q is 0, 1, 2, or 3.
Specifically, Ra and R each independently can be H, (C1-C6)alkyl, (Q- C6)alkoxy, halo(C1-C6)alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form C=O, C=NO(C1-C6)alkyl, or a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, Ra and Rb are each independently H, methyl, ethyl, fluoro, fluoromethyl, trifluoromethyl, fluorethyl, methoxy, MeO-N=, or taken together with the carbons to which they are attached form a cyclopropyl ring.
Specifically, R', R", R'", and R"" each independently can be H, (Q- C6)alkyl, -O(C1-C6)alkyl, halo(C1-Ce)alkyl, aryl,or heteroaryl. More specifically, R', R", R1", and R"" are each independently H, fluoro, methyl, ethyl, flouromethyl, fluoroethyl, phenyl, benzyl, or methoxy.
Specifically, B is
Figure imgf000065_0001
Rf Re R-RW
However, when B is "h Rc in
Figure imgf000065_0002
or R* wherein " WΛ " indicates the point of attachment, R' is not -O(Cι-C6)alkyl.
Specifically, Rc and R each independently can be H, (C1-C6)alkylnitrile,
— P-OH — P-0(C C6)alkyl OH , 0(C C6)alkyl ^ (C1-C6)alkyl, (C3-C6)cycloalkyl, heteroaryl, SO2- (Cχ-C6)alkyl, SO2-aryl, or SO2-heteroaryl. More specifically, Rc and R each independently are H, methyl, or ethyl.
Specifically Re and Rf each independently can be H, -Cβ alkyl, haloalkyl, halo, or Re and Rf taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, Re and Rf each independently are H, methyl, or ethyl.
Specifically, Rg and Rh each independently can be H, Ci-C6 alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, Rg and Rh each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl, carboxyethyl, or O )
■^ NHMe , or taken together with the carbons tro which they are attached form
Δ Specifically Rj and Rk each independently can be H, ( -C^alkyl, haloalkyl, (d-C6)alkyl-NRcRd, (C1-C6)alkyl-ORc, aryl, heteroaryl, heterocycle,
O (C-i -C6)alkyl Z— Rd ^ wherein z is 0 or j^ or Rj and Rk tB^sa together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring. More specifically, Rj and Rk each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl,
O phenyl, isoxazolyl, carboxymethyl, carboxyethyl, or NHMe , or taken together
with the carbons tro which they are attached form Δ
Thus, in compounds of formula I wherein A is
Figure imgf000066_0001
, and z is 0, 1,
or 2, and
Figure imgf000066_0002
A is thus exemplified by any of the following structures:
Figure imgf000067_0001
wherein " '^v ~ " indicates the point of attachment.
Furthermore in compounds of formula I wherein A is
Figure imgf000067_0003
, wherein z is 0, 1, or 2 and q is 0, 1, 2, or 3, A is exemplified by any of the following structures wherein
Figure imgf000067_0004
or
Figure imgf000067_0005
Figure imgf000068_0001
wherein " n ~^ru " indicates the point of attachment
As indicated previously, B can
Figure imgf000068_0002
or
Figure imgf000068_0003
, wherein Rc, Rd, Re, Rf, Rg, Rh, Rj, and Rk and have any of the definitions provided above. Thus B can have any of the following structures:
NC- NC- NC- NC ^ NC.
^ ^
H Me Et Me
Figure imgf000068_0004
rC6)alkyl NH∑
Figure imgf000069_0001
Thus, given the description of A and B, includes any of the following structures:
Figure imgf000070_0001
Figure imgf000071_0001
wherein R is CH2CH2CN.
Also given the description of A and B,
Figure imgf000071_0002
further includes any of the following structures:
Figure imgf000072_0001
wherein R is CH2CN.
Also given the description of A and B,
Figure imgf000072_0002
encompasses any of the following structures:
Figure imgf000072_0003
wherein R is CH2CH2CN. Also given the description of A and B,
Figure imgf000073_0001
encompasses any of the following structures r
Figure imgf000073_0002
wherein Rc is H or (C1-C6)alkyl and R is CH2CN.
We turn now to compounds of formulas II and LTI, which have the structures:
Figure imgf000073_0003
Specific values and embodiments for compounds of formulas π and HI are as provided for compounds of formula I with respect to q, z, X, Rls R2, R3, R4, R5 and Ra, Rb, Rc, Re, Rf, Rg, Rh, Rj, and Rk.
We turn now to a compound of formula IN, which has the structure:
Figure imgf000074_0001
Specific values and embodiments for compounds of formula IV are as provided for compounds of formula I with respect to n, X, Ri, R2, R3, R , R5 and Ra, Rb, Rc, Rd, Re, and Rf.
We turn now to a compound of formula V or VI .
Figure imgf000074_0002
Specific values and embodiments for compounds of formulas V are as provided for compounds of formula I with respect to to n, q, X, R1? R2, R3, R4, R5 and R', R", R"', and R"".
Preparation of Invention Compounds
Strategies for the preparation of invention compounds are depicted in in the following Schemes.
As is readily apparent from this disclosure, compounds of the present invention are characterized by a quinolone core, covalently bound to a C-7 sidechain
Figure imgf000075_0001
, 0r . As is retrosynthetically depicted in Scheme I, the invention compounds can be prepared via coupling of a suitably C-7 substituted quinolone core, wherein X2 is halo, triflate, or a similar reactive group known to the skilled artisan, and an appropriately substituted azetidine, pyrollidine, piperidine.
Scheme I
Figure imgf000075_0002
Quinolone Core X2= halo, OS02CF3, R= QH, 0(C C6)alkyl, OBF2
Reflecting the synthetic strategy summarized in Scheme I, the following section describing the preparation of the invention compounds has several parts.
The first part describes the synthesis of the requisite quinolone core precursors.
The second part describes the synthesis of the requisite C-7 sidechain precursors.
The final part describes the coupling of the C-7 sidechain and quinolone core precursors to provide the invention compounds, and details any further chemical elaboration of invention compounds to produce other invention compounds.
A. Synthesis of Quinolone Core Precurors
The quinolone core precursors that are used to prepare the invention compounds are generally known to the skilled artisan and can be commercially obtained, or alternatively, can be prepared using routine synthetic methods. The following sections provide relevant citations that describe the preparation of the quinolone core precursors used to practice the invention disclosed herein. Preparation of Quinolone Core Precursors
Figure imgf000076_0001
Figure imgf000076_0002
EP 0167763; EP 0195841
Figure imgf000076_0003
US 5,869,991
Figure imgf000076_0004
Figure imgf000077_0001
Preparation of Quinolone Core Precursors
Figure imgf000077_0002
Figure imgf000077_0003
As provided for IA, above, except fluorocyclopropyl amine is used instead of cyclopropyl amine
b.
Figure imgf000077_0004
As provided for 1 A, above, except fluorocyclopropyl amine is used instead of cyclopropyl amine As provided for IC, above, except fluorocyclopropyl amine is used instead of cyclopropyl amine
Figure imgf000078_0002
As provided for ID, above, except fluorocyclopropyl amine is used instead of cyclopropyl amine
Figure imgf000078_0003
As provided for IF, above, except fluorocyclopropyl amine is used instead of cyclopropyl amine
Figure imgf000078_0004
As provided for IH, above, except fluorocyclopropyl amine is used instead of cyclopropyl amine Preparation of
Figure imgf000079_0001
c.
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000080_0002
B. Synthesis of C-7 Sidechains and Sidechain Precurors
1. Preparation of
Figure imgf000080_0003
Figure imgf000080_0004
were prepared as provided in
Scheme 1. Thus, 3-formyl-pyrrolidine-l-carboxylic acid benzyl ester was allowed to undergo reaction with cyanomethyl-phosphonic acid diethyl ester in the presence of cesium carbonate to provide 3-(2-cyano-vinyl)-pyrrolidine-l- carboxylic acid benzyl ester. Ammonia or methylamine addition to 3-(2-cyano- vinyl)-pyrrolidine-l-carboxylic acid benzyl ester provided the corresponding
Michael adduct, which was subsequently tert-butoxycarbonyl (Boc)-protected. Removal of the benzyl ester group under conventional conditions provided the target compound as the protected Boc analogue, which can be submitted to silica gel chromatography to provide each diastereomer and chiral HPLC separation to provide each enantiomer. Purification by chromatography as described herein
provides pure samples of
Figure imgf000081_0001
and , as well as the associated diastereomers, for coupling. Removal of the Boc protecting groups
after coupling provides the unprotected amines
Figure imgf000081_0002
and
Figure imgf000081_0003
wherein " - " indicates a point of attachment.
Scheme 1
Figure imgf000081_0004
H or Me
Figure imgf000081_0005
2. Preparation of H
Figure imgf000081_0006
H was prepared according to Scheme 2. Thus, 1-benzhydryl- azetidine-3-carbonitrile was converted to l-(l-benzhydryl-azetidin-3-yl)- cyclopropylamine as provided by Chem. Rev., 1979, Vol. 79, No. 4 and Tet. Lett. 44, 2003, 2485. l-(l-Benzhydryl-azetidin-3-yl)-cyclopropylamine was converted to N-[l-(l-Benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-txifluoro-acetarnide as provided by J. Med. Chem. 1993, vol. 36, No. 7. Hydrogenation of N-[l-(l- benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-trifluoro-acetamide provided the title compound, which can be converted to the free amine and subsequently derivatized after the coupling reaction to the quinolone core.
Scheme 2
Figure imgf000082_0001
3. Preparation of
Figure imgf000082_0002
was prepared as provided in Scheme 3. Thus, Grignard reaction of ethylmagnesium bromide with l-benzhydryl-azetidin-3-one provided the corresponding alcohol, l-benzhydryl-3-ethyl-azetidin-3-ol. Mesylation of the alcohol moiety in l-benzhydryl-3-ethyl-azetidin-3-ol under conventional conditions, followed by nucleophilic addition of CN, provided l-benzhydryl-3- ethyl-azetidine-3-carbonitrile, which was subsequently reduced using lithium aluminum hydride (LAH) to provide C-(l-benzhydryl-3-ethyl-azetidin-3-yl)- methylamine. Protection of C-(l-benzhydryl-3-ethyl-azetidin-3-yl)-methylamine as the trifluoroacetate, followed by hydrogenation, provided the target compound, which can be converted to free amine and subsequently deprotected after the coupling reaction to the quinolone core.
Scheme 3
Figure imgf000083_0001
Preparation of
Figure imgf000083_0002
HCl
Figure imgf000083_0003
HCl Was prepared as provided in Scheme 4. Thus, 1- benzhydryl-azetidine-3-carbonitrile was hydrolyzed under conventional conditions to provide l-benzhydryl-azetidine-3-carboxylic acid, which was subsequently treated with l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and N,0-dimethyl-hydroxyl-amine hydrochloride in the presence of triethyamine to give l-benzhydryl-azetidine-3-carboxylic acid methoxymethylamide. Grignard addition of ethylmagnesium bromide to 1- benzhydryl-azetidine-3-carboxylic acid methoxymethylamide provided the corresponding ketone, l-(l-benzhydryl-azetidin-3-yl)-propan-l-one. Reductive amination of l-(l-benzhydryl-azetidin-3-yl)-propan-l-one using ammonium acetate and sodium cyanoborohydride, followed by treatement with trifluoroacetic anhydride in the presence of an amine base provided l-(l-benzhydryl-azetidin-3- yl)-propan-l-one. Hydrogenation of l-(l-benzhydryl-azetidin-3-yl)-propan-l-one gave the target compound, which can be converted to the free amine and subsequently deprotected after the coupling reaction to the quinolone core.
Figure imgf000085_0001
53%
Figure imgf000085_0002
5. Preparation of
Figure imgf000086_0001
Figure imgf000086_0002
was prepared as provided in Scheme 5. Thus, similar
to the synthesis of
Figure imgf000086_0003
as depicted in Scheme 3, Grignard reaction of methylmagnesium bromide with l-benzhydryl-azetidin-3-one provided the corresponding alcohol, l-benzhydryl-3-methyl-azetidin-3-ol. Mesylation of the alcohol moiety in l-benzhydryl-3-methyl-azetidin-3-ol under conventional conditions, followed by nucleophilic displacement with CN, provided 1- benzhydryl-3-methyl-azetidine-3-carbonitrile, which was subsequently reduced using lithium aluminum hydride (LAH) to provide C-(l-benzhydryl-3-methyl- azetidin-3-yl)-methylamine. Protection of C-(l-benzhydryl-3-methyl-azetidin-3- yl)-methylamine as the trifluoroacetate, followed by hydrogenation, provided the target compound, which can be converted to free amine and subsequently deprotected after the coupling reaction to the quinolone core.
Scheme 5
Figure imgf000087_0001
6. Preparation of H2N and
Figure imgf000087_0002
The target compounds ^2 ^N '"•CNH an(j H2 ^N -GNH were r r d as provided in Scheme 6. Thus, N-(trimethylsilylmethyl)-α-methylbenzylamine was prepared from the corresponding amine using trimethylsilyl chloride under conventional conditions. Reaction of N-(trimethylsilylmethyl)-α-methylbenzyl amine with formaldehyde in the presence of potassium carbonate and methanol provided N-(methoxymethyl)-N-(trimethylsilylmethyl)-α-methylbenzylamine, which was subsequently converted to l-(l-ρhenyl-ethyl)-pyrrolidine-3-carboxylic acid dibenzylamide as a mixture of stereoisomers. Treatment of the amide with ethylmagnesium bromide in the presence or Ti(OfPr)4 provided the protected target compounds as a separable mixture. The separable diastereomers were deprotected by hydrogenation to give the target compounds. Scheme 6
Figure imgf000088_0001
7. Preparation of
BocHN -^ -Λ
I NH
^-Z was prepared as provided in Scheme 7. Thus, mesylation of S-l-benzyl-pyrrolidin-3-ol, followed by followed by nucleophilic addition using CN, provided R-l-benzyl-pyrrolidine-3-carbonitrile. LAH reduction of R-l-benzyl-pyrrolidine-3-carbonitrile provided R-C-(1-Benzyl- pyrrolidin-3-yl)-methylamine. Boc-protection of the amine group in R-C-(l- Benzyl-pyrrolidin-3-yl)-methylamine provided (l-benzyl-pyrrolidin-3-ylmethyl)- carbamic acid tert-butyl ester, which was hydrogenated to provide the target compound.
Scheme 7
Figure imgf000089_0001
BocHN
Figure imgf000089_0003
Figure imgf000089_0002
BocHN \^' ''
8. Preparation of >
BocHN'^/'- -\
I NH
^- ' was prepared as provided in Scheme 8. Thus, treatment of 5-oxo-l-(l-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester with lithium aluminum hydride provided [l-(l-phenyl-ethyl)-pyrrolidin-3-yl]- methanol. Treatment of [l-(l-phenyl-ethyl)-pyrrolidin-3-yl]-methanol with isoindole-l,3-dione in the presence of triphenyl phosphine and diisopropyl azodicarboxylate gave the phthalimide, 2-[l-(l-phenyl-ethyl)-pyrrolidin-3- ylmethyl]-isoindole-l,3-dione. Treatment of the phthalimide with hydrazine hydrate gave C-[l-(l-phenyl-ethyl)-pyrrolidin-3-yl]-methylamine, which was
BOC-protected and hydrogenated to provide the target compound, which was converted to free amine and subsequently derivatized after the coupling reaction to the quinolone core. Scheme 8
Figure imgf000090_0001
9. Preparation of H
Figure imgf000090_0002
was prepared as provided in Scheme 9. Thus, 1-benzyl- pyrrolidine-3-carboxylic acid ethyl ester was hydrogenated under conventional conditions to provide pyrrolidine-3-carboxylic acid ethyl ester, which was subsequently BOC-protected to provide pyrrolidine-l,3-dicarboxylic acid 1-tert- butyl ester 3-ethyl ester. Reduction of pyrrolidine-l,3-dicarboxylic acid 1-tert- butyl ester 3-ethyl ester provided 3-hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester, which was oxidized to the corresponding aldehyde 3-formyl- pyrrolidine-1-carboxylic acid tert-butyl ester under Swern-type conditions. 3-(l- tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-l-carboxylic acid tert-butyl ester was prepared from 3-formyl-pyrrolidine-l -carboxylic acid tert-butyl ester by the addition of lithiated isopropylcyanide to the intermediate a- amidoalkyl sulfone. Deprotection of 3-(l-tert-butoxycarbonylamino-2-cyano-2,2- dimethyl-ethyl)-pyrrolidine-l -carboxylic acid tert-butyl ester provided the title compound 3-amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile as the dihydrochloride salt.
Scheme 9
Figure imgf000091_0001
HCl
CH CI2
73% step 7
Figure imgf000091_0002
Boc
10. Preparation of
Figure imgf000091_0003
The compound was prepared as provided in WO 96/39407.
11. Preparation of
Figure imgf000091_0004
Figure imgf000091_0005
and
Figure imgf000092_0001
and can be prepared as provided in Scheme 11. Thus, [3+2] cycloaddition of cyclopent-1-enecarboxylic acid methyl ester or the like with benzyl-methoxymethyl-trimethylsilanylmethyl- amine under conditions readily available to the skilled artisan and discussed herein provides 2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid methyl ester.
Preparation of
Figure imgf000092_0002
commences with hydride reduction of 2- benzyl-hexahydro-cyclopenta[c]ρyrrole-3a-carboxylic acid methyl ester using an aluminum hydride or borohydride to provide (2-benzyl-hexahydro- cyclopenta[c]pyrrol-3a-yl)-methanol. Conversion of the alcohol moiety in (2- benzyl-hexahydro-cyclopenta[c]pyrrol-3a-yl)-methanol to a leaving group such as the mesylate or tosylate, followed by displacement with a primary or secondary amine, and a protection deprotection sequence, provides (2-benzyl-hexahydro-
cyclopenta[c]pyrrol-3a-ylmethyl)-carbamic acid tert-butyl ester,
Figure imgf000092_0003
Alternatively, if the reduction of the ester moiety in 2-benzyl-hexahydro- cyclopenta[c]pyrrole-3a-carboxylic acid methyl ester is stopped at the aldehyde oxidation state (for example, by employing DIBALH as the reducinig agent), a reductive amination using ammonium formate or a primary alkyl amine such as methyl or ethyl amine can be employed to provide the aminated product. Reductive amination conditions and reagents are readily known to the skilled artisan.
Preparation of
Figure imgf000092_0004
commences with saponification of the ester moiety in 2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid methyl ester top provide 2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid. Curtius rearrangment of 2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid using conditions and rearrangements readily available to the skilled artisan
provides
Figure imgf000093_0001
, (hexahydro-cyclopenta[c]pyrrol-3a-yl)-carbamic acid tert- butyl ester.
Preparation of
Figure imgf000093_0002
commences with DB3 ALH reduction of 2- benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid methyl ester to provide the corresponding aldehyde. Methyleneation of the aldehyde under Wittig- or Horner-Wadsworth-Emmons-type conditions provides 3-(2-benzyl- hexahydro-cyclopenta[c]pyrrol-3a-yl)-acrylonitrile. Michael addition of ammonia or a primary alkyl amine to 3-(2-benzyl-hexahydro-cyclopenta[c]pyrrol-3a-yl)- acrylonitrile provides [2-Cyano-l-(hexahydro-cyclopenta[c]pyrrol-3a-yl)-ethyl]- carbamic acid tert-butyl ester.
Figure imgf000094_0001
C. Coupling of C-7 Sidechain and Quinolone Core Precurors to Provide Invention Compounds
Coupling of the sidechain precursor to the quinolone core precursor to provide the compounds of the present invention or precursors to compounds of the present invetnion can occur from either the core precursor as the free acid, alkyl ester, or borate ester, as depicted in Scheme II. Scheme II
Figure imgf000095_0001
Typically, when a free acid is used in the coupling reaction, a molar excess of the side chain precursor is combined with the quinolone core in a polar solvent such as acetonitrile. A molar excess of an amine base such as triethylamine is added, and the reaction mixture is heated to about 80 °C. Typically, the reaction mixtures becomps homogenous. The mixture is heated for sufficient time to drive the raction to completion, typically from about 3 to about 12 hours. The mixture is then worked up according to procedures widely uused by the skilled artisan to provide a compound of the invention.
When an alkyl ester is used in the coupling reaction, the quinolone core, sidechain, and triethylamine are combined in a solvent such as acetonitrile. The resulting reaction mixture is heated to 80 °C and stirred for 12 hours, is heated to about 80 °C. Typically, the reaction mixtures becomes homogenous. The mixture is heated for sufficient time to drive the raction to completion, typically from about 3 to about 12 hours. The mixture is then worked up according to procedures widely uused by the skilled artisan to provide a compound of the invention. When a borate ester is used in the coupling reaction, the requisite borate ester is typically prepared from the free acid upon reaction with BF3 according to conditions available to the skilled artisan. The borate ester is typically combined with the side chain in a solvent such as acetonitrile and treated with an amine base such as triethylamine. The resulting reaction mixture is typically stirred at room temperature for sufficient time to drive the reaction to completion, typically from about 24 to about 96 hours. The mixture is then worked up according to procedures widely used by the skilled artisan (i.e., deprotection of the borate ester in ethanol in the presence of triethylamine) to provide a compound of the invention.
D. Post-Coupling Transformations
Coupling of the sidechain precursors to the quinolone core precursors may give rise to invention compounds. Alternatively, post-coupling transformations may be necessary to give rise to invention compounds. Typical post-coupling transformation include deprotection of protected amines to provide invention compounds of formula TJ, as depicted in Scheme IH. Deprotection, as well as reaction with acrylonitrile or the like, gives rise to invention compounds of formulas III and IV.
Figure imgf000097_0001
"PG" = Protecting Group
Pharmaceutical Formulations
The present invention also provides pharmaceutical compositions which comprise a bioactive invention compound or a salt such or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. The compositions include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in mammals including humans. The compounds, such as antibiotic compounds, also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other bioactive agents such as antibiotics. Such methods are known in the art and are not described in detail herein. The composition can be formulated for administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parenteral. The compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations may also.contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present, for example, from about 1% up to about 98% of the formulation. For example, they may form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods will known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain, for example, from about 0.1% by weight, e.g., from about 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will contain, for example, from about 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will range, for example, from about 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 1.5 to 50 mg/kg per day. Suitably the dosage is, for example, from about 5 to 20 mg/kg per day.
Biological Activity The invention compounds can be screened to identify bioactive molecules with different biological activities using methods available in the art. The bioactive molecules, for example, can possess activity against a cellular target, including but not limited to enzymes and receptors, or a microorganism. A target cellular ligand or microorganism is one that is known or believed to be of importance in the etiology or progression of a disease. Examples of disease states for which compounds can be screened for biological activity include, but are not limited to, inflammation, infection, hypertension, central nervous system disorders, and cardiovascular disorders. In one embodiment, the invention provides methods of treating or preventing a bacterial infection in a subject, such as a human or other animal subject, comprising administering an effective amount of an invention compound as disclosed herein to the subject. In one embodiment, the compound is administered in a pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier. As used herein, an "infectious disorder" is any disorder characterized by the presence of a microbial infection, such as bacterial infections. Such infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. The compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically. Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The specific dosage of antimicrobial to be administered, as well as the duration of treatment, may be adjusted as needed.
The compounds of the invention may be used for the treatment or prevention of infectious disorders caused by a variety of bacterial organisms. Examples include Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphylococci, for example S. aureus; Enterococci, for example E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.' Other examples include Mycobacteria, for example M. tuberculosis; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example M. pneumoniae. The ability of a compound of the invention to inhibit bacterial growth, demonstrate in vivo activity, and enhanced pharmacokinetics are, demonstrated using pharmacological models that are well known to the art, for example, using models such as the tests described below.
Test A — Antibacterial Assays
The compounds of the present invention were tested against an assortment of Gram-negative and Gram-positive organisms using standard microtitration techniques (Cohen et. al., Antimicrob., 1985;28:766; Heifetz, et. al., Antimicrob., 1974;6:124). The results of the evaluation are shown in Tables IA and B.
Table IA
Minimum Inhibitory Concentrations μg/mL Gram Negative Bacteria
Compound Structure H. influenzae M. catarrhalis E. coli
Figure imgf000102_0001
Figure imgf000103_0001
Table IB
Minimum Inhibitory Concentrations μg/mL Gram Positive Bacteria
Compound Structure or E. faecalis S. pneumo S. aureus S pyogenes Example No. MGH-2 SV-1 UC-76 C203
Figure imgf000104_0001
Figure imgf000104_0002
Compound Structure or E. faecalis S. pneumo S. aureus S pyogenes Example. No. MGH-2 SV-1 UC-76 C203
Figure imgf000105_0001
The following examples are provided to illustrate but not limit the claimed invention.
A. Synthesis of Sidechain Precursors
Example 1 Preparation of (2-Cyano-l-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl ester
Figure imgf000105_0002
A. 3-(2-Cyano-vinyl)-pyrrolidine-l-carboxylic acid benzyl ester
Figure imgf000106_0001
A solution of 3-formyl-pyrrolidine-l-carboxylic acid benzyl ester (2.25 g, 9.65 mmol), cyanomethyl-phosphonic acid diethyl ester (1.88 g, 10.6 mmol) and cesium carbonate (3.46 g, 10.6 mmol) in dry THF (100 mL) was heated at 50 °C 5. for 3 hours. The solvent was removed in vacuo. The crude residue was taken up in ethyl acetate (100 mL) and washed with saturated NH C1 (100 mL), brine (100 mL), dried with MgSO4 and concentrated in vacuo. The crude residue was purified on a 40 g silica gel column (0 to 60% ethyl acetate in hexanes) to give 2.22 g of the title compound as a mixture of E and Z isomers (yield: 90%). MS0 (APCI+): m/z 257 (M+H)+.
B. 3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-l- carboxylic acid benzyl ester
Figure imgf000106_0002
5 To a solution of 3-(2-cyano-vinyl)-pyrrolidine-l -carboxylic acid benzyl ester (8.24 g, 32.1 mmol) in absolute ethanol (100 mL) was added ammonia (ca. 5 mL) and the solution was heated in a sealed reactor at 80-100 °C for 3 days. The solution was concentrated in vacuo. The resulting amine was dissolved in THF (100 mL), Boc anhydride (8.76 g, 40.2 mmol) was added, and the solution was0 stirred at room temperature for 18 hours. The solution was concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL), washed with saturated aqueous NϊLCl (100 mL) and brine (100 mL), dried with MgSO and concentrated in vacuo. The crude product was purified on a 330 g silica gel column (10 to 50% ethyl acetate in hexanes) to give 9.28 g of the title compound as a 1:1 mixture of diastereomers (yield: 77%). MS (APCI+): m/z 274 (M+H- Boc)+.
C. (2-Cyano-l-pyrrolidin-3-yl-ethyI)-carbamic acid tert-butyl ester
Figure imgf000107_0001
A solution of 3-(l-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine- 1-carboxylic acid benzyl ester (2.00 g, 5.36 mmol) and ammonium formate (1.00 g, 16.1 mmol) in methanol (50 mL) was purged with nitrogen and then 10% Pd C (0.5 g) was added. The mixture was stoppered and stirred at room temperature for 17 hours. The solution was filtered through Celite and solids were rinsed with methanol. The filtrate was concentrated in vacuo to give 1.25 g of the title compound (yield: 97%). MS (APCI+): m/z 240 (M+H)+.
Example 2
Preparation of N-(l-Azetidin-3-yl-cyclopropyI)-2,2,2-trifluoro-acetamide
Figure imgf000107_0002
A. l-(l-Benzhydryl-azetidin-3-yI)-cycIopropylamine
Figure imgf000107_0003
See Chem. Rev., 1979, Vol. 79, No. 4; let. Lett. 44, 2003, 2485
To a solution of l-benzhydryl-azetidine-3-carbonitrile (10 g) in THF (200 mL) were added successively at room temperature titanium isopropoxide (Ti(OiPr>4) (1 equivalent) and ethylmagnesium bromide (2.2 equivalents). The resulting reaction mixture was stirred for 30 minutes. Boron trifluoride diethyl etherate (BF3OEt2)(2 equivalents) was then added. Stirring was continued for a period of 30 minutes. A solution of 10% sodium hydroxide was added, and the mixture was extracted three times with ethyl acetate (EtOAc). The combined ethyl acetate layers were dried over Na2SO4, and concentrated. The crude material was purified by chromatography (EtOAc to 7:3 EtOAc:EtOH) to yield the title compound as a yellow solid (4.96 g, 44 % yield). MS (APCI+): m/z 279 (M+H)+.
B. N-[l-(l-Benzhydryl-azetidin-3-yI)-cyclopropyl]-2,2,2-trifluoro- acetamide
Figure imgf000108_0001
See J. Med. Chem. 1993, Vol. 36, No. 7
To a stirred solution of l-(l-benzhydryl-azetidin-3-yl)-cyclopropylamine
(2.5 g) in chloroform (60 mL) was added a solution of trifluoroacetic anhydride (1.25 equivalents) in chloroform (30 mL) dropwise at room temperature. The reaction was stirred for two hours, then washed with 10% NaHCO3, and subsequently brine. The solution was then concentrated and purified by chromatography (gradient: 3:1 hexanes:EtOAc to EtOAc) yielding 0.57 g (17 % yield) of the title compound. MS(APCI+): m/z 375 (M+H)+. C. N-(l-Azetidin-3-yI-cyclopropyl)-2,2,2-trifluoro-acetamide
Figure imgf000109_0001
To N-[l-(l-benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-trifluoro- acetamide in methanol was added 10% Pd/C (20%) and hydrochloric acid (1 equivalent). The resulting mixture was stirred under an atmosphere of hydrogen gas overnight. The mixture was then filtered through a pad of celite and the filtrate was concentrated to yield a mixture of the azetidinium hydrochloride and diphenylmethane (0.56 g, 90 % yield). The crude mixture was taken on to the next reaction without purification, MS(APCI+): m/z 209 (M+H)+.
Example 3 Preparation of N-(3-Ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide
Figure imgf000109_0002
A. l-Benzhydryl-3-ethyl-azetidin-3-ol
Figure imgf000109_0003
To a solution of l-benzhydryl-azetidin-3-one (10 g) in diethylether (200 mL) cooled to 0 °C with an ice bath was added dropwise a solution of ethylmagnesium bromide in ether (3.0 M, 2 equivalents). The reaction was allowed to stir at 0 °C until the bath warmed and then reacted at room temperature for three days. The reaction was quenched with aqueous ammonium chloride and then extracted three times with EtOAc. The organic extract was washed with brine, dried, and then concentrated. The product was purified by flash chromatography (2:1 hexanes :EtO Ac) to give the title compound (6.33 g, 56%), MS (APCI+): m/z 268 (M+H)+.
B. Methanesulfonic acid l-benzhydryl-3-ethyl-azetidin-3-yl ester
Figure imgf000110_0001
To a cooled (0 °C) solution of the l-benzhydryl-3-ethyl-azetidin-3-ol (6.33 g) and triethylamine (1.3 equivalents) in dichloromethane (100 mL) was added a solution of methanesulfonyl chloride (1.3 equivalents) in dichloromethane (30 mL) dropwise. As soon as all of the methanesulfonyl chloride had been added, the cooling bath was removed, and the reaction was allowed to stir at room temperature for 1 hour. The solution was then diluted with more dichloromethane and washed with water two times. The organic solution was then dried and concentrated (8.01 g, 98 % yield). The crude material was used in the next step without further purification.
C. l-Benzhydryl-3-ethyI-azetidine-3-carbonitrile
Figure imgf000110_0002
To a solution of methanesulfonic acid l-benzhydryl-3-ethyl-azetidin-3-yl ester (8.01 g) in dimethylformamide (DMF) (120 mL) at room temperature was added sodium cyanide (2.5 equivalents) in water (40 mL) dropwise. The solution was then heated to 60°C and stirred overnight The solution was then diluted with 500 mL water and the precipitate was extracted into EtOAc 3 times. The organic extract was washed with water 2 times and then dried over Na2SO4 and concentrated in vacuo. The product was purified by chromatography (gradient: 9:1 hex:EtOAc to EtOAc) to give the title compound (5.50 g, 86 % yield), MS (APCI+): m/z 277 (M+H)+.
D. C-(l-Benzhydryl-3-ethyl-azetidin-3-yl)-methylamine
Figure imgf000111_0001
To a solution of l-benzhydryl-3-ethyl-azetidine-3-carbonitrile (5.50 g) in THF (60 mL) was added LAH (3.5 equivalents) in THF (1 M) slowly. The solution was refluxed for 2 hours. The reaction was then cooled to room temperature and 100 mL diethylether was added followed by 2.8 mL water then 2.8 mL 10% NaOH then 5.6 mL water. After 30 minutes of vigorous stirring the mixture was filtered. The aluminum salts were washed 5 times with THF. The combined organic filtrates were dried, and concentrated. The crude product was used in the next step without further purification. 5.16 g, 92 % yield, MS (APCI+): m/z 281 (M+H)+.
E. N-(l-Benzhydryl-3-ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro- acetamide
Figure imgf000111_0002
To a stirred solution of C-(l-benzhydryl-3-ethyl-azetidin-3-yl)- methylamine (5.16 g) in chloroform (120 mL) was added a solution of trifluoroacetic anhydride (1.25 equivalents) in chloroform (60 mL) dropwise at room temperature. The reaction was stirred for two hours, then washed with 10% NaHCO3, then brine. The solution was then dried, then concentrated and purified by chromatography (3:1 hexanes:EtOAc to EtOAc) to provide the title compund (3.67 g, 53 % yield), MS (APCI+): m/z 377.3 (M+H)+.
N-(3-Ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide
Figure imgf000112_0001
N-(l-Benzhydryl-3-ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide (3.67 g) was hydrogenated (Pd/C in 100 mL MeOH) with one equivalent of HCl overnight to give 2.40 g, (100 % yield) of the title compound which was used without purification. MS (APCI+): m/z 211 (M+H)+.
Example 4 Preparation of N-(l-Azetidin-3-yl-propyl)-2,2,2-trifluoroacetamide hydrochloride
Figure imgf000112_0002
l-Benzhydryl-azetidine-3-carboxylic acid
Figure imgf000112_0003
A suspension of l-benzhydryl-azetidine-3-carbonitrile (2.09 g, 8.42 mmol) in concentrated hydrochloric acid (12 M, 15 mL) was heated at reflux for 30 minutes. The resulting solution was cooled to 0 °C, and 6 M sodium hydroxide was added until the mixture reached a pH of about 7. The aqueous mixture was then extracted with dichloromethane (3 x 150 mL) and dichloromethane:methanol (10:1, 3 x 150 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure to give the title compound (1.60 g, 71 % yield). MS (APCI): m/z 268 (M+H)+.
B. l-BenzhydryI-azetidine-3-carboxylic acid methoxymethylamide
Figure imgf000113_0001
l-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0 g, 42 mmol) was added to a suspension of l-benzhydryl-azetidine-3-carboxylic acid (7.42 g, 27.8 mmol), N,O-dimethyl-hydroxyl-amine hydrochloride (4.24g, 43.5 mmol), and triethylamine (11.6 mL, 83.3 mmol) in dichloromethane (150 mL). The suspension was then stirred at room temperature for 60 minutes. The suspension was diluted with dichloromethane (300 mL), and the resulting solution was washed with water (3 x 100 mL). The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting solid was purified via medium pressure liquid chromatography eluting with dichloromethane:methanol (40:1) to deliver 4.76 g (55 % yield) of the title compound as a white solid (mp 103-106 °C); MS (APCI+): m/z 311 (M+H)+.
C. l-(l-Benzhydryl-azetidin-3-yl)-propan-l-one
Figure imgf000113_0002
A solution of ethylmagnesium bromide in tetrahydrofuran (1.0 M, 32.5 mL) was add to a solution of l-benzhydryl-azetidine-3-carboxylic acid methoxymethylamide (3.36 g, 10.8 mmol) at -70 °C in tetrahydrofuran (60 mL). The resulting reaction mixture was then stirred at 0 °C for 1 hour. The reaction was then poured into a saturated aqueous solution of ammonium chloride (75 mL) at 0 °C. The mixture was then extracted with diethyl ether (300 mL); the aqueous layer was then extracted again with diethyl ether (2 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography eluting with dichloromethane:methanol (40:1) to afford 2.69 g (89 % yield) of the title compound as a waxy yellow solid (mp 73-75 °C); MS (APCI+): m/z 280 (M+H)+.
D. N-[l-(l-BenzhydryI-azetidin-3-yI)propyl]-2,2,2-trifluoroacetamide
Figure imgf000114_0001
53% Ammonium acetate (6.00 g, 77.8 mmol) was added to a mixture of 1-(1- benzhydryl-azetidin-3-yl)-propan-l-one (2.59 g, 9.27 mmol) and 4 angstrom molecular sieves (2.60 g) in methanol (80 mL). The mixture was cooled to 0 °C, and sodium cyanoborohydride (1.17 g, 18.5 mmol) was added in several portions.
The mixture was then stirred at room temperature for 22 hours. The suspension was filtered, and filtrate was concentrated under reduced pressure. The resulting residue was partially dissolved in dichloromethane (500 mL). The mixture was then washed with saturated aqueous sodium carbonate (100 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (100 mL).
The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2.59 g of a clear oil which was used without further purification. A solution of the crude diamine (2.59 g) and triethylamine (3.86 mL, 27.7 mmol) in dichloromethane (60 mL) at 0 °C was treated with trifluoroacetic anhydride (1.06 mL, 13.9 mmol). The resulting solution was then stirred at room temperature for 45 minutes. After 45 minutes, an additional amount of trifluoroacetic anhydride (350 μL) was added, and stirring continued for 15 minutes at room temperature. The solution was cooled to 0 °C, and saturated aqueous sodium bicarbonate (10 mL) was added. The mixture was then partitioned between dichloro-methane (300 mL) and saturated aqueous bicarbonate (40 mL). The layers were separated; the organic layer was washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was purified via medium pressure liquid chromatography eluting with a gradient of hexanes:ethyl acetate (80:20 to 60:40) to give 1.84 g (53 % yield) of the title compound. MS (APCI+) m/z 377 (M+H)+.
E. N-(l-Azetidin-3-yl-propyl)-2,2,2-trifluoroacetamide hydrochloride
Figure imgf000115_0001
A mixture of N-[l-(l-benzhydryl-azetidin-3-yl)propyl]-2,2,2- trifluoroacetamide (1.72 g, 4.57 mmol), 10% Pd/C (2.02 g), concentrated hydrochloric acid (12.0 M, 0.380 mL) in methanol (60 mL) was hydrogenated at 50 psi for 6 hours. An additional amount of 10% Pd/C (1.5 g) was added, and the hydrogenation continued for 22 hours. The solvent was removed under reduced pressure to deliver a yellow residue. The residue was then concentrated several times with toluene and then dried in vacuo at 50 °C for several hours to deliver the title compound contaminated with diphenylmethane. The crude material was triturated with hexanes to provide 1.13 g, (100 % yield) of the title compound. MS (APCI+): m/z 211 (M+H)+. Example 5 Preparation of 2,2,2-Trifluoro-N- (3-methyl-azetidin-3-yImethy l)-acetamide hydrochloride
Figure imgf000116_0001
A mixture of N-(l-Benzhydryl-3-methyl-azetidin-3-ylmethyl)-2,2,2- trifluoro-acetamide (3.19 g, 8.80 mmol), 10% Pd/C (2.5 g), concentrated hydrochloric acid (12 M, 0.732 mL) in methanol (50 mL) was hydrogenated at 50 psi for 8 hours. The solvent was removed under reduced pressure to deliver a yellow residue. The residue was then concentrated several times with toluene. The resulting solid was then triturated with hexanes, and the supernatant was discarded. The resulting white solid was dried in vacuo to provide 1.91 g (93 % yield) of the title compound. MS (APCI+): m/z 197 (M+H)+.
Example 6 Preparation of (R) and (S)-l-Pyrrolidin-3-yl-cyclopropylamine
Figure imgf000116_0002
N,N-Dibenzylacrylamide
Figure imgf000116_0003
-78 °C - rt A round bottom flask was charged with tetrahydrofuran (3750 mL) and cooled to -78 °C under nitrogen. Acryloyl chloride. (55.7 g, 48.9 mL, 0.615 mol) and diisopropylethylamine (87.3 g, 118 mL, 0.676 mol) were added followed by the slow addition (over a period of 20 minutes) of dibenzylamine (109.6 g, 106 mL, 0.555 mol). The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 1.0 hour. A large quantity of white precipitate was observed and thin layer chromatography indicated the reaction was complete. The solids were removed by filtration and the filtrate was concentrated under vacuum to afford a quantitative yield of the title compound.
B. N-(Trimethylsilylmethyl)-α-methylbenzylamine
Figure imgf000117_0001
A mixture of (S)-(-)- -methylbenzylamine (100 g, 106.4 mL, 0.82 mol), chloromethyltrimethylsilane (115.1 mL, 101.2 g, 0.82 mol), and triethylamine (126.5 mL, 96.2 g, 0.95 mol) was heated at reflux for 24 hours until LCMS indicated the reaction was complete. The reaction mixture was triturated with heptane and the HCl salt was filtered off. The heptane filtrate was concentrated to an oily residue which was distilled under vacuum (42-50 °C/0.4-0.7 m Hg) to furnish 67.8 g (40% yield) of the title compound.
N-(Methoxymethyl)-N-(trimethylsilylmethyl)-α-methylbenzylmine
Figure imgf000117_0002
To a stirred solution of aqueous formaldehyde (37%, 152.1 g, 1.9 mol) at 0 °C was added the N-(trimethylsilylmethyl)-α-methylbenzylamine from the previous step (310 g, 1.5 mol) over a period of 0.5 hour followed by the addition of methanol (100 mL) and potassium carbonate (200 g). The reaction mixture was stirred at 0-10 °C for 1-2 hours. The mixture was filtered and the filtrate was extracted with diethyl ether (1 time). The ether layer was dried with sodium sulfate and concentrated to an oil which was distilled using a Kugelrohl apparatus to furnish 210 g (56%) of the title compound. D. l-(l-Phenyl-ethyI)-pyrrolidine-3-carboxylic acid dibenzylamide
Figure imgf000118_0001
NN-Dibenzylacrylamide (79.5 g, 0.317 mol) and Ν-(methoxymethyl)-Ν- (trimethylsilylmethyl)-α-methylbenzylmine (103 g, 0.412 mol) were dissolved in CH2C12 (1500 mL) and cooled to 0 °C. Trifluoroacetic acid solution (1.0 M in CH2C12, 27 mL) was added over a period of 20 minutes and the resulting reaction mixture was stirred at room temperature overnight. The mixture was washed with aqueous NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (heptane-EtOAc-Et3N/10:2:0.1) to furnish 97.7 g of the title compound (77% yield) as a mixture of two diasteromers.
E. Dibenzyl-{l-[l-(l-phenyl-ethyl)-pyrrolidin-3-yl]-cyclopropyl}-amine NBn2
Figure imgf000118_0002
To a round bottom flask charged with tetrahydrofuran (1400 mL) was added ethylmagnesium bromide (EtMgBr) (3.0 M in Et20, 178 mL, 0.534 mol) at -78 °C. A solution of Ti(OiPr)4 (64.8 g, 66.0 mL, 0.228 mol) in THF (150 mL) was added then added at a rate to maintain the temperature below -68 °C. The dark solution was allowed to stir at -68 °C for 3 minutes before a solution of 1-(1- phenyl-ethyl)-pyrrolidine-3-carboxylic acid dibenzylamide (86.6 g, 0.218 mol) in THF (150 mL) was added below -68 °C. The reaction mixture was allowed to warm to room temperature, and then was stirred at room temperature for 1.0 hour and then was heated at reflux for 1.0 hour. The reaction mixture was then cooled to 8 °C. EtMgBr (3.0 M in ether, 150 mL, 0.450 mol) was added followed by the rapid addition of Ti(OzPr)4 (54.6 g, 55.6 mL, 0.192 mol) in THF (150 mL). The resulting mixture was stirred at room temperature for 1.0 hour before it was quenched with aqueous ammonium chloride (3000 mL) and water (800 mL). The mixture was filtered through Celite, rinsed with ether. The organic layer was separated. The aqueous layer was made basic (pH ~ 8.5) with aqueous NaOH and extracted with ether. The combined organic layers were dried over Na2SO , concentrated and purified by flash chromatograph (heptane-EtOa\Ac- Et3N/10:l:0.1) to provide the title compound as a mixture of stereoisomers, which were separated prior to subsequent transformations. Isomer 1 (31.3 g, 35%) as colorless crystals (mp 76-76.5 °C). The stereochemical structure of isomer 1 was confirmed by a single crystal X-ray diffraction experiment.
Isomer 2: The impure oil (18 g) from the above purification was further chromatographed with heptane/methyltbutyl ether (MTBE)/Et3N (100:0.5:0.5) to furnish 11 g of isomer 2 which was about 90% pure as a colorless oil. This oil was dissolved in Et2O (350 mL) and titrated with 2.0 M Et2O-HCl (12.8 mL). The resulting white solid was collected by filtration, rinsed with ether, dissolved in MeOH, neutralized with 15% NaOH, extracted with ether (2 times), washed with brine, dried over Na2SO4, concentrated under vacuum to afford a thick oil which was recrystallized in EtOH at -30 °C to furnish 10.1 g of the title compound (22% yield) as colorless crystals (mp 61-61.3 °C).
F. S-l-Pyrrolidin-3-yl-cyclopropylamine
Figure imgf000119_0001
Dibenzyl- { 1 -[ 1 -(1 -phenyl-ethyl)-pyrrolidin-3-yl]-cyclopropyl } -amine
(3. OOg, 7.32 mmol) was charged with 20% Pd/C and subjected to 50 psi hydrogenation conditions. After 48 hours the reaction was filtered and concentrated to give 764 mg of the title compound, (yield: 83%). MS (APCI+): m/z 127 (M+H)+.
G. (R)- 1 -Pyrrolidm-3-yI-cyclopropyIamine
Figure imgf000120_0001
Dibenzyl- { 1 - [ 1 -( 1 -phenyl-ethyl)-pyrrolidin-3-yl] -cyclopropyl } -amine (3.01g, 7.32 mmol) was charged with 20% Pd/C and subjected to 50 psi hydrogenation conditions. After 48 hours the reaction was filtered and concentrated to give 844 mg of the title compound, (yield: 91%). MS (APCI+): m/z 127 (M+H)+.
Example 7 Preparation of Pyrrolidin-3-ylmethyI-carbamic acid tert-butyl ester
A. (S)-Methanesulfonic acid l-benzyl-pyrrolidin-3-yl ester
Figure imgf000120_0002
l-Benzyl-pyrrolidin-3-ol (Synthetic Communications, 1985) (25.01g, 141 mmol) was taken up in dichloromethane and charged with triethylamine (29 mL). The resulting solution was cooled to 0 °C and charged with mesyl chloride (13.1 mL). After 14 hours the reaction was washed with saturated sodium bicarbonate followed with water and brine. The organic layer was dried and concentrated to give the title compound (30.2g, 84 % yield). MS (APCI+): m/z 256 (M+H)+. B. (R)-l-Benzyl-pyrrolidine-3-carbonitrile
Figure imgf000121_0001
(R)-l-Benzyl-pyrrolidine-3-carbonitrile (29.8g, 117 mmol) was taken up in acetonitrile and charged with sodium cyanide (20.2g, 412 mmol) and tetra butyl ammonium cyanide (3.1 lg, 11.6 mmol) then heated to reflux. After 48 hours the reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water and brine. The organic layer was dried, concentrated and purified via column chromatography (3:1 hexanes/ethyl acetate) leaving 15.4g of the title compound (71 % yield). MS (APCI+): m/z 187 (M+H)+.
(R)-C-(l-Benzyl-pyrrolidin-3-yl)-methylamine
Figure imgf000121_0002
l-Benzyl-pyrrolidine-3-carbonitrile (5.08g, 27.3 mmol) was taken up in
THF and cooled to 0 °C. After 10 minutes LAH (2.09g, 55.1 mmol) in THF at 0 °C was slowly added to the pyrrolidine solution. Gas evolution was observed, and the reaction was allowed to continue at 0 °C for 30 minutes. The reaction was allowed to warm to room temperature and stirred for 2 additional hours. The reaction was quenched with water (2mL), IN NaOH (2 mL), and again water (6 mL). The resulting slurry was filtered over a pad of celite which was washed with dichloromethane and the combined filtrates were concentrated to give 4.2 g of the title compound (yield: 82%). MS (APCI+): m/z 191 (M+H)+. D. (R)-(l-Benzyl-pyrrolidin-3-ylmethyI)-carbamic acid tert-butyl ester
Figure imgf000122_0001
R-C-(l-Benzyl-pyrrolidin-3-yl)-methylamine (2.033g, 10.7 mmol) was taken up in THF and charged with boc anhydride (6.787g, 31 mmol). The resulting solution was heated gently to 46 °C. After 6 hours the resulting solution was cooled to room temperature and concentrated. The crude residue was taken up in dichloromethane and washed with 1.0 N HCl. The organic washes were purified via chromatography (0-10% MeOH/CB^C^) to provide 2.4 g of the title compound (yield: 76%). MS (APCI+): m/z 291 (M+H)+.
E. Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester
Figure imgf000122_0002
(R)-(l-Benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester
(l.OOg, 3.44 mmol) was charged with 20% Pd/C and hydrogenated at 50 psi. After 48 hours, the reaction was filtered and concentrated to give 511 mg of the title compound (yield: 74%). MS (APCI+): m/z 201 (M+H)+.
Example 8
Preparation of Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester A. [l-(l-Phenyl-ethyl)-pyrrolidin-3-yl]-methanol
Figure imgf000123_0001
5-Oxo-l-(l-phenyl-ethyl)-ρyrrolidine-3-carboxylic acid methyl ester (Journal of Heterocyclic Chemistry, 1992) (lO.Og, 40.5 mmol) was taken up in diethyl ether and added slowly to a slurry of LAH (2.3 lg, 60.86 mmol) in diethyl ether. The resulting solution was heated at reflux for 4 hours. The reaction was cooled to room temperature and quenched with a water/ether mixture. The resulting solution was allowed to stir for 1 additional hour at room temperature. The slurry was filtered and washed with dichloromethane. The filtrates were concentrated at reduced pressure to give 7.76 g of the title compound (yield: 94%). MS (APCI+): m/z 206 (M+H)+.
B. 2-[l-(l-Phenyl-ethyl)-pyrrolidin-3-ylmethyl]-isoindole-l,3-dione
Figure imgf000123_0002
[l-(l-Phenyl-ethyl)-pyrrolidin-3-yl]-methanol (4.4g, 21.5 mmol) was taken up in THF and charged with triphenyl phosphine (6.27g, 23.9 mmol), and phthalimide (3.61g, 24.6 mmol) followed by diisopropylazodicarboxylate (DIAD) (5.08g, 25.1 mmol) dropwise. After 4 hours the reaction was concentrated and the resulting oil was chromatographed (1-10 % isopropyl alcohol/dichloromethane) to provide 5.6 g of the title compound (yield: 77%). MS (APCI+): m/z 335 (M+H)+. C. C-[l-(l-Phenyl-ethyl)-pyrrolidin-3-yl]-methylamine
Figure imgf000124_0001
The phthalimide (5.00g, 14.9 mmol) was taken up in isopropyl alcohol and charged with hydrazine hydrate (7.04g, 149 mmol). The resulting solution was heated to 60 °C. After 1 hour a colorless precipitate had formed. The reaction was diluted with isopropyl alcohol and filtered. The filter cake was washed with isopropyl alcohol and the combined filtrates were concentrated to give an off white oily solid. This residue was partitioned between water and 1:3 dichloromethane:ether and the organic layer was washed with water then dried over sodium sulfate to give 1.68 g of the title compound (yield: 55%): MS (APCI+): m/z 205 (M+H)+.
D. [l-(l-Phenyl-ethyl)-pyrrolidin-3-ylmethyl]-carbamic acid tert-butyl ester Boc
Figure imgf000124_0002
C-[l-(l-Phenyl-ethyl)-pyrrolidin-3-yl]-methylamine (4.01g, 19.6 mmol) was taken up in THF and charged with boc anhydride (15.3g, 70.1 mmol). The resulting solution was heated gently to 50 °C. After 6 hours the resulting solution was cooled to room temperature and concentrated. The crude was taken up in dichloromethane and washed with IN HCl. The organics were concentrated to provide the title compound 3.4g (yield: 58%). MS (APCI+): m/z 305 (M+H)+. E. Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester
Figure imgf000125_0001
[l-(l-Phenyl-ethyl)-pyrrolidin-3-ylmethyl]-carbamic acid tert-butyl ester (3.50g, 11.5 mmol) was taken up in methanol and charged with 20% Pd/C then subjected to 50 psi hydrogenation conditions. After 24 hours the reaction was filtered and concentrated leaving 1.75g of title compound (yield: 76%). MS (APCI+): m/z 201 (M+H)+.
Example 9
Preparation of C-Oxazol-2-yl-C-pyrrolidin-3-yl-methylamine
Figure imgf000125_0002
A. 3-(Hydroxy-oxazoI-2-yl-methyl)-pyrroIidine-l-carboxylic acid benzyl ester
Figure imgf000125_0003
To a solution of oxazole (2.0 g, 29 mmol) in tetrahydrofuran (30 mL) was added borane-tetrahydrofuran complex (32 mL, IM in THF) dropwise at room temperature. The reaction mixture was cooled to -78 °C and tert-butyllithium (19 mL, 1.7 M in hexanes) was added dropwise. After stirring for 30 minutes, a solution of 3-formyl-pyrrolidine-l -carboxylic acid benzyl ester (2.0 g, 29 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at -78 °C for 5 h, then 5% acetic acid in ethanol (180 mL) was added. The mixture was warmed to room temperature, poured into brine and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (40% to 100% ethyl acetate in hexanes) to afford the title compound (4.9 g, 56%). MS (APCI+): m/z 303 (M + H)+.
B. 3-(Aζido-oxaζol-2-yl-methyl)-pyrroIidine-l-carboxylic acid benzyl ester
Figure imgf000126_0001
To a cooled (0 °C) solution of 3-(hydroxy-oxazol-2-yl-methyl)- pyrrolidine-1-carboxylic acid benzyl ester (4.9 g, 16 mmol) in dichloromethane (80 mL) was added triethylamine (2.9 mL, 21 mmol), followed by methanesulfonyl chloride (1.51 mL, 19.4 mmol). The solution was warmed to room temperature and stirred overnight. Dichloromethane was added, and the solution was washed with saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting mesylate was used in the next step without futher purification.
To a solution of the crude mesylate in N,N-dimethylformamide (80 mL) was added sodium azide (10 g, 160 mmol). The resulting mixture was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (0 to 40% ethyl acetate in hexanes) to afford the title compound (4.9 g, 94%) as a colorless oil. MS (APCI+): m/z 328 (M + H)+. C. 3-(Amino-oxazol-2-yl-methyl)-pyrrolidine-l-carboxylic acid benzyl ester
Figure imgf000127_0001
To a solution of 3-(azido-oxazol-2-yl-methyl)-pyrrolidine-l-carboxylic acid benzyl ester (1.0 g, 3.1 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (1.85 g, 7.03 mmol) and water (0.60 mL, 31 mmol), and the mixture was allowed to stir at 50 °C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:9 methanol/dichloromethane) to afford the title compound (0.66 g, 71%). 1H NMR (400 MHz, CDC13) δ 7.64-7.01 (m, 7H), 5.19-5.08 (m, 2H), 4.01-3.12 (m, 5H), 2.74-2.53 (m, IH), 2.21-1.55 (m, 4H).
D. C-Oxazol-2-yl-C-pyrrolidin-3-yl-methylamine
Figure imgf000127_0002
To a solution of 3-(Amino-oxazol-2-yl-methyl)-pyrrolidine-l -carboxylic acid benzyl ester (0.65 g, 2.2 mmol) in methanol (10 mL) was added ammonium formate (0.68 g, 11 mmol) and 10% palladium on carbon (0.70, 0.65 mmol). The reaction mixture was heated at 65 °C for 2.5 hours, cooled to room temperature, and filtered. The filtrate was concentrated in vacuo to afford the title compound (0.36 g, 100%). 1H NMR (400 MHz, CDC13) δ 7.95 (s, IH), 7.14 (s, IH), 4.04- 3.92 (m, IH), 3.39-2.58 (m, 7H), 2.18-1.51 (m, 3H).
Example 10 Preparation of (2-Cyano-l-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl ester
M
Figure imgf000128_0001
3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrroIidine-l- carboxylic acid benzyl ester
Figure imgf000128_0002
The 3-(l-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-l- carboxylic acid benzyl ester isomeric mixture was first purified over silica gel column with 25 to 75% ethyl acetate in hexanes over 50 minutes to give diastereomers A and B. Diastereomer A was subjected to chiral HPLC (Chiralpak AD, 10% ethanol in methanol) to give enantiomers Al (8.4 minutes) and A2 (12.2 minutes).
To a solution of 3-(l-tert-butoxycarbonylamino-2-cyano-ethyl)- pyrrolidine-1 -carboxylic acid benzyl ester (0.53g, 1.41mmol) in methanol (25mL) under nitrogen atmosphere were added ammonium formate (0.27g, 4.23mmol) and 10% Pd/C (0.25g). The nitrogen source was removed and the reaction flask was capped. After 2 days, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 0.34g of title compound as a mixture of isomers (100%). MS (APCI+): m z 240 (M+H)+. Example 11 Preparation of Pyrrolidin-3-yl-acetonitrile
Figure imgf000129_0001
A. 3-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-l-carboxylic acid benzyl ester
Figure imgf000129_0002
To a solution of 3-hydroxymethyl-pyrrolidine-l -carboxylic acid benzyl ester (1.80 g, 7.65 mmol) in dichloromethane (10 mL) were added triethylamine (1.60 mL, 11.48 mmol) andp-toluenesulfonyl chloride (1.75 g, 9.18 mmol). After 3 hurs, the reaction mixture was washed with satuarated sodium bicarbonate, water and brine. The organic layer was dried over MgSO4, filtered and filtrate concentrated. Purification via flash column chromatography (ethyl acetate/hexanes gradient) afforded 2.63 g of the title compound (88% yield). MS (APCI+): m/z 390 (M+H)+.
B. 3-Cyanomethyl-pyrrolidine-l-carboxylic acid benzyl ester
Figure imgf000129_0003
To a solution of 3-(toluene-4-sulf onyloxymethyl)-pyrroli dine- 1 -carboxylic acid benzyl ester (1.52 g, 3.90 mmol) in DMSO (3 mL) was added sodium cyanide (0.25 g, 5.07 mmol). The reaction mixture was heated to 70 °C. After 4 hours, the reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated at reduced pressure. Purification via flash column chromatography (ethyl acetate/hexanes gradient) afforded 0.8 lg of the title compound (85%). MS (APCI+): m/z 245 (M+H)+.
C. Pyrrolidin-3-yl-acetonitrile
Figure imgf000130_0001
To a solution of 3-cyanomethyl-pyrrolidine-l-carboxylic acid benzyl ester (0.80 g, 3.27 mmol) in methanol (50 mL) were added triethylamine (0.5 mL) and 10% Pd/C (0.2 g). The reaction vessel was pressurized to 50 psi for 24 hours, filtered through celite, and the filtrate was concentrated at reduced pressure to give 0.36 g of the title compound (100% yield). MS (APCI+): m/z 111 (M+H)+.
Example 12
Pereparation of 3-Amino-3-[l-(3-amino-l-cycIopropyl-6-fluoro-8-methyl-2,4- dioxo-l,2,3,4-tetrahydro-quinaζolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl- propionitrile Hydrochloride salt
Figure imgf000130_0002
Pyrrolidine-3-carboxyIic acid ethyl ester
Figure imgf000130_0003
A solution of l-benzyl-pyrrolidine-3-carboxylic acid ethyl ester (10.00 g, 42.9 mmol) in ethanol (200 mL) was hydrogenated in the presence of 10% Pd/C (2.0 g) at 60 psi for 6 hours. The resulting suspension was filtered through celite, washed with CH2C12, and concentrated under reduced pressure to leave the crude title compound (7.12 g, 100% yield). 1H NMR D(CDC13) 4.16 (q, 2H), 3-02 - 3.17 (m, 3H), 2.82 - 2.94 (m, 2H), 1.91 - 2.07 (m, 2H), 1.26 (t, 3H). LCMS (APCf) 144 (100%, MH+).
B. Pyrrolidine-l,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester
Figure imgf000131_0001
To a solution of crude pyrrolidine-3-carboxylic acid ethyl ester (7.12 g) in CH2C12 (50 mL) at 0 °C was added a solution of di-tert-butyl dicarbonate (10.30 g, 47.2 mmol) in CH C12 (50 mL) over 10 minutes. After warming to room temperature over 18 hours, the reaction mixture was washed with water, then brine, dried (Na2SO4) and concentrated under reduced pressure to leave the title compound which was used without further purification (10.4 g, 100% yield). 1H NMR D(CDC13) 4.14 (q, 2H), 3.27 - 3.69 (m, 4H), 3.02 (m, IH), 2.07 - 2.16 (m, 2H), 1.46 (s, 9H), 1.27 (t, 3H).
C. 3-HydroxymethyI-pyrrolidine-l-carboxylic acid tert-butyl ester
Figure imgf000131_0002
To a solution of pyrrolidine-l,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (10.4 g, 42.9 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL) at 0 °C was added sodium borohydride (NaBFL (3.25 g, 86 mmol) in portions over 30 minutes. After 18 hours, more NaBBU (3.25 g, 86 mmol) was added. After a further 24 hours, the reaction mixture was diluted with ethyl acetate, quenched with saturated aqueous Na2CO3 and stirred for 15 minutes. The layers were separated, the aqueous layer extracted with ethyl acetate, and then the combined organic layers washed twice with water, once with brine, dried (Na2SO ) and concentrated under reduced pressure. The crude product was purified by column chro atography (CH2C12 to CH2Cl2:MeOH 95:5 to 9:1) to give the title compound (8.09 g, 94% yield). 1H NMR D(CDC13) 3.25 - 3.69 (m, 5H), 3.11 (m, IH), 2.40 (m, IH), 1.97 ( , IH), 1.67 (m, IH), L46 (s, 9H).
D. 3-Formyl-pyrrolidine-l-carboxylic acid tert-butyl ester
Figure imgf000132_0001
To a solution of oxalyl chloride (3.86 mL, 44.2 mmol) in CH2C12 (80 mL) at -78 °C under N2 was added a solution of dimethyl sulfoxide (6.28 mL, 88.5 mmol) in CH2C12 (20 mL). After 10 minutes, a solution of 3-hydroxymethyl- pyrrolidine-1 -carboxylic acid tert-butyl ester (8.09 g, 40.2 mmol) in CH2C12 (30 mL) was added over 15 minutes. After a further 30 minutes, triethylamine (28.0 mL, 201 mmol) was added, and the reaction mixture was stirred for 1 hour at -78 °C then 1 hour at room temperature. The reaction mixture was washed twice with water then with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (hexanes :ethyl acetate 9:1 to 1:1) to give the titiecompound (6.98 g, 87%). 1H NMR D(CDC13) 9.69 (d, J 1.7 Hz, IH), 3.26 - 3.80 (m, 4H), 3.03 (m, IH), 2.02 - 2.29 (m, 2H), 1.46 (s, 9H).
E. 3-(Benzenesulfonyl-tert-butoxycarbonylamino-methyl)-pyrrolidine-;l- carboxylic acid tert-butyl ester
Figure imgf000132_0002
To a suspension of tert-butyl carbamate (589 mg, 5.03 mmol) and sodium benzenesulfinate (1.24 g, 7.55 mmol) in water (50 mL) was added a solution of 3- formyl-pyrrolidine-1 -carboxylic acid tert-butyl ester (1.00 g, 5.03 mmol) in methanol (5 mL), followed by formic acid (0.19 mL, 5.03 mmol). The reaction mixture was heated to 60 °C for 2 hours, then stood at room temperature for 7 days. The resulting white solid was filtered off, washed with water and dried thoroughly under reduced pressure to give the title compound (868 mg, 39% yield). 1H NMR D(CDC13) 7.91 (d, 2H), 7.50 - 7.68 (m, 3H), 4.82 - 5.18 (m, 2H), 3.71 (m, IH), 3.54 (m, IH), 3.31 (m, IH), 2.90 - 3.19 (m, 2H), 2.35 (m, 0.5H), 2.18 (m, 0.5H), 1.76 - 1.99 (m, IH), 1.47 (s, 9H), 1.21 (s, 4.5H), 1.18 (s, 4.5H).
F. 3-(l-tert-Butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)- pyrrolidine-1-carboxylic acid tert-butyl ester
Figure imgf000133_0001
To solution isobutyronitrile (4.07 mL, 45 mmol) in dry THF (100 mL) at - 78 °C under an atmosphere of nitrogen was added lithium diisopropylamide (30.3 mL of a 1.5 M solution in cyclohexane, 45 mmol). After 1 hour, this solution was transferred by cannula to a stirred suspension of 3-(benzenesulfonyl-tert- butoxycarbonylamino-methyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (2.00 g, 4.55 mmol) in dry THF (100 mL) at -78 °C. After 7 hours, the reaction was slowly warmed to room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride (NE C1) and extracted twice with CH2C12. The organic phase was washed with saturated aqueous NaHCO3, then dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography, firstly with hexanes: EtOAc 3:1 to 2:1, and then with CH2C12: MeOH 99.5:0.5 to 99:1) to give the title compound (1.52 g, 91% yield): 1H NMR CICDC13) 4.64 - 4.79 (m, IH), 3.42 - 3.85 (m, 3H), 2.93 - 3.29 (m, 2H), 2.54 (m, IH), 1.96 - 2.14 (m, IH), 1.74 - 1.80 (m, IH), 1.35 - 1.47 (m, 24H). LCMS (APCL) 366 (100%, (M-H)"). G. 3-Amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile dihydrochloride salt
Figure imgf000134_0001
To a solution of 3-(l-tert-butoxycarbonylamino-2-cyano-2,2-dimethyl- ethyl)-pyrrolidine-l -carboxylic acid tert-butyl ester (1.52 g, 4.3 mmol) in CH2C12 (100 mL) at 0 °C was added HCl (21.5 mL of a 4 M solution in dioxane, 86 mmol). After 10 minutes, the reaction mixture was warmed to room temperature and stirred for 18 hours before it was concentrated under reduced pressure. The oily residue was taken up in water, extracted twice with CH2C1 , and the aqueous phase concentrated under reduced pressure to give the title compound (704 mg, 73%). 1H NMR D(D2O) 3.68 - 3.82 (m, 2H), 3.52 - 3.63 (m, IH), 3.17 - 3.45 (m, 2H), 2.86 - 3.12 (m, IH), 2.46 (m, IH), 1.89 - 2.10 (m, IH), 1.60 (s, 1.5H), 1.59 (s, 1.5H), 1.57 (s, 1.5H), 1.56 (s, 1.5H). LCMS (APCf) 168 (100%, MH*).
Example 13 Preparation of (±)-N-[l-azetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoroacetamide hydrochloride
Figure imgf000134_0002
A. Cis/trans-3-(l-Benzhydrylazetidin-3-yl)-acrylonitrile
Figure imgf000134_0003
A solution of l-benzhydrylazetidine-3-carbaldehyde (1.55 g, 6.17 mmol), diethyl (cyanomethyl)phosphonate (1.30 mL, 8.02 mmol), and cesium carbonate (2.61 g, 8.02 mmol) in tetrahydrofuran (30 mL) was heated at 50 °C for 2 hours. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The solution was then washed with saturated aqueous ammonium chloride (20 mL). The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting residue was purified via medium pressure liquid chromatography eluting with a gradient of hexanes: ethyl acetate (90:10 to 75:25) to deliver 913 mg (54%) of the title compound as a 1:1 mixture of cis/trans-iso eτs. The isomers were collected separately but later combined, -isomer: MS (APCI) (M+l)/Z 275.0; m.p. = 117-120 °C. trans- isomer: MS (APCI) (M+l/Z) 275.0; m.p. = 108-110 °C.
B. (±)-3-Amino-3-(l-benzhydrylazetidin-3-yl)-propionitrile
Figure imgf000135_0001
A saturated solution of ammonia in methanol (30 mL) was added to a 1:1 mixture of cw/trαn5,-3-(l-benzhydrylazetidin-3-yl)-acrylonitrile (863 mg, 3.15 mmol) . The resulting suspension was then heated in a sealed tube at 100 °C for 19 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to deliver 912 mg (99.5%) of the title compound as an oil. MS (APCI) (M+l)/Z 292.1.
C. (±)-N-[l-(l-benzhydryl-azetidin-3-yl)-2-cyanoethyl]-2,2,2- trifluoroacetamide
Figure imgf000136_0001
A solution of 3-amino-3-(l-benzhydrylazetidin-3-yl)-propionitrile (905 mg, 3.11 mmol) and triethylamine (1.30 mL, 9.32 mmol) in dichloromethane (30 mL) at 0 °C was treated with trifluoroacetic anhydride (0.659 mL, 4.67 mmol). The solution was then stirred at room temperature for 45 minutes. The solution was then cooled to 0 °C, and water (5 mL) was added. The mixture was then further diluted with dichloromethane (50 mL) and water (15 mL). The layers were separated, and the organic layer was washed with water (2 x 20 mL). The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting residue was purified via medium pressure liquid chromatography eluting with a gradient of hexanes:ethyl acetate (75:25 to 55:45) to deliver 952 mg (79%) of the title compound. MS (APCI) (M+l)/Z 388.0.
D. (±)-N-[l-azetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoroacetamide hydrochloride
Figure imgf000136_0002
A solution of N-[l-(l-benzhydrylazetidin-3-yl)-2-cyanoethyl]-2,2,2- trifluoroacetamide (491 mg, 1.27 mmol) in dichloroethane (15 mL) was cooled to 0 °C, whereupon, 1-chloroethyl chloroformate (0.410 mL, 3.80 mmol) was added. The resulting solution was heated at reflux for 2 hours. The solution was then concentrated under reduced pressure to deliver an oil. Methanol (15 mL) was added to the oil, and the resulting solution was heated at reflux for 2 hours. The solvent was removed under reduced pressure to deliver a thick yellow oil. The oil was triturated with hexanes several times, and the supernatant was discarded. The title compound was delivered as a yellow residue, 391 mg. MS (APCI) (M+l)/Z 222.0.
Example 14 Preparation of (2-Cyano-l-pyrrolidin-3-yl-ethyl)-methyl-carbamic acid tert- butyl ester
A. 3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-l- carboxylic acid benzyl ester
Figure imgf000137_0001
To a solution of 3-(2-cyano-vinyl)-pyrrolidine-l-carboxylic acid benzyl ester (4.40 g, 17.2 mmol) in absolute ethanol (50 mL) was added methyl amine (approximately 3 mL) and the solution was heated in a sealed reactor at 80 °C for 14 hours. The solution was concentrated in vacuo. The resulting amine was dissolved in THF (100 mL), Boc anhydride (5.62 g, 25.7 mmol) was added, and the solution was stirred at room temperature for 17 hours. The solution was cone, in vacuo. The residue was taken up in ethyl acetate (100 mL), washed with satd. aq. NH4CI (100 mL) and brine (100 mL), dried with MgSO and concentrated in vacuo. The crude product was purified on a 120 g silica gel column eluted with 20 to 60% ethyl acetate in hexanes over 60 minutes at 50 mlJmin to give 6.08 g of the title compound in multiple fractions (combined yield: 91%). MS (APCI+): m/z 288 (M+H-Boc). Diastereomer A (top spot) yield was 2.59 g (39%) and diastereomer B (bottom spot) yield was 2.82 g (42%).
Chiral HPLC separation of enantiomers
Figure imgf000138_0001
Diastereomer B (2.1 g) was separated by chiral HPLC using a ChiralPak AD column eluted with a methanol/ethanol gradient to give 0.87 g of isomer Bl (41%) and 0.53 g of isomer B2 (25%).
B. (2-Cyano-l-pyrrolidin-3-yl-ethyl)-methyl-carbamic acid tert-butyl ester
Figure imgf000138_0002
A solution of 3-(l-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine- 1-carboxylic acid benzyl ester (diastereomer B, 0.690 g, 1.78 mmol) in THF (50 mL) was hydrogenated with 10% Pd/C. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 0.436 g of title compound (yield: 97%). MS (APCI+): m/z 254 (M+H).
Example 15 Alternative Preparation of 3-(l-tert-ButoxycarbonyIamino-2-cyano-ethyl)- pyrrolidine-1-carboxylic acid benzyl ester
Figure imgf000139_0001
To a solution of 3-(l-tert-butoxycarbonylamino-2-cyano-ethyl)- pyrrolidine-1-carboxylic acid benzyl ester (isomer B2) (586 mg, 1.57 mmol) in anhydrous DMF (12 mL) was added NaH (60 wt%, 188 mg, 4.71 mmol) and the solution was stirred at room temperature for 1 hour. Methyl iodide (1.78 g, 12.5 mmol) was then added to the mixture and it was stirred at room temperature for 1 hour. The solution was poured into satd. aq. NH4C1 (80 mL) and extracted with diethyl ether (120 mL). The organics were washed with brine (50 mL), dried with MgSO4 and concentrated in vacuo. The crude was run on a 10 g silical gel column eluted with 20 to 70% ethyl acetate in hexanes over 1 hour to give 0.44 g of the title compound (yield: 72%). MS (APCI+): m/z 288 (M+H-Boc).
B. Coupling of Sidechain Precursors to Quinolone Cores
Coupling Example 1 Preparation of 9-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-8-fluoro-3- methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid
Figure imgf000140_0001
A. 9- [3- (1 -tert-Butoxycarbonylamino-2-cyano-ethyl)-py rrolidin-1-yl] -8- fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5- carboxylic acid
Triethyl amine
Figure imgf000140_0002
Figure imgf000140_0003
To a solution of (2-cyano-l-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl ester (256 mg, 1.07 mmol) and 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-l- oxa-3a-aza-ρhenalene-5-carboxylic acid (281 mg, 1.00 mmol) in acetonitrile (8 mL) was added triethylamine (506 mg, 5.00 mmol) and the solution was heated at 80 °C for 4 days. The solution was concentrated in vacuo. The residue was taken up in chloroform (50 mL), washed with saturated aqueous ammonium chloride (50 mL), dried with MgSO4 and concentrated in vacuo. The crude was run on a 40 g silica gel column eluted with 0 to 8% methanol in dichloromethane over 1 hour to give 241 mg of title compound (yield: 48%). MS (APCI+): m/z 501 (M+H).
B. 9-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6- oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid ήe
Figure imgf000141_0001
To a solution of 9-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)- pyrrolidin-l-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza- phenalene-5- carboxylic acid (241 mg, 0.481 mmol) in dichloromethane (5 mL) was added a 10 wt% solution of HCl in ethanol (1 mL) and the solution stirred at room temperature for 16 hours. The mixture was diluted with methylene chloride. The precipitate was collected by vacuum filtration and rinsed with ethyl acetate. The bright yellow solid was dried at 45 °C under vacuum to give 62 mg of the title compound as the hydrochloride salt (yield: 32%). MS (APCI+): m/z 401 (M+H).
Coupling Example 2
Preparation of 7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-
6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000141_0002
To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile (200 mg, 1.44 mmol) and 1 -cyclopropyl-6 ,7-difluoro-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid (265 mg, 1.00 mmol) in acetonitrile (10 mL) was added triethylamine (505 mg, 5.00 mmol) and the solution was heated at 80 °C for 17 hours. The precipitate was collected by vacuum filtration and rinsed with acetonitrile. The solid was dried overnight at 45 °C under vacuum to give 281 mg of title compound (yield: 73%). MS (APCI+): m/z 385 (M+H). Coupling Example 3 Preparation of 7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-
6-fluoro-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid
Figure imgf000142_0001
To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile (200 mg, 1.44 mmol) and 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro- [l,8]naphthyridine-3-carboxylic acid (282 mg, 1.00 mmol) in acetonitrile (10 mL) was added triethylamine (505 mg, 5.00 mmol) and the solution was heated at 80 °C for 17 hours. The precipitate was collected by vacuum filtration and rinsed with acetonitrile. The solid was dried overnight at 45 °C under vacuum to give 240 mg of the title compound (yield: 62%). MS (APCI+): m/z 386 (M+H).
Coupling Example 4
Preparation of 7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-
8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
7-[3-(l-tert-ButoxycarbonyIamino-2-cyano-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid difluoroboronate ester
Figure imgf000142_0002
To a solution of l-cyclopropyl-7-fluoro-8-methoxy-4-oxo-l,4-dihydro- quinoline-3-carboxylic acid difluoroboronate ester (0.45 g) and the (2-Cyano-l- pyrrolidin-3-yl-ethyl)-carbamic acid t-butyl ester (1.3 equiv.) in acetonitrile (4 mL) was added triethylamine (5 equiv.) and the solution was heated at 80 °C for 24 hours. The solution was then concentrated and the crude was used directly in the next reaction. MS(APCI+): m/z 497.3 (M - BF2 + H).
B. 7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidin-l-yl]-l- cycIopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000143_0001
To a solution of 7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)- pyrrolidin- 1 -yl] - 1 -cyclopropyl-8 -methoxy-4-oxo- 1 ,4-dihydro-quinoline-3- carboxylic acid difluoroborate ester in EtOH (4 mL) was added triethylamine (5 equiv.), and the reaction was heated to 80 °C for 6 hours. The crude solution was concentrated, then taken up in chloroform, washed with NH4CI (aqueous), dried over Na2SOφ and concentrated. The crude material was purified by flash chromatography (isocratic; 97:3 EtOAc:EtOH) to deliver the pure carboxylic acid (0.50 g, 72% for two reactions). MS(APCI+): m/z 497.3 (M + H).
C. 7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000143_0002
To a solution of crude 7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)- pyrrolidin-l-yl]-l-cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid (0.698 g) in dichloromethane (5 mL) was added 10% ethanolic HCl (5 mL) and the reaction was stirred at room temperature overnight. The crude reaction mixture was concentrated, taken up in EtOAc (15 mL), and sonicated for 20 minutes. The resulting precipitate was collected by filtration, delivering the pure product as a yellow solid (0.315 g, 57%), MS(APCI+): m z 397.3 (M + H).
Coupling Example 5
Preparation of 7-[3-(l-Amino-cyclopropyl)-azetidin-l-yl]-l-cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoIine-3-carboxylic acid
Figure imgf000144_0001
A. l-Cyclopropyl-6-fluoro-8-methyl-4-oxo-7-{3-[l-(2,2,2-trifluoro- acetylamino)- cyclopropyl]-azetidin-l-yl}-l,4-dihydro-quinoline-3 carboxylic acid difluoroboronate ester
Figure imgf000144_0002
To a solution of the l-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-l,4- dihydro-quinoline-3-carboxylic acid difluoroboronate ester (0.400 g) and N-(l- azetidin-3-yl-cyclopropyl)-2,2,2-trifluoro-acetamide (1.5 equiv.) in DMSO (3 mL) was added triethylamine (5 equiv.), and the solution was heated to 80 °C overnight. The crude solution was loaded on a reverse-phase medium pressure liquid chromatography (MPLC) column. The acetonitrile was removed from the eluent, and the remaining aqueous slurry was immediately subjected to the next reaction, MS(APCI+): m/z 468.2 (M - BF + H).
B. 7-[3-(l-Amino-cyclopropyl)-azetidin-l-yl]-l-cycIopropyl-6-fluoro-8- methyl-4-oxo- l,4-dihydro-quinoIine-3-carboxylic acid
Figure imgf000145_0001
To a solution of the l-cyclopropyl-6-fluoro-8-methyl-4-oxo-7-{3-[l- (2,2,2-trifluoro-acetylamino)-cyclopropyl]-azetidin-l-yl}-l,4-dihydro-quinoline- 3-carboxylic acid difluoroboronate ester in 75% aqueous methanol (30 mL) was added 10 mL of saturated sodium bicarbonate and the reaction was heated to 70 °C for 3 days. The solution was then concentrated to 10 mL, decanted away from precipitated NaHCO3, and loaded directly onto a reverse-phase MPLC column. The product eluted in pure form delivering 0.23 g (51% for two steps) of the title compound, MS(APCI+): m/z 372.3 (M + H).
C. 7-{3-[l-(2-Cyano-ethyIamino)-cyclopropyl]-azetidin-l-yl}-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoIine-3- carboxylic acid
Figure imgf000145_0002
7-[3-(l-Amino-cyclopropyl)-azetidin-l-yl]-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (free base) (0.23 g) was dissolved in MeOH (20 mL), and acrylonitrile (10 equiv.) and triethylamine (5 equiv.) were added. The solution was stirred at room temperature overnight, and then heated to 50 °C for several hours. The crude material was then concentrated and dissolved in a small amount of water, and loaded onto a reverse-phase MPLC for purification, (0.11 g, 42%) MS(APCI+): m/z 425.3 (M + H). Coupling Example 6 Preparation of 7-{3-[(2-Cyano-ethylamino)-methyl]-3-ethyl-azetidin-l-yl}-l- cyclopropyI-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000146_0001
A. l-Cyclopropyl-7-{3-ethyl-3-[(2,2,2-trifluoro-acetylamino)-methyl]- azetidin-l-yl}-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid difluoroboronate ester
Figure imgf000146_0002
To a solution of l-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-l,4-dihydro- quinoline-3-carboxylic acid difluoroboronate ester (1.0 g) and N-(3-ethyl-azetidin- 3-ylmethyl)-2,2,2-trifluoro-acetamide (2 equiv.) in DMSO (8 mL) was added triethylamine (5 equiv.), and the solution was heated to 80 °C for four hours. The crude solution was applied to the top of a reverse-phase MPLC directly delivering a mixture of the product and the carboxylic acid (boronate hydrolysis (0.70 g, 49%). MS(APCI+): m/z 470.1 (M + H).
B. 7-(3-Aminomethyl-3-ethyl-azetidin-l-yl)-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000146_0003
To a solution of 7-(3-Aminomethyl-3-ethyl-azetidin-l-yl)-l-cyclopropyl- 6-fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester in 50 mL water and 100 mL methanol was added 50 mL of saturated potassium carbonate and the reaction was heated to 60 °C overnight. The solution was then concentrated to 30 mL, and loaded directly onto a reverse phase column. 0.41 g product recovered (74%), MS(APCI+): m/z 374.2 (M + H).
C. 7-{3-[(2-Cyano-ethylamino)-methyI]-3-ethyl-azetidin-l-yl}-l- cyclopropyl-6-fluoro-8-methyI-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid
Figure imgf000147_0001
7-(3-Aminomethyl-3-ethyl-azetidin-l-yl)-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (0.410 g) was dissolved in 10 mL MeOH, and acrylonitrile (3 equiv.) was added. The solution was stirred at room temperature overnight, and then heated to 50 °C for several hours. The crude material was then concentrated and dissolved in a small amount of water, and loaded onto a reverse-phase MPLC for purification.
Coupling Example 7
Preparation of 7-{3-[l-(2Cyanoethylamino)-propyl]-azetidin-l-yl}-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid
A. l-Cyclopropyl-6-fluoro-8-methyl-4-oxo-7-{3-[l-(2,2,2- trifluoroacetyIamino)-propyl}azetidin-l-yl}l,4-dihydroquinoline-3- carboxylic acid
Figure imgf000148_0001
A solution of l-Cyclopropyl-6,7-difluoro-8-methyl-4-oxo-l,4-dihydro- quinoline-3-carboxylic acid difluoroboronate ester (350 mg, 1.07 mmol), N-(l- azetidin-3-yl-propyl)-2,2,2-trifluoroacetamide hydrochloride (660 mg, 2.68 mmol), and diisopropylethylamine (0.932 mL, 5.35 mmol) in DMSO (3 mL) was heated at 80 °C for 20 hours. The solution was cooled to room temperature and diluted with ethanol (20 mL) and then triethylamine (1.05 mL, 7.50 mmol) was added. The resulting solution was then heated at reflux for 4 hours. The ethanol was removed under reduced pressure to deliver a red solution. The solution was diluted with dichloromethane (100 ml) and washed with 1 Ν hydrochloric acid (20 mL), water (2x20 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. A red semi-solid was afforded. Dichloromethane (8 mL) was added to partially dissolve the semi-solid. Hexanes (6 mL) were slowly added to cause additional solid formation. The mixture was then placed in the refrigerator for 1 hour. The suspension was then filtered to deliver 278 mg (55%) of the title compound as an orange solid. Melting point =220-223 °C; MS (APCI) m/z 470.0.
B. Sodium 7-[3-(l-aminopropyl)-azetidm-l-yl]-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l,4-dihydroquinoline-3-carboxylate
Figure imgf000148_0002
Saturated aqueous sodium carbonate (4.5 mL) was added to a suspension of 1 -Cyclopropyl-6-fluoro-8-methyl-4-oxo-7- { 3-[ 1 -(2,2,2-trifluoroacetylamino)- propyl}-azetidin-l-yl}-l,4-dihydroquinoline-3-carboxylic acid (260 mg, 0.554 mmol) in a mixture of methano water (8 mL:4 mL). The mixture was then heated at 50 °C. After 2 hours, starting material was still present, so the temperature was raised to 70 °C; stirring continued at 70 °C for 6 hours. The methanol was then removed under reduced pressure, to give a solution. The resulting solution was then loaded directly on a reverse phase column. Elution of the column was done with a gradient of water: acetonitrile (99:1 to 30:70) to deliver a yellow solid. The solid was dissolved in a minimum amount of water and lyophilized to deliver 164 mg (75%) of the title compound as a fluffy yellow solid. Melting point = 160-170 °C; MS (APCI) m/z 374.0.
7-{3-[l-(2Cyanoethylamino)-propyI]-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid
Figure imgf000149_0001
Acrylonitrile (1 mL) was added to a solution of sodium 7-[3-(l- aminoproρyl)-azetidin- 1 -yl]- 1 -cyclopropyl-6-fluoro-8-methyl-4-oxo- 1 ,4- dihydroquinoline-3-carboxylate (87 mg, 0.220 mmol) in methanol (1.5 mL), The solution was then stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to deliver an oil. The oil was purified via medium pressure liquid reverse phase chromatography eluting with a gradient of water: acetonitrile (99:1 to 50:50) to deliver 32 mg of a yellow solid. The solid was further purified via preparatory high performance liquid reverse phase chromatography eluting with a gradient of water (0.1% formic acid): acetonitrile (0.1% formic acid) (95:5 to 50:50) to afford a yellow residue. The residue was dissolved in a minimum amount of water and lyophilized to deliver 19 mg (20%) of the title compound as a yellow solid. The compound was approximately 75% parent and 25% formate salt by 1H NMR. LC/MS (APCI) 427.2; HPLC purity = 100%.
Couplin Example 8
Preparation of Sodium 7-{3-[(2-cyanoethylamino)-methyl]-3rmethyIazetidin- l-yl}-l-cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dyhydroquinoline-3- carboxylate
Figure imgf000150_0001
A. l-Cyclopropyl-6-fluoro-8-methyl-7-{3-methyl-3-[(2,2,2- trifluoroacetylamino)-methyl]azetidin-l-yl}-4-oxo-l,4- dihydroquinolone-3-carboxylic acid
Figure imgf000150_0002
A solution of l-Cyclopropyl-6-fluoro-8-methyl-7-{3-methyl-3-[(2,2,2- trifluoroacetylamino)-methyl] azetidin- 1 -yl } -4-oxo- 1 ,4dihydroquinolone-3- carboxylic acid difluoroborate ester (1.43 g, 4.37 mmol), 2,2,2-Trifluoro-N-(3- methyl-azetidin-3-ylmethyl)-acetamide hydrochloride (1.88 g, 8.08 mmol), and diisopropylethylamine (3.81 mL, 21.9 mmol) in dimethylsulfoxide (10 mL) was heated at 80 °C for 4 hours. The solution was cooled to room temperatureand diluted with ethanol (80 mL) and then triethylamine (4.27 mL, 30.6 mmol) was added. The resulting solution was then heated at reflux for 4 hours. The ethanol was removed under reduced pressure to deliver a red solution. The solution was diluted with dichloromethane (300 ml) and washed with 1 N hydrochloric acid (50 mL), water (3 x 30 mL), dried (magnesium sulfate), filtered, and concentrated under reduced pressure. An orange solid was afforded. Dichloromethane (15 mL) was added to partially dissolve the solid. Hexanes (20 mL) were slowly added to cause additional solid formation. The mixture was then placed in the refrigerator for 1 hour. The suspension was then filtered to deliver 1.59 g (80%) of the title compound as an orange solid. MS (APCI) m z 456.1; mp 215-218 °C.
B. Sodium 7-(3-aminomethyl-3-methylazetidin-l-yl)-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydroquinolone-3-carboxylate
Figure imgf000151_0001
Saturated aqueous sodium carbonate (25 mL) was added to a suspension of l-Cycloρroρyl-6-fluoro-8-methyl-7-{3-methyl-3-[(2,2,2-trifluoroacetylamino)- methyl]azetidin-l-yl}-4-oxo-l,4-dihydroquinolone-3-carboxylic acid (1.24 g, 2.72 mmol) in a mixture of methanokwater (45 mL:20 mL). The mixture was then heated at 70 °C for 2 hours. The methanol was then removed under reduced pressure, to give a solution. The resulting solution was then loaded directly on a reverse phase column. The crude product was then purified via medium pressure reverse phase chromatography eluting with a gradient of 100% water to 50% water: 50% acetonitrile to deliver 616 mg (59%) of the title compound as a white powder. MS (APCI) m/z (COOH) 360.1. HPLC purity = 96.4% (254 nm).
C. Sodium 7-{3-[(2-cyanoethylamino)-methyl]-3-methylazetidin-l-yl}-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dyhydroquinoline-3- carboxylate
Figure imgf000152_0001
Acrylonitrile (1.47 mL, 22.3 mmol)) was added to a solution of sodium 7- (3-aminomethyl-3-methylazetidin-l-yl)-l-cyclopropyl-6-fluoro-8-methyl-4-oxo- l,4-dihydroquinolone-3-carboxylate (425 mg, 1.11 mmol) in methanol (10 mL), The solution was then stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to deliver a white residue. The residue was dissolved in a minium amount of water, and the resulting solution was loaded on a reverse phase column. The crude product was purified via medium pressure liquid reverse phase chromatography eluting with a gradient of 100% water to 50%water: 50% acetonitrile to deliver 73 mg (15%)of the title compound as a yellow solid. LC/MS (APCI) m/z (COOH) 413.2. mp= 190-200 °C (decomposition); HPLC purity = 97.4% (254 nm).
Coupling Example 9
Preparation of 7-(3-{l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l- yl)-l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid
Figure imgf000152_0002
l-Cyclopropyl-6-fluoro-8-methoxy-7-[3-(l-methylamino-ethyl)- pyrrolidin-l-yl]-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (WO9209596A1, 1992) (0.274g, 0.679 mmol) was taken up in acrylonitrile (4 mL) and charged with triethylamine (0.1 mL). After 4 hours the solution was concentrated. The residue was taken up in dichloromethane and charged with 2.0 N HCl ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 97 mg of the title compound as the HCl (yield: 31%). MS (APCI+): m/z 457 (M+H).
Coupling Example 10 Preparation of 7-{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoIine-3-carboxylic acid
Figure imgf000153_0001
7-[3-(l - Amino-ethyl)-pyrrolidin- 1 -yl] - 1 -cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-quinoline-3-carboxylic acid HCl salt (WO9914214A1, 1999) (0.347, 0.854 mmol) was taken up in methanol and charged with Et3N (0.5 mL). The reaction was charged with acrylonitrile (1 mL). After 24 hours the solution was concentrated. The residue was taken up in dichloromethane and charged with 2.0 N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 104 mg of the title compound as the HCl salt (yield: 30%). MS (APCI+): m/z 425 (M+H).
Coupling Example 11 Preparation of 7-(3-{l-[(2-Cyano-ethyl)-ethyl-amino]-ethyl}-pyrrolidin-l-yl)- l-cyclopropyl-6-fluoro-8-hydroxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000153_0002
l-Cyclopropyl-7-[3-(l-ethylamino-ethyl)-pyrrolidin-l-yl]-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (WO9209596A1, 1992) (0.103g, 0.240 mmol) was taken up in methanol and charged with triethylamine (0.05 mL). The reaction was charged with acrylonitrile (0.10 mL) and shaken on the orbit shaker. After 12 hours the reaction was concentrated and taken up in dichloromethane and charged with 2.0 N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 62 mg of the title compound as the HCl salt (yield: 55%). MS (APCI+): m/z 471 (M+H).
Coupling Example 12 Preparation of 7-(3-{[(2-Cyano-ethyl)-ethyl-amino]-methyl}-pyrrolidin-l-yl)- l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000154_0001
1 -Cyclopropyl-7-(3-ethylaminomethyl-pyrrolidin- 1 -yl)-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (EP230295, 1987) (0.05g, 0.124 mmol) was taken up in methanol and charged with triethylamine (0.02 mL). The reaction was charged with acrylonitrile (0.1 mL) and the resulting solution was shaken on the orbit shaker. After 12 hours the reaction was concentrated and taken up in dichloromethane and charged with 2N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 29 mg of the product as the HCl salt (yield: 51%). MS (APCI+): m/z 457 (M+H).
Coupling Example 13 Preparation of 7-(3-{l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l- yl)-l-cyclόpropyl-6-fluoro-8-hydroxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid
Figure imgf000155_0001
The fluoroquinolone (WO9209596A1, 1992) (0.05g, 0.124 mmol) was taken up in methanol and charged with triethylamine (0.02 mL). The reaction was charged with acrylonitrile (0.1 mL) and the resulting solution was shaken on the orbit shaker. After 12 hours the reaction was concentrated and taken up in dichloromethane and charged with 2N HCl ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 33 mg of the product as the HCl salt (yield: 58%). MS (APCI+): m/z 457 (M+H).
Coupling Example 14 Preparation of 7-(3-{l-[(2-Cyano-ethyl)-amino]-ethyl}-pyrrolidin-l-yl)-l- cycIopropyl-6-fluoro-8-hydroxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000155_0002
The fluoroquinolone HCl salt (Chemical & Pharmaceutical Bulletin 1994,
42(7), 1442-54) (0.804g, 2.142mmol) was taken up in methanol and charged with triethylamine (0.5 mL). The reaction was charged with acrylonitrile (1 mL). After 12 hours the reaction was concentrated and taken up in dichloromethane and charged with 2N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 850 mg of the product as the HCl salt (yield: 92%). MS (APCI+): m/z 427 (M+H). Coupling Example 15 Preparation of 7-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000156_0001
7-(3-Aminomethyl-pyrrolidin-l-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester
Figure imgf000156_0002
The pyrrolidine (EP153163, 1985) (0.247g, 2.47 mmol) and the 6- desfluoroquinolone (WO9914214, 1999) (0.506g, 1.56 mmol) were taken up in acetonitrile and charged with triethylamine (1.0 mL). After 18 hours the reaction was concentrated leaving 545 mg of the title compound (yield: 87%). MS (APCI+): m/z 406 (M+H). The compound was Boc-protected according to methods readily available to the skilled artisan prior to the hydrolysis step below.
B. 7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000156_0003
7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester (0.600g, 1.19 mmol) was taken up in ethanol and charged with triethylamine (1.0 mL). The resulting solution was heated to 60 °C. After 24 hours the reaction was concentrated, taken up in dichloromethane, and washed with ammonium chloride leaving 523 mg of the title compound (yield: 96%). MS (APCI+): m/z 458 (M+H).
C. 7-{3-[(2-Cyano-ethylamino)-methyI]-pyrrolidin-l-yl}-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000157_0001
7-(3- Aminomethyl-pyrrolidin-1 -yl)- 1 -cyclopropyl-8-methoxy-4-oxo- 1 ,4- dihydro-quinoline-3-carboxylic a cid as the HCl salt (0.332, 0.846 mmol) was taken up in methanol and charged with triethylamine (0.5 mL). The reaction was charged with acrylonitrile (1 mL). After 24 hours the solution was concentrated and taken up in dichloromethane and charged with 2N HCl ether until cloudy.
The resulting precipitate was collected via filtration and washed with diethyl ether leaving 176 mg of the title compound as the HCl salt (yield: 51%). MS (APCI+): m/z 411 (M+H).
Coupling Example 16
Preparation of 7-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin-l-yl}-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000157_0002
7-[3-(l-Amino-cyclopropyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoIine-3-carboxylic acid difluoroboronate ester
Figure imgf000158_0001
l-Pyrrolidin-3-yl-cyclopropylamine (0.886g, 7.00 mmol) was charged with the fluoroquinolone borate ester (EP241206, 1987) (2.01g, 5.85 mmol) taken up in acetonitrile, and charged with triethylamine (4.0 mL). After 20 hours, the reaction was concentrated, leaving 1.76 g of the title compound (yield: 67%). MS (APCI+): m/z 450 (M+H). The compound was submitted to hydrolysis as provided in Example 15, Step B, prior to the following step.
B. 7-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin-l-yl}-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- arboxylϊc acid
Figure imgf000158_0002
7- [3-( 1 -Amino-cyclopropyl)-pyrrolidin- 1 -yl] - 1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid HCl salt (0.8477g, 1.93 mmol) was taken up in methanol and charged with triethylamine (0.40 mL). The reaction was charged with acrylonitrile (1 mL) and shaken. After 12 hours the reaction was concentrated and taken up in dichloromethane and charged with 2N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 647 mg of the title compound as the HCl salt (yield: 67%). MS (APCI+): m/z 455 (M+H). Coupling Example 17
Preparation of 7-(3-Aminomethyl-pyrrolidin-l-yl)-l-cyclopropyl-8-methoxy-
4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000159_0001
7- [3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin- 1 -yl] - 1- yclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid difluoroboronate ester
Figure imgf000159_0002
The pyrrolidine (0.496g, 2.48 mmol) and the 6-desfluoroquinolone (WO9914214, 1999) (0.682g, 2.10 mmol) were taken up in acetonitrile and charged with triethylamine (1.5 mL). After 18 hours the reaction was concentrated leaving 752 mg of the title compound (yield: 69%). MS (APCI+): m/z 506 (M+H).
B. 7-[3-(tert-Butoxycarbonylamino-methyI)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoIine-3-carboxylic acid
Figure imgf000159_0003
7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l-yclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid difluoroboronate ester (0.747g, 1.48 mmol) was taken up in ethanol (50 mL) and charged with triethylamine (1.00 mL). The resulting solution was heated to 80 °C. After 20 hours the reaction was cooled to room temperature and concentrated. The crude oil was taken up in dichloromethane and washed with ammonium chloride. The organics were dried and concentrated leaving 544 mg of the title compound (yield: 80%). MS (APCI+): m/z 458 (M+H).
C. 7-(3-Aminomethyl-pyrroIidin-l-yl)-l-cyclopropyl-8-methoxy-4-oxo- l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000160_0001
The 7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid (O.lOlg, 0.219 mmol) was taken up in dichloromethane and charged with 2N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 55 mg of the title compound as the HCl salt (yield: 70%) MS (APCI+) m/z 358 (M+H).
D. 7-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000160_0002
7-(3-Aminomethyl-pyrrolidin-l -yl)- 1 -cyclopropyl-8-methoxy-4-oxo- 1 ,4- dihydro-quinoline-3-carboxylic acid HCl salt (0.923, 2.35 mmol) was taken up in methanol and charged with triethylamine (0.5 mL). The reaction was charged with acrylonitrile (2 mL). After 24 hours the solution was concentrated and taken up in dichloromethane and charged with 2N HCl/ether until cloudy. The resulting precipitate was collected via filtration and washed with diethyl ether leaving 863 mg of the title compound HCl salt (yield: 75%). MS (APCI+): m/z 411 (M+H).
Coupling Example 18
Preparation of 7-[3-(l -Amino-2-cyano-ethyl)-pyrroIidin-l-yl]-l-cyclopropyl-
6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000161_0001
7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid
Figure imgf000161_0002
To a solution of (2-cyano-l-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl ester (1:1 mixture of diastereomers) (256 mg, 1.07 mmol) and l-cyclopropyl-6,7- difluoro-8-methyl -4-oxo- l,4-dihydro-quinoline-3-carboxylic acid (280 mg, 0.86 mmol) in acetonitrile (10 mL) was added triethylamine (433 mg, 4.3 mmol) and the solution was heated at 80 °C for 3 days. The solution was concentrated in vacuo. To the residue was added ethanol (8 mL) and triethylamine (433 mg, 4.3 mmol) and the mixture was heated at 80 °C for 5 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 mL), washed with saturated aqueous ammonium chloride (50 mL), dried with MgSO and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 8% methanol in dichloromethane over 1 hour to give 100 mg of the title compound (yield: 23%). MS (APCI+): m/z 499 (M+H). B. 7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro- 8-methyI-4-oxo-l,4-dihydro-quinoline-3-carboxy lie acid
Figure imgf000162_0001
To a solution of 7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)- pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid (100 mg, 0.20 mmol) in dichloromethane (5 mL) was added a 10 wt% solution of HCl in ethanol (0.5 mL) and the solution stirred at room temperature for 18 hours. The solvent was removed in vacuo. The yellow solid was slurried in ethyl acetate and dichloromethane, collected by vacuum filtration and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 44 mg of the title compound as the hydrochloride salt (85% parent, yield: 47%). MS (APCI+): m/z 399 (M+H).
Coupling Example 19 Preparation of 9-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-8-fluoro-3- methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aζa-phenalene-5-carboxylic acid
Figure imgf000162_0002
A. 9-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidin-l-yl]-8- fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5- carboxylic acid
Figure imgf000163_0001
To a solution of (2-cyano-l-pyrrplidin-3-yl-ethyl)-carbamic acid tert-butyl ester (270 mg, 1.13 mmol) and 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-l- oxa-3a-aza-phenalene-5-carboxylic acid (313 mg, 0.95 mmol) in acetonitrile (8 mL) was added triethylamine (481 mg, 4.75 mmol) and the solution was heated at 50 °C for 17 hours. The solution was concentrated in vacuo. To the residue was added ethanol (4 mL), dioxane (4 mL) and triethylamine (481 mg, 4.75 mmol) and the mixture was heated at 80 °C for 4.5 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 mL), washed with saturated aqueous ammonium chloride (50 mL), dried with MgSO4 and concentrated in vacuo. The crude was run on a 40 g silica gel column eluted with 0 to 8% methanol in dichloromethane over 1 hour to give 227 mg of the title compound (yield: 48%). MS (APCI+): m/z 501 (M+H).
B. 9-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6- oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid
Figure imgf000163_0002
To a solution of 9-[3-(l-tert-butoxycarbonylamino-2-cyano-ethyl)- pyrrolidin-l-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza- phenalene-5-carboxylic acid (225 mg, 0.45 mmol) in dichloromethane (8 mL) was added a 10 wt% solution of HCl in ethanol (1 mL) and the solution stirred at room temperature for 5 days. The solvent was removed in vacuo. The yellow solid was slurried in methylene chloride and ethyl acetate, collected by vacuum filtration and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 177 mg of the title compound as the hydrochloride salt (88% parent, yield: 87%). MS (APCI+): m/z 401 (M+H).
Coupling Example 20 Preparation of 7-[3-(l-Aminoτ2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-
6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000164_0001
7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrroIidin-l-yl]-l- cyclopropyI-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid
Figure imgf000164_0002
To a solution of (2-cyano-l-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl ester (63 mg, 0.26 mmol) and l-cyclopropyl-6,7-difluoro-8-rnethoxy-4-oxo-l,4- dihydro-quinoline-3-carboxylic acid difluoroboronate ester (86 mg, 0.25 mmol) in acetonitrile (5 mL) was added triethylamine (127 mg, 1.25 mmol) and the solution was heated at 50 C for 22 hours. The solution was concentrated in vacuo. To the residue was added ethanol (5 mL) and triethylamine (127 mg, 1.25 mmol) and the mixture was heated at 80 °C for 6 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 mL), washed with saturated aqueous ammonium chloride (50 mL), dried with MgSO and concentrated in vacuo. The crude product was purified on a 10 g silica gel column eluting with 0 to 8% methanol in dichloromethane over 1 hour to give 39 mg the title compound (yield: 30%). MS (APCI+): m/z 515 (M+H).
B. 7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro- 8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000165_0001
To a solution of 7-[3-(l-tert-Butoxycarbonylamino-2-cyano-ethyl)- ρyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline- 3-carboxylic acid (39 mg, 0.08 mmol) in dichloromethane (5 mL) was added a 10 wt% solution of HCl in ethanol (0.5 mL) and the solution stirred at room temperature for 30 hours. The solvent was removed in vacuo. The yellow solid was slurried in ethyl acetate and dichloromethane, collected by vacuum filtration and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 19 mg of title compound as the hydrochloride salt (85% parent, yield: 51%). MS (APCI+): m/z 415 (M+H).
Coupling Example 21 Preparation of (±)-Sodium 7-[3-(l-amino-2-isocyanoethyl)-aζetidin-lyl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydroquinoline-3- carboxylate
Figure imgf000165_0002
A. (±)-l-CyclopropyI-6-fluoro-7-{3-[2-isocyano-l-(2,2,2- trifluoroacetylamino)-ethyl]-azetidin-l-yl}-8-methyl-4-oxo-l,4- dihydroquinoline-3-carboxylic acid
Figure imgf000166_0001
A solution of l-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-l,4-dihydro- quinoline-3 -carboxylic acid difluoroborate ester (230 mg, 0.703 mmol), N-[l- azetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoroacetamide hydrochloride (326 mg, 1.27 mmol), and diisopropylethylamine (0.613 mL, 3.52 mmol) in dimethylsulfoxide (3 mL) was heated at 80 °C for 12 hours. The solution was cooled to room tempearture and diluted with ethanol (15 mL), and then triethylamine (0.687 mL, 4.93 mmol) was added. The resulting solution was then heated at reflux for 3.5 hours. The solvent was removed under reduced pressure. The residue thus afforded was dissolved in dichloromethane (100 mL), and the resulting solution was washed with saturated aqueous ammonium chloride (20 mL). The layers were separated, and the organic layer was dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting yellow residue was dissolved in ethyl acetate (5 mL). After a few minutes at ambient temperature, some precipitation began. Hexanes (1 mL) were added slowly, followed by slow addition of dichloromethane (1 mL) and then followed by hexanes (3 mL) to deliver 171 mg (51%) of the title compound. LC/MS (APCI) (M+l)/z 481.2.
B. (±)-Sodium 7-[3-(l-amino-2-isocyanoethyl)-azetidin-lyl]-l- cyclopropyl-6-fluoro-8-methyI-4-oxo- 1 ,4-dihydroquinoline-3- carboxylate
Figure imgf000167_0001
Saturated aqueous sodium carbonate (3 mL) was added to a suspension of l-cyclopropyl-6-fluoro-7-{3-[2-isocyano-l-(2,2,2-trifluoroacetylamino)-ethyl]- azetidin-l-yl}-8-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (134 mg, 0.279 mmol) in a mixture of methanokwater (5 mL:2.5 mL). The mixture was then heated at 70 °C for 5 hours. The methanol was then removed under reduced pressure to give a solution. The resulting solution was then loaded directly on a reverse phase column and purified via medium pressure liquid chromatography eluting with a gradient of water: acetonitrile (99:1 to 50:50) to deliver a yellow solid. The solid was dissolved in a minimum amount of water and lyophilized to deliver 73 mg (64%) of the title compound. LC/MS (APCI) (M+l)/z 385.2.
Coupling Example 22 Preparation of 9-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-8-fluoro- 3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid
Figure imgf000167_0002
9-{3-[l-(tert-butoxycarbonyl-methyl-amino)-2-cyano-ethyl]- pyrrolidin-l-yl}-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a- aza-phenalene-5-carboxylic acid
Figure imgf000167_0003
To a solution of (2-cyano-l-pyrrolidin-3-yl-ethyl)-methyl-carbamic acid tert-butyl ester (372 mg, 1.47 mmol) and 8,9-difluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid difluoroborate ester (411 mg, 1.25 mmol) in acetonitrile (15 mL) was added triethylamine (632 mg, 6.25 mmol) and the solution was heated at 50 C for 24 h. The solution was concentrated in vacuo. The residue was taken up in ethanol (8 mL) and dioxane (8 mL) and heated at 80 C for 5 hours. The solution was concentrated in vacuo. The residue was taken up in chloroform (50 mL), washed with satd. aq. ammonium chloride (50 mL), dried with MgSO4 and concentrated in vacuo. The crude was run on a 40 g silica gel column eluted with 0 to 6% methanol in dichloromethane over 1 hour to give 528 mg of 9-{3-[l-(tert-butoxycarbonyl- methyl-amino)-2-cyano-ethyl]-pyrrolidin-l-yl}-8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid as the hydrochloride salt (yield: 82%). MS (APCI+): m/z 515 (M+H).
B. 9-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yI]-8-fluoro-3- methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid hydrochloride salt
Figure imgf000168_0001
To a solution of 9-{3-[l-(tert-butoxycarbonyl-methyl-amino)-2-cyano- ethyl]-pyrrolidin-l-yl}-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza- phenalene-5-carboxylic acid hydrochloride salt (143 mg, 0.28 mmol) in dichloromethane (10 mL) was added 4 N HCl in dioxane (1 mL) and the solution stirred at r.t. for 16 hours. The solvent was removed in vacuo. The yellow solid was slurried in dichloromethane and ethyl acetate, collected by vacuum filtration, rinsed with ethyl acetate and dried under high vacuum (ca. 0.5 torr) overnight to give 109 mg of the title compound as the hydrochloride salt (yield: 95%). MS (APCI+): m/z 415 (M+H)
Coupling Example 23
Preparation of 7-[3(R)-(2-Cyano-l(S)-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoliηe-3-carboxylic acid
Figure imgf000169_0001
A. 7-{3-[l-(tert-Butoxycarbonyl-methyl-amino)-2-cyano-ethyl]- pyrroIidin-l-yl}-l-cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro- quinoline-3-carboxylic acid
Figure imgf000169_0002
To a solution of (2-cyano-l-pyrrolidin-3-yl-ethyl)-methyl-carbamic acid tert-butyl ester (isomer B2) (345 mg, 1.36 mmol) and l-cyclopropyl-6,7-difluoro- 8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester (377 mg, 1.10 mmol) in acetonitrile (8 mL) was added triethylamine (557 mg, 5.50 mmol) and the solution was heated at 50 °C for 4 hours. The solution was concentrated in vacuo. To the residue was added ethanol (10 mL) and triethylamine (557 mg, 5.50 mmol) and the mixture was heated at 80 °C for 4 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 mL), washed with saturated aqueous ammonium chloride (50 mL), dried with MgSO and concentrated in vacuo. The crude was run on a 40 g silica gel column eluted with 0 to 6% methanol in dichloromethane over 1 hour to give 459 mg of the title compound (yield: 79%). MS (APCI+): m/z 529 (M+H).
B. 7-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxy lie acid
Figure imgf000170_0001
To a solution of 7-{ 3-[l-(tert-Butoxycarbonyl-methyl-amino)-2-cyano- ethyl]- pyrrolidin- 1 -yl } - 1 -cyclopropyl-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro- quinoline-3-carboxylic acid (459 mg, 0.87 mmol) in dichloromethane (20 mL) was added a 4 M solution of HCl in dioxane (2.2 mL) and the solution stirred at room temperature for 18 hours. The solvent was removed in vacuo. The yellow solid was slurried in ethyl acetate and dichloromethane, collected by vacuum filtration and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 458 mg of the tit;e compound as the hydrochloride salt (80% parent, yield: 98%). MS (APCI+): m/z 429 (M+H).
Coupling Example 24 Preparation of 7-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l- cyclopropyl-6-fluoro-8-hydroxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000171_0001
7-(3-Aminomethyl-pyrrolidin-l-yl)-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-quinoline-3-carboxylic acid (J. Med. Chem. 1993, 36, 871-882) (0.098g, 0.232 mmol) was taken up in methanol (12 mL) and charged with acrylonitrile (0.016 mL). After 2 days the solution was concentrated leaving 100 mg of the title compound (yield: 98%). MS (APCI+): m/z 429 (M+H).
Coupling Example 25 Preparation of 7-{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000171_0002
7-[3-(l -Amino-ethyl)-pyrrolidin- 1 -yl]- 1 -cyclopropyl-6-fluoro-8-methoxy-
4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (WO9209596A1, 1992) (0.401 lg, 1.03 mmol) was taken up in methanol (50 mL). The resulting solution was charged with triethylamine (0.14 mL) to convert to the free base insitu. The reaction was then charged with acrylonitrile (0.1 mL). Another equivalent of triethylamine (0.15 mL) and acrylonitrile (0.1 mL) were added. After 12 additional hours the reaction was concentrated. The crude was chromatographed (2-15% gradient isopropanol/dichloromethane) to yield 101 mg. PF-00646714-00 (yield: 22%). MS (APCI+): m/z 443 (M+H).
Coupling Example 26 Preparation of 7-{3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l- i cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxyIic acid
Figure imgf000172_0001
7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l- cycIopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid difluoroborate ester
Figure imgf000172_0002
l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid difluoroborate ester (0.280g, 0.816 mmol) and (R)- pyrrolidin-3- ylmethyl-carbamic acid tert-butyl ester (0.321g, 1.60 mmol) were charged with triethylamine (0.45 mL) and taken up in acetonitrile (3 mL). After 24 hours the solution was concentrated leaving 276 mg of the title compound (yield: 90%). MS (APCI+) m/z 524 (M+H).
B. 7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3- carboxylic acid
Figure imgf000173_0001
7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4rθxo- 1 ,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester (0.274g, 0.523 mmol) was taken up in ethanol (5 mL) and charged with triethylamine (0.4 mL). The resulting red solution was heated to 55 °C. After 16 hours the reaction was concentrated leaving 231 mg of the title compound (yield: 92%). MS (APCI+) m/z 476 (M+H).
C. 7-(3-Aminomethyl-pyrrolidin-l-yl)-l-cyclopropyl-6-fluoro-8-methoxy- 4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000173_0002
7-[3-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (0.198g, .416 mmol) was taken up in dichloromethane (5 mL) and charged with 2N HCI/Ether (3 mL). The resulting solution stirred for 2 hours. The solvent was decanted off to afford 147 mg of the title compound (yield: 93%). MS (APCI+) m/z 376 (M+H).
D. 7-{3-[(2-Cyano-ethylamino)-methyl]-pyrroIidin-l-yl}-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000174_0001
7-(3-Aminomethyl-pyrrolidin-l-yl)-l-cycloρropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-quinoline-3-carboxylic acid (0.1995g, 0.471 mmol) was taken up in methanol (25 mL) and charged with triethylamine (0.07 mL) to provide the free base. The reaction was then charged with acrylonitrile (0.05 mL). After 20 hours the reaction was concentrated leaving 162 mg of the title compound(yield: 80%) MS. (APCI+) m/z 429 (M+H).
Coupling Example 27
Preparation of 7-[l-(2-Cyano-ethyϊamino)-5-aζa-spiro[2.4]hept-5-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000174_0002
7-(l-Amino-5-aza-spiro[2.4]hept-5-yl)-l-cyclopropyl-6-fluoro-8-methoxy- 4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (Eur. Pat. Appl. EP550016A1, 1993)(0.140g, 0.361 mmol) was taken up in methanol (3 mL) and charged with triethylamine (0.5 mL). After 5 minutes the reaction was charged with acrylonitrile (0.1 mL). After 12 hours the reaction was concentrated. The crude was chromatographed (1-10% methanol/dichloromethane) to yield 102 mg of the title compound (yield: 61%) MS (APCI+) m/z 441 (M+H). Coupling Example 28
Preparation of 7-[l-(2-Cyano-ethylamino)-5-aza-spiro[2.4]hept-5-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000175_0001
The 7-(3 - Aminomethyl-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-;3-carboxylic acid (J. Med. Chem. 1993, 36, 871-882) (0.1510g, 0.400 mmol) was taken up in methanol (1 mL) in a microwave vial and charged with 2-butenenitrile (0.1 mL). The reaction was subjected to the microwave again for 25 minutes at 160 °C. The reaction was concentrated and purified through column chromatography (2-15% methanol/dichloromethane) to afford 47 mg of the title compound (yield: 26%) MS (APCI+) m/z 443 (M+H).
Coupling Example 29
Preparation of 7-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Figure imgf000175_0002
The 7-(3- Amino-pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-8-methoxy-4- oxo-l,4-dihydro-quinoline-3-carboxylic acid (J. Med. Chem. 1993, 36, 871-882) (0.4955g, 1.37 mmol) was taken up in methanol (50 mL). The resulting suspension was charged with acrylonitrile (0.1 mL). After 16 hours the reaction was heated to 40 °C and a third equivalent of acrylonitrile was added. After 20 hours the reaction was concentrated to afford 550 mg of the title compound (yield: 95%) MS (APCI+) m/z 415 (M+H). C. Pharmaceutical Formulations
The following illustrates representative pharmaceutical dosage forms, containing a compound of Formula I ("Invention Compound"), for therapeutic or prophylactic use in humans, (i) Tablet mg/tablet
'Invention Compound' 25 . 0
Lactose 50.0
Corn Starch (for mix) 10.0
Corn Starch (paste) 10.0
Magnesium Stearate (1%) 3.0
300.0
The invention compound, lactose, and com starch (for mix) are blended to uniformity. The corn starch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand screen and dried at 80°C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. Such tablets can be administered to a human from one to four times a day for treatment of pathogenic bacterial infections.
(ii) Tablet mg/capsule
'Invention Compound 10 . 0
Colloidal Silicon Dioxide 1.5
Lactose 465.5
Pregelatinized Starch 120.0
Magnesium Stearate (1%) 3.0
600.0
(iii) Preparation for
Oral Solution Amount 'Invention Compound' 400 mg
Sorbitol Solution (70 % N.F.) 40 mL
Sodium Benzoate 20 mg
Saccharin 5 mg
Cherry Flavor 20 mg
Distilled Water q.s. 100 mL
The sorbitol solution is added to 40 mL of distilled water, and the invention compound is dissolved therein. The saccharin, sodium benzoate, flavor, and dye are added and dissolved. The volume is adjusted to 100 mL with distilled water. Each milliliter of syrup contains 4 mg of invention compound.
(iv) Parenteral Solution
In a solution of 700 mL of propylene glycol and 200 mL of water for injection is suspended 20 g of an invention compound. After suspension is complete, the pH is adjusted to 6.5 with 1 N hydrochloric acid, and the volume is made up to 1000 mL with water for injection. The Formulation is sterilized, filled into 5.0 mL ampoules each containing 2.0 mL, and sealed under nitrogen.
(v) Injection 1 (1 mg/mL) Amount {
'Invention Compound' 1.0
Dibasic Sodium Phosphate 12.0
Monobasic Sodium Phosphate 0.7
Sodium Chloride 4.5
N Sodium hydroxide solution q.s.
(pH adjustment to 7.0-7.5)
Water for injection q.s. ad 1 mL
(vi) Injection 2 (10 mg/mL) Amount
'Invention Compound' 10.0
Dibasic S odium Phosphate 1.1 Monobasic Sodium Phosphate 0.3
Polyethylene glyco 400 200.0
N hydrochloric acid solution q.s.
(pH adjustment to 7.0-7.5)
Water for injection q.s. ad 1 mL
(vii) Injection 2 (10 mg/mL) Amount
'Invention Compound' 20.0
Oleic Acid 10.0
Trichloromonofluoromethane 5,000.0
Dichlorodifluoromethane 10,000.0
Dichlorotetrafluoroethane 5 ,000.0.
All patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

Claims
What is claimed is:
A compound of formula I:
Figure imgf000179_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, provided that when X is N, R5 is absent at that position;
Ri is ( -Q alkyl, halo(C C6)alkyl, (C3-C6)cycloalkyl , halo(C3-C6)cycloalkyl, heterocyclic, aryl, heteroaryl; and CH2(C3-C6)cycloalkyl;
R2 is OH,
OBF2
Figure imgf000179_0002
O(C3-C6)cycloalkyl,
O 0-(CHR2a)m-0 QR2b s wherein m is an integer from 1 to 10, Q is O or NH or N(C1-C6)alkyl or is absent, and R2a is H or
(d-C6)alkyl and R2b is (Cι-C6)alkyl, aryl, or heteroaryl, O— (CHR2a)n — " s wherein R2a is as defined above, n is an integer of from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2fj are each independently H, (CrC6)alkyl, or (C3-C6)cycloalkyl, or NR2a, wherein R2a is as defined above,
Figure imgf000180_0001
wherein " *"""• " indicates the point of attachment, 2a is as defined above, R2e and R2e- are each independently H or (C1-C6)alkyl or taken together with the carbon to which they are attached form a 3, 4, 5, or 6- membered substituted or unsubstituted ring, e is an integer of from 1 to 10, p is an integer of from 2 to 10, and Xi and Yi are each independently NH or O;
R3, R , and R5 are each independently H,
OH, halo, NRyRz, wherein Ry and Rz are each independently H or (Ci-
C6)alkyl,
(Cι- )alkyl, halo(Cι-C6)alkyl,
O(Cι-C6)alkyl, O(Cι-C6)haloalkyl, nitrile;
Ri and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1, or 2 heteroatoms selected from
O, S, SO, SO2, or NRX, wherein Rx is H or (C1-C6)alkyl; and A is
Figure imgf000181_0001
, wherein z is 0, 1, or 2 and q is O, 1, 2, or 3;
Ra and R are each independently H, (Cι-C6)alkyl, (C1-C6)alkoxy, halo(Cr C6)alkyl, halo, or Ra and Rb taken together with the carbon to which they are attached form C=O, C=NO(C1-C6)alkyl, or a 3,4,5 or 6-membered substituted or unsubstituted ring;
R', R", R'", and R"" are each independently H, (Cι-C6)alkyl,
-O(Cι-C6)al yl, halo(C1-C6)alkyl, aryl,or heteroaryl;
and B is
Figure imgf000181_0002
provided that when B is
Figure imgf000181_0004
in B Ra Rb" or
Figure imgf000181_0003
, R' is not -O(C1-C6)alkyl, and wherein " WΛ " indicates the point of attachment; Rc and Rd are each independently H, (C1-C6)alkylnitrile; 0 II
— P-OH
I
OH
0 — P-0(CrC6)alkyl 0(C C6)alkyl
(Cι-Qs)alkyl, (C3-C6)cycloalkyl, heteroaryl, SO2-(Cι-C6)alkyl, SO2-aryl,
SO2-heteroaryl,
O — (CR2aR2a.)g-0 QR2b ^ wnerein g 1S an integer from 1 to 10, Q is as defined above, and R2a and R2a> are each independently H or (C1-C6)alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and R2b is (C1-C6)alkyl, aryl, or heteroaryl,
O O
(CR2aR2a.)g-0-P-(OH)2 or (CR2aR2a)g-0-P-(0(C1-C6)alkyl)2 wherein R a and R2a>are as defined above,
Figure imgf000182_0001
" indicates the point of attachment, p is
O or 1, and R2c is H,
(Cj-Co alkyl,
O(Cι-C6)alkyl, (C3-C7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
O
— (CHR2a)h-θJJ-QR2b of — (CHR^-Y wherein
R2a, R2b, and Q are as defined above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO(OH)2, OPO(O(Cχ-
C6))2, or NR2dR2e, wherein R2d and R2e are each independently H, (Cj-C6)alkyl, or (C3- C7)cycloalkyl,
Figure imgf000183_0001
, wherein q is 0 or 1 , R2f and R2f are each independently H, (Cι-Cg)alkyl, aryl, or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5, or 6 membered substituted or unsubstituted ring, and R2g is
(Cι-C6)alkyl,
(C3-C7)cycloalkyl, aryl, or heterocyclo, or heteroaryl;
Re and Rf are each independently H, Cι-C6 alkyl, haloalkyl, halo, or Re and Rf taken together with the carbon to which they are attached form a 3,4,5 or 6-membered substituted or unsubstituted ring;
Rg and Rh are each independently H, -Cό alkyl, haloalkyl, or taken together with the carbon to which they are attached to form a 3,4,5 or 6-membered substituted or unsubstituted ring.; and Rj and Rk are each independently H, (C1-C6)alkyl, haloalkyl, (Cι-C6)alkyl- NRcRd, (CrC6)alkyl-ORc, aryl, heteroaryl, heterocycle,
O (CT -Cβ)alky I 2— Rd ^ wherein z is O or NRC, or Rj and Rk taken together with the carbon to which they are attached to form a
3,4,5 or 6-membered substituted or unsubstituted ring.
2. The compound of claim 1, wherein X is C or N; Ri is (Cι-C6)cycloalkyl and halo(C1-C6)cycloalkyl, aryl, or heteroaryl;
R3 is H or NH2;
R is H or halo;
R5 is halo, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy when X is C.
3. The compound of claim 2, wherein X is C or N;
Ri is cyclopropyl or fluorocyclopropyl; R3 is H or NH2; R4 is H orF;
R5 is halo, methyl, or methoxy.
4. The compound of claim 1, wherein Ri, R3, and R5 are as provided in the following structures, and wherein R2 is OH, OBF2, or O(C1-C6)alkyl, R is
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
5. The compound of claim 1 , wherein z is 0, 1, 2, when q is 2 or 3 or z is 1 or 2 when q is 0, 1, 2, or 3; Ra and Rb are each independently H, methyl, ethyl, fluoro, fluoromethyl, trifluoromethyl, fluorethyl, methoxy, MeO-N, or taken together with the carbons to which they are attached'form a cyclopropyl ring; R', R", R'", and R"" are each independently H, fluoro, methyl, ethyl, flouromethyl, fluoroethyl, phenyl, benzyl, or methoxy;
Rc and Rd each independently are H, methyl, or ethyl; Re and Rf each independently are H, methyl, or ethyl; Rg and Rh each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl,
O carboxyethyl, or NHMe s or taken together with the carbons tro which they are attached form ^ ; and
Rj and Rk each independently are H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl, O carboxyethyl, or NHMe } or taken together with the carbons tro which they are
attached form — .
6. The compound of claim 1 , wherein A is κa b , and z is 0, 1 , or 2, selected from the group consisting of: 7
Figure imgf000188_0001
Me __X> F Nw "X> _ FaCrO
Figure imgf000188_0002
wherein " 'VVΛ' " indicates the point of attachment, or A is
Figure imgf000188_0003
or
Figure imgf000188_0004
, wherein z is 0, 1, or 2 and q is 0, 1, 2, or 3, selected from the group consisting of:
Figure imgf000188_0005
wherein " 'VVΛ' " indicates the point of attachment. The compound of claim 6 or 7, wherein B is Re Rf Rc , or
Figure imgf000189_0001
, and is selected from the group consisting of:
NC- NC- NC- NC.
N H Me Et H
Figure imgf000189_0002
Et Me C6)alkyl
Figure imgf000189_0003
H and Me wherein " 'w^ » indicates the point of attachment. The compound of claim 6, wherein
Figure imgf000190_0001
is selected from the group consisting of:
Figure imgf000190_0002
Figure imgf000191_0001
Me RH '^ — \
wherein R is CH2CH2CN and wherein " 'ww, " indicates the point of attachment.
9. The compound of claim 6, wherein κa b is selected from the group consisting of:
Figure imgf000192_0001
wherein R is CH2CN, and wherein " ' ΛΛΛ' " indicates the point of attachment.
10. The compound of claim 6, wherein
Figure imgf000192_0002
is selected from the group consisting of:
Figure imgf000192_0003
wherein R is CH2CH2CN and wherein " 'ww » indicates the point of attachment. 11. The compound of claim 6, wherein
Figure imgf000193_0001
is selected from the group consisting of:
Figure imgf000193_0002
wherein Rc is H or (CrC^alkyl, R is CH2CN, and wherein " ^^ " indicates the point of attachment.
12. The compound of claim 1 , which is a compound of formulas II, III, , V, or VI.
Figure imgf000193_0003
Figure imgf000194_0001
13. A compound which is: 7-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methoxy-4- oxo-1 ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methyl-4- oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7- { 3-[(2-Cyano-ethyl)-methyl-amino] -pyrrolidin- 1 -yl } - 1 -cyclopropyl -6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[(2-Cyano-ethyl)-methyl-amino]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-ethylamino)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl-4-oxo-l,4- dihydro-quinoline-3-carboxylic acid;
7-{3-[(2-Cyano-ethyl)-methyl-amino]-pyrrolidin-l-yl}-l-cyclopropyl-8-methoxy-
4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7- { 3- [(2-Cyano-ethyl)-methyl-amino]-pyrrolidin- 1 -yl } - 1 -cyclopropyl-8-methyl-4- oxo- l,4-dihydro-quinoline-3-carboxylic acid; 9-[3-(2-Cyano-ethylamino)-cyclopentyl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro- 6H-l-oxa-3a-aza-phenalene-5-carboxylic acid; -{3-[(2-Cyano-ethyl)-methyl-amino]-cyclopentyl}-8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid; - { 3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin- 1 -yl } - 1 -cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3R-[(2-Cyano-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; - { 3-[(2-Cyano-ethylamino)-methyl]-pyrrolidin- 1 -yl } - 1 -cyclopropyl-6-fluoro-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -(3- { [(2-Cyano-ethyl)-methyl-amino] -methyl } -pyrrolidin-1 -yl)- 1 -cyclopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-ρyrrolidin-l-yl)-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -(3-{l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; 7-{3-[(2-Cyano-l-methyl-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3-[(2-Cyano-l-methyl-ethylamino)-methyl]-pyrrolidin-l-yl}-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -{3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l-yl}-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cycloproρyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7- { 3- [ 1 -(2-Cyano-ethylamino)-cyclopropyl] -pyrrolidin- 1 -yl } - 1 -cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl -4-oxo- l,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{l-[(2-Cyano-ethyl)-methyl-amino]-cyclopropyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-(3- { 1 -[(2-Cyano-ethyl)-methyl-aminoj -cyclopropyl } -pyrrolidin- 1 -yl)- 1- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; 7- { 3 -[2- Acetylamino- 1 -(2-cyano-ethylamino)-ethyl]-pyrrolidin-l -yl } - 1 - cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[2-Acetylamino-l-(2-cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -(3- { 2- Acetylamino- 1 -[(2-cyano-ethyl)-methyl-amino]-ethyl } -pyrrolidin- 1 -yl)-l - cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -(3-{2-Acetylamino-l-[(2-cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cycloρropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7- { 3-[(2-Cyano-ethylamino)-methyl] -pyrrolidin- 1 -yl } - 1 -cyclopropyl-8-methoxy- 4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3-[(2-Cyano-ethylamino)-methyl]-pyrroIidin-l-yl}-l-cyclopropyl-8-methyl-4- oxo-1 ,4-dihydro-quinoline-3-carboxylic acid; -(3- { [(2-Cyano-ethyl)-methyl-amino]-methyl } -pyrrolidin- 1 -yl)- 1 -cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-pyrrolidin-l-yl)-l-cyclopropyl-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l-cyclopropyl-8-methoxy-
4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3-[l-(2-Cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l-cyclopropyl-8-methyl-4- oxo-1 ,4-dihydro-quinoline-3-carboxylic acid; -(3- { 1 -[(2-Cyano-ethyl)-methyl-arnino]-ethyl } -pyrrolidin- 1 -yl)- 1 -cyclopropyl-8- methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l-cyclopropyl-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -{3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l-yl}-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -{3-[(2-Cyano-ethylamino)-methyl]-3-methyl-pyrrolidin-l-yl}-l-cyclopropyl-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cycloρropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{[(2-Cyano-ethyl)-methyl-amino]-methyl}-3-methyl-pyrrolidin-l-yl)-l- cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[l-(2-Cyano-ethylamino)-cycloproρyl]-pyrrolidin-l-yl}-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-pyrrolidin-l-yl}-l-cyclopropyl-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-cyclopropyl}-pyrrolidin-l-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[2-Acetylarnino-l-(2-cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[2-Acetylamino-l-(2-cyano-ethylamino)-ethyl]-pyrrolidin-l-yl}-l- cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -(3- { 2- Acetylamino- 1- [(2-cyano-ethyl)-methyl-amino]-ethyl } -pyrrolidin- 1 -yl)-l - cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -(3-{2-Acetylamino-l-[(2-cyano-ethyl)-methyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[l-(2-Cyano-ethylamino)-5-aza-sρiro[2.4]hept-5-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[l-(2-Cyano-ethylamino)-5-aza-spiro[2.4]hept-5-yl]-l-cyclopropyl-6-fluoro-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[l-(2-Cyano-ethylamino)-propyl]-azetidin-l-yl}-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[l-(2-Cyano-ethylamino)-propyl]-azetidin-l-yl}-l-cyclopropyl-6-fluoro-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -(3- { 1 - [(2-Cyano-ethyl)-methyl-amino] -propyl } -azetidin- 1 -yl)- 1 -cyclopropyl-6- fluoro-8-mefhoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-propyl}-azetidin-l-yl)-l-cyclopropyl-6- fluoro-8-methyl -4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7- { 3-[ 1 -(2-Cyano-ethylamino)-cyclopropyl] -azetidin- 1 -yl } - 1 -cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7- { 3-[ 1 -(2-Cyano-ethylamino)-cyclopropyl]-azetidin- 1-yl } - 1 -cyclopropyl-6- fluoro-8-rnethyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{l-[(2-Cyano-ethyl)-methyl-amino]-cyclopropyl}-azetidin-l-yl)-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; 7-(3-{ l-[(2-Cyano-ethyl)-methyl-amino]-cyclopropyl}-azetidin-l-yl)-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{ l-[(2-Cyano-ethyl)-ethyl-amino]-cyclopropyl } -pyrrolidin- 1-yl)- 1- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-(3-{ l-[(2-Cyano-ethyl)-ethyl-amino]-cyclopropyl}-pyrrolidin-l-yl)-l- cycloρroρyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -(3-{2-Acetylamino-l-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -(3-{2-Acetylamino-l-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-pyrrolidin-l-yl)-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
Sodium; 7-{3-[l-(2-cyano-ethylamino)-propyl]-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylate. ;
Sodium; 7-{3-[(2-cyano-ethylamino)-methyl]-3-methyl-azetidin-l-yl}-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylate;
7-{3-[l-(2-Cyano-ethylamino)-cyclopropyl]-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl -4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[(2-Cyano-ethylamino)-methyl]-3-ethyl-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-{3-[(2-Cyano-ethylamino)-methyl]-3-ethyl-azetidin-l-yl}-l-cyclopropyl-6- fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -{ 3-[(2-Cyano-ethylamino)-methyl]-cyclopentyl } -8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid; -(3-{ [(2-Cyano-ethyl)-methyl-amino]-methyl}-cyclopentyl)-8-fluoro-3-methyl- 6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid;
9-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6-oxo-2,3- dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid;
9-[3-(R)-(2-Cyano-l-(S)-methylamino-ethyl)-ρyrrolidin-l-yl]-8-fluoro-3-(S)- methyl-6-oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid - [3 -( 1 - Amino-2-cyano-ethyl)-pyrrolidin- 1 -yl] - 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydro-quinoline-3-carboxylic acid; -[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4-oxo-l,4- dihydro-[l ,8]naphthyridine-3-carboxylic acid;
7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8-methyl- 4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methoxy-4-oxo-
1 ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(l-Amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
5-Amino-7-[3-(l-amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -Amino-7-[3-('l-amino-2-cyano-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl- 4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3rcarboxylic acid;
7-[3-(l-Amino:2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(l-Amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
5-Amino-7-[3-(l-amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
5-Amino-7-[3-(l-amino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidin-l-yl]-l- cycloρropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; - [3 -( 1 - Amino-2-cy ano-ethyl)-pyrrolidin- 1 -yl] - 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4- dihydro-quinoline-3-carboxylic acid; -[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4- oxo- l,4-dihydro-quinoline-3-carboxylic acid;
9-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6-oxo- 2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid; -[3(R)-(2-Cyano-l(S)-methylamino-ethyl)-pyrrolidin-l-yl]-8-fluoro-3-methyl-6- oxo-2,3-dihydro-6H-l-oxa-3a-aza-phenalene-5-carboxylic acid;;
7-[3-(2-Cyano-l-methylamino-ethyl)-ρyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-4- oxo-1, 4-dihydro-[l,8]naphthyridine-3-carboxylic acid;
7-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8- -methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3(R)-(2-Cyano-l(S)-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-6-fluoro-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methoxy- 4-oxo- l,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8-methyl-4- oxo-l,4-dihydro-quinoline-3-carboxylic acid;
5-Amino-7-[3-(2-cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
5-Amino-7-[3-(2-cyano-l-methylamino-ethyl)-pyrrolidin-l-yl]-l-cyclopropyl-8- methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; 7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[3-(2-Cyano-2,2-dimethyl-l-methylamino-ethyl)-ρyrrolidin-l-yl]-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
5-Arnino-7-[3-(2-cyano-2,2-dimethyl- 1 -methylamino-ethyl)-pyrrolidin- 1 -yl]- 1 - cyclopropyl-8-methoxy-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid;
5-Amino-7-[3-(2-cyano-2,2-dimethyl-l-methylamino-ethyl)-pyrrolidin-l-yl]-l- cyclopropyl-8-methyl-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid; -[4-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl-6- fluoro-8-methy]-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -[4-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl-6- fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -[4-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl-8- methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -[4-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrro]-2-yl]-l-cyclopropyl-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; 7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[4-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cycloρropyl-8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -[3a-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl- 6-fluoro-8-methyl-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -[3a-(2-Cyano-ethylamino)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l-cyclopropyl- 6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid; -[3a-(2-Cyano-ethylamino)-hexahydro-cycloρenta[c]pyrrol-2-yl]-l-cyclopropyl- 8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; -[3a-(2-Cyano-ethylamino)-hexahydro-cycloρenta[c]pyrrol-2-yl]-l-cyclopropyl- 8-methoxy-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]ρyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid;
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-8-methyl-4-oxo-l ,4-dihydro-quinoline-3-carboxylic acid; or
7-[3a-(l-Amino-2-cyano-ethyl)-hexahydro-cyclopenta[c]pyrrol-2-yl]-l- cyclopropyl-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid;
14. A pharmaceutical formulation comprising a compound of formula I, π, HI, IV, V, or VI admixed with a pharmaceutically acceptable diluent, carrier, or excipient.
15. A method of treating a bacterial infection in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of formula I, π, IE, IV, V, or VI .
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