TW200524930A - Quinolone antibacterial agents - Google Patents

Abstract

Compounds of formula I, II, III, IV, V, and VI and methods for their preparation are disclosed. Further disclosed are methods of making biologically active compounds of formula I, II, III, IV, V, and VI as well as pharmaceutically acceptable compositions comprising compounds of formula I, II, III, IV, V, and VI. Compounds of formula I, II, III, IV, V, and VI as disclosed herein can be used in a variety of applications including use as antibacterial agents.

Description

200524930 IX. Description of the invention: [Technical Field of the Invention of the Genus Genus 3 Field of the Invention The present invention relates to a compound having a core structure of linoxone and having antibacterial agent 5 activity, a preparation method thereof, and a pharmaceutically acceptable compound containing the compound Compositions. [PRIOR ART 3 BACKGROUND OF THE INVENTION] In recent years, warnings of antimicrobial resistance have rapidly emerged. This is an overall clinical and public health issue. Drug resistance is an important issue in communities and medical care settings where bacterial infections can greatly expand. Because multidrug resistance is a growing problem, physicians now face infections that are not effectively treated. The prevalence, mortality and financial costs of this infection will generally increase the burden on health care systems. As a result, there is a need for another and improved agent 15 for the treatment of bacterial infections, particularly for the treatment of infections caused by bacteria resistant to the drug-resistant strains. SUMMARY OF THE INVENTION The present invention can meet these and other needs. The present invention relates to a compound of formula I 20:

K X N I I

Re Ri or a pharmaceutically acceptable salt thereof, in which: 200524930 X may be N or C ’with the limitation that at that time, there is no

Halo (CVC6) cycloalkyl, heterocyclic, aryl, heteroaryl and Ch2 (C3_C6)

, Where m is an integer from 1 to 10, q is 04NH; and ^ is Η or (CrC6) alkyl and R2b is or N (CrC6) alkyl or lacking; (CrC6) alkyl, aryl, or heteroaryl ; 0- (CHR2a) nY 'where 1 ^ is as defined above, n is an integer from 2 to 0, and Y is OH or NR ^ Rw, where I. And each may be independently H, (Ci-C6) alkyl or (CVC6) cycloalkyl; or NR ^, where ^ is as defined above;

15 As defined above, R2e & R2e, each of which may be independently fluorene or alkyl, or connected to carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; e is Integers 1 to 10, p is an integer 2 to 10, and & and ^ each may be independently NH or 〇; and I may each be independently H, OH, halo, NRyRz (which is 20 Each of Ry and & may be independently η or (cvc: 6) alkyl), (Cl_C6) alkyl, iS group (crc6) alkyl, 0 (Cl-c6) alkyl, 0 (Cl_C6) _ Alkyl, nitrile; Ri and & can be linked to carbon to form a substituted or unsubstituted 5 or 6 membered or unsubstituted ring of 200524930 containing 0, 1 or 2 selected from Heteroatoms of 0, S, SO, S02 or NRX, wherein Rx may be fluorene or (CrC6) alkyl; and R ·, A may be

Where z is 0, 5 1 or 2 and q is 0, 1, 2 or 3;

Each of Ra & Rb can be independently fluorene, (CrC6) alkyl, (CrC6) alkoxy, halo (CrC6) alkyl, halo; or Ra and Rb are linked to carbon to form a C = 0 , C = NO (CrC6) alkyl or a 3, 4, 5 or 6-membered substituted or unsubstituted ring; 10 11 ', 11 ", 11,, and 11" "each may be independently 11, ((: 1-(: 6) alkyl, -CKCrCd alkyl, halo (crc6) alkyl, aryl or heteroaryl; and B may be NC_R, or

Rf ', e X Rc ^ e W Rc in Re Rb or Qin

The limitation is that when B is, R 'is not -CXCVC6) alkyl group, and "~~~" in the figure refers to the connection position;

0 -P-OH OH

Each of Rc & Rd can be independently Η, (CrC6) alkyl, O ^^ ((^-(; 6 > alkyl ^ (CVCe> alkyl, (CrC6) alkyl, (C3_C6) cycloalkane Group, heteroaryl, S02_ (CrC6) alkyl, S02-aryl, S02-heteroaryl; 15 200524930 — (cfwwl — oJLqr ^, where g is the integer u1O, Q is as defined above; and Rh and each Each may be independently H or (CrC6) alkyl, or linked to carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; and may be (CrC0) alkyl, aryl Or heteroaryl;

0 Q 〇〇 一 p 一 (〇H) 2 or (CR2aR2a.) 广 〇- 技 一 (〇 (〇ι · ^) 炫 基) 2, where R2a and R ^ a, as defined above;

OS where "~~~" refers to the attachment position, p is 0 or 1, and; R2c is Η, (crc6) alkyl, 〇 (crc6) alkyl, (c3_c7) cycloalkyl, aryl, heterocyclic group , Heteroaryl; or 10- < CHR2e > h-〇i〇R2b or-(cmM_Y, its center, r ^ q is as defined above, and h and j each may be an integer of 0 to 1 each independently 〇, and Ya can be OH, 0P0 (0H) 2, OPO (〇 (Ci_C6)) 2_R2dR2e, where ~ and each can each independently be H, (CrC6) alkyl or (C ^ C?) Cycloalkyl Where q is 0 or 1; R2f and R2f, each of which may be independently fluorene, (Cl-C6 aryl, aryl or heteroaryl, or may be linked to form -3,4,5 Or 6-member substituted or unsubstituted materials; and ^ may be (CVC6) silk, (C3_C7) ring silk, aryl, heterocyclyl, or heteroaryl; each of RARf may be independently H, Ci_Q , Halogenated, dentate; or RARf and carbon are linked together to form a 3, 4, 5, or 6-membered ring 15 200524930 generation or unsubstituted ring;

Rg and Rh may each independently be H, CA, or halo; or attached to a carbon to form -3, 4, 5, or 取代 substituted or unsubstituted rings; and

Each of Rj and Rk may be independently H, (c-C6) alkyl, alkynyl, (CVC6) alkyl-NRcRd, (cvc6) fluorenyl-ORe, aryl, heteroaryl, hetero0 ring , (Cvc6_izi 'wherein 2 is 0 or NRe, or & and the heart and the carbon are connected at-starting into -3, 4, 5, or 6 ring substituted or unsubstituted ring. The present invention also provides a formula II Compound:

Or a medically acceptable salt thereof, in beans: X may be N or C ′ and the restriction is that at that time, there is no r5 at this position;

Ri may be (CVC6) alkyl, dentyl (Ci_c6) alkyl, (C3_c6) cycloalkyl, 15 halo (Cs-C6) cycloalkyl, heterocyclic, aryl, heteroaryl, and CH2 (C3- C6) cycloalkyl; R2 may be OH, OBF2, 0 ((^-(: 6) alkyl, 0 (c3-C6) cycloalkyl; 0 0- (CHRynroiQR ^, where m is an integer isio, Q Is 0 or or N (CrC6) alkyl or lacking; and 1 ^ is 11 or ((: 1-€: 6) alkyl and R2b is 200524930 (CVC6) alkyl, aryl or heteroaryl; CKCHRJn-Y ' Wherein n is an integer from 2 to 10; Υ is 0Η or NRuRw where I. and each may be independently η, (CrQ) alkyl or (CVQ) cycloalkyl; or 5 10 NR2a, Where 1 ^ is as defined above;

KCHRJp—YrH where "~~~" refers to the connection position, 2a

Alkyl, or linked to carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; e is an integer from 1 to 10, p is an integer from 2 to 10; and & and \ each May each be independently NH or 0;

Each of R3, R4, and Rs may be independently fluorene, halo, NRyRz (where R # Rz may be each independently fluorene or (CVC6) alkyl), (CrC6) alkyl, or dentyl (CrC6) Carbo, O (CrC6) o, O (crC6) from alkyl, nitrile; the heart and the heart are connected to the carbon to form a substituted or unsubstituted 5 15 or 6-membered substituted or unsubstituted ring, It contains 0, 1 or 2 heteroatoms selected from 0, s, so, so: or nrx, wherein RjH or (CrC6) alkyl; and z is 0, i or 2; R may be Η, (CrC6 ) Alkyl, halo (crC6) alkyl, aryl, or hetero 20 aryl;

Each of Ra and Rb may be independently fluorene, (crC6) alkyl, (Ci_c6) alkoxy, dentyl (CrC0) alkyl, halo; or C and C are linked together with carbon to form a CK), C = N0 (CrC6) alkyl or a 3, 4, 5 or 6 member substituted 10 200524930 or unsubstituted ring;

Rc-r ^ H. (Cl-c6) ^^. ~! Η〇η. ^ 〇 ^ t ^ Cl-c6) alkyl, (CVC6) cycloalkyl, heteroaryl, s02_ (Ci_C6) alkane Group, 3〇2_aryl group, so2_heteroaryl group; 0 5 —, where g is an integer ml 0, Q is as defined above, and Rza and R ^, each may be independently Η or (Ci_C6 ) Alkyl, or linked to carbon to form -3, 4, 5, or 6-membered substituted or unsubstituted Yuyi 'and R ^ b is (Ci_C6) alkyl, aryl, or heteroaryl; 0 〇 (CR2aR2a) g—〇-P- (〇H) 2 or one (〇 (Ci Ce > Hyunji &, where 10 R2a and R2a, as defined above; \ / p, where "~~~" means Is a linking position, p is 0 or 1; and R2c is fluorene, (CrC6) alkyl, 0 (CrC6) alkyl, (C3-C7) cycloalkyl, aryl, heterocyclyl, heteroaryl; or— (CHR ^ h-

〇X 〇R2b or— < CHRd factory γ, wherein R2a, R2b and Q are as defined in the above 15; and h and j may each independently be integers 0 to 10, and Y is 0, 0, 0 Ii) 2, 0P0 (0 (CrC6)) 2 or NR2dR2e, wherein R2d and R2e each may be independently Η, (CrC6) alkyl or (C3_C7) cycloalkyl;

, Where q is 0 or 1; R2f and R2f, each may be 200524930 independently of H, (CrC6) alkyl, aryl, or heteroaryl; or linked to carbon to form a 3, 4, 5, or 6 A substituted or unsubstituted ring; and R2g is (CVC6) alkyl, (C3-C7) cycloalkyl, aryl, heterocyclic or heteroaryl;

Re and Rf each may be independently fluorene, C! -C6 alkyl, haloalkyl, 5 halo; or Re and Rf are linked to carbon to form a 3, 4, 5, or 6 member substituted or unsubstituted Substituted rings; and

Rg and Rh may each be independently fluorene, CrC6 alkyl, haloalkyl; or attached to carbon to form a 3, 4, 5 or 6-membered substituted or unsubstituted ring. 10 The present invention also provides a compound, which may be:

7- [3- (2-cyano-ethylamino) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-fluorenyl-4-oxo-1,4- Dihydro-xantolin-3-carboxylic acid;

7- [3- (2.N-Amino-ethylamino) Bilobit-1-yl] -1-¾propyl-6-gas

t 8-fluorenyl-4- pendant oxygen-1,4-dihydroxantolin-3-carboxylic acid; 〇 Ο

12 200524930 group-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-fluoroline-3-carboxylic acid; oxy-ethyl) -methyl-amino group N-l-yl} -1-badpropyl-6-gas-8-methyl-4- pendant oxygen-1,4-diazine-sigmaquine-3-carboxylic acid, 0

7- [3_ (2-cyano-ethylamino) -pyrrolidin-1-yl] -1-cyclopropyl-8-methyl -3- Junic acid, 〇 0 广 Ν

NC-7- {3-[(2-cyano-ethyl) -methyl-amino] -pyrrolidin-1-yl} -1-cyclopropanyl-10-methoxy-4 pendant oxygen -1,4-dihydro-pyridoline-3-carboxylic acid; 0 0

7-{3-[(2-Gasyl-ethyl) -methyl-amino] biloxodine-1 -yl} -1 -oxopropyl-8-fluorenyl-4-oxo-1, 4-dihydro-pyridin-3-carboxylic acid; 0 0 NC "

13 200524930 9- [3- (2-cyano-ethylamino) -cyclopentyl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1- 噚-3a-az · 葩 -5-carboxylic acid; or 0 0

9- {3-[(2-Gasyl-ethyl) -methyl-amine] -¾pentyl} -8-Gas-3-methyl 5-6-lanthoxy-2,3_dirat- 6H-1 was deficient in 3a-mouth-fat-5-junic acid.

The invention also provides a compound of formula III:

Or a pharmaceutically acceptable salt thereof, wherein: X may be N or C, and the restriction is that when X is N, there is no

10 R5; I may be (CrC6) alkyl, _ ((^-(: 6) alkyl, (c3-c6) cycloalkyl, halo (C3-C6) cycloalkyl, heterocyclic, aryl , Heteroaryl and CH2 (C3-C6) cycloalkyl; R2 may be OH, obf2, o (crc6) alkyl, o (c3-c6) cycloalkyl;

〇 one (CHRJnrO 0

〇R2b, where m is an integer from 1 to 10, Q is 0 or NH or N (CrC6) alkyl or lack thereof; and R2a is fluorene or (CrC6) alkyl; and R2b is (CrC6) alkyl, aryl or hetero Aryl; 14 15 200524930 〇, (CHR2a) nY 'wherein R2a: ^ the above household definition; η is an integer from 2 to ι〇; Υ is 0Η or NR2cR2d' wherein R2 (^ R2d each can be independently (CrC6) alkyl or (C3-C6) cycloalkyl; or NR2a, wherein R2a is as defined above;

As defined above; each of ^ and 乂 may be independently Η or (CrC6) alkyl, or linked to carbon to form a 3, 4, 5, or 6 substituted or unsubstituted ring; e is an integer of 1 to 10, and ρ is an integer of 2 to 10; and & and ¥ 1 each may be independently NH or 0; 10 R3, R4, and I may each be independently H, halo , NRyRz (where

Each of Ry and Rz may be independently fluorene or (Cl_C6) alkyl), (CVC6) alkyl, dentyl (crc6) alkyl, 0 (Cl_C6) alkyl, 0 (Cl_C6) alkyl, or nitrile; Ri and Rs are linked to the carbon to form a substituted or unsubstituted 5 or 6-membered substituted or unsubstituted ring, which contains 0, 1 or 2 selected from 0, S, 15 s〇, s〇 2 or > 1-center heteroatom, the center of which is 11 or (CrC6) alkyl; and z is 0, 1 or 2; is fluorene, (crc6) alkyl, -CKCrQ) alkyl, halo (crC6) Alkyl, aryl or heteroaryl;

Each of Ra and Rb may be independently fluorene, (Ci_c6) alkyl, (Ci_c6) monooxyhalo (Ci-C6) alkyl, halo; or Ra and Rb are bonded to carbon to form C0, C = N0 (CrC6) alkyl or a 3, 4, 5, or 6-membered substituted or unsubstituted ring; 15 200524930

Rc may be HqcVQ) alkyl, Οιι-Ρ-OH OH, -optional OiCVCe) alkyl (C * | -Ce) alkyl (CrC6) alkyl, (C3-C6) cycloalkyl, heteroaryl Group, soyCi-CJ alkyl group, S〇2-aryl group, S〇2-hetero square group;-(CR2aR2aV " 0 "LQR2b, where g is an integer from 1 to 10; Q is as defined in the above 5; and Each may be independently fluorene or (CrC6) alkyl, or linked to carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; and Rn may be (CrC6) alkyl, Aryl or heteroaryl; 9 〇 (CR2aR2a_) wide 0-P- (0H) 2 or (CRaaR ^ g ~ 0-bee one (〇 ((^ _ (: 6 > Yuanji) 2, where R2a & R2a , As defined above; 10 p, where "~~~" refers to the connection position, p is 0 or 1; and r2c is Η, (CrC6) alkyl, 0 (crc6) alkyl, (c3-C7) ring Alkyl, aryl, heterocyclyl, heteroaryl; or — (CHR2a) h—— or — (CHRz>) “y, where and q are as defined above; and each of h and j may be independently independent Ground is an integer from 0 to 10; and γ15 can be OH, OPO (OH) 2, 0P0 (0 (CrC6)) 2, or NR2dR2e, where ~ and each can be independently H, (q-C6) Group or (C3_C7) cycloalkyl;

Where q is 0 or 1; R2f & R2f, each of which may be independently H, (CrC6) alkyl, aryl, or heteroaryl, or linked to carbon to form -3, 4, 5, or 6-membered substituted or unsubstituted ring; and ^ may be (cvc6) alkyl, (c3-c7) cyclyl, aryl, heterocyclyl, or heteroaryl g;

Each of Re and Rf may be H, Ci_C6 alkyl, southern alkyl, or halo; or Re and carbon are linked together to form a 3,: soil) 6 members of our 6 after 5 generations or unsubstituted Each of which may be independently H, Ci_Q alkyl, fluorenyl; or linked to a carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; and,

Each of Rj and Rk may be independently fluorene, (CrC6) alkyl, self-alkyl, 10 (c! -C6) alkyl-NReRd, (Crc6) alkyl_0Rc, aryl, heteroaryl, hetero

, Where Z is 0 or NRc; ^ Rk and carbon The present invention also provides a compound which may be linked together to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring.

15 7 {3 — [(2-Cyano · ethylamino) -methyl l · 11 than pyrrolidin-1-yl-1-cyclopropylfluoromethoxy_4-oxo-1,4- Dihydro-phosphonium carboxylic acid;

7 {3R _ [(2-cyano_ethylamino) _fluorenyl] · π ratio bite small base 1 · cyclopropylfluoromethoxy-4- pendant oxygen-1,4-dihydro-fluorene _3_carboxylic acid; Yi 17 200524930 ο ο

Me human nitrogen-ethylamino) -methyl] -11 than hexyl-1-yl} -1-poropropyl-6-air-8-fluorenyl-4-oxo-1,4-di Rat-17 quelin-3-conc, 0 0

7- (3-{[(2-Amino-ethyl) -fluorenyl-amino group] -methyl ethyl 11 to 17 each 1-1-yl) -1-cyclopropyl-6-fluoro_8_ Phenoxy-1,4-dihydro-pyridin-3-carboxylic acid; 0 0

10 7- (3-{[(2-cyano-ethyl) -fluorenyl-amino] -fluorenyl} -pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-fluorene Phenyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 0 0

NC VOM?

, OH reference 7- {3- [1- (2-Gasyl-ethylamino) -ethyl]-° Biloliden-1-yl} -1-badpropyl-6-fluoro-8- Phenoxy-4-lanthoxy-1,4-dihydro-pyridin-3-carboxylic acid; 〇 Ο

NC ^ X, W Me Human 7- {3- [1- (2-Gasyl-ethylamino) -ethyl] -σBilodolidine-1-yl} -1-phosphine 18 200524930 group- 6-Ga-8-Methyl-4-lateral oxygen-1,4-dirat-halin-3-conic acid, 〇 0

Me L \ 7- (3- {l-[(2-cyano-ethyl) -methyl-amino] -ethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro- 8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 0 0

7- (3- {1-[(2-cyano-ethyl) .methyl-amino] -ethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl Phenyl-4- pendant oxygen-1,4-dihydro · pyridin-3-carboxylic acid; 0 0

7- {3-[(2-cyano-1-methyl-ethylamino) -methyl] -pyrrolidine-1-10yl} -1 -cyclopropyl-6-amino-8-methyl -4-lateral oxygen-1,4-dimurine quinolin-3-conic acid, 0 0

7-{3-[(2 · Ranyl-1-methyl-ethylamino) -methyl] -11 Billodine-1-yl} -1-badpropyl-6-air-8-form Lactyl-4-lateral milk-1,4-one mouse-intimidation ^-3-peroxy acid; 19 200524930

5 7- {3-[(2-cyano-ethylamino) -fluorenyl] -3-methyl-pyrrolidin-1-yl} -1-cyclopropyl_6-fluoro-8-methoxy Phenyl-4- pendant oxygen-1,4-dihydro · pyridin-3-carboxy

7- {3-[(2-cyano-ethylamino) -methyl] -3 · methyl-pyrrolidin-1-yl} -1-cyclopropyl-6 · Ga-8-fluorenyl- 4-lateral oxygen-1,4-dirat-. Quelin-3-junc acid,

7- (3-{[(2-cyano-ethyl) -methyl-amino] -methylbu 3-methyl-pyrrolidine 10 -1 -yl) -1 -cyclopropyl-6-gas -8-Lacyl-4-phenyloxy-1,4-di-rat-Lin-3-jun

7- (3-{[(2-cyano-ethyl) _methyl-amino] -methyl} -3-methyl-pyrrolidin-1_yl) -1-cyclopropyl-6-gas -8-methyl-4-oxo-1,4-dimurine-σ Charin-3-wei 15 acid; 20 200524930 NC- ο ο

7- {3- [1- (2-cyano-ethylamino) _cyclopropyl] Billow 17-M-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1 , 4-dihydro-pyridoline-3-carboxylic acid; 0 0

Η 7- {3- [1- (2-cyano-ethylamino) -cyclopropyl] -pyrrolidin-1-yl M-cyclopropyl-6-fluoro-8-fluorenyl-4- side Oxy-1,4-dihydro-pyridoline-3-carboxylic acid; 0 0

7- (3- {1-[(2-cyano-ethyl) -fluorenyl-amino] -cyclopropylpyrrolidine + yl) -1-cyclopropyl-6-air-8-fluorene 4-Alanyl-1,4-dihydroquinine-3-carboxylic acid; NC, 10 0 0

7- (3- {1-[(2-cyano-ethyl) -methyl-amino] -cyclopropyl} -pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8 -Methyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 〇 Ο

7- {3- [2-Ethylamino-1- (2-cyano-ethylamino) -ethyl] -pyrrolidine 21 200524930-1-yl} -1-cyclopropyl-6-gas -8-methoxy-4-lanthoxy-1,4-dirat-junlin-3-junic acid; 0 0

Η 7- {3- [2-Ethylamino-1- (2-arsyl-ethylamino) -ethyl]-° Biloxan-1-yl} -1-cyclopropyl-6- Qi-8-methoxy-4-lateral oxygen-1,4-dimurine-linophilic acid; 〇 0

7- (3- {2-Ethylamino-l-[(2-cyano-ethyl) -fluorenyl-amino] -ethyl 1ο Bilolide-l-yl) -1-cyclopropyl -6- qi · 8 · lactamyl-4-lateral milk-1,4-dimur-jun 10 phthaloline-3-carboxylic acid; 0 0

Me 7 · (3- {2-Ethylamido-1--1-((2-cyano-ethyl) -fluorenyl-amino] -ethyl} -17 biloxo-1-yl) -1- Cyclopropyl-6-gas-8-fluorenyl-4-lanthoxy-1,4-dimurine-carboxine-3-conc, 0

22 15 200524930 7_ {3-[(2-Gasyl-ethylamino) -methyl] -σbilolidene-1-yl} -1- $ alanyl-8-methyllactyl-4- Lateral breast-1,4-dirat-17 quinine-3-conc,

7-Gaso-ethylamino) -methyl] _ σbiloxo stilbyl-1-yl} -1-oxopropyl-8-methyl-4-oxo-1,4-dirat-σ Quelin-3-junc acid,

7- (3-{[(2-Ranyl-ethyl) _methyl-amino] -methyl} -σ ratio 17 each 1-1-yl) -1-¾propyl-8-methoxy -4-lateral milk-1,4-dimurine quinine-3-weiric acid,

10 7 · (3-{[(2-cyano-ethyl) -fluorenyl-amino] -methyl} -pyrrolidine-1-

Yl) -1-cyclopropyl-8-methyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 0 0

7- {3- [1- (2-Gas-ethylamino) -ethyl] -0 Billox stilbidine-1 -yl} -1-¾propyl-8-fluorenyl-4- side Oxy-1,4-dihydro-pyridoline-3-carboxylic acid; 23 200524930

7- {3- [l- (2-Gasyl-ethylamino) -ethyl] Billot sigma-1 -yl} -1-¾propyl-8-methyl-4- pendant oxygen-1 , 4-dihydro-pyridoline-3-carboxylic acid; 0 0

5 7- (3- {1-[(2-Gasyl-ethyl) -methyl-amino] -ethyl} · 17 Billoxan · 1-Axylpropyl-8-fluorenyl_4 _ Lateral oxygen-1,4-dimurine quinolin-3-conic acid, 〇 0

7- (3- {1-[(2-lactyl-ethyl) -methyl-amino] -ethyl) -1-cyclopropyl-8-fluorenyl-4-oxo-1,4 -Dihydro-xantolin-3-carboxylic acid;

10 7-{3-[(2-Gasyl-ethylamino) -methyl] -3-methyl-11 biloxo-1 -yl 1-cyclopropyl-8-methoxy-4 -Pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 24 200524930 Η

5 10 NC, 7- {3-[(2-cyano-ethylamino) -methyl] -3-methyl-pyrrolidine-l-yl} -1-¾propyl-8-methyl- 4-lateral milk-1,4-diaza-σ quinine-3-conc acid,

7- (3-{[(2-Amino-ethyl) -methyl-amino] -methyl} -3-methylbiruoline-1-yl) -1-¾propyl-8- 曱Milky base_4 · lateral oxygen-1,4-diqi quinine-3-conc acid,

7- (3-{[(2-Amino-ethyl) -fluorenyl-amino] -fluorenyl} -3-methyl-17biloden-1-yl) -1-cyclopropyl-8 -Methyl-4- pendant oxygen · 1,4-dihydro-pyridoline-3-carboxylic acid; 0 0

7- {3- [1- (2-Amino-ethylamino) -¾propyl] biloxo 17d-1-yl} -1-phostopropyl-8-fluorenyl-4-lanthoxyl -1,4-diazequinine-3-weiric acid,

7- {3- [1- (2-Gasylethylamino) -¾propyl] Biloxidine-1 -yl} -1-ϊ 25 200524930 propyl-8-methyl-4- side Oxygen-1,4-dihydro-pyridoline-3-carboxylic acid;

7- (3-{1-[(2-Gasyl-ethyl) -methyl-amino] -cyclopropylbiloxo stilbyl-1-yl) -1-¾propyl-8-methoxy _4-Side milk-1,4-Digas-Linophil-3-conic acid, 〇 0

5 7- {3- [2-Ethylamino-1- (2-amino-ethylamino) -ethyl-pyrrolidine-1-yl} -1-cyclopropyl-8-form Oxy-4-lanoxy-1,4-dimur-11 quinine-3-weilic acid, 〇 〇

7- {3- [2-Ethylamino-1- (2-cyano-ethylamino) -ethyl] -pyrrolidine 10-1 -yl} -1-¾propyl-8-fluorenyl -4-lateral oxygen-1,4-dirat-sigmaquinine-3-weiric acid,

7- (3- {2-Ethylamido-1--1-((2-cyano-ethyl) -methyl-amino] -ethyl} -J Billot ° -1-yl) -1_ Porylpropyl-8-methyl-4-oxo-1,4-dirat-bianline-3-weiric acid; 26 200524930 Ο Ο

7- (3- {2-Ethylamino-1--1-((2-cyano-ethyl) -methyl-amino] -ethyl} -11 biloxan-1-yl) -1-ring Propyl-8-methoxy-4-lanthoxy-1,4-dihydro-4a-3-carboxylic acid;

7- [1- (2-cyanoethylamino) -5-acyl-spiro [2.4] hept-5-yl] -1-cyclopropyl-6-fluoro-8-fluorenyl-4- side Oxygen-1,4-dihydro-pyridoline_3_carboxylic acid;

7- [1- (2-cyano-ethylamino) -5-acyl-spiro [2.4] hept-5-yl] -1-cyclopropyl 10 6-fluoro-8-methyl-4- Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid; 0 0

7- {3- [1- (2-cyano-ethylamino) -propyl] -acridan-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4 -Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid; 27 200524930 ο ο

7- {3- [1- (2 · cyano-ethylamino) -propyl] _azoldan-1-yl} -1-cyclopropyl-6-speak-8-methyl-4- Lateral oxygen-1,4-dimurine quinine-3-conc, 〇 0

7- (3- {1 · [(2 · Cyanoethyl) _methyl · amino] • propyl} acryldenyl) -1-cyclopropyl_6-fluoro-8-fluorenyloxy -4-Pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 〇 〇

10 7- (3- {1-[(2-cyano-ethyl) -fluorenyl-amino] -propyl} -acridan-1-yl) -1-cyclopropyl-6-fluoro- 8-methyl-4-oxo-1,4-dihydro-pyridoline-3-carboxylic acid; 0 0

7- {3- [1- (2-cyano-ethylamino) -cyclopropyl] -azor-1-yl} -1-cyclopropyl-6-gas-8-methoxy-4 -Pendant oxygen-1,4-diazepine- ° Quulin 3-Marine acid, 〇 Ο

28 200524930 7- {3- [l- (2-Gasyl-ethylamino) -¾propyl]-// 17-den-1-yl} -1-phosphorimyl-6-fluoro-8-methyl Phenyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 0 0

7- (3-{1-[(2-Mentyl-ethyl) -methyl-amino]-propylpropyl 17-1-5yl) -1-cyclopropyl-6- -8-Methoxy-4-lateral breast-1,4-dimurine_linophilin-3-conic acid, 〇 0

7- (3- {1-[(2-cyano-ethyl) -fluorenyl-amino] -cyclopropylbuazur-1-yl) -1-cyclopropyl-6-fluoro-8-methyl -4-Pendant oxygen-1,4-dihydro-pyridoline-3 · carboxylic acid;

10 7- (3- {1-[(2-Ranyl-ethyl) -ethyl-amine] -L-propyl} -lobiten-1-yl) -1-cyclopropyl-8-formyl Oxy-4-lateral oxygen-1,4-dimurine-σ quinine-3-weiric acid,

7- (3- {1-[(2-cyano-ethyl) -ethyl-amino] -cyclopropyl} -pyrrolidin-1-yl) -1 -cyclopropyl-6 -gas-8 -Methyl-4-lateral milk-1,4-dimurine-σ quinine-3-conc, 29 200524930

7- (3- {2-Ethylamine-1-[(2 -Ranyl-ethyl) -ethyl-amino] -ethyl} -Obiloline-1 -yl) -1-ring Propyl-8-methyllactyl-4-lateral lactam-1,4-dirat-sigmaine-3-carboxylic acid;

7- (3- {2-Ethylamino-1,1-((2-cyano-ethyl) · ethyl-amino] -ethyl} -pyrrolidin-1-yl) -1-cyclopropyl -8-fluorenyl-4-oxo-1,4-dihydro-pyridin-3-carboxylic acid;

10 7- {3- [1- (2-cyano-ethylamino) -propyl] -azor-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4- Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid sodium; 0 0

7- {3-[(2-cyano-ethylamino) -methyl] -3-methyl-acyl-1-yl} -1-cyclopropyl-6-fluoro-8-methyl- Sodium 4-lanthoxy-1,4-dihydro-pyridoline-3-carboxylate; 30 200524930

7- {3- [l- (2-Gasyl-ethylamino) -¾propyl] -diamidino-1 -yl} -1-¾propyl-6-amino-8-fluorenyl- 4-lateral breast-1,4-dirat-philim-3 · junic acid, 〇 Ο

5 7- {3-[(2-cyano-ethylamino) -methyl] -3-ethyl-azine-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy Phenyl-4- pendant oxygen_1,4-dihydroxantolin-3-carboxylic acid;

7- {3-[(2-cyano-ethylamino) -methyl] -3-ethyl-acyl-1-yl} -1-cyclopropyl-6-fluoro-8-methyl- 4-oxo-1,4-dihydro-pyridoline-3-carboxylic acid;

9- {3-[(2-cyano-ethylamino) -methyl] -cyclopentyl} -8-fluoro-3-fluorenyl-6-oxo-2,3-dihydro-6H- 1- 唠 -3a-azepine-5-carboxylic acid; or 31 10 200524930 ο ο

9_ (3-{[(2-cyano-ethyl) · fluorenyl_amino] _fluorenylcyclopentyl) _8_fluoro-3-methyl-6-oxo-2,3-dihydro collar ] 令 3 心口 丫 务 5_carboxylic acid. The invention is also directed to a compound of formula IV:

Or a pharmaceutically acceptable salt thereof, wherein: X may be N * C ', and its limitation is that when X is N, there is no r5 at this position; RA (CrC6) alkyl group, -based (Ci_C6) compound base, (C3_C6) cycloalkyl, 10 halo (C3_C6) cycloalkyl, heterocyclic, aryl, heteroaryl, and CH2 (C3-C6) cycloalkyl; R2 is OH, 〇BF2, 〇 (Cl_c6) alkyl 0 (C3_C6) cycloalkyl; 0-, where m is an integer m; Q is 0 or Li or N (CrC6) alkyl or lack thereof; and 1 is fluorene or (Cl_C6) alkyl; and R2b is 15 (crC6 ) Alkyl, aryl or heteroaryl; 0- (CHR2a) n_Y, where ~ is as defined above; η is an integer from 2 to 10; Υ is 0Η or NR ^ Rm 'wherein ^. And each may independently be n, (Ci_C6) alkyl or (C3-C6) cycloalkyl; or 32 200524930

NR

2a, where ^ is as defined above; `` where `` ~~~ '' refers to the connection position, 2a is as defined above; R2e and R2e, each can independently take care of (Cl-C6) alkyl , Or connected with carbon to form-3, 4, 5, or 6 substituted or unsubstituted rings; 6 is an integer from 1 to 1G, and P is an integer from 2 to H); and each of them may be independently independent Ground is NH or 0; R3, and R5 each may be independently Η, dentate, NRyRz (where Ry and Rz may each be independently reeled), sintered, li-based (CVC6), 0 (Crc6) courtyard, 0 (CVC6) tooth burning, riding; 10 heart and anti-5 are connected with carbon to form a substituted or unsubstituted 5 or 6 member substituted or unsubstituted ring, which Contains 0, 1, or 2 heteroatoms selected from 0, S, SO, S02, or NRx, where D is 11 or (CVC6) alkyl, and z is 0, 1 or 2; each can be Each independently H, (CVC6) alkyl, (Cl_C6 :) alkoxy, halo (CrC6) alkyl, halo; or Ra & Rb and carbon are joined together to form a 3, 4, 5, or 6 member Substituted or unsubstituted ring; R 'is H, halo, (Cl-C6) alkane Group, 0 (Cl_C6) alkyl, halo (Ci_c6) alkyl, aryl or heteroaryl; each of RC and Rd may be independently fluorene, (C! -C6) alkylnitrile, 0 0 _ ^ 0Η-h〇 (CrCe > alkylOH, 0 (crCe) alkyl, (Ci-C6) alkyl, (C3-C6) cycloalkyl, miscellaneous radical, S02- (crc6) alkyl, S〇2-aryl, S〇2-heteroaryl; 33 200524930— (CR2aR2a,) 0—〇JL〇 »^, where g is an integer from 1 to 10; Q is as defined above, and Rh and Rh ' Each may be independently an H * (c plant C6) alkyl group, or may be anti-linked to the stone to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; and (CVC6) alkyl , Aryl or heteroaryl; 0 0 (CR2aR2a.) G ~ 0-P- (〇H} 2 or 〇 一 prepare (〇 (〇々) alkynyl) 2, wherein R2a and R ^, as described above Definition; t «y ^ R2c P, where" ~~~ "refers to the attachment position, p is 0 or 1; and R2e is Η, (cvc6) alkyl, 0 (Crc6) alkyl, cyclohexyl, aryl , Heterocyclic group, heteroaryl group; or 10- (CHR2a) h-OO0R2b or a "CHRJ wide γ, wherein R2a, r2aq are as defined above; and each of h and j can be an integer independently 〇 to 10; and ¥ is O H 0P0 (0H) 2, 〇p〇 (G (Cl-C6)) 4NRMRk, wherein each of R2AR2e can be independently fluorene, (crc6) alkyl or (C3_C7) cycloalkyl; Wherein q is 0 or 1; each of R2f and R2r may be 15 independently of H, (Cl-C6) alkyl, aryl or heteroaryl, or connected to carbon to form -3, 4, 5 or 6 substituted or unsubstituted rings; and% is (CVC6) alkenyl, (c3_c7) ring silk, aryl, heterocyclyl, or heteroaryl; and each may be independently fluorene, Ci_Q alkyl , Alkyl, or alkyl; or Re and R are linked to carbon to form a 3, 4, 5, or 6-membered ring. The invention also provides a compound, which may be: 0 0

9- [3- (1-Amino-2-amino-ethyl) -σ-biloxamine-l-yl] -8-Ga-3-methyl-6-oxo-2,3-dihydro -6Η-1-oxin-3a-acyl- 葩 -5-carboxylic acid; 0 0

9- [3- (R)-(2-cyano-1_ (S) -methylamino-ethyl) -pyrrolidin-1-yl] -8-fluoro-3- (S) -fluorenyl- 6-oxo-2,3-dihydro-6H-1-H-3a-acyl- 葩 -5-carboxylic acid 0 0

^ CN

HN 、 0H 10

NCW A 7- [3- (l-Amino-2-lactyl-ethyl) -0 Biloprodin-1 -yl] -1 -Axylpropyl-6-fluoro-4-oxo-1 , 4-dihydro-pyridoline-3-carboxylic acid; 0 0

H2N 〆NC ^ 〇 and 7- [3- (l-amino-2-ranyl-ethyl) -σbilo sigma-1 -yl] -1 -badpropyl-6-fluoro-4-side Oxy-1,4-dihydro- [1,8] naphthyridin-3-carboxylic acid; 35 15 200524930 ο ο

7- [3- (1-Amino-2-cyano-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1 , 4-dihydro-pyridoline-3-carboxylic acid; 0 0

7- [3- (1-Amino-2-cyanoethyl) · pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8 · methyl_4-oxo-1,4 -Dihydro-pyridin-3-carboxylic acid; 0 0

〇Me ^ 7- [3- (l-amino-2-cyano-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8- methoxy-4- pendant oxygen-1, 4-diazine-sigmaine-3-weilic acid, Ο Ο

7- [3- (1-Amino-2-lanyl-ethyl) -pyrrolidine-1 -yl] -1 -badpropyl-8-10 methyl-4-oxo-1,4 -Two rats_σ 奎琳 -3- 竣 酸,

ΝΗ2 Ο 0 36 200524930 5 -Amino-7 · [3- (1-Amino-2-oxanyl-ethyl) -σbilo sigma-1 · yl] -1 · propyl-8-methoxy Pyridyl-4-lanthoxy-1,4-dimuridine-carboxine-3-endoic acid, ΝΗρ Ο Ο

5-Amino-7- [3- (1-Amino-2-Isyl-ethyl) -u-bilol °° -1-yl] _1-bad 5 propyl-8-methyl-4- side Milk-1,4-Dimurine-sigmaquinine-3-weiric acid, 〇 0

〇Η

7- [3- (1-Amino-2-lactyl-2,2-dimethyl-ethyl) -1: J Billot-l-yl] -l-cyclopropyl-6-fluoro- 8-methoxy-4- pendant oxygen-l, 4-dihydro-pyridoline-3-carboxylic acid; 〇 Ο

10 7- [3- (1-Amino-2-cyano-2,2-diamidino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl Phenyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 〇 Ο

7- [3- (1-Amino-2-amino group) " * 2,2-Difluorenyl-ethyl) -11 Billot 11Adeyl-1-yl] -1- 37 200524930 Cyclopropyl-8 -Methoxy-4- pendant oxygen-1,4-difluorene-pyridin-3-carboxylic acid; 0 0

7- [3- (1-Amino-2-carbyl-2,2-dimethyl-ethyl) -17 Billox stilb-1-yl] -1-cyclopropyl-8-methyl- 4-oxo-1,4-dihydro-pyridoline-3-carboxylic acid;

5-amino-7- [3- (1-amino-2-cyano-2,2-dimethyl · ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-methyl Oxy-4- pendant oxygen-1,4-dihydropyridin-3-carboxylic acid;

5-amino-7- [3- (1-amino-2-cyano-2,2-diamidino-ethyl) -pyrrolidine 10 -1 -yl] -1-¾propyl-8- Methyl-4-oxo-1,4-dirat-. Kui commanded ^ 3- Jun acid, 〇 0

7- [3- (1-Amino-2-nitro-ethyl) -σbiropin-1-yl] -1-¾propyl-6-fluoro-4-oxo-1,4-di Hydrogen-colin-3-weilic acid; 38 200524930 ο ο

7- [3- (2-lactyl-1-methylamino-ethyl) -σbilo sigma · 1-yl] -1-¾propyl-6-gas-4-side oxygen-1, 4-Diaza-Linophil-3-carboxylic acid, 0 0

5 9- [3- (2-Amino-1 -methylamino-ethyl)-. Billot sigma-1 -yl] -8-gas-3 · methyl-6-oxo-2,3-dihydro-6Η-1-hum-3a-acyl- 葩 -5-carboxylic acid; Ο Ο

9- [3 (R)-(2-cyano-1 (S) -methylamino-ethyl) -pyrrolidine-1_yl] -8-fluoro_3_fluorenyl-6-oxo- 2,3-dihydro-6H-1- 噚 -3a-acyl- 葩 -5-carboxylic acid; 0 0

10 7- [3- (2-Amino-1 -fluorenylamino-ethyl)-° Bilodol ° -1 -yl] -1-¾propyl • 6-fluoro-4-oxo-1 , 4-dihydro- [1,8] naphthyridin-3-carboxylic acid; 〇 〇

43- (2-cyano-1-methylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl 39 200524930 -6-fluoro-8-methoxy-4- pendant oxygen- 1,4-dihydro-pyridoline-3-carboxylic acid;

7- [3 (R)-(2-cyano-1 (S) -fluorenylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy Phenyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid;

MeHN NC ^ 7- [3- (2-cyano-1-fluorenylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4_ Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid; 〇 〇

7- [3_ (2-cyano-1-methylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl

10 -8-fluorenyl-4-lanthoxy-1,4-bisfluorene-phosphonline_3_carboxylic acid; 0 0

MeHN NC '' 7- [3- (2-cyano-1-methylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-fluorenyl-4-oxo-1 , 4-dihydro-pyridoline-3-carboxylic acid; νη2 ο ο

ΜθΗΝ HC ^ / 40 200524930 5 -Amino-7- [3- (2-oxy-1-methylamino-ethyl) -π ratio Hip -1 -yl] -1-¾propyl-8 -Fluorenyl-4-lanthoxy-1,4-dimur-17 quinine-3-conc, νη2 ο p

MeHN NC ^ X 5 -Amino-7- [3- (2-Gas-1-methylamino-ethyl) -11 Billot-1 -yl] -U-propyl-8 -4-lateral breast-1,4-dimurine-linophilic acid-3, 〇 0

7- [3- (2-cyano-2,2-diamidino-1-fluorenylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8- Methoxy-4- pendant oxygen-1,4-dihydro-pyridoline · 3-carboxylic acid; 0 0

10 7- [3- (2-cyano-2,2-diamidino-1-fluorenylamino-ethyl) -pyrrolidin-1-yl] -1-¾propyl-6 -ran-8 -Methyl-4-lateral lactam-1,4-dimurine-3-junconic acid, 〇 0

7- [3- (2-cyano-2,2-diamidino-1-methylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-fluorenyl-4 -Pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 41 200524930 ο ο

7- [3- (2-Gas-2,2-dimethyl-1-methylamino-ethyl) -1-cyclopropyl-8-methyl-4-oxo-1,4 -Dihydro-xantolin-3-carboxylic acid;

5 5-amino-7- [3- (2-Gas-2,2-dimethyl-1-fluorenylamino-ethyl)-. Biloxido-1-yl] -1-¾propyl-8-fluorenyl-4-lanthoxy-1,4-dimuridine-quinolinol-3-weilic acid, or

5-amino-7- [3- (2-cyano-2,2-dimethyl-1-methylamino-ethyl) -pyrolodin-1 -yl] -1 -badpropyl -8-Methyl-4-lateral oxygen t-1,4-dimurine-quinolin-3-weiric acid. 10 The present invention also provides a compound of formula V or VI

42 200524930 or a pharmaceutically acceptable salt thereof, wherein: X may be N or C, and the restriction is that when it is ^^, there is no R5 at this position;

Ri is (CrC6) alkyl, alkynyl) alkyl, (c3_C6) cycloalkyl, halo (C3_c0) cycloalkyl, heterocyclic, aryl, heteroaryl, and CH2 (C3-c6) cycloalkane R2 is OH, OBF2, 0 (CrC6) alkyl, 0 (c3-C6) cycloalkyl;

〇- (CHRynroJLQF ^, where m is an integer e1〇, Q is (^ NH 10 15 or N (CrC6) alkyl or lacking; and R2a is η or (crC6) alkyl and R2b is (Ci-C6) alkyl) , Aryl or heteroaryl; 0- (CHR2a) n_Y, where R2a is as defined above; n is an integer from 2 to 10; Y is OH or NR2cR2d, wherein each of R2c and R2d may be η, ( CVC6) alkyl or (C3-C6) cycloalkyl; or NR2a, wherein R2a is as defined above;

丨 One (CHRA-VH

Wherein "~~~" refers to the connection position, 2a is as defined above; each of R2e & R2e 'can be independently Η or (C ^ CJ alkyl, or connected with carbon to form a 3, 4, 5 Or 6-membered substituted or unsubstituted ring; e is an integer from 1 to 10, p is an integer from 2 to 10; and each may be independently NH or 0; each of R3, R4, and Rs may be independently Η , Halo, NRyRz (where Ry and Rz each may be independently fluorene or (Crc6) alkyl), (CVC6) alkyl, halo (C "C6) alkyl, 0 (Ci_C6) alkyl, ((^ -〇6) halohalo, nitrile; 43 200524930 R1 and R5 are linked with the slave to form a substituted or unsubstituted 5 or 6-membered substituted or unsubstituted ring, which contains 0, 1 or 2 heteroatoms selected from 0, S, SO, S02 or NRX, wherein 仏 is H4 (Ci-C6) alkyl; and 5 q is 0, 1, 2 or 3 and Z is 〇, 1 or 2; ^ Is!, (Eve: 6) alkyl, halo (Ci_c6) alkyl, halo; or d and Rb are linked to the carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring;

Each of R ', R ", R'", and R "" may be independently fluorene, (c-alkyl 10-yl, -0 (Cl-C6) alkyl, halo (CrC6) alkyl, aryl Or heteroaryl;

Rc B is Rf \, ReW, full

The limitation is that when B is RiTr, R is not 0 (Cl_Q group, and "~~~" in this refers to the connection position; and

Each of Rc and Rd may be independently fluorene, (crc6) alkylnitrile, 0 〇— ^ 〇H —jL〇 (crC6) alkyl〇H, 0 < C1-C6 > alkyl, (C1-C6) alkyl , (C3-c6) cycloalkyl, heterosquaryl, SC ^ -CCrC ^) xyl, S02-aryl, so2-heteroaryl;-23 ~) 0-〇 丄 〇 吆, where g Is an integer m; Q is as defined above, and Rh and Rh, each of which may be independently (or (crc6) alkyl, or linked to carbon to form a 3, 4, 5, or 6 member substituted or Unsubstituted 44 200524930% 'and Rn is (C ^ -C6) xyl, aryl or heteroaryl; (CR2aR2a) g-〇4- (OH > 2 or (CF ^ F ^ Vo-μ 一 ( 〇 (CrC6) alkyl, where R2a and R2a are as defined above; ☆ 'where ~~~ refers to the connection position, p is 0 or 1; and R2c is Η, (CrC6) alkyl, 0 (CrC6) alkane , (Crc7) cycloalkyl, aryl, heterocyclyl, heteroaryl; or — (CHf ^ — 〇0 wherein R2a, R2b and Q are as defined above in 10 15; and each of h and j may be independent of each other The ground is an integer of 0 to 10, and γ is 〇Η, ΟΡΟ (ΟΗ) 2, 〇〇 (〇 ((^-(: 6))) ^ ΝΚ2ίΐΚ26, where ~ and the heart can each be independent Is fluorene, (CrC6) alkyl or (C3_c7) cycloalkyl;

Where q is 0 or 1; R2f and R2f, each of which may be independently Η, (< ^ 6) alkyl, aryl or heteroaryl, or linked to carbon to form -3, 4, 5 or 6-membered substituted or unsubstituted ring; and ^ is (C "C6) alkyl, (CVC7) cycloalkyl, aryl, heterocyclyl, or heteroaryl; each of WRf may be independently Cl_C6_, fluorenyl, halo; or Re & Rf and carbon are attached to a 3-, 4, $, or 6-membered substituted or unsubstituted ring; ', Ci-C6 alkyl, haloalkyl, 5 Or 6 members replaced or not taken

Rg and Rh can each independently be H or linked to carbon to form a 3, 4, and ring; and 45 20 200524930

Each of Rj and Rk may be independently Η, ((^-(36) alkyl, haloalkyl, (CrC6) alkyl-NRcRd, (CVC6) alkyl-ORc, aryl, heteroaryl, hetero Ο ring, (Crc6) alkyl-Z-Rd, where Z is 〇 or NRC; or Rj and Rk are linked with carbon 5 to form a 3, 4, 5 or 6-membered substituted or unsubstituted ring The invention also provides a compound, which may be

10 7- [4- (2-Gasyl-ethylamino) -hexamethylene-spentamyl [c] 17 to σ each · 2 · yl] -1-¾propyl-6-Ga-8-methyl -4- lateral milk-1,4-dimurine quinine-3-conic acid,

7- [4- (2-Ranyl-ethylamino) -hexamethylene-¾ 戍 [c] tσσ-2-yl] -1 -¾propyl-6-Ga-8-methoxy- 4-side oxygen-1,4-diaza-. Quelin-3-weilic acid,

7- [4- (2 · Gas-ethylamino) -hexazine · L-pentyl [c] Bilo-2-yl] -1 -¾propyl-8-methyl-4- pendant oxygen- 1,4-dimurine quinine-3-weiric acid,

46 15 200524930 7- [4- (2-lactyl-ethylamino) -hexazine- [1] [pyrrol-2-yl] · 1-¾propyl-8-fluorenyl- 4-lateral oxygen-1,4-dimurine-linophilic acid-3,

7- [4- (1-Amino-2-nitro-ethyl) -hexaaza-cyclofluorene [c] 11 to 17 each-2-yl] -1 -5 bad propyl-6-gas-8 -Methyl-4- pendant oxygen-1,4-diazequinine-3-conc

7- [4- (1-Amino-2 -amino-ethyl) -hexakis-L-pentyl [c] utbHa-2 -yl] -1 -cyclopropyl-6-fluoro-8-fluorene Oxy-4- pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid;

10 7- [4- (1-Amino-2 · amino-ethyl) -hexaaza-¾ 戍 [c] 17 Billo-2 · yl] -1-cyclopropyl-8 · methyl-4 -Pendant oxygen-1,4-dihydro-pyridoline_3_carboxylic acid;

7- [4- (1-Amino-2-oxanyl-ethyl) -hexaaza-¾ 戍 [c]. Bilo-2-yl] -1 -badpropyl-8-methoxy-4- pendant oxygen-1,4-diazepine-linophilic acid, 47 200524930

7- [3a- (2-cyano-ethylamino) -hexahydro-cyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-side Oxygen-1,4-dihydro-pyridoline-3-carboxylic acid;

5 7- [3a- (2-Gas-ethylamino) -hexagas-¾ 戍 [c] Bilo-2-yl] -1-¾propyl-6-Ga-8-fluorenyl- 4-side milk-1,4-diaza-π quinine-3-weiric acid,

7- [3a- (2-cyano · ethylamino) -hexahydro-cyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methyl-4- pendant oxygen-1, 4-diaza-. Quelin-3-weilic acid,

7- [3a- (2-Gasethylethylamino) -hexaaza-¾penta [c] 0bilo-2-yl] -1-¾propyl-8-methoxy-4- pendant oxygen- 1,4-dihydro-pyridoline-3-carboxylic acid; 48 200524930

7- [3a- (l-amino-2-cyanoethyl) -hexahydro-cyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4 -Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid;

5 7- [3a- (l-amino-2-cyano-ethyl) -hexahydrocyclopentyl [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro-8-methoxy Phenyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid;

7- [3a- (l-Amino-2-nitro-ethyl) -hexaki-Jazone [c] ° Bilo-2-yl] -1 -cyclopropyl-8-methyl-4 -Pendant oxygen-1,4-diazine-11 quinolin-3-weiric acid, or

7- [3a- (l-amino-2-cyano-ethyl) -hexahydro-cyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methoxy-4-side Oxy-1,4-dihydro-pyridoline-3-carboxylic acid. 49 10 200524930 5 10 15 The present invention also provides a pharmaceutical formulation comprising a compound of formula I, U, III, IV, V or VI ', mixed with a pharmaceutically acceptable diluent or excipient. The present invention also provides a method for treating a bacterial infection in a mammal. F includes administering an effective amount of a compound of formulas 11, 111, ^ to a mammal in need of treatment. [Embodiment; detailed description of the preferred embodiment] Now, reference will be made in detail to the presently preferred composition or examples and methods of the present invention, which will constitute the best known implementation mode of the present invention. As used herein, the name "alkyl" refers to a straight or branched chain hydrocarbon having 1 to 6 interfering atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-I, di Butyl, isobutyl, tertiary butyl, n-fluorenyl, n-hexyl, and the like. The carrier group can also be-one selected from the following substituted mei two-chain (w-oxyl, (C1_C _Brokenyloxy 1 element, i group, heteroaryl, pendant oxygen, thio group, -OH,, -F, -CF3, _〇cf3, -no2, -C〇2h, _c〇2 (CVC6) Or, ^ ^ o the name "(CVC6) cycloalkyl, meaning ~ ~ eight cigarettes, such as cyclopropyl, cyclobutyl, cyclopentyl minus 3 to 6 carbon atoms of the cycloalkyl It may contain a double bond, for example, 3-cyclohexylhexyl. If possible, it may be unsubstituted or selected from one or more of the following groups. The cycloalkylcyclo, alkoxy, thio Methoxy, peptyl, and substituents of 'J. Substitute · Alcohol, Nansu, f 醯,

50 20 200524930 Carboxyl, -C02 (Ci-c6) alkyl, -C0 (c "c6) alkyl, aryl, heteroaryl, the alkyl, aryl and heteroaryl groups thereof are as defined herein. As indicated above in alkyl groups. Examples of substituted cycloalkyl groups include fluorocyclopropyl groups. The name 'southern' includes chlorine, fluorine, bromine and moth. The name "dentate alkyl" means (Crc6) alkyl substituted with multiple halo groups. The name "aryl" means a monocyclic or polycyclic aromatic ring having 5 to 12 carbon atoms, which is unsubstituted or substituted with one or more of the substituents described above for alkyl groups, including: halogen , Nitro, cyano, _〇H, _SH, _F, 10 15

3, -ocf3, monofluorene, -C〇2h, the name 〇2CrC6 alkyl or _s〇2 alkyl Examples include (but are not limited to) phenyl, 2chlorophenyl, p-phenyl, methylphenyl, 3_f-silyl, " ylphenyl, 2-methoxyphenylmethoxyphenyl, 4-methoxyphenyl, 2-amino_3_methylphenyl, H4 methyl, benzyl, 2_ Gas-5-methylphenyl, 3 | 2_methylphenyl, 3_

Benzyl, 4-Gas_2-methylphenyl, 4-Gas-I-methylphenyl, 5-Gas-methyl, 2,3-Difluorophenyl, 2,5-Dichlorophenyl, 3, 4-dichlorophenyl, 2,3-fluorenylphenyl, 3,4-dimethylphenyl, naphthyl, 4-thionaphthyl, Cai Manji,, phenanthryl, benzonaphthyl Base, 2-acetamidine, and 4, / stilbene. The name "heterocubic group" means a ring system having an aromatic ring or polycyclic ring selected from the heteroatoms of N, 0, and ^. Typical heteroaryl groups include 2-stilbyl ~ 2-phenoyl, 2_ Or 3-creosyl, 2 or 3.Weiji, 2_, * or 5_fluorenyl, 3-, 4- or 5-pyrazolyl, 2_, 4_ or 5_thiazolyl, 3_, 4 · or 5_ Iso 1 51 20 200524930 Sialyl, 2-, 4- or 5-, fluorenyl, 3-, 4- or 5-iso. Sialyl, 3- or 5-1,2,4-triazolyl, 4 -Or 5-l, 2,3-trisialyl, tetrazolyl, 2-, 3- or 4-radyl, 3-, 4-, or 5-talyl, 2-0 pyridyl, 2 -, 4- or 5-mouth bite base, 2 ·, 3-, 4-, 5-, 6-, 7- or 8 · mouth Charinki, 1-, 3-, 4-, 5-, 6- , 7- or 8-iso-5 oxalinyl, 2-, 3-, 4-, 5-, 6-, or 7 'bowbendyl, 2-, 3-, 4-, 5-, 6-, or 7-benzene Acene [chrysinyl, 2-, 4-, 5. ·, 6- or 7-benzoπ-fluorenyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl. The heteroaryl may be unsubstituted or substituted with one to three substituents selected from those described above for alkyl, alkenyl and alkynyl, For example, cyanothenyl and fluorenyl 10-pyrrolyl Preferred aromatic fused heterocycles of 8 to 10 atoms include (but are not limited to) 2-, 3-, ζμ, 5-, 6-, 7- or 8-fluorenyl m, 5_, 6 7 Or 8-isoπ quelinyl_; 2-, 3-, 4, ·, 5-, 6-, or 7 "tombido, 2-,, 4_, 5-, 6-, or 7_benzo [b] thiophene Base, 2_, 4 ... 孓, 6 •, or 'benzo ° salyl, 2_, 4_, 5, ·, 6_ or benzoyl, 2_, 4_, 5-, 6-, or 7-benzon Salyl ~ a hard-to-open base. The heteroaryl group also includes 2- and 3-aminofluorenyl heptamidine, 2- and 3-aminomethylthiophene, and the like.

20 52 200524930 Including propylene oxide, phenyloxybenzyl (oxy-field (Linben)), cis-2-butene-oxide (2,3--methyl is called 3-gas tetrahydrocondensate, Class 2,6_: Heterocyclic groups such as nitrogen, oblique, tetranitrogen, and substituted groups (such as 3 · amine base, 4-methyl yarn 1 · base) and the like Typical sulfur-containing heterocycles include tetraazathiophene, —7 | alcohol-2-yl, hexahydrophenan-4-yl, and substituted groups (such as acetomethylmethylphen). Other commonly used Heterocycles include digas, phenone 10 radical, dihydro · 1Η · isofluorene, tetrahydro, silk, tetrahydro ^ difluorenyl, tetrachloroicosylamino, hexahydrotrisene, tetrahydrodecayl , ㈣ ^ thiomorpholine, tetrahydrobenzyl, dioxoyl (dioxoiyi), octabenyl, hydrogen benzimidyl, and human hydrobenzoyl. P ^ The term "thiocycles" also includes the thiazines containing oxidized sulfonium groups. Examples include the sulfoxide and hydrazone forms of tetrahydrothiophene. 20

In some examples, in order to prepare the compound of the present invention disclosed herein, a protecting group may be used to facilitate the synthesis and manipulation of only one functional group in the presence of other functional groups. Those skilled in the art are quite well aware of the appropriate use and selection of protecting groups. It is also important to understand that this group not only provides a protected chemically reactive site, but also increases solubility or changes its physical properties. The general reference materials for the preparation and deprotection of protecting groups are Greene, Theodora, Minghe Hehe, and the paint protection is very poor; Wiley · New York, US, 1991 and later. Therefore, it is necessary to further understand that an inventive compound characterized by the presence of a compliant group as disclosed and described in Greene is also considered to be a compound of the present invention. 53 200524930 Tian ~ bond is represented by a symbol such as "", A sound, 砉-+ 矣 士 are missing 々 士> 7 Ding Yu wants to express the key. 4 exists, but the compound produced needs to be stable and meet the required valence. & To be "bonded by a spirit bar such as" ~~~ "+ n main I», this is intended to indicate that the yttrium is the attachment position between two molecular subunits. Name "Patient" Means all mammals, including humans. Examples of other patients include cattle, dogs, t, and rabbits. Tesha, 帛 flat cheeks, pigs 10 15 20 "Therapeutic Effective Amount" is- The amount of the compound, when it is administered to a patient, can provide the desired effect; that is, it can reduce the severity of the symptoms related to the offense. It should be understood by those skilled in the art that the present invention has one or more The compounds in the center of the palm can exist in optically active and racemic forms, as well as in the form of cleavage. Certain compounds may exist in polymorphism. It should be understood that the present invention includes the compounds of the present invention as well as any medial, optical Active, polymorphic, geometric or stereoisomeric forms or mixtures thereof, and have useful properties described herein; already well-known in the art how to prepare photonic tongues! • Formula 7 (eg, by 'recrystallization technique' Analysis of racemic forms Initiation, synthesis by palm, or chromatographic separation using a preparative stationary phase), and how to measure activity using standard tests described herein or other similar tests well known in the art Cytotoxicity. Some compounds of the present invention can also be useful as intermediates to prepare other compounds of the present invention. Therefore, a compound of 1 and 2 can be hydrolyzed to form another compound of the invention (where R2 is Ii). Certain compounds of formula I can further form pharmaceutically acceptable acid additions and / or base salts. These forms are all within the scope of the present invention. Therefore, pharmaceutically acceptable acid additions of compounds of formula I Salt formation includes salts from non-toxic, non-organic acids (such as hydrochloric acid, song acid, filling acid, sulfuric acid, hydrogen acid, hydrofluoric acid, hydrofluoric acid, phosphorous acid, and the like), and from non-toxic Salts of organic acids (such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.) This salt therefore includes Sulfate, pyrosulfate, bisulfate, bisulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, acetate, trifluoro Acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate Diacid salt, mandelate, benzoate, chlorobenzoate, fluorenylbenzoate, dinitrate 15-benzoate, phthalate, benzenesulfonate, tosylate, benzene Acetate, citrate, lactate, maleate, tartrate, sulfonate and the like. Also considered are salts of amino acids, such as spermine and Analogs, gluconates, galacturates (see, eg, Berge, SM, et al., "Pharmaceutical Salts", # 学 催 ⑽r⑽ / 20 of Pharmaceutical Science), \ 9ΊΊ ·, ·· \-\9). The acid addition salt of the basic compound can be prepared in a conventional manner by contacting the free base form with a sufficient amount of the desired acid to produce the salt. Pharmaceutically acceptable base addition salts can be formed from metals or amines, such as alkali gold and alkaline earth metals or organic amines. Examples of metals that can be used as cations 55 200524930 =, magnesium, ma, and the like. Examples of suitable amines are n, n, -bisamine: ethyl :: amine, chloroprocaine, cholestyramine, diethanolamine, dicyclohexylamine ethylene monoamine, N-reducing glucosamine, and general SM. Id., 1977). 〇caine (see, for example, a base addition salt of a Bergy compound may be prepared in acid form with a sufficient amount of the desired test compound to produce the salt. Unsolvated forms and formulas (including " Human ^ 3 AW) exists. Generally speaking, the solvated form (including 3 water _ formula) and Wei ㈣ # 10 are within the scope of the present invention. ⑽ Formula ㈣1 is intended to include "prodrugs" as A non-reactive street organism of a drug molecule that requires chemical or enzyme biotransformation to release Hua in the body. 15 列 Compilation: The specific and preferred groups, substituents, and ranges of the compounds of the invention are as follows: It does not exclude other defined values or other values within the meanings of f and substituents. Unless otherwise described or defined, the abbreviations used in this document follow the American Chemical Society Journal. (A darken ⑽ ch_cal 80〇 kissing journals). So 'we now return to the compound of formula m with the following structure:

The special value of X is C or N. The specific value of Ri is (Ci_c6) cycloalkyl and halo %% aryl or aryl. The specific value of & is thief muscle. The specific value of 56 20 200524930 R4 is fluorene or halo. When X is C, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy. In another embodiment of the compound of formula I, the specific value of X is c * N. The specific value of the core is cyclopropyl or fluorocyclopropyl. The specific value of & is 2 or, and the specific value of 2 ° is 仏 or F. The specific value of X is C or N. Specific values for R5 are dentyl, fluorenyl, or methoxy. In another specific embodiment of the compound of formula I, Ri, r3, and R, R are provided as follows, wherein R 2 may be OH, 0BF240 (CrC6) alkane 10 R ′ may be η or F; and A can be

B

N) 2 Rb

or

57 200524930 Ο Ο 0 0 0 0 0

〇〇 0 0 Me Ο Ο

Ο Ο Ο Ο Ο Ο

58 200524930 Ο Ο Me Ο Ο 0 0

0 0 0 0 ΝΗ〇 Ο Ο

0 0 0 0 Me Ο Ο

Ν

Β

As previously indicated, in the compounds of the present invention, A may be Rb Β0〇ΐ Β ,,, > > Οΐ Β WRb or 11 " ", where q may be 0, 1, 2 or 3 and z may Is 0, 1, or 2. In particular, when Q is 2 or 3, z may be 0, 1, 2; moreover, when q is 0, 1, 2, or 3, z is 1 or 2. 59 200524930 In particular, each of Ra and Rb may be independently Η, ((^ ό, (CVQ) alkoxy, halo (CrC6) halo, halo; or d and & attached to the carbon Together form a C = 0, C = NO (CrC6) alkyl group or a 3, 4, 5, or 6-membered substituted or unsubstituted ring. More specifically, each of daggers and hearts can be independent from each other. Ground is fluorene, methyl, ethyl, fluoro, fluoromethyl, trifluoromethyl, fluoroethylmethyl, MeO_N =; or linked with carbon to form a cyclopropyl group.

In particular, each of R ,, R ,,, R ,,, and R ,,, may be independently H, (ci-c0) alkyl, _0 (Ci_C6) alkyl, halo (Ci_C6) alkane Radical, aryl or hetero10aryl. More specifically, R ,, R ", R ,, and R ,,,, each may be independently fluorene, fluoro, methyl, ethyl, fluorofluorenyl, fluoroethyl, phenyl, Benzyl or methoxy.

15 is the connection position, R, not -0 (CrC6) alkyl.

In particular, each of Re & Rd can be independently fluorene, (crc6) alkyl J 基 nitrile, ~ t〇H — ^ 〇 (CrCe > alkyl #H, 〇 (Ci-C6> Alkyl, (C3_C6) cycloalkyl, heteroaryl, S (V (CrC6) alkyl, S02_aryl, or S02_heteroaryl. More particularly, each of the 'RARd's can be independently independently Is fluorenyl, fluorenyl, or ethyl. 20 In particular, each of Re and Rf may be independently fluorene, CrC6 alkyl, 60 200524930 haloalkyl, halo, or Re and Rf are linked together with carbon to form a 3 , 4, and $ 6 6-membered substituted or unsubstituted rings. More specifically, each of the two may be independently Η, methyl, or ethyl. In particular, each of Rg and Rh may be each independently Independently η, Ci-C6 alkyl, 5-alkyl, or linked to carbon to form a 3, 4, 5 or 6-membered substituted or unsubstituted ring. More specifically, Rg and Rh Each may be independently H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl,

Phenyl, isoxazolyl, carboxymethyl, carboxyethyl, or ANHMe, or linked to carbon to form delta. 10 In particular, each of Rj and Rk may be independently h, (cvcd alkyl, dental, (CrC6) alkyl_NRcRd, (CVC6) alkyl_0Rc, aryl, heterooxo, Miscellaneous, (CrC6) alkyl—Z—Rd, where Z is 0 or] SfRc; 戍

Rj and Rk are joined to the carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring. More specifically, each of Rj and Rk may be independently fluorene, 15methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, Carboxymethyl, carboxyethyl or obituary NHMe, or linked to carbon to form eight. Therefore, in the compound of formula I, eight is Ra Rb, and B is 61 200524930.

It can therefore be exemplified by any of the following structures:

5 Furthermore, in the compound of formula I, wherein A is

, Where z is 0, 1, or 2 and q is 0. Any structure example, where 2 or 3, A can be

62 200524930

B

Νλ

Cb

B

B

B

^ * WV p. Where

B FN

B

‘Refers to the connection position As previously indicated, B may be

Rc, NCV ^ Rf ϊ β, where Rc, Rd, Re, Rf, Rg, Rh, Rj and Rk have any of the definitions provided above. Therefore B can have any of the following structures: NC-χ NO ^ ΛΛΛ Η. NC-

Me .Nw NC \ ^ n ^ S Et H Me

Me, cf3

^ Enter NC, H

'NT

H

H

H

Uz

Me Me People NC Me

, Nc ^ n person NC, Η H, NC, ^^ eight NC, Et, Et, F F Η

Me Me, NXn

H

Into NC H

NC, Me H

NC, x \ n〆 ^ H 63 200524930

NCs

Οχ / NHR

nc ~ n Η R = H, (CrC6) alkyl OMe

, LT

Me

Therefore, for the description of A and B, Ra Rb includes any of the following structures:

64 200524930

MeHN

Me

Where R is CH2CH2CN. Similarly, the descriptions of A and B are provided for any of the following structures:

Further includes

65 200524930

H2N

H2N MeO *

R

R / OMe H2NT w

nh2

h2n f3c

R

h2n

R H2N

Where R is CH2CN

Similarly, the description of A and B provided, 1 or R, ", J) 2 R " " includes any of the following structures: RHN. RHN ^ 03 ^ RHN rhn

RHN

RHN

F,

RHN

NHR

RHN

Where R is CH2CH2CN

Similarly, the description of A and B provided, R " \ B ^ J) 2 R " " MRb includes any of the following structures:

RcHN- ^

RcHN ^ R RcHN ^ R RcHN ^ .R

CD

RcHN

RcHN

RcHN ^ R DUK1 R;:

Its center is 11 or (CrC6) alkyl, and R is CH2CN. Now, we return the compounds of formula II and III with the following structure: 66 10 200524930

π mSpecific values and specific examples of compounds of formulas II and III on q, ζ, X, R, R2, R3, R4, R5 and Ra, Rb, Re, Re, Rf, Rg, Rh, R ^ Rk As provided by compounds of formula I. We now return the compound of formula IV with the following structure:

r2

IV Compounds of formula IV with respect to specific values and specific examples of η, X, Ri, R2, R3, R4, R5 and Ra, Rc, Rd, Re and Rf are provided as compounds of formula I. 10 Now we return to compounds of formula V or VI.

r2 67

V VI200524930

Specific values and specific examples of compounds of formula V for η, q, X, Ri, R2, R3, R4, R5 and R ', R ", R'" and R "" are as described for the compounds of formula I provide. Preparation of Compounds of the Invention The preparation strategies of the compounds of the present invention are described in the following methods. As can be easily understood from this announcement, the compounds of the present invention are characterized by

C-7 side chain

B

N Rb

)Z

10 A fluorenone core, which is covalently bonded to J) z "Rb. As described retrospectively synthetically in Method I, the compounds of the invention can be obtained by appropriately replacing a C-7 fluorenone core ( Where X2 can be a halo group, a trifluoromethanesulfonate or a similar reactive group known to those skilled in the art) and coupled with an appropriately substituted acryl, pyrrolidine, piperidine

Prepare

Method I

The core of linoxone 乂 2 = dentate, OSO2CF3, R = OH, xenyl, obf2 68 200524930 In order to reflect the synthetic strategy of method i, the preparation of the compound of the present invention in the next section will be described in several sections. The first section describes the synthesis of the required limonone core precursor. The second section describes the synthesis of the required C-7 side chain precursors. The last section describes the details of coupling the C-7 side chain with the pinorone core precursor to provide the compound of the invention, and any further chemical purification of the compound of the invention to produce other compounds of the invention. A. Synthesis of the Pinorone Core Precursor The pinorone core precursor used to prepare the compounds of the present invention is generally known and commercially available to those skilled in the art; or, in addition, the synthetic method of Example 10 can be used to preparation. The following section provides relevant illustrations that will describe the preparation of the limonone core precursors of the present invention for use in the disclosure herein.

EP 0357047; EP 0167763; EP 0195841 JP8-9958 US 5,869,991 69 200524930

EP 0357047 EP 0172651

US 5,859,026

f. Me〆. A EP 0610958 0 0 OH US 5,639,886

70 200524930 ο ο

ο ο

As provided in the above IA, except that cyclopropylamine was replaced with fluorocyclopropylamine. ο ο

As provided in 1A above, except that cyclopropylamine is replaced with fluorocyclopropylamine. ο ο

As provided in the above 1C, except that cyclopropylamine is replaced with fluorocyclopropylamine. As provided in 1D above, except that cyclopropylamine is replaced with fluorocyclopropylamine. 71 10 200524930

e. F

0 O

As provided in the above IF, except that cyclopropylamine is replaced with fluorocyclopropylamine.

As provided in 1H above, except that cyclopropylamine is replaced with fluorocyclopropylamine.

72 200524930 ο ο

US 5,998436 ο ο

US 5,998436

ΝΗ〇 Ο Ο

US 5,998436

73 200524930 B. Synthesis of C-7 side chains and side chain precursors Μ ΝΗ2 Νν ΝΗΜθ

Preparation NR is prepared as provided in Method 1

Therefore, in the presence of cesium carbonate, 3-g-methylpyrrolidine-1-carboxylic acid g is reacted with 5 cyanomethyl-phosphonic acid diethyl ester to provide 3- (2-cyano-ethylene ) ° Bilobit-1-carboxylic acid benzyl ester. Ammonia or methylamine was added to the 3- (2-cyano-ethenyl) -pyrrolidine-1-carboxylic acid benzyl ester to provide a corresponding Michael complex, which was subsequently Oxycarbonyl (Boc) protected. The benzyl ester group is removed under conventional conditions to provide the target compound, such as a Boc-protected Class 10 analog; it can be subjected to silica gel chromatography to provide each non-mirromeric isomer; and Palm HPLC separation to provide each mirror image. Use as described in this

The chromatographic analysis of this paper can provide pure N, BCICI samples' and related non-mirromeric isomers for coupling. After the round, the Boc protecting group is removed to provide the unprotected amine

Where "~~~" refers to the connection position. 74 200524930 Method 1

2. Preparation of ϋ

Prepare 制备 according to Method 2. Therefore, 1-benzyl · acridine 5-3-carbonitrile is converted into 1- (1-benzyl-acryl.dan-3-yl) -cyclopropylamine, as described by

Chem. Rev., 1979, Book 79, No. 4 and Tet. Lett. 44, 2003, 2485. Conversion of 1- (1-diphenylfluorenylacryl-3-yl) -cyclopropylamine to N- [l- (l-diphenylmethyl-acryl-3-yl) -cyclopropyl] -2,2,2-trifluoroacetamide, as provided by J. Med. Chem. 1993, Vol. 36, No. 7. The hydrogenation reaction of N- [l- (l-di10phenylfluorenyl-decan-3-yl) -cyclopropyl] _2,2,2-trifluoro-acetamidine provides the title compound, which is convertible It becomes a free amine and is subsequently derivatized into a pinorone core after a coupling reaction. 75 200524930 Method 2 Η

cf3 O men NH L Canton

Prepared as provided in Method 3. Therefore, the Grignard reaction of ethylene 5-bromomagnesium bromide with 1-benzyl-acyl-3-one can improve

The corresponding alcohol was 1-diphenylfluorenyl-3-ethyl-acrid-3-ol. Under conventional conditions, the alcohol moiety is sulfonated into 1-diphenylfluorenyl-3-ethyl-acryl-3-ol, followed by a nucleophilic addition of CN 'to provide 1-diphenyl Fluorenyl-3.ethyl-0yanodan-3-carbonitrile, which is subsequently reduced using lithium aluminum hydride (LAH) to provide C- (l-diphenylfluorenyl-10yl-3-ethyl-acyl-3 -Yl) -methylamine. C- (l-diphenylmethyl-3-ethyl-acryl-3-yl) -methylamine is protected with trifluoroacetate, followed by hydrogenation to provide the target compound, which can be reacted in the coupling to a pinorone core It is then converted to the free amine and subsequently deprotected. 76 200524930 Method 3

HN, CF3 Mθ ^ Λ. C ^ NH_HCI was prepared as provided in Method 4. Therefore, 5 hydrolyzes 1-diphenylsulfenyl-acrylic acid " dan-3-carbonitrile under conventional conditions to provide 1-diphenylmethyl-acyl-3-carboxylic acid; subsequently, in the presence of triethylamine, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and N, 0-dimethyl-hydroxy-amine hydrochloride are treated to provide 1-diphenylmethyl- Azurol_3_carboxylic acid methoxymethylamidamine. Ethylmagnesium bromide can be added to 1-benzyl-acryl-3-carboxylic acid methoxy 10-methylmethylsulfonium amine to provide a corresponding ketone, 1- (1-dibenzoyl -Acryl-3-yl) -propan-1-one. Reductive amination of 1- (1- 77 200524930 diphenylfluorenyl-acryl-3-yl) -propan-1-one using ammonium acetate and sodium cyanoborohydride; then, trifluoroacetic acid in the presence of an amine base Anhydride treatment to provide 1- (1-benzyl-azetidin-3-yl) -propan-1-one. The hydrogenation of 1- (1-benzyl-/-denan-3-yl) -propan-1-S also provides the target compound, which can be converted to a free amine after coupling reaction to a fluorenone core and subsequently After 5 go to protect. Method 4

Me

78 200524930 5 ·

Preparation As provided in Method 5

H.HCI. Therefore, it is synthesized similar to that described in Method 3.

Glynamate methylmagnesium bromide with 1-benzyl-azol-3-one to provide a corresponding alcohol, diphenyl 5methylmethyl-azol. Under conventional conditions, the sulfonyl alcohol moiety in 1-diphenylmethyl-3-methyl-azigdan-3_ol is followed by nucleophilic substitution with cn to provide dibenzoyl 3-methyl-4-denyl-3-carbonitrile, followed by reduction using lithium aluminum hydride (LAH) to provide (^ (buthenyl_3_methyl_, y0denyl) _methylamine Protected with trifluoroacetate (> (benzylmethyl_3_methyl_acridone_3_10yl) _methylamine, followed by hydrogenation to provide the target compound, which can be reacted into hydrazone in a coupling reaction The norketone core is converted to a free amine and subsequently deprotected. 79 200524930

Method 5

NC

6.

Preparation

The target compound was prepared as provided in Method 6

5 and H2N ^ VJ. Therefore, under conventional conditions, N- (trimethylsilylmethyl) -α-methylbenzylamine was prepared from the corresponding amines using trimethylishiyin base gas. Reaction of N- (trimethylsilylmethyl) -α-methylbenzylamine with formaldehyde in the presence of potassium carbonate and methyl alcohol to provide N- (fluorenyloxy) · N- (trimethylsilane Methylmethyl) -α-methylbenzylamine, which is then converted to 1- (1.phenyl-ethyl) -pyrrolidine-3-10carboxylic acid dibenzylfluorenamine as a mixture of stereoisomers. The amidine is treated with ethylmagnesium bromide in the presence of Ti (OiPr) 4 to provide the protected target compound as a separable mixture. Hydrogenation was used to protect the 80 200524930 separable non-mirromeric isomer to provide the target compound. Method 6

5 Prepared as provided in Method 7. Therefore, sulphur

Si-S 1-benzyl group "each bite alcohol, followed by cN for nucleophilic group addition, in order to extract i, R-segment group" roughly bite_3 • nitrile. Reducing R-segment group "than pyrrolidine 1-nitrile ' In order to provide R-center (1 节 基 ♦ 基 基 基 基。 基 基 基 gt gt> methylamine. In the r _ 仆 仆 基 比 ratio σ each bite a 3- group)-amine ⑽ ⑽ ⑽ ⑽ 保护 保护 ⑽ ⑽ ⑽ ⑽ ⑽ 可 heart protection can be provided (Bu H ) Each bite · 3 · methyl group) -Aminomethyl terephthalate, which can be gasified to provide compounds of the standard of Haihai. 81 200524930 Method 7

Prepared as provided in Method 8

BocHN

So taking hydrogen

5 Lithium aluminum oxide treats 5-lanthoxy-1- (1-phenyl-ethyl) -pyrrolidine-3_carboxylic acid methyl vinegar to provide [1- (1-phenyl-ethyl) -pyrrolidine -3-yl] -methanol. Treatment with isoindole-1,3-dione in the presence of triphenylphosphine and diisopropyl azodicarboxylate [1- (1-phenyl-ethyl) -pyrrolidin-3-yl] -Fluorenol to provide phthaliminoimine, 2- [1- (1-phenyl-ethyl) -pyrrolidin-3-ylmethyl] -isoindole-1,3-dione. The phthalocyanine is treated with 10 hydrazine hydrate to provide C- [l- (l-phenyl-ethyl) -pyrrolidin-3-yl] -methylamine, which is BOC protected and hydrogenated to provide the target The compound is converted to a free amine and subsequently derivatized after coupling reaction to a linoxone core. 82 200524930 Method 8

LAH ether

9 · Preparation of Η

Rhenium was prepared as provided in Method 9. Therefore, hydrogenated P-cellulose under normal conditions was used to read the ethyl carboxylic acid esters, which were subsequently protected by Boc to provide the heart, 3-dilin 1-secondary butyl S Purpose 3-ethyl ester. Reduction of each of these lakes], 3 di-tertene, tertiary butyl ester, 3-ethyl ester, to provide a 3-hydroxy hydroxymethyl_pyrrolidine, 丨 _carboxylic acid tert-butyl acetate, which can be used in Shi Wen ( Under the conditions of Swem) type, it is oxidized to the corresponding aldehyde 3-methyl-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester. 3- (1) can be prepared by adding lithiated isopropionitrile to the intermediate a_amidoaminoalkyl hydrazone from 3-methylpyrroloxolium tributyl heptadecanoate -Tertiary butoxycarbonylamino 2 sulfanyl-2,2-dimethyl-ethyl) -u than p each bite a small carboxylic acid tert-butyl g. Deprotection 83 10 200524930 Protect 3- (1-tert-butoxycarbonylamino-2-cyano-2,2-diamidino-ethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester, To provide the title compound 3-amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile as the dihydrochloride salt. Method 9 C02Et, C02Et C02Et OH H2> Pd / c Β〇〇〇〇 NaBH4 r \ EtOH ch2ci2 THF, MeOH Η Boc Boc quant. Quant. 94% Step 1 2 Step 2 3 Step 3 4

Ph 1

(COCIfe, DMSO NEt3f CH2CI2

H2NBoc, PhS02Na HCOgH, MeOH, h2o 39% step 5 87% step 4

Boc 5

HCI CH2〇2 73% Step 7

10.

Preparation of BocHN The compound is prepared as provided in WO 96/39407. 11.

And rhn, / ^ cn

Preparation 84 200524930

RHN, ^^ u were prepared as provided in Method 11. Therefore 'Under the conditions readily available to those skilled in the art and discussed in this article, cyclopent-1-encarboxylic acid methyl ester or its analogues are substituted with benzyl_ ethoxyfluorenyl dimethylsulfonylfluorenyl • The amine undergoes a [3 + 2] cycloaddition to provide 2-benzyl-hexahydro-cyclopenta [c], and each _3a-carboxylic acid methyl ester is intended. Reduction of 2-benzyl_hexahydrocyclopenta [c] pyrrole-3a-carboxylic acid phosphonium ester with a hydride (using hydrogenation or aluminum borohydride) to begin the preparation of <3nh to provide (2- Benzyl-hexahydro-cyclopentyl [c] pyrrole_3yl) _methanol. The alcohol moiety in (2_benzyl_hexahydro · cyclopenta [c] pyrrole-3a-yl) -methanol is converted into a leaving group 10 (such as mesylate or tosylate), followed by Primary or secondary amine substitution and a protective deprotection procedure to provide (2-benzyl_hexahydro_cyclopenta [c] pyrrole-3a-ylfluorenyl) · tertiary butyl aminoformate,

Furthermore, if the termination of the ester moiety in the 2-benzyl_hexamidine_cyclopenta [c] pyrrole_3 carboxylic acid methyl ester is terminated in the aldehyde oxidation reaction state (eg, using DIBALH as the reducing agent 15) ' A reductive amination using ammonium formate or a primary alkylamine such as methyl or ethylamine can be used to provide the amination product. Reductive amination conditions and reagents are readily known to those skilled in the art. Start by saponifying the ester moiety in the top end of 2-benzyl-hexahydro-cyclopenta [c] pyrrole-3a-carboxylic acid methyl ester

It was prepared to provide 2-benzyl-hexahydro-85 200524930 cyclopenta [C] pyrrole-3a-carboxylic acid. Use conditions and recombination readily available to skilled persons to perform 2-benzyl-six-rats-l-amyl [c] nbilo-3a-kuric acid NHBoc

Curtius was recombined to provide \ ^^ / "·, (hexahydro-cyclopentyl [cp 比 卩 三 -3 ··) -aminocarbamic acid tertiary butyl ester. 5 10 Reduction with DIB ALH 2- Benzyl-hexahydro-cyclopenta [c] pyrrole-3a-carboxylic acid methyl

QN esters were prepared to provide the corresponding aldehydes. The aldehyde is methyleneated under Wittig or Horner-Wadsworth-Emmons-type conditions to provide 3- (2-benzyl- Hexahydro-cyclopenta [c] 12 bilo-3a-yl) -acrylonitrile. Michael addition is performed to add ammonia or primary alkylamine to 3- (2-benzyl-hexahydro-cyclopenta [c] pyrrole-3a-yl) -propene ride 'to provide [2-muryl -1- (Six-rats-Lycopyrene [cp than σ each -3a-yl) -ethyl] -aminotricarboxylic acid tert-butyl ester. 86 200524930 Method 11 / ^^ C02Me + MeO ^ N ^ TMS O- ^ OMe Ph

d &gt; '

C. Coupling the C-7 side chain with the pinorone core precursor to provide a compound of the invention Coupling the side chain precursor with the pinorone core precursor to provide the compound of the invention 5; or the precursor may be coupled to the core precursor The free acid, alkyl ester or borate is coupled to provide a compound of the invention as described in Method II. 87 200524930

Method II

Typically, when a free acid is used in a coupling reaction, an excess molar side chain precursor is bound to the pinorone core in a polar solvent such as acetonitrile. A molar excess of an amine base (such as triethylamine) was added and the reaction mixture was heated to about 80 ° C. The reaction mixture will typically become homogeneous. The mixture is heated for a sufficient time (typically from about 3 to about 12 hours) to drive the reaction to completion. The mixture can then be manipulated according to procedures widely used by those skilled in the art to provide the compounds of the invention. When an alkyl ester is used in the side-coupling reaction, the fluorenone core, the side chain, and triethylamine are combined in a solvent such as acetonitrile. The resulting reaction mixture was heated to 80C and stirred for 12 hours. The reaction mixture will typically become homogeneous. The mixture is heated for a sufficient time (typically from about 3 to about 12 hours) 'to drive the reaction to completion. The mixture can then be manipulated according to procedures widely used by those skilled in 200524930 to provide the compounds of the invention. When a butterfly salt is used in a synthetic reaction, the required borate is typically prepared from a free acid after reacting with egg 3, according to conditions available to a skilled person. The boric acid is irradiated with a solvent (such as acetonitrile) and bound to a side bond 5 and treated with an amine test (such as triethylamine). The reaction mixture produced is typically stirred at room temperature for a sufficient period of time (typically about 24 to about% hours) to drive the reaction to completion. The mixture can then be manipulated according to procedures widely used by a skilled person (i.e., the boric acid is deprotected in ethanol in the presence of triethylamine) to provide a compound of the present invention. 10 D. Face-to-face conversion The face-chain precursor can be combined with the norphostolone core precursor to produce the inventive compound. In addition, post-face conversion is required to produce the compounds of the invention. A typical post-coupling conversion involves deprotecting the protected amine to provide an inventive compound of the formula (as described in the method claw). Deprotection and reaction with acrylonitrile or its analog 15 can produce compounds of the invention of formulae III and IV. 200524930

Pharmaceutical formula The present invention also provides a medicinal composition card, and a mouthpiece, which comprises a biologically active invention compound or-this salt or-a pharmaceutically acceptable salt thereof; and optionally a 5 pharmaceutically acceptable Vehicle. The composition includes those forms which can be used orally, topically or parenterally and can be used to treat bacterial infections in mammals, including humans. According to the present invention, the compound (such as an antibiotic compound, also referred to herein as an antibacterial compound) can be formulated similar to other biologically active agents (such as antibiotics) to any compound that is convenient for use in human or veterinary medicine. Method of administration. Such methods are well known in the art and are not described in detail herein. The composition can be formulated to be administered by any route well known in the art, such as subcutaneous, inhaled, oral, topical or parenteral. The composition can be in any form well known in the art, including (but not limited to) lozenges, gels, 200524930 capsules, powders, granules, lozenges, creams, or liquid preparations such as oral or sterile parenteral solutions Or suspension). The topical formulations of the present invention may exist, for example, as ointments, creams or lotions, eye weakness and eye or ear drops, immersion dressings and aerosols, and may include suitable formulas in ointments and creams. Known additives (such as preservatives), solvents (to help drug penetration) and emollients. The formulation may also contain compatible conventional vehicles such as cream or ointment bases and ethanol or oleyl alcohol for lotions. This carrier may be present, for example, from about 1% to up to about 98% of the formulation. For example, they can form up to about 80% of the formula. Lozenges and capsules for oral administration may be in a unit dosage form, and may contain conventional excipients such as binders such as syrups, locusts, gelatin, sorbitol, tragacons gum, or polyethylene η Billot fillers, such as milk bran, sugar, corn starch, calcium phosphate, sorbitol, or glycine; 15 tablet lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; An antidote, such as potato starch; or an acceptable wetting agent, such as sodium lauryl sulfate. The lozenges can be applied according to well-known methods of normal medical practice. Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or medicinal solutions; or they can be present as dried products which can be reconstituted with water or other suitable vehicle before use. This liquid formulation may contain conventional additives such as suspending agents such as sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated Edible fats; emulsifiers such as phospholipids, sorbitan monooleate or locust; non-aqueous vehicles (which may include edible oil 91 200524930) such as almond oil, oils such as glycerol, Propylene glycol or ethanol); preservatives such as methyl or propyl paraben or sorbic acid; and, if necessary, conventional flavors or colorants. For parenteral administration, the compound and a sterile vehicle (water 5 is preferred) are used to prepare a fluid unit dosage form. The compound (depending on the vehicle and concentration used) can be suspended or dissolved in the vehicle or other suitable solvent. In preparing the solution, the compound can be dissolved in water for injection and can be filtered and sterilized before filling into a suitable vial or ampoule and sealing. It is advantageous to dissolve agents such as local anesthetics, preservatives, and buffers in the vehicle. In order to improve the stability, the composition can be cooled after filling into a vial and removing water under vacuum; east. The dried and cooled powder is then sealed in a vial and a companion vial containing water for injection can be provided to reconstitute the liquid when in use. A parenteral suspension can be prepared in substantially the same manner, except that the compound is suspended in a vehicle instead of dissolving and it cannot be disinfected by hydration through I5. The compound can be sterilized by exposure to ethylene oxide institute before suspending in a sterile vehicle. It may be advantageous to include a surfactant or a dragon agent in the composition so that the compound can be easily and uniformly distributed. This, and e substances contain, for example, about 1% by weight, for example, about 10-60% by weight of the active material, depending on the method of administration. If the composition contains a dosage of 20 units, each unit will contain, for example, about 500 mg of the active ingredient. Dosages that can be used in the treatment of adults range, for example, from about 1000 to 3,000 milligrams per day (e.g., 1500 milligrams per day), depending on the route and frequency of administration. This dose corresponds to about 1.5 to 50 mg / kg per day. A suitable dose is, for example, about 5 to 20 mg / kg per day. 92 200524930 Biological activity 5 10 15 20 The compounds of the present invention can be screened using methods available in the art to identify biologically active molecules and different biological activities. Biologically active molecules can have, for example, activity against cellular targets, including (but not limited to) enzymes and receptors or microorganisms. The target cell ligand or microorganism is a species that is well known or has been "important in etiology or disease development. Examples of disease states that can be used to screen biological activity of a person include, but are not limited to, inflammation, infection, Hypertension, central nervous system disorders, and cardiovascular disorders. In a specific embodiment, the invention provides a method of treating or preventing a bacterial infection in a patient, such as a human or other animal patient, comprising administering two effective amounts as disclosed herein The inventive compound is administered to a patient. In one embodiment, the '§ 19 compound can be administered in a pharmaceutically acceptable form (which can be selected = in a pharmaceutically acceptable carrier). As used herein: Bacteria = disease ::: is characterized by the presence of microbial infections, such as the central nervous system, external ear sensory cavity infection, genital membrane infection), upper respiratory tract infection, lower exhalation disease, bone and I, stomach and Intestinal infections, gynecological infections, septic meningitis, skin and skin structure, bacterial endocardial cancer, anti-ribs, and immunosuppressed patients (such as anti. (F patients or organ transplant patients), such as local administration: the administration of the compound and the group containing the compound will lead the compound into the body; systemic application. Systemic application includes any body, And weaving methods, such as intrathecal, epidural, intramuscular 93 200524930, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral administration. The specific antibacterial to be administered can be adjusted as needed Dosage and cycle of treatment. The compounds of the present invention can be used to treat or prevent infectious conditions caused by a variety of bacterial organisms. Examples include Gram-positive and Gram-negative aerobic and anaerobic bacteria, including grapes Staphylococci, such as S. aureus; Enterococci, such as E. faecalis; Streptococci, such as S. pneumoniae; Haemophilus Haemophilus, such as H. influenza; Moraxella, such as M. catarrhalis; and Escherichia coli richia), such as E. coli. Other examples include Mycobacteria, such as M. tuberculosis; intercellular microorganisms, such as Chlamydia and Rickettsiae; and mold pulp Mycoplasma, such as M. pneumoniae. 15 The compounds of the present invention have the ability to inhibit bacterial growth, elucidation of in vivo activity, and improved pharmacokinetics. Pharmacological models well known in the art can be used to clarify For example, test models such as those described below can be used. Test A-Antibacterial test uses standard micro-titration techniques to test the compounds of the present invention against a variety of 20 Gram-negative and Gram-positive organisms (Cohen et al., Eg, 1985; 28: 766; Heifetz (Jjeifetz), et al., Eg, 1974; 6 · 124). The evaluation results are shown in Tables ία and B. 94 200524930 Table IA Minimum inhibitory concentration of gram-negative bacteria, μg / ml Compound structure Haemophilus HI-3542 M. mucositis BC-3531 E. coli 2066 OsMe 0.015 0.25 0.015. … A 0.03 0.25 0.008 0.03 0.25 0.008 NC ^ N 0.06 0.06 0.004 OMe ^ 0.5 1 0.06 0.03 0.06 0.004 NC &gt; lfO L person 0.06 0.06 0.004 N. : 0.25 0.125 0.008 0.25 0.25 0.5 0.03 0.25 0.5 95 200524930 Compound structure Haemophilus epidemic HI-3542 M. mucositis BC-3531 E. coli 2066 0MeA 0.015 0.25 0.5 NCV ^ VJ 〇Μβ ^ 0.06 0.125 0.5 NC ^ X ^ J 0Me ^ 0.03 0.06 0.125

0.06 0.125 0.15 0.25 0.125 0.06 0.03 0.03 0.25 0.125 0.125 0.5 .Pχ / Λ 0.03 0.015 0.004 0.015 OMe ^ 1 0.25 0.125 0.5 0.25 0.125 0.03 0.5 NC ^ An OMe ^ 0.06 0.03 0.008 0.03 0.5 0.5 0.03 1 0.5 1 0.06 0.25 0.5 1 0.125 1 97 200524930 NC,

0.5 0.125

0.125 0.125 0.015 0.125

The following examples are provided to clarify the invention, but they do not limit the scope of the patentable invention. A. Synthesis of side chain precursors Example 15 Preparation of (2-cyano-1-pyrrolidin-3-yl-ethyl) -aminocarboxylic acid tert-butyl ester

A. 3- (2-Ranyl-Ethyl) -13 Billot bite-1-Junic acid radicals 98 200524930 Η

3-Methylmethyl-pyrrolo-1-carboxylic acid benzyl ester (2.25 g, 9.65 mmol), cyanomethyl-phosphine, heated in dry THF (100 ml) at 50 ° C Diethyl ammonium acid (1.88 g, 10.6 mmol) and cesium carbonate (Mg, 10.6 mmol) were mixed for 3 hours. The solvent was removed in vacuo. The crude product residue was mixed with ethyl acetate (100 ml) and washed with saturated NH4C1 (100 ml), brine (100 pens), dried over MgS04 and concentrated in vacuo. The crude product residue (0 to 60% ethyl acetate in hexanes) was purified on a 40 g silica gel &amp; column to provide 2.22 g of the title compound as the E and Z isomers 90% yield (90% yield). MS (APCI +): m / z 257 (M + H) +. Beta 3- (1-tert-butoxycarbonylamino-2_cyanoethylpyrrolidine small carboxylic acid benzyl ester

To a solution of 3- (2-cyano-vinyl) -pyrrolidine-carboxylic acid benzyl group (8.24 g, 32.1 mmol) in absolute ethanol (100 ml), ammonia (about 5 ml) ); And heating the solution in a sealed reactor at 80-100 ° C for 3 days. The solution was concentrated in vacuo. The produced amine was dissolved in THF (100 ml), Boc anhydride (8.76 g '40.2 mmol) was added, and the 99 15 200524930 solution was stirred at room temperature for 18 hours. The solution was concentrated in vacuo. The residue was mixed in ethyl acetate (100 ml), washed with saturated aqueous NH4C1 (100 ml) and brine (100 ml), dried over MgS04 and concentrated in vacuo. The crude product (10 to 50% ethyl acetate in hexanes) was purified on a 330 g silica gel column to provide 9.28 g of the title compound as a 1: 1 non-mirror isomer Mixture (yield: 77%). MS (APCI +): m / z 274 (M + H-Boc) +. C · (2-Gas-1 ~ ^ σsigma-3-yl-ethyl) -aminophosphonic acid tert-butyl ester

3- (1-tertiary butoxycarbonyl 10 amine-2 · ranyl-ethylhexyl acid) g (2.00 g '5.36 mol) filled with nitrogen in methanol (50 ml) and A solution of ammonium phosphonate (1.00 g, 16.1 mmol) and then 10% Pd / C (0.5 g) was added. The mixture was stoppered and stirred at room temperature for hr. The solution was filtered through a stopper Plastic and rinse the solid with methanol. The filtrate was concentrated in vacuo to provide 1.25 g of the title compound (yield: 15 97%). MS (APCI +): m / z 240 (M + H) +. Example 2 Preparation of N- (l-acryl-cyclopropyl) -2,2,2-trifluoro-acetamidamine

100 200524930 A 1- (1-Diphenylmethyltetra-3-yl) -cyclopropylamine

So, 1979, Book 79, No. 4; 44, 2003, 2485 5 A solution of 1-benzyl-acrylic acid_3 · nitrile (10 g) in THF (200 ml) at room temperature In the process, titanium isopropoxide (Ti (OiPr) 4) (1 equivalent) and ethyl magnesium bromide (2.2 equivalents) were added successively. The resulting reaction mixture was stirred for 30 minutes. Diethyl ether trifluoride (BF30Et2) was then added (2 equivalents). Stir continuously for 30 minutes. A 10% sodium hydroxide solution was added, and the mixture was extracted three times with ethyl acetate (EtOAc). The combined ethyl acetate layer was dried over Na2S04 and concentrated. The crude material was purified by chromatography (EtOAc to 7: 3 EtOAc: EtOH) to give the title compound as a yellow solid (4.96 g, 44% yield). MS (APCI +): m / z 279 (M + H) +. Β · N- [l- (l-Diphenylfluorenyl "yah! Yl) -cyclopropyl] -2,2,2-tridecyl-acetamidamine

See No. Med 1993, Vol. 36, No. 7 at room temperature in 1- (1-diphenylmethyl-acryl-3-yl) -cyclopropylamine in aeroform (60 ml) 2.5 g) of the stirred solution was added dropwise a solution of trifluoroacetic anhydride (1.25 equivalents) in aeroform (30 mmol 101 200524930 liters). The reaction was stirred for two hours and then at 10 ° /. NaHC03 and subsequent brine wash. The solution was then concentrated and purified by chromatography (gradient: 3: 1 hexanes: EtOAc to EtOAc) to give 0.57 g (yield 17%) of the title compound. 5 MS (APCI +): m / z 375 (M + H) +. C.N- (l-azine-3-yl-cyclopropyl) -2,2,2-trifluoro-acetamidamine

In N- [l- (l-diphenylmethyl-azigdanyl) -cyclopropyl] -2,2,2-trifluoro-acetamidamine in methanol, add; [〇〇 / (Pd / C (200 / 〇) and hydrochloric acid (0.10 equivalents). The resulting mixture was shaken under a hydrogen atmosphere overnight. Then, the mixture was filtered through a plastic plug and the filtrate was concentrated to produce a mixture of acridine hydrochloride and diphenylmethane (0.56 g, yield 90%). The crude product mixture was used directly in the next reaction without purification, MS (APCI +): m / z 209 (M + H) + 〇15 Example 3 N- (3-ethyldedan-3 · ylfluorenyl) · Preparation of 2,2,2-trifluoro-acetamide

A · 1-diphenylfluorenyl-3 · ethyl-butyl. Denier 3-ol 102 200524930

A solution of diphenylmethyl-acryl-3-anone (10 g) in diethyl ether (200 ml) was cooled to 0 ° C in an ice bath, and bromine in ether was added dropwise Ethylmagnesium solution (3.0M, 2 eq). The reaction was stirred at 0 ° C until the bath temperature rose, and then reacted at room temperature for two 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 concentrated. The product was purified using flash chromatography (2: 1 hexanes: Eto-Ac) to provide the title compound (6.33 g, 56%), ms (APCI +): m / z 268 (M + H) + 〇10 B · Methanesulfonic acid

In dichloromethane (100 ml); U dibenzyl methyl ethyl dandenyl alcohol (6.33 g) and triethylamine (1.3 equivalents) in a cooled (0.0 solution), added dropwise A solution of formazan chloride (1.3 equivalents) in kimono (30 ml). Once all of the formazan has been added, remove the cooling bath, and teach the reaction for 1 hour at room temperature. Then The solution was diluted with more dichloromethane and washed twice with water. The organic solution (80 g, 98% yield) was then dried and concentrated. The crude material was used in the next step without further purification. 103 15 200524930 C. 1-Benzyl-3-ethyldandan-3-monthgreen

At room temperature, in a solution of 1-diphenylsulfanyl-3-ethyldan-3-yl methyl luteinate (8.01 g) in dimethylformamide (DMF) (120 ml), Dropwise 5 was added sodium cyanide (2.5 equivalents) in water (40 mL). The solution was then heated to 60 ° C and the solution was stirred overnight, then diluted with 500 ml of water and the precipitate was extracted 3 times with EtOAc. The organic extract was washed twice with water, then dried over Na2S04 and concentrated in vacuo. The product was purified by chromatographic analysis (gradient: 9: 1 hexane: EtOAc to EtOAc) to provide the title 10 compound (5.50 g, yield 86%), MS (APCI +): m / z 277 (M + H) + 〇 ·· C- (l-diphenylfluorenyl-3-ethyl ^ y.denyl 3-yl) -fluorenylamine

To a solution of 1.benzyl-3-ethyl-acryl-3-nitrile (5.50 g) in THF (60 mL), LAH (3.5 equivalents) in THF (IM) was slowly added. 15 Reflux the solution for 2 hours. The reaction was then cooled to room temperature, and 100 ml of diethyl ether was added, followed by 2.8 ml of water, then 2.8 ml of 10% NaOH, and then 5.6 ml of water. After stirring for 30 minutes, the mixture was filtered. The aluminum salt was washed 5 times with THF. The combined organic filtrate was dried and concentrated. This crude product was used in the next step without further purification. 5.16 g, yield 92%, MS (APCI +): m / z281 (M + H) + 〇 ·· N- (l-diphenylmethyl-3-ethylfluorenyl) _2,2,2-tri Fluoro-acetamide

5 C- (l-diphenylmethyl-3-ethyl) in chloroform (120 ml) at room temperature

-Acri-3-yl) -amidamine (5.16 g) was added dropwise to a solution of trifluoroacetic anhydride (1.25 equivalents) in chloroform (60 ml). The reaction was stirred for two hours and then washed with 10% NaHC03 and then brine. The solution was then dried, then concentrated and purified by chromatography (3: 1 hexane: EtOAc 10 to EtOAc) to provide the title compound (3.67 g, yield 53%), MS (APCI +): m / z 377.3 (M + H) + 〇F. N- (3-ethyl-methyl ° -3-ylmethyl) -2,2,2-trifluoro-acetamidamine

1 equivalent of HC1 hydrogenated (Pd / C in 100 ml of MeOH) N_ (l_15 diphenylfluorenyl-3-ethyl- ^ dan-3.ylmethyl) _2,2,2_trifluoro_ Acetamide (3.67 g) overnight to provide 2.40 g (100% yield) of the title compound, used directly without purification. MS (APCI +): m / z 211 (M + H) +. Example 4 105 200524930 Preparation of N- (l-acyl-3-yl-propyl) · 2,2,2-trifluoroacetamidine hydrochloride 〇 唧 cf3

NH-HCI Α · 1-diphenylfluorenyldan-3-weiric acid

5 A suspension of 1-benzyl-acene ηE-3-carbonitrile (2.09 g &apos; 8.42 mmol) in concentrated hydrogen acid (12 M, 15 L) was heated to reflux for 30 minutes. The resulting solution was cooled to 0 ° C, and 61 V [sodium hydroxide was added until the pH of the mixture reached about 7. The aqueous mixture was then extracted with dichloromethane (3 x 150 ml) and digas methane: methanol (10: 1, 3 x 150 ml). The combined 10 organic layers were dried, filtered and concentrated under reduced pressure to provide the title compound (1.60 g, 71% yield). MS (APCI): m / z 268 (M + H) +. B · 1_Diphenylmethyl-acyl-3-carboxylic acid

1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8.05 g, 42 mmol) was added to -Carboxylic acid (7.42 g '27.8 mmol), N, 0-dimethyl-acyl-amine hydrochloride (4.24 g, 43.5 mmol) and 200524930 diethylamine (11.6 ml' 83.3 mmol) Moore) suspension in methylene chloride). Then stir at room temperature for _floating coffee for minutes. Dilute the solution with dichloromethane (three liters) and wash the solution (3xl⑼ml). It was then dried (fine organic layer of sulfuric acid, transitioned and concentrated under reduced pressure. The resulting solid was purified using medium pressure liquid chromatography and extracted with alcohol (40: υ to yield 4.76 g (55% yield)). The title compound, as a white solid (mp 103-106): MS (Apci +): _ 3u (m + h) +. C · 1- (1-benzyl_acyl-3) _Yl) _propan- 1-one

10 Bromination in tetrahydrocran (ι · Μ, 32.5 mL) at -70 C

Ethyl ballast solution was added to i-diphenylmethyl_acridan-3-carboxylic acid methoxymethylamidamine (3.36 g, 10.8 Millimoles) solution. The resulting reaction mixture was then stirred at 0 ° C for 1 hour. Then, a saturated aqueous ammonium chloride solution (75 ml) was poured into the reaction at 0 ° C. The mixture was then extracted with di 15 ethyl (300 ml); then, the aqueous layer was again extracted 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 by distilling with dichloromethane: methanol (40 ·· 1) using medium pressure chromatography to obtain 2.69 g (89% yield) of the title compound as a waxy yellow solid (mp 73- 75 ° C); 20 MS (APCI +): w / z 28o (M + H) +. D · N_ [l- (1-benzyl_, y_0_denyl_3-yl) propyl] -2,2,2_trifluoroacetamide 107 200524930

1. NH4OAc, NaCNBHa 4 human molecular sieve shoulder 60 ℃ room temperature

, Cf3, tea, ch2ci2 53%

Ammonium acetate (6.00 g, 77.8 mmol) was added to 1- (1-diphenylmethyl-az.denyl-3-yl) -propan-1-one (2.59 g, 9.27) in methanol (80 mL). Millimoles) and a mixture of 4 angstrom molecular sieves (2.60 g). The mixture was cooled to 0 ° C, and sodium cyanoborohydride (1.17 g, 18.5 mmol) was added in several portions. Then, the mixture was stirred at room temperature for 22 hours. The suspension was filtered, and the filtrate was shrunk under reduced pressure. The resulting residue was partially dissolved in dichloromethane (500 ml). Then, the mixture was washed with a saturated aqueous sodium carbonate solution (100 ml). The layers were separated and the aqueous layer was extracted with methane (100 ml). The combined organic layer was dried over 10 magnesium sulfate, filtered and concentrated under reduced pressure to provide 2.59 g of a clear oil, which was used directly without further purification. The crude diamine (2.59 g) and triethylamine (3.86¾ liters) in dimethyl methane (60ml) were treated with trifluoroacetic anhydride (1.06ml, 13.9mmol) at 0 ° C. , 27.7¾ mole) solution. Then, the resulting solution was stirred at room temperature for 45 minutes. After 45 minutes, another amount of trifluoroacetic anhydride (350 microliters) was added and stirring was continued for 15 minutes at room temperature. The solution was cooled to 0 t :, and a saturated aqueous sodium bicarbonate solution (10 ml) was added. The mixture was then partitioned between dichloromethane (300 ml) and a saturated aqueous bicarbonate solution (40 ml). The layers were separated, and the organic layer was washed with water (50 ml), dried over magnesium sulfate 20, filtered, and concentrated under reduced pressure. Medium pressure liquid chromatography was used to purify the oil produced by 108 200524930, and it was extracted with a hexane: ethyl acetate gradient (80:20 to 60:40) to provide 1.84 g (yield). 53%) of the title compound (&gt; MS (APCI +): m / z 377 (M + H) + O · N- (l-acyl-3-yl-propyl) -2,2,2- Trifluoroacetamide hydrochloride

Diphenylmethyl azulide-3-yl) propyl] 2,2,2-trifluoroacetamidamine (1.72 g, 4.57 mmol) in methanol (60 ml) at 50 psi Ear), 10% Pd / C (2.02 g), concentrated hydrochloric acid (12.0M, 0.380 ml) for 6 hours. Additional amounts of 10% Pd / C (1.5 g) were added and hydrogenation was continued for 22 hours. The solvent was removed under reduced pressure to give a yellow residue. The residue was then concentrated several times with toluene and then dried in a vacuum at 50 ° C for several hours to give the title compound contaminated with diphenylmethane. This crude material was triturated with hexanes to provide 1.13 g (yield 100 ° /.) Of the title compound. MS (APCI +): m / z211 (M + H) +. 15 Example 5 Preparation of 2,2,2-trifluoro-N- (3-methyl-acyl-3-ylfluorenyl) -acetamidine hydrochloride

H2,10% Pd / C HCI, MeOH 93%

I-NH-HCI 109 200524930 Hydrogenated N- (l-diphenylfluorenyl-3-methyl-azirdan-3-ylmethyl) in methanol (50 ml) at 50 psi A mixture of 2,2,2-trifluoro-acetamidamine (3.19 g '8.80 mmol), 10% Pd / C (25 g), concentrated hydrogen acid (12] \ 4, 0.732 ml) for 8 hours. The solvent was removed under reduced pressure to give 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 +): w / z 197 (M + H) + 〇 Example 6 Preparation of 10 (R) and (S) -l-pyrrolidine-3 · yl-cyclopropylamine

Canton NH H ^ N ^ and ^ VJ Α · N, N-Dibenzylpropenamide

CI

Bn2NH // Pr2NEt THF • 780C-rt ^ γΝΒη2

Fill a round bottom flask with tetrahydrofuran (3750 ml) and cool under nitrogen to 15 ° -78 ° C. Add acryl hydrazone (55.7 g, 48.9 ml, 0.615 moles) and diisopropylethylamine (87.3 g '118 ml, 0.676 moles), followed by slowly adding (over 20 minutes) dibenzylamine ( 109.6 g, 106 ml, 0.555 mole). The reaction mixture was warmed to room temperature and allowed to cool at room temperature for 0 hours. A large number of white precipitates were observed, and thin layer chromatographic analysis indicated that the reaction was complete. The solid was removed by filtration, and the filtrate was concentrated in vacuo to obtain the title compound in a certain yield. 110 200524930 Β N- (trimethylsilylmethyl) -α-methylbenzylamine NH2 Me3SiCH2CI H ^ N ^ Si (CH3) 3

Ph into Me —Ph ^ Me

Heat (SH-)-O-methylbenzylamine (100 g, 106.4 ml, 0.82 mol), tris (trifluoromethyl) silyl (115.1 ml, 101.2 g, 0.82 5 mol) and triethylamine under reflux (126.5 ml, 96.2 g, 0.95 moles) of the mixture for 24 hours until the reaction is complete as indicated by LCMS. The reaction mixture was triturated with heptane and the HC1 salt was filtered off. The heptane filtrate was concentrated to an oily residue and distilled under vacuum (42-50 ° C / 0.4-0.7 mmHg) to provide 67.8 g (40% yield) of the title compound. 10 C.N- (methoxyethoxy) -N- (trimethylsilylmethyl) -α-methylbenzylamine HJ ^ Si (CH3) 3 HCHO ^ H3C, 〇JJSi (CH3) 3

Ph ^ Me MeOH ^

At 0 ° C, in an aqueous formaldehyde (37%, 152.1 g, 1.9 mol) solution, add N- (trimethylsulphonylmethyl) _port_methylbenzyl from the previous step. Amine (310 g '1.5 mol) was exceeded for 0.5 hours, followed by addition of methanol (1 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 'using a Kugelrohl apparatus to steam the hall to provide 210 g (56%) of the title compound. D. 1- (1-Phenyl-Ethyl) -Hydroxybenzyl-3-carboxylic acid dibenzylamine 111 200524930 〇

Combine N, N-dibenzylpropenamide (79.5 g, 0.317 moles) with s- (methoxyfluorenyl) (trimethylsilylmethyl) -o: -fluorenylbenzylamine (1 (3 g, 0.412 mol) was dissolved in CH2C12 (1500 ml) and cooled to 0. 〇. Triacetic acid 5 acid solution (27 ml in CH2Cl2) was added for more than 20 minutes, and the resulting reaction mixture was stirred at room temperature overnight. The mixture was washed with aqueous NaHC03 solution and brine, dried over NajCU and concentrated. The residue was purified by flash chromatography (heptane-EtOAC-EtsN / lO: 2 ·· 0.1) to provide 97.7 g of the title compound (77% yield), as a mixture of two non-mirromeric isomers 10 物 0 E. Dibenzyl- {1- [1_ (1_phenyl] -ethyl) _pyrrolidin_3_yl] _cyclopropylimine

At -78 ° C, a round bottom flask filled with tetrahydrofuran (1 400 ml) was charged with 'EtMgBr' (3.0M in Et20, 178 ml, 0.534 mol). Then, to keep the temperature below _68. A solution of Ti (OiPr) 4 (64.8 g, 66.G ml, 0.228 mol) in THF (15 G ml) was added at a rate of 0. Add 1- (1-phenyl_ethyl) -pyrrolidin-3-carboxylic acid dibenzylamine (86.6 g, 0.218) in THF (150 ml) at below 48 ° C. Before dissolving 112 15 200524930 solution, stir the dark solution at -68 ° C for 3 minutes. The reaction mixture was heated to / m, then stirred at room temperature for 10 hours, and then heated at reflux for 1.0 hour. The reaction mixture was then cooled to 8 ° C. EtMgBr (3.0 M in ether, 150 ml, 0.45 mol) was added, followed by rapid addition of 5 Ti (〇iPr) 4 (54 6 g, 55 6 ml, 0.5 ml) in THF (150 ml). 192 Mol). The resulting mixture was stirred at room temperature for 10 hours before stopping with a gasified aqueous ammonium solution (3,000 ml) and water (800 ml). The mixture was filtered through a plug of plastic and rinsed with ether. The organic layer was separated. This aqueous layer was made alkaline (pH ~ 8.5) with NaOH solution and extracted with ether. The combined organic layer was dried over NajO4, concentrated and purified by flash chromatography (heptane-EtOa \ Ac-Et3N / l0: 1: ο]) to provide the title compound as a stereo A mixture of isomers is separated before subsequent conversion. Isomer 1 (31.3 g, 35%), if it is colorless crystal (mp 76-765. 0. The stereochemical structure of isomer 1 can be confirmed by single crystal X-ray diffraction experiments. 15 Isomer 2: will be from the above purification The impure oil (18 g) was further chromatographed with heptane / fluorenylbutyl i | (MTBE) / Et3N (100: 0.5: 0.5) to provide 11 g of isomer 2 with a purity of about 90%, as a colorless oil. This oil was dissolved in Et20 (350 ml) and titrated with 2.0 M Et20-HCl (12.8 ml). The resulting white solid was collected by filtration, rinsed with ether, Dissolved in 20 MeOH, neutralized with 15 ° / 0 NaOH, extracted with ether (2 times), washed with brine, dried over NajO4, and concentrated in vacuo to obtain a thick oil, Recrystallization of EtOH provided ιοο of the title compound (22% yield) as colorless crystals (mp 61-61.3. 0. F · S-1-pyrrolidin-3-yl-cyclopropylamine 200524930

20% of pd / c was charged into dibenzyl- {1- [1- (1-phenyl-ethyl ratio ^ each fluoren-3-yl] -cyclopropylimine (300 g, 7.32 mmol Mol), and subjected to hydrogenation conditions of 50 psi. After 48 hours, the reaction was filtered and concentrated to provide 5 764 mg of the title compound (yield: 83%). MS (APCI +): w / z 127 (M + H) + 〇G · (R) -l-pyrrolidin-3-yl-cyclopropylamine

Charge 20% Pd / C into dibenzyl- {1- [1- (1-phenyl-ethyl) _pyrrolidin 10-3-yl] -cyclopropyl} -amine (3.01 g, 7.32 mmol Mol), and accept hydrogenation conditions of 50 pieces per square inch. After 48 hours, the reaction was filtered and concentrated to provide 844 mg of the title compound (yield: 91%). MS (APCI +): m / z 127 (M + H) +. Example 7 Preparation of 15-Pyrrolidin-3-ylfluorenyl-carbamic acid tert-butyl ester A. (S) -Methyl transverse acid 1-benzyl-σbilo sigma-3-yl group 114 200524930 Η〇 /, ΓΛ ^^ + MsC 丨 Ms〇 / ^ r- \ ^ L ^ N ch2ci2 〇n ^ The 1-benzyl_σ is slightly biter than -3_ alcohol (Synthetic

Communications), 1985) (25.01 g, 141 mmol) was mixed in dichloromethane and filled with triethylamine (29 ml). The resulting solution was cooled to 0 ° C and filled with tritium trioxide (13.1 ml). After 14 hours, the reaction was washed with saturated sodium bicarbonate, followed by water and brine. The organic layer was dried and concentrated to provide the title compound (30.2 g, yield 84%). MS (APCI +): m / z 256 (M + H) +. Β (R) -l-benzyl-pyrrolidine_3_nitrile

MsO / \ = /

NaCN 10 ^

Mix each of the nitriles (29 · 8 g, 117 mmol) with acetonitrile and fill with sodium cyanide (20.2 g, 412 mmol) and tetrabutylammonium cyanide (3.11 g '11.6 Millimoles) and 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 by column chromatography (3: 1 hexanes / ethyl acetate) to give 15.4 g of the title compound (71% yield). MS (APCI +): w / z 187 (M + H) +. C. (R) -C- (l-benzyl) bilodine-3-yl) -methylamine

115 200524930 Mix 1-benzylbilodol-3-nitrile (5.08 g, 27.3 mmol) in THF and cool to 0 ° C. After 10 minutes', LAH (2.09 g, 55.1 mmol) in THF was slowly added to the pyrrolidine solution at 0 ° C. The evolution of gas was observed and the reaction was allowed to continue at 0 ° C for 30 minutes. The reaction 5 was warmed to room temperature and stirred for an additional 2 hours. The reaction was stopped with water (2 ml), NaOH (2 ml) and water (6 ml) again. The resulting slurry was filtered on a plastic plug, and the combined effluent was washed with dichloromethane and concentrated to provide 4.2 g of the title compound (yield: 82%). MS (APCI +): m / z 191 (M + H) +. 10 D · (R)-(l-benzyl-pyrrolidin-3-ylmethyl) -carbamic acid tert-butyl ester

R_C- (1-benzyl than pyridin-3-yl) -methylamine (2.033 g, 10.7 mmol) was mixed in THF and charged with Boc anhydride (6.787 g, 31 mmol). The resulting solution was gently heated to 46 ° C. After 6 hours, the resulting solution 15 was cooled to room temperature and concentrated. The crude product residue was mixed in methane gas and washed with 1.0N HC1. This organic washing solution was purified by chromatography to provide 2.4 g of the title compound (yield: 76%). MS (APCI +): m / z 291 (M + H) + 〇 E · Lalobit-3-ylmethyl-aminocarboxylic acid tert-butyl vinegar

116 200524930 Charge 20% Pd / C into (R)-(l-benzyl-pyrrolidin-3-ylmethyl) -aminocarboxylic acid secondary butyl ester (1.0 g, 3.44 mmol) ) And hydrogenated at 50 psi. The reaction was then 'filtered and concentrated' to provide 511 mg of the title compound (yield: 74%). MS (APCI +): m / z201 (M + H) +. 5 Example 8 Preparation of pyrrolidin-3-ylmethyl-aminocarboxylic acid tert-butyl ester A · [1- (1-phenyl-ethyl) -pyrrolidin-3-yl] -methanol

5-Phenoxy-1- (1-phenyl-ethyl) -pyrrolidine-3-carboxylic acid methyl ester (Journal of Heterocyclic Chemistry, 1992) (10.0 g, 40.5 mmol) Mol) was mixed in diethyl ether, and it was slowly added to the LAH slurry in diethyl ether (2.31 g, 60.86 mmol). The resulting solution was heated under reflux for 4 hours. The reaction was cooled to room temperature and quenched with a water / ether mixture. The resulting solution was stirred for an additional hour at room temperature. The slurry was filtered and washed with methane. The filtrate was concentrated under reduced pressure to provide 7.76 g of the title compound (yield: 94%). MS (APCI +): m / z206 (M + H) +. Β · 2- [1- (1-Benzyl_ethylpyrrolidin-3-ylmethyl) -isoindole_; ι, 3-dione

Factory 0H

117 200524930 [1- (1-phenyl-ethyl) -pyrrolidin-3-yl] -methanol (4.4 g, 21.5 mmol) was mixed with THF, and triphenylphosphine (6.27 G, 23.9 mmol, 23.9 mmol) and phthalimide (3.61 g, 24.6 mmol), followed by dropwise addition of diisopropyl azodiisopropionate (DIAD) (5.08 g '25.1 mmol). After 4 hours, the oil produced by the reaction and chromatography (Mo% isopropyl alcohol / dichloromethane) was concentrated to provide 5.6 g of the title compound (yield: 77%). MS (APCI +): m / z 335 (M + H) + 〇 C. C- [l- (l-phenyl-ethyl) -pyrrolidin-3-yl] -methylamine

10 Mix phthalimide (5.00 g, 14.9 mmol) in isopropanol and charge

Hydrazine hydrate (7.04 g &apos; 149¾ mole). 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 isopropanol and the combined concentrate was concentrated to provide an off-white oily solid. This residue was partitioned between water and 15 1: 3 dichloromethane: ether, the organic layer was washed with water, and then dried over sodium sulfate to provide 1.68 g of the title compound (yield: μ%) MS (APCI +) m / z 205 (M + H) + 〇D [1- (1-phenyl-ethyl) -pyrrolidin-3-ylmethyl;] Ester 118 200524930

C- [l- (l-phenyl) • ethyl) -pyrrolidinyl] -methylamine (4.01 g, 19.6 mmol) was mixed in THF and charged with Boc anhydride (15.3 G, Chuan Ermoer). The resulting solution was gently heated to 50 ° C. After 6 hours, the resulting solution was cooled to room temperature and concentrated. The crude product was mixed in dichloromethane and washed with 1N HC1. The organic was concentrated to provide 3.4 g (yield: 58%) of the title compound. MS (APCI +): m / z 305 (M + H) + 〇 E. pyrrolidin-3-ylmethyl-aminotricarboxylic acid tert-butyl ester

10 Comparing Benzo-Ethyl) -σ to 17th-3-ylmethyl] -aminocarboxylic acid tertiary

The butyl ester (3.50 g, 11.5 mmol) was mixed in methanol and charged with 20% Pd / C, and then subjected to 50 psi hydrogenation conditions. After 24 hours, the reaction was filtered and concentrated to yield 1.75 g of the title compound (yield: 76%). MS (APCI +): m / z 201 (M + H) +. 15 Example 9 Preparation of C-humazol-2-yl-C-pyrrolidin-3-yl · amidamine NHMe

A. 3- (hydroxy-oxazolyl-2-yl-fluorenyl) -pyrrolidine small carboxylic acid ester 119 200524930 〇CN +

BH3THF f-BuLi 56% Boron-tetrahydrofuran complex (32 ml, 1 M in THF) was added dropwise to a solution of oxazole (2.0 g, 29 mmol) in tetrahydrofuran (30 ml) at room temperature. in). The reaction mixture was cooled to -78 ° C, and tertiary 5 butyl lithium (19 ml, 1.7 M in hexanes) was added dropwise. After stirring for 30 minutes, a solution of 3-methylfluorenyl-pyrrolidine-1-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 hours, and then 5% acetic acid (180 ml) in ethanol 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 sulfuric acid 10, filtered, and concentrated in vacuo. The crude product residue was purified by flash column chromatography (40% to 100% ethyl acetate in hexanes) to obtain the title compound (4.9 g, 56%). MS (APCI +): m / z 303 (M + H) +. Β · (3-Azidofluoren-2-yl-methyl) -sigma

Cooling of 3- (Amino-2-yl-fluorenyl) to pyridin-1-carboxylic acid benzyl ester (4.9 g, 16 mmol) in chloroarsine (80 liters) ( To the solution, triethylamine (2.9 ml, 21 mmol) was added, followed by methanesulfonium (151 ml, 19.4 mmol). The solution was warmed to room temperature and stirred overnight. 120 200524930 was added. Dichloromethane, and washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated. The mesylate produced was used in the next step without further purification. In N, N-di The methyl formazan salt (80 ml) was dissolved in 5 liquid, and sodium azide (160 mmol) was added. 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 product residue was purified by flash column chromatography (0 to 40% ethyl acetate in hexane) to obtain the title compound (49 g, 10 94%) as a colorless oil. MS (Apci +): 328 (M + H) +. C. 3- (Amino-oxazol-2-yl-fluorenyl) -benzyl pyrrolidine carboxylate

3- (Azido_ $ azole_2_yl_methyl) _pyrrolidine-1-carboxylic acid benzyl ester in tetrahydrofuran (20 ml) (1.0 g, 3.1 mmol) To the solution, triphenylphosphine 15 (1.85 g, 7.03 mmol) and water (0.60 ml, 31 mmol) were added, and the mixture was stirred 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 / dioxane) to obtain the title compound (0.66 g, 71%). lH NMR (400MHz, CDCl3) 6 7.64-7.01 (m, 7Η), 5.19-5.08 (m, 20 2H), 4.01-3.12 (m, 5H), 2.74-2.53 (m, 1H), 2.2l-1.55 ( m, 4H). D · C-Hemazole-2_ylpyrrolidin_3_yl-methylamine 121 200524930

Ph in a solution of benzyl 3- (amino-humazol-2-yl-methyl l · pyrrolidin-1-carboxylate (0.65 g, 2.2 mmol) in methanol (10 ml), and formic acid added Ammonium (0.68 g, 11 mmol) and 10% palladium / carbon (0.70, 0.65 mmol). The reaction mixture was heated at 65 ° C for 2.5 hours, cooled to room temperature and filtered. Concentrated in vacuo The filtrate was obtained to obtain the title compound (0.36 g, 100%). 4 NMR (400 MHz, CDC13) 57.95 (s, 1H), 7.14 (s, 1H), 4.04-3.92 (m, 1H), 3.39-2.58 (η, 7H), 2.18-1.51 (m, 3H). Example 10 10 (2-cyano-1-pyrrolidin-3-yl-ethyl) -aminophosphonic acid tertiary Preparation of butyl ester

A. 3- (1-tert-butoxycarbonylamino-2-cyano-ethyl) -pyrrolidine-1-carboxylic acid benzyl ester

122 200524930 The 3- (1 -tertiary butoxyepiaminoamino-2-cyano-ethyl) was first purified on a silica gel column with 25 to 75% ethyl acetate in hexanes. _a is more than a 50-minute isomeric mixture of benzyl esters of each bitrate to provide the non-mirromeric isomers A and B. The non-mirror isomer was subjected to palmar hplc (chiralPak 5AD, 10% ethanol in methanol) to provide mirrors A1 (8.4 minutes) and A2 (12 · 2 minutes). Under nitrogen atmosphere, 3- (1-tertiary butoxycarbonylamino-2-cyano-ethyl) -pyrrolidine-1-carboxylic acid benzyl ester (0.53 G, 141 millimoles) solution, ammonium formate (0.27 grams, 4.23 millimoles) and 10% 10 Pd / C (0.25 grams) were added. Remove the nitrogen source and cover the reaction flask. After 2 days, the reaction mixture was filtered through a plug of plastic and the filtrate was concentrated in vacuo to provide 0.34 g of the title compound as a mixture of isomers (100%). MS (APCI +): m / z 240 (M + H) + 〇 Example 11 15 Preparation of pyrrolidin-3-yl-acetonitrile

A. 3- (Toluene-4-lithium oxymethyl benzyl carboxylate than pyridyl carboxylic acid Ph Ph

To a solution of 2-hydroxymethyl-pyrrolidine-1-carboxylic acid benzyl 20 ester (1.80 g, into 65 mmol) in methane (10 ml) was added triethylamine (1.60 ml, 11.48 mmol). Mol) and p-toluenesulfonyl (1.75 g, 9.18 mmol). After 3 hours' the reaction mixture was washed with saturated sodium bicarbonate, water and brine. At 123 200524930

The organic layer was dried over MgSO4, and the filtrate was filtered and concentrated. Purification by flash column chromatography (ethyl acetate / hexane gradient) gave 2.63 g of the title compound (yield 88 ° /.). MS (APCI +): m / z 390 (M + H) +. B · 3-cyanomethyl-pyrrolidine-;

To a solution of 3- (toluene-4-lithium oxymethyl) _σ bilobitate (1.52 g, 3.90 mmol) in DMSO (3 liters) was added sodium nitride ( (0.25 g, 5.07 mmol). The reaction mixture was heated to hexane. After 4 hours, saturated sodium bicarbonate was poured into the reaction mixture and extracted with ethyl acetate. 10 The organic layer was dried over MgS04, transitioned and the eluate was concentrated under reduced pressure. Purification by flash column chromatography (ethyl acetate / hexane-based gradient) gave 0.81 g of the title compound (85%). (Αρα +): _

245 (M + H) + 〇 C · pyrrolidin-3-yl-acetonitrile

111 (M + H) +. 124 200524930 Example 12 3-amino-3- [l_ (3-amino-1-cyclopropyl each fluoro-8 · fluorenyl_2,4-dioxo-1,2,3,4-tetrahydro- Preparation of oxazoline-7-yl) -pyrrolidin-3-ylb 2,2-dimethyl-propionitrile hydrochloride

Α-Toxanthine-3-Ethyl Ester

C02Et $: ςΓ, Ph 1 1-benzyl biloacetate ethyl ester (1) benzyl biloacetate hydrogenated in ethanol (200 ml) at 60 psi in the presence of 10% Pd / C (2.0 g) OOg, 10 42.9 millimoles) solution for 6 hours. The resulting suspension is filtered through a selenium

This material was washed with CH2Cl2 and concentrated under reduced pressure to give the crude title compound (7.12 g, 100% yield). 4 NMR S (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 (APCI +) 144 (100%, MH +). 15 B. Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester

Boc20 CH2CI2 C02Et Η 02 C02Et Boc was added to a solution of the crude product pyrrolidine-3-carboxylic acid ethyl ester (7.12 g) in CH2C12 (50 ml) at 0 ° C. 1120: 12 (50 ml) of dicarbonate 125 200524930 tertiary butyl ester (10.30 g, 47.2 mmol) solution over 1 minute. After heating to room temperature for more than 18 hours, the reaction mixture was washed with water and then brine, dried (NajO4) and concentrated under reduced pressure to give the title compound, which was used directly without further purification (10.4 g, yield 100%). 4 NMR 5 S (CDC13) 4.14 (q, 2H), 3.27-3.69 (m, 4H), 3.02 (m, 1H), 2.07-2.16 (m, 2H), 1.46 (s, 9H), 1.27 (t, 3H). C. 3-Hydroxyfluorenyl-pyrrolidine-1-carboxylic acid tert-butyl ester C02Etς? Boc

NaBH4 THF, MeOH

Boc

OH

Pyridine 10 in tetrahydrofuran (50 ml) and methanol (50 ml) at 0 ° C], 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (10.4 g, 42.9 mmol) Ear) solution, sodium borohydride (NaBH4) (3.25 g, 86 mmol) was added portion by portion for more than 30 minutes. After 18 hours, more NaBH4 (3.25 g, 86 mmol) was added. After another 24 hours, the reaction mixture was diluted with ethyl acetate, stopped and stirred for 15 minutes with a saturated aqueous NafO3 solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate, then washed twice with water, and once with brine. The combined organic layers were washed with brine, dried (Na2S04), and concentrated under reduced pressure. The crude product was purified using column chromatography (CH2C12 to CH2C12: MeOH 95: 5 to 9: 1) to provide the title compound (8.09 g, yield 94%). NMR S (CDC13) 3.25-3.69 (m, 5H), 3.11 (m, 1H), 2.40 (m, 1H), 20 h97 (m, 1H), I67 (m, 1H), 1.46 (s, 9H) . D. 3-Amidino-pyrrolidine; ^ carboxylic acid tert-butyl ester 126 200524930

(C0CI) 2 &gt; DMSO NEt3, CH2CI2 〇

At -78 ° C, in N2, in a solution of ethylene difluoride (3.86 ml, 44.2 mmol) in CH2C12 (80 ml), add dimethyl ether in CH2cl2 (20 ml). Chia (6.28 ml, 88.5 mmol) solution. After 10 minutes, 5 was added a solution of 3-trimethylpyridine · 1-tricarboxylic acid tertiary butyl g (8.09 g '40.2¾ mole) in CH2C12 (30 ml) for more than 15 minutes. After another 30 minutes, triethylamine (28.0 ml, 201 mmol) was added, and the reaction mixture was stirred at -78 ° C for 1 hour, and then at room temperature for 1 hour. The reaction mixture was washed twice with water and then 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 provide the title compound (6.98 g, 87%). 4 NMR 3 (CDCl3) 9.69 (d, J = 1.7 Hz, 1H), 3.26-3.80 (m, 4H), 3.03 (m, 1H), 2.02-2.29 (m, 2H), 1.46 (s, 9H). Ε 3- (phenylfluorenyl-tertiary butoxycarbonylamino_methyl) pyrrolidine tricarboxylic acid 15-butyl ester

To a suspension of tert-butyl carbamate (589 mg, 503 mmol) and sodium benzylsulfinate (1.24 g, 7.55 mmol) in water (50 ml) was added methanol (5 Solution of tert-butyl 3-methylfluorenyl-pyrrolidine_1-carboxylic acid (.00 20 g '5.03 mmol), followed by formic acid (0.19 ml, 5.03 mmol) . 127 200524930 The reaction mixture was heated to 60 ° C for 2 hours and then kept at room temperature for 7 days. The resulting white solid was filtered off, washed with water and completely dried under reduced pressure to provide the title compound (868 mg, 39% yield). hNMll 8 (CDCl3) 7.91 (d, 2Η), 7.50_7.68 (m, 3Η), 4.82-5 · 18 (ιη, 2Η), 5 3.71 (m, 1Η), 3.54 (m, 1Η), 3.31 (m, 1Η), 2.90-3.19 (m, 2H), 2.35 (m, 0.5H), 2.18 (m, 0.5H), 1.76-1.99 (m, 1H), 1.47 (s, 9H), 1.21 ( s, 4.5H), 1.18 (s, 4.5H).

F. 3- (1-tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethylpyridine-1-carboxylic acid tert-butyl ester NHBoc nc NHBoc V thf 10 Boc Boc

To a solution of isobutyronitrile (4.07 ml, 45 mmol) in dry THF (100 ml) under nitrogen at -78 ° C, add lithium diisopropylamidamine (303 ml, 1.5M solution in cyclohexane, 45 mmol). After 1 hour, at -78 ° C, use a pipette to transfer this solution to 15 3- (benzyl-secondary butoxy ^ amino-fluorenyl) in dry THF (100 ml). ) Σ bilox σ fixed _ 1 _ end acid = stirred suspension of butyl ester (2.00 g, 4.55 mmol). After 7 hours, the reaction was slowly warmed to room temperature overnight. The reaction was then stopped with a saturated aqueous solution of gasified ammonium (NHUC1) and extracted twice with CH ^ 2. The organic phase was washed with a saturated aqueous NaHCCh solution, then dried (Na2SO4) and concentrated under reduced pressure for 20 minutes. The crude product was purified by column chromatography, starting with hexane:

EtOAc = 3: 1 to 2: 1, then CH2C12: MeOH = 99.5: 0.5 to 99: 1 to provide the title compound (1.52 g, 91% yield). iH nmr 128 200524930 S (CDCl3) 4.64-4.79 (m, 1H), 3.42-3.85 (m, 3H), 2.93-3.29 (m, 2H), 2.54 (m, 1H), 1.96-2.14 (m, 1H) , 1.74-1.80 (m, 1H), 1.35-1.47 (m, 24H). LCMS (APCI +) 366 (100%, (M-Η) ·). G. 3-Amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile dihydrochloride

HCI CH2CI2

3- (1-tertiary butoxycarbonylamino-2-amino-2,2-difluorenyl-ethyl) -0 bilobit in CH2C12 (100 ml) at 0 ° C- HC1 (21.5 ml, 4M solution in dioxin, 86 mmol) was added to a solution of 1- Junic acid secondary butyl pyridine (1.52 g, 4.3 mmol). After 10 minutes, the reaction mixture was warmed to room temperature and stirred for 18 hours before being concentrated under reduced pressure. This oily residue was mixed with water, extracted twice with CH2C12 and the aqueous phase was concentrated under reduced pressure to provide the title compound (704 mg, 73%). 4 NMR δφ20) 3.68-3.82 (ιη, 2H), 3.52-3.63 (m, 1H), 3.17-3.45 (m, 2H), 2.86-3.12 (m, 1H), 2.46 (m, 1H) , 1.89-2.10 (m, 1H), 15 1.60 (s, 1.5H), 1.59 (s, 1.5H), 1.57 (s, 1.5H), 1.56 (s, 1.5 ·). LCMS (APCI +) 168 (100%, MH +). Example 13 Preparation of (Acridyl_3_yl) _2-cyanoethyl] -2,2,2-trifluoroacetamidine hydrochloride

20 A. Cis / trans_3- (1-Diphenylmethyl adenyl-3-yl) -acrylonitrile 200524930

ο

10 heated at 50 ° C in tetrahydrocondensate (30 ml) ^ _ Dibenjiaqi ^ 口 口 -3--3- (carbaldehyde) (1.55 g '6.17 mmol), (cyanomethyl Solution) of diethylphosphonic acid (1.30 ml, 8.02 mmol) and cesium carbonate (2.61 g, 802 mmol) for 2 hours. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The solution was then washed with a saturated aqueous solution of gasified ammonium (20 ml). The organic layer was then dried (magnesium sulfate), filtered and concentrated under reduced pressure. Purified by medium pressure liquid chromatography, the resulting residue was stripped with a hexanes: ethyl acetate gradient (90:10 to 75:25) to give 913 mg (54%) of the title compound, As a 1: 1 cis / trans isomer mixture. The isomers were collected separately, but bound later. Cis isomer: Ms0 \ pa: KM + iyz 275.0; m.p. = 117-12 ° C. Trans isomer: MS (APCI) (M + 1 / Z) 275.0; mp = 108_110 ° C 0 B · (±) -3 · amino-3- (1-diphenylmethylazol-3- ) -Propionitrile

A saturated ammonia solution in methanol (30 ml) was added to a 1: 1 cis / trans-3- (1-diphenylmethyl acryl.dan-3-yl) -acrylonitrile mixture (863 mg, 315 mmol 130 200524930 Mol). Then, the resulting suspension was heated in a sealed tube at 100 ° C for 19 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to give 912 mg (99.5%) of the title compound as an oil. MS (APCI) (M + 1) / Z 292Λ. 5 C. (Shi) -N_ [1-(1-Diphenylmethyl-methyl-O-Dan-3 -yl) -2-lactylethyl] -2,2,2-digas

Treat 3-amino-3- (1-diphenylfluorenylazol-3-) in dichloromethane (30 ml) with trifluoroacetic anhydride (0.659 ml, 4.67 mmol) at 0 ° C. ) -10 Propionitrile (905 mg, 3.11 mmol) with triethylamine (1.30 ml, 9.32 mmol). The solution was then stirred at room temperature for 45 minutes. Then, the solution was cooled to 0 ° C, and water (5 ml) was added. The mixture was then further diluted with methane (50 ml) and water (15 ml). The layers were separated and the organic layer was washed with water (2x20 ml). The organic layer was then dried (magnesium sulfate), filtered and concentrated under reduced pressure. Purified by medium pressure liquid chromatography, the resulting residue was stripped with a gradient of hexanes · ethyl acetate (75:25 to 55 · 45) to give 952 mg (79%) of the title compound. MS (APCI) (M + 1) / Z 388.0. D. (Shi) N- [1-Azine-3-yl) -2-cyanoethyl] -2,2,2-trifluoroacetamidine hydrochloride 131 200524930

Diphenylmethylazil-3-yl) -2-cyanoethyl] -2,2,2-trifluoroacetamidamine (491 mg, ΐ · 27 mmol) in digas (15 ml) Mol) solution, cooled to 0 ° C; consequently, chloroformic acid ^ chloroethyl (0.410 ml, 3.805 mmol) was added. The resulting solution was heated to reflux for 2 hours. The solution was then concentrated under reduced pressure to produce an oil. Methanol (15 ml) was added to the oil, and the resulting solution was heated to reflux for 2 hours. The solvent was removed under reduced pressure to produce a thick yellow oil. Grind the oil several times with burnt oil and discard the supernatant. The title compound was obtained as a yellow residue, 391 milligrams. MS (APCI) (M + 1) / Z 222.0. Example 14 Preparation of (2-cyano such as pyridyl-3-yl-ethyl) methyl-aminocarboxylic acid tert-butyl vinegar A. 3 tertiary butoxyalkylamino 1 cyano-ethyl ) _La slightly bite benzyl vinegar ^

In an absolute ethanol (50 ml) of 3-N-cyano_ethoxy) _Weng bite vinegar (4.40 g,! 7.2 mmol) solution, add methylamine (about 132 200524930 3 pens) L), and the solution was heated at 80 ° C for 14 hours in the side-sealing reaction. The solution was concentrated in vacuo. The produced 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 concentrated in vacuo. The residue was mixed with ethyl acetate (100 mL), washed with saturated NKUC1 aqueous solution (100 mL) and brine (100 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified on a 120 g silica gel column using 20 to 60% ethyl acetate in hexanes at a rate of 50 ml / min for more than 60 minutes to provide a 6.08 g multi-part title. Compound (combined yield: 91%). MS (APCI +): 10 288 (M + H-Boc). The yield of non-image isomer a (top point) was 2.59 g (39%) and the yield of non-image isomer B (bottom point) was 2.82 g (42%). Mirror Palm HPL ^^

Separate HPLC was used to separate non-mirromeric isomers B (2.1 g) with a gradient gradient methanol / ethyl 133 200524930 alcohol column using a palmar ad column to provide 0.87 g of isomer Bl (41 %) And 0.53 g of isomer B2 (25%). B · (2-cyano-1′pyrrolidine_3-yl-ethyl) _methyl-aminocarboxylic acid tert-butyl ester

5 Hydrogenated 3- (1-tertiary-butoxyluridylaminoamino-2-cyano-ethyl) -u-bilodine-1- in hydrogenated 10% Pd / C in THF (50 ml) Benzyl ferulate (non-mirromeric isomer B, 0.690 g, 1.78 ¾ mole) solution. The catalyst was removed using transition and the filtrate was concentrated in vacuo to provide 0.436 g of the title compound (yield: 97%). MS (APCI +): m / z 254 (M + Η) 〇10 Example 15 3- (1-tertiary butoxyepiaminoamino-2-cyanoethyl) -u ratio _Another Preparation of Benzyl Chitoate

3- (1-tertiary butoxycarbonylamino group_2-15 cyano-ethyl) · σ than pyrrolidine-1-carboxylic acid s-group in isomers of anhydrous DMF (12 ml) (isomer B2 ) (586 mg, 1.57 mmol), NaH (60% by weight, 188 mg, 4.71 mmol, 134 200524930 ears) was added, and the solution was stirred at room temperature for 1 hour. Then 78 g of methyl iodide (12.5 mmol) was added to the mixture, and stirred at room temperature for 1 hour. A saturated aqueous NHUC1 solution (80 ml) was poured into the solution, and extracted with diethyl ether (120 ml). The organics were washed with brine (50 mL), dried over MgS04 and concentrated in vacuo. Purification of the crude product was performed on a 10 g silica gel column, and it was eluted with 20 to 70% ethyl acetate in hexanes for more than 1 hour to provide 0.44 g of the title compound (yield: 72 %). MS (APCI +): w / z 288 (M + H-Boc). Β · Coupling the side chain precursors to the Nuo_Core 10 Coupling Example 1 9- [3_ (1-Amino-2-cyano-ethyl) -0 than Cridine-1-yl] -8- Preparation of Dun-3-methyl-6-oxo-2,3-dihydroazepine-fluorene-5-weilic acid

A. 9- [3- (1-tertiary butoxycarbonylamino group 2-cyanoethyl) -pyrrolidine-1-15 group] each fluoro-3-fluorenyl-6- pendant oxygen_ 2,3-dihydro-6H-1-. Isocarboxylic acid

Triethylamine

(2Cyanopyrrolidin-3-yl-ethyl) -carbamic acid tert-butyl ester in acetonitrile (8 ml) (256 mg, ι.07 mmol) and 8,9-di Triethylamine was added to a solution of fluoro-3-methyl-6-oxo-2,3-dihydro-6H-lUa-acylhydrazone-5-carboxylic acid (281 mg, l.oo 200524930 mmol). (506 mg, 5.0 mmol), and the solution was heated at 80 ° C for 4 days. The solution was concentrated in vacuo. The residue was mixed in chloroform (50 ml), washed with a saturated aqueous ammonium chloride solution (50 ml), dried over MgSO4 and concentrated in vacuo. Purification of this crude product was performed on a 40 g silica gel column 5 and was eluted with 0 to 8% methanol in methane over 1 hour to provide 241 mg of the title compound (yield: 48%). MS (APCI +): m / z 501 (M + H). Β 9- [3- (l-amino-2-cyano-ethyl) -pyrrolidin-1-yl] each fluorine_3_methyl_6_ pendant oxygen-2,3-dihydro-6H- 1- 唠 -3a-acyl- 葩 -5-carboxylic acid

9- [3- (1-tertiary-butoxycarbonylamino-2-cyano-ethyl-l-phenyl-1-yl] -δ-fluoro-3 -fluorene in dioxane (5 ml) To a solution of stilbene-6-oxo_2,3-diaza-6H nodular carboxylic acid (241 mg, 0.481 mmol), add 10% by weight HC1 solution in ethanol (1 ml), and at room temperature The solution was allowed to bleed for 16 hours. The mixture was diluted with dichloromethane. The precipitate was collected by tears in a vacuum and rinsed with ethyl acetate. The yellow solid was dried in a vacuum at 45 ° C to provide 62 mg of the title compound If it is the hydrochloride (Yield: 32%). MS (APCI +): m / z 401 (M + H) 〇Coupling Example 2 20 7- [3- (1-amino-2-cyano-ethyl) ) "Phaviol-1-yl] -1-cyclopropyl-6-gas-4 Preparation of pendant oxygen-1,4-dihydroxantolin-3-carboxylic acid 136 200524930

5

3-amino-3-11 billow in Bet (10 liters). Amidin-3-yl-propane (200 g, 1.44 mmol) and 1-cyclopropyl-6,7-difluoro-4-p-oxo-1,4-dihydro-pyridin-3-carboxyl To a solution of acid (265 mg, 1.00 mmol), triethylamine (505 mg, 5.00 mmol) was added, 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 under vacuum at 45 ° C overnight to provide 281 mg of the title compound (yield: 73%). MS (APCI +): m / z 385 (M + H). Coupling example 3 10 7- [3- (1-Amino-2-ranyl-ethyl) -0 ratio Hipidine-1 -yl] -1-bad propyl-6-gas-4 · side oxygen · 1 Of 4,4, -dihydro- [1,8] naphthyridin-3-carboxylic acid

3-Amino-3-pyrrolidin-3-yl-propionitrile (200 mg, 1.44 mmol) in acetonitrile (10 ml) with 7-Ga-1-cyclopropyl-6-fluoro-4-side Oxy-1,4-dihydro- [1,8] 15 naphthyridin-3-carboxylic acid (282 mg, 1.00 mmol) was added with triethylamine (505 mg, 5.00 mmol), and 8 (The solution was heated at TC for 17 hours. The precipitate was collected by vacuum filtration and rinsed with acetonitrile. The solid was dried under vacuum at 45 ° C overnight to provide 240 mg of the title compound (yield: 62%). MS ( APCI +): m / z 386 (M + H). 137 200524930 Coupling Example 4 7- [3- (l-Amino-2-amino-ethyl) -pyrlopyridine-1 -yl] -1- Preparation of oxopropyl-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid A. 7- [3- (1-secondary butoxyweilylamino -2-Gasyl-ethyl-5-yl] -1 -Axylpropyl-8-methoxy-4- pendant oxygen-1,4-dimurine-calycin-3-dicarboxylic acid difluoroborate

1-Cyclopropyl-7-fluoro-8-fluorenyl-4-lanthoxy-1,4-dihydro-pyridin-3-carboxylic acid difluoroborate (0.45) in acetonitrile (4 ml) G) and (2-cyano-1_pyridine 10-pyridin-3-yl-ethyl) -carbamic acid tert-butyl ester (1.3 equivalents), triethylamine (5 equivalents) was added, and The solution was heated at 80 ° C for 24 hours. The solution was then concentrated and the crude product was used directly in the next reaction. MS (APCI +): m / z 497.3 (m -BF2 + H).

Beta 7- [3- (l-tertiary butoxycarbonylamino-2-cyano-ethyl) -pyrrolidine-1-15yl] -1-cyclopropyl-8-fluorenyl-4 -Pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid

7- [3- (1-tertiary butoxycarbonylamino-2-cyano-ethylpyrolodin-1 -yl] -1-¾propyl-8- in EtOH (4 ml) To the solution of methyllactyl-4-lateral milk-1,4-dirat-pyridin-3-carboxylic acid difluoroborate, triethylamine (5 equivalents) was added, and the reaction was heated to 80 ° C. 6 hours. The crude product solution was concentrated, then mixed with 138 200524930 chloroform ', washed with NH4C1 (aqueous solution), dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (isocratic; 97: 3EtOAc: EtOH) Product material 'to produce pure carboxylic acid (0.50 g, 72% for both reactions). MS (APCI +): rn / z 497.3 (M + Η). C · 7- [3- (1-amine -Yl-2-cyano-ethyl) -i17 each sigma · 1-yl] _1-cyclopropylmethoxy-4- pendant oxygen-1,4-dihydro-pirin-3-carboxylic acid

Crude product 7- [3- (1-tertiary butoxyl-fe-2-yl-cyano-ethyl) -pyrrolidine-i-yl] -1- To a solution of cyclopropylfluorenyloxy_4_10 pendant oxygen-1,4-dihydrophosphino-3-carboxylic acid (0.698 g), 10% ethanol (11 ^^ ml) was added and the solution was stirred at room temperature. React overnight. The crude reaction mixture was concentrated, mixed in EtOAc (15 mL) and sonicated for 20 minutes. The resulting precipitate was collected by filtration. The pure product produced was a yellow solid (0.315 g, 57%). MS (APCI +): m / z 397.3 (M + H). 15 Coupling Example 5 7 Amine- Cyclopropyl) -decadan-1-yl] -1-cyclopropyl-6-fluoromethyl-4 · Preparation of pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid

nc ~ nh Oct'1-cyclopropyl-6-fluoro-8-methyl-4-oxo-7- {3- [1_ (2,2,2-trifluoro_acetamidine 200524930 aminoamino)- ¾propyl] 0-den-1-yl} -l, 4-dimuridine-calycin-3-dicarboxylic acid digas borate

1-cyclopropyl-6,7-difluoro-8-methyl-4- pendant oxygen 5 -1,4 · dihydro-pyridoline-3_carboxylic acid difluoroboronic acid in DMSO (3 ml) Esters (0.400 g) with N- (l-acryl-3-

To a solution of phenyl-cyclopropyl) -2,2,2-trifluoro-acetamide (1.5 equivalents), triethylamine (5 equivalents) was added, and the solution was heated to 80 ° C overnight. This crude product 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, 10 MS (APCI +): m / z 468.2 (m -BF2 + H). Β · 7- [3- (1-Amino-¾propyl)-// dandan-1-yl] · 1-¾propyl-6-ran-8-fluorenyl-4- pendant oxygen-1, 4-dihydro-pirin-3-carboxylic acid

1-Cyclopropyl-6_fluoro_8-methyl15yl-4-side oxygen_7- {3_ [1_ (2,2,2-digas-B Amino group)-? Aryl propyl] -Kojiyadan_ 1 group} -1,4-dihydro-pyridin-3-carboxylic acid difluoroborate solution, 10 ml of saturated sodium bicarbonate was added And the reaction was heated to 70 ° C for 3 days. The solution was then concentrated to 10 mL, poured out of the precipitated NaHC03, and directly loaded on a reverse-phase MPLC column. The eluted product was in pure form, yielding 0.23 g (51% two steps) of the title compound, mS (APCI +): w / z 372.3 (M + Η). 5 C. 7- {3- [1- (2-Cyano • ethylamino) -cyclopropyl] σdenylcyclopropyl-6-fluoro-8-methyl-4-oxo-1 , 4-dihydrocharin_3_weilic acid

nc / Ns / NH

7- [3- (1-Amino-cyclopropyl) _; μcyclopropyl_6_fluoro_8_ fluorenyl-4- pendant oxygen_1,4-dihydro-quinolin-3-carboxy The acid (free base) (0.23 g) was dissolved in 10 MeOH (20 ml), and acrylonitrile (10 equivalents) and triethylamine (5 equivalents) were added. The solution was stirred at room temperature overnight and then heated It was kept for several hours. Then the crude product material was concentrated and dissolved in a small amount of water, and loaded on a reverse phase MPLC for purification, (〇11 g, 42〇 / 〇) ms (APCI +): m / z 425 · 3 (Μ + Η) 〇15 Coupling Example 6 7- {3-[(2-cyano-ethylamino) _methyl] ethyl_tendanyl 丨 cyclopropyl-6-fluoro- Preparation of 8-fluorenyl-4- pendant oxygen-1,4-dihydro-fluoroline_3_carboxylic acid

141 200524930 A.1-Cyclopropyl-7- {3-ethyl-3-[(2,2,2-trifluoro-ethylamidoamino) -methyl] -acridyl group} -6- Fluoro-8-methyl-4-oxo-1,4-dihydro-pyridoline-3-carboxylic acid difluoroborate

5 1-cyclopropyl-6,7-difluoro-8-methyl-4- pendant oxygen in DMSO (8 ml)

-1,4-dihydro-pyridoline-3-carboxylic acid difluoroborate (1.0 g) and N · (3-ethyl-acryl-3-ylmethyl) -2,2,2 -Triton-acetamide (2 equivalents), add triethylamine (5 equivalents), and heat the solution to 80 ° C for four hours. This crude product solution was applied to the top of the reverse-phase MPLC, resulting in a mixture of the product and the carboxylic acid directly (hydrolysis of borate 10 (0.70 g, 49%)). MS (APCI +) .. m / z 470.1 (M + Μ). B. 7- (3-Aminomethyl-3-ethyl-acridan-1-yl) small cyclopropyl-6-fluoro-8-methyl-4- pendant oxygen-1,4-dihydro -Zoline-3-carboxylic acid〇〇

7- (3-Aminofluorenyl-3-15 ethyl ° den-1-yl) small cyclopropyl-6-fluoro-8-fluorenyl-4- in 50 ml of water and 100 ml of methanol To the pendant oxygen-1,4_dihydro-phosphino-3-carboxylic acid difluoroborate solution, 50 ml of saturated potassium carbonate was added and the reaction was heated to 60 ° C. overnight. The solution was then concentrated to 30 ml and loaded directly onto a reversed-phase column. 0.41 g of product (74%) can be obtained, MS (APCI +): m / z 374.2 (M + H) 〇2〇C · 7- {3-[(2-cyano-ethylamino) -methyl ] -3-ethyl-acryl. Denyl-1_yl} -1-ring 142 200524930 propyl-6-fluoro-8-fluorenyl-4- pendant oxygen_i, 4-diargon_σquinine carboxylic acids

7- (3-Aminomethyl-3-ethyl-az.denyl-; 1-yl) cyclopropyl-6_fluoro-8_methyl-4-oxo-1,4-dihydro-fluorene Porphyrin-3-carboxylic acid (0.410 g) was dissolved in 10 ml of 5 MeOH, and acrylonitrile (3 equivalents) was added. The solution was stirred at room temperature and then heated to 50C for several hours. The crude product material was then concentrated and dissolved in a small amount of water and loaded onto reverse phase MpLC for purification. Coupling Example 7 7_ {Η1- (2_cyanoethylamino) _propyl] denieryl} small cyclopropyl_6_fluoro_8_ 10methyl-4-oxo-1,4-dihydro 4 Preparation of Lin-3-Methylacid 1-1-kib 1,4-dihydrocaline_3_carboxylic acid

Place r-cyclopropyl-6,7-difluoro each methyl methyl group in dmso (3 ml) 15-oxy-1,4-dihydro-. Quelin _3_ Dundweirone vinegar (35 mg, 107 mmol) ^ Adan 3.yl-propyl) -2,2'2-trifluoroacetamide hydrochloride (660 mg, 2.68 pen moles) and diisopropylethylamine (G.932 ml, 5.35 mmol) 143 200524930, heated at 80 ° C for 20 hours. The solution was cooled to room temperature and diluted with ethanol (20 liters), and then triethylamine (1.05 ml, 7.50 mmol) was added. The resulting solution was then heated to reflux for 4 hours. The ethanol was removed under reduced pressure to produce a red solution. The solution was diluted with dichloromethane (100 ml) and washed with 1N hydrogen acid (20 ml), water (2 x 20 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. A red semi-solid was obtained. Dichloromethane (8 ml) was added to partially dissolve the semi-solid. Hexanes (6 ml) 'were added slowly to produce other solid forms. Then, the mixture was placed in a freezer for 1 hour. The suspension was then filtered to produce 278 mg (55%) of the title compound as an orange solid. Melting point = 220-223. (:; MSCAPCI) m / z 470.0. Beta 7- [3- (1-aminopropyl) -acyl. Dan-Bu ^^ cyclopropyl_6_fluoro_8_methyl-4_ pendant oxygen-1,4-dihydropyridin-3-carboxylic acid sodium

〇 〇

O-Na · »OH Na2C03

MeOH, H20, 70 C H2N 75% Me. 15 Saturated aqueous sodium carbonate solution (4.5 ml) was added to 1-cyclopropyl_6_fluoro_ in a mixture of methanol · water (8 ml · 4 ml) 8-methyl_4_ pendant oxygen-7- {3- [l- (2,2,2-trifluoroethylamidoamino) _propyl] _acridyl group, 4-dihydrofluorene Porphyrin-3-carboxylic acid (260 mg, 0.554 mmol) in suspension. The mixture was then heated at 50 ° C. After 2 hours, the starting material was still present, so the temperature was increased to 7 ° C; stirring was continued at 7 ° C for 6 hours. The methanol was then removed under reduced pressure to provide a solution. Then, the resulting The solution was directly loaded on the reverse column. The water: acetonitrile gradient (99: 13G: 70) was used to complete the 144 200524930 column extraction to produce a yellow solid. The solid was dissolved in the minimum amount of water and freeze-dried to This gave 164 mg (75%) of the title compound as a fluffy yellow solid. Melting point = 160-170 ° C; MS (APCI) m / z 374.0. C · 7- {3- [1- (2cyanoethyl Amino group &gt; propyl] •, sigma small group 丨 small cyclopropyl each fluoro-8-methyl-4- pendant oxygen-1,4-dihydrofluorin-3-carboxylic acid

Acrylonitrile (1 ml) was added to 7_ [3XingaminopropylPyringyl] in cyclopentyl, fluoro, fluorenyl, and ice side oxygen in methanol (1.5 ml). A solution of quinine sodium (87 mg, 0.220 mmol) was then stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to produce an oil. The oil was purified by medium pressure liquid reverse phase chromatography using a water: acetonitrile gradient (99:

1 to 50:50) stripping to produce 32 mg of a yellow solid. The solid was further purified by preparative hydrazone-effect liquid reversed phase chromatography, and was eluted with a gradient of water (01% formic acid 15): acetonitrile (0.1 ° / formic acid) (95: 5 to 50: 50), To obtain a yellow residue. This residue was dissolved in a minimal amount of water and freeze-dried 'to produce 19 mg (20 ° /.) Of the title compound as a yellow solid. This compound is approximately 75 ° / 0 of the parent compound and 25/0 of the osmium salt (using 4 NMR). lc / MS (APCI) 427.2; HPLC purity = 100%. 20 Example 8743. [(2-cyanoethylamino) -fluorenyl] -3-fluorenylazine. Dentan-1-yl} -1-cyclopropyl-6_ 145 200524930 Preparation of fluoro_8_fluorenyl_4-oxo-1,4-dihydrofluoroline-3-carboxylic acid sodium

A. 1-Cyclopropyl-6-fluoro-8-methyl-7- {3-methyl-3-[(2,2,2-trifluoroethylamidoamino) -methyl] acryl- 1-kib-4-oxo-1,4-dihydronoroxone-3-carboxylic acid

80%

Add 1-cyclopropyl-6-fluoro-8-methyl-7- {3-methyl-3-[(2,2,2-trifluoroacetamidine) in difluorenimidine (10 ml) Amino))-methyl] acryl. Dentan-1-yl} -4-oxo-M-dihydronordone-3-carboxylic acid difluoroborate (1.43 g, 4.37 mmol), 2,2,2-trifluoro-N- (3-fluorenyl-acryl-3-ylmethyl) -acetamidine hydrochloride (1.88 10 g, 8.08 mmol) and diisopropylethylamine (3.81 ml, 21.9 mmol) ) The solution was heated at 80 ° C for 4 hours. The solution was cooled to room temperature and diluted with ethanol (80 ml), then triethylamine (4.27 ml, 30.6 mmol) was added. The resulting solution was then heated to reflux for 4 hours. The ethanol was removed under reduced pressure to produce a red solution. The solution was diluted with dichloromethane (300 ml) 15 and washed with 1N hydrochloric acid (50 ml), water (3 x 30 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. An orange solid was obtained. Dioxane (15 ml) was added to partially dissolve the solid. Slowly add hexanes (20 mmol 146 200524930 liters) to produce other solid forms. The mixture was then placed in a freezer for 1 hour. The suspension was then filtered to give 1.59 g (80%) of the title compound 'as a colorless solid. MS (APCI) / ζ456 · 1 ′ mp 215-218 ° C. 5 B. 7- (3-Aminomethyl-3_methyl 1 ^ γσdan-1-yl) -1-cyclopropyl-6-fluoro-8-fluorenyl-4-oxo-1, 4-Dihydropinenone-3-carboxylic acid sodium

A saturated aqueous solution of sodium carbonate (25 ml) was added to 1-cyclopropyl-6-fluoro-8-methyl-7- {3_methyl10 group in a mixture of methanol: water (45 ml: 20 ml) -3-[(2,2,2-trifluoroethylamino) -fluorenyl] // 0-denyl-1_yl} -4-oxo_1,4_dihydronornorone-3-carboxyl Acid (1.24 g, 2.72 mmol) suspension. The mixture was then heated at 70 ° C for 2 hours. The methanol was then removed under reduced pressure to provide a solution. The resulting solution was then directly loaded on a reversed column. The crude product was then purified using medium pressure reversed phase chromatography and washed with a 1000/0 water to 15 50% water: 50% acetonitrile gradient to yield 616 mg (59%) of the title compound , As a white powder. ] \ 48 (A? (: 1)) ((: 〇〇360.1. HPLC purity = 96.4% (254 nm). C. 7- {3-[(2-cyanoethylamino) -methyl ] -3-Azoylacryl-1-denyl-1-cyclohexyl-6-fluoro-8-fluorenyl-4-lanthoxy-1,4-dihydrolinol-3-sulfonate

147 20 200524930

Acrylonitrile (1.47 ml, 22.3 mmol) was added to each of the 7- (3-aminomethyl Winterbornyl and small groups) cyclopropyl winter air methyl groups in methanol (10 ml) A solution of 4-oxo-1,4-dihydronoroxone-3-carboxylic acid sodium (425 mg, L11 mmol). The solution was then stirred at room temperature for 18 hours. The 5 solvent was removed under reduced pressure to give a white residue. This residue was dissolved in a minimum amount of water, and the resulting solution was supported on a reverse column. The crude product was purified using medium-pressure liquid reversed phase chromatography, with a gradient of 100% water to 50% water: 50% acetonitrile to yield 73 mg (15%) of the title compound as a yellow solid. LC / MS (APCI) m / z (COOH) 413.2. 10 mp = 190-200 ° C (decomposed); HPLC purity = 97 · 4% (254 nm). Coupling Example 9 7- (3- {1-[(2-cyano-ethyl) _methyl-amino] _ethyl} _pyrrolidine "-yl ^ cyclopropyl-6-fluoro-8- Preparation of methoxy-4- pendant oxygen-1,4-dihydro-pirin-3-acid acid 0 0

NC ^

ΜθΟΗ Et3N

15 1-Cyclopropyl-6-fluoro-8-fluorenyl-7- [3- (l-methylamino-ethyl) -pyrrolidin-1-yl] -4-lanthoxyl-1, 4-Dihydro-pyridin-3-carboxylic acid (WO 9209596A, crude 1) (0.274 g, 0.679 mmol) was mixed with acrylonitrile (4 ml), and triethylamine (0.1 ml) was charged. . After 4 hours, the solution was concentrated. The residue was mixed in digas methane and charged with 2.0 N HC1 / ether until turbid. The resulting precipitate was collected by filtration 20 and washed with diethyl ether to give 97 mg of the title compound as HC1 (yield: 31%). MS (APCI +): m / z 457 (M + H) 〇148 200524930 Coupling example ο 7- {3- [l- (2-Packing-ethylamino) _ethyl] -σ ratio slightly determined_ Preparation of 1-yl} -1- $ Arylpropyl 8-methoxy-4-lanthoxy-μ-dihydro-quinoline-3-carboxylic acid

5 7-0 (1-Amino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy

4-Pentaoxol-1,4-dihydro-quinoline-3-carboxylic acid HC1 salt (WO 9914214A1, 1 ^) (0.347, 0.8854 mmol) was mixed with methanol and charged with Et3N (0.5 ml ). Acrylonitrile (1 ml) was charged to the reaction. After 24 hours, the solution was concentrated. The residue was mixed in dichloromethane and filled with 2.0 N HC1 / ether until turbid. The resulting precipitate was collected by filtration and washed with diethyl ether to give 104 mg of the title compound as a HC1 salt (yield: 30%). MS (APCI +) · m / z 425 (M + H) 〇 Coupling example 11

7- (3- {1-[(2-cyano-ethyl) · ethyl-amino] -ethylpyrrolidin-1-yl) -1-15 cyclopropyl-6-fluoro-8- Preparation of hydroxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid

0 0 0 0

1-Cyclopropyl-7- [3- (l-ethylamino-ethyl) -pyrrolidin-1-yl] -6-fluoro-8-fluorenyl-4-oxo-1,4 -Dihydro-quinoline-3-carboxylic acid (WO 9209596A1, 1992) (0.103, 0.24 mmol) was mixed with methanol and filled with triethylamine (0.055 149 200524930 ml). Fill the reaction with propionitrile (0 · 10 ml) and shake in the eye socket 5 | After 12 hours, the reaction was concentrated and mixed in digas methane and charged with 2.0 N HC1 / ether until turbid. The resulting precipitate was collected by filtration and washed with diethyl ether 'to give 62 mg of the title compound as a HC1 5 salt (yield: 55%). MS (APCI +): m / z 471 (M + H) 〇Coupling Example 12 7- (3-{[(2-cyano-ethyl) -ethyl-amino] -methyl} -11 to 17 each Preparation of fluoren-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydroquinine-3-metanoic acid

10 Cyclopropyl · 7 · (3 · Ethylaminomethyl-々b11 each sigma · 1-yl) -6-gas-8-methoxy-4- pendant oxygen-1,4-di Hydrogen-oxoline-3-carboxylic acid (EP 230295, 1987 KQ.05 g, 0.124 mmol) was mixed in methanol and filled with triethylamine (0.02 ml). Acrylonitrile (0.1 ml) was charged to the reaction and the resulting solution was shaken in an orbital shaker. After 12 hours, the reaction was concentrated and mixed in methane, and filled with 2N HC1 / ether until turbid. The resulting precipitate was collected by filtration and washed with diethyl ether to produce 29 mg of the product, such as HC1 salt (yield: 51%). MS (APCI +): m / z 457 (M + H) 〇Coupling Example 13 7- (3-{1-[(2-cyano-ethyl) -fluorenyl-amino] -ethyl} -0 ratio Rockbit-1-yl) -1-20 Preparation of oxopropyl-6-air-8-acyl-4-lanthoxy-1,4-diazine-σquinine-3-weiric acid 150 200524930

Fluorexone (WO 9209596 A1, 1992) (0.05 g, 0.124 mmol) was mixed in methanol and filled with triethylamine (0.02 ml). Put acrylonitrile (0.1ml)

Fill the reaction and shake the resulting solution in an orbital shaker. After 12 hours, the reaction was concentrated and mixed in digas methane, and charged with 2NHC1 / ether until turbid. The resulting precipitate was collected by filtration and washed with diethyl ether to produce 33 mg of the product, such as HC1 salt (yield: 58%). MS (APCI +): m / z 457 (M + H). Coupling Example 14 10 7- (3- {1 _ [(2-cyano · ethyl) -amino] -ethyl} -sulphone-1-yl) -1-L-propyl-6-fluoro- Preparation of 8-Cyclo-4_lanthoxy-1,4-dihydro_thienine_3-carboxylic acid

NC ^ MeOH Et3N Ο Ο

Fluoroxonone HC1 salt (Chemical &amp; Pharmaceutical Bulletin, 1994, 42 (7), 1442-54) (0.804 g '15 2.142 mmol) is mixed in alcohol and charged Triethylamine (0.5 ml). Acrylonitrile (1 ml) was charged to the reaction. After 12 hours, the reaction was concentrated and mixed in dichloromethane, and 2NHC1 / ether was charged until turbid. The resulting precipitate was collected by filtration and washed with diethyl ether to produce 850 mg of the product, such as HC1 salt (yield: 92%). MS (APCI +): m / z 427 (M + H). 20 Coupling Example 15 151 200524930 7-{3-[(2 -Ranyl-ethylamino) -methyl] -17 Than slightly 12-deoxy-1-yl} -1-phosphono-8-fluorenyloxy Preparation of 4--4-oxo-1,4-dihydro-pyridoline-3-carboxylic acid

A. 7- (3-Aminofluorenyl-σbiloxo stilbyl-1-yl) -1-L-propyl-8-methyllactyl-4-side 5'-1,4-dihydro-fluorene Porphyrin-3-carboxylic acid difluoroborate

Pyrrolidine (EP 153163, 1985) (0.247 ^, 2.47 mmoles) and 6_ desfluridone (WO 9914214, 1999X0.506, 1.56 mmoles) were mixed in acetonitrile and filled with triethylamine ( 1.0 ml). After 18 hours, the reaction was concentrated to give 545 mg of the title compound (yield: 87%). MS (APCI +): m / z 406 (M + H). The compound is protected by BOC prior to the following hydrolysis steps according to methods readily available to those skilled in the art. B. 7- [3- (Secondary butoxyepiamino-methyl) -11 bilobit-1-yl] -1-¾propyl-8-fluorenyl-4-oxo-1 , 4-Diazaquinine-3-conc

7- [3- (tertiary butoxycarbonylamino-methyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-fluorenyl-4-oxo-1,4-di Hydro-pyridoline-3-carboxylic acid difluoroborate (0.600 g, 1.19 mmol) was mixed with ethanol and filled with triethylamine (1.0 ml). 200524930 The resulting solution was heated to 60 ° C. After 24 hours, the reaction was concentrated, mixed in digas methane and washed with gasified ammonium to give 523 mg of the title compound (yield: 96 ° / °). MS (APCI +): m / z 458 (M + H). C. 7- {3-[(2-Gasyl-ethylamino) -methyl] -11 than slightly 11-N-l-yl} -1-badpropyl 5-8-methoxy-4- Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid

7- (3-Aminomethyl-11 Billobit-1-yl) -1-¾propyl-8-fluorenyl-4-oxo-1,4-dihydro-phosphon-3- Carboxylic acid (as HC1 salt) (0.332, 0.846 mmol) was mixed with methanol and filled with triethylamine (0.5 ml). Acrylonitrile (1 ml) 10 was charged to the reaction. After 24 hours, the solution was concentrated and mixed in dioxane, and 2NHC1 / ether was charged until turbid. The resulting precipitate was collected by filtration and washed with diethyl ether to give 176 mg of the title compound as a HC1 salt (yield: 51%). MS (APCI +): m / z411 (M + H).

Coupling Example 16 15 7- {3- [1- (2-cyano-ethylamino) -cyclopropyl] -pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8- Preparation of methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid 0 0

A. 7- [3- (1-Amino-Baclopropylpyridoxine-1-yl] -1-¾propyl gas-8-methoxy-4- pendant oxygen-1,4-dihydro -Porphyrin-3-carboxylic acid difluoroborate 153 200524930

ο ο

obf2 Et3N ch3cn ο 〇

1-pyrrolidin-3-yl-cyclopropylamine (0.886 g, 7.00) was charged with flunornone borate (EP 241206, 1 ^) (2.01 g, 5.85 mmol) in acetonitrile. Millimoles), and filled with triethylamine (4.0 ml). After 20 hours 5 the reaction was concentrated to yield 1.76 g of the title compound (yield: 67%). MS (APCI +): m / z 45 ° (M + H). Prior to the following steps, the compound was subjected to hydrolysis as provided in step B of Example 15. Ug. 7- {3- [1- (2-Gasyl-ethylamino) -cyclopropyl]-. Than 11-bital 1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydroquinine-3-carboxylic acid

Set 7- [3- (1-amino-cyclopropyl) -σ to 17 in each case &gt; 1-yl] small cyclopropyl-6-gas-8-fluorenyloxy ice side oxygen-1,4- Dihydro-pyridoline-3-carboxylic acid 11 (: 1 salt (0.8477 g, 1.93 mmol) was mixed with methanol and filled with triethylamine (0.40 ml). Acrylonitrile (1 ml) Charge the reaction and shake. After 12 hours, concentrate the reaction and mix 15 in dioxane, and fill with 2NHC1 / ether until turbid. Collect the precipitate produced by filtration and wash with diethyl ether. Produces 647 mg of the title compound, such as HC1 salt (yield: 67 ° /.). MS (APCI +): w / z 455 (M + H). Coupling Example 17 20 Amidine-aminomethyl Bihar Small group M-cyclopropyl-8-methoxy-4- pendant oxygen 154 200524930 Preparation of 1,4-dihydro-pyridoline-3-carboxylic acid 0 0

A. 7- [3- (tertiary butoxycarbonylamino-methyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4- pendant oxygen-1,4- Dihydro-phosphonium-3-carboxylic acid difluoroborate

Pyrrolidine (0.496 g, 2.48 mmol) and 6-desfluridone (W09914214, 1999) (0.682 g, 2.10 mmol) were mixed in acetonitrile and filled with triethylamine (1.5 Ml). After 18 hours, the reaction was concentrated to yield 752 mg of the title compound (yield: 69 ° / 0). MS (APCI +): m / z 10 506 (M + H). Β · 7- [3- (Secondary butoxyepiamino-methyl) _π Billow bite small group] _ 丨 _ ring. 8-8methoxy-4 pendant oxygen-1,4- Dihydro-Colinine

0 0 BocHN

OBF2

Ο Ο BocHN

Et3N one

EtOH will be 7- [3- (tertiary butoxyepiaminoamino group), each bite-butylpropyl, each methoxy_4_ pendant oxygen_1,4 · dihydro ___ 3, acid di Sheath acid (0.747 g, 1.48 mmol) was mixed in ethanol (50 ml) and filled with triethyl ether (L00 ml). The resulting solution was heated to 8 Torr. After 20 hours, the reaction was cooled to room temperature and concentrated. Mix crude oil with dichloromethane and wash with 155 15 200524930 beryllium. Drying the organic and concentrating 'yielded 544 mg of the title compound (yield: 80%). MS (APCI +): m / z 458 (M + H) 〇7 · (3-aminomethyl-pyrrolidin-1_yl) -1-cyclopropyl each methoxy_4_ pendant oxygen- 1,4-dihydro-pirin-3-carboxylic acid

7- [3- (tertiary butoxycarbonylamino-methyl) -pyrrolidine small group] _; ^ cyclopropyl-8-fluorenyl-4- pendant oxygen-1,4 · dihydro- Porphyrin-3-carboxylic acid (0.01 g, 0.219 mmol) was mixed in dichloromethane and filled with 2N HC1 / ether until turbid. Collecting the precipitate produced by tritium and washing it with diethyl ether, 10 can produce 55 mg of the title compound, such as HC1 salt (yield: 70%) MS (APCI +) m / z 358 (Μ + Η) . D · 7- {3-[(2-Ranyl-ethylamino) -methyl] -σBiloxidyl-fluorenylcyclopropyl-8-methoxy-4- pendant oxygen-1,4 -Dihydro · pyridin-3-carboxylic acid

156 200524930 75/0). MS (APCI +): m / z411 (M + H) 〇Coupling Example 18 7- [3- (1-Amino-2-cyano-ethyl) -11 slightly smaller group] -1_cyclopropyl _6_ 气 _8 Preparation of methyl-4-lanthoxy-1,4-dihydro-pirin-3-weilic acid

ΜΘΔ Α · 7- [3- (1-tertiary butoxycarbonylamino-2_cyano_ethyl) _pyrrolidinyl q group: M-cyclopropyl-6-fluoro-8-methyl-4 -Pendant oxygen-1,4-dihydro-pyridoline_3-carboxylic acid

(2-Cyano-1-pyrrolidin_3_yl_ethyl) _amine in acetonitrile (10 mL) secondary butyl carboxylic acid ester (1: 1 non-mirromeric mixture) (256 Mg, 1.07 millimolar) and ^ cyclopropyl-6 ... difluoro-8_methyl_4_oxoquinone dihydro · pyridoline-3 ** carboxylic acid (280 mg, 0.86 millimolar ) To the solution, triethylamine (433 g, 4.3 mmol) was added, and the solution was heated at 80 ° C for 3 days. In a vacuum / agricultural contraction, grain fluid. To the residue were added ethanol (8 ml) and triethylamine (MM M 4 · 3 mmol), and the mixture was heated at 80 ° C for 5 hours. Remove solvents in the air. The residue was mixed in chloroform (50 ml), washed with a saturated aqueous solution of gaseous money (50 ml), dried over MgSO4 and concentrated in vacuo. The crude product was purified by Shijiao chromatography, and was stripped with 0 to 8% methanol in digas methylbenzene for more than 1 hour to provide 1 GG 亳 g of the title compound (yield 157 200524930 yield: 23%). MS (APCI +): m / z 499 (M + H). Beta 7- [3- (l-Amino-2 -amino-ethyl) -0 Biloprodin-1 -yl] -1-¾propyl-6-Ga-8-methyl-4- Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid

7- [3- (l-tertiary-butoxycarbonylamino-2-amino-ethyl) -σ ratio in slightly gaseous methane (5 ml) ¾propyl-6-gas-8-methyl-4-oxo-1,4-dihydro-pyridin-3-carboxylic acid (100 mg, 0.20 mmol) was added to a solution of 10% by weight in ethanol HC1 solution (0.5 ml), and the solution was 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 washed with ethyl acetate. The bright yellow solid was dried in vacuo to provide 44 mg of the title compound as the hydrochloride salt (85% parent compound, yield: 47%). MS (APCI +): m / z 399 (M + H). Coupling Example 19 15 9- [3- (1-Amino-2-cyano-ethyl) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3- Preparation of dihydro-6H_1-hum-3a-acryl-5-carboxylic acid

A. 9- [3- (1-tertiary butoxycarbonylamino-2-cyano-ethyl) -pyrrolidin-1-yl] -8-fluoro-3-fluorenyl-6-oxo- 2,3-dihydro-6H-1-hum-3a-acyl-fluorene-5-carboxylic acid 158 200524930

9 〇 F

10 15 (2-cyano-1 ^ pyrrolidin-3_yl_ethyl) -tricarboxylic acid tert-butyl ester (270 mg, L13 mmol) in acetonitrile (8 ml) and 8, 9_difluoro_3 • methyl ^ -6-oxo-2,3-dihydro-6H-1- 噚 -3a-acyl- 葩 -5-carboxylic acid (313 mg, 0.95 mmol) solution To this, triethylamine (481 mg, 4.75 mmol) was added and the solution was heated at 50 ° C for π hours. The solution was concentrated in vacuo. The residue was added to ethanol (4 ml), dioxin (4 ml) and triethylamine (481 mg, 4.75 mmol), and the mixture was heated at 80 ° C for 4.5 hours. Remove the solvent in vacuum. The residue was mixed with chloroform (50 ml), washed with a saturated aqueous solution of ammonium vaporized (50 ml), dried over MgSO4 and concentrated in vacuo. This crude product was purified on a 40 g silica gel column, and was stripped with 0 to 8% methanol in digas methylbenzene for more than 1 hour to provide 227 mg of the title compound (yield: 48% ). MS (APCI +): m / z 501 (M + H). Beta 9- [3- (l-amino-2-cyano-ethyl) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-difluorene -6H-1- 唠 -3a-acyl- 葩 -5-carboxylic acid

Ο Ο OH HCI / EtOH

9- [3- (1-tert-butoxycarbonylamino-2-muryl-ethyl) -σbilodol-1-1-yl] -8-gas in methane (8 ml) -3-methyl-6-oxo-2,3-diazine 159 200524930 -6H-1- 唠 -3a-acyl- 葩 -5-carboxylic acid (225 mg, 0.45 mmol) A 10% by weight solution of HC1 in ethanol (1 ml) was added and the solution was stirred at room temperature for 5 days. The solvent was removed in vacuo. The yellow solid was slurried in dichloromethane and ethyl acetate, collected by vacuum filtration and washed with ethyl acetate for 5 times. The bright yellow solid was dried in vacuo to provide 177 mg of the title compound as the hydrochloride salt (88% parent compound, yield: 87%). MS (APCI +): m / z 401 (M + H) 〇Coupling Example 20 7- [3- (1-Amino-2-cyano-ethyl) -σ ratio slightly bite-1-yl] -1- Preparation of cyclopropyl-6-fluoro-8-10 alkoxy-4-side oxygen-1,4-dihydro · σcharin-3-brasic acid

Α 7- [3- (1-tert-butoxycarbonylamino-2-cyano-ethyl) -pyrrolidin-1-yl] -1-¾propyl-6-air-8-lactone Benzyl-4-lanthoxy-amidine, 4-diazepine-linolenic acid

15 (2-cyano-1 ^ pyrrolidinyl-ethyl) -carbamic acid tert-butyl ester in acetonitrile (5 ml) (63 mg, 0.26 mmol) and μcyclopropyl -6,7-difluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid difluoroborate (86 mg, 0.25 mmol), Triethylamine (127 mg, 1.25 mmol) was added and the solution was heated at 50 ° C for 22 hours. The solution was concentrated in vacuo. This residue was added to ethanol (5 ml) and triethylamine (127 mg, 125 mmol) and the mixture was heated at 80 ° C for 6 hours. Remove the solvent in vacuum. The residue was mixed in chloroform (50 ml), washed with a saturated aqueous ammonium chloride solution (50 ml), dried over MgS04 and concentrated in vacuo. The crude product was purified on a 105 g silica gel column and was stripped with 0 to 8% methanol in dichloromethane for more than 1 hour to provide 39 mg of the title compound (yield: 30%). MS (APCI +): m / z 515 (M + H) 〇 ·· 7- [3- (1_Amino_2_cyano-ethyl) pyrrolidin + yl] _ 丨 _cyclopropyl_6_ Fluoro-8-fluorenyloxy-4-lateral oxygen

7- [3- (1-tert-butoxycarbonylamino-2-cyano-ethylpyridin-1-yl] -1-cyclopropylfluoro_ in digas methane (5 ml) To a solution of 8-fluorenyloxy_4_ pendant oxygen-1,4 · dihydro-caine-3-carboxylic acid (39 mg, 0.08 mmol), 10% by weight of HC1 in ethanol was added. Solution (0.5 ml), and the solution was stirred at room temperature for 15 hours for 30 hours. The solvent was removed in vacuo. The yellow solid was slurried in ethyl acetate and digasmethane, collected by vacuum filtration and extracted with ethyl acetate. Rinse. Dry the bright yellow solid in vacuo to provide 19 mg of the title compound as the hydrochloride salt (85% parent compound, yield 51%). MS (APCI +): m / z415 (M + H ). 20 Coupling Example 21 (Shi) -7- [3_ (1-Amino_2_isocyanoethyl X-Small Group) Small Cyclopropyl Group &amp; 161 200524930 Fluorenyl-4- pendant oxygen-1 Of Sodium 4-Dihydropyridoline-3-carboxylate

A · (Shishi)-1-J-propyl-6-gas- 7- {3- [2-Isopropyl-l- (2,2,2-digasethylamino) -ethyl] -p 丫 ϋ 旦 -1 -yl} -8-methyl-4_ lateral milk-1,4_dirat ° quelin-3_ 5 carboxylic acid

1-Cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-pyridinoline-3 · carboxylic acid in dimethyl sulfene (3 ml) Difluoroborate (230 mg, 0.703 mmol), N-II-azul-3-yl) -2 · cyanoethyl] -2,2,2-trifluoroacetamide hydrochloride 10 (326 mg , 1.27 mmoles) and diisopropylethylamine (0.613 ml, 3.52 mmoles) were heated at 80 ° C. for 12 hours. The solution was cooled to room temperature and diluted with ethanol (15 mL), and then triethylamine (0.687 mL, 4.93 mmol) was added. The resulting solution was then heated to reflux for 3.5 hours. Remove the solvent under reduced pressure. The residue thus obtained was dissolved in methane (100 milliliters, 15 liters), and the resulting solution was washed with a saturated aqueous ammonium chloride solution (20 ml). The layers were separated and the organic layer was dried (sulfuric acid), transitioned and concentrated under reduced pressure. The resulting yellow residue was dissolved in ethyl acetate (5 ml). After a few minutes at ambient temperature, some precipitates started to appear. Hexanes (1 162 200524930 ml) were slowly added, followed by digas methane (1 ml) and then hexanes (3 ml) to give π mg (51%) of the title compound. LC / MS (APCI) (M + 1) / z 481.2. B. (Shi) -7- [3- (1-Amino-2-isocyanoethyl) _azepine. Denier]] cyclocyclo-6-fluoro-8-methyl-4-lanthoxy-1,4 · dihydronaphthoic acid

A saturated aqueous solution of sodium carbonate (3 ml) was added to 1-cyclopropyl_6_fluoro_7_ {3- [2_isocyano] in a mixture of methanol: water (5 ml·L · 2.5¾L) -l- (2,2,2-difluoroethenylamino) -ethyl] _acryldenyl group 丨 _ 8-fluorenyl side 10 oxodihydroxoline-3-carboxylic acid (134 Mg, 0.279 mmol) suspension. The mixture was then heated at 70 C for 5 hours. The methanol was then removed under reduced pressure to provide a solution. Then, the resulting solution was directly loaded on a reverse column and purified by medium pressure liquid chromatography, and was eluted with a water: acetonitrile gradient (99: 1 to 50:50) to produce a yellow solid. The frontal body was dissolved in water with a minimum of I5ϊ and cooled; dried to yield 73 mg of the title compound of Calyx. φ LC / MS (APCI) (M + 1) / z 385.2 〇Coupling example 22. h3- (2-cyanoberinoamido-ethyl ratio's 小 small group _3_methyl · -6 -Pendant oxygen-2,3-dihydro-6H-1-hum-3a-acrylic acid

163 20 200524930 Α 9- {3- [1- (Secondary butoxy domain group-fluorenyl-amino group) -2-muryl-ethyl] -pyrrolidin-1-yl} -8- Fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1- 噚 -3a_acyl- 葩 -5-carboxylic acid

5 of 2 (15 ¾ liters) of (2-Alkyl-1-17 Billot 17-D-3-yl-ethyl) -A

-Butylaminocarbamate (372 mg, 1.47 mmol) and 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6Η-1- 噚- To a solution of 3a-acridyl-5-carboxylic acid difluoroborate (411 mg, 1.25 mmol), triethylamine (632 mg, 6.25 mmol) was added, and the solution was heated at 50 ° C 24 hours. The solution was concentrated in vacuo. The residue was mixed with ethanol (8 ml) and dioxane (8 ml) and heated at 80 ° C for 5 hours. The solution was concentrated in vacuo. The residue was mixed in aeroform (50 ml), washed with a saturated aqueous ammonium chloride solution (50 ml), dried over MgS04 and concentrated in vacuo. The crude product was purified on a 40 g silica gel column and stripped with 0 to 6% methanol in dichloromethane for more than 1 15 hours to provide 528 mg of 9- {3- [1- (tertiary butane) Oxycarbonyl-methyl-amino) -2-amino-ethyl] -〇bilol-1-yl} -8-gas-3-methyl-6-oxo 1_2,3-dihydro- 6H-1- 唠 -3a-acyl- 葩 -5-carboxylic acid, as the hydrochloride (yield: 82%). MS (APCI +) m / z 515 (M + H). Β 9- [3- (2-oxy-1-fluorenylamino-ethyl) -σbilobit-1-yl] -8-qi-3-methyl20-yl-6- pendant oxygen-2 , 3-dihydro-6Η-1- 噚 -3a-acyl- 葩 -5-carboxylic acid hydrochloride 164 200524930

9- {3- [1- (tertiary butoxycarbonyl-methyl-amino) -2-oxanyl-ethyl]-in dichloromethane (10 ml). Billot sigma-1 -yl} -8 -gas-3-methyl-6-lateral milk-2,3-dihydro-6 氢 -1-hum-3a-acyl- 葩 -5-carboxylic acid hydrochloride (143 mg, 0.28 5 mmol), 4N HC1 (1 ml) in Ershan Shan was added and the solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The yellow solid was slurried in methane and ethyl acetate, collected by vacuum filtration, rinsed with ethyl acetate and dried under high vacuum (about 0.5 Torr) overnight to provide 109 mg of the title compound as Hydrochloride (yield: 95% hMS (APCI +): 10 m / z415 (M + H). Coupling Example 23 7- [3 (R)-(2-cyano-1 (S) -fluorenylamine -Ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid preparation

15 A. 7- {3- [1- (Tertiary butoxycarbonyl-methyl-amino) -2-cyanoethyl] -pyrolodenidine-1 -yl} -1-¾propyl -6-Disorder-8-methoxy-4-p-oxo-1,4-dimurine-3-weiric acid 165 200524930

(2 · cyano] "ratio in acetonitrile (8 liters) slightly bite each group_ethyl) _methyl_aminocarbamic acid secondary butyl ester (isomer B2) (345 g, 136 mmol Mol) with 1-¼propyl-6,7-difluoro-8-methoxy-4- pendant oxygen-fluorene, 4-dihydro-pyridoline-3-carboxylic acid 5 difluoroborate (377 To a solution of 1 mg, 1.10 mmol, triethylamine (557 mg, 5.50 mmol) was added, and the solution was heated at 50 t for 4 hours. The solution was concentrated in vacuo. The residue was added with 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 mixed in chloroform (50 ml), washed with a saturated 10% aqueous solution of gasified ammonium (50 ml), dried over MgSCU and concentrated in vacuo. The crude product was purified in a 40 g silica gel column and was stripped with methanol from 0 to 6% in dioxane for more than one hour to provide 459 mg of the title compound (yield: 79%). MS (APCI +): m / z 529 (M + H) 〇 ·· 7- [3- (2-cyano small methylamino-ethyl) biruoline_ι_yl] _ι_cyclopropyl 15 _6ϋmethoxy-4 · lateral oxygen-1,4-dihydroquinoline-3-carboxylic acid 166 200524930

7- {3- [1- (tertiary butoxycarbonyl-methyl-amino) -2-cyano-ethyl] _pyrrolidine_1_ylb in digas methylbenzene (20 ml) ^ Cyclopropyl-6-fluoro-8-methoxy-4-pentoxy-1,4-dihydro_σquinoline-3-carboxylic acid (459 mg, 0.87 mmol) in solution 5, A 4M HC1 solution (2.2 ml) in Ershan Sigma was added, and the solution was 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 in vacuo to provide 458 mg of the title compound as the hydrochloride salt (80% parent compound, yield: 98%). 10 MS (APCI +): m / z 429 (M + H). Coupling Example 24 7- {3-[(2-Aryl-ethylamino) -methyl] -11 to 11 each 11- 1-yl} -1-cyclopropyl-6-fluoro-8 &quot; Of phenyl-4- pendant oxygen-1,4-dihydro-π quinine-3-carboxylic acid

7- (3-Aminofluorenyl-pyrrolidin_1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-fluoroline- 3-carboxylic acid (乂 MW. C / zem 1993, 36, 871-882) (0.098 g, 0.232 mmol) was mixed with methanol (12 ml) and filled with acrylonitrile (0.016 ml). After 2 days, the solution was concentrated to give 100 mg of the title compound (yield: 98%). MS (APCI +): m / z 167 200524930 429 (M + H). Coupling Example 25 7- {3- [l- (2-cyano-ethylamino) _ethyl] _pyrrolidine small group M-cyclopropyl-6-fluoro-8-methoxy-4- Preparation of pendant oxygen-1,4-dihydro-quinoline-3-carboxylic acid

7- [3- (1-Aminoethyl) -pyrrolidine small group] small cyclopropyl-6-fluoro-8-methoxy_4_ pendant oxygen-1,4-dihydro · pirin- 3-carboxylic acid (WO 9209596 A1, 1992 K 0.4011 g, 1.03 mmol) was mixed in methanol (50 ml). Triethylamine (0.14 ml) was charged into the resulting solution to convert in situ to the free base. After 10 minutes, propylene chloride (0.1 ml) was charged to the reaction. Another equivalent of triethylamine (0.15 ml) and acrylonitrile (0.1 ml) were added. After another 12 hours, the reaction was concentrated. The crude product (2 to 15% gradient isopropanol / digasmethane) was chromatographed to yield 101 mg of PF-00646714_00 (yield: 22%). MS (APCI +) · m / z 443 (M + H). 15 Coupling Example 26 7- {3-[(2-Gasyl-ethylamino) -methyl]-° ratio slightly π-determined_1_yl} _1_cyclopropyl-6-fluoro-8-methoxy Of phenyl_4_ pendant oxygen-1,4-dihydro-linophilic acid

A. 7- [3- (tertiary butoxycarbonylamino-methyl) _pyrrolidine + yl] _; μcyclopropyl 20- 6-fluoromethoxy side oxygen-1,4-difluorene -Jin Lin—3-carboxylic acid difluoroborate 168 200524930

Filling monoethylamine (0.45 liters) with cyclodioxoyl dioxyhydroxanthoxyl from dihydrodihydrofluoric acid difluoroxanthine (Yg, 嶋 mmol) and (R) ratio slightly Pyridyl-3-ylmethyl-aminocarboxylic acid tert-butyl vinegar (mi g · 60 mmol) and acetonitrile (3 ml) order. After 24 hours, the solution was concentrated to produce 276 mg of the title compound (yield: 90%). MS (APCI +) m / z 524 (M + H) 〇 B. 7- [3- (tertiary butoxyepiamino-methyl ratio slightly smaller group) small cyclopropyl-6-gas-8 -Methoxy_4_ side oxygen from: hydrogen_linoleic acid

Put H3- (tertiary butoxylinamino_methyl) _tqqqqqqqq] small cyclopropyl-6 | 8 · oxo pin ⑸ red hydrogen driving acid digas vinegar (0.274 g, 0.523 MM) was mixed with ethanol (5 ml) and filled with triethylamine (0.4 ml). The resulting red solution was heated to room temperature. The reaction was concentrated after 6 hours and 15 minutes to yield 231 mg of the title compound (yield: 92%). MS (APCI +) m / z 476 (M + H). C. 7-aminomethyl groups (each small group) · κ ring two groups heptadeca · 8 · methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid 169 200524930

2N HCI / ether _ CH2CI2

7- [3_ (tertiary butoxycarbonylamino · methyl> pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy_4_ pendant oxygen_; ι , 4-Dihydro · pyridoline_3-carboxylic acid ((U98 g '0.416 mmol) was mixed in dichloromethane (5 ml) and charged with a2NhC1 / 5 ether (3 ml). The resulting product was stirred The solution was for 2 hours. The solvent was decanted to obtain 147 mg of the title compound (yield: 93%). MS (APCI +) m / z 376 (M + H). D · 7- {3 _ [(2-cyano "Ethylamino) -methyl] -pyrrolidine small group} Cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-linolenic acid

7- (3-Aminomethyl-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-fluorenyl-4-lanthoxy-M-dihydro-phosphon-3- A carboxylic acid (0.1995 g, 0.471 mmol) was mixed in methanol (25 ml) and filled with triethylamine (0.07 ml) to provide a free assay. Acrylonitrile (0.05 ml) was then charged to the reaction. After 20 hours, the reaction was concentrated to yield 162 mg of the title compound (yield: 80 ° / °). MS (APCI +) 429 (M + H) 〇Coupling Example 27 7- [1- (2-cyano-ethylamino) _5_azepine-spiro [2 · 4] heptyl 1.1-cyclopropyl- Preparation of 6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro- ° charin-3-brothermic acid 200524930

7- (1-Amino-5-//-spiro [2 · 4] hept-5-yl) -1-cyclopropyl-6_ι_8 · methoxy-4- pendant oxygen-1,4-di Hydrogen-quinoline-3-carboxylic acid (European Patent Application No. 550016A1, im) (0.140 g, 0.361 mmol) was mixed with methanol (3 ml) 5 and filled with triethylamine (0.5 ml). After 5 minutes, acrylonitrile (0.1 ml) was charged to the reaction. After 12 hours, the reaction was concentrated. The crude product (M0% methanol / dichloromethane) was chromatographed to give 102 mg of the title compound (yield: 610/0) MS (APCI +) m / z 441 (M + H). Coupling Example 28 107- [1- (2-cyano-ethylamino) -5-acyl-spiro [2.4] hept-5-yl] cyclocyclo-6-fluoro-8-fluorenyl- Preparation of 4-lanthoxy-1,4-dihydro-pirin-3-weilic acid

7- (3-Aminomethyl- ° ratio σ each fluoren-1-yl) -1 cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro -Linolin-3-carboxylic acid (J · M ^ / · CT ^ m · 1993, 36, 15 871-882) (0.1510 g, 0.400 mmol) mixed with formazan in a microwave vial

Alcohol (1 ml) and filled with 2-butenenitrile (0.1 ml). The reaction was allowed to microwave again at 160 ° C for 25 minutes. The reaction was concentrated and purified by column chromatography (2-15% methanol / dichloromethane) to obtain 47 mg of the title compound (yield: 26%). MS (APCI +) m / z 443 (M + H). 20 Coupling Example 29 171 200524930 7- [3- (2-cyano-ethylamino) -pyrrolidin-1-yl] small cyclopropyl-6-fluoro each methoxy-4- pendant oxygen-1, Preparation of 4-dihydro-phosphonium · 3-carboxylic acid

7- (3-Amino-pyrrolidin-yl) -1-cyclopropyl-6-fluoro-8-fluorenyl-4-5 pendant oxygen-1,4-dihydro-σ quinine gallic acid (J. Me./. CAem. 1993, 36, 871-882) (0.4955 g, 1.37 mmol) were mixed in methanol (50 ml). Acrylonitrile (0.1 ml) was charged into the resulting suspension. 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 obtain 550 mg of the title compound (yield: 95%). 10 MS (APCI +) m / z 415 (M + H). C. Pharmaceutical Formulations The following elucidates typical pharmaceutical dosage forms comprising a compound of Formula I ("Inventive Compound"), which can be used in humans for treatment or prevention. ⑴ Lozenges_mg / Lozenges 6 Invention compound 25 ^ 0 Lactose 50.0 Maize powder (for mixing) 10.0 Maize powder (paste) 10.0 Magnesium stearate (1%) 3.0 300.0 The compound of the present invention, Mix lactose and maize flour (for mixing) evenly for 15 minutes. The maize powder (for paste) was suspended in 200 ml of water and stirred with heating to form a paste. The paste is used to granulate the mixed powder. The wet granules were passed through a No. 8 hand sieve and dried at 80 ° C. Lubricate the dry granules with 1% stearic acid 172 200524930 and press into tablets. This lozenge can be administered to humans one to four times a day and it can be used to treat diseases caused by bacterial infections. ⑼ Lozenge mg / capsule 'Inventive Compound' 10.0 Colloidal Silicon Dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium Stearate (1%) 3.0 600.0 (iii) Preparation of oral solution 'Inventive Compound' 400 mg Sorbose Alcohol solution (70% NF) 40 ml sodium benzoate 20 mg saccharin 5 mg cherry seasoning 20 mg distilled water q. S · 100 ml Add sorbitol solution to 40 ml distilled water and dissolve the compound of the invention 5 in among them. Add saccharin, sodium benzoate, seasonings and dyes and dissolve. The volume was adjusted to 100 ml with distilled water. Each milliliter of syrup contains 4 mg of the compound of the invention. (iv) Parenteral solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 10 g of the inventive compound was suspended. After the suspension was completed, the pH was adjusted to 6.5 with 1N hydrochloric acid, and the volume was made to 1000 ml with water for injection. The formulation was sterile and filled into 5.0 ml ampoules (each containing 2.0 ml) and sealed under nitrogen. 200524930 (V) Injection 1 (1 mg / ml) Amount of 'Inventive Compound' 1.0 Sodium Sodium Diacetate 12.0 Sodium Sodium Monophosphate 0.7 Sodium Chloride N Sodium Hydrochloride Solution (pH adjusted to 4.5 r \ C 7.0-7.5) q · is · Water for injection qs ad 1 ml (Vi) Injection 2 (10 mg / ml) Amount of 'Inventive Compound' 10.0 Sodium dibasic phosphate 1.1 Sodium monobasic phosphate 0.3 Polyethylene glycol (polyethylene glycol) 400 200.0 N Hydrogen acid Solution (pH adjusted to 7.0-7.5) qs water for injection qs ad 1 ml (vii) injection 2 (10 mg / ml) amount 'inventive compound' 20.0 oleic acid 10.0 trigas monofluoromethane 5000.0 digas difluoromethane 10,000.0 2 All the patents and patent documents of chlorotetrafluoroethane 5000.0 are hereby incorporated herein by reference, as if 5 were individually incorporated herein by reference. The present invention and its manufacturing and use methods and methods are now described in this complete, clear, concise and precise name so that anyone skilled in the relevant art can manufacture and use it. It should be understood that the foregoing describes the preferred specific embodiments of the present invention, and modifications can be made therein without departing from the spirit or scope of the present invention as proposed in the scope of the patent application. In order to specifically point out and clearly claim the subject matter related to the present invention, the following patent application scope may make the final decision on this patent specification. 174 200524930

L diagram brief description I (none) [Description of main component symbols]

(None) 175

Claims (1)

200524930 10. Scope of patent application: 1. A compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein: X may be N or C ′ with the limitation that when X is n, there is no R5 at this position; Ri may be (CrC6) alkyl, dentyl &amp; pinane (C3_C6) cycloalkyl, halo (crC6) cycloalkyl, heterocyclic, aryl, heteroaryl, and CH2 (CrC6) cycloalkyl; 10 15 20 R2 can be OH, OBF2, 0 (Cl_c6) Alkyl, 0 (C3_C6) cycloalkyl; 0 0-(CHFWfO JLQR2b, where m is an integer from i to J 〇; Q is 〇 or NH or N (CrC6) alkyl or lack thereof; and 1 ^ is 11 or (( ^ (: 6) alkyl and Ra are (Ci-C6) alkyl, aryl, or heteroaryl; 0- (CHR2a) nY, where Rh is as defined above; n is an integer from 2 to 10; Υ is 0Η or NR ^ Rw, where ruler 2. and ruler each may be independently Η, (CrC0) alkyl or (C3-C6) cycloalkyl; or NR] a 'where R2a is as defined above;-(chr2 «Wh 吣 ^, where" ~~~ "refers to the connection position, 2a is as defined above; each of URv can be independently H or (Ci-C6) alkyl 'or connected to carbon to form a 3 1, 4, member 176 200524930 substituted or unsubstituted ring; e is an integer from 1 to 10, and p is an integer from 2 to 10; XjuYi each may be independently NH or 0; 5 10 15 R3, R4, and R5 may each be independently Η, OH, halo, NRyRz (where Ry &amp; Rz may each be independently η or ( CrC6) alkyl), (Cl_C6) alkyl, haloxyl, o (Cl-C6) alkyl, o (CrC6) haloalkyl, nitrile; Ri and R5 are linked with carbon to form a substituted or unsubstituted A substituted 5 or 6-membered substituted or unsubstituted ring, which includes 0, 1 or 2 heteroatoms selected from 0, 3, 30, 30, or 2, where 1 is 11 or (( : 1-0: 6) Alkyl; and BV): R • Say A is Bao ~, B%, or, where 2 is 0, 1 or 2 and q is 0, 1, 2 or 3; RARb each Each may be H, (CrC6) alkyl, (CrC6) alkyloxy, alkynyl (Ci_C6) alkyl, or _yl; or Ra and Rb are linked to carbon to form 00, C = NO (CrC6) Alkyl or a 3, 4, 5, or 6-membered substituted or unsubstituted member, R ', R ,, R' ", and R" "may each independently be H, alkyl, -0 (CrC6) alkyl, halo (CrC6) alkyl, aryl or heteroaryl A 20 The limitation is when B is Or 177 200524930 When R ′ is not -〇 (Ci_c6) alkyl, and "~~~" in the above means the connection position; each of Rc & Rd can be independently H, (CrC6) alkyl nitrile; 〇0 -f- OH — ^ 0 ((ν〇6> alkyl0Η, 〇 (CVC6> alkyl), (CrC6) alkyl, (C3-C6) cycloalkyl, heteroaryl, S02- (Ci_C6) alkyl, S〇2_aryl, S〇2-heterocyclyl '一 (CR2aR2a') 〇—〇 ″ —QR2b, where g is an integer from 1 to 10; Q is as defined above; and R2a and R2a, each of which can be Independently fluorene or (Ci_C6) alkyl, or linked to carbon to form a 3, 4, 5, or 6-membered substituted or unsubstituted bad, and R2b is (Cl_C6) alkyl, aryl, or heterocyclic Square base '0 0 (CR2aR2a.) F0-Beiyi (0H &gt; 2 or (CR2aR2a) g—0-1 ^ (0 (0 ^ -06) Hyunji &gt; 2, where R2a &amp; R2a, as above definition; R2c, where "~~~" refers to the attachment position, p is 0 or 1; and R2c is fluorene, (Q-C6) alkyl, 0 (CrC6) alkyl, (c3-c7) cyclohexyl, aromatic Group, heterocyclic group, heteroaryl group; or — (CHR2a) h-0 QR2b or — (CHR2a) factory, wherein R2a, R2b and Q are as defined above; and each of h and j may be an integer independently of each other 0 to 10; and Y is OH, 0P0 (0H) 2, 0P0 (0 (CrC6)) 2, or NR2dR2e ', wherein each of R2d and R2e may be independently Η, (CrC6) alkyl, or 178 200524930 (c3- c7) cycloalkyl; Each of Re and Rf may be H, CrQ wire, gibase, or tooth base; or RARf and carbon are connected at __ to form a 3, 4, 5, or 6-membered substituted or unsubstituted ring; 10 Each of the heart and the heart may be independently H, Ci_C6, alkynyl, or "radical," or linked to carbon to form -3, 4, 5, or ㈣ unsubstituted rings; and Rj and Rk each Each may be independently H, (Ci_C6) alkyl, alkynyl, (Q-C6) alkyl-NRcRd, (CVC6) alkyl-〇Rc, aryl, heteroaryl0, heterocyclic, (CrC6 ) Alkyl "I-Z-Rd, where 2; is 0 or take. Ge Rj and Rk are linked to the carbon to form a 3, 4, 5 or 6-member substituted ring. 2. The compound according to item 1 of the scope of patent application, wherein X is C or N; Ri is a (Ci-C6) ring alkyl group and a (crC6) ring alkyl group, an arylaryl group; R3 is fluorene or NH2; 179 200524930 R4 is fluorene or halo; R5 is halo, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, when X is C. 3. For the compound in the second item of the patent application, where X is C or N; 1 is cyclopropyl or fluorocyclopropyl; R3 is fluorene or NH2; R4 is fluorene or F; R5 is halo, fluorenyl or Methoxy. 10 4. For the compound in the scope of patent application item 1, wherein &amp;, R3 and R5 can have the structure provided below; and R2 can be OH, OBF2 or 0 (CrC6) 180 200524930 181 200524930 5. The compound according to item 1 in the scope of patent application, wherein: when 2 or 3, when q is 2 or 3, ζ is 0,; 1, 2; or when q is 0, 1 or 2; 5 heart And Rb may be independently selected from the group consisting of fluorene, methylol: methyl, trifluoromethyl, fluoroethyl, methoxy, di: yl, or: carbon is linked together to form a cyclopropyl ring; / 尺 〃 ', Each of ", ruler" and "" may be independently ^, fluorine, subgroup, ethyl, ethyl, fluoroethyl, phenyl, benzyl, or foxy; 182 200524930 Rc and Rd each Each may be independently fluorene, methyl, or ethyl; each of Re and Rf may be each independently fluorene, methyl, or ethyl; Rg &amp; Rh each may be each independently fluorene, methyl, ethyl, fluorine Methyl, difluorofluorenyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl, carboxyethyl or ^ NHMe, or linked to carbon to form △; and Rj and Rk may each independently be fluorene, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, Carboxymethyl, carboxyethyl, or ΙνθΜθ, or linked together to form Δ. 10 6. The compound according to item 1 of the scope of patent application, wherein eight is Ra Rb and z is 0, 1 or 2, which can be selected from the group consisting of: 183 200524930 Or "---" means the connection position; or A is Rb, where z is 0, 1 or 2 and q is 0, 1, 2 or 3, which can be selected from the group consisting of: Where "~~~" refers to the connection position. 7. For the compound in the scope of patent application No. 6 or 7, where B is Re Rf Rc, NC Rfv / Re RR., N or Rf Re and may be selected from The following groups: NC Η Η NC, ^^ n, Me NC, ^ \ NC, ^ \ NC, / \ N H 184 200524930 Me Me NC ^ .r Me Et NC, / \ f »NCv ^^ N ^ S NC \ ^ \: 乂% NC Et FFH NC, H Me NC ^ \ J ^ NC ^ / ^ nx &lt; J NC, a YR = H, (C1-Ce &gt; alkyl Η H, NHR R = H, (CrC6) alkyl is called NHMe y,. OMe OMe NC, ^ \ Wherein "~~~" refers to the linking position mr ^ 8. The compound as claimed in item 6 of the scope of patent application, wherein the male Rb may be selected from the group consisting of: RHN's, ^ RHN I'n—Μθ〇. RHN RHN N RHN o RHN Fly, NT Me F F RHNT Rr〇 Me Eight NT, R &quot; N RHN, RHN RHN〆 RHN- RHN 185 200524930 RHN- RHN- RHN RHN〆 RHNF3c ^ ~ y RHN &quot; RHN F, RHN〆 RHN RHN〆 F3CwF RHN F3C, RHN H ~ Ov RHN &quot; RHN &quot; R, if RHN &quot; RHN RHN RHN Me. , RHN &quot; RHN &quot; RHN RHN RHN RHN-Me, RHN RH &gt; RHN ^ X &gt; RHNT RHN RHN H2N RHN RHN RHN : y &gt; RHN RHN F Me RHN Me RHN Wherein R is CH2CH2CN and "~~~" in it refers to the connection position. 9. The compound according to item 6 of the patent application, wherein Ra ^ Rb may be selected from the group consisting of: 186 200524930 Wherein R is CH2CN, and "~~~" means the connection position. 10. The compound according to item 6 of the scope of patent application, which can be selected from the group consisting of: Among them, R &amp; CH2CH2CN, and "~~~" in it refers to the connection position. pv R \ /-N ^ 11. If the compound in the 6th scope of the patent application, &quot; HqRb or 187 200524930 Wherein Rc may be fluorene or (CVC6) alkyl; R is CH2CN, and "~~~" in this refers to the position of attachment. 5 12. The compound according to item 1 of the patent application scope may be a compound of formula II, III, IV, V or VI. 188 200524930 13. —A compound, which is: 7- [3- (2-Quanyl-ethylamino) -π Billot sigma-1 -yl] -1-propyl-6-6 -Methoxy-4- pendant oxygen-1,4-diaze-17 quelin-3-weiric acid; 7- [3- (2-aryl-ethylamino) -11 ratio slightly 11-1 -Yl] -1-cyclopropyl-6-5 fluoro-8-methyl-4- pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid; {3-[(2-Gasyl- (Ethyl) -methyl-amino] -0-Bilobit-1-yl} -1-cyclopropyl-6-air-8-fluorenyl-4-oxo-1,4-dimur-17 Quinine-3-endoic acid; 7- {3-[(2-amino-ethyl) -fluorenyl-amino] -0 bilobit-1-yl} -1-cyclopropyl-6-fluoro -8-methyl-4-oxo-1,4-dihydro-pyridin-3-carboxylic acid; 10 7- [3- (2-cyano-ethylamino) -pyrrolidin-1 · yl ] -1-Cyclopropyl-8-methyl-4-oxo-1,4-difluorene-phosphonium-3-carboxylic acid; 7- {3-[(2-lactyl-ethyl) -formaldehyde -Amino group] -lacloridine-1-yl} -1 ?? propyl-8-methyllactyl-4-lateral lactam-1,4-dimurine-sigmaine-3_weilic acid, 7-{3-[(2-Amino-ethyl) -fluorenyl-amino] biloxo 17d-1-yl} -1-5 an 15 propyl-8-methyl-4- pendant oxygen- 1,4-dimurine ^ -3-conjudic acid, 9- [3- (2-nitro-ethylamino) -cyclofluorenyl] -8-qi-3 -methyl-6-oxo -2,3-dihydro-6 1- 噚 3a-acyl- 葩 -5-carboxylic acid; 9- {3-[(2-cyano-ethyl) -methyl-amino] -cyclopentyl} -8-fluoro-3-methyl 6-6 pendant oxygen-2,3-dihydro-6H-1- 噚 3a-acyl- 葩 -5-carboxylic acid; 20 7- {3-[(2-amino-ethylamino)-曱Yl] -11 bilodine-1 -yl} -1-tilnyl-6-lactam-8-methoxy-4-lanthene-1,4-diazine-11 quinine-3-weilic acid , 7-{3R-[(2-Gasyl-ethylamino) -fluorenyl] -11 to 17 each 1-1-yl} -1_cyclopropyl-6-Ga-8-methoxy-4 -Pendant oxygen-1,4-diazepine-calycin-3-weilic acid, 7-{3-[(2-Gasyl-ethylamino) -fluorenyl] ratio sigma-1-yl}- 1-Cycle 189 200524930 Propyl-6-Ga-8-Methyl-4-Pancolate-1,4-Dirhamoleline-3-Conc acid; 7- (3-{[(2-Gasyl-B Group) -methyl-amino group] -methyl} -σ ratio slightly bitten-1_ group) -1-¾propyl-6-air-8-methoxy-4- pendant oxygen-1,4-dirat -Scare ^ -3-Junic acid; 5 7- (3-{[(2-cyano-ethyl) -methyl-amino] -fluorenyl} -pyrrolidin-1-yl) -1-¾ Propyl-6-air-8-fluorenyl-4-oxo-1,4-diazepine-linolenic acid; 7- {3- [1- (2-airyl-ethylamino) ) -Ethyl] · σ Bilopidine-1 -yl} -1 _ cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3- Carboxylic acid; 10 7- {3- [1- (2- -Ethylamino) -ethyl] -σBiloxσ-1 -yl} -1 _ cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro- Pyridin-3-carboxylic acid; 7- (3-{1-[(2 · muryl-ethyl) -fluorenyl-amino] -ethyl} -σbilobit-1-yl) -1- Cyclopropyl-6-gas-8-methoxy-4- pendant oxygen-1,4-dimurine-calycin-3-carboxylic acid; 15 7- (3- {1-[(2-lactyl- (Ethyl) -fluorenyl-amino] -ethyl} -11 Billofluorene-1 -yl) -1 -L-propyl-6-gas-8-methyl-4-oxo-1,4- Dimuridine-quinolinol-3-carboxylic acid; 7- {3-[(2-cyano-1-methyl-ethylamino) -methyl] -pyrrolidin-1-yl} -1- Cyclopropyl-6-air-8-fluorenyl-4-pendant oxygen-1,4_dimurine-σ quinine-3-end 20 acid; 7- {3-[(2-Amino-1-methyl -Ethylamino) -fluorenyl] -stilbene-1-yl} _1-cyclopropyl-6-fluoro-8-fluorenyl-4-oxo-1,4-dihydro-fluorin -3-carboxylic acid; 7- {3-[(2-Ranyl-ethylamino) -fluorenyl] -3-methylpyridine sigma-1-190 200524930 group} -1-cyclopropyl- 6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 7- {3-[(2-cyano-ethylamino) -methyl ] -3-Methyl-pyrrolidin-l-yl} -1 -cyclopropyl-6-air-8-methyl-4-lateral breast-1,4-dimurine-σQuulin-3-End 5 acid ; 7- (3-{[(2-Gasyl-ethyl) -methyl-amino] -methyl} -3-amidinobilopidine-1 -yl) -1-¾propyl-6 -Disorder-8-methyllactyl-4-lateral milk-1,4-diazaquine-3-carboxylic acid, 7- (3-{[(2-sulfanylethyl) -methyl-amino group ] -Methyl} -3-methyl- ° ratio 10 Lodin-1-yl) -1-¾propyl-6-ran-8-methyl-4-lateral milk-1,4-dimur-a Lynn-3-carboxylic acid; 7- {3- [1- (2-cyano-ethylamino) -cyclopropyl] -pyrrolidin-1-yl} -1-cyclopropyl-6-gas- 8-fluorenyl-4-lanthoxy-1,4-dimurine-πquinine-3-carboxylic acid; 15 7_ {3- [1- (2-cyano-ethylamino) -cyclopropyl ] -Pyrrolidin-1-yl} -1-cyclopropyl-6 · fluoro-8-methyl-4-oxo-1,4-dihydro-pyridin-3-carboxylic acid; 7- (3- {1-[(2-cyano-ethyl) -methyl-amino] -cyclopropyl} -pyrrole. N-l-yl) -1-cyclopropyl-8-methoxy-4- pendant oxygen-1,4-diazine-sigmaine-3-benzyl 20 acid; 7- (3- {1- [ (2-cyano-ethyl) -methyl-amino] -cyclopropylpropyridine-1 -yl) -1 -oxopropyl-6-air-8-methyl-4-lateral milk-1 , 4-Diazo-. Quizol-3-carboxylic acid; 7- {3- [2 · Ethylamino-1- (2-amino-ethylamino) -ethyl] · 11 Billot 191 200524930 1-1-yl } -1-5 ethylpropyl-6-fluoro-8-methoxy pendant oxygen ^, cardiodiazepine_phosphino-3-carboxylic acid; 7- {3- [2-ethylamidoamino-1- ( 2-cyano-ethylaminoethyl] -pyrrolidin-1-yl} _1-cyclopropyl-6-fluoro-8-fluorenyloxy side oxygen_ 丨, each dihydro_fluorene-5 morpholine-3_ Carboxylic acid; 7- (3- {2-acetamido-i-[(2-cyano-ethyl) _methyl_amino] _ethylpyrrolidin-1-yl) _1_cyclopropane -6-fluoro-8-methoxy-4_ pendant oxygen-L4-dihydro-pyridin-3-carboxylic acid; 7- (3- {2-ethylamino-i-[(2-cyano -Ethyl) -methyl-amino] -ethyl 10-yl) -pyrrolidinyl) -1-cyclopropyl-6-fluoro-8-methoxy-4 pendant oxygen-1,4-dihydro -Porphyrin-3-carboxylic acid; 7- {3-[(2-Gasyl-ethylamino) -methyl group 1-cyclopropyl-8-fluorenyl- 4 · Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid; 7- {3-[(2-Ranyl-ethylamino) -methyl] _. Billot bite} _1 _Ring 15 propyl-8-fluorenyl-4- pendant oxygen-l, 4-dihydroquinine-3-brasic acid; 7- (3-{[(2-cyanoethyl) -methyl- Amine] -methyl} -pyrrolidinyl) -1-cyclopropyl-8-methoxy-4- pendant oxygen-1, 4-dihydro-pirin-3-carboxylic acid; 7- (3 &quot; · [[(2-Gasyl-ethyl) -methyl-amino] -methylbiloxo-1-yl) -1 -¾-propyl-8-methyl-4-sacral-1,4-diazine-sigmaine-3-weilic acid; 20 7- {3- [1- (2-cyano-ethylamino) ) -Ethyl] • pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4- pendant oxygen-1,4-dihydro-quinoline-3_carboxylic acid; 7. · 3 -[1 · (2-cyano-ethylamino) -ethyl] -pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro Quinine-3-junic acid; 7- (3- {1-[(2-cyano-ethyl) -methyl-amino] _ethyl} _pyrrolidin 192 200524930-1-yl) -1- Cyclopropyl-8-fluorenyl-4-oxo-M-dihydro-quinoline-3-carboxylic acid; 7- (3- {1-[(2-cyano-ethyl) -methyl- Amine] _Ethylpyrrolidine-1-yl) -1-cyclopropyl-8-methyl-4- pendant oxygen-1,4-dihydro-linophil-3-carboxylic acid '5 7- { 3-[(2-cyano-ethylamino) -methyl] -3-methyl-pyrrolidin-1-yl} -1-cyclopropyl-8-fluorenyl-4-oxo-1 , 4-Difluorene · • pyridin-3-carboxylic acid; 7- {3-[(2-cyano-ethylamino) -methyl] -3-methyl-pyrrolidin-1-yl}- 1-Cyclopropyl-8-fluorenyl-4-oxo-1,4-dihydro-fluoroline-3-carboxylic acid; 7- (3-{[(2-cyano-ethyl) -methyl -Amine] -Amidib 3 -Methyl-pyridine-0-pyridin-1-yl) small cyclopropyl-8-fluorenyloxy-4- pendant oxygen-1,4-dihydro-quinoline-3-carboxylic acid; 7- (3- { [(2-cyano-ethyl) -fluorenyl-amino] -fluorenyl} -3-methylpyrrolidin-1-yl) -1-cyclopropyl-8-fluorenyl-4-oxo -1,4-dihydro-pyridoline-3-arsinic acid; 5 7- {3- [1- [2- (cyano-ethylamino) -cyclopropyl] · σbilobityl} -1 -Cyclopropyl-8-methoxy-4- pendant oxygen-1,4-dihydro-σquinine-3-weilic acid; 7- {3- [1- (2-cyano-ethylamino) ) -Cyclopropyl] _α than T7 each σ adenyl group 1-Cyclopropyl-8-methyl-4- pendant oxygen-1,4-dioxoquinine_3-weilic acid; 1-[(2-cyano-ethyl) -methyl, yl] _cyclopropyl} _pyridine ° ° small groups) -1-cyclopropyl-6-fluoro-8-fluorenyl-4 -Pendant oxygen_1,4_dihydro-pirin-3_carboxylic acid; 7_ {3- [2-ethylamido-1- (2-cyano-ethylamino) _ethyl] each bite Small group} -1-cyclopropyl-8-fluorenyl ice side oxygen_1,4_dihydro_σquinine_3, slow acid; 193 200524930 7- {3- [2-ethylamine-1 -(2-Gasyl-ethylamino) -ethyl] pyridine-1 -yl} -1 -pyrimidyl-8-methyl-4-lateral breast-1,4-dimur ► -3- Junic acid; 7- (3- {2-Ethylamino-1--1-((2-aryl-ethyl) -methyl · amino] -ethyl 5 Base}-. Biloxa stilbene-1 -yl) -1 -Bropropyl-8-pyrimidyl-4-side milk-1,4-diazepine_line_3_carboxylic acid; 7- (3- {2- Ethylamine-1-[(2-Gas-ethyl) -methyl-amino] -ethyl} -11 Billot bite-1 -yl) -1 -L-propylpropyl-8-methoxy Phenyl-4-lateral milk-1,4-dimur · pyridin-3-carboxylic acid; 10 7- [1- (2 · Ranyl-ethylamino) -5 -mouth-spiro [2.4] heptane -5-yl] -1 -badpropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 7- [1- (2- (Gas-ethylamino) -5-//-spiro [2.4] hept-5-yl] -1-¾propyl-6-gas-8-methyl-4-oxo-1,4-di N-quinine-3-weilic acid, 7- {3- [1- (2-Gasyl-ethylamino) -propyl] -methylol-1-yl} -1 -pyridine 15-propyl -6-fluoro-8-fluorenyl-4-lanthoxy-1,4-dihydro-phosphon-3-carboxylic acid; 7- {3- [1- (2-cyanoethylamino)- Propyl] -acyl. Dentan-1-yl} -1-cyclopropyl-6-gas-8-methyl-4-lanthoxy-1,4-dimurine-sigmaquine ►-3-contained acid, 7- (3- { 1-[(2-Gas-ethyl) -methyl-amino] -propyl} -port / 11denyl-1 · yl) -1-cyclopropyl-6-fluoro-8-fluorenyl- 4-oxo-1,4-dihydro-pyridoline-3-carboxylic acid 20; 7- (3- {1 _ [(2 · cyano-ethyl) -methyl-amino] -propyl}- Acryl-l-yl) -1 -oxopropyl-6-gas-8-methyl-4-lanthoxy-1,4 · dimurine-quinolin-3-weiric acid; 7- {3- [ 1- (2-Ranyl-ethylamino) -¾propyl] Yadan-1-yl} -1- 200524930 cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1 , 4-dihydro-pyridoline-3-carboxylic acid; 7- {3- [1- (2-Gasyl-ethylamino) -bad-propyl] -kouya aJL-1 -yl} -1 * Cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-diargon-pyridoline-3-carboxylic acid; 7_ (3- {1-[(2-aryl-ethyl) -Methyl-amino group] -¾propylpropanyl 5-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro -Porphyrin-3-carboxylic acid; 7- (3- {1-[(2-Gasyl-ethyl) -methyl-amino] -Linylpropylbutanyl-1-denyl-1 -yl)- 1-bad propyl-6-gas-8-methyl-4-pendant oxygen-1,4-dirat-11 quinine-3-carboxylic acid; 10 7- (3- {1-[(2-Ga -Ethyl) -ethyl- [] Yl] -badpropyl} -pyrolodin-1-yl) -1-cyclopropyl-8-fluorenyl-4-oxo-1,4-dihydro-fluorin-3-ylcarboxylic acid; 7- (3- {1-[(2-Gasyl-ethyl) -ethyl-amino] -pyroxypropyl} -σbiloden-1 -yl) -1 -pyroxypropyl-6 -Ga-8-methyl-4-lanthoxy-1,4-,-mouse-coquinone ^ 15-3-carboxylic acid; 7- (3- {2-ethylamino-1-[(2 -Lactyl-ethyl) -ethyl-amino] -ethyl} -u-bilol 11-deoxy-1-yl) -1-¾propylfluorenyl-4-oxo-1,4_dimo -Porphyrin-3-carboxylic acid; 7- (3- {2. Ethylamino-l-[(2-cyano-ethyl) -ethyl-amino] -ethyl 20-yl}-. Ratio. Amine-1 -yl) -1-propyl-8-fluorenyl-4-lanthoxy-1,4--murine-quinine-3-weiric acid, 7 · {3- [1- (2- Carbo-ethylamino) -propyl]-"yaldan-1 _yl} -1 -oxopropyl-6-say-8-methyl-4-oxo-1,4-dimurine Linthyl-3-weirate, 7- {3-[(2-lactyl-ethylamino) -methyl] -3-fluorenyl 200524930 group} -l-cyclopropyl-6-fluoro-8- Methyl-4- pendant oxygen-1,4-dihydroquineline-3 · sodium Wei; 7- {3- [1- (2-cyano-ethylamino) -cyclopropyl] -acyl. Dentanyl group _ propyl-6-fluoro-8-methyl-4- pendant oxygen-1,4-dihydro-σ-talin-3_carboxylic acid; 7- {3-[(2-cyano - Ethylamino) -methyl] -3-ethyl-butanol_yl_yl} _1_cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro_喳 琳 _3_ arsenic acid; 7- {3-[(2-cyano-ethylamino) -methyl] -3-ethyl-acryloyl} -1-phosphorimyl-6-fluoro- 8-methyl-4- pendant oxygen-1,4-dihydro-linophylline-3_acid; 9- {3-[(2-cyano-ethylamino) -methyl] -cyclopentyl Bu 8-fluoro_3_methyl-6-oxo-2,3-dihydro-6Η-1-hum-3a-acyl- 葩 -5-carboxylic acid; 9_ (3-{[(2-cyano -Ethyl) -methyl-amino] -fluorenyl} -cyclopentyl) _8_ gas &quot; * 3-methyl-6- pendant oxygen-2,3-diaza-6H-1-11 kwa-3a -p-γ-shielding-5-percarboxylic acid; 9- [3- (1-Amino-2 · cyano-ethyl) -pyrrolidin-1-yl] | Fluoro-3 · methyl-6-lateral oxygen -2,3-dihydro-6H_1-fluorene-3a-acyl-fluorene-5-carboxylic acid; 9- [3- (R)-(2-cyano-1_ (S) -methylamino-ethyl )-° Bihar 1 group> 8-fluoro-3- (S) -methyl-6-lateral oxygen_2,3_dihydro-6H-1- 噚 -Ya, absolute 5-quinic acid; 7- [3- (1-Amino_2-ranyl-ethyl) -0 than slightly bite-1-yl] -1, ring @ & -6-fluoro_4_ pendant oxygen_ι, 4-dihydro · Pyridinoline_3_carboxylic acid; 7- [3- (1-amino-2-cyano-ethyl) -σ than slightly σ-den-1-yl] -i_in-ring & -6-fluoro -4-lateral oxygen-fluorene, 4-dihydro- [1,8] naphthyridine-3- Acid; 7- [3- (1-amino-2-cyano-ethyl) -mandatory; slightly 17--1-yl ring meaning 196 200524930 6-fluoro_8_methoxy-4_ side Oxy-I, 4-dihydro-pyridoline-3-carboxylic acid; 7- [3- (1-Amino-2-cyano-ethyl) _pyrrolidine small group] small cyclopropyl-6-fluoro -8-fluorenyl-4-lateral oxygen · 1,4-dihydro-caine-3-weilic acid; 7- [3- (1-amino-2-cyano-ethyl) -π ratio slightly bite — 丨 ―yl] _ 丨 _cyclopropyl-8-methoxy ice side oxygen-1,4-dihydro-pyridinoline-3-chinic acid; 7- [3- (1-amino-2-cyano -Ethyl) -π Billow bite_ 丨 _yl] _ 丨 _cyclopropyl-8-methyl ice side oxygen-1,4-dihydro- ° quinine_3-acid; 5-amino -7 · [3_ (1-Amino_2_cyano_ethyl each octyl group) cyclopropyl-8-methoxy-4- pendant oxygen-1,4 · dihydro-uQuulin_3 • Acetic acid; 5-amino-7- [3- (1-amino-2-cyano-ethyl) _πbilodine_ι_yl] _ι_ cyclopropyl-8-methyl-4- pendant oxygen -1,4-dihydro-linophilic acid; 7- [3- (1-Amino-2-cyano-2,2-dimethylethyl) -σ is smaller than that of oxomethyl Cyclopropyl-6-fluoro-8-fluorenyloxy-4-lanthoxy], 4-dihydroquinine each acid, hydrazone 3- (1 -amino-2-cyano-2,2-difluorenyl -Ethyl &gt; pyrrolidine small group] -1-cyclopropyl-6-fluoro-8-methyl ice side -l, 4- dihydro-_. Quirin_3_acid; 7- [3- (1-amino-2-cyano-2,2-diamidino_ethyl &gt; pyrrolidine small group] -1-¼propyl-8- Methoxy-4 ·-pendant oxygen-1,4-dihydro-σ quinine ammonium acid; 7- [3- (1-amino-2-cyano-2,2-diamidino · ethyl) _Pyrrolidin-; 1-yl] -1-cyclopropyl-8-fluorenyl-4- pendant oxygen-1,4-dihydro-phosphorin acid; 5-amino-7- [3- (1- Amino-2-cyano-2,2-diamidino_ethyl) _pyrrolidinylpyridinium · cyclopropyl-8-methoxy-4- pendant oxygen-1,4_dihydro_Lin Each acid; 197 200524930 5-amino-7- [3- (l-amino-2-cyano-2,2-diamidino-ethyl) -pyrrole-1-yl] -1-ring Propyl_8_methyl-4-oxo-1,4-dihydrolin-3-dicarboxylic acid; 7- [3- (1-amino-2-cyano-ethyl) -pyrrolidine-1 -Yl] -1-cyclopropyl 5-6-fluoro-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 7- [3 · (2-muryl-1-methyl Amine-ethyl) "Bilo sigma-1-yl] _1-cyclopropyl-6-fluoro-4- pendant oxygen-1,4-dihydro-halin-3-weiric acid; 9- [3 -(2-cyano-1-methylamino-ethyl) -σ ratio υ each 唆 -1 · yl] -8-fluoro-3 · fluorenyl-6-oxo-2,3-dihydro- 6Η-1- 唠 -3a-azine 葩 -5-carboxylic acid; 109- [3 (R)-(2 · cyano-1 (S) -fluorenylamino-ethyl) -pyrrolidine -1_yl] -8-fluoro-3-fluorenyl-6-oxo-2,3-dihydro-6H-1-fluorene-3a-acyl-fluoren-5-carboxylic acid; 7_ [3- (2- Cyano-1-methylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthalene Pyridin-3-carboxylic acid; I5 7- [3- (2-Gasyl-1 -methylamino-ethyl ratio σ-Each-1-yl] -1-cyclopropyl-6-fluoro-8- Methoxy-4- pendant oxygen-1,4-dihydro-caine-3-carboxylic acid; 7- [3 (R)-(2-cyano-1 (S) -methylamino-ethyl ) Billot sigma-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-quinqueline-3-carboxylic acid; 20 7 -[3- (2-cyano-1-fluorenylaminoethyl) _π ratio υ each bit-1-yl] -1-cyclopropyl-6-fluoro-8-fluorenyl-4- pendant oxygen- 1,4-dihydrocharin_3_weilic acid; 7- [3- (2-cyano-1-fluorenylamino-ethyl) _σ ratio u each 1-1-yl] -1-cyclopropane -8-methoxy-4- pendant oxygen-1,4-dihydro-coline · 3-weilic acid; 7- [3- (2-cyano-1-fluorenylamino-ethyl)- σ ratio u each -l-yl] -1-ring 198 200524930 propyl-8-methyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 5 -amino-7 -[3- (2-Gasyl-1 -fluorenylamino-ethyl)-° than slightly fluorenyl-1 -yl] -1-cyclopropyl-8-methoxy-4- pendant oxygen-1, 4-dihydro-pyridoline-3-carboxylic acid; 5 -Amino-7- [3- (2-Gasyl-1 -fluorenylamino-ethyl) -11 Biloprotidine-1 _ 5yl] -1-cyclopropyl-8-methyl- 4-oxo-1,4-difluorene-pyridin-3-carboxylic acid; 7- [3- (2-cyano-2,2-dimethyl-1-methylamino-ethyl)- Pyrrolidin-1-yl] -l-hexanyl-6-gas-8-methoxy-4-lanthoxy-1,4-dimurine-σquinine-3-carboxylic acid; 7_ [3_ ( 2-cyano-2,2-difluorenyl-1 · methylamino-ethyl) -pyrrolidine 1〇-1 -yl] -1 -badpropyl-6-air-8-methyl-4 -Side milk-1,4_-one murine-Aquinine-3 · Acid acid; 7- [3- (2-cyano-2,2-dimethyl-1-methylamino-ethyl)- Pyrrolidin-1-yl] _1-cyclopropyl-8-fluorenyl-4-oxo-1,4-dihydro-fluorin-3-ylcarboxylic acid; 15 7- [3 · (2-cyano -2,2-Difluorenyl-1 · methylamino-ethyl) -pyrrolidin-1-yl] -1_cyclopropyl-8-fluorenyl-4-oxo-1,4-dihydro -. Quinine-3-acid, 5-amino-7- [3- (2-cyano-2,2-dimethyl-1-amidoamino-ethyl) -pyrrolidin-1-yl] 1-cyclopropyl-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 20 5-amino-7- [3- (2-cyano- 2,2-dimethyl small methylamino-ethyl) _pyrrolidin-1-yl] -1-cyclopropyl-8-fluorenyl-4-oxo-M-dihydrofluorin-3- Grade acid; 7_ [4 · (2-cyanoethylamino) -hexahydro-cyclopentyl [cpbilo-2-yl] -1-cyclopropyl-6-fluoro-8-fluorenyl-4- Pendant oxygen_1,4_dihydro &quot; · quinoline winter carboxylic acid; 199 200524930 7_ [4 · (2_cyano-ethylamino) hexahydro-cyclopenta [debilo_2_yl] Cyclopropyl-6_fluoro_8_methoxy-4- pendant oxygen-1,4-dihydro-pyridolinecarboxylic acid; 7 · [4- (2-cyano-ethylamino) · hexahydro -Cyclopentyl [Decoryl] 1 Cyclopropyl-8-methyl-4-oxo-1,4-dihydro-pyridin-3-carboxylic acid; 7_ [4- (2-cyano-ethyl Ylamino) -hexahydro-cyclopentyl [decapyr-2-yl] heptacyclopropyl-8 · fluorenyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid; 7_ [4- (1 -Amino-2-cyano-ethyl) -hexahydro-cyclopentyl Mpyrrole-I-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydro-pyridoline I carboxylic acid;! 〇7_ [4_ (1 · amino-2-cyano-ethyl -Hexahydro-cyclopentamidinepyrrole 1-yl H-cyclopropyl-6-fluoro-8-fluorenyl-4-lanthoxy-1,4-dihydro-fluorolinecarboxylic acid; 7_ [4 · (1- Amino-2-cyano-ethyl) -hexahydro-cyclopenta [c] pyrrole-2, H-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-pyridoline Each carboxylic acid; 15 7- [4- (1-amino-2-cyano-ethyl) -hexahydro-cyclopentyl [c] pyrrolyl] -1-cyclopropyl-8-methoxy-4 -Pendant oxygen-1,4-dihydro-pyridoline-3-carboxylic acid; 7- [3a_ (2-lactyl-ethylamino) -hexazine-ί 辰 戍 [c] 11 比 peach · 2 , Group] -1-cyclopropyl-6-fluoro-8-fluorenyl-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid; 207- [3a- (2-cyano -Ethylamino) -hexahydro-cyclopentyl [c] pyrrolyl] -1_cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-quinoline -3- Junic acid; 7- [3a- (2-cyano-ethylamino) -hexahydro-cyclopentyl [c] pyrrolyl] -1-cyclopropyl-8-fluorenyl-4- pendant oxygen -1,4-diaza-σ-charin-3-junic acid; 200 200524930 7- [3a- (2-Amino-ethylamino) -hexamethylene-Liaoyue [c] σ 比 洛 -2 -Yl] -1-cyclopropyl-8-methoxy-4- pendant oxygen-1,4-diazepine-3-brothermic acid; 7- [3 &amp; _ (1-amino-2-ammonia -Ethyl) -hexakis-oxa [0] 0Biha-2_yl] -1-¾propyl- 6-^-8-methyl-4-lateral lactam-1,4-dimurine-linophilic acid; 7- [3a- (1 -amino-2-cyano-ethyl) -hexa Hydrogen-cyclopentyl [c] pyrrole-2-Vyl] -1-cyclopropyl-6-fluoro-8-methoxy-4- pendant oxygen-1,4-dihydro-pyridin-3-carboxylic acid ; '7- [3a- (l-amino-2-cyano-ethyl) -hexahydro-cyclopenta [c] ° than each 2-10 group] _1-cyclopropyl-8-methyl 4-lanthoxy-1,4-dihydro-pyridin-3-carboxylic acid; or 7- [3a- (l-amino-2-cyano-ethyl) _hexahydro-cyclopenta [cp ratio Pyr-2-yl] small cyclopropyl-8-methoxy-4- pendant oxygen_1,4_dihydro-σquinine_3_endacid; 14. A pharmaceutical formula comprising formulae I, II , III, IV, V, or VI compounds, mixed with a pharmaceutically acceptable diluent, carrier, or excipient. 15. A method of treating a bacterial infection in a mammal, comprising administering an effective amount of a compound of formula I, II, III, IV, V or VI to the mammal in need of treatment. ^ 201 200524930 VII. Designated representative map (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative picture: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: