NL1027545C2 - Chinolones as antibacterial agents. - Google Patents

Description

5 10

CHINOLONES AS ANTIBACTERIAL MEANS

Field of the invention

The present invention relates to compounds bearing a quinolone core structure and exhibiting antibacterial activity, methods of their preparation, as well as pharmaceutically acceptable compositions containing such compounds.

Background of the invention

Bacterial resistance is a worldwide problem for clinics and public health that has developed at alarming rates in recent years. Resistance is a problem for the population, as well as for health clinics, where the transfer of bacteria takes place to a much greater extent. Because multiple drug resistance is a growing problem, doctors are now confronted with infections for which there is no effective therapy. The morbidity, mortality and costs of such infections are a growing burden on healthcare worldwide. Consequently, alternative and better means are needed for the treatment of bacterial infections, in particular for the treatment of infections caused by resistant strains of bacteria.

1027545-2

Summary of the invention

These and other needs are met by the present invention, which is directed to a compound of the formula I: 5 R 3 O 9 R 4 Yr! R 2, R 5 B 1 or a pharmaceutically acceptable salt thereof, wherein: X is N or C, provided that when X is N, R 5 is missing in that position,

R 1 is (C 1-6) alkyl, halogen (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, halogen (C 3 -C 6) cycloalkyl, heterocycle, aryl, heteroaryl and CH 2 (C 3 -C 6) cycloalkyl, R 2 is OH OBF 2, O (C 1 -C 6) alkyl, O (C 3 -C 6) cycloalkyl,

O

O (CHR ») m-Q-QR« h Sat / m wn2b, where m a

30 is an integer from 1 to 10, Q is O

or NH or N (Οχ-ββ) alkyl, or missing, and R 2a is H or (C 1 -C 6) alkyl and R 2b is (alkyl-ββ) alkyl, aryl or heteroaryl, 1027545-3 '0 - (CHR ^) "- r wherein R2a has the meaning given above, n is an integer from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2d are each independently H, (Οχ-alkylβ) alkyl or (C3-) C6) cycloalkyl or NR2a, wherein R2a has the meaning given above,

10 iH u V

rr \ 'N'XJ7Xi' - (CHR2e) p-YrH

R2e * R *? .

, wherein the bonding point denotes, 2a has the meaning given above, R2e and R2e 'are each independently H or (C1 -C6) alkyl, or are combined with the carbon to which they are attached 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 Xi and Yi are each independently NH

or O, R 3, R 4 and R 5 are each independently H, OH, halogen, NR y R z, wherein R y and R z are each independently H or (C x -C 6) alkyl,. . (C 1 -C 6) alkyl,.

halogen (Οχ-Οβ) alkyl, O (Οχ-Οβ) alkyl, O (Οχ-Οβ) haloalkyl, nitrile, 1027545-4

R 1 and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1 or 2 heteroatoms. to become . selected from O, S, SO, SO 2 or NR X, wherein R * is H or (C 1 -C 6) alkyl and A is R a R b, or R Mq R b z wherein z is 0, 1 or 2 and q is 0, '1, 2 or 3,

R a and R b are each independently H, (C 1 -C 8) alkyl, (C 1 -C 8 alkoxy / halogen (C 1 -C 6) alkyl, halogen, or R 15 and R b taken together with the carbon to which they are attached C = 0, C = NO (C 1 -C 6) alkyl or a 3, 4, 5 or 6-membered substituted or unsubstituted ring, R ', R ", R'" and R "" are each independently H, 20 (C 1 -C 6) alkyl, -O (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, aryl or heteroaryl, and B is "• v * N CyM" 30R / Rf Rc or V · STk.

1027545-5 with the proviso that when B is% R1 Re R1 / -t'T * NC-VN ^ B "V) n * OG) * 5 ^ Rc in Ra Rb or, R 'none -0 (Ci -C6) alkyl, and wherein the binding point indicates,

R c and R c each are independently H, (C 1 -C 6) alkyl nitrile, 10 -P-OH-6 H, 0-P-0 (C 1 -C 6) alkyl-C 1 -C 6 alkyl (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, heteroaryl, 2Q SO2- (Cx-C6) alkyl, SO2-aryl, SO2-heteroaryl.0 (CR2aR2a) g - O - ^ - QR ^. .

wherein g is an integer from 1 to 10, Q has the meaning given above, and R 2a and R 2a are each independently H or (C 1 -C 6) alkyl, or taken together with the carbons to which they are attached a 3- , 4, 5 or 6-membered substituted or unsubstituted ring, and R 2b is (C 1 -C 6) alkyl, aryl or heteroaryl, p 0 (CR 2aR 2a ') g OP (OH) 2 or (CR 2aR 2a') g-0 -P- (O (C 1 -C 6) a, ky,> 2, wherein R 2a and R 2a have the meaning given above, 1027545-6

O

"'' / N | ~" R2c U n '\ H / p wherein "w," indicates the bonding point, 5 p is O or 1 and is H, (C 1 -C 6) alkyl, 0 (C 1 -C 6) alkyl , (C 3 -C 7) cycloalkyl, aryl, hetero ring, heteroaryl or

O

15 - (CHR2a) h-0 - ^ - QR2b or - (CHRja)] - Y, wherein R2a, R2b and Q have the meaning given above, and h and j are each independently integers from 0 to 10, and Y is OH, OPO (OH) 2, 0 PO (O (C 1 -C 6)) 2, or NR 2 d R 2 e, wherein R 2 d and R 2e are each independently H, (C 1 -C 6) alkyl or (C 3 -C 7) cycloalkyl, 7 J 11 O 0 - R 2 g where q is 0 or 1, R 2 f and R 2 f - are each independently Η, (Οχ-Οβ) alkyl, aryl or heteroaryl, or taken together with the carbon to which they are attached a 3-, 4-, 5- or 6-membered substituted or unsubstituted ring, and R 2 is 35 (C 1 -C 6) alkyl, {C 3 -C 7) cycloalkyl, 1027545-7 aryl, heterocycle or heteroaryl,

R e and R f are each independently H, C 1 -C 6 alkyl, haloalkyl, halogen, or Re and Rf. taken together with the carbon to which they are attached a 3, 4, 5 or 6-membered substituted or unsubstituted ring. R 10 and R 8 are each independently H, C 1 -C 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached, a 3-, 4-, 3. 5 or 6-membered substituted or unsubstituted ring and Rj and Rk are each independently H, (C1 -C6) alkyl, haloalkyl, (C1 -C6) alkyl-NRc Rd, (C1 -C6) alkyl-ORc, aryl heteroaryl, heteroring,

O

(C 1 -C 18 alkyl - ^ - Z-Rd, wherein Z is O or NRC, or Rj and Rk taken together with the carbon to which they are bonded a 3-,.

4, 5 or 6-membered substituted or unsubstituted ring.

A compound of the formula II: R3 or H4vSrr2 R2 is also provided

* cr

30 ** B "Π

R a R b or a pharmaceutically acceptable salt thereof, wherein: X is N or C, provided that when X is N,

Rs in that position is missing, 1 027545-8. R 1 is (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, halogen (C 3 -C 6) cycloalkyl, heterocycle, aryl, heteroaryl and CH 2 (C 3 -C 6) cycloalkyl, R 2 is OH 10 OBF 2, 0 (C 1 -C 6) alkyl, 0 (C 3 -C 6) cycloalkyl, 0- (CHR 2a) m

15 is a number from 1 to 10, Q is O or NH

or N (C 1 -C 6) alkyl, or missing and R 2a is H or (C 1 -C 6) alkyl and R 2b is (C 1 -C 6) alkyl, aryl or heteroaryl, O- (CHR 2 a) n where R 2a is the above given 20 ·. meaning, n is an integer from 2 to 10, Y is OH or NR2cR2df where R2t and R2d. each independently is H, (C1 -C6) alkyl or (C3 -C6) cycloalkyl or NR2a / wherein R2a has the meaning given above, 1027545- (η οΥ 9 R2e 'R2 * 1 ^ Υη Η, where the binding point indicates, 2a has the meaning given above, R2e and R2e 'are each independently H or (C1 -C6) alkyl, or taken together with the carbon to which they are attached 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 is 10, and Xi and Yi are each independently NH

or O, R 3, R 4 and R 5 are each independently H 1. halogen, NR y R z, wherein R y and R 2 are each independently H or (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, 0 (C 1 -C 6) alkyl, 0 (C 1 -C 6) haloalkyl, nitrile, R; and R5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1 or 2 heteroatoms selected from O, S, SO, SO2 or NRX, wherein Rx is H or (C 1 -C 6) alkyl and z is 0, 1 or 2, R 1 is H, (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, aryl or heteroaryl, 1027545- --- - - -------------- 10

R a and R b are each independently H, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halogen (C 1 -C 6) alkyl, halogen, or R a and R b taken together with the carbon to which they are attached C = 0.5 C = NO (C1 -C6) alkyl or a 3-, 4-, 5-. or 6-membered substituted or unsubstituted ring,

R c is H, (C 1 -C 6) alkyl nitrile, 10

O

n

-P-OH

6h, 15o-P-O (C 1 -C 6) alkyl, C 1 -C 6 alkyl (C 1 -C 6) alkyl,.

(C 3 -C 6) cycloalkyl, heteroaryl, SO 2 - (C 1 -C 6) alkyl, SO 2 aryl, SO 2 - heteroaryl, 25

O

(CR2aR2a1) g-0 ^ QR2br wherein g is an integer from 1 to 10, Q has the meaning given above and R2a and R2a 'are each independently H or (C1 -C6) alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring, and R2b is 35 (C1 -C6) alkyl, aryl or heteroaryl, 1027545-11 (CR2aR2a) 9-0- P- (OH) 2 or (CR 2a R 2a.) B-O-P- (O (C 1 -C 1) alkyl) 2 j wherein R 2a and R 2a 'have the meaning given above,

5 O

'' P, where 'Λ * ΛΑ' indicates the binding point, p is 0 or 1 and R2c is H, 10 (C1 -C6) alkyl, O (C1 -C6) alkyl, (C3 -C7) cycloalkyl, aryl, heterocycle , Heteroaryl or O '- (CHR ^ -O ^ -QR *, or J - (CHR ^ -Yf where R2a, R2b and Q have the meaning given above, and h and j each independently represent integers from 0 to and with 10, and Y is OH, OPO (OH) 2, PO (O (C 1 -C 6)) 2 or NR 2 d R 2 e, wherein R 2 d and R 2e are each independently H, (C 1 -C 6) alkyl or (C 3 -C 7) cycloalkyl, 30 H / q 2 fl / wherein q is 0 or 1, R 2 f and R 2 f are each independently H, (C 1 -C 6) alkyl, aryl or heteroaryl, or taken together with the carbon to which they are attached a 3-, 4, 5 or 6-membered substituted or unsubstituted ring form, and R 2 is (C 1 -C 6) alkyl, 1027545-12 (C 3 -C 7) cycloalkyl, aryl, hetero ring or heteroaryl, 5 Re and Rf are each independently H , C1 -C6 alkyl, haloalkyl, halogen, or Re and Rf taken together with the carbon to which they are attached are substituted by a 3, 4, 5 or 6-membered substitute form an or unsubstituted ring and R 8 and R 8 are each independently H, C 1 -C 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring.

A connection is also provided, which is: 0 0

fXXj 0H

OMeJ ^ (1) 7- [3- (2-Cyanoethylamino) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-carboxylic acid, on fXXjn 30 KC ^ IjO1 * ^ (2) 7- [3- (2-Cyanoethylamino) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, 1 02 75 45-13

O O

Ylu 0H / ~~ N

. 5 nc ^ k ^ oMeA

(3) 7- {3 - [(2-Cyanoethyl) methylamino] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10

° O

[0154] VI-R (4) 7- {3 - [(2-Cyanoethyl) methylamino] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo -1,4-dihydroquinoline-3-carboxylic acid, 20

O O

25 (5) 7- [3- (2-Cyanoethylamino) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 30 0 0

JOcV'OH

OMel

35 Me ZA

1027545-14 (6) 7- {3 - [(2-Cyanoethyl) methylamino] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10 ( 7) 7- {3 - [(2-Cyanoethyl) methylamino] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, DOC10 20 (8) 9- [3- (2-Cyanoethylamino) cyclopentyl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalen-5-carboxylic acid or

° O

FWJSr0H

Me II i jJ

_____ nn / yysn / NC \ '1 30 ^ ° ^ /> m; (9) (9- {3 - [(2-Cyanoethyl) methylamino] cyclopentyl} -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalene) -carboxylic acid.

1027545-15

A compound of the formula III: 9 5 is also provided. 5 "• ^ r? V

Rs Ri

RfvA ^ -RhRa Rb

Re-η Rg ΙΠ

CN

10 or a pharmaceutically acceptable salt thereof, wherein: X is N or C, provided that when X is N, R 5 is missing in that position, R 1 is (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, halogen (C 3 -C 6) cycloalkyl, heterocycle, aryl, heteroaryl and CH 2 (C 3 -C 6) cycloalkyl, R 2 is OH, obf 2, (C 1 -C 6) alkyl,

O (C 1 -C 4) cycloalkyl, O

O - (CHR ^ nfO * f wherein m is an integer from 1 to 10, Q is O or NH or N (C1 -C6) alkyl, or missing, 30 and R2a is H or (C1 -C6) alkyl and R2b is (C1 -C6) alkyl, aryl or heteroaryl, O- (CHR2a) n - Yr wherein R2a has the meaning given above, n is an integer from 2 to 10, Y is OH or NR2cR2d, where 35 R2c and R2d are each independently Η, (Ci ~

C 6) alkyl or (C 3 -C 6) cycloalkyl or 1 02 75 45-16 NR 2a / in which R 2a has the meaning given above, 5 Yh

"N7wXi" (CHR2a) p "" Yi "H

Rze · R *, in which the binding point indicates, 2a has the meaning given above, R2e and R2e are each independently H or (C1 -C6) alkyl, or taken together with the carbon to which they are attached 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 Xi and Yi are each independently NH or 0 , R 3, R 4 and R 5 are each independently H, halogen, NR y R z, wherein R y and R z are each independently H or (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, O (C 1 -C 6) alkyl, O (C 1 -C 6) haloalkyl, nitrile,

R a and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1 or 2 heteroatoms selected from 0, S, SO, SO 2 or NRX, wherein R x is H or (C 1 -C 6) alkyl and z is 0, 1 or 2, 35. R 'is H, (C 1 -C 6) alkyl,.

-0 (.C1-C6) alkyl, 1027545-halogen, (C1 -C6 alkyl, aryl or heteroaryl)

R a and R b are each independently H, (C 1 -C 6) alkyl, 5 (C 1 -C 6) alkoxy, halogen (C 1 -C 6) alkyl,. halo, or R a and R b taken together with the carbon to which they are attached form C = O, C = NO (C 1 -C 6) alkyl or a 3, 4, 5 or 6-membered substituted or unsubstituted ring,

R c is H, (C 1 -C 6) alkyl nitrile,

O

-P-OH

15 - 6H ·

O

-P-O (C 1 -C 6) alkyl-6 (C 1 -C 6) alkyl (C 1 -C 6) alkyl,.

(C 3 -C 6) cycloalkyl, heteroaryl, SO 2 - (C 1 -C 6) alkyl, SO 2 aryl, SO 2 - heteroaryl, 0 (CR 2aR 2e) g-O-QRa> where g is an integer from 1 to with 10, Q has the meaning given above, and R 2a and R 2a are each independently H or 30 (C 1 -C 6) alkyl, or taken together with the carbons to which they are attached a 3-, 4-, 5- or 6- long-substituted or unsubstituted ring, and R 2b is {C 1 -C 6) alkyl,. Aryl or heteroaryl, 1027545-18

O O

(CR2aR2a0g-OP- (OH) 2 Qf (CR2aR2B ') g-O-P (O (C 1 -C 6) alkyl) 2, wherein R 2a and R 2a have the meaning given above, binding point denotes, p is 0 or 1 and R 2c is H, 10 (C 1 -C 6) alkyl, O (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, aryl, heterocycle, heteroaryl or 20 - - (CHR - -) O ^ -QR *, or (CHR ^)] - Y ^ where R2a, R2b and Q have the meaning given above, and h and j are each independently 25 integers from 0 to 10, and Y is OH, 0P0 (0 H) 2, PO (0 (C 1 -C 6)) 2 or NR 2 d R 2e, wherein R 2d and R 2e are each independently H, (C 1 -C 30 Ce) alkyl or (C 3 -C 7) cycloalkyl, 1027545-

- ----- ------------- I

19? R2 \ 1 * · - ^ NT ^ O? -HR2 f1 / o where q is 0 or 1, R2f and R2f '·' ** '** are each independently H, (C 1-6) alkyl, aryl or heteroaryl, or taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring and R 2 is (C 1 -C 6) alkyl, 10 (C 3 -C 7) cycloalkyl, aryl; heteroring or heteroaryl,

R e and R f are each independently H, C 1 -C 6 alkyl, haloalkyl, halogen, or R e and R f taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring,

R 8 and R 8 are each independently H, (C 1-6) alkyl, haloalkyl, or taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring and

R 1 and R k are each independently H, (C 1 -C 6) alkyl, haloalkyl, (C 1 -C 6) alkyl-NR c R d, (C 1 -C 6) alkyl-OR c, aryl, heteroaryl, heterocycle,

O

(C 1 -C 6) alkyl Z-R 1, wherein Z is O or NRC, or R 13 and R k taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring. " A connection is also provided, which is: 1 027545-20

0ι 0H

0ΜθΛ

5 H

(1) 7 - {3 - [(2-Cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

10 O O

FrYV0H

0MeA

· (2) 7- {3R - [{2-Cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid , 20 FJ? j? ^ rrvv NC - ^ N VJ Me A.

(3) 7- {3 - [(2-Gyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

30 th JL X.

XYj 0H

λ / 'νΎιι ^

° “eA

1027545-21 (4) 7- (3 - {[(2-Cyanoethyl) methylamino] iaethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-inethoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, 5%

: FrrroH

10 (5) 7- (3 - {[(2-Cyanoethyl) methylamino-3-methyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3 -carboxylic acid, O o

Me D C C ^ H

NCS ^ N OMe ^ 20 (6). 7- {3- [1- (2-Cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25

MeΧΥΧΥΧΥΓΗ NC · - / V-1 Me ^ 30 (7) 7- {3- [1- (2-Cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8'-methyl-4 oxo-1/4-dihyclroquinoline-3-carboxylic acid, 10275545-22

O O

FrrY ° H

"V ^ VY

5 ΟΜβλ

Me 1- (8) 7- (3- {1 - [(2-Cyanoethyl) methylamino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-inethoxy-4-oxo-10 1,4-dihydroquinoline-3-carboxylic acid,

O O

FTI-OH

VrT '(9) 7- (3 - {1 - [(2-Cyanoethyl) inethylamino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, F 9 °

. Y ^ V ^ iT ^ OH

25 Me Jl J

NC-J ^ 'C

(10) 7- {3 - [(2-Cyano-1-methylethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid,

O O

YrV ^ 35

NC ^ -N OMe A

1027545-23 (11) 7- {3 - [(2-Cyano-1-methylethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, 5 0 0

FrrY-on

JyL J

NC ^^ N OMe i.

xo H. Δ (12) 7- {3 - [(2-Cyanoethylamino) methyl] -3-methylpyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid, 15 0 0.

Y X j 0 H

2b NO- ^ N ^ O A

(13) 7- {3 - [(2-Cyanoethylamino) methyl] -3-methylpyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4. dihydroquinoline-3-carboxylic acid, 25 '.

0 0

FrrY ° H

, n NC ^ N Λ ^>. Uncle/.

30 Me ΖΛ (14) 7- (3 - {[(2-Cyanoethyl) methylamino] methyl) -3-methylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 102 1024545-24 oo

FrVr ° H

5 JiV'N'V ^ N

a (15) 7- (3 - ([(2-Cyanoethyl) methylamino] methyl} -3-methylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-10 oxo-1,4 -dihydroquinoline-3-carboxylic acid,

O O

Frry ° H

Vs-y'j'i1

15 NC ^ -N OMeX

H '' (16) 7- (3- [1- (2-Cyanoethylamino) cyclopropyl] pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro- Quinoline-3-carboxylic acid,

O O

YrY * · NC- ^ ~ N for Me ^ (17) 7- (3- [1- (2-Cyanoethylamino) cyclopropyl] pyrrolidin-1-30-yl) -1-cyclopropyl-6-fluoro-8-methyl- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid,.

0

35 V

NC - N / A OMe / 1 Me / 1 02 75 4 5 25 (18) 7- (3- (1 - [(2-Cyanoethyl) methylamino] cyclopropylpyrrolidin-1-yl) -1-cyclopropyl- 6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonic acid, 5

° O

Y 10 H 10 (19) 7- (3- {1- [(2-Cyanoethyl) methylamino) -cyclopropyl} -pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, 15

O O

^ A A

T TTrOH

HN ^ \ L II Ij 20 ββΛ (20) 7- {3- [2-Acetylamino-1- (2-cyanoethylamino) ethyl] -pyrrolidin-1-yl. } -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25 0 0

Ββ-^ ° F 11 YY

hnV oh

30 NC ^ N ^ O

(21) 7- {3- [2-Acetylamino-1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-nonhoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, 10275545-26

O O

"Ύ0 fvVSA> h

HhK JL JL

5 0 MeA

Me 1- (22) 7- (3- {2-A.cetylamino-1- [(2-cyanoethyl) methylamino] -ethyl) pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10 oo

t VYff 0H

HN "X J1 ββ λ 25 Me» (23) 7- (3- {2-Acetylamino-1 - [(2-cyanoethyl) methylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6- fluorine-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 20

O O

N-NC-N-N OMeJv 25 ΖΛ (24) 7- {3 - [(2-Cyanoethylamino) methyl] pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, 30 OO Me 1 H ^^ 35 - 1027545-27 (25) 7 - {3 - [(2-Cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 0 0 λ ¥ ° η ° Me ^

Me 10 (26) 7- (3 - {[(2-Cyanoethyl) methylamino] methyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 11

Ck10H

MeA

(27) 7- (3 - {[(2-Cyanoethyl) methylamino] methyl} pyrrolidin-1-yl) -1-cyciopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

25 O O.

Me fTY'0 ”) λνΥν;

NC ^ N OMeX

30 (28) 7- {3- [1- (2-Cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 35 L 027545 - ". 28

O O

f # 0H

NC, N, N, O, (29) 7- {3- [1- (2-Cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 10

° O

iVp »

Me Jk. JL 11 OMe> 1 15 Me (30) 7- (3- {1 - [^ - Cyanoethylamethylaminomethyl] pyrrolidin-ne-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydrochino-line -3-carboxylic acid, 20 0 0 ηΛΛ0 * Μ \ / ~ Ν ^ ν ^ Ν

Νό ^ ϊΓ'ν * Μβ A

25 Me (31) 7 - (3 - {1 - [(2-Gyanoethyl) xnethylamino) ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-ethyl-4-oxo-1,4-dihydroquinoline-3- 30 carboxylic acid,

O O

jfVj oh 35

0MeA

Π 1 02 7545, 29 (32) 7- (3 - [(2-Cyanoethylamino) methyl] -3-methylpyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid,

5 I

Nc ^ fV

10 (33) 7- {3 - [(2-Cyanoethylamino) methyl] -3-methylpyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 15? \? \ OMel

Me 20 (34) 7- (3 - ([{2-Cyanoethyl) methylamino] methyl} -3-methylpyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro -quinoline-3-carbon acid,

25 X A

ΠΡ

jvVyS

(35) 7- (3 - {[(2-Cyanoethyl) methylamino] methyl} -3-methylpyrrolidin-1-yl) -1-cyclopropyl-8-methyl-4 -oxo-1,4-dihydro-quinoline-3-carboxylic acid 35 102 ^ 545- 30 0 0 5 NC ^^ N [^ (36) 7- {3- [1 "(2-Cyanoethylamino) cyclopropyl] pyrrolidine-1 -yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 10

O O

nrY ™ NC- ^ N VJ Me 1 15 H Δ (37) 7- {3- [1- (2-Cyanoethylamino) cyclopropyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid, 20

O O

NC ^^ N VJ ΟΜθ X

25 Me Δ (38) 7- (3- {1- [(2-Cyanoethyl) methylamino] cyclopropyl} -pyrrolidin-1-yl) -1-cyclopropy-8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid, 30

O O

Me - ** 0 JL

T ί ^ ιΓιΓ 0H

hn-. JL 11 I)

0MeA

35 H

1027545-31 (39) 7- {3- [2-Acetylamino-1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic acid,. .

i? 9

h * k jfYjf 0H

NC ^ -N Me ^ 10 (40) 7- {3- [2-Acetylamino-1- (2-cyanoethylamino) ethyl] -pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid, 15 -. O O ·

Ub ^ II 11 II

hIC oh OMel

Me ΖΛ 20 (41) 7- (3- {2-Acetylamino-1 - [(2-cyanoethyl) methylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methyl-4-oxo-1, 4-dihydroquinoline - 4 - carboxylic acid, 25%

Me —___ U U

Λ. / ΥγΝ) Η

HhS JL II J

\ ΛΝ / γ ^ Ν Μθ Λ

Me 30 · (42) 7- (3- {2-Acetylamino-1 - [(2-cyanoethyl) methylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, V 35 1027545 - 32 32 5 {43) 7- [1- (2-Cyanoethylamino) -5-azaspiro [2.4] hept-5-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid, 10 o / x / o / h / y-f / n NC / ^ N Me k

"15 - H

(44) 7- [1- (2-Cyanoethylamino) -5-azaspiro [2.4] hept-5-yl] -1-cyclopropyl-6-fluoro-8'-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid , 20. '0

CN Fs ^ \ AAnH

k TTT

HNY ^ L ·! Et.

(45) 7- {3- [1- (2-Cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid , 30

O O

CN A

C npH

hny ^ Li 35 Et ^ 1027545-33 (46) 7- {3- [1- (2-Cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo 1,4-dihydroquinoline-3-carboxylic acid,

5. O O

s fxi Voh

^ nY ^ N

Et ^ 10 (47) 7- (3- [(2-Cyanoethyl) methylamino] propyl} azetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, 15 CN F? j?

V TY 1 0H

"° A

(48) 7- (3 - {1 - [(2-Cyanpethyl) methylamino] propyl} azetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro -quinoline-3-carboxylic acid,

25 O O.

CN c>. X 1

C.

HNs /) N T f

0 MoA

(49) 7- {3- [1- (2-Cyanoethylamino) cyclopropyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-inethoxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, 35.

1027545- 34 o o CN ργΎ ^ Α ° Η

5 ηνα ^ A

(50) 7- {3- [1- (2-Cyanoethylamino) cyclopropyl] azetidine-1-yi} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid, 10 -. · _ 0 0

cn r / v A A

C ni "

oMeA

(51) 7- (3- {1- [(2-Cyanoethyl) methylamino] cyclopropyl} azetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, 20 0 0

* ί. λ Λ A

k XTVoh

Me A

(52) 7- (3- {1- [(2-Cyanoethyl) methylamino] cyclopropyl} -azetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylic acid,

30 O O

"'0 "35 1027545-35 (53) 7- (3- {1- [(2-Cyanoethyl) ethylamino] cyclopropyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo 1,4-dihydro-quinoline-3-carboxylic acid, 50

FnrYoH

NC - ^^ N Me λ

Et ΔΛ 10 (54) 7- (3- (1- [(2- Cyanoethyl) ethylamino] cyclopropyl) -pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid,

o o

HN ^ 20 (55) 7-3- {2-Acetylamino-1 - [(2-cyanoethyl) ethylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, 25

O O

MeY ° ι ^ ΛΛοη

HN ^ 11J Μθ A

(56) 7- (3- (2-Acetylamino-1 - [(2-cyanoethyl) ethylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, 35.

O O

5 \ Me A

. (57) Sodium 7- {3- [1- (2-cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1/4-dihydro-quinoline -3-carboxylate, 10

O O

CN c = £ 1 or ^ T11 '0' +

hn-3Cn t V

Me 1

15 A

(58) Sodium 7- {3 - [(2-cyanoethylamino) methyl] -3-methylazididin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylate, 20

O O

cn c. JL · Jl

S ΛΠΓ) H

ΜΘ ^. 25.

(59) 7- {3- [1- (2-Cyanoethylamino) cyclopropyl] azetidine-1-yi} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline- 3-carboxylic acid, 30 0 0

CN ρ Λ Jl JL

S XXJ 0H

P- 'ββ λ 35 kMe ^ 1027545-37 (60) 7- {3 - [(2-Cyanoethylamino) methyl] -3-ethylazetidin-1-ylH1-cyclopropyl-6-fluoro-8-methoxy-4-OXO- 1,4-dihydroquinoline-3-carboxylic acid, 5 CN F? J?

V lYj 0H

Me 10.

(61) 7- {3 - [(2-Cyanoethylamino) methyl] -3-ethylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoinline -3-carbon acid,

15 O O

NC ^ vyYf

H w (y A

(62) 9- {3 - [(2-Cyanoethylamino) methyl] cyclopentyl} -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalen-5- carboxylic acid or 25 O 9

fYYj0H

Me VJ O ^ AMe 30 (63) 9- (3 - {[(2-Cyanoethyl) methylamino] methyl} cyclopentyl) -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6 H -1- oxa-3a-aza-phenalene-5-carboxylic acid.

35 1027545- 38

The present invention is also directed to a compound of the formula IV:

: R3 O O

5 R4 \ J \ AA

Rcv, Rd (I ^ e 2 eR a R *> or a pharmaceutically acceptable salt thereof, wherein: X is N or C, provided that when X is N, Rs in that position is missing.

R 1 is (C 1 -C 6) alkyl,.

Halogen (C 1 -C 6) alkyl, {C 3 -C 6) cycloalkyl, halogen (C 3 -C 6) cycloalkyl, heterocycle, aryl, heteroaryl and CH 2 (C 3 -C 6) cycloalkyl, R 2 is OH, OBF 2, O (C 1 -C 6) alkyl, O (C 3 -C 6) cycloalkyl,

O

0 ~ (CHR2a) m-0-QR2b f where m is an integer from 1 to 10, Q is O or NH or 30 N (Οχ-Οβ) alkyl, or is missing, and R2a is H or (Ci- C 6) alkyl and R 2b is (C 1-6) alkyl, aryl or heteroaryl, 1027545-39 O - (CHR 2a) n Y 2 wherein. R2a has the meaning given above, n is an integer from 2 to 10, Y is OH or NR2cR2d / wherein R2c and R2 <i are each independently H, 5 (C1 -C6 alkyl or (C3 -C6) cycloalkyl or NR2 ar wherein R2a has the meaning given above, φ 28 "2e, wherein the point of attachment indicates, 2a has the meaning given above, R2e and R2e are each independently H or (C1 -C6) alkyl, or taken together with the carbon to which these are bound 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 Xi and Υχ each independently is NH or O, R 3, R 4 and R 5 are each independently H, halogen, NR y R z, wherein R y and R z are each independently H or (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, halogen (C 1) Ce) alkyl, O (C1 -C6) alkyl, O (C1 -C6) haloalkyl, nitrile,> 1027545-40

R 1 and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring 5 which contains 0, 1 or 2 heteroatoms selected from O, S, SO, SO 2 or NRX / wherein R * is H or (C 1 -C 6) alkyl and z is 0, 1 or 2,

R a and R b are each independently H, (C 1 -C 6) alkyl, 10 (C 1 -C 6) alkoxy, halogen (C 1 -C 6) alkyl, halo, or R a and R b taken together with the carbon to which they are attached is a 3-, 4, 5 or 6-membered substituted or unsubstituted ring forms, R 'is H, halogen.

(C 1 -C 6) alkyl, O (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, aryl or heteroaryl,

Rc and Rd are each independently H, (C 1 -C 6) alkyl nitrile, 25 °

-P-OH

OH,

O

- C 1-10 C 1-6 alkyl or C 1-6 alkyl, (C 3-6) cycloalkyl, heteroaryl, SO 2 - (C 1-6) alkyl, SO 2 aryl, SO 2 heteroaryl, 02 02 7545- ____ -__________—---- --- i 41

O

- (CR 2 BR 2a) g 0 ^ 2b ^ wherein g is an integer from 1 to 10, Q has the meaning given above, and R 2a and R 2a 'are each independently H or (C 1 -C 6) alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring, and R 2b is (C 1 -C 6) alkyl,

aryl or heteroaryl, O

/ pd d \ Λ 1 or (CR 2 f R 2 e.) a-O-P- (O (C 11 -C 6) alkyO 2 (CR 2 a R 2 -a) B-O-P- (0 H) 2 wherein R 2a and R 2a have the meaning given above, 15.

K, wherein the bond point denotes, p is 0 or 1 and R 2c is H, (C 1 -C 6) alkyl, O (C 1 -C 6) alkyl, (C 3) -C7) cycloalkyl, aryl, hetero ring, heteroaryl or 1027545-42

O

- (CHR2a) h ~ “2 QR2b or - (CHR2a) j Y, where R2a, R2b and Q have the meaning given above, and h and j are each independently 5 integers from 0 to 10, and Y OH, 0 PO (0 H) 2, PO (O (C 1 -C 6)) 2 or NR 2 d R 2e, wherein R 2d and R 2e are each independently H, (C 1 -C 6) alkyl or (C 3 -C 7) cycloalkyl, ^ ο-β2β ', wherein q is 0 or 1, R2f and R2f' are each independently H, (C1 -C6) alkyl, aryl or heteroaryl, or taken together with the carbon to which they are attached a 3-, 4-, 5 or 6-membered substituted or X-ray-substituted ring, R 2 is (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, aryl, heterocycle or heteroaryl and

Re and Rf are each independently Η, Οχ-ββ alkyl, haloalkyl, halogen, or Re and Rf taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring, and

A connection is also provided, which is: 35 1027545-43 o o

FYYiT 0H

h2n jL 1 Ij · s «o-^ Cf'XX ^ (1) 9- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo 2,3-dihydro-6H-1-oxa-3a-azapalenalene-5-carboxylic acid, 10

O O

h2n

NC

15 Me (2) 9- [3- (R) - (2-Cyano-1- (S) -methylaminoethyl) -pyrrolidin-1-yl] -8-fluoro-3- (S) -methyl-6-oxo 2,3-dihydro-6H-1-oxa-3α-azapalenalene-5-carboxylic acid, 20

O O

FYVVs H 2 H Jn JL JJ NC 4 O 25 (3) 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid,

30 O O

FTYr 0H

H2.1 / - n "nn NC ^ - O ^ 35 1027545-44 (4) 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4 -oxo-14-dihydro [1,8] naphthyridine-3-carboxylic acid,

O O

5 Yi 0H

OMe ^ 10 (5) 7 - [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropiyl-6-fluoro-8-nonhoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid,

° O

Fni is OH

H 2 Nv / - β β 20 (6) 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylic acid,

O O

25 h2n 0.30 (7) 7 - [3 - (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 102,27545 , 45

O O

5 Me 1 (8) 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-10 carboxylic acid, n · n 2, r

h2n JL II

(9) 5-Amino-7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ,

nh2 o O

fVin) H

h2n _nAJV.

Me ^ (10) 5-Amino-7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3 - 30 carboxylic acid, 0 0

FYYir 0H

h2n JL 1 J

Ύ &. H

1027545-46. (.11) 7 - [3- (1-Amino-2-cyano-2,2-dimethylethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid, 5 ° C, H 2 N Y 2 Y 4. (12) 7- [3- (1-Amino-2-cyano-2,2-dimethylethyl) pyrrolidin-1-yl] -1-cycloplopyl-6-fluoro-8-methyl-4-oxo -1,4-dihydro-chirioline-3-carbonazole. .

15

HjN Z11 / OH

(13) 7- [3- (1-Amino-2-cyano-2,2-dimethylethyl) pyrrolidin-1-yl] -1-cyciopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid, 25 0 0

Y 1 H 2 H 2 JL II J

NCT <^^ '

Me7 Me Δ 30 (14) 7- [3- (1-Amino-2-cyano-2,2-dimethylethyl] pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid, 35 1 027545- 47 nh 2 or PVV n n 2

5 NC / V OMeX

Μθ M (15) 5-Amino-7- [3- (1-amino-2-cyano-2,2-dimethylethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo -1,4-dihydro-. Quinoline-3-carboxylic acid,

nH 2 O O

fYi oh

15 Me A

mT * (16) 5-Aino-7- [3- (1-amino-2-cyano-2,2-dimethylethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1 4-dihydroquinoline-3-carboxylic acid,

O O

Yi 0H

H2 N

(17) 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 30

O O

°ί ° Η

MeHN JL II U

NcJ'-Jj χ 35 ^ 1027545-48 (18) 7- [3- (2-Cyano-1-methylaminethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid,

5 O O

-κπΧ 10 (19) 9- [3- (2-Cyano-1-methylaminoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa -3a-azafenalene-5-carboxylic acid, 9

wr ° H

MeHI 10 - Me 20 (20) 9- [3 (R) - (2-Cyano-1 (S) -methylaminoethyl) -pyrrolidin-1-yl] -8-fluoro-3-pythy 1 -6-oxo-2ψ 3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid, 9 9

MeHN j — μ N N

NC> ^ A

(21) 7- [3 - [(2-Cyano-1-roethylaminoethyl) pyrrolidin-1-yl] -. 1-cyclopropyl-6-fluoro ** 4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid, 35 1027545-49

° O

ρχγ1ί> 0Η

MeHN / Ν γ ^ ^ Ν 5; NC-ΛΌ OMe ^ (22) 7- [3- (2-Cyano-1-nonhylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8- methoxy-4-oxo-r, 4-dihydroquinoline-3-carboxylic acid,

O O

FrfjrOH

N

NC- / - [omega] (23) 7- [3 (R) - (2-Cyano-1 (S) -methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-inethoxy -4-oxo-1,4-dihydro-quinoline-3-carboxylic acid,

° O

Yyt ° h

MeHN

- 25: (24) 7- [3- (2-Cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-inethyl-4-oxo-1,4-dihydroquinoline - * 3- 30 carboxylic acid, 0 0

Μ0ΗΝ jfiCj ° H

35 Mete 0 02 7545-5 ° (25) 7- [3- (2-Cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid,

5 0 O

NCVV M® A

1 ° (26) 7- [3- (2-Cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

NH 2 O 0

ΛτΥ ™

MeHN

NC-XJ ^ 20 (27) 5-Amino-7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline - 3-carboxylic acid,

NH 2 O 0

ΓχίΛ0Η

MeHN JLJL j) ιλνΧν

NC — Me A

(28) 5-Amino-7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 35 1 027545- 51 0 0

PHY111H

MeHN JWJk J1 (29) 7- [3- (2-Cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4- oxo-1, 4-dihydroquinoline-3-carboxylic acid,

O O

ΜθΗ LTM ί 15 Μθ

Me Me (30) 7- [3- (2-Cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo 1,4-dihydroquinoline-3-carboxylic acid, O 0

MeHN

25 0¾

Me Me (31) 7- [3- (2-Cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4 dihydro-quinoline-3-carboxylic acid, 0 fYy ™. I!

Me Me-1 1027545-52 (32) 7- [3- (2-Cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4- oxo-1,4-dihydroquinoline-3-carboxylic acid,

5 NH 2 O O

MeHVy ~ N

OMe λ

Me 'Me' (33) 5-Amino-7- [3- (2-cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4 -oxo-1,4-dihydroquinoline-3-carboxylic acid or

15 nh 2 O O

MVNYr

Me A

μΛ *.

(34) 5-Amino-7- [3- (2-cyano-2,2-dimethyl-1-methylamino-ethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-inethyl-4-oxo-1 1,4-dihydroquinoline-3-carboxylic acid.

25 Also; a compound of formula V or VI is provided:

R3 is O

v 35 1027545v 53:

R3 is O

B ^ XkJ1 R "" \ Λ ό \ τ <ΐ vyi1 Rs Ri

5 R '· "Μ * ΓΗι>., VI

or a pharmaceutically acceptable salt thereof, wherein: X is N or C, provided that when X is N, R 5 is missing in that position, R 1 is (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, ( C 3 -C 6 cycloalkyl, halogen (C 3 -C 6) cycloalkyl, heterocycle, aryl, heteroaryl and CH 2 (C 3 -C 6) cycloalkyl, R 2 is OH, BO 2, O (C 1 -C 6) alkyl, O (C 3 -C 6) cycloalkyl,

O

O- (CHR2a) m-0-1LQR2b, where m is an integer 25. from 1 to 10, Q is 0 or NH or N (C 1 -C 6) alkyl, or is missing, and R 2a is H or (C 1 -C 6) alkyl and R 2b is (C 1 -C 6) alkyl, aryl or heteroaryl, O- (CHR2a) n X, wherein R2a has the meaning given above, n is an integer from 2 to 10, Y is OH or NR2cR2d, wherein R2c and R2d are each independently Η, (Οχ-C6) alkyl or (C3 -C6) cycloalkyl or NR2a, wherein R2a has the meaning given above, 1027545-54 ^ V ^ x - ^ RA-Vh where the blinding indicates ** ^ 8 'Rgp point, 2a has the meaning given above , R2e and R2e are each independently H or (C1 -C6) alkyl, or taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring 10, e an integer from 1 to 10, p is an integer from 2 to 10, and Χχ and Υχ are each independently NH or O, R3, R4 and Rs are each independently H, halogen, NRyRz, where Ry and Rz each independently is H or (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, hal ogenic (C1 -C6) alkyl, O (C1 -C6) alkyl, O (C1 -C6) haloalkyl, nitrile,

R 1 and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1 or 2 heteroatoms selected from 0, S, SO, SO 2 or NRX, wherein R x is H or (Οχ-β) alkyl and q is 0, 1, 2 or 3 and z is 0, 1 or 2,

Rb is H1. (C 1 -C 6) alkyl, halogen (C 1 -C 8) alkyl, halogen, or R a and R b taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring 35, R ", R", R "" and R "" are each independently H, (C 1 -C 6) alkyl, 1027545-5-O (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, aryl or heteroaryl, 5 B is

Rc \, ¾

N

NC ^ J ^ 10 Rf Re, or R / Rf Rc RVRe 15 NC-V_R £ 7 “^ Γ« h Rc,

Ve

NC-V

R 8 / C provided that when B is H, R c, R 12 is not O (C 1 -C 6) alkyl, and wherein the binding point denotes and R c and R d are each independently H, (C 1 -C 6) alkyl nitrile, 25 o

II

-P-OH OH,

O

-P-0 (CrC6) alM

O (C 1 -C 6) alkyl, (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, heteroaryl, SO 2 - (C 1 -C 6) alkyl, SO 2 aryl, SO 2 heteroaryl, 1027545- --- - - - - __.

56

O

(CRaaRaeOg-O ** QR2b ^ wherein g is an integer from .1 to 10, Q has the meaning given above, and R2a and R2a 'are each independently H or (C1 -C6) alkyl, or taken together with the carbons to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring, and R 2b is (C 1 -C 6) alkyl, aryl or heteroaryl,

O O

(CH 2 R 3) O-P (OH) 2 or (CR 2 R 5 O 4 -O (P 1 -C 1 -C 6 alkyl) wherein R 2a and R 2a have the meaning given above.

Ah) m - "20" P, wherein the binding point denotes, p is 0 or 1 and R 2c is H, (C 1 -C 6) alkyl, O (C 1 -C 6) alkyl, 25 (C 3 -C 7) cycloalkyl, aryl, hetero ring, heteroaryl or 30 o - (CHR ^ ln-oJ-QR) or - (CHRaJj-Y, where 1 02 75 45-. 2 R 2a, ^ 2b and Q have the meaning given above, and h and j each independently integers from 0 to 5 are 10, and Y is OH, .PO (0H) 2, .PO (0 (C 1 -C 6)) 2, or NR 2 dR 2e / wherein R 2d and R 2e are each independently H, (C 1 -C 6 ) alkyl or (C 3 -C 7) cycloalkyl, 9 R 10 v R 2 R 5 nys) O-R 2 n 1 H / q, wherein q is 0 or 1, R 2 f and R 2 f are each independently Η, (Οχ-C 6) alkyl, aryl or heteroaryl, or together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring and R 2 is 20 (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, | aryl, hetero ring or heteroaryl, Re and Rf are each independently H, C1 -C6 alkyl, haloalkyl, halogen, or Re and Rf taken together with the carbon to which they are attached and n 3, 4, 5 or 6-membered substituted or unsubstituted ring, R 8 and Rh are each independently H, C 1 -C 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached, a 3-, 4- 5, 6 or 6-membered substituted or unsubstituted ring and Rj and Rk each independently. H, (C 1 -C 6) alkyl, haloalkyl, (C 1 -C 6) alkyl-NR c R d, (C x C 6) alkyl-OR c, aryl, heteroaryl, heterocycle, 1027545-58

O

(C 1 -C 6) alkyl Z-R (if wherein Z is O or NRC, or Rj and Rk together with the carbon to which they are attached, a 3-, 4-, 5- or 6-membered substituted or unsubstituted ring to shape.

A connection is also provided, which is: 10

O O

NCTX ^ N FVY || 0H

15 Aβ A

(1) 7- [4- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-di-hydroquinoline- 3-carboxylic acid, 20

O G

> h FYTif0H

N = ^ VN r-N'Y'N '' 'βΑ (2) 7- [4- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro- 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 30

K'rSr OH

H JL II IJ

xy xa 35 1027545-59 (3) 7- [4- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydrochi- noline-3-carboxylic acid, O 0 5

H I. I

xy, ° MeA

10 (4) 7- [4- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydrochino-3-carboxylic acid , 15 OO Me λ.

... 20 '· (5) 7- [4- (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid, 25

O O

wr / NH 2 f 11 ΡγΎ |) ° Η OMe λ 30 Δ (6) 7- [4- (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6- fluoro-8-inethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 1027545-60 o nh 2 11 5 (7) 7- [4- (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methyl-4-oxo 1,4-dihydroquinoline-3-carboxylic acid,

15 0 ^ TT

OMe λ (8) 7- [4- (1-Aino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-20 quinoline-3-carboxylic acid,

Ne oo (9) 7- [3a- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4,4-dihydroquinoline -3-carboxylic acid, NCno ^ NtH VVV ™ 35 rh-102 1024545-61 (10) 7- [3a- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6 -fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

5 O O

NCV J [

VNH

". / Hrvw

Me ^ 10 (11) 7- [3a- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydrochino-line-3 -carboxylic acid, 15 NC n oo; ; OMe ^ 20 (12) 7- [3a- (2-Cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid, CN 0 0 h2nv / ^ -λ 30 (13) 7- [3a- (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro- 8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

CN o O

H2Nv> / OMe ^ (14) 7- [3a- (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo 1,4-dihydroquinoline-3-carboxylic acid,

N O O

w- ^ υΛΛη 15 CC ”Ij

a

(15) 7- [3a- (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-quinoline- 3-carboxylic acid or

CN O O

H 2 Ny y ^ T ^ S 1 OH

25: ÓM eA

(16) 7- [3? - (1-Amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-30. quinoline-3-carboxylic acid.

A pharmaceutical composition is also provided which comprises a compound with one of the. formulas I, II, III, IV, V or VI in admixture with a pharmaceutical 35. acceptable (a) r diluent, carrier or excipient.

1027545-63

A method for treating a bacterial infection in a mammal is also provided, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, II, III, IV, V or VI. .

Detailed description of the invention

In the following, details will be given of the presently preferred compositions, embodiments, and methods, and constitute the best practice for practicing the present invention currently known to the inventors.

The term "alkyl" as used herein refers to a linear or branched hydrocarbon of 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n pentyl, n-hexyl and the like. The alkyl group can also be substituted with one or more of the 20 substituents selected from lower (C 1 -C 6) alkoxy, (C 1 -C 6) thioalkoxy, halogen, aryl, heteroaryl, oxo, thio, -OH,. -SH, -F, -CF 3, -OCF 3, -NO 2, -CO 2 H, -CO 2 (C 1 -C 6) alkyl or "V.

25. "—O.

1027545-64

The term "(C 3 -C 6) cycloalkyl" means a hydrocarbon ring containing 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclpentyl or cyclohexyl. Where possible, the cycloalkyl group may contain 5 double bonds, for example 3-cyclohexen-1-yl. The cycloalkyl ring can be unsubstituted or. are substituted with one or more substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, halogen, formyl, carboxyl, -CO 2 (C 1 -C 6) alkyl, CO (C 1 -C 6) alkyl, aryl, heteroaryl, wherein alkyl, aryl and heteroaryl have the meaning given herein, or have the meaning given above for alkyl. Examples of substituted cycloalkyl groups include fluoroclopropyl.

The term "halogen" includes chlorine, fluorine, bromine and iodine.

The term "haloalkyl" means a (C 1 -C 6) alkyl group that is substituted with one or more halogens.

The term "aryl" means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms that is unsubstituted or substituted with one or more of the alkyl group substituent groups mentioned above, including halogen, nitro, halo, nitro, cyano, -OH, -SH, -F, -CF3, -OCF3, -, -CO2H, -CO2C1-C6 alkyl or -SO2 alkyl. Examples include, but are not limited to, phenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 2- chloro-5-methylphenyl, 3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, naphthyl. 4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, fluorenyl, 2-acetamidofluoro-9-yl and 4'-bromophenyl.

1027545- 66

The term "heteroaryl" means an aromatic cyclic or polycyclic ring system with 1 to 4 heteroatoms selected from N, 0 and S. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3- furanyl, 2- or 3- pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4-. or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5- 1,2,4-thiazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridinyl, 3-, 4- or 5-10 pyridazinyl, 2-pyrazinyl, 2- , 4- or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1- ,. 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo [b] thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 15 5-, 6- or 7-benzothiazolyl. The heteroaryl groups can be unsubstituted or substituted with 1 to 3 substituents selected from those described above for alkyl, alkenyl and alkynyl, e.g. cyanothienyl and formylpyrroleyl. Preferred aromatic condensed heterocyclic rings with 8 to 10 atoms include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3- , 4-, 5-, 6 ^, 7- or 8-isoquinolinyl-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6 - or 7-benzo [b] thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 5 - 6- or 7-benzothiazolyl.

Heteroaryl also includes 2- and 3-aminomethyl furan, 2- and 3-aminomethyl thiophene and the like.

1027545-67

The term "heterocyclic" means monocyclic, condensed, bridged or spiro-bicyclic heterocyclic ring system. Monocyclic heterocyclic rings contain about 3 to 12 ring atoms, with 1 to 5 heteroatoms being selected from N, 0 and S, and preferably 3 to 7 atoms as members in the ring. Bicyclic heterocycles contain about 5 to about 17 ring atoms and preferably 5 to 12 ring atoms. Bicyclic heterocyclic rings can be condensed, spiro or bridged ring systems. Examples of heterocyclic groups include cyclic ethers (oxiranes), such as ethylene oxide, tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein the substituents are those described above for the alkyl and cycloalkyl groups. Typical substituted cyclic ethers include propylene oxide, phenyioxirane (styrene oxide), cis-2-butene oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofuran, 2,6-dimethyl-1,4-dioxane and the like. Hetero rings containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrothiazine, tetrahydropyrazole and substituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-1-yl and the like. Typical heterocycles containing sulfur include tetrahydrothiophene, dihydro-1,3-dithiol-2-yl and hexahydrothiophen-4-yl, and substituted groups such as aminomethylthiophene. Other commonly used heterocycles include dihydrooxathiol-4-yl, dihydro-1H-isoindole, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholobenzoyl-octahydo-benzoyl-octahydo-benzoyl-benzoyl-octahydo-benzoyl-octahydo-benzoyl-benzoyl-azo-diazoyl-octahydo-benzoyl-benzoyl-azo-diazoyl-benzoyl-azo-diazoyl-octahyl-azo-diazoyl-benzoyl-azo-diazoyl-benzoyl-azo-diazoyl-azo-di-azo-benzoyl-azo-di-azo-benzoyl-azo-di-azo-benzoyl-azo-di-azo-benzothyloxy-azo-3.alpha. For heterocycles containing sulfur, oxidized sulfur heterocycles are also included which contain SO2 or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene.

1 02 75 45 - 68

In some cases, protecting groups may be used to prepare the compounds of the invention described herein to allow synthetic manipulation of a functional group in the presence of other functional groups. It. proper use and the appropriate choice of protecting groups is for a person skilled in the art. It will also be appreciated that such groups serve not only to protect chemically reactive sites, but also to increase solubility or otherwise alter physical properties. A good general reference work for the preparation of protecting groups, and the protection thereof, is from Greene, Theodora, Protective Groups in Organic Synthesis; Wiley; New York, USA, 1991, and 15 subsequent editions. Moreover, it will be understood that compounds of the present invention characterized by the presence of a protecting group as mentioned in described by Greene should also be considered as compounds of the present invention.

When a bond is represented by a symbol such as "------" it is meant that the bond may be both absent and present, provided that the resulting compound is stable and complies with the rules regarding valence.

When a compound is represented by a line such as the binding is meant to be the binding point between two molecular subunits.

The term "patient" means all mammals, including human persons. Other examples of patients include cows, dogs, cats, goats, sheep, pigs, and rabbits.

1027545- 69

A "therapeutically effective amount" is an amount of a compound of the present invention that, when administered to a patient, provides the desired effect; that is, it reduces the severity of the symptoms associated with one. bacterial infection.

It will be apparent to those skilled in the art that the compounds of the present invention with one or more chiral centers may exist in and are isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It will be understood that the present invention encompasses all racemic, optically active, polymorphic, geometric or stereoisomeric forms, or mixtures thereof, of a compound of the present invention that have the useful properties described herein. It is well known in the art how the optically active forms (e.g. by separation of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis or by chromatographic separation with a chiral stationary phase) are prepared and how the activity whether cytotoxicity is determined with the standard tests described herein, or by using similar prior art tests.

Certain compounds of the present invention are also useful as intermediates for preparing other compounds of the present invention. Thus, a compound wherein R 2 is BF 2 can be hydrolyzed to form another compound of the present invention wherein R 2 is H.

1027545-70

Some compounds of the formula I are capable of forming other pharmaceutically acceptable acid addition and / or base salts. All of these forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds of the formula I thus include salts derived from non-toxic inorganic acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide, hydrogen fluoride, nitric acid, phosphorus, sulfur, phosphorous acid and the like, as well as the salts derived from non-toxic 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. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, mono-hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates, suberate, sebacate, fumarate, maleate, benzoate, mandelzoate, methyl benzoate, mandelzoate , dinitrobenzoate, phthalate ,. benzene sulfonate, toluene sulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methane sulfonate and the like. Also contemplated are salts of 25 amino acids such as arginate and the like, and gluconate, galacturonate (see, e.g., Berge, S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977; 66: 1-19).

The acid addition salt of the basic compounds .30 is prepared by contacting the free base form with a sufficient amount of the desired acid. which forms the salt in the usual manner.

1027545-71

Pharmaceutically acceptable basic addition salts. formed with metals or amines such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are. N, N'-dibenzyl ethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexyl amine, ethylenediamine, N-methylglucamine and procaine (see, for example, Berge, S.M., supra, 1977).

10. The base addition salts of these acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in the usual manner.

Certain compounds of the present invention can be used in both. unsolvated and solvated forms exist, including the hydrated forms. In general, the solvated forms, including the hydrated forms, are equivalent to unsolvated forms and are included within the scope of the present invention.

A "prodrug" is an inactive derivative of a drug molecule that requires a chemical or an enzymatic biotransformation. to release the active original drug in the body.

Specific and preferred values for the compounds of the present invention are listed below for groups and substituents. Scopes are merely illustrative and do not exclude other defined values or other values within the defined ranges for the groups and substituents.

Unless otherwise stated or defined, the abbreviations used herein are in accordance with the statement given in the American Chemical Society journals.

35 We now therefore focus on a compound of the formula I that has the structure: 1 027545-r3 o o 72 c A '

5 Re R) I

has.

A specific value of X is C or N. A specific value of R 1 is (C 1 -C 6) cycloalkyl and halogen (C 1 -C 6) cycloalkyl, aryl or heteroaryl. A specific value of R3 is H or NH2. A specific value of R 4 is H or halogen. A specific value of R 5 is halogen, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy when X is C.

In another embodiment of a compound of the formula I, a specific value of X is C or N. A specific value of R 1 is cyclopropyl or fluorocyclopropyl. A specific value of R3 is H or NH2.

A specific value of R 4 is H or F. A specific value of X is C or N. A specific value of R 5 is halogen, methyl or methoxy.

In another embodiment of a compound of the formula I, R 1, R 3 and R 5 are as in the following structures, wherein R 2 is OH, OHF 2 or O (Οι-Οε) alkyl, R 30 is H or F, and A is R® Rb t Or ^: 1027545- OO 0 0 0 0 73 '2 "ΪΪΓ"' "'ΠΤ" 2 Α' ^ γ ^ Ν Α - '^ γ ^ Ν ^ Α' ^ Ν ^^ Νγ C 'Δ Me "0 Δ Μθ Λ V» "Λ * ο Ο νη2 ο ο νη2 ο ο R4iW" R4rtY- A '^ N ^ Ijr A- ^ N ^ N ^ a -' ^ Y ^ N ^ j

A Me- ° A Cl A

o O O O Me O O

^ vys "-yv1 / ^

κ N tr ^ f ^ VT A "" ^ f * KfT

A ° ^ 3A OMe X

O O O O O O

XXji R * jfY $ * *% A] T N A, 'y ^ y A "jp ™ C' A ^ Me'0 y" Ά oo nh2 o o nh2 o o R4XA ^ R2 R4xrR2 YïYR ’

A ^ N ^ IJT K '^ fKn'J

A Μβ ^ ° A, 01A

F. F F,

0 0 0 0 Me O O

"Vyy * ^" "ttY * 2" 'ΔΛι Rz Α' ^^ ψ A '^ y ^ H Α’-γ' ^ Ν A ° f * A OMoA,>,, f, 1027545- 74

00 00 O O

^ i ^ rVR2 ^ ïXT'R2 1 Α, / γ ^ Ιί Α · ^ γ ^ Ν Α, / Ν [Ν “nV ΜβΝ <γ ^ 'τΎ *

^ίΝ '^ ν ^ HjN'y' ^ Η, Ν- ^ Q

F, F F

0 0 ΝΗ2 Ο Ο ΝΗ2 ο ο ^ ύύΥ '^ R4ibuR2 "ύτγ * Α' ^ Ν ^ Ν Α, χηρ" Ν ^ Λ '. ^ Χ ^ Ν Ν * ^ Ρ 01Ν J | ^ F Μβ ^ ° Ν ^ ΎΡ H2 N "S ^ H2 N" ^ y H2 N ^ y ^

F F. F

0 0 Me O O O O

^ ύυΥ'1% ^ ïxt ^ 112 n, Txj'v & <r &

h2n · I T

F, F F

0 0 0 0 nh2 0 0 "" ïV "2" "TïV ^ 2 R4 / X Rs

A, y * ^ f * n A, x ^ p "N

cV ° '° φ "

T. f F

0 0 0 0 Me O O

T 1 T 2 IT Y IJ J

Α ^ 'γ'κ A ’^ f'W A ^ y ^ N

Yr - "" ó "* Λά"

F, F, F

1027545-nh2 o 75 p T 5? i? o o '' Y ^ S'ir ^ Rj Β, ν ^ ν ^ ν ^ -ι> A '^ r •• V / ΧζΡ - "/ r"

"A . U. V

or 10 As previously indicated in compounds of the

present invention A

or Hb, wherein q can be 0, 1, 2 or 3 and z can be 0, 1 or 2. In a specific sense, z is 0, 1 or 2 when q is 2 or 3; alternatively z is 1 or 2 when q is 0, 1, 2 or 3.

In a specific sense, R a and R b can each be independently H, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halogen (C 1 -C 6) alkyl, halogen, or R a and R b taken together with the carbon to which they are bonded C = O, C = NO (C 1 -C 6) alkyl, or a 3, 4, 5 or 6-membered substituted or unsubstituted ring. In a more specific sense, R a and R b are each independently H, methyl, ethyl, fluoro, fluoromethyl, trifluoromethyl, fluoroethyl, methoxy, MeO-N =, or taken together with the carbons to which they are attached, form a cyclopropyl ring. ', R ", R"' and R, # // are each independently H, (C 1 -C 6) alkyl, -O (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, aryl or heteroaryl. In a more specific sense, R ', R ", R" "and R" "are each independently H, fluoro, methyl, ethyl, fluoromethyl, fluoroethyl, phenyl, benzyl or methoxy.

1027545-76

Rcs, R (J

i Rh Rib Rf o V- 5 In a specific sense, B "e t R © Rf Rc or.% / 1 nh π © $$.

However, when B is h * c * n ^ or, wherein the binding point denotes, R 'is not - O (C 1 -C 6) alkyl.

In a specific sense, Rc and Rd can each be independent

15 o O

-P-OH-P-O (C 1 -C 6) alkyl are H, (C 1 -C 6) alkyl nitrile, OH 2 (C 1-6) 8, (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, heteroaryl , SO 2 - (C 1 -C 6) alkyl, SO 2 aryl or SC> 2 heteroaryl. In a more specific sense, Rc and Rd are each independently H, "methyl or ethyl."

In a specific sense, Re and Rf can each be independently, H, C 1 -C 6 alkyl, haloalkyl, halogen, or Re and Rf taken together with the carbon to which they are attached form a 3, 4, 5 or β-long substituted or 25 unsubstituted ring. In a more specific sense, Re and Rf are each independently H, methyl or ethyl.

In a specific sense. R 8 and R 8 can each be independently H, C 1 -C 6 alkyl, haloalkyl, or taken together with the carbon to which they are attached, form a 3, 4, 5 or 6-membered substituted or unsubstituted ring. In a more specific sense, Rg. and Rh are each independently H,. methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxa

O

χ zolyl, carboxymethyl, carboxyethyl or rf ^ NHMe or form these together with the carbons to which they are bound ^ Specifically, Rj and Rk can each be independently H, (C1 -C6) alkyl, haloalkyl (C1 -C6) alkyl -NRcRd / (C 1 -C 6) alkyl-ORc, aryl, heteroaryl, heterocycle,

O

10 (C 1 -C 6) alkyl ^ z Rd ^ wherein Z is O or NRC, or Rj and

Rk taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring. In a more specific sense, Rj and Rk are each independently H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazo

O

a

lyl, carboxymethyl, carboxyethyl or NHMe,. or form them together with the carbons to which these 20 Δ are attached ·

In the compounds of the formula I, wherein A is 25, and z is 0, 1 or 2, and / \ / \ i or

RaARb Hf Re, R * Rf Rc

Rf. The NC-V® r-Λ — Ν - «30 ft. Examples of A are therefore one of the following structures: 35 '·. ·' 1027545- 78 B“ CN ”B'CN“ B ^ <C> ~ * -o * ~ ·· ^ z> * “· bt> ~ Jxy * - & * - Ά> b- £> ^ <Ρ" ~

bV

I'n '"' 15: ^ in which" rvA / w "indicates the binding point.

In addition, in compounds of the formula I, "Oei", yy * where A is B / v '/ WVRb or ^, where z is 0, 1 or 2 and q is 0, 1, 2 or 3, examples of A are one of .de B'V '' B9VR "Ίί" »

25 NC J ~ NCVS

"R." Rf Bo following structures in which Bi Re, or NC-. RC-V-N · ^ 30 RC: "te * - d> et" - ^ 3n ”35 o

F 1 Λ B

Ρ ^ ΎΛ- ^ CC ^ r <^ Qn- 1 0275 45 -

------- - - - I

79 where "ΛΛΛ / ν" indicates the binding point.

R, Rh%, RK R1 R.

ncJ * n- <nc- <5 As previously indicated, B can be A, 'or Rs-11

Re Hh Rc,

RhVR- or R »Re are wherein Rc, Rd, Re # Rf / Rg / Rh / Rj and Rit have one of the definitions given above. Thus, B can have one of the following structures: NC- \ NC "V K1 NC" X_K1 NC ^ \ xs, \ [<JW Λ Ishw N — Nw N ^ N.

H Me, Et, H, Me, - V Y Γ NCs ^^ A ^, A, NCn / \ nA,

Η, Η, Η, H

γ O <0 nc ^ nJL, νο ^ νΛ, nc ^ nJs nc ^ n ^

. Η Η H

Me Me Me Me nc ^ n ^, nc ^ nX,

Me, Et, Et, H>

F F

NC ^ N ^ ncVv ^ nXh nc ^ .nX | H, Me, Η H,

O ^ OR O ^ NHR

nc ^ nX b = h · ι ° "'nc ^ nX r = h · <C'-Ce) alkyl NC Z *

H, H

1027545-80 OMe OMe NHMe A, Λ, NCV ^ H Me J ».

5

Given the description of A and B, 10 therefore comprises one of the following structures: RHN ·· <) “" Kr'Q-

Jk> - "OP- ^ y.

Me Me Me RHN \ ^ R'N ^ V \ Me ^ N ^ V ^ Me'N ^ V ^ v Μθ- ^ νΑ ^ JLy ** "

Et | __ / N ~ R R Γ ^ Ν ~ R l ^ N ~ Me · ^^

Me Me / - \ RHN RHN \ rhn ^ O ~ RHN ™ Γ ^ * ~ o * ~ 0 "~

F3C F

/ - \ RHnJ * ® -Ph RHN— \ 3 Y-F

"K> t> RrtN ^ t> M.J ^>" ^ xy

RHV rhn y z \ / \ FaS

MBrO ~ ρ, ο- ^ ν- βηνΛον ~ “0 ^” "» <A ^ y.

F η-o rhnX-λ Jl · rhnX-λ ^ RHN ^ RHN ^ Q ^ N- ~

f = N

V> FYF, rA> "Λ> 1027545-81 OMe Me rum

MeHN V VN ~ X> ~?> MeV “Χ · ^ M ° -

Mtó HO 0 fF Γ 1 I> rhn- ^ 4 ^ rhn'V ^ RHN- ^ y ^ RHN ^ N ^ RHN- ^ f-Λ, ΓΝ- JLz l ^ N- LyNw - Me ^ "" "" n> , JU ^ ”0>" "ï>

F ,, / "" MoO ^ Mecr ^ F

f6 Me HHN.

~ JJ "VD -." 1 ^ -¾, *> '15 ^ fj Me RHNn BO ^ O H2N o Me 20 Γ nLJK, JL RHN "^ V ^

RHN-R-RHN-γ-N [NH

I Ν “I N'1” c'T ^

^ F F

wherein R is CH 2 CH 2 CN.

The description of A and B also includes 25 '·. ··.

Ra Rb also one of the following structures:

R f f R Me R

Η, Η ^ '^ xy & U η ,, - V VO- ^ κΛ \ i N ~ - Me / [^ / Nw H2N' -. \ _Γ V ~ 1027545-

- -----—--. _ J

82 R F Me

HiN-C hA> ^ Λ> ~ m ~ \ y ~ sy E f R R P. T? ^^ YV- Η, Ν- ^ γχ ^ CD ^^ L) - -fc ^ F c F Pp R / OMe R ^ F H2N "V" \ 1 10 h ^ u- η! ΝΛ6- ^ do-wP ~ .

JVy ^ do- cd ^ jct ^ dp-

k> <0 "" T fT

Wherein R is CH 2 CN.

With also given the description of A and B

β \ λν ^ r. „βκΓ- ^

20 W> Z

βΛ ^ _ r "·· KqV

encloses b or one of the following structures:

RHN RHN-, RHNv1 RHN / NHR

25 do-cc-^ y ~ '<o * ~

RHN RHN RHN

rhn ^ c-0 (d>;> do-dc-30 wherein R is CH 2 CH 2 CN.

With also given the description of A and B 35 1027545. 83 rOGv r- v ^ 1 encloses R or V / X / J) * one of the following structures: R "" Vwr ^

5 R HCHNVR RcHNyR rchn ~~ / R RcHN- <R

"^ todo 0> <o CO

RcHN ^ R RcHN - ^ / R

Wherein R c is H or (C 1 -C 6) alkyl and R is CH 2 CN.

We now focus on compounds with formulas II and III, which have the structures: 1-5 r3 O o »> .. 'jGcV' i 20 Ra Rb n

R3 is 0

r i x R x N

Rc-N ^> r ^) z Rs Ri 25 0 ”νν ΓΒ ΓΒ>, ,® Rb" β1 Rg CN ffl.

Specific values and embodiments of compounds of the formulas II and III are as given for the compounds of the formula I with respect to q, z, X, R 1, R 2, R 3, R 4, R 5 and R 8 Rbf Rcr Ref Rff Rg / Rhf Rj and. R * ·

We now focus on a compound of the formula 35 IV, which has the structure: 1027545-

R3 is O

84 ^ YTi Ri

Rcv / Rd I 11 J

c 1 * / ^ N ^ X ^ N

^ Rn

Rt% Ra Rb IV

has.

Specific values and embodiments of compounds of the formula IV are as given for the compounds of the formula I with respect to η, X, Rif R2, R3 / R4 / R5 and Ra / rb / Rc / Rd / R © and Rf ·

We are now focusing on a connection with formula V

15 or VI

R 3 or X 1 Cl 2 R 2! ~ ν? Λ * ν 20 ’fcV * A. R,

B M ’Rb V

R3 O o ,, R ... χ ^ ** 25 XV * Rs Rn R, "V / MRpb v. Specific values and embodiments of compounds of the formula V are as given for compounds of the formula I. with respect to n , q, X, R 1, R a, R a / R 4 / R 5 and R ', R ", R" "and R" ".

Preparation of compounds of the invention 1027545-85

Strategies for the preparation of the compounds of the present invention are depicted in the following schemes.

As is apparent from this description, the compounds of the present invention are characterized by a quinolon nucleus covalently bonded to a C-7 side chain Ra 'Rb' ^ Rj, or B ^ R "11 '' 'Rb. retrosynthetically depicted in Scheme I, the compounds of the present invention can be prepared via coupling of a suitable quinolone nucleus substituted on C-7, wherein X 2 is halogen * triflate or a similar reactive group known to those skilled in the art, and a suitably substituted azetidine, pyrrolidine, piperidine.

Schedule I

25 I3 or R3 OO

: ^ pggr ^ - = -> * -gs vrr "'

J. 1 11-X-X 2 X N

V) n Rs R, Ra Rb 2 1 1

Ra Rb 5 Rl 30

Quinoline core X2 = halogen, OSO2 CF3, R * OH, O (C1 -C6) alkyl, OBF2 35 1027545-86

As a reflection of the synthetic strategy briefly summarized in Scheme I, the following section describing the preparation of the compounds of the present invention consists of several sections. The first part describes the synthesis of the required precursors of the quinolon core. The second part describes the synthesis of the required precursors of the C-7 side chain. The latter part describes the coupling of the C-7 side chain and precursors of the quinolon core, which provides the compounds of the present invention, and lists any additional chemical details of compounds of the present invention with which other compounds of the present invention are produced .

A. Synthesis of precursors of the quinolon core

The precursors of the quinolon core used to prepare the. Compounds of the present invention are generally known to those skilled in the art and may be obtained commercially or, alternatively, prepared by synthetic routine methods. The following sections provide relevant references describing the preparation of the quinolon core precursors used to practice the invention described herein.

30 1027545

R3 0 O

87 1. Preparation of precursors of the quinolon core

Rs Δ 0 0

FnV ° H

Η'η-'ϊΓ ci x a. Δ EP 0357047; EP 0167763; EP0195841

O O

fVV-1b Me "° A JP8-9958 US 5,869,991

O O

fyy \ Aoh

X '^ f'N

Me 1 c. Δ EP 0357047

O O

YrV ^

X ^ N ^ N

d. A EP 0172651

NH 2 O O

fyV) Aoh

N

Me 1 st Δ US 5,859,026 1027545 · nh2 o o 88 f. ME "A EP 0610958

5 O O

ρώΥ ° η

10 S · A US5,639'886 Bi.6 O

w- x'y ^ rr

2. Preparation of precursors of the ohinolon core Rs / V

15

O O

20 ^ JL JL

vVi ° h JL IL I) As given for IA, above,

Ij except that fluorocyclopropyl

Clamine is used in place a. R of cyclopropylamine 25

30 o

FYYT <) H

Jl Jl IJ As given for IA, above,

Χ '^' Γ N

Except that fluoroclopropylamine is used in place F> 35 b. of cyclopropylamine 1027545- 89

O O

Yiv ^ 5

MeA

c. >

As given for IC, above, except that fluorocyclopropyl-amine is used instead of cyclopropylamine

O O

FXXVA ° H

X ^ N ^ N

a

As given for 1D, above, except that fluorocyclopropylamine is used in place of cyclopropylamine nh2 o o phySV0h

Me''0 Λ e. > 30 As given for 1F, above, except that fluorocyclopropylamine is used instead of cyclopropylamine 35 1027545- 90 ° §

ΡΥΎΤ 0H

χΧΛν κ f.

As given for 1H, above, except that fluorocyclopropyl-amine is used instead of cyclopropylamine

R3 is O

fyW-

X 'f' N

Rsn ^ Yf 20 H ^ V1 3. Preparation of £

O O

n

01 N-SrF

h2n "V

F us 5.9998436 p ·

O O

F ^ Cu 0 R

X ^ N

MeN ^ VF

h2N-V

US $ 5,998,436, 1 027545-91, or "Tide."

5 X N ^ N

/ rF

C 'F US 5,998436

NH 2 O 0

10 ρ \ λΑΛ

XXjj 0R

CinV

h2n ^ Y "15 d · F US 5,998436 ƒ 20 h §

FiYr ° R

λ ✓F

ΓΤ 25 Η2Ν ^ γ US 5,998436 e.

30 1027545 - 92, 92, 11

4. Preparation of X '^ Vv [S'N

°? fyVSt or

5 YYY <YYY

xY ^ N

U.S. Pat. No. 5,553,407 a.

10 B. Synthesis of C-7 side chains and side chain precursors VT Va "L> O" "15 1. Preparation of and V T! Thus, 3-formylpyrrolidine-1-carboxylic acid benzyl ester was reacted with cyanomethylphosphonic acid dimethyl ester in the presence of cesium carbonate to give 3- (2-cyanovinyl). pyrrolidine-1-carboxylic acid gave benzyl ester. The addition of ammonia or methylamine to 3- (2-cyanovinyl) pyrrolidine-1-carboxylic acid benzyl ester gave the corresponding Michael adduct, which was then protected with a tert-butoxycarbonyl (Boe) group. Removal of the benzyl ester group under conventional conditions afforded the target compound as the protected Boc analog, which can be subjected to silica gel chromatography, which delivers each diastereomer, and separation by chiral HPLC, which delivers each enantiomer. Purification by chromatography as described herein yields pure samples of 1027545-93

Boc ^ N ^ NHBoc N N NMe

hfT 4 NH H 1 T / NH

and, as well as the related diastereomers, for coupling. Removal of the protecting Boc groups gives after

N £ 1HZ

10 coupling the unprotected amines Hs [__ ^ Nw and \ rHM® H ', wherein.

H Scheme 1 J. Me.

k) * - 1. + -— X 1> - <0 0 o

Me

Me-J Me R .H O Me Mè ^: i .thën N. RN "S> HCO 2 NH 4? Me ~ yy ~ ^

25 NHNH

mJ> Me / "V - ·

Me ^ Me Me "^ Me R = H or Me

30 FsCyN ^ A

O yL · Ή

H

2. Preparation of 35 Ρ30γΝΝΑ

Ö <V

N

H

1027545-94 was prepared according to scheme 2. 1-Benzhydrylazetidin-3-carbonitrile was converted to 1- (1-benzhydrylazetidin-3-yl) cyclopropylamine as given by Chem. Rev. 1979, vol. 79, No. 4, and Tet. Lett., 44, 2003, 2485. 1 - (1 - 5 Benzhydrylazetidin-3-yl) cyclopropylamine was converted to N- [1- (1-benzhydrylazetidin-3-yl) cyclopropyl] -2,2,2-trifluoroacetamide as given by J. Med. Chem. 1993 vol. 36, No. 7. Hydrogenation of N- [1- (1-benzhydrylazetidin-3-yl) cyclopropyl] -2,2,2-trifluoroacetamide provided the title compound, which can be converted to the free amine and then can become . derivatized after the coupling reaction to the quinolon core.

Schedule 2 '.

15 CN h2nnA Ρ3 ° ΥΝνΔ i -i- O 1

H

CF3 <Ah 3. Preparation of ^ Me 30 cp3

CT'NH

1027545-95 was prepared as given in Scheme 3. The Grignard reaction of ethyl magnesium bromide with 1-benzhydrylazetidin-3-one thus yielded the corresponding alcohol, 1-benzhydryl-3-ethylazetidin-3-ol. Mesylation of the alcohol moiety in 1-benzhydryl-3-ethylazetidin-3-ol under conventional conditions, followed by the nucleophilic addition of CN, gave 1-benzhydryl-3-ethylazetidin-3-carbonitrile, which was subsequently reduced with lithium aluminum hydride (LAH ) which gave C- (1-benzhydryl-3-10 ethylazetidin-3-yl) methylamine. Protection of C- (1-benzhydryl-3-ethylazetidin-3-yl) methylamine as the trifluoroacetate, followed by hydrogenation, afforded the target compound, which can be converted to the free amine and then deprotected after the coupling reaction to the quinolon core.

Schedule 3

H ° f U

^ Me ^ Me

-X ~ NH 2 T

NC ^ N iQ

Me Me cf3 Q cf3 O ^ NH 1 - O ^ NH 'ψΌ ψΗ ^ Me 1 02 75 45-96

O

u HN'XFg

4. Preparation of I-nh * HCl

5 O

X

HN4 CF3 —NH · HCl • was prepared as given in Scheme 4. Thus, 1-benzhydrylazetidine-3-carbonitrile was hydrolyzed under conventional conditions to give 1-benzhydrylazetidine-3-carboxylic acid, which was then treated with 1- [3- (dimethylamino) propyl] -3-ethyl-carbodiimide hydrochloride and N, O-dimethylhydroxylamine hydrochloride in the presence of triethylamine to give 1-benzhydrylazetidine-3-carboxylic acid methoxymethylamide. Addition of ethyl magnesium bromide according to a Grignard reaction to 1-benzhydrylazetidine-3-carboxylic acid methoxy-methylamide gave the corresponding ketone, 1- (1-20 benzhydrylazetidin-3-yl) propan-1-one. Reductive amine ring of 1- (1-benzhydrylazetidin-3-yl) propan-1-one with ammonium acetate and sodium cyanoborohydride, followed by treatment with trifluoroacetic anhydride in the presence of an amine base yielded 1- (1-benzhydryl-azetidin-3-25 yl) propane 1-one. Hydrogenation of 1- (1-benzhydrylazetidin-3-yl) propan-1-one gave the target compound, which can be converted to the free amine and then deprotected after the coupling reaction to the quinolon core.

30 1 027545

Scheme 4 97% n ho \ j n edcM> + ci · HCl, A [LN y V Me T "71%. EtgN, CH 2 Cl 2, k y y y y 55 y%

o o

Me'N "Vl Me ^ MgBr Μβν ^ Ν-η j> LnJJ) -

·. Me y TH F, -70 to 0 C T

score 890/0 n ^ y? hn ^ xf3 I.NH4 OAC, NaCNBH3 Me ^

4 A. nol. Seven '' MeOH, kt | ^]) Hg, 10% Pd / C

2 0 0 1 HCl.MeOH

, TEA, CH 2 Cl 2 ζΐ 100% 53%

O

X

HN "XF3

M ^ L

L-nH. hci 1027545-98 T3

CT ^ NH

5. Preparation of L ^ T ^ NH.HCl

Me CF3

CT'NH

^ QNH.HCl

was prepared as given in Scheme 5. Similar to the synthesis of 10 CF 3

CT ^ NH

Et, depicted in Scheme 3, gave the Grignard-15 reaction of methyl magnesium bromide with 1-benzhydryl-azetidin-3-one the corresponding alcohol, 1-benzhydryl-3-methylazetidin-3-ol. Mesylation of the alcohol moiety in 1-benzhydryl-3-methylazetidine-3-ol under conventional conditions, followed by nucleophilic displacement with CN, 1-benzhydryl-3-methylazetidine-3-carbonitrile, which was subsequently reduced with lithium aluminum hydride (LAH) giving C- (1-benzhydryl-3-methylazetidin-3-yl) methylamine. Protection of C- (1-benzhydryl-3-methylazetidin-3-yl) methylamine as the trifluoroacetate, followed by hydrogenation, provided the target compound, which can be converted to the free amine and then deprotected after the coupling reaction to the quinolone core .

30 1027545

Schedule 5 99

Me Me - * "NH 2 ** 0 ^ 0 S ^ N> 0 m 7 ^ Me ^ cf3

CF3 or J T

15 cA, H - 0 ΓΓΝΗ, Ηα,. ^ ΠΠΓϊ r-7 n7 Kj? Me

Me

^ '- CT XLy ^ NH

6. Preparation of H 2 N J: and h 2 N V - / 20

<1, / ^ NH h ^ ONH

The target compounds ^ 2 N 'and 2 were prepared as given in Scheme 6. Thus, N-25 (trimethylsilylmethyl) -α-methylbenzylamine was prepared from the corresponding amine with trimethylsilyl chloride under conventional conditions. The reaction of N- (trimethylsilylmethyl) -α-methylbenzylamine with formaldehyde in the presence of potassium carbonate and methanol gave N-. (Methoxymethyl) -N- (trimethylsilylmethyl) -α-methylbenzyl amine, which was subsequently converted to 1- (1-phenylethyl) pyrrolidine-3-carboxylic acid dibenzylamide as a mixture of. stereoisomers. Treatment of the amide 1 027545-100 with ethyl magnesium bromide in the presence of Ti (0-i-Pr) 4 afforded the protected target compounds as a separable mixture. The separable diastereomers were deprotected by hydrogenation to give the target compounds.

5

Scheme 6 H H 3 ClO 4 N 4 Si (CH 3) 3

NH 2 Me 3 SiCH 2 Cl 1 N 4 Si (CH 3) 3 HCHO

Ph ^ Me EtaN Ph ^ Me MeOH

O

CF3COOH J— ^ NBn2 EtMgBr y— ^ NBnz, ^^ ΝΒηζ

^ ΝΒπΓ l γ + V

1 Cr "θ" qV

BocHN '^ Sr ^ \

7. Preparation of I NH

ΒοοΗΝγ ^ ΝΗ * —f was prepared as given in scheme 7.

Thus mesylated S-1-benzylpyrrolidin-3-ol, followed by nucleophilic addition using CN, R-1-benzylpyrrolidine-3-carbonitrile. Reduction with RH-1-benzylpyrrolidine-3-carbonitrile provided R-C- (1-benzylpyrrolidin-3-yl) methylamine. Boc protection of the amine group in R-C- (1-benzylpyrrolidin-3-yl) methylamine gave (1-benzylpyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester, which was hydrogenated and provided the target compound.

1 02 7545

Scheme 7 101 5 HvV + MsCl EtaN · Ms0 / '· ^ / == ^ L ^ n- / ch2ci2 XyN ^ 10 bunnn Mr O uu ^ ir, ncVa) = 7. h2n ^ N ^ \ /

NaCN ™ F UN

O O

<ΛΛ> 15 xK 80 ° ΗΝ ^. Hg Α Λ 20% Pd / C L ^> / 50 psi

BocHN-V

Λ NH

8. Preparation of 20

BocHN "^" - f— \

f NH

was prepared as given in scheme 8. Thus. Concerned treatment of 5-oxo-1- (1- phenylethyl) pyrrolidine-3-carboxylic acid methyl ester with lithium aluminum hydride [1- (1-phenylethyl) pyrrolidin-3-yl] methanol. Treatment of [1- (1-phenylethyl) pyrrolidin-3-yl] methanol with isoindole-1,3-dione in the presence of triphenylphosphine and diisopropylazodicarboxylate gave the phthalimide, 2- [1- (1-phenylethyl) pyrrolidine- 3-ylmethyl] isoindole-1,3-dione. Treatment of the phthalimide with hydrazine hydrate gave C - [1- (phenylethyl) pyrrolidin-3-yl] methylamine, which was protected by a BOC group and hydrogenated to give the target compound. This was converted to the free amine and then derivatized after the coupling reaction to the quinoline core.

5

Schedule 8.

O

VdMe. · Ί · ~ 0Η PPh3 ·· 'LAH ΓΛ DIAD r-s elher Y TOF 0 7. “HQ MeA0

15 O O

* -NH2 IA ^ NHBoc O ^ O ^ O / - \ HNNH2'H20 Y) / * <20% Pd / C _ BocHN ^ · ^ - ----- V --— "1 · 50 psi W.

THF M®

H2 N CN

r- \ MeMe

H

9. Preparation of 25

h2N ^ CN

/ (W Μθ

H

30 1 02 75 45-103 was prepared as given in Scheme 9. Thus, 1-benzylpyrrolidine-3-carboxylic acid ethyl ester was hydrogenated under conventional conditions to give the pyrrolidine-3-carboxylic acid ethyl ester. This was then protected with a BOC group, whereby the pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester, 3-ethyl ester was obtained. Reduction of the pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester, 3-ethyl ester gave the 3-hydroxymethylpyrrolidine-1-carboxylic acid tertio-butyl ester, which was oxidized to the corresponding aldehyde, the 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester under conditions for a reaction of the Swern type. 3- (1-tert-Butoxycarbonyl-amino-2-cyano-2,2-dimethyl-ethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester by the addition of lithium. isopropyl cyanide on the intermediate, an amidoalkyl sulfone. Protection of the 3- (1-tert-butyoxycarbonylamino-2-cyano-2,2-dimethylethyl) -20-pyrrolidine-1-carboxylic acid tert-butyl ester gave the title compound 3-amino-2,2-dimethyl-3-pyrrolidine-3 - yl-propionitrile as the dihydrochloride salt.

1027545.

104

Schedule 9

C0 2 a Et 2 CO 2 Et 2 CO 2 EtOH

ΓΛ H2, Pd / C f - (Boc2Q / - / NaBhU

P EtOH CH 2 Cl 2 THF MeOH

5 ^ Ph quant. H quant. Boc g4% Boc 1 step 1 2 step 2 3 step 3 4 (0001) 2, DMSO NEt3, CH2 Cl2 87% step '4

BocHN CN BocHN

PrCN.LDA / -S02Ph H2NBoc, PhS02Na / - (

10 / \ Μβ ΜΘ - / - (-i- O

THF {J ΗΟΟζΗ, ΜβΟΗ, ΗΛ N

N N Boc

Boc 91% Boc 39% 7 step 6 6 step 5 ®

HI

CH 2 Cl 2 73% step 7

15 T

H2 N CN

H .. 2HCl

8

10. Preparation of BocHN

OCNH

The compound was prepared as given in WO 96/39407.

rNHBoc nh2 rhnv ^ cn 25 (. ^ NH / ^ \ | R / 1 ^ uo

11. Preparation of and /

.NHBoc NH4 RHN4 -CN

30 CO ™ CONR NO

and can be prepared as given in Scheme 11. Thus, the [3 + 2] cycloadddition of cyclopent-1-enecarboxylic acid gives methyl 1027545-105. ester and the like with benzylmethoxymethyl-trimethylsilanylmethylamine under conditions available to those skilled in the art and discussed herein, 2-benzylhexahydrocyclopenta [c] pyrrole-3α-carboxylic acid methyl ester.

.NHBOC

/

The preparation of starts with the hydride reduction of 2-benzylhexahydrocylopenta [c] pyrrole-3a-10 carboxylic acid methyl ester with. aluminum hydride or borohydride to give (2-benzylhexahydrocyclopenta [c] pyrrol-3α-yl) methanol. Conversion of the alcohol moiety to (2-benzylhexahydrocyclopenta [c] pyrrol-3α-yl) methanol in a leaving group such as the mesylate or tosylate, followed by displacement with a primary or secondary amine, and protection and then deprotection, delivery (2 -benzyhexahydrocyclopenta [c] pyrrol-3α-ylmethyl) carbamic acid tert-butyl ester, 20.NHBoc CCNH.

Alternatively, as the reduction of the ester residue in. 2-benzylhexahydrocyclopenta [c] pyrrole-3α-carboxylic acid methyl ester is terminated in the: oxidation state of an aldehyde (for example by using DIBALH as a reducing agent), a reductive amination with ammonium formate or a primary alkylamine such as methyl or ethylamine, are used to obtain the aminated product. Conditions and reagents for a reductive amination are known to the skilled person.

1027545, NHBoc 1 106

The preparation of starts with saponification of the ester residue in 2-benzylhexahydroxycyclopenta [c] pyrrole-3α-carboxylic acid methyl ester to give 2-benzylhexahydrocyclopenta [c] pyrrole-3α-carboxylic acid. A Curtius rearrangement of 2-benzylhexahydrocyclopenta [c] pyrrole-3α-carboxylic acid with. using conditions and diversions known to those skilled in the art, gives NHBoc

<Ci / NH

(hexahydrocyclopenta [c] pyrrol-3α-yl) carbamic acid tert-butyl ester.

15

H 2 NY + -CN.

The preparation of - starts with a reduction using DIBALH of 2-. benzylhexahydrocyclopenta [c] pyrrole-3α-carboxylic acid methyl ester, giving the corresponding aldehyde. Methylation of the aldehyde under conditions for a Wittig reaction. Horner-Wadsworth-Emmons type 25 gives 3- (2-benzylhexahydrocyclopenta [c] pyrrole-3-yl) acrylonitrile. A Michael addition of ammonia or a primary alkylamine to 3- (2-benzylhexahydrocyclopenta [c] pyrrole-3a-yl) acrylonitrile provides [2-cyano-1- (hexahydrocyclopenta [c] pyrrole-3a-yl) ethyl] carbamic acid 30 tert-butyl ester.

1027545.

'107

Scheme 11 O ^ OMe / ^ CO2Me ^ x ^ <j; Me0s ™ OCN- ^ Ph - .OH __.____ CCN ~> Ph R = CH2 Ph y / ° γ · Η / ct> 10

Γ O ^ OH

.NHBoc

Hf> ^ <Xnr I

VX '/ "> I., - CN

J / "V ^ 15, NHBoc -" Ph> NHBoc co <T, NH j BOCHN ^ y ^,

<cbNH

C. Coupling of precursors of the C-7 side chain and precursors of the quinolone nucleus, whereby compounds of the invention are obtained.

Linking the precursor of the side chain to the precursor of the quinolone nucleus gives the compounds of the present invention, or precursors of the compounds of the present invention, and this can be from the core precursor comprising both the free acid, an alkyl ester and a borate ester can be as depicted in scheme 30 II.

1027545-

Schedule II

108

Rs 0 O

f f i * YYV ^ * 'c *' k> '-Km.? ·.' K K | B-js, r'x ^ Vom V \ x ^ S ^ Sr --- b / ^ nAx ^ n 10 Rs R,. R «R1 X = halog6s., OS02CFs" * Rb "

Rs O O 3 O O

4.1 B-0) n *. k «.R.

When a free acid is used in the coupling reaction, typically a molar excess of the precursor of the side chain is combined with the quinolone core in a polar solvent such as acetonitrile. A molar excess of an amine base such as triethylamine is added, and the reaction mixture is heated to about 80 ° C. In a typical case, the reaction mixture becomes homogeneous. The mixture is heated for a sufficiently long period of time to complete the reaction; in a typical case, it is about 3 to about 12 hours. The mixture is then worked up .30 according to procedures generally accepted by those skilled in the art. wherein a compound of the present invention is obtained.

1027545-109

When an alkyl ester is used in the coupling reaction, the quinolone core, the side chain and triethylamine are combined in a solvent such as acetonitrile. The resulting reaction mixture is stirred for 12 hours and heated to 80 ° C. In a typical case, the reaction mixture becomes homogeneous. The mixture is heated for a sufficiently long period of time to complete the reaction; in a typical case, it is about 3 to about 12 hours. The mixture is then worked up according to procedures commonly used by those skilled in the art to obtain a compound of the present invention.

When a borate ester is used in the coupling reaction, the required borate ester is typically prepared from the free acid by reaction with BF3 under conditions known to those skilled in the art. The borate ester is typically combined with the side chain in a solvent such as acetonitrile and treated with an amine base such as triethylamine. The resulting reaction mixture is typically stirred at room temperature for a sufficiently long period of time to complete the reaction; in a typical case, it is about 24 to about 96 hours. The reaction mixture is then worked up according to procedures commonly used by those skilled in the art (i.e. deprotection of the borate ester in ethanol in the presence of triethylamine), thereby obtaining a compound of the present invention.

30 D. Conversions after coupling

Coupling of the side chain precursors to quinolone nucleus precursors can lead to compounds of the present invention. Alternatively, conversions after coupling may be necessary to obtain compounds of the present invention. A typical conversion that occurs after the coupling includes the protection of protected amines, the compounds of the formula II of the present invention being obtained, as depicted in scheme III. Deprotection, as well as reaction with acylonitrile and the like, leads to compounds of the present invention with formulas III and IV.

10

Schedule III

Rs O o

pg. Rd YrV ° H

V> N "x" V ^ ontsch ^ ·. V »Xij“ 20 iCV, n Rt R ”« ίΗΚΛ 2, g

II

vv ^ y '—_., -Αν »» * · * K ^ 5 «s

Rh NC-RcR / X

PG "= protecting group ^, H

Pharmaceutical preparations

The present invention also provides pharmaceutical compositions comprising a bioactive compound of the present invention, or a salt thereof, or a compound of the present invention. 111 pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. The compositions include those in a form adapted for oral, topical or parenteral use, and may be used to treat bacterial infection in mammals, including human subjects.

The compounds of the present invention, such as antibiotic compounds, also referred to herein as antimicrobial compounds, can be formulated for administration in a suitable manner for use in human or veterinary medicine, by analogy with other bioactive compounds such as antibiotics. Such methods are state of the art and are not described in detail.

The composition may be formulated for administration by a route of the prior art, such as a subdermal, oral, topical or parenteral, or by inhalation. The compositions may take any known form of the prior art, including, but not limited to, tablets, capsules, powders, granules, pastilles, creams, or liquid compositions such as oral or sterile parenteral solutions or suspensions.

The topical compositions of the present invention may be presented, for example, as ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may be suitable. contain conventional additives, such as preservatives, solvents that assist in the penetration of. the drug and emollients in ointments and creams.

The compositions may also contain compatible conventional carriers, such as raw materials for a cream or ointment, and ethanol or oleyl alcohol for lotions. Such 1027545-712 carriers may be present in, for example, about 1% to about 98% of the composition. These can, for example, form up to about 80% of the composition.

Tablets and capsules for. oral administration may be presented in unit dosage form and may contain conventional excipients, such as binders, for example, syrup, acacia, gelatin, sorbitol, tragacant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Lubricants for tableting, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, e.g. potato starch, or acceptable wetting agents such as. sodium lauryl sulfate. The tablets can be coated according to methods known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle prior to use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or 113.

sorbic acid, and, if desired, conventional fragrance and flavor or colorants.

Liquid dosage unit forms are used for parenteral administration. prepared by using the compound and a sterile vehicle, with water being preferred. The compound may, depending on the vehicle and the concentration used, be either suspended or dissolved in the vehicle or other suitable solvent. In the preparation of solutions, the compound can be dissolved in water for injection and sterilized by means of a filter before filling a suitable vial or ampoule and then closing. In a favorable case, means such as. a local anesthetic, preservative and buffering agent are dissolved in the vehicle. To increase the stability, the preparation can be frozen after it is in the bottle. and the water removed in vacuo. The dry freeze-dried powder is then sealed in the vial 20 and an enclosed vial with water for injection can be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and that sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide before being suspended in the sterile vehicle. In a favorable case, a surfactant or wetting agent is included in the composition so that an even distribution. connection is facilitated.

1027545.

114

The compositions may contain, for example, about 0.1% by weight, for example from about 10-60% by weight of the active material, which is dependent on the method of administration. When the preparations 5. dosing units, each unit will contain, for example, about 50-500 mg of the active ingredient. The dosage used for treatment of an adult human subject will, for example, range from about 100 to 3000 mg per day, for example 1500 mg per day, depending on the route and frequency of administration. Such a dosage corresponds to approximately 1.5 to 50 mg / kg per day. For example, in a suitable case the dosage is about 5 to 20 mg / kg per. .day.

15

Biological activity

The compounds of the present invention can be investigated to identify bioactive molecules with different biological activities, using the methods available in the art. The bioactive molecules may, for example, have activity against a cellular target, including, but not limited to, enzymes and receptors, or a microorganism. A target cellular ligand or microorganism is one that is known or believed to be important for the etiology or progression of a disease. Examples of disease states for which compounds can be tested for biological activity include, but are not limited to, inflammation, infection, hypertension, central nervous system disorders, and cardiovascular disorders.

1027545-115

In one embodiment, the present invention provides methods for treating or preventing a bacterial infection in a patient, such as a human or other animal patient, which comprises administering to the patient an effective amount of a compound of the present invention. as described herein. In one embodiment, the compound is administered in a pharmaceutically acceptable form in optionally a pharmaceutically acceptable carrier. As used herein, a "contagious disorder" is a disorder characterized by the presence of a microbial infection, such as bacterial infections. Such infectious disorders include, for example, central nervous system infections, infections of the outer ear, infections of the middle ear, such as acute otitis media, infections of the cavities of the head, eye infections, infections of the oral cavities, such as infections of the teeth, gums and mucous membranes, upper respiratory tract infections, deeper respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, infections of bone tissue and joints, skin and skin infections, bacterial endocarditis, burns, antibacterial prophylaxis or surgical procedures, and antibacterial prophylaxis in patients with suppressed immune systems, such as patients receiving cancer chemotherapy, or patients undergoing organ transplantation. The compounds and compositions containing the compounds can be administered by routes such as the topical, local or systemic. Systemic use includes any method whereby the compound is introduced into the tissues of the body, for example, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The specific dosage of the antimicrobial agent to be administered, as well as the duration of treatment, may be adjusted as required.

The compounds of the present invention can be used for. the treatment or prevention of infectious disorders caused by all kinds of bacterial organisms. Examples of gram positive and gram negative aerobic and anaerobic bacteria include staphylococci, e.g. S. aureus; Enterococci, e.g. E. faecalis; Streptococci, e.g. S. pneumoniae; haemophilus, for example H. influenzae; Moraxella, for example M. catarrhalis, and Escherichia, for example E. coli. Other examples include Mycobacteria, for example M. tuberculosis, intercellular microbes, for example Chlamydia and Rickettsiae, and Mycoplasma, for example M. pneumoniae.

The ability of a compound of the present invention to inhibit bacterial growth, to exhibit in vivo activity and increased pharmacokinetics are demonstrated using prior art pharmacological models, for example using models such as 25 tests described below.

Test A - Antibacterial assays

The compounds of the present invention were tested against an assortment of gram-negative and gram-positive organisms using standard microtitration techniques (Cohen et al., Antimicrob., 1985; 28: 766; Heifetz et al., Antimicrob.

1027545.

117 1974; 6: 124). The results of the evaluation are shown in Tables IA and B.

1 027545- 118 \

Table IA

Minimum inhibitory concentrations in pg / ml gram-negative bacteria

Structure of compound H. influenzae M. catarrhalis E. coli HI-3542 BC-3531 2066

Ö O

"° 015 0.25 0.015

xo ^ O

- "" - 1; h: h 2n, XJCnJJ 0.03 0.25 0.008 ° M, A ^

YyV ^ HZN \ / "νΉΑ [/ 0 03 ° · 25 0008 NC ^ -O l i * ~: ~ ö ö 1;;:

uB L II IJ

Vm? ° · 06 ° · 06 0 · 004 OMe ^ ö ö; : 0.5 1 0.06 NC-X-N OMe ^. - ö ö; ~: “0.03 0.06 0.004

NC ^ 0MeA

ö ö; : M \ 0.06 0.06 0.004 NC ^ N OMe ^ ö ö: - -; ρηΥ ”/ γΤ'Ι1 I f O · 25 0.125 0.008 nc ^ nVv OMe ^ ö o" "! ~ ".

0.25 0.25 0.5

<0 ^ “e A

- - -fTTii 0H

0.03 0.25 0.5 X. -A 1027545-119

Structure of compound H. influenzae M. catarrhalis E. coli HI-3542 BC-3531 2066

O O

V.W "0.015 0.25 0.5

° "" A

ΜΘ - δ "o ~ ~

MeHN / -NX / CNT 0.06 0.125 0.5

NC ^ V

"~: O O"

MeHia XjCNJ 0.03 0.06 0.125 s OMe ^ - | : ~ ö 5 ':'! - ^ η, ΟΟΟΓ H 0.015 0.125 0.125 ~ C ^ O λΛ „.

——; 1 'ö δ N% ^ N ^ PÖ ^ 0H 0.5 1 2 NC - / "" YY OMe ^ 1 02 75 45 - 120

Table 1B

Minimum inhibitory concentrations in pg / ml gram-positive bacteria

Structure of E. faecalis S. pneumo S. aureus S. pyogenes compound or MGH-2 SV-1 UC-76 C203

Example #

_ 5 Q

Fr? V ° H

JL Jl Yj 0.06 0.125 0.15 0.25 NC OM ek _ _:; H ~ n 0.125 0.06 0.03 0.03.

F / ‘N y N

° ^ Λω. ___: 0 o / -nXXn ^ ° H 025 0.125 0.125 0.5 1. j

Q

0.03 0.015 0.004 0.015 ^β ^ o o

YyV- 1 0.25 0.125 0.5 OM ek H ^ ___ __

O O

phyVoh η 0.25 0.125 0.03 0.5 nc ^ NX> Xm ^ o o

Me 0.06 0.03 0.008 0.03 OMe ^ Ö ö ΥκΥ ^ »/ * νγΝτ 0.5 0.5 0.03 1 NC ^ -nWI OMe ^ '! ö ö "

VYir ° H

nc ^ JJ AnV ^ n; 0.5 1 0.06 0.25 o FYYi ° n NC ^ ï ΛνΜν ^ 0.5 1 0.125 1 χ: τλ _ 1027545- 121

Structure of E. faecalis S. pneumo. S. aureus S. pyogenes compound or MGH-2 SV-1 UC-76 C203

Example #

0 0

: 05 1 0125 Me ° MeA

5 O O

0H

0.125 ° · 125 ° · 015 ° · 125 NC "/ \ J TMe ^ —g - ·;::; _ fYYY ^ h ΜθΗΙ * λ-μΑΛμ ^ 0.06 0.06 0.015 0.06 - ·.,» Ο ο 0Η 1 2 0.125 1.

ο ο J 0 25 ο.25 0.03 0.25 NC ^ N OMel 15. 20

The following examples are provided for illustrative purposes, but do not limit the present invention as claimed.

A. Synthesis of precursors of the side chain

Example 1 102 75 45 * 122

Preparation of (2-cyano-1-pyrrolidine-3-ylethyl) carbamic acid tert-butyl ester C Me

MeJ

1 Me nnV hnA0

L / NH

A. 3- (2-Cyanovinyl) pyrrolidine-1-carboxylic acid benzyl ester

H

^ o vj 20 "^ ==)

A solution of 3-formylpyrrolidine-1-carboxylic acid benzyl ester (2.25 g, 9.65 mmol), cyanomethylphosphonic acid diethyl ester (1.88 g, 10.6 mmol) and cesium carbonate (3.46, 25 g, 10.6 mmol) in dry THF (100 ml) was heated to 50 ° C for 3 hours. The solvent was removed in vacuo. The crude residue was taken up in ethyl acetate (100 ml) and washed with saturated NH 4 Cl (100 ml), concentrated saline (100 ml), dried with MgSO 4 and concentrated in vacuo. The crude residue was purified on a column with 40 g of silica gel (0 to 60% ethyl acetate in hexanes). to give 2.22 g of a title compound as a mixture of E and Z isomers (yield: 90%).

MS (APCI +): m / z = 257 (M + H) +.

B / 3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrr-5-memberin-1-carboxylic acid benzyl ester V γ 'Me L' N - (MH JL 1 / Me 2 - vp ° * b.

15

To a solution of 3- (2-cyanovinyl) pyrrolidine-1-carboxylic acid benzyl ester (8.24 g, 32.1 inmol) in absolute ethanol (100 ml) was added ammonia (ca. 5 ml) and the solution in a closed reactor heated to 80-100 ° C for 3 days. The solution was concentrated in vacuo.

The resulting amine was dissolved in THF (100 ml), Boc anhydride (8.76 g, 40.2 mmol) was added and the solution stirred for 18 hours at room temperature.

. 25. The solution was concentrated in vacuo. It. residue was taken up in ethyl acetate (100 ml), washed with saturated NH 4 Cl. in water (100 ml) and concentrated saline (100 ml), dried with MgSO 4 and concentrated in vacuo. The crude product was purified over a column with 330 g of silica gel (10 to 50% ethyl acetate in hexanes) to give 9.28 g of the title compound as a 1: 1 mixture of diastereomers (yield: 77%).

MS (APCI +): m / z = 274 (M + H-Boc) +.

1 027545.

124 C. (2-Cyano-1-pyrrolidine-3-ylethyl) carbamic acid tert-butyl ester 5 Me P Me Me V 7 ° C + HCO 2 NH 4 + - ^ N HN 2 O

In- \ ° ^ K>

A solution of 3- (1-tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester (2.00 g, 5.36 nunol) and ammonium formate (1.00 g, 16.1 inmol) in methanol ( 50 ml) was purged with nitrogen and then 10% Pd / C (0.5 g) added. The vessel with the mixture was closed and stirred at room temperature for 17 hours. The solution was filtered through Celite and the solids were rinsed with methanol. The filtrate was concentrated in vacuo to give 1.25 g of the title compound (yield: 97%). MS (APCI +): m / z =

240 (M + H) V

Example 2

Preparation of N- (1-azetidin-3-yl-cyclopropyl) -2,2,2-trifluoroacetamide

H

f3CVNnA

.o Tr h 1027545-125 A. 1- (1-Benzhydrylazetidin-3-yl) cyclopropylamine

N 2 N 2 N 2

»Λ__. Γ 10

Zié Chem. Rev. 1979 Vol. 79, No. 4; Tet. Lett., 44, 2003, 2485

To a solution of 1-benzhydrylazetidine-3-carbonitrile (10 g) in THF (200 ml) were added successively at room temperature titanium isopropoxide (Ti (OiPr) 4) (1 equivalent) and ethyl magnesium bromide (2.2 equivalents). The resulting reaction mixture was stirred for 30 minutes.

Boron trifluoride diethyl etherate (BF30 Et2) (2 equivalents) was then added. Stirring was carried out for a period of. Continued for 30 minutes. A solution of 10% sodium hydroxide was added and the mixture extracted three times with ethyl acetate (EtOAc). The combined ethyl acetate layers were. dried over Na 2 SO 4 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) +.

B. N- [1- (1-Benzhydrylazetidihe-3-yl) cyclopropyl] -2,2,2-trifluoroacetamide 1027545-126 Η

HgN ^ A ρ3 ° γΝνΔ 10. See J. Med. Chem., 1993r Vol. 36, No. 7.

To a stirred solution of 1- (1-benzhydrylazetidin-3-yl) cyclopropylamine (2.5 g) in chloroform (60 ml) was added a solution of trifluoroacetic anhydride (1.25 equivalents) in 15. chloroform at room temperature. The reaction mixture was stirred for 2 hours, then washed with 10% NaHCO 3 and then with concentrated saline. The solution was then concentrated and purified by chromatography (gradient from 3: 1 = hexanes: EtOAc to EtOAc) to give 0.57 g (17% yield) of the title compound.

MS (APCI +): m / z = 375 (M + H) + C. N- (1-Azetidinium-3-yl-cyclopropyl) -2,2,2-trifluoroacetamide

H

F3 C ^ N ^ A H λ

30 [IJ [I J

. To N- [1- (1-benzhydrylazetidin-3-yl) cyclopropyl] -2,2,2-trifluoroacetamide in methanol, 10% Pd / C (20%) 1 02 7545- 127 and hydrochloric acid (1 equivalent) were added. The resulting mixture was stirred under a hydrogen gas atmosphere overnight. The mixture was then filtered through a layer of Celite and the filtrate concentrated. yielding a mixture of azetidinium hydrochloride and diphenylmethane (0 ^ 56 g, 90% yield). The crude mixture was used in the next reaction without purification.

MS (APCI +): m / z = 209 (M + H) +.

10

Example 3

Preparation of N- (3-ethylazetidin-3-ylmethyl) -2,2,2-trifluoroacetamide 15 f '

CT ^ NH

CNH

A. 1-Benzhydryi-3-ethylazetidine-3-ol

To a solution of i-benzhydrylazetidin-3-one (10 g) in diethyl ether (200 ml) cooled to 0 ° C in an ice bath was added dropwise a solution of ethyl magnesium bromide in ether (3.0 M, 2 equivalents) . Meh allowed the reaction mixture to stir at 0 ° C

1027545-128 until the bath was warmed up and then reacted at room temperature for 3 days. The reaction was quenched with aqueous ammonium chloride and the reaction mixture was then extracted three times with EtOAc.

The organic extract was washed with brine, dried and then concentrated. The product was purified by flash chromatography (2: 1 = hexanes: EtOAc) to give the title compound (6.33 g, 56%).

MS (APCI +): m / z = 268 (M + H) +.

B. Methanesulfonic acid 1-benzhydryl-3-ethylazetidin-3-yl ester

15 / O Q

HOnPn iQ ~~ Ms0fjN <0

Me Me 20

To a cooled (0 ° C) solution of 1,4-benzhydryl-3-ethylazetidin-3-ol (6.33 g) and triethylamine (1.3 equivalents) in dichloromethane (100 ml) was added a solution of methanesulfonyl chloride ( 1.3 equivalents) in dichloromethane (30 ml) added dropwise. Once all methanesulfonyl chloride was added, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 1 hour. The solution was then diluted with more dichloromethane and washed twice with water. The organic solution was then dried. and concentrated. (8.01 g, 98% 1027545-129 yield). The crude material was used in the next step without further purification.

C. 1-Benzhydryl-3-ethylazetidine-3-carbonitrile 5

~ "c <rO

10 · Μβ. Me

To a solution of methanesulfonic acid 1-benzhydryl-3-ethylazetidin-3-yl ester (8.01 g) in dimethylformamide (DMF) (120 ml) was added dropwise sodium cyanide 15 (2.5 equivalents) in water (40 ml) at room temperature . The solution was then stirred overnight and heated to 60 ° C. The solution was then diluted with 500 ml of water and the precipitate extracted three times in EtOAc. The organic extract was washed twice with water and then dried over Na 2 SO 4 and concentrated in vacuo. The product was purified by chromatography (gradient from 9: 1 = hex: EtOAc to EtOAc) to give the title compound (5.50 g, 86% yield).

MS (APCI +): m / z = 277 (M + H) +.

D. C- (1-Benzhydryl-3-ethylazetidin-3-yl) methylamine

30 T ^ ____ ► NH 2 T

.'ψΧ) ·,: Qr '^ Me ^ Me 1027545-130

To a solution of 1-benzhydryl-3-ethylazetidine-3-carbonitrile (5.50 g) in THF (60 ml), LAH (3.5 equivalents) in THF (1 M) was added slowly. The solution was refluxed for 2 hours. The reaction mixture was then allowed to cool to room temperature, and 100 ml of diethyl ether was added, followed by 2.8 ml of water, 2.8 ml of 10% NaOH and 5.6 ml of water. After vigorous stirring for 30 minutes, the mixture was filtered. The aluminum salts were washed five times with THF. The combined organic filtrates were dried and concentrated. The crude product was used in the next step without further purification; 5.16 g, 92% yield.

MS (APCI +): m / z = 281 (M + H) +.

'' 15 · ·.

E. N- (1-Benzhydryl-3-ethylazetidin-3-ylmethyl) -2,2,2 ^ trifluoroacetamide 20 Cp? NH 2 NH 2 -1 ------ O ^ NH J 1 · ^ ψ ^ Ο ψκ)

Me Me 25 To a stirred solution of O (1-benzhydryl-3-ethylazetidin-3-yl) methylamine (5.16 g) in chloroform (120 ml) was added one. solution of trifluoroacetic anhydride (1.25 equivalents) in chloroform (60 ml) at room temperature added dropwise. The reaction mixture was stirred for 2 hours, then washed: with 10% NaHCC> 3 and then concentrated saline. The solution was then dried, concentrated and purified by chromatography (3: 1 = 1 02 75 45-131 'hexanes-EtOAc to EtOAc) to give the title compound (3.67 g, 53% yield).

MS (APCI +): m / z = 377.3 (M + H) +.

5 F. N- (3-Ethylazetidin-3-ylmethyl) -2,2,2-trifluoroacetamide (fS CF 3)

CFg II J X

------ 0 Inn ..

ψΝ u r V Me

Me N- (1-Benzhydryl) -3-ethylazetidin-3-ylmethyl) -2,2,2-trifluoroacetamide (3.67 g) was hydrogenated overnight (Pd / C in 100 ml MeOH) with one equivalent of HCl to give 2.40 g (100%) of the title compound that was used without purification.

MS (APCI +): m / z = 211 (M + H) +.

Example 4

Preparation of N- (1-azetidin-3-yl-propyl) -2,2,2-trifluoroacetamide hydrochloride .0

X

25 HN + CF 3

* —NH * HCl

A. 1-Benzhydrylazetidine-3-carboxylic acid 1027545-

132 O

V1 ho ^ V-jfh, QjJ HCl, Δ.

]. 71% ^ A suspension of 1-benzhydrylazetidine-3-carbonitrile (2.09 g, 8.42 mmol) in concentrated hydrochloric acid (12 M, 15 ml) was heated under reflux for 30 minutes. The resulting solution was cooled to 0 ° C and 6 M sodium hydroxide added until the mixture reached a pH of about 7. The aqueous mixture was then extracted with dichloromethane (3 x 150 ml) and dichloromethane: methanol (10: 1, 3 x 150 ml). The combined organic layers were dried, filtered and concentrated under reduced pressure to give the title compound (1.60 g, 71% yield).

MS (APCI): m / z = 268 (M + H) +.

B. 1-Benzhydrylazetidine-3-carboxylic acid methoxymethylamide

20 o O

HO EDC ^ 6 ^ NH 2 + CI-M® ^ N - | Νγ ^ Me- ° '- "ykj

Jv. Et 3 N, CH 2 Cl 2, fr

L 55% Γ J

1- [3- (Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8.0 g, 42 mmol) was added to a suspension of 1-benzhydrylazetidine-3-carboxylic acid (7.42 g, 27.8 mmol) ), N, O-dimethylhydroxylamine hydrochloride (4.24 g, 43.5 mmol) and triethylamine (11.6 mL, 83.3 mmol) in dichloromethane (150 mL). The suspension was then stirred at room temperature for 60 minutes. The 1027545-123 suspension was diluted with dichloromethane (300 ml) and the resulting solution washed with water (3 x 100 ml). The organic layer was then dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resulting solid was purified by medium pressure liquid chromatography, eluting with dichloromethane: methanol (40: 1) to give 4.76 g (55% yield) of the title compound as a white solid (m.p. = 103-) 106 ° C).

MS (APCI +): m / z = 311 (M + H) +.

C. 1- (1-Benzhydrylazetidin-3-yl) propan-1-one 15'β'Α- | -Λη, | f)

Me' ° THF, -70 Μ0¾ '89% 0 A solution of ethyl magnesium bromide in tetrahydrofuran (1.0 M, 32.5 ml) was added to a solution of 1-benzhydrylazetidine-3-carboxylic acid at -70 ° C methoxymethylamide (3.36 g, 10.8 mmol) in tetrahydrofuran (60 ml). The resulting reaction mixture was then stirred for 1 hour at 0 ° C. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (75 ml) at 0 ° C. The mixture was then extracted with diethyl ether (300 ml), and the aqueous layer was then re-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 medium pressure liquid 1027545-134 chromatography, eluting with dichloromethane: methanol (40: 1) to give 2.69 g (89% yield) of the title compound as a waxy, yellow, solid (m.p. = 73-75 ° C).

MS (APCI +): m / z = 280 (M + H) \ D. N- [1- (1-Benzhydrylazetidin-3-yl) propyl] -2,2,2-trifluoroacetamide

O

10 m S HfACF3 ββν ^ Ν — I 1.NH4OAc, NaCNBH3 Me ^ l I — f [| IJ 4 A molecular sieves (MeOH, kt T11)

----- l-nvA

A 2. 0 0 T

kj f3c ^ o ^ cf3 .tea.ch2ci2 Ö 15 53%

Ammonium acetate (6.00 g, 77.8 mmol) was added to a mixture of 1- (1-benzhydrylazetidin-3-yl) propan-1-one (2.59 g, 9.27 mmol) and 4 Angstrom molecular sieves ( 2.60 g) in methanol (80 ml). The mixture was cooled to 0 ° C and sodium cyanoborohydride (1.17 g, 18.5 mmol) added in various portions. The mixture was then stirred at room temperature for 22 hours. The suspension was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was partially dissolved in dichloromethane (500 ml). The mixture was then washed with a saturated aqueous solution of sodium carbonate (100 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure (1027545-135) to give 2.59 g of clear oil which was used without further purification.

A solution of the crude diamine (2.59 g) and triethylamine (3.86 ml, 27.7 inmol) in dichloromethane (60 ml was treated with trifluoroacetic anhydride (1.06 ml, 13.9 mmol) at 0 ° C) The resulting solution was then stirred at room temperature for 45 minutes, an additional amount of trifluoroacetic anhydride (350 μΐ) was added after 45 minutes, and stirring was continued for 15 minutes at room temperature.The solution was cooled to 0 ° C and saturated aqueous sodium bicarbonate (10 ml) was added The mixture was then partitioned between dichloromethane (300 ml) and Saturated bicarbonate in water (40 ml) The layers were separated, the organic layer was washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure The resulting oil was purified by medium pressure liquid chromatography, eluting with a gradient of hexanesrethylacetate (80:20 to 60:40) to give 1, 84 g (53% yield) of the title compound.

MS (APCI +) m / z = 377 (M + H) + 25 E. N- (1-Azetidin-3-yl-propyl) -2,2,2-trifluoroacetainide hydrochloride O HN ^ CF3 HN ^ CF3 ^ η— | H2.10% Pd / C - | 30 ^ lnh. hci

T. HCl, MeOH

| ^ j | 100% 1027545-136

A . mixture . of N- [1- (1-benzhydrylazetidin-3-yl) propyl] -2,2,2-trifluoroacetamide (1.72 g, 4.57 mmol), 10% Pd / C (2.02 g), concentrated hydrochloric acid (12.0 M, 0.380 ml) in methanol (60 ml) was hydrogenated at 50 psi for 6 hours. An additional amount of 10% Pd / C (1.5 g) was added and the hydrogenation continued for 22 hours. The solvent was removed under reduced pressure to give a yellow residue. The residue was then concentrated several times from toluene and then dried in vacuo at 50 ° C for several hours to yield the title compound contaminated with diphenyl methane. The crude material was triturated with hexanes to give 1.13 g (100% Yield) of the title compound.

MS (APCI +): m / z - 211 (M + H) +.

Voox picture 5

Preparation of 2,2,2-trifluoro-N- (3-methylazetidin-3-ylmethyl) acetamide hydrochloride 20 fVT Me MeΑη H2 »1 °% pd / C h F | Me

HCl, MeOH NH-HCl

25 Jv. 93% A merge of N- (1-benzhydryl-3-methylazetidin-3-ylmethyl) -2,2,2-trifluoroacetamide (3.19 g, 8.80 mmol), 10% Pd / C (2.5 g), concentrated hydrochloric acid (12 M, 0.732 ml) in methanol (50 ml) was hydrogenated at 50 psi for 8 hours. The solvent was removed under reduced pressure to give a yellow residue. The 1027545-137 residue was then concentrated several times from toluene. The resulting solid was then triturated with hexanes and the supernatant removed. The resulting white solid was dried in vacuo to give 1.91 g (93% yield) of the title compound.

MS (APCI +): m / z = 197 (M + H) \

Example 6

Preparation of (R) - and (S) -1-pyrrolidin-3-yl-10 cyclopropylamine

h2n W h2n \ J

and * A. N, N-Dibenzylacrylamide

Bn2NH // Pr2NEt ^ - ^ NBna

C1 THF

-78 ° C

A round bottom flask was filled with tetrahydrofuran (3750 ml) and cooled to -78 ° C under nitrogen.

Acryloyl chloride (55.7 g, 48.9 ml, 0.615 mol) and diisopropylethylamine (87.3 g, 118 ml, 0.676 mol) were added, followed by the slow addition (over a 20 minute period) of dibenzylamine (109.6 g, 106 ml, 0.555 mol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1.0 hour. A large amount of white precipitate was observed and thin layer chromatography indicated that the reaction had proceeded. The solids were removed by filtration and the filtrate concentrated in vacuo to give a quantitative yield of the title compound.

1 02 75 45-138 B. N- (Trimethylsilylmethyl) -α-methylbenzylamine

^ NH 2 Me 3 SiCH 2 Cl

Ph ^ Me Et3 N Ph Me

A mixture of (S) - (-) - α-methylbenzylamine (100 g, 106.4 ml, 0.82 mol), chloromethyl trimethylsilane (115.1 ml, 101.2 g, 0.82 mol) and triethylamine ( 126.5 ml, 96.2 g, 0.95 mol) was heated under reflux for 24 hours until LCMS indicated that the reaction had proceeded. The reaction mixture was triturated with heptane and the HCl. salt filtered. The heptane filtrate was concentrated to an oily residue which was distilled in vacuo (42-50 ° C / 0.4-0.7 mm Hg) to provide 67.8 g (40% yield) of the title compound.

C. N- (Methoxymethyl) -N- (trimethylsilylmethyl) -α-methyl-benzylamine H 4, H 3 C "O / N 2 N 4 Si (CH 3) 3 'N Si (GHa) 3 HCHO 2

Ph ^ Me | Q j M <> 25

To a stirred solution of formaldehyde in water (37%, 152.1 g, 1.9 mol) was added the N- (trimethylsilylmethyl) -α-methylbenzylamine at 0 ° C.

. The previous step (310 g, 1.5 mol) was added over a period of 0.5 hours, which was followed by the addition of methanol. . (100 ml) and potassium carbonate (200 g). The reaction mixture was stirred at 0-10 ° C for 1-2 hours.

1027545-139

The mixture was filtered and the filtrate extracted with diethyl ether (1 time). The ether layer was dried with sodium sulfate and concentrated to an oil that was distilled using a bulb tube apparatus 5 (Kugelrohr), yielding 210 g. (56%) title compound.

D. 1- (1-Phenylethyl) pyrrolid ± ne-3-carboxylic acid ± benzylamine

O

10 H 3 C-O ^ NXN * Si (CH 3) 3 CF 3 COOH = ~ ^ ΝΒη 2 ^ N <NBn 2 1 U I.

N, N-Dibenzylacrylamide (79.5 g, 0.317 mol) and N- (methoxymethyl) -N- (trimethylsilylmethyl) -α-methylbenzyl amine (103 g, 0.412 mol) were dissolved in CH 2 Cl 2 (1500 ml) and cooled up to 0 ° C. A solution of trifluoroacetic acid (1.0 M in CH 2 Cl 2, 27 ml) was added over a 20 minute period and the resulting reaction mixture stirred at room temperature overnight. The mixture was washed with aqueous NaHCO 3, concentrated saline, dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography (heptane-EtOAc-Et 3 N / 10: 2: 0.1) to give 97.7 g of the title compound. (77% yield) as a mixture of two diastereomers.

E. Dibenzyl {1- [1- (1-phenylethyl) pyrrolidin-3-yl] cyclopropyl} amine. .140 r-λ ^ EtMgBr,

1 u Ti (0 / Pr) 4 S'V. + Y

Ι ^ γ ^ Μθ Me 5:.

Ethyl magnesium bromide was added to a round bottom flask filled with tetrahydrofuran (1400 ml)

(EtMgBr) (3.0 M in Et 2 O, 178 ml, 0.534 mol) at -78 ° C

added. A solution of Ti (OiPr) 4 (64.8 g, 66.0 ml, 0.228 mol) in THE (150 ml) was then added at such a rate that the temperature was maintained below -68 ° C. The dark solution was allowed to stir for 3 minutes at -68 ° C before a solution of 1- (1-phenylethyl) pyrrolidine-3-carboxylic acid dibenzylamide (86.6 g, 0.218 mol) in THF (150 ml) below -68 ° C was added.

The reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 1.0 hour, followed by heating under reflux for 1 hour. The reaction mixture was then cooled 20 to 8 ° C. EtMgBr (3.0 M in ether, 150 ml, 0.450 mol) was added, which was followed by the rapid addition of Ti (0iPr) 4 (54.6 g, 55.6 ml, 0.192 mol) in THF (150 ml). The resulting mixture was stirred at room temperature for 1.0 hour before the reaction was quenched with aqueous ammonium chloride (3000 ml) and water (800 ml).

The mixture was filtered through Celite, and rinsed with ether. The. organic layer was separated. The aqueous layer was made basic (pH ~ 8.5) with aqueous NaOH and extracted with ether. The combined organic layers were dried over Na 2 SO 4, concentrated and purified by flash chromatography (heptane-EtOAc-Et 3 N / 10: 1: 0.1) to give the title compound as a mixture of stereoisomers which were separated 1027545 -

• "*" I

-; ---; _; __ _ ί 141 prior to the subsequent conversions. Isomer 1 (31.3 g, 35%) as colorless crystals (m.p. = 76-76.5 ° C). The stereochemical structure of isomer 1 was confirmed by an X-ray diffraction experiment of a single crystal.

Isomer 2: The crude oil (18 g) from the above purification was further chromatographed with heptane / methyl butyl ether (MTBE) / Et 3 N (100: 0.5: 0.5), yielding 11 g of isomer 2 which as a colorless oil was approximately 90% pure. This oil was dissolved in Et 2 <3 (350 ml) and triturated with 2.0 M Et 2 O-HCl (12.8 ml). The resulting white solid was collected by filtration / rinsed with ether, dissolved in 15 MeOH, neutralized with 15% NaOH, extracted with ether (twice), washed with brine, dried over Na 2 SO 4, concentrated in vacuo to give a thick oil which was recrystallized from EtOH at -30 ° C and provided 10.1 g of the title compound (22% yield): as colorless crystals (m.p. 61-61.3 ° C).

F. (S) -1-Pyrrolidin-3-ylcyclopropylamine ..... G ^ Me <) ··· Γν »

Nv MeOH HM7 / 50 psi 30

To dibenzyl {1- [1- (1-phenyiethyl) pyrrolidin-3-yl] cyclopropyljamine (3.00 g, 7.32 mmol) was added 20% Pd / C, and subjected to. hydrogenation at 1 02 75 45-142 ..

50 psi. After 48 hours, the reaction mixture was filtered and concentrated to give 764 mg of the title compound (yield: 83%).

MS (APCI +): m / z = 127 (M + H) +.

G. (R) -1-Pyrrolidin-3-yl-cyclopropylamine 9 10 "M ° <L / -nh.

50 psi. To dibenzyl {1- [1- (1-phenylethyl) pyrrolidin-3-yl] cycopropyl} amine (3.01 g, 7.32 mraol) was added 20% Pd / C, and this was subjected to hydrogenation at 50 psi. After 48 hours, the reaction mixture was filtered and concentrated to give 844 mg of the title compound (yield: 91%).

MS (APCI +): m / z - 127 (M + H) +

Example 7

Preparation of pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester A. (S) -Methanesulfonic acid 1-benzylpyrrolidin-3-yl ester

Pf \

EtaN MsO ,. 1-Benzylpyrrolidin-3-ol (Synthetic Communications, 1985) (25.01 g, 141 mmol) was taken up in dichloromethane and triethylamine (29 ml). The resulting solution was cooled to 0 ° C and mesyl chloride (13.1 ml) was added After 14 hours, the reaction mixture was washed with saturated sodium bicarbonate, followed by water and concentrated saline, and the organic layer was dried and concentrated to give the 10 gave the title compound (30.2 g, 84% yield).

MS (APCI +): m / z = 256 (M + H) +.

B. (R) -1-Benzylpyrrolidine-3-carbonitrile

Bu _ 15 r \ nc'n: Bu f \

NacN —— '. xy- (R) -1-Benzylpyrrolidine-3-carbonitrile (29.8 g, 117 mmol) was taken up in acetonitrile, sodium cyanide (20.2 g, 412 mmol) and tetrabutylammonium cyanide (3.11 g, 11.6 mmol) were added and then heated under reflux. After 48 hours, the reaction mixture 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 provide 15.4 g of the title compound 30 (71% yield).

MS (APCI +): m / z = 187 (M + H) \ C. (R) -C- (1-Benzylpyrrolidin-3-yl) methylamine 1027545-144 NCV ^ LAH Η2Ν ^ ν ^ Λ LAX ΊήΓ IyN "\ 5 /λ / "Λ 1-Benzylpyrrolidine-3-carbonitrile (5f08 g, 27.3 mmol) was taken up in THF and cooled to 0 ° C. After 10 minutes, LAH (2.09 g, 55.1 mmol) in THF at 0 ° C was slowly added to the pyrrolidine solution. Gas evolution was observed and the reaction was allowed to proceed for 30 minutes at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours. The reaction was quenched with water (2 ml), 1N NaOH (2 ml) and again water (6 ml).

The resulting slurry was filtered through a layer of Celite which was washed with dichloromethane, and the combined filtrates were concentrated to give 4.2 g of the title compound (yield: 82%).

MS (APCI +): m / z = 191 (M + H) +.

D. (R) - (1-Benzylpyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester H 2 N-4 S-4-BocHN 4 V-Λ

LvN "V AA THF 1 λ — λ ooo -L'-y \ k \ / UMe L-Me // \ \ = / Me ^ Me Me ^ Me \ __ / 30 ii 1 02 75 45- '145 RC ( 1-Benzylpyrrolidin-3-yl) methylamine (2.033 g, 10.7 in mol) was taken up in THF and Boc anhydride (6.787 g, 31 mmol) was added.The resulting solution was gently heated to 46 ° C. After 6 hours The resulting solution was allowed to cool to room temperature and concentrated.The crude residue was taken up in dichloromethane and washed with 1.0 N HCl The organic washings were purified by chromatography (0-10% MeOH / CH 2 Cl 2) to give 2, 4 g of the title compound (yield: 76%).

MS (APCI +): m / z = 291 (M + H) +.

E. Pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester

BocHN ^ p ^ H2 BocHN ^ SpNH

20% Pd / Cl 2/50 psi To (R) - (1-benzylpyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester (1.00 g, 3.44 mmol) was added 20% Pd / C and. hydrogenation at 50 psi. After 48 hours, the reaction mixture was filtered and concentrated to give 511 mg of the title compound (yield: 74%).

MS (APCI +): m / z = 201 (M + H) V

Example 8

Preparation of pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester A. [1- (1-Phenylethyl) pyrrolidin-3-yl] methanol 1 027545-146

Ov Me c.-OH

LAH / (%% fi Me 111, 5 m ", 5-Oxo-1- (1-phenylethyl) pyrrolidine-3-carboxylic acid methyl ester (Journal of Heterocyclic Chemistry, 1992) (10.0 g, 40.5 mmol ) was taken up in diethyl ether and slowly added to a slurry of LAH (2.31 g, 60.86: mmol) in diethyl ether.The resulting solution was heated under reflux for 4 hours, the reaction mixture was allowed to cool to room temperature and the reaction The mixture was decomposed with a water / ether mixture and the resulting solution was allowed to stir at room temperature for an additional hour. The slurry was filtered and washed with dichloromethane.The filtrates were concentrated under reduced pressure to give 7.76 g of the title compound (yield: 94%).

MS. (APCI +): m / z = 206 (M + H) +.

B. 2- [1- (1-Phenylethyl) pyrrolidin-3-ylmethyl] isoindole-1,3-dione 25 o O ** o H

". O cyW

L ^ THF V / O

O N

Kj? Metalline [1- (1-Phenylethyl) pyrrolidin-3-yl] methanol (4.4 g, 21.5 mmol) was taken up in THF, triphenylphosphine (6.27 g, 1.02.75.45-) 147 (23.9 iranol) and phthalimide (3.61 g, 24.6 mmol) were added, followed by the dropwise addition of diisopropyl azodicarboxylate (DIAD) (5.08 g, 25.1 mmol). After 4 hours, the reaction mixture was concentrated and the resulting oil was chromatographed (1-10% isopropyl alcohol / dichloromethane) to give 5.6 g of the title compound (yield: 77%).

MS (A.PCI +): m / z = 335 (M + H) +.

C. C- [1- (1-Phenylethyl) pyrrolidin-3-yl] methylamine

O

^ NH 2 rNvJ /. I \ ΓΛ? H2

0 + H-N-NH 2 -V

1 ^ H ΜθΝ ', Λνν%

Me ""> 0 ^ 20

The phthalimide (5.00 g, 14.9 mmol) was taken up in isopropyl alcohol and hydrazine hydrate (7.04 g, 149 mmol) added. The resulting solution was heated to 60 ° C. A colorless precipitate had formed after 1 hour. The reaction mixture was diluted with isopropyl alcohol and filtered. The filter cake was washed with isopropyl alcohol and the combined filtrates were concentrated to give an off-white, oily solid. This residue was partitioned between water and 1: 3 = dichloromethane: ether and the organic layer was washed with water and then dried over sodium sulfate to give 1.68 g of the title compound (yield: 55%). .

1027545-. 148 MS (APCI +): m / z = 205 (M + H) +.

D. [1- (1-Phenylethyl) pyrrolidin-3-ylraethyl] carbamic acid tert-butyl ester 5.

NH2 ƒ — NHBo 0 t ΑΛ -Eti 9 ___ + L.Me L, Me .λ a

Μθ '' ΐΓ ^ Ι μθ ^ μθ Me Me iQ

C- [1- (1-Phenylethyl) pyrrolidin-3-yl] methylamine (4.01 g, 19.6 inmol) was taken up in THF, and Boc anhydride (15.3 g, 70.1 mmol) added. . The resulting solution was gently heated to 50 ° C. After 6 hours, the resulting solution was allowed to cool to room temperature and concentrated. The crude product was taken up in dichloromethane and washed with 1N HCl. The organic liquids were concentrated to give the title compound (3.4 g; yield: 58%).

MS (APCI +): m / z = 305 (M + H) V

E. Pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester

20% P * C B00 HN pNH

[1- (1-Phenylethyl) pyrrolidin-3-ylmethyl] carbamic acid tert-butyl ester (3.50 g, 11.5 mmol) was taken up in methanol, 20% Pd / C was added and then hydrogenated at 50 psi. After 24 hours.

The reaction mixture was filtered and concentrated to provide 1.75 g of the title compound (yield: 76%).

MS (APCI +): m / z = 201 (M + H) +.

5

Example 9

Preparation of C-oxazol-2-yl-C-pyrrolidin-3-ylmethylamine NHMe 10: A. 3- (Hydroxyoxazol-2-ylmethyl) pyrrolidine-1-carboxylic acid benzyl ester

O OH

^ X n BH 3 THF 0

H / N_ ^ f-BuLi ^ -o 1— / N \ 20 O 56%

Ph Ph 25 To a solution of oxazole (2.0 g, 29 inmol)

tetrahydrofuran (30 ml) was added dropwise borane-tetrahydrofuran complex (32 ml, 1 M in THF) at room temperature. The reaction mixture was cooled to -78 ° C and tert-butyl lithium (19 ml, 1.7 M in hexanes) was added dropwise 30 times. After stirring for 30 minutes, a solution of 3-formylpyrrolidihe-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

1 027545. 150 and then 5% acetic acid in ethanol (180 ml) was added. The mixture was allowed to warm to room temperature, poured into concentrated saline and extracted three times with ethyl acetate.

The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (40% to 100% ethyl acetate in hexanes) to give the title compound (4.9 g, 56%).

MS (APCI +): m / z = 303 (M + H) +.

B. 3- (Azidooxazol-2-ylmethyl) pyrrolidine-1-carboxylic acid benzyl ester 15 OH N3

o MeSOzCI O

uX) ^ 0 -ssi / 94% ζ> h Ph 20

To a cooled (0 ° C) solution of 3- (hydroxyoxazol-2-ylmethyl) pyrrolidine-1-carboxylic acid benzyl ester (4.9 g, 16 mmol) in dichloromethane (80 ml) was added triethylamine (2.9 ml, 21 mmol), followed by methanesulfonyl chloride (1.51 ml, 19.4 mmol). The solution was allowed to warm to room temperature and stirred overnight. Dichloromethane was added and the solution washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting mesylate was used in the next step without further purification.

102 75 45. 151

To a solution of the crude mesylate in N, N-dimethylformamide (80 ml) was added sodium azide (10 g, 160 mmol). The resulting mixture was heated to 80 ° C overnight. The reaction mixture was allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (0 to 40% ethyl acetate in hexanes). yielding the title compound (4.9 g, 94%) as a colorless oil.

MS (APCI +): m / z = 328 (M + H) +.

C. 3- (Aminooxazol-2-ylmethyl) pyrrolidine-1-carboxylic acid benzyl ester N3 NH2

W'N-'NO PPH3.THF O

O 71% -0 / T / N-f

((0 20> h · V

Aart a solution of. 3- (azidooxazol-2-ylmethyl) pyrrolidine-1-carboxylic acid benzyl ester (1.0 g, 3.1 mmol) in tetrahydrofuran (20 mL) became triphenyl phosphine (1.85 g, 7.03 mmol) and water ( 0.60 ml, 31 mmol) was added and the mixture was allowed to stir at 50 ° C for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was purified by flash chromatography (1: 9 = methanol: dichloromethane) to yield the title compound (0.66 g, 71%).

1027545-152 1 H NMR (400 MHz, CDCl 3): δ 7.64-7.01 (m, 7H), 5.19-5.08 (m, 2H), 4.01-3.12 (m, 5H), 2.74-2.53 (m, 1H), 2.21-1.55 (m, 4H).

5 D. C-Oxazol-2-yl-C-pyrrolidin-3-ylmethylamine NH 2 fHMe 0 Pd / C, HCl 2 NH 4

Vo MeOH 100% -0 Ly NH

10. <0

Ph

To a solution of 3- (aminooxazol-2-ylmethyl) pyrrolidine-1-carboxylic acid benzyl ester (0.65 g, 2.2 mmol) in methanol (10 ml) were added ammonium formate (0.68 g, 11 mmol) and 10 % palladium-on-carbon (0.70 g, 0.65 mmol) added. . The reaction mixture was kept for 2.5 hours. heated to 65 ° C, allowed to cool to room temperature and filtered. . The filtrate was in. concentrated in vacuo to give the title compound (0.36 g, 100%).

1 H-NMR (4.10 MHz, CDCl 3): δ 7.95 (s, 1H), 7.14 (s, 1H), 4.04-3.92 (m, 1H), 3.39-2, 58 (m, 7H), 2.18-1.51 (m, 3H).

Example 10

Preparation of (2-cyano-1-pyrrolidine-3-ylethyl) carbamic acid tert-butyl ester

Me LMe

Me ^ O

30, 10275453, t 153.

A. 3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester

Me Me JUMe JLMe c Me'TD Me ^ t).

0 T

O ^ NH NH 4 Cl) 2 H - O ^ NH 1

NC ^ V \ P i

T Ν-Γ T NH

The isomeric mixture of 3- (1-tert-butoxycarbonyl-10-amino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester was first purified over a column with silica containing 25 to 75% ethyl acetate in hexanes for 50 minutes, resulting in diastereomers A and B gave. Diastereomer A was subjected to chiral HPLC (Chiralpak AD, 10% ethanol in methanol) to give the enantiomers A1 (8.4 minutes) and A2 (12.2 minutes).

To a solution of 3- (1-tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester (0.53 g, 1.41 mmol) in methanol (25 ml) was added under one. 20 nitrogen atmosphere ammonium formate (0.27 g, 4.23 mmol) and 10% Pd / C (0.25 g) added. The nitrogen feed was removed and the reaction flask closed. After 2 days, the reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give 0.34 g of the title compound as a mixture of isomers (100%).

MS (APCI +): m / z = 240 (M + H) +.

Example 11

Preparation of pyrrolidine-3-ylacetonitrile 30.

NCtN ^ N NH

1 027545 J

154 A. 3- (Toluene-4-sulfonyloxymethyl) pyrrolidine-1-carboxylic acid benzyl ester 5 Ph.sub.-Ph.H. - carboxylic acid benzyl ester (1.80 g, 7.65 mmol) in dichloromethane (10 ml), triethylamine (1.60 ml, 11.48 mmol) and p-toluenesulfonyl chloride (1.75 g, 9.18 mmol) were added. After 3 hours, the reaction mixture was washed with saturated sodium bicarbonate solution, water and concentrated saline. The organic layer was dried over MgSO 4, filtered and the filtrate concentrated. Purification by flash column chromatography (ethyl acetate / hexanes gradient) gave 2.63 g of the title compound (88% yield).

MS (APCI +): m / z = 390 (M + H). +.

B. 3 'Cyanomethylpyrrolidine-1-carboxylic acid benzyl ester

Ph, Ph, 0/30 To a solution of 3- (toluene-4-sulfonyloxy-methyl) pyrrolidine-1-carboxylic acid benzyl ester (1.52 g, 3.90 mmol) in DMSO (3 mL) was added sodium cyanide (0.01 25 g, 5.07 mmol). The reaction mixture was heated to 1 02 75 45. ' . 155 70 ° C. After 4 hours, the reaction mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over MgSO 4, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography (ethyl acetate / hexanes gradient) afforded 0.81 g of the title compound (85%).

MS (APCI +): m / z = 245 (M + H) +.

C. Pyrrolidine-3-ylacetonitrile

Ph

· - "" "O

15

To a solution of. 3-cyanomethylpyrrolidine-1-carboxylic acid benzyl ester (0.80 g, 3.27 mmol) in methanol (50 ml), triethylamine (0.5 ml) and 10% Pd / C (0.2 g) were added. The reaction vessel was kept under a pressure of 50 psi for 24 hours, the mixture filtered through Celite and the filtrate concentrated under reduced pressure to give 0.36 g of the title compound (100% yield). MS (APCI +): m / z = 111 (M + H). Example 12

Preparation of 3-amino-3- [1- (3-aniino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl) pyrrolidine] 3-yl] -2,2-dimethylpropionitrile hydrochloride salt 102104545 156 NCv / Me V-Me

1.2 HCl

^ L> 5 A. Pyrrolidine-3-carboxylic acid ethyl ester _P ° zB CO2Et) H2t Pd / C r

N Et0 H V Sh H

10

A solution of 1-benzylpyrrolidine-3-carboxylic acid ethyl ester (10.00 g, 42.9 mmol) in ethanol (200 ml) was hydrogenated at 60 psi for 6 hours in the presence of 10% Pd / C (2.0 g ). The resulting suspension was filtered through Celite, washed with CH 2 Cl 2 and concentrated under reduced pressure to provide the crude title compound (7.12 g, 100% yield).

1 H NMR. (CD.CI3): δ = 4.16 (k, 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 +).

B. Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester, 3-ethyl ester dCO 2 Et CO 3 Et

Boc 2 Q j (im CH 2 Cl 2 H Boe 30 02 75 45 157:

To a solution of crude pyrrolidine-3-carboxylic acid ethyl ester (7.12 g) in CH 2 Cl 2 (50 ml) was added a solution of d-tert-butyl dicarbonate (10.30 g, 47.2 mmol) in CH 2 Cl 2 (50 ml) at 0 ° C ) added in 10 minutes. After warming to room temperature for 18 hours, the reaction mixture was washed with water and then brine, dried (Na 2 SO 4) and concentrated under reduced pressure to provide the title compound that was used without further purification (10.4 g, 100% yield) .

X H NMR (CDCl 3): δ = 4.14 (k, 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-Hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester

, CO2 Et / OH

I— (NaBH 4) - (

THF.MeOH

20 Boe Boe

To a solution of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester, 3-ethyl ester (10.4 g, 42.9 mmol) in tetrahydrofuran (50 ml) and methanol (50 ml) was added sodium borohydride (NaBH 4) at 0 ° C ) (3.25 g, 86 mmol) added in portions in 30 minutes. After 18 hours, more NaBH 4 (3.25 g, 86 mmol) was added. After a further 24 hours, the reaction mixture was diluted with ethyl acetate, the reaction was quenched with saturated Na 2 CC> 3 µl of water and stirred for 15 minutes. The layers were separated, the aqueous layer was extracted with ethyl acetate, and then the combined organic layers were washed twice with water, once with brine, dried (Na 2 SO 4) and concentrated under reduced pressure. The impure. product was purified by column chromatography (CH 2 Cl 2 to CH 2 Cl 2: MeOH = 95: 5 to 9: 1) to give the title compound (8.09 g, 94% yield).

X H NMR (CDCl 3): δ = 3.25-3, 69 (m, 5H), 3.11 (m, 1H), 2.40 (m, 1H), 1.97 (m, 1H), 1 , 67 (m, 1 H), 1.46 (s, 9 H).

D. 3-Fonnylpyrrolidine-1-carboxylic acid tert-butyl ester OH (COCl) 2, DMSO 0-1 NEt 3, CH 2 Cl 2 or L ^ NBoc H | ^ NBoc 15

To a solution of oxalyl chloride (3.86 ml, 44.2 mmol) in CH 2 Cl 2 (80 ml) was added a solution of dimethyl sulfoxide (6.28 ml, 88.5 mmol) in CH 2 Cl 2 (20) at -78 ° C under N 2 ml). After 10 minutes, a solution of 3-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (8.09 g, 40.2 mmol) in CH 2 Cl 2 (30 mL) was added over 15 minutes. After an additional 30 minutes, triethylamine (28.0 ml, 201 mmol) was added and the reaction mixture stirred for 1 hour at -78 ° C and then for 1 hour at room temperature. The reaction mixture was twice. washed with water and then with brine, dried (Na 2 SO 4) and concentrated under reduced pressure. The crude product was purified by column chromatography (hexanes: ethyl acetate = 9: 1 to 1: 1) to give the title compound (6.98 g, 87%). . .

1027545-159 1 H NMR (CDCl 3): δ = 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).

E. 3- (Benzenesulfonyl-tert-butoxycarbonylaminomethyl) -5-pyrrolidine-1-carboxylic acid tert-butyl ester on NHBoc) -V HgNBoc, PhSOgNa phO 2 S - (

Sr HCO 2 H, MeOH, H 2 O V / 10: 600 L ·

To a suspension of tert-butyl carbamate (589 mg, 5.03 mmol) and sodium benzene sulfinate (1.24 g, 7.55 mmol) in water (50 ml) was added a solution of 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 5.03 mmol) in methanol (5 ml) was added, followed by formic acid (0.19 ml, 5.03 mmol). The reaction mixture was heated to 60 ° C for 2 hours and then allowed to stand for Stand at room temperature for 7 days. The resulting white solid was filtered off, washed with water and dried thoroughly under reduced pressure to provide the title compound. (868 mg, 39% yield).

X H NMR (CDCl 3): δ = 7.91 (d, 2H), 7.50-7.68 (m, 3H), 4.82-5.18 (m, 2H) ,. 3.71 (m, 1H), 3.54 (m, 1H), 3.31 (m, 1H), 2.90-3.19 (m, 2H), 2.35 (m, 0.5H) ), 2.18 (m, 0.5 H), 1.76-1.99 (m, 1 H), 1.47 (s, 9 H), 1.21 (s, 4.5 H), 1.18 ( s, 4.5 H).

30 '' F. 3- (1-tert-Butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester 1 02 75 45- 160.

NHBoc NC NHBoc

Ph02S— ('PrCN.LDA / T \ _) —V - Μβ Μθ ί ~ Λ

{} THF

5 N N

Boe Boe

To a solution of isobutyronitrile (4.07 ml, 45 mmol) in dry THF (100 ml) was added lithium diisopropylamide (30.3 ml of a 1.5 M solution in cyclohexane, 45 mmol) at -78 ° C under a nitrogen atmosphere. added. After 1 hour this solution was transferred via a cannula into a stirred suspension of 3- (benzenesulfonyl) -tert-butoxycarbonylaminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.55 mmol) in dry THF (100 ml) of -7 8 ° C. After 7 hours, the reaction mixture was allowed to warm slowly to room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride (NH 4 Cl) and extracted twice with CH 2 Cl 2. The organic phase was washed with saturated. NaHCO 3 in water, then dried (Na 2 SO 4) and concentrated under. reduced pressure. The crude product was purified by column chromatography, first with hexanes: EtOAc = 3: 1 to 2: 1, and then with CH 2 Cl 2: MeOH = 99.5: 0.5 to 99: 1, which is the. title compound (1.52 g, .91% yield).

^ -NMR (CDCl3): δ = 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-H) +).

G. 3-Amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile dihydrochloride salt 1 027545, 161 NCV. Me HCI Kin Me pMe CH 2 Cl 2 V-Me

5 BocHN T ^ mr ~ "η2ν '\ - λ' 2HCI

L ^ NBoc I nh

To a solution of 3- (1-tert-butoxycarbonylamino-2-cyano-2,2-dimethylethyl) pyrrolidine-1-cabanoic acid tert-butyl ester (1.52 g, 4.3 mmol) in CH 2 Cl 2 (100 mL) was added at 0 ° C HCl (21.5 ml of a 4 M solution in dioxane, 86 mmol) added. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 18 hours before being concentrated under reduced pressure. The oily residue was taken up in water, extracted twice with CH 2 Cl 2 and the aqueous phase concentrated under reduced pressure to give the title compound (704 mg, 73%).

1 H NMR (D 2 O): δ = 3.68-3.82 (m, 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), 1.60 (s, 1.5H), 1.59 (s , 1.5 H), 1.57.

(s, 1.5 H), 1.56 (s, 1.5 H).

LCMS (APCI +): 168 (100%, MH +).

25

Example 13

Preparation of (+) - N - [1-azetidin-3-yl) -2-cyanoethyl] - 2,2,2-trifluoroacetamide hydrochloride

O

30 HN + CF 3

"—NHHC

1027545 - 162 A. Cis / trans 3- (1-benzhydrylazetidin-3-yl) acrylonitrile

5: ηΛον η J

JL · .CS2CO3, THF, 50 C /

Qjü. , 54%

A solution of 1-benzhydrylazetidine-3-carbaldehyde (1.55 g, 6.17 rrunol), diethyl (cyanomethyl) phosphonate (1.30 ml, 8.02 iranol). and cesium carbonate (2.61 g, 8.02 mmol) in tetrahydrofuran (30 mL) was heated to 50 ° C for 2 hours. The solution was allowed to cool to room temperature and was diluted with ethyl acetate (100 ml). The solution was then washed with saturated aqueous ammonium chloride (20 ml). The organic layer was then dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography, eluting with a gradient of hexanes: ethyl acetate (90:10 to 75:25), yielding 913 mg (54%) of the title dressing as a 1: 1 mixture cis / trans isomers. The isomers were collected separately, but later combined.

cis isomer: MS (APCI) (M + 1) / Z 275.0; m.p. Mp 117-120 ° C.

Trans isomer: MS (APCI) (M + 1 / Z) 275.0; m.p. Mp = 108-110 ° C.

B. (+) - 3-Amino-3- (1 "benzhydrylazetidin-3-yl) propionitrile. NH 2 ^] | nh3 · closed tube LjJj f j) 30 lNnJLJ1 -:

J MeOH, 100C

Hj | "" 5% 1 02 7545. " 163

A saturated solution of ammonia in methanol (30 ml) was added to a 1: 1 mixture of cis / trans 3- (1-benzhydrylazetidin-3-yl) acrylonitrile (863 mg, 3.15 mmol). The resulting suspension was then heated in a closed tube to 100 ° C for 19 hours. After cooling to room temperature, the solution was concentrated under reduced pressure to provide 912 mg (99.5%) of the title compound as an oil.

MS (APCI) (M + 1) / Z: 292.1.

C. (+) - N - [1- (1-Benzhydrylazetidin-3-yl) -2-cyanoethyl] -15 2,2,2-trifluoroacetamide X, X 1 N x HAF 3 ^ F 3 C ^ O ^ CF 3 -1 Et 3 N _ jL Jl --- S-- Lj i4 ^]) on CH ^ OCtOtkt NyV1 79% Ίί

A solution of 3-amino-3- (1-benzhydrylazetidin-3-25 yl) propionitrile (905 mg, 3.11 mmol) and triethylamine (1.30 mL, 9.32 mmol) in dichloromethane (30 mL) was added at 0 ° C treated with trifluoroacetic anhydride (0.659 ml, 4.67 mmol). The solution was then stirred at room temperature for 45 minutes. The solution was then cooled to 0 ° C and water (5 ml) added. The mixture was then further diluted with dichloromethane (50 ml) and water (15 ml). The layers were separated and the organic layer was washed with water (2 x 20 ml). The organic layer was then dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography, eluting with a gradient of hexanes: ethyl acetate (75:25 to 55:45) to provide 952 mg (79%) of the title compound.

MS (APCI) (M + 1) / Z: 388.0.

D. (+) - N - [1-Azetidin-3-yl) -2-cyanoethyl] -2,2,2-trifluoroacetamide hydrochloride 0 · 10% O boiling under 11 HNACF 3 1; N HN CF 3

Jf Cl. c.f. (1.27 itanol) in dichloroethane (15 ml) was cooled to 0 ° C, after which 1-chloroethyl chloroformate (0.410 ml, 3.80 mmol) was added. The resulting solution was heated under reflux for 2 hours. The solution was then concentrated under reduced pressure to provide an oil. Methanol (15 ml was added to the oil and the resulting solution heated under reflux for 2 hours. The solvent was removed under reduced pressure to provide a thick, yellow oil. The oil was triturated several times, discarded with hexanes and the supernatant. The title compound was obtained as a yellow residue, 391 mg.

1027545- 165 MS (APCI) (M + 1) / Z: 222.0.

Example 14

Preparation of (2-cyano-1-pyrrolidine-3-5 ylethyl) methylcarbamic acid tert-butyl ester A. 3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzylesber

Me

Me ^ \ Me Me Me ^ Me ^ "b

To a solution of 3- (2-cyanovinyl) pyrrolidine-1-carboxylic acid benzyl ester (4.40 g, 17.2 rranol) in absolute ethanol (50 ml) was added methylamine (about 3 ml) and the solution was added for 14 heated to 80 ° C in a closed reactor for 1 hour. The solution was concentrated in vacuo. The resulting amine was dissolved in THF (100 ml), Boc anhydride (5.62 g, 25.7 mmol) was added and the solution stirred at room temperature for 17 hours. The solution was concentrated in vacuo. The residue was taken up in ethyl acetate (100 ml), washed with sat. NH 4 Cl in water (100 ml) and concentrated saline (100 ml), dried with. MgSO 4 and concentrated in vacuo. The crude product became. purified on a column with 120 g of silica gel eluted with 20 to 60% ethyl acetate in hexanes for 60 minutes at 50 ml / min, yielding 6.08 g of 1027545-1666 '.

title compound in multiple fractions (combined. yield: 91%).

MS (APCI +): m / z = 288 (M + H-Boc).

Diastereomer A (upper spot): the yield was 2.59 g (39%) and from diastereomer B (lower spot) the yield was 2.82 g (42%).

Chiral separation of enantiomers with HPLC

Me

10 Me »J

m? Me Me, L

\ rS>

Me, X Μθ 15 N N ^ 0 is B2 \ = / ^ O __ diastereaneer B \ _ /. p N0.0

H

Diastereomer B (2.1 g) was separated by chiral HPLC with a ChiralPak AD column eluted with a methanol / ethanol gradient, yielding 0.87 g of isomer B1 (41%) ) and 0.53 g of isomer B2 (25%).

B. (2-Cyano-1-pyrrolidine-3-ylethyl) methylcarbamic acid tert-butyl ester 1 02 75 45. ' 167

Me Me

Meü. Me-J

O Me 9 Me

Blade 1. Me. 1.

N N ^ O H2 \ N ^ p 5 ^ P “Pd / c" *

r n - (L / NH

A solution of 3- (1-tert-butyoxycarbonylamino-2-.10 cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester (diastereomeric B, 0.690 g, 1.78 mmol) in THF (50 ml) was hydrogenated with 10% Pd / C . The catalyst was removed by filtration and the filtrate concentrated in vacuo to give 0.436 g of the title compound (yield: 97%).

MS (APCI +): m / z = 254 (M + H).

Example 15

Alternative preparation of 3- (1-tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester. Me ^ ΜΟ ^ Μβ

? Mexβ Mex I

N. HN ^ o Mel V J * 0 o

To a solution of 3- (1-tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidine-1-carboxylic acid benzyl ester (isomer B2) (586 mg, 1.57 mmol) in anhydrous DMF (12 ml) was added NaH

(60 wt%, 188. mg, 4.71 mmol) and the solution stirred at room temperature for 1 hour.

1 02 75 45-> 168

Methyl iodide (1.78 g, 12.5 nvmol) was then added to the mixture and this was stirred at room temperature for 1 hour. The solution was poured into sat. NH 4 Cl aq. (80 ml) and extracted with diethyl ether (120 ml). The organic liquids were washed with brine (50 ml), dried with MgSO 4 and concentrated in vacuo. The crude product was placed on a column with 10 g of silica gel which was eluted with 20 to 70% ethyl acetate in hexanes for 10 hours to give 0.44 g of the title compound (yield: 72%).

MS (APCI +): m / z = 288 (M + H-Boc).

B. Linking of precursors of the side chain to 15 quinolon cores

Linking example 1

Preparation of 9- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] 8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-20a zafenalene-5-carboxylic acid OO 25 A. 9- [3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrro-30-lidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3 dihydro-6H-1-oxa-3a-azapalenalen-5-carboxylic acid 1 02 75 45- 169? ? O Me Μβ- ^ ο

Triawnina ν ^? Η fyy \ a ° h XA * + ι> · '° ΆΜβ p

To a solution of (2-cyano-1-pyrrolidine-3-ylethyl) carbamic acid tert-butyl ester (256 mg, 1.07 mmol) and 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro -6H-1-oxa-3a-aza-phenalene-5-carbonic acid (281 mg, 1.00 mmol) in acetonitrile (8 ml) became triethylamine. (506 mg, 5.00 mmol) added and the solution heated to 80 ° C for 4 days. The solution was concentrated in vacuo. The residue was taken up in chloroform (50 ml), washed with saturated aqueous ammonium chloride (50 ml), dried with MgSO 4 and concentrated in vacuo. The crude product was placed on a column of 40 g of silica gel eluted with 0 to 8% methanol in dichloromethane for 1 hour to give 241 mg of the title compound (yield: 48%).

MS (APCI +): m / z = 501 (M + H).

B. 9- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α azafenalene-5-carboxylic acid 25 Me '.

Me ^ O π o? 9

A. »11 HCl · NH F

0 *> iH ΡΝ ^ γΑΝ) Α0Η --- N ^. ) II T.

30 1027545-170.

To a solution of 9- [3- (1-tert-butoxycarbonyl-amino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H -1 -oxa-3a-azaphenalene-5-carboxylic acid (241 mg, 0.401 mmol) in dichloromethane (5 ml), a 5 wt% solution of HCl in ethanol (1 ml) was added and the solution was stirred at room temperature for 16 hours . The mixture was diluted with methylene chloride. The precipitate was collected by filtration under vacuum and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum at 45 ° C to give 62 mg of the title compound as the hydrochloride salt (yield: 32%).

MS (APCI +): m / z = 401 (M + H) ..

15 Linking example 2

Preparation of 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid IX. - N / A

F y L ^ NH

A ^ X 'A

25

To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile (200 mg, 1.44 mmol) and 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (265 mg, 1.00 mmol) in acetonitrile (10 ml), triethylamine (505 mg, 5.00 mmol) was added and the solution heated to 80 ° C for 17 hours. The precipitate was collected by vacuum filtration and rinsed with acetonitrile. The 1027545-. 171 solid was dried under vacuum overnight at 45 ° C to give 281 mg of the title compound (yield: 73%).

MS (APCI +): m / z = 385 (M + H) 5

Linking example 3

Preparation of 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3- carboxylic acid 10 o F / JA 3 H EtN N NH 3

Δ - A

To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile (200 mg, 1.44 mmol). and 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid (2.82 mg, 1.00 mmol) in acetonitrile (10 ml) was triethylamine (505 mg, 5.00 mmol), and the solution heated to 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 give 240 mg of the title compound (yield: 62%).

MS (APCI +): m / z = 386 (M + H).

Linking example 4 102 75 45- '172'

Preparation of 7- [3- (1-amino-2- * cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 A. 7- [3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-xnethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester in Ve

o o CN Me — j — Me O O

rVV'o-BF, -% o iTYt ^ · ®12

r-V · - / jF "i, _ / sArV

"W'A Q ί" · Α

H

15

To a solution of 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydrquinoline-3-carboxylic acid difluoroboronate ester (0.45 g) and the (2-cyano-1-pyrrolidine) 3-ylethyl) carbamic acid t-butyleter (1.3 g.) In acetonitrile (.4 ml), triethylamine (5 equiv.) Was added and the solution heated to 80 ° C for 24 hours. The solution was then concentrated and the crude product used directly in the next reaction.

MS (APCl +): m / z = 497.3 (M-BF 2 + H).

B. 7- [3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-aethoxy-4-oxo-1, 4-30 dihydroquinoline-3-carboxylic acid 1 02 7545- 173 oo ° CtBU X O-tBu · NI?

HN J JL W ukf ° fl fl II OH

w ^ Nwr ^ -; - * HH AllJU, J

NC '' ^^ 6, NC- ^ O OMe ^ 5 To a solution of 7- [3- (1-tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4- oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroborate ester in EtOH (4 ml), triethylamine (5 equiv.) was added and the reaction mixture heated to 80 ° C for 6 hours. The crude solution was concentrated, then taken up in chloroform, washed with NH 4 Cl (in water), dried over Na 2 SO 4 and concentrated. The crude material purified by flash chromatography (isocratic, 97: 3 = EtOAc: EtOH) to provide the pure carboxylic acid (0.50 g, 72% for two reactions).

MS (APCI +): m / z = 497.3 (M + H).

C. 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-20 cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

O-tBu. · XX SS

) = ° 'if ^ Tiii h or Hhj XX 3 - HiN ^ Jl JL 3 NC - / Λ - 7 0Me / \ NC · ^' OMe ^ 30 To a solution of impure 7- [3- (1- tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.69 g) in dichloromethane (5 ml) was 10 % 1027545, 174.

HCl in ethanol (5 ml) was added, and the reaction mixture stirred at room temperature overnight. The crude reaction mixture was concentrated, taken up in EtOAc (15 ml) and treated in an ultrasonic bath for 20 minutes. The resulting precipitate was collected by filtration to provide the pure product as a yellow solid (0.315 g, 57%).

MS (APCI +): m / z ≤ 397.3 (M + H).

10 Linking example 5

Preparation of 7- [3- (1-aminocyclopropyl) azetidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 15 Π

FVr ^ A.COOH

A '

Me 1 nc ^ nh 20 'A. 1-Cyclopropyl-6-fluoro-8-methyl-4-oxo-7- {3- [1- (2,2,2-trifluoroacetylaminojayclopropyl] azetidin-1-yl} -1 1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester 25 o Fv ^ JvC0 ° bf2 HA p JC ^ COOBF2 W - O * · AF! ° ynh

H O

30 1 027545

To a solution of the 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 175 difluoroboronate ester (0.400 g) and N- (1-azetidin-3-ylcyclopropyl) -2,2,2-trifluoroacetamide (1.5 equiv.) In DMSO (3 ml), triethylamine (5 equiv.) Was added and the solution was added overnight. heated to 80 ° C. The crude solution was applied to a column for reverse phase medium pressure liquid chromatography (MPLC). The acetonitrile was removed from the eluent and the remaining aqueous slurry immediately subjected to the following reaction.

MS (APCl +): m / z = 468.2 (M-BF 2 + H).

B. 7- [3- (1-Aminocyclopropyl) azetidin-1-yl] -1-cyclopropyl-6-fluoro ** 8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 15 o

Fv ^ A ^ COOBF2 T i T

jf Jl JJ '/' N / SrsN ^: 2o fsCynh o

To a solution of 1-cyclopropyl-6-fluoro-8-methyl-4-oxo-7- {3- [1- (2,2,2-trifluoroacetylamino) cyclopropyl] aze-tidin-1-yl) -1. 4-dihydroquinoline-3-carboxylic acid difluoroboronate ester in 75% aqueous methanol (30 ml), 10 ml of saturated sodium bicarbonate was added and the reaction mixture was heated to 70 ° C for 3 days. The solution was then concentrated to 10 ml, decanted from the precipitated NaHCO 3 and applied directly to a reverse-phase MPLC column. The product was eluted in pure form to give 0.23 g (51% for two steps) of the title compound.

1027545-176 MS (APCI +): m / z = 372.3 (M + H).

C. 7- {3- [1- (2-Cyanoethylamino) cyclopropyl] azetidin-1-yl> -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-5-quinoline-3 -carboxylic acid

O

O

. | T J

II j ___- ΊΓ I *

v0, -I "A

7- [3- (1-Aminocyclopropyl) azetidin-1-yl] -1-15 cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (free base) (0, 23 g) was dissolved in MeOH (20 ml), and acrylonitrile (10 equiv.) And triethylamine (5 equiv.) Were added. The solution was stirred at room temperature overnight and then heated to 50 ° C for several hours. The crude material was then concentrated, dissolved in a small amount of water and applied to a reverse-phase MPLC column for purification (0.11 g, 42%).

MS (APCI +): m / z = 425.3 (M + H).

25

Linking example 6

Preparation of 7- {3 - [(2-cyanoethylamino) methyl] -3-ethylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 30 1027545- 177

MC. O O

\ fYYf0H

NH 1 JL JJ

L rN'y ^ N

r -A Me 5 A. 1-Cyclopropyl-7- {3-ethyl-3 - [(2,2,2-trifluoroacetyl-amino) methyl] azetidin-1-yl} -6-fluoro-8-methyl-4 -oxo-1,4-dihydro-quinoline-3-carboxylic acid difluoroboronate ester 10 DEG C.

0 ’krpn rY> ^ Μθ A

j-1 Me λ Me 15 ... Me

To a solution of 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester (1.0 g) and N- (3-ethylazetidin-3-ylmethyl) -2,2,2-trifluoroacetamide (2 equiv.) In DMSO (8 ml) was added triethylamine (5 equiv.) And the solution heated to 80 ° C for 4 hours. The crude solution was placed on top of a reverse phase MPLC column, which directly provided a mixture of the product and the carboxylic acid (boronate hydrolysis: 0.70 g, 49%). .

MS (APCI +): m / z = 470.1 (M + H).

B. 7- (3-Aminomethyl-3-ethylazetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1 02 75 45 - 178

o O O O

-Λ- 'i ___ O .: "• γχι ψΧΐ • Me ^ Me

To a solution of 7- (3-aminomethyl-3-10 ethylazetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester in 50 ml water and 100 ml of methanol, 50 ml of saturated potassium carbonate was added and the reaction mixture heated to 60 ° C overnight. The solution was then concentrated to 30 ml and applied directly to a reverse phase column. 0.41 g of product was obtained (74%).

MS (APCI +): m / z = 374.2 (M + H).

C. 7- {3 - [(2-Cyanoethylamino) methyl] -3-ethylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl "4" Oxo-1,4-dihydro-quinoline- 3-carboxylic acid

FYVt OH ____ ^ NH IJL jJ

nh2: J

Ββ A ^ 30 7- (3-Aminomethyl-3-ethylazetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 0.410 g) was dissolved in 10 ml MeOH, and acrylonitrile (3 equiv.) Added. The solution became 7027545.

179 stirred at room temperature overnight and then heated to 50 ° C for several hours. The crude material was then concentrated and dissolved in a small amount of water, and placed on a reverse-phase MPLC column for purification.

Linking example 7

Preparation of 7- {3- [1- (2-cyanoethylamino) propyl] azetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-10 dihydroquinoline-3-carboxylic acid A. 1 "Cyclopropyl-6-fluoro-8-methyl-4-oxo-7- {3- [1- (2,2,2-trifluoroacetylamino) propyl] azetidin-1-yl) -1,4-dihydro- quinoline-3-carboxylic acid 15

HfVF

Me ^ F o O

0 0 1. II FP II N

ρΎ ^ ΥιΓ ^ 0'ΒΡζ n'h sA fTtVoh dipea, dmso, bo c

20 Me k 2 EtgN, EtOH, Δ M A

L— * Me 55%

A solution of 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester (350 mg, 1.07 mmol), N- (1 -azetidin-3-yl-propyl) -2,2,2-trifluoroacetamide hydrochloride (660 mg, 2.68 mmol) and diisopropylethylamine (0.932 mL, 5.35 mmol) in DMSO (3 mL). was heated to 80 ° C for 20 hours. The solution was allowed to cool to room temperature and was diluted with ethanol (20 ml) and then triethylamine (1.05 ml, 7.50 mmol) was added. The resulting solution was then heated for 4 hours 1027545 ^ 180.

under reflux. The ethanol was removed under reduced pressure to provide a red solution. The solution was diluted with dichloromethane (100 ml) and washed with 1 N hydrochloric 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 obtain the formation of more solid 10. The mixture was then kept in the refrigerator for 1 hour. The suspension was then filtered to give 278 mg (55%) of the title compound as an orange solid. provided.

Melting point = 220-223 ° C.

MS (APCI): m / z = 470.0.

B. Sodium 7- [3- (1-aminopropyl) azetidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate 20.

or ff AA FYVr ° Na4-1b2co3 M JL Jl.

° γ ~ ρ ji jC X —- ', Γ HzNny ^ On ^ i'j nJ, MeOH. H2O.70C Me ^ J ^ Me A 75% Me ^

Me 25

Saturated aqueous sodium carbonate (4.5 ml) was added to a suspension of 1-cyclopropyl-6-fluoro-8-methyl-4-oxo-7- {3- [1- (2,2,2-trifluoroacetylamino) propyl ] -azetidin-1-yl} -1,4-dihydroquinoline-3-carboxylic acid (260 mg, 0.554 mmol) in a mixture of methanol: water (8 ml: 4 ml). The mixture was then heated to 50 ° C. After 2 hours, starting material was still present so that the temperature was raised to 70 ° C; stirring at 70 ° C 1027545-18 continued for another 6 hours. The methanol was then removed under reduced pressure to give a solution. The resulting solution was then placed directly on a reverse phase column. Elution from the column was done with a gradient of water racetonitrile (99: 1 to 30:70) to provide a yellow solid. The solid was dissolved in a minimum amount of water and freeze-dried to provide 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- (2-Cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquino-3-line-3 -carboxylic acid

O O N

F- ^ Al \ _ lil ° O

—— s fyvVw 20 Μβ0Η · te * vCBirr

^ 'Δ' 7 ^ MeA

Acrylonitrile (1 ml) was added to a solution of sodium 7- [3- (1-aminopropyl) azetidin-1-yl] -1-cyclo-propyl-6-fluoro-8-methyl-4-oxo-1 1,4-dihydroquinoline-3-carboxylate (87 mg, 0.220 mmol) in methanol (1.5 ml). The solution was then stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to provide an oil. The oil was purified by medium pressure liquid reverse phase chromatography, eluting with a gradient of water: acetonitrile (99: 1 to 50:50), yielding 32 mg of yellow solid. The solid was further purified by preparative high performance liquid reverse phase chromatography, eluting with a gradient of water (0.1% formic acid): acetonitrile (0.1% formic acid (95: 5 to 50:50), which The residue was dissolved in the minimum amount of water and freeze-dried to provide 19 mg (20%) of the title compound as a yellow solid.The XH NMR was approximately 75% of the original and 25 % the formate salt.

LC / MS (APCI): 427.2; HPLC, purity = 100%.

Coupling Example 8 Preparation of sodium 7- {3 - [(2-cyanoethylamino) methyl] -3-methylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylate

20 N o O

l | l UI

YYif. Na +

^ Me A

A. 1-Cyclopropyl-e-fluoro-e-methyl-VO-methyl-S-ti2,2,2-trifluoroacetylamino) methyl] azetidin-1-yl) -4-oxo-1,4-dihydroquinoline-3- carboxylic acid 102 1024545.

183 Λ; fi / o'bF2 ι ^ α

DIPEA, DMSO, 80 ° C

5 Μθ Λ 2. Et3 N, EtOH, Δ Me · M® A

80%

A solution of 1-cyclopropyl-6-fluoro-8-methyl-7- {3-methyl-3 - [(2,2,2-trifluoroacetylamino) methyl] azetidin-1-yl} -4-oxo-1,4 -dihydroquinolin-3-carboxylic acid difluoroborate ester (1.43 g, 4.37 mmol), 2,2,2-trifluoro-W- (3-methylazetidin-3-ylmethyl) acetamide hydrochloride (1.88 g, 8, 08 mmol) and diisopropylethylamine (3.81 mL, 21.9 mmol) in dimethyl sulfoxide (10 mL) was heated to 80 ° C for 4 hours. The solution was allowed to cool to. Room temperature and this was diluted with ethanol (80 ml) and then triethylamine (4.27 ml, 30.6 mmol) was added. The resulting solution was then heated under reflux for 4 hours. The ethanol was removed under reduced pressure to provide a red solution. The solution was diluted with dichloromethane (300 ml) and washed with. 1 N hydrochloric acid (50 ml), water (3 x 30 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. An orange solid was obtained. Dichloromethane (15 ml) was added to partially dissolve the solid. Hexanes (20 ml) was added slowly to obtain the formation of more solid. The mixture was then kept in the refrigerator for 1 hour. The suspension was then filtered to provide 1.59 g of 30 (80%) title compound as an orange solid.

MS (APCI): m / z = 456.1; m.p. 215-218 ° C.

1 027545-184. .

B. Sodium 7- (3-aminomethyl-3-methylazetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate. 5 n 2 = STvVA N »2CO, ΥυΥ0 ** υν .. p II I U ---" Me HN MeOH, HzO, 70 ° C H2NOC / NT j

"" "V Me ^ 59% ββ A

10

Saturated aqueous sodium carbonate (25 ml) was added to a suspension of 1-cyclopropyl-6-fluoro-8-methyl-7- {3-methyl-3 - [(2,2,2-trifluoroacetylamino) methyl] azetidine- 1'-yl} -4-oxo-dihydroquinolone-3-carboxylic acid (1/24 g, 2.72 mmol) in a mixture of methanol: water (45 ml: 20 ml). The mixture was then heated to 70 ° C for 2 hours. The methanol was then removed under reduced pressure to give a solution. The resulting solution was then directly applied to a reverse phase column. The crude product was then purified by medium pressure reverse phase chromatography, eluting with a gradient from 100% water to 50% water: 50% acetonitrile to provide 616 mg (59%) of the title compound as a white powder.

MS (APCI): m / z (COOH) = 360.1.

HPLC, purity = 96.4% (254 nm).

C. Sodium 7- {3 - [(2-cyanoethylamino) methyl] -3-inethylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline -3-carboxylate 1 02 75 45- o.

185 o O ^ Rave O o, ΥγΥΰΝι -—ZZÜ * 'Υ ^ ιΥ ^ 0 ^ 31 ·

MeOH.kt HN ^ / ^ N'y ^ N ^ t'A. iZ '<*> 15

Acrylonitrile (1.47 ml, 22.3 mmol) was added to a solution of sodium 7- (3-aminomethyl-3-methylazetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4 -oxo-1,4-dihydroquinoline-3-carboxylate (425 mg, 1.11 mmol) in methanol: (10 mL). The solution was. then stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to provide a white residue. The residue was dissolved in a minimum amount of water, and the resulting solution was applied to a reverse phase column. The crude product was purified by medium pressure liquid reverse phase chromatography. eluted with a gradient from 100% water to 50% water: 50% acetonitrile to give 73 mg (15%) of the title compound. 20 provided a yellow solid.

LC / MS (APCI): m / z (COOH) = 413.2. M.p. Mp 190-200 ° C

(decomposition).

HPLC, purity = 97.4% (254 nm).

Coupling example 9

Preparation of 7- (3- {1 (2-cyanoethyl) methylamino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 30 0 027545- 186

FV'5VAVuh Nr. F'Y ^ V] fvOH

Me H JL Jk J> NCv ^ Me H ^ i i Jl HN V- ^ OMe 1 MeOH / —N \ - ^ OMeJl

Me ^ EtgN NC - ^ - / Me Me 5 1-Cyclopropyl-6-fluoro-8-methoxy-7- [3- (1-methylamino-ethyl) pyrrolidin-1-yl] -4-oxo-1,4 dihydroquinoline-3-carboxylic acid (WO 9209596 A1, 1992), (0.274 g, 0.679 mmol) was taken up in acrylonitrile (4 ml), and triethylamine (0.1 ml) was added. After 4 hours the solution was concentrated. The residue was taken up in dichloromethane and 2.0 N HCl / ether was added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether, leaving 97 mg of the title compound as the HCl salt (yield: 31%).

MS (APCI +): m / z = 457 (M + H). .

Coupling Example 10 Preparation of 7- {3- [1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid O Θ ° O ÏÏÏÏ ___JL (ί '^ Τ ^ ιΓ'ΟΗ OH NC ^ Me, H.

y ~ Kj OMeJ1 · M · 0H / ~~ HH OMe λ H2 N 0 MeeN EtNN NC - 7 ^ [3- (1-Aminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo -1,4-dihydroquinoline-3-carboxylic acid HCl salt 1027545.

187 (WO 9914214A1, 1999) (0.347 g, 0.854 mmol) was taken up in methanol, and Et 3 N (0.5 ml) was added. To the reaction mixture was added acrylonitrile (1 ml). After 24 hours the solution was concentrated. was taken up in dichloromethane and 2.0 N HCl / ether was added until cloudiness occurred.The resulting precipitate was collected by filtration and washed with diethyl ether, leaving 104 mg of the title compound as the HCl salt (yield: 30%).

MS (APCI +): m / z = 425 (M + H).

Coupling Example 11 Preparation of 7- (3- {1- [(2-cyanoethyl) -ethylamino] -ethyl} -pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-hydroxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

O O O O

,., ΗλΠΤ NC ^ “4 S / nAAJ '20 OMei MeOH Kir _ / - N ΟΜβλ \ L \ Etch N Ne- / \ i-Λ M Me 25 l-Cyclopropyl-7- [3- (1-ethylaminoethyl) pyrrolidine- 1-yl] -6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (WO 9209596 A1, 1992) (0.103 g, 0.240 mmol) was taken up in methanol, and triethylamine (0.05 ml) was added. Acrylonitrile (0.10 ml) was added to the reaction mixture and shaking with the orbital shaker. After 12 hours, the reaction mixture was concentrated, taken up in dichloromethane and 2.0 N HCl ether was added until turbidity occurred. The resulting precipitate became. collected by filtration and washed with diethyl ether to give 62 mg. title compound if it left HCl salt (yield: .55%).

MS (APCI +.): M / z - 471 (M + H).

5

Coupling Example 12 Preparation of 7- (3 - {[(2-cyanoethyl) ethylamino] methyl) pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline- 10 3-carboxylic acid OO oo yV | ° h NC ^ Ργϊγΐν ^ 0Η 15 Μθ ° η * J Γ \ Μθ Ζλ EtgN NC— 'V Me / \

Me Me, 20 1-Cyclopropyl-7- (3-ethylaminomethylpyrrolidin-1-yl) -6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (EP230295, 1987) (0.05 g, 0.124 mmol) was taken up in methanol, and triethylamine (0.02 ml) was added. Acrylonitrile (0.1 ml) was added to the reaction mixture .25 and the resulting solution, shaken with the orbital shaker. After 12 hours, the reaction mixture was concentrated, taken up in dichloromethane and 2 N HCl / ether was added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether, leaving 29 mg of the product as the HCl salt (yield: 51%).

MS (APCI +): m / z = 457 (M + H).

1 027545- 189

Coupling Example 13 Preparation of 7- (3- {1 - [(2-cyanoethyl) methylamino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-hydroxy-4-oxo-1,4-dihydroquinoline -5 3-carboxylic acid

0 0 0

VViOH wn y VVV ^ OH

Me 1 JL Jl NC ^ Me H J Ji Ji 1ft HN ^ W_0 i MeOH J> ï 10 Me Μβ ^ EtsN NC— '' Me Δ

The fluoroquinolone (WO 9209596 A1, 1992) (0.05 g, 0.124 in mol) was enumerated in methanol, and triethylamine (0.02 ml) was added. Acrylonitrile (0.1 ml) was added to the reaction mixture and the resulting solution was shaken with the orbital shaker. After 12 hours, the reaction mixture was concentrated, taken up in dichloromethane and 2N HCl / ether was added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether, leaving behind 33 mg of product as the HCl salt (yield: 58 pounds).

MS (APCI +): m / z = 457 (M + H).

25.

Coupling Example 14 Preparation of 7- (3- (1 - [(2-cyanoethyl) amino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-hydroxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid 30 102 75 45- _________ 190 0.0 11 nc ^ YYT "oh I Me JL> * L s MVV'N'V" Njl --- ΗΓ? Τ ^ Ϊ

/ \ J * L 1 MeOH J - NH - * Me A

we ^ EiaN NC - / ^ n Δ 5

The fluoroquinolone HCl salt (Chemical & Pharmaceutical Bulletin, 1994, 42 (7), 1442-54) (0.804 g, 2.142 mmol) was taken up in methanol, and triethylamine (0.5 mL) was added. Acrylonitrile (1 ml) was added to the reaction mixture. After 12 hours, the reaction mixture was concentrated, taken up in dichloromethane and 2 N HCl / ether was added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether. which left 850 mg of product as the HCl salt (yield: 92%).

MS (APCI +): m / z = 427 (M + H).

Coupling example 15

Preparation of 7- (3 - [(2-cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

0 O

25 rrVoH

r-fy'VS.

NC - / r ~ NH Me "° A

A. 7- (3-Amino-methyl-pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester 027545- Ύ] M ^ '^ ue'0 Λ. Me "° Δ

O

The pyrrolidine (EP 153163, 1985) (0.247 g, 2.47 mmol) and the 6-desfluoroquinolone (WO 9914214, 1999) (0.506 g, 1.56 mmol) were included in acetonitrile, and triethylamine. (1.0 ml) was added. After 18 hours, the reaction mixture was concentrated to leave 545 mg of the title compound (yield: 87%).

MS (APCI +): m / z = 406 (M + H). The compound was protected with a Boc group prior to the following hydrolysis step according to methods available to those skilled in the art.

B. 7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

20 O O O O

/ Vil 0BFs rVV ^ °

O'mAA. / EtsN. Jl A IJ

SocnN-EtOH-7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroborate ester (0.600 g, 1 / 19 mmol) was taken up in ethanol, and triethylamine (1/0 ml) was added. The resulting solution was heated to 60 ° C.

30 After 24 hours. the reaction mixture was concentrated, taken up in dichloromethane and. washed with. ammonium chloride, which. 523 mg of the title compound (yield: 96%).

MS (APCI +): m / z = 458 (M + H).

C. 7 - {3 - [(2-Cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-5 carboxylic acid O o. o o ^ XXf0H NC ^

J1 · 1} H2 N N -10 O MeOH l'f

10 Δ EW. . NC - ^ 'NH ^ - Ye' ° A

7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was taken up as the HCl salt (0.332 g, 0.846 mmol) in methanol, And triethylamine (0.5 ml) was added. Acrylonitrile (1 ml) was added to the reaction mixture. After 24 hours the solution was concentrated, the residue taken up in dichloromethane and 2 N HCl / ether added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether, leaving 176 mg of the title compound as the HCl salt (yield: 51%).

MS (APCI +): m / z * 411 (M + H).

25 Coupling example 16

Preparation of 7- {3- [1- (2-cyanoethylamino) -cyclopropyl] pyrrolidin-1-yl] -1-cyclopropyl-e-fluoro-e-methoxy-4-oxo-1-di-dihydroquinoline-3-carboxylic acid 193 O-phyl-5-NC-Me-1 A. 7- [3- (1-Aminocyclopropyl) pyrrolidin-1-yl] -1,2-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1 1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester: 10 DEG C.

^ A

To 1-pyrrolidin-3-ylcyclopropylamine (0.886 g, 7.00 irimol) the fluoroquinolone borate ester (EP 241206, 1987) (2.01 g, 5.85 iranol) was added, the whole was taken up in acetonitrile and triethylamine (4, 0 ml) was added After 20 hours, the reaction mixture was concentrated to leave 1.76 g of the title compound (yield: 67%).

MS (APCI +): m / z = 450 (M + H). .

The connection. was subjected to hydrolysis as mentioned in Example 15, step B, prior to the next step.

B. 7- {3- [1- (2-Cyanoethylamino) cyclopropyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3 -carboxylic acid

O O o O

0H Kir ^ FY \ iT OH

30 '- A AT NOk 1 027545- 194 7- [3- (1-Aminocyclopropyl) pyrrolidin-1-yl] -1-cyclo-propyl-6-fluoro-8-methoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic HCl salt (0.8477 g, 1.93 mmol) was taken up in methanol, and triethylamine (0.40 mL) was added.

Acrylonitrile (1 ml) was added to the reaction mixture and shaken. After 12 hours, the reaction mixture was concentrated, taken up in dichloromethane and 2 N HCl / ether was added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether to leave 647 mg of the title compound as the HCl salt (yield: 67%).

MS (APCI +): m / z = 455 (M + H).

15 Linking example 17

Preparation of 7- (3-aminomethylpyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

O O

a

A. 7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester

O O O O

30 ΓίΓ ° BF2 Et3 N1 TYF ° BF2

F'VV BooHN ^ pNH CH 3 CN

1027545-195

The pyrrolidine (0.496 g, 2.48 mmol) and the 6-desfluoroquinolone (WO 9914214, 1999) (0.662 g, 2.10 mmol) were taken up in acetonitrile, and triethylamine (1.5 mL) was added. After 18 hours, the reaction mixture was concentrated to leave 752 mg of the title compound (yield: 69%).

MS (APCI +): m / z = 506 (M + H).

B. 7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydrochino-1-lin-3-carboxylic acid

0 O O O

1 EtoH 17- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-20 yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroboronate ester (0.777 g, 1.48 mmol) was taken up in ethanol (50 ml), and triethylamine (1.00 ml) was added. The resulting solution was heated to 80 ° C. After 20 hours, the reaction mixture was allowed to cool to room temperature and was concentrated. The crude oil was taken up in dichloromethane and washed with ammonium chloride. The organic liquids were dried and concentrated to leave 544 mg of the title compound (yield: 80%).

MS (APCI +): m / z = 458 (M + H).

C. 7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1 027545. "196 o o o o

TVV'OH OH

II 2 N HCl / ether II J IJ

ch CIj

5 ^^ - Vo 1 A

7 "[3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.101 g, 0.219 mmol) was taken up in dichloromethane and 2N HCl / ether was added until turbidity occurred. The resulting precipitate was collected by filtration and washed with diethyl ether, leaving 55 mg of the title compound as the HCl salt (yield: 70%).

MS (APCI +): m / z = 358 (M + H).

D. 7- {3 - [(2-Cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 20 || o o

jTYjj OH nc ^ jrrYV

O 1 MeOH * / -NCl 2

Μβ Δ E «3N NC ^ NH Me" ° A

7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid HCl salt (0.923 g, 2.35 mmol) was taken up in methanol and triethylamine (0.5 ml) was added. Acrylonitrile (2 ml) was added to the reaction mixture; After 24 hours, the solution was concentrated, the residue taken up in dichloromethane, and 2 N HCl / ether was added until cloudiness occurred. The resulting precipitate was collected by filtration and washed with diethyl ether, leaving 863 mg of the title compound as the HCl salt (yield: 75%).

MS (APCI +): m / z = 411 (M + H).

Linking example 18

Preparation of 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,2,4-dihydroquinolin-3-carboxylic acid

O O

15 Aβ A

A. 7- [3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-20,4-dihydroquinoline- 3-carboxylic acid

Me. Me p 9 f ".Vy 0 0 YVV ^ ·";

Me ^ LANH ^ Μθ A

To a solution of (2-cyano-1-pyrrolidin-3-yl-ethyl) carbamic acid tert-butyl ester (1: 1 mixture of diastereomers) (256 mg, 1.07 mmol) and 1-cyclopropyl-6.7 -difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (280 mg, 0.86 mmol in acetonitrile (10 ml) was 1027545-198.

triethylamine (433 mg, 4.3 mmol) and the solution heated to 80 ° C for 3 days. The solution was concentrated in vacuo. Ethanol (8 ml) and triethylamine (433 mg, 4.3 mmol) were added to the residue, and the mixture was heated to 80 ° C for 5 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 ml), washed with saturated aqueous ammonium chloride (50 ml), dried with MgSC> 4 and concentrated in vacuo. The crude material was purified by chromatography on silica gel, eluting with 0 to 8% methanol in dichloromethane for 1 hour to give 100 mg of the title compound (yield: 23%).

MS (APCI +): m / z = 499 (M + H).

B. 7- [3- (1 'Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquino-3- carboxylic acid

MVMe o O

20 Me 0 0 k, NH 2. HCl / EtOH X 1 | f \ Γ FrYi “——

^ «· A

Μβλ

To a solution of 7- [3- (1-tert-butoxy-carbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-, cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid (100 mg, 0.20 mmol) in dichloromethane (5 ml), a 10 wt% solution of HCl in ethanol (0.5 ml) was added and the solution was added for 18 hours. stirred at room temperature. The solvent was removed in vacuo. The yellow solid was slurried in ethyl acetate and dichloromethane, the solid collected by filtration in vacuo and rinsed with 1 02 75 45-199 ethyl acetate. The bright yellow solid was dried under vacuum to give 44 mg of the title compound as the hydrochloride salt (85% original substance, yield: 47%).

MS (APCI +): m / z = 399 (M + H).

Coupling example 19

Preparation of 9- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a -aza-10 phenalene-5-carboxylic acid, for example, N. NH2 1, 1, 9, 9- [3- (1-tert-Butoxycarbonylamino-2 "cyanoethyl) -pyrrolidin-1-yl] -8-fluoro- 3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azapalenalene-5-carboxylic acid

20 Me M

.Me O O F Me- ^ o

O Me JC O O

vyy ^

UN T ^ V

To a solution of (2-cyano-1-pyrrolidine-3-ylethyl) carbamic acid tert-butyl ester (270 mg, 1.13 mmol) and 8,9-difluoro-3-methyl-6- oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid (313 mg, 0.95 mmol) in acetonitrile (8 mL), triethylamine (481 mg, 4.75 mmol) was added. 30 and the solution heated to 50 ° C for 17 hours. The solution was concentrated in vacuo. Ethanol (4 ml), dioxane (4 ml) and triethylamine (481 mg, 4.75 mmol) were added to the residue and the mixture was heated to 80 ° C for 4.57545-200 for 4.5 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 ml), washed with saturated aqueous ammonium chloride (50 ml), dried with MgSO4 and concentrated in vacuo. The crude product was placed on a column with 40 g of silica gel, eluting with 0 to 8% methanol in dichloromethane for 1 hour to give 227 mg of the title compound (yield: 48%).

MS (APCI +): m / z = 501 (M + H).

B. 9- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalene -5-carboxylic acid 15

Me v Me

Me ^> o y o o o o

VrY "HCUEt0>: LN0.1FTYy 0H

ΤΝΝ / γνΝ> ΐΥΎΎ 20 0ν / ^ Μβ 0ν ^ Μβ

To a solution of 9- [3- (1-tert-butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa -3a-Azapalenalene-5-carboxylic acid (225 mg, 0.45 mmol) in dichloromethane (8 ml), a 10 wt% solution of HCl in ethanol (1 ml) was added and the solution stirred at room temperature for 5 days. The solvent was removed in vacuo. The yellow solid was slurried in methylene chloride and ethyl acetate, the solid collected by. filtration under vacuum and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 177 mg of the title compound as 102 75 45-20 201 the hydrochloride salt (88% original compound, yield: 87%).

MS (APCI +): m / z = 401 (M + H).

5 Linking example 20

Preparation of 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 0

M NH 2 Fw JIX

B i Γ 0H

Me '° A

A. 7- [3- (1-tert-Butoxycarbonylamino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid M (yMe oo F n Me-^ o

20

χγγ 0 F "* ^ JX ^ TeMe EtaN->

F1 + 1 NH

MeT Δ. To a solution of (2-cyano-1-pyrrolidine-3-ethyl) carbamic acid tert-butyl ester (63 mg, 0.26 mmol) and 1-cyclopropyl-6,7-difluoro-8- methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid difluoroboronate ester (86 mg, 0.25 mmol) in acetonitrile (5 ml), triethylamine (127 mg, 1.25 mmol) was added and the solution was Heated to 50 ° C for 22 hours. The solution was in vacuo. concentrated. To the residue, ethanol (5 ml) and triethylamine (127 mg, 1.25 mmol) were added and the 1027545.

The mixture is heated to 80 ° C for 6 hours. The solvent was removed in vacuo. The residue was taken up in chloroform (50 ml), washed with saturated ammonium chloride. in water (50 ml), dried with MgSO 4 and concentrated in vacuo. The crude product was purified on a column with 10 g of silica gel, eluting with 0 to 8% methanol in dichloromethane for 1 hour to give 39 mg of the title compound (yield: 30%).

MS (APCI +): m / z = 515 (M + H).

B. 7- [3- (1-Amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

15 o O

we 1? ? ^ p fyyV ° h

'0H

M0X ° ^

Μθ "° A

To a solution of 7- [3- (1-tert-butoxycarbonylamino-2-cyanoethyl.) Pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline 3-carboxylic acid (39 mg, 0.08 mmol) in dichloromethane (5 ml), a 10 wt% solution of HCl in ethanol (0.5 ml) was added and the solution stirred at room temperature for 30 hours. The solvent was removed in vacuo. The yellow solid was slurried in ethyl acetate and dichloromethane, the solid collected by filtration in vacuo and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 19 mg of the title compound as the hydrochloride salt (85% original compound, yield: 51%).

1 027545 ·? 203 MS (APCI +): m / z = 415 (M + H).

Coupling Example 21 Preparation of (+) -sodium-7- [3- (1-amino-2-5 isocyanoethyl) azetidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylate

O O

F0Na +

H2NV ^ ON

io J Me λ nct.

A. (+) - 1-Cyclopropyl-6-fluoro- {3- [2-isocyano-1- (2,2,2-trifluoroacetylamino) ethyl] azetidin-1-yl} -O-methyl-4-oxo 1,4-dihydroquinoline-3-carboxylic acid 15

O

.11 HN ^ CF3

i A A P O O

"-NHHCI O ^ Af ΥΥΥόΠ N Ί T ^ DMSO, DIPEA, 80 C T λ-.AA.J

PAAJ '----

0. T Γ 2. Et3N, EtOH, other cooking Γ Me A

2 0. , Me A 51% back, NC / Δ flow

A solution of 1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroborate ester (230 mg, 0.70 mmol), .. N- [1-azetidine -3-yl) -2-cyanoethyl] - 2,2,2-trifluoroacetamide hydrochloride (326 mg, 1.27 mmol) and diisopropylethylamine (0.613 ml, 3.52 mmol) in dimethyl sulfoxide (3 ml) was heated for 12 hours to 30 80 ° C. The solution was allowed to cool to room temperature and was diluted with ethanol (15 ml), and then triethylamine (0.687 ml, 4.93 mmol) was added. The resulting solution was then heated under reflux for 3.5 hours. . The solvent was removed under reduced pressure. The thus obtained residue was dissolved in dichloromethane (100 ml) and the resulting solution was washed with saturated aqueous ammonium chloride (20 ml). The layers were separated and the organic layer became. dried (magnesium sulfate), filtered and concentrated under reduced pressure. The resulting yellow residue was dissolved in ethyl acetate (5 ml). After a few minutes at ambient temperature some precipitation started. Hexanes (1 ml) was added slowly, followed by slow addition of dichloromethane (1 ml) and then hexanes (3 ml), yielding 171 mg (51%) of the title compound.

LC / MS (APCI) (M + 1): m / z = 481.2.

B. (+) - Natritun-7- [3- (1-amino-2-isocyanoethyl) azetidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4 dihydroquinoline-3-carboxylate j? F 1.1 oy ^ F YY |

L 1 MeOH, H 10 O, 70 C

NC ^ ΒΛ% nc ^ Saturated sodium carbonate in water (3 ml) was added to a suspension of 1-cyclopropyl-6-fluoro-7- {3- [2-isocyano-1- (2,2,2-trifluoroacetylamino) ethyl] azetidin-1-yl) -8-methyl-4-oxo-1,4-dihydroquinoline-3-carbon. acid (134 mg, 0.299 mmol) in a mixture of methanol: water (5 ml: 2.5 ml). The mixture was then heated to 70 ° C for 5 hours. The methanol was then removed under reduced pressure to give a solution. The resulting solution then became 1 027545.

205 directly onto a reverse phase column and purified by medium pressure liquid chromatography, wherein. was eluted with a. gradient of water racetonitrile (99: 1 to 50:50), which afforded a yellow solid. The solid was dissolved in the minimum amount of water and freeze-dried to provide 73 mg (<64%) of the title compound.

LC / MS (APCI) (M + 1): m / z = 385.2.

10 Linking example 22

Preparation of 9- [3- (2-r-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azapalenalene -5-carboxylic acid 15

Mev 9 9 Ν ^^ ργχίΥν ° Η ° ^ * Μθ 20.

A. 9- {3- [1- (tert-Butoxycarbonylmethylamino) -2-cyanoethyl] pyrrolidin-1-yl} -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a -azapalene-5-carboxylic acid at J Jl JL O Me Me "> 0

Fp (/ X, <V · vA * ™ ° ^ Μβ I>.

° '-' 30

To a solution of (2-cyano-1-pyrrolidin-3-yl-ethyl) methyl carbamic acid. tert-butyl ester (372 mg, 1.47 1027545.

206 mmol) and 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalene-5-carboxylic acid difluoroborate ester (411 mg, 1.25 mmol) in acetonitrile ( 15 ml), triethylamine (632 mg, 6.25 mmol) was added and the solution was added for 24 hours.

5 heated to 50 ° C. The solution was concentrated in vacuo. The residue was taken up in ethanol (8 ml) and dioxane (8 ml), and heated to 80 ° C for 5 hours. The solution was concentrated in vacuo. The residue was taken up in chloroform (50 ml), washed with sat.

Ammonia chloride aq. (50 ml), dried with MgSO 4 and concentrated in vacuo. The crude product was placed on a column with 40 g of silica gel, eluting with 0 to 6% methanol in dichloromethane for 1 hour, yielding 528 mg of 9- {3- [1- (tert-butoxycarbonylmethylamino) -2-cyanoethyl] pyrrolidin-1-yl} -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-aza-phenalene-5-carboxylic acid as the hydrochloride salt (yield: 82%) gave .

MS (APCI +): m / z = 515 (M + H).

20 B. 9- [3- (2-Cyano-1-methyl-amino-ethyl) -pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-aza-phenalene -5-carboxylic acid hydrochloride salt l> e 25 0 0 ^ «1 κΛ * ργ0ΛΗ - O ^ Aute ° ^ Me 30

To a solution of 9- {3- [1- (tert-butoxycarbonyl-methyl-mino) -2-cyanoethyl] pyrrolidin-1-yl} -8-fluoro-3-methyl-.6-oxo-2,3- dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid hydrochloride salt (143 mg, 0.28 inmol) in dichloromethane (10 ml), 4 N HCl in dioxane (1 ml) was added and the solution is stirred for 16 hours at. room temperature. The solvent was removed in vacuo. From the yellow solid matter.

dichloromethane and ethyl acetate slurried, the solid collected by filtration under vacuum, rinsed with ethyl acetate and dried under high vacuum (ca. 0.5 Torr) during the. overnight to give 109 mg of the title compound 10 as the hydrochloride salt (yield: 95%) * MS (APCI +): m / z = 415 (M + H).

Coupling Example 23 Preparation of 7- [3 (R) - (2-cyano-1 (S) -15 methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid

20 N

0H

Me "0" A. 7- {3- [1- (tert-Butoxycarbonylmethylamino) -2-cyanoethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo -1,4-dihydroquinoline-3-carboxylic acid 1027545.

30 208

O O F

fyWs ° 'b'f f'VS Me, Me

Me "0 Δ MeA6> ..f- ν π« ** A '5 ^ or'W ’° ^ y lartnppr B2'

To a solution of (2-cyano-1-pyrrolidine-3-ylethylmethylcarbamic acid tert-butyl ester (isomer B2) 10 (345 mg, 1.36 mmol) and 1-cyclopropyl-6,7-difluoro-8-methoxy-4- oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroborate ester (377 mg, 1.10 mmol) in acetonitrile (8 ml), triethylamine (557 mg, 5.50 mmol) was added and the solution heated to 50 ° C for 4 hours The solution was concentrated in vacuo, ethanol (10 mL) and triethylamine (557 mg, 5.50 mmol) were added to the residue and the mixture was heated to 80 ° C for 4 hours. The residue was taken up in chloroform (50 ml), washed with 20 saturated aqueous ammonium chloride (50 ml), dried with MgSO 4 and concentrated in vacuo The crude product was placed on a column with 40 g of silica gel, eluting with 0 up to 6% methanol in dichloromethane for 1 hour to give 459 mg of the title compound (yield: 79%).

MS (APCI +): m / z = 529 (M + H).

B. 7- [3- (2-Cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4,4-hydrohydro-3-line-3 carboxylic acid 2097545. 209

Mfoe? ï O O · ΗΝ'Μθ FyVl'On Μβ '' Δ

Me''0 Δ 5 To a solution of 7- {3- [1- (tert-butoxycarbonylmethylamino) -2-cyanoethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4 -oxo-1,4-dihydroquinoline-3-carbonic acid (459 mg, 0.87 mmol) in dichloromethane (20 ml), a 4 M solution of HCl in dioxane (2.2 ml) was added and the solution for 18 hours stirred at room temperature. The solvent was removed in vacuo. From the yellow solid. slurried in ethyl acetate and dichloromethane, the solid collected by filtration under vacuum and rinsed with ethyl acetate. The bright yellow solid was dried under vacuum to give 458 mg. title compound as the hydrochloride salt (80% original compound, yield 98%).

MS (APCI +): m / z = 429 (M + H).

20 Linking example 24

Preparation of 7- {3 - [(2-cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

o o FV ^ Y11 OH

MeOH / -NH, 0H-η / ~ NC-7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid (J. Med. Chem., 1993, 36, 871-882) (0.098 g, 0.232 mmol) 2107545.

was taken up in methanol (12 ml), and acrylonitrile (0.016 ml) was added. After 2 days, the solution was concentrated to leave 100 mg of the title compound (yield: 98%).

5 MS (APCI +): m / z = 429 (M + H) ...

Coupling Example 25 Preparation of. 7- {3- [1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-10 fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

O O

f / νΛΛη FY5ir0H

YYY 0H NC ^ Me

15 Me ^ KIA ^ A J - V-ΑϊΟΓ V

HTT1 MeOH / -nhyl]

A EtjN NcV

7- [3- (1-Aminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-20 fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (WO 9209596ΑΓ, 1992) ( 0.4011 g, 1.03 mmol) was taken up in methanol (50 ml). Triethylamine (0.14 ml) was added to the resulting solution to obtain the free base in situ. Acrylonitrile (0.1 ml) was then added to the reaction mixture. Another equivalent of triethylamine (0.15 ml) and acrylonitrile (0.1 ml) was added. After a further 12 hours, the reaction mixture was concentrated. The crude product was chromatographed (gradient of 2-15% isopropanol / dichloromethane) to give 101 mg of PF-00646714-00 (yield: 22%).

MS (APCI +): m / z = 443 (M + H).

1 02 75 45 "211

Coupling example 26

Preparation of 7- {3-t (2 "cyanoethylamino) methyl] pyrrolidine-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 0 0

FYYj 0H

<RTI ID = 0.0> NHVu>> 0.10 NC </RTI> A. 7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-15 dihydroquinoline -3-carboxylic acid difluoroborate ester oo

o o f ^ JL JL

p _ Jl Jl Me .. O c * ki || OBF2 -W JUKOT.

2 0 μ.'0 A% {* · Δ / -Me

Me

To 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid difluoroborate ester (0.280 g, 0.816 nrniol) and (R) -pyrrolidin-3-ylmethylcarbamic acid tert-butyl ester (0.321 g, 1.60 mmol), triethylamine (0.45 mL) was added and the whole was taken up in acetonitrile (3 mL). After 24 hours, the solution was concentrated to leave 276 mg of the title compound (yield: 90%).

MS (APCI +): m / z = 524 (M + H).

1 027545.

212 B. 7- [3- (tert-Butoxycarbonylaminomethyl-pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Sr.

55 ° C.

7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid difluoroborate ester (0.274 g, 0.523 15 mmol) was taken up in ethanol (5 ml), and triethylamine (0.4 ml) was added. The resulting red solution was heated to 55 ° C. After 16 hours, the reaction mixture was concentrated to give 231 mg of the title compound (yield: 92%).

MS (APCI +): m / z = 476 (M + H).

C. 7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8 "methoxy-4-oxO" 1,4-dihydroquinoline-3-carbon acid 25 OO oo FïW ™ FlVVA ° 2NHCl /Ether

0 ^ .ΝίΓΛ ^ »· '0 A. CH 2 <% A

Me

Me 30 7- [3- (tert-Butoxycarbonylaminomethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.198 g, 0.416 mmol) became 1 027545.

213 taken up in dichloromethane (5 ml), and 2 N HCl / ether (3 ml) was added. The resulting solution was stirred for 2 hours. The solvent was decanted to yield 147 mg of the title compound (yield: 93%).

MS (APCI +): m / z = 376 (M + H).

D. 7- {3 - [(2-Cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydrochi.no-line-3 -carboxylic acid

10

o o o o FYYi oh fyW ^ oh

15H / A

Et3N

7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-6-20 fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.1595 g, 0.441 mmol) was taken up in methanol (25 ml), and triethylamine (0.07 ml) was added to give the free base, then aicrylonitrile (0.05 ml) was added to the reaction mixture, and after 20 hours the reaction mixture was concentrated to give 162 mg of the title compound (yield: 80%).

MS (APCI +): m / z = 429 (M + H).

Coupling Example 27 Preparation of 7- [1- (2-cyanoethylamino) -5-aza-spiro [2,4] -hept-5-yl] -1-cyclopropyl-e-fluoro-e-methoxy-4-oxo-1 4-dihydroquinoline-S-carbonyl 1027545, 214

0 0 0 0 h2V 0H NC ^ NC- / ~ T .W ° H

5 Ι ^ Υϊ 1μ3ΪηΓ)> ΟνΛΑ 1 'Μθ "° Λ Et3N' μθ'0 Λ 7- (1-Amino-5-azaspiro [2,4] hept-5-yl) -1-cyclopropyl-6-fluoro- 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (European patent application EP 550016A1, 1993) (0.140 g, 0.321 mmol) was taken up in methanol (3 ml), and triethylamine (0.5 ml) After 5 minutes, acrylonitrile (0.1 ml) was added to the reaction mixture, after 12 hours the reaction mixture was concentrated.The crude product was chromatographed (1 - 10% methanol / dichloromethane) to give 102 mg of the title compound (yield: 61%).

MS (APCI +): m / z = 441 (M + H).

20 Coupling example 28

Preparation of 7 "[1- (2-cyanoethylamino) -5-azaspiro [2,4] hept-5-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid

25 O O O O

vvy- · fyyj ° h

^ «/ 1: ¾. a

30 1 02 7545.

215 7- (3-Aminomethylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (J. Medf Chem., 1993, 36, 871-882) (0.1510 g, 0.400 inmol) was taken up in methanol (1 ml) in a vial suitable for a microwave, and 2-butenitrile (0.1 ml) was added. The reaction mixture was again at 25 minutes. 160 ° C in the microwave. The reaction mixture was concentrated and purified by column chromatography (2-1.5% methanol / dichloromethane) to yield 47 mg of the title compound (yield: 26%).

MS (APCI +): m / z = 443 (M + H)

Coupling example 29

Preparation of 7- [3- (2-cyanoethylamino) pyrrolidin-1-yl] -1- ^ cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 20 S 8 II : J NC ^ _ 1 i J ΗζΝ · ~ 0 ^ ï Me0H _5N '~ Ol ol

A NC ^ ^ A

7- (3-Amino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (J. Med. Chem., 1993, 36, 871-882) (0.4955 g, 1.37 mmol) was taken up in methanol (50 ml). To the resulting suspension: acrylonitrile (0.1 ml) was added. After 16 hours, the reaction mixture was heated to 4.0 ° C and a third equivalent of acrylonitrile was added. After. The 10275 45- 216 reaction mixture was concentrated for 20 hours to yield 550 mg of the title compound (yield: 95%).

MS (APCI +): m / z = 415 (M + H).

C. Pharmaceutical preparations

The following illustrates typical pharmaceutical dosage forms containing a compound of the formula I ("compound of the invention"), for therapeutic or prophylactic use in human subjects.

(i) Tablet____ mg / capsule "Compound of the invention" 25.0

Lactose 50.0 Corn starch (for mixture) 10.0

Corn starch (pasta) 10.0

Magnesium stearate (1%) 3.0 300.0 • 20. 1027545- 217 '.

The compound of the present invention, lactose and corn starch (for a mixture) are mixed evenly. Corn starch (for a paste) is suspended in 200 ml of water and heated with stirring to form a paste. The paste is used for granulating the mixed powders. The wet granules are passed through a No. 8 hand screen and these are dried at 80 ° C. The dry granules are added with 1% magnesium stearate as a lubricant and are compressed into a tablet. Such tablets can be administered to a human person one to four times a day for treatment of pathogenic bacterial infections.

(ii) Tablet / capsule / "Compound of the invention" 10.0

Colloidal silica .1.5

Lactose 465.5

Pre-gelatinized starch 120.0

Magnesium stearate (1%) 3.0 - - - - - - 600.0 (iii) - Preparation for oral solution - Amount.

"Compound of the invention" 400 mg of Sorbitol solution (70% N.F.) 40 ml

Sodium benzoate 20 mg

Saccharin 5 mg

Cherry fragrance and flavor. 20 mg

Distilled water q.s. 100 ml 30

The sorbitol solution is added to 40 ml of distilled water and the compound of the present invention dissolved therein. Saccharin, sodium benzoate, flavoring and flavoring and coloring agents are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each milliliter of syrup contains 4 mg of compound of the present invention.

1027545-21 (iv) Parenteral solution

20 g of a compound of the present invention are suspended in a solution of 700 ml of propylene glycol and 200 ml of water for injection. After the suspension is complete, the pH is adjusted to 6.5 with 1 N hydrochloric acid, and the volume adjusted to 1000 ml with water for injection. The preparation is sterilized, placed in 5.0 ml ampoules, each containing 2.0 ml, and sealed under nitrogen.

(v) Injection 1 (1 mg / ml). Amount of "Compound of the invention" 1.0

Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7

Sodium chloride 4.5 N sodium hydroxide solution q.s.

(pH adjusted to 7.0-7.5)

Water for injection q.s. ad 1 ml (vi) Injection 2 (10 mg / ml) Amount of "Compound of the invention" 10.0

Dibasic sodium phosphate 1.1

Monobasic sodium phosphate 0.3 Polyethylene glycol 400 200.0 N hydrochloric acid q.s.

(pH adjusted to 7 .0-7.5)

Water for injection q.s. ad 1 ml 30 (vii) Injection 2 (10 mg / ml) Amount of "Compound of the invention" 20.0

Oleic acid 10.0

Trichlorofluoromethane 5,000.0 Dichlorofluoromethane 10,000.0 .. Dichlorotetrafluoroethane 5,000.0 1027545.

219

All patents and patent documents are incorporated herein by reference as if they were listed separately by reference. The present invention, the method and method for making and using it are now described in such complete, clear, concise and accurate terms that a person skilled in the art to which they relate is able to make it complete and use. It will be understood that the foregoing preferred embodiments of the present invention describe and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. For the purpose of specifically indicating and clearly claiming the subject matter that is considered to be an invention, the following claims conclude this description.

1027545-

Claims (15)

00. OOO ^ 4sy ^^ ÏT ^^ NV ^> 'R ^' V ^ 5 ^ fr ^^ SNrx ^ N'R ^ 4'V ^ - ^ i ^^ sV ^ S'R Yl T yy m2 jl T IJ -2 || T || h2 Α '^ γ ^ ΝΓ A' ^ Y ^ N · ^ CIN ^ yF% <M Me "0 n <YF H2N ^ Y HjN '^ Y h2n ^ YFFFO ° nh2 oo Γο o" tïj' '! "ώτ, ! w 112 / «V: * Yr A ijTF hV yY Me 'Yt AvJ um ^ V Η2Ν ^ ητ h2n τ h2n T h F, F 1027545-0. Me OO 0 0 χΧ J * Y ij * Trlr 2 \ A' "<^ '' ^ N AV ^ N ^ NT A '^ hTV \ rr' ór 'rr' 1. ï. .τ, 9. o o nh 2 o o ó ^ yxf * w-2 ü '^ f ^' VT Α ^ Ύ'Ν ^ J ^ Y ¥ Cl Cl Jk ^ F 10. sJ v f. f, T 9. o O Me OO R z "xxY ^ 2 ^ xlxY ^ 2 A- ^ T ^ N A '^ Y ^ N ^ A'Y'N' Me''0 A ^ F Me" 0 ^ N " FF 'F. 2 ^ .. nh2 oo 20 Τβ uuoo, JLA J 2 "' XiCj R 'R'XTVl'B! AMe, X, A, A, Y, N, A, Os, *, or Y A compound of the formula I: 5 @ 3 * 9. 2. A compound according to claim 1, wherein X is C or N, R 1 is (C 1 -C 6) cycloalkyl and halogen (C 1 -C 6) cycloalkyl, aryl or heteroaryl, R 3 is H or NH 2, R 4 is H or halogen, R 5 is halogen, methyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy when X is 30 C. A compound according to claim 2, wherein X is C or N, R 1 is cyclopropyl or fluorocyclopropyl, R 3 is H or NH 2, 35. R 1 is H or. F, R 5 is halogen, methyl or methoxy. 1 027545 A compound according to claim 1, wherein R 1, R a and R 5 are the following structures, and wherein R 2 is OH, OBF 2 or O (C 1 -C 6) alkyl, R 4 is H or F and A'is ^ Ba / Rb,. 10 0 0 S Ü 9 y? "XX; Bï W α Δ μ ΛΙ," Δ 1027545- OO NHa o O NH2 OO TTT Rz TTT Rz. YTT 2 A '^ N ^ N A' ^ Y ^ N ^ A '^ Y ^ NA m "" A Cl A »·» * 0 0 0 0 Me 0 O j Π II T y 2 li T iT Hz ii ι ir a.An ^ Α '/ γνΝ ^ Α,' ^ γ> Κ A cp3A ° MeA. · _ »*» OOOOOO ^ V ^ V ^ Ar ITT ** TTT 2 ITT A '^ T ^ N A' ^ Y ^ N α A «o ^ 0 A“ * A. F. FF, O 0 NH2 0 O NH2 oo ^ <'sr ^ - ^ r ^^ sS ^^ S'R ^ NV ^ "^ YxX ^ V'V ^ S'R 11 aT iT li ίΓ II - z li τΓ ιΓ Hz A'T ^ N ^ N ^ Α '^ γ ^ Ντ. A'T ^ Y ^ N ^ K.. - ° K. ° K. y U 0 0 Me O O I ^ ΥίΗ * ^ γ ^ γίΙνΑ ^ A '^ N A,' ^ Y? ^ N ^ ’λ <** k 0MeA! F,: Or combined with the carbons to which they are attached form and Rj and Rk are each independently H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl, carboxymethyl, carboxyethyl or other NHM or taken together with the carbons to which they are attached form. The compound of claim 1, wherein z is O, 1 or 2 when q is 2 or 3, or z is 1 or 2 when q is O, 1, 2 or 3, Ra and Rb are each independently H, methyl, ethyl , fluoro, fluoromethyl, trifluoromethyl, fluoroethyl, methoxy, MeO-N, or taken together with the carbons to which they are attached form a cyclopropyl ring, R ', R ", R"' and R "" are each independently H, fluoro, methyl , ethyl, fluoromethyl, fluoroethyl, phenyl, benzyl or methoxy, Rc and Rd are each independently H, methyl or ethyl, Re and Rf are each independently H, methyl or ethyl, 1027545. Rg and Rh are each independently H, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl , carboxymethyl, carboxyethyl or 5. O or 1 and R 2c is H, (C 1 -C 6) alkyl, O (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, aryl, heterocycle, heteroaryl or X - (CHRja)] - Y 'wherein - (CHRaJu-O-JL-ORab or ** R2a, R2b and Q have the meaning given above, and h and j are each independently integers from 0 to 10 inclusive , and Y is OH, OPO (OH 12, PO (O (C 1 -C 6)) 2, or NR 2 d R 2e, wherein R 2d and R 2e are each independently H, (C 1 -C 6) alkyl or (C 3 -C 7) cycloalkyl, 25 " t1 / "0 0-1.29 wherein g is 0 or 1, R2f and R2f 'are each independently Η, (Οι-Οβ) alkyl, aryl or heteroaryl, or taken together with the carbon to which they are attached a 3-, 4, 5 or 6-membered substituted or unsubstituted ring forms and (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, aryl, heterocycle or heteroaryl, R c and R f are each independently H, C 1 -C 8 alkyl, haloalkyl, halogen, or R c and R f taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring, R 8 and Rh are each independently H, C 1 -C 6 alkyl, haloalkyl, or taken together with the carbon f to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring and R 1 and R c are each independently H, (C 1 -C 6) alkyl, haloalkyl, (C 1 -C 6) alkyl- NRcRd, (C1-15) alkyl-ORc, ary.1, heteroaryl, heterocycle, .. O-. (C 1 -C 6) alkyl-2-C where z is O or NRC, or Rj and Rk taken together with the carbon to which they are attached form a 3-, 4-, 5- or 6-membered substituted or unsubstituted ring. 5 VA in "*" or B "v R" is not -0 {C 1 -C 6) alkyl, and wherein the binding point denotes, R c and R d are each independently H, (C 1 -C 6) alkyl nitrile, 10 O II - P-OH ·... O., .Beta.-C 1-6 alkyl, C 1-6 alkyl, (C 1-6) alkyl, (C 3-6) cycloalkyl, heteroaryl, SO 2 - (C 1 -C 6) alkyl, SO 2 - aryl, SO 2 - heteroaryl, o - - - - QRa, wherein g is an integer from 1 to 10, Q has the meaning given above, and R2a and R2a each is independently H or (C 1 -C 6) alkyl, or taken together. with the carbons to which they are attached a 3, 4, 5 or 6-membered substituted or. unsubstituted ring, and R 2b is (C 1 -C 6) alkyl, aryl or heteroaryl, o (CR 2 R 6 O 2 - O - p - (OHh q 6 (CR 2 a R 2a)) OP (O (C 1) -C 6) alkyl) wherein R2a and R2a * have the meaning given above, 1027545 - where the binding point indicates, The compound of claim 1, wherein A is 20, and z is 0, 1 or 2, which is selected from the group consisting of: Βχ> - tl Me ^ "13» - b ~ o ~ tv Btv Etxv a ~ tv Fsc ^ -y 'xv FtC “- Fs0X>%> - tx>. 1027545- where“' www '”indicates the binding point, or A is r vy) z 5 ^ qRb or, where z is 0, 1 or 2 and q is 0, 1, 2 or 3, which is selected from the group consisting of: 10 'co-ct> ~ BrXy F> clx> - .15 where "ivwv" denotes the binding point. A compound according to claim 6 or 7, wherein B is v. V ·. Re ^ R. Rc NC ^ VN-NCX ^ or V Rc Or R, R, / and is selected from the group consisting of: NC— \ NC-v NC v NCk / v ^. ^%, \ —N — N— '- N— ^ - ^^ N. H; Me, Et, H j γ NC --- NC ^^ A, ncv ^ -nX, NCv ^ n ^ Me, Η, Η, H 1027545 · / *> v y O. NC ^ NA, nc - ^, A ncv ^ nJs nc ^^ nJ ^ s H "." : 'H · H · H ·; Me Me NC ^, A νο ^ νΛ, νο ^ νΛ, η, Me> Et Me Me \ 7 \ “7 10 nc ^ -n ^ ncv ^ nX> nc ^ nX ncv ^ nX, Et, Η, H, Me, F, p, jr, V, R, NCV, N, X, N, ^,, X,, NC, S,. 15 C ^ NHR NC ^^ s. ^ ^ «. (C 1 -C 4 alkyl nh 2 NHMe H NCy / U-7 * · * * / OMe OMe nc ^ nX," nc ^ nX, 20. and Me in which "" ww »indicates the binding point. ^.. ^ A compound according to claim 6, wherein ^ R b is selected from the group consisting of: - Me Me RHN'v-> 027545- ^ - <> - «Γ <> -" Τ! Γχ> -; v Me Me / - RHN RHN-X λ> -Ο- -fy-'iyT ^ y "n'V RHN V V'C" "FjC ^>" "" ΛοrOP *: - ¾. . / = Ν V Υ R ~> rV ^ k RHN '^ sr ^ \ M_ Μβ RHN -C- 1 MS Me MeO HV F ieF T RHN i> RHN o ~ rhn ^ n-rhn un ~ rhnJ3 ^ ~ 2> ” \ y 3> J>> · C11 Me RHN ^ ^ Me EtO. H2N ^ 0 Me enJkl ~ ^> ~ V 7> Me RHN ^ S-Λ X / - 102 75 45- "233 where R is CH2 CH2 CN and where" vwa. "denotes the binding point. A compound according to claim 6, wherein ^ 'Rb is selected from the group consisting of: BR' Me RI 10. ry R · τ v Ηΐΐ> - "θ'1" * SR Τ Me 15 ^ "Cx« Λ> . ^ 1 Λ>. Rr *? ^ ^ - ^ J> - ~ VAA 25 where R is CH 2 CN and where "'Άλλ." Indicates the binding point. A compound according to claim 6, wherein b 35 * V ^) n or B "" * - (- kiftte.) Is selected from the group consisting of: 1027545-RHNL RHN. NHR RHN VY RHNv / CC-CX) * "R1 - <C" - "F RHN RHN RHN rhn ^ Qmw fF> C Cnw 0θ * ~ 10 wherein R is CH 2 CH 2 CN and wherein λ,» denotes the binding point. R5, R1 * or a pharmaceutically acceptable salt thereof, wherein: X is N or C, provided that when X is N, R5 is missing in that position, R 1 is (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, halogen (C 3 -C 6) cycloalkyl. heterocycle, aryl, heteroaryl and CH 2 (C 3 -C 6) cycloalkyl, R 2 is OH, OBF 2, 25. O (C 1 -C 6) alkyl, O (C 3 -C 6) cycloalkyl, OO - (CHR 2a) m -0 2 OR 2b where m is an integer from 1 to 10, Q is O 30 or NH or N (C 1-6) C 6) alkyl, or missing, and R 2a is H or (Οχ-ββ) alkyl and R 2b is (C 1 -C 6) alkyl, aryl or heteroaryl, 1027545-O- (CHR 2 e) n-Y f wherein R 2a is the above given meaning, n is an integer from 2 to 10, Y is OH or NR2cR2d / wherein R2c and R2d are each independently H, (C1 -C6) alkyl or (C3 -C6) cycloalkyl or NR2a, where R2a has the meaning given above, 10 / ho \ ΛΝΛγ (0Η ,, 2 «) ρ-Υ1 · Η R / \, 'e' '* *' R2®, where the 'binding point indicates, 2a has the meaning given above, R 2e and R 2e 'are each independently H or (C 1 -C 6) alkyl, Or taken together with the carbon to which they are attached form a 3, 4, 5 or 6-membered substituted or unsubstituted ring, e an integer from 1 to 20 is 10, p is an integer from 2 to 10, and Xi and Yi are each independently NH or O, R 3, R 4 and R 5 are each independently H, OH, halogen, NR y R z, wherein R y and R z are each independently H or. (C 1 -C 6 alkyl), (C 1 -C 6) alkyl, halogen (C 1-6) alkyl, 30 (C 1 -C 6) alkyl, O (C 1 -C 6) haloalkyl, nitrile, 1027545 R 1 and R 5 taken together with the carbons to which they are attached form a substituted or unsubstituted 5- or 6-membered substituted or unsubstituted ring containing 0, 1 or 2 heteroatoms. are selected from O, S, SO, SO 2 or NRX, wherein Rx is H or (C1 -C6) alkyl. and A is R a R b, R b or, wherein z is 0, 1 or 2 and q is 0, 1, 2 or 3, R a and R b are each independently H, (C 1 -C 6) alkyl, (C 1 -C 6 alkoxy, halogen (C 1 -C 6) alkyl, halogen, or R 15 and R b taken together with the carbon to which they are attached C = O, C = NO (C 1 -C 6) alkyl or a 3-, 4-, 5- or 6- tall substituted or unsubstituted ring forms, R ', R ", R" "and R" "are each independently H, 20 (C 1 -C 6) alkyl, -O (C 1 -C 6) alkyl, halogen (C 1 -C 6) alkyl, aryl or heteroaryl, 25 and B is Bc'n ^ R, Re, R0> ^ Rk NCTC 1 Re R1 Rc rV · ot 5r 35. R1. 1 02 7545 - provided that when B is A compound according to claim 6, wherein - a &. Γ * ~, M "b or rWRb is selected from the group consisting of: 20% HN--^ RcHNYR R%! ReHNY ^ RcHN- <R πυ cb" R 0 H 2 O R R HHN - ^ - R 25 wherein R c is H or (C 1 -C 6) alkyl, R 5 is CH 2 CN and wherein "'νΛΛΛ" indicates the binding point. 12. A compound according to claim 1, which is a compound of the formulas II / III, IV, V or VI: 1027545. - I Ra O O -c-K-XW *; Ra Rb π ^ R3 O O 'τΓ · Rs R, 10 * \ Λ *** ^ R *> "*" 1 Rg CN m r3 o o v »: · ΉΑ n, I, 20 R3 O 9: 'SS? ^ »R3 o o 25 Β4νΐΧΧΒ2 ryV) * r5 ri R.«, wRb VI A compound which is: (1) 7- [3- (2-cyanoethylamino) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, 7- [3- (2-cyanoethylaino) pyrrolidin-1-yl] -1-cyclo-35-propyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 027545-7- [3- [(2-cyanoethyl) methylamino] pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid, 7- {3 - [(2-cyanoethyl) methylamino] pyrrolidin-1-yl} -1-5 cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, ( 5) 7 - [3- (2-cyanoethylamino) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- {3- [(2-cyanoethyl) methylamino] pyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- {3 - [(2-cyanoethyl) methylamino] ] pyrrolidin-1-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 9- [3- (2-cyanoethylamino) cyclopentyl] -8-fluoro- 3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azapalenalene-5-carbjon -acid, 9- {3 - [(2-cyanoethyl) methylamino] cyclopentyl} -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalen-5-20 carboxylic acid, (10) 7- (3 - [(2-cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 7- {3 R - [(2-cyanoethylamino) methyl] pyrrolidin-1-yl} -1-25 cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, * 7 - {3- [(2-cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3 - {((2-cyanoethyl) methylamino] methyl) pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- ( 3 - {[(2-cyanoethyl) methylamino] methylpyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1027545- ( 15) 7 - {3 - [1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, -. . 7- {3- [1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-5 cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7 - (3- {1 - [(2-cyanoethyl) methylamino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-. quinoline-3-carboxylic acid, 7- (3 - {1 - [(2-cyanoethyl) methylamino] ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid, 7- [3 - [(2-cyano-1-methylethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo 1,4-dihydro-15-quinoline-3-carboxylic acid, (20) 7- {3 - [(2-cyano-1-methylethylamino) methyl] pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8 -methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- {3 - [(2-cyanoethylamino) methyl] -3-methylpyrrolidin-20-1-yl] -1-cyclopropyl-6-fluoro -8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. 7- {3 - [(2-cyanoethylamino) methyl] -3-methylpyrrolidin-1-yl} -1-cyclopropyl-6-flupr-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 7- (3- {[4-cyanoethyl-methyl-amino] -methyl-5-methyl-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3 - {[(2-cyanoethyl) methylamino] methyl} -3-methyl-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline -3-carboxylic acid. (25) 7- {3- [1- (2-cyanoethylamino) cyclopropyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3 -carboxylic acid, 7- {3- [1- (2-cyanoethylamino) cyclopropyl] pyrrolidin-1-35 yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydrochino-line- 3-carboxylic acid, 1027545-. 7- (3- {1 - [(2-cyanoethyl) methylamino] cyclopropyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-chirioline-3-carboxylic acid 7- (3- {1 - [(2-cyanoethyl) methylamino] cyclopropyl} pyrro-5-lidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, 7- {3- [2-acetylamino-1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, 10 (30) 7- {3- [2-acetylamino-1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- {2-acetylainino-1 - [(2-cyanoethyl) methylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-6 -fluoro-8-methoxy-4-15 oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- {2-acetylamino-1 - [(2-cyanoethyl) methylamino] -ethyl} pyrrolidin-1-yl ) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7- {3 - [(2-cyanoethylaraino) methyl] pyrrolidin-1-yl} -1-20 cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7 -13 - [( 2-cyanoethylamino) methyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 25 (35) 7- (3 - {[(2 -cyanoethyl) methylamino] methyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3 - ([(2-cyanoethyl) methylamino] methyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-30 carboxylic acid, 7- (3- [1- (2-cyanoethylamino) ethyl] pyrrolidine-1 -yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- [1- (2-cyanoethylamino) ethyl] pyrrolidin-1-yl} - 1-35 cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1027545. 7- (3 - {1 - [(2-cyanoethyl) methylamino] ethyl} pyrrolidin-1-yl) - 1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (40) 7- (3- {1 - [(2-cyanoethyl) methylamino] ethyl] pyrrolidin-5-1-yl) -1. -cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, 7- {3 - [(2-cyanoethylamino) methyl] -3-methylpyrrolidin-1-yl} -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- {3 - [(2-cyanoethylamino) methyl] -3-methylpyrrc> lidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- ([(2-cyanoethyl) methylamino] methyl} -3-methyl-pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-15 dihydroquinoline-3-carboxylic acid 7- (3- {[(2-cyanoethyl) methylamino] methyl} -3-methyl-pyrrolidin-1-yl) -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (45) 7 - {3 - [1- (2-cyanoethylamino) cyclopropyl] pyrrolidin-1-20 yl} -1-cylopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- [1- (2-cyanoethylamino) cyclopropyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- {1 - [( 2-cyanoethyl) methylamino] cyclopropyl} pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- [2 -acetylamino-1- (2-cyanoethylamino) ethyl] pyrro -lidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- (3- [2-acetylamino-1- (2-cyanoethylamino)) ethyl] pyrrolidin-1-yl} -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (50) 7- (3- (2-acetylamino-1-) [(2-cyanoethyl) methylamino] -35 ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1027545-_____: _____! 7- (3- {2-acetylamino-1 - [(2-cyanoethyl) methylamino] -ethyl} pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid, 7- [1- (2-cyanoethylamino) -5-azaspiro [2.4] hept-5-yl] -1-5 cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid, 7- [1- (2-cyanoethylamino) -5-azaspiro [2.4] hept-5-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3 -carboxylic acid, 7- {3- [1- (2-cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid, (55) 7- {3- [1- (2-cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-met hyl-4-oxo-1,4-dihydroquinoline-3-15 carboxylic acid, 7- (3 - {1 - [(2-cyanoethyl) methylamino] propyl} azetidin-1-yl) -1-cyclopropyl-6-fluoro- 8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- (3 - {1 - ((2-cyanoethyl) methylamino] propyl} azetidin-1-yl) -1-cyclopropyl- 6-fluoro-8-methyl-4-oxo-1,4-dihydro-chirioline-3-carboxylic acid, 7- (3- [1- (2-cyanoethylamino) cyclopropyl] azetidin-1-yl} -1-cyclopropyl -6-fluoro-8-methoxy-4-oxo-1,4-dihydro-chiholine-3-carboxylic acid, 7- {3- [1- (-2-cyanoethylamino) cyclopropyl] azetidin-1-yl} -1 -cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, (60) 7- (3- {1 - [(2-cyanoethyl) methylamino] cyclopropyl} -azetidine -1-yl) -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,2,40. dihydroquinoline-3-carboxylic acid, 7- (3- {1 - [(2-cyanoethyl) methylamino] cyclopropyl} -azetidin-1-yl) -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 7- (3- {1 - [(2-cyanoethyl) ethylamino] cyclopropyl} -35-pyrrolidin-1-yl) -1-cyclopropyl-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, (02) 457-7 (3 - {1 - [(2-cyanoethyl) ethylamino] cyclopropyl} pyrrolidin-1-yl) -1-cyclopropyl-6-flupr-8-methyl-4 -oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- (3- {2-acetylamino-1- [(2-cyanoethyl) -ethylamino] -5-ethyl) -pyrrolidin-1-yl) -1-cyclopropyl-8- methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (65) 7- (3- {2-acetylamino-1 - [(2-cyanoethyl) ethylamino] -ethyl} pyrrolidin-1-yl) -1. -cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, sodium 7- {3- [1- (2-cyanoethylamino) propyl] azetidin-1-yl} -1-cyclopropyl- 6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate, sodium 7- {3 - [(2-cyanoethylamino) methyl] -3-methyl-azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydr ochinolin-3-carboxylate, 7- {3 - [(1- (2-cyanoethylamino) cyclopropyl] azetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro -quinoline-3-carboxylic acid, 7- {3 - [(2-cyanoethylamino) methyl] -3-ethylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid, (70) 7- {3 - '[(2-cyanoethylamino) methyl] -3-ethylazetidin-1-yl} -1-cyclopropyl-6-fluoro-8-methyl- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 9- {3 - [(2-cyanoethylamino) methyl] cyclopentyl} -8-fluoro-3-methyl-6-oxo-2,3-dihydro -6H-1-oxa-3a-azafenalene-5-. carboxylic acid, 9- (3 - {[(2-cyanoethyl) methylamino] methyl} cyclopentyl) 8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-30 phenalene-5-carbonic acid, 9- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa -3a-azaphenalene-5-carboxylic acid, 9- [3- (R) - (2-cyano-1- (S) -methylaminoethyl) pyrrolidin-1-yl] -8-fluoro-3- (S) -methyl -6-oxo-2,3-dihydro-6H-1-oxa-3α-azapalenalene-5-carboxylic acid, 1 027545-242. (75) 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclo-propyl-6-fluoro-4-oxo-1,4-dihydro [1,8] naphthyridine-3-carbon-5 acid, 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7 - [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -Ι-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [ 3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclo-propyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (80) 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclo-propyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 5-amino-7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (82) 5-amino-7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -20 1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- (1-amino -2-cyano-2,2-dimethylethyl) p yrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- [3- (1-amino-2-cyano) 2,2-dimethylethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, (85) 7- [3- (3- 1-amino-2-cyano-2,2-dimethylethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- ( 1-amino-2-cyano-2,2-dimethylethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline-3. carboxylic acid, 5-amino-7- [3- (1-amino-2-cyano-2/2-dimethylethyl) -35-pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4 -dihydroquinoline-3-carboxylic acid, 1 027545- '243' 5-amino-7- [3- (1-amino-2-cyano-2,2-dimethylethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8 -methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- (1-amino-2-cyanoethyl) pyrrolidin-1-yl] -1-5 cyclopropyl-6-fluoro-4-oxo -1,4-dihydroquinoline-3-carboxylic acid, (90) 7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 10 (91) 9- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl-6-oxo-2,3-dihydro -6H-1-oxa-3a-azapalenalen-5-carboxylic acid, 9- [3 (R) - (2-cyano-1 (S) -methylaminoethyl) pyrrolidin-1-yl] -8-fluoro-3-methyl- 6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-15-phenalene-5-carboxylic acid, 7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid, 7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1 -20 cyclop ropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, (95) 7- [3 (R) - (2-cyano-1 (S) -methylaminoethyl) pyrrolidine-1 -yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- [3- (2-cyano-1-methylaminoethyl) pyrrolidine-1] -yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-30 carboxylic acid, 7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8 -methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 5-amino-7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8 -methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1027545. (100) 5-amino-7- [3- (2-cyano-1-methylaminoethyl) pyrrolidin-1-yl] -1. -cyclopropyl-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- [3- (2-cyano-2,2-dimethyl-1-methylaminoethyl) pyrro-5-lidine-1- yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- (2-c yano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [3- (2-cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-ca : carboxylic acid, 7- [3- (2-cyano-2,2-dinmethyl-1-methylaminoethyl) -pyrrolidin-1-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, (105) 5-amino-7- [3- (2-cyano-2,2-dimethyl-1-methylaminoethyl) pyrrolidin-1-yl] -1-cyclopropyl-8-methoxy-4 -oxo-1,4-dihydroquinoline-3-carboxylic acid, 5-amino-7- [3- (2-cyano-2,2-dimethyl-1-methylamino-ethyl) pyrrolidin-1-yl] -1-cyclopropyl -8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [4- (2-cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro- 8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, .25 7- [4- (2-cyanoethylamino) hexahydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-6-fluoro -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [4- (2-cyanoethylamino) hexah ydrocyclopenta [c] pyrrole-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydrochino-30-line-3-carboxylic acid, (11.0) 7- [4- (2- cyanoethylamino) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- [4- (1-amino-2-) cyanoethyl) hexahydrocyclopenta [c] -35 pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1027545-7- [4 - (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 7- [4- (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7- [4- (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 10 (115) 7- [3a- (2-cyanoethylamino) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4. dihydroquinoline-3-carboxylic acid, 7- [3a- (2-cyanoethylamino) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-15. dihydroquinoline-3-carboxylic acid, 7- [3a- (2-cyanoethylamino) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid, 7- [3a- (2-cyanoethylamino) hexahydrocyclopenta [c] -20 pyrrole-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 7 - [3a- (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (120) 7- [3a- (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1 / 4- dihydroquinoline-3-carboxylic acid, 7- [3a- (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methyl-4-oxo-1,4-dihydro- Quinolin-3-carboxylic acid or (122) 7- [3a- (1-amino-2-cyanoethyl) hexahydrocyclopenta [c] pyrrol-2-yl] -1-cyclopropyl-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid. 14. A pharmaceutical preparation comprising a compound of the formula I, II, III, IV, V or VI mixed with a. pharmaceutically acceptable diluent, carrier or excipient. 1027545- A method of treating a bacterial infection in a mammal, which comprises administering to a. mammal in need thereof for an effective amount of the compound of formula I, II, III, IV, V or VI. 1027545.