MX2008005177A

MX2008005177A - Peri condensed tricyclic compounds useful as antibacterial agents

Info

Publication number: MX2008005177A
Application number: MXMX/A/2008/005177A
Authority: MX
Inventors: Neil David Pearson; Nathalie Cailleau; David Thomas Davies; Alan Joseph Hennessy; Roger Edward Markwell; Timothy James Miles; Joel Michael Esken; Sukumar Senthil Kumar Kusalakumari
Original assignee: Nathalie Cailleau; David Thomas Davies; Joel Michael Esken; Glaxo Group Limited; Alan Joseph Hennessy; Sukumar Senthil Kumar Kusalakumari; Roger Edward Markwell; Timothy James Miles; Neil David Pearson
Priority date: 2005-10-21
Filing date: 2008-04-21
Publication date: 2008-10-03

Abstract

Tricyclic nitrogen containing compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate and their use as antibacterials.

Description

COMPOUNDS DESCRIPTIVE MEMORY Specific examples of R include hydrogen; hydroxy optionally substituted; optionally substituted amino; halogen; I rent (C1 4); 1-hydroxy-alkyl (C1); optionally substituted aminocarbonyl. Plus particularly, the groups R ^ are hydrogen; CONH2; 1-hydroxyalkyl by CH2OH example; optionally substituted hydroxy for example methoxy; Not me optionally substituted; and halogen, in particular fluoro. More particularly 3 R is hydrogen, hydroxy or fluoro.

In a specific aspect, when A is (ia), n is 1. In other 3 aspect R is in position 3 or 4. In another more specific aspect, A is 3 (ia), n is 1 and R is in the 3 position, and more particularly is in the relative position 2 cis with respect to the group NR.

In specific embodiments, A is a group (ia) in which n is 1 3 and R is hydrogen or hydroxy. 4 8 8 In a specific aspect, when A is (ii), X is CR R and R is H or OH and more particularly OH is in relative position trans with respect to R7 In another aspect W1 is a link. In another aspect R7 is H. In specific embodiments W1 is a link, X, V \ / 2 and W3 are each of them CH2 and R7 is H.

In certain embodiments U is CH2. In certain embodiments R is an aromatic heterocyclic ring (B) with 8-1 1 ring atoms including 2-4 heteroatoms of which 13 2 at least one is N or NR in which, in specific embodiments, Y contains 2-3 heteroatoms, one of which is S and 1 -2 are N, with an N linked to x3.

In alternative embodiments the heterocyclic ring (B) has the aromatic ring (a) selected from benzo, pyrido, and optionally substituted pyridazine and the non-aromatic ring (b) and Y has 3-5 atoms, more particularly 4 atoms, including at least one heteroatom, with O, S, 13 5 13 CH2 or NR linked to X where R is other than hydrogen, and either 3 NHCO is linked via N to X, or O, S, CH2 or NH is bonded to 3 X In a specific aspect ring (a) contains aromatic nitrogen, and more particularly ring (a) is pyridine or pyrazine. The examples of rings (B) they include the following, optionally substituted: (a) and (b) aromatics 1 H-pyrrolo [2,3-b] -pyridin-2-yl, 1 H -pyrrolo [3,2-b] -pyridin-2-yl, 3 H -imidazo [4,5-b] -pyrid-2 -yl, 3H-quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo [1,2,3] -thiadiazol-5-yl, benzo [1, 2,5] -oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo [b] thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo [1,2- a] pyridin-2-yl, imidazo- [1,2-a] -pyrimidin-2-yl, indol-2-yl, indol-6-yl, so-quinolin-3-yl, [ 1,8] -naphyridin-3-yl, oxazolo [4,5-b] -pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan -2-yl, naphthalen-2-yl, 1,3-dioxo-isoindol-2-yl, benzimidazol-2-yl, benzothiophen-2-yl, 1 H-benzotriazol-5-yl, 1 H-indole 5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione-6-yl, 3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2- ilo, 3H-quinazolin-4-one-6-yl, 4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl, benzo [1,2,3] thiadiazol-6 -yl, benzo [1, 2,5] thiadiazol-5-yl, benzo [1,4] oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinolin-3-yl; lo, imitazo [1, 2-a] pyridazin-2-yl, imidazo [1, 2-b] pyridazin-2-ylo, pyrazolo [1, 5-a] piraz N-2-yl, pyrrazolo [1,5-a] pyridin-2-ylo, pyrrazolo [1,5-a] pyrmidin-6-yl, pyrazolo [5] 1-c] [1, 2,4] triazin-3-yl, pyrido [1,2-a] pyrimidin-4-one-2-yl, pyrido [1,2-a] pyrim din-4-one-3-yl, quinazolin-2-yl, quinoxali n-6-yl, thiazolo [3,2-a] pyrimidin-5-one-7-yl, thiazolo [5,4-b] pyridin-2-yl, thieno [3,2- b] pyridin-6-yl, thiazolo [5,4-b] pyridin-6-yl, 4-oxo-4 H -pyrido [1,2-a] pyrimidin-2-yl, 1 -oxo-1, 2-dihydro-isoquinolin-3-yl, thiazolo [4,5-b] pyridin-5-yl, [1,2,3] thiadiazolo [5,4-b] pyrid n-6-yl, 2H-isoquinolyl-1 -one-3-yl (a) it is not aromatic (2S) -2,3-d¡h¡dro-1 H-indol-2-yl, (2S) -2,3-dihydro-benzo [1,4] dxoxin-2 -yl, 3- (R, S) -3,4-dihydro-2H-benzo [1,4] thiazin-3-yl, 3- (R) -2,3-dihydro- [1,4] ] dioxino [2,3-b] pyridin-3-yl, 3- (S) -2,3-dihydro- [1,4] dioxin [2,3-b] pyridin-3- ilo, 2,3-dihydro-benzo [1,4] dioxan-2-yl, 3-substituted-3H-quinazoln-4-on-2-yl, (7S) -6,7-dihydro [ 1, 4] dioxino [2,3-c] pyridazin-7-yl (b) is not aromatic / 6 1, 1, 3-trioxo-1, 2,3,4-tetrahydro-1-benzo [1, 4] ] tiazin-6-ilo, benzo [1,3] d, oxo-5-yl, 2,3-d, h -dro-benzo [1,4] dioxin-6-yl, 2-oxo-2,3-dihydro-benzooxazole-6 ilo, 3-substituted-3H-benzooxazol-2-one-6-yl, 3-substituted-3H-benzooxazol-2-thonane-6-yl, 3-substituted-3H-benzothiazole- 2-one-6-yl, 4H-benzo [1,4] oxazin-3-one-6-yl (3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6- ilo), 4 / - / - benzo [1,4] thiazin-3-one-6-ylo (3-oxo-3,4-dihydro-2 / -benzo [1,4] tiazin-6 ilo), 4H-benzo [1,4] oxazin-3-one-7-yl, 4-oxo-2,3,4,5-tetrahydro-benzo [b] [1,4] thiazepin-7-yl, -oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyrimidin-6-yl, 1 H-pyrido [2,3-b] [1,4] thiazin-2-one-7-yl (2-oxo-2,3-dihydro-1 H -pyrido [2,3-b] thiazion - 7-yl), 2,3-dhydro-1 H -pyrido [2,3-b] [1,4] t aazn-7-yl, 2-oxo-2,3- Hydro-1 H- pyridyl [3,4-b] thiazin-7-yl, 2,3-dihydro- [1,4] dioxino [2,3-b] pyridin-6-yl, 2,3-dihydro- [1,4] dioxino [2,3-c] pyridin-7-yl, 2,3-dihydro- [1,4] d -oxin [2,3-] b] pyridin-7-yl, 3,4-dihydro-2H-benzo [1,4] oxazin-6-yl, 3,4-d-hydroxy-2H-benzo [1,4] thiazin-6 ilo, 3-oxo-3,4-dihydro-2 / - / - pyrida [3,2-b] [1,4] oxazin-6-yl, 3,4-dihydro-2H-p, rido [3,2-b] [, 4] thiazin-6-yl, 3-oxo-3,4-dihydro-2H-pyrid [3,2-b] [1,4] tázin -6-ylol, 3,4-dihydro-1 / - / - quinolin-2-one-7-yl, 3,4-d -hydro-1 H-quinoxalin-2-one-7-yl, 6 , 7- dihydro-4 / - / - pyrazolo [, 5-a] pyrimidin-5-one-2-yl (5,6,7,8-tetrahydro- [1,8] naphthyridin- 2-yl, 2-oxo-3,4-dihydro-1 H- [1,8] naphthyrin-6-yl, 6-oxo-6,7-dihydro-5H-8-thia -1, 2,5-triaza-naphthalen-3-yl, 2-oxo-2,3-dihydro-1 H -pyrido [3,4-b] [1,4] oxazin-7-yl, 2-oxo - 2,3-dihydro-1 H -pyrido [2,3-b] [1,4] oxazin-7-i lo, 6,7-dihydro- [1,4] dioxino [2,3- d] pyrimidin-2-yl, [3] oxathiolo [5,4-c] pyridin-6-yl, 3 , 4-D-Hydro-2 / - / - pyran [2,3-c] pyridin-6-yl, 2,3-dydro-1,4-benzodioxin-7-yl, 2,3-d HYDRO [1,4] oxatid [2,3-c] pyridin-7-yl, 2,3-dihydrofuro [2,3-c] pyridin-5-yl, 2, 3-dihydro-1-benzofuran-5-yl, 2,3-dihydro [1,4] oxathino [2,3-6] pyridin-7-yl, 6,7-dihydro [1,4] oxathino [3,2-c] pyridazin-3-yl, 6,7-dihydro [1,4] oxathino [2,3-c] pyridazin-3-yl, 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3 -yl, 2,3-dihydro-1 H -pyrido [3,4- £ > ] [1,4] oxazin-5-yl, 5-oxo-1, 2,3,5-tetrahydroindolizin-7-yl, 6,7-dihydro-5 / - / - pyran [2,3- c] pyridazin-3-ylo, 6-oxo-6,7-dihydro-5H-pyridazino [3,4-b] [1,4] thiazin-3-yl, benzo [1,2,3] thiadiazol-5-yl, benzo [1, 2,5] thiadiazol-5-yl, benzothiazol-5-yl, thiazolo- [5,4-b] pyridin-6-yl, 2-oxo-2,3-dihydro-1 H-pyrid [2,3-b] [1,4] thiazin-7-yl, 3-methyl -2-oxo-2,3-dihydro-benzooxazol-6-yl, 4-oxo-4 / - / - pyrido [1,2- a] pyrimidn-2-yl, l O 7-0X0-1, 5,6,7-tetrahydro-, 8-naphthyridin-2-yl. 13 In some embodiments R is H if it is in ring (a) or also alkyl (C 1 4) as methyl or isopropyl when it is in ring (b). 13 13 3 More particularly, in ring (b) R is H when NR is linked to X 13 5 and (C 1 4) alkyl when NR is linked to X. 14 15 1 5 In other embodiments R and R are selected independently of hydrogen, halo, hydroxy, (C1-4) alkyl, (C1-4) alkoxy, nitro and cyano. More particularly R is hydrogen. More particularly, each R is selected from hydrogen, chlorine, fluoro, hydroxy, methyl, methoxy, nitro and cyano. Even more particularly, R 0 is selected from hydrogen, fluorine or nitro. 14 15 More particularly R and R are each H.

Specific R5 groups include: [1, 2,3] thiazole [5,4-b] pyridin-6-yl 1 Hyrrolo [2,3-b] pyridin-2-yl! 2,3-dihydro- [1,4] dioxino [2,3-b] pyridin-6-yl 2,3-dihydro- [1,4] dioxino [2,3-b] pyridin-7-yl, 3-dihydro- [1,4] dioxino [2,3-c] pyridin-7-yl 2,3-dihydro-benzo [1,4] dioxan-6-yl 2-oxo-2,3-dihydro -1 H -pyrido [2,3-b] [1,4] oxazin-7-yl-2-yl-2,3-dihydro-1 H -pyrido [2,3-b] [1,4] thiazin-7-yl 3,4-dihydro-2 H -benzo [1,4] oxazin-6-yl-3-methyl-2-oxo-2,3-dihydro-benzooxazol-6-yl 3-0X0-3, 4- Hydro-2H-benzo [1,4] oxazin-6-yl 3-oxo-3,4-dhydro-2H-pyrido [3,2-b] [1,4] oxazin- 6-Ilo 3- 0X0-3, 4-D-Hydro-2 H -benzo [1,4] tiazin-6-yl (4 H -benzo [1,4] thiazin-3-one-6-yl ) 4-oxo-4H-pyrido [1,2-a] pyrimidin-2-ylo-6-nitro-benzo [1,3] dioxol-5-yl-7-fluoro-3-oxo-3, 4-Hydro-2H-benzo [1, 4] oxazin-6-yl 8-hydroxy-1-oxo-1,2-dihydro-isoquinolin-3-yl 8-hydroxy-quinolin-2-yl benzo [1,2,3] thiadiazole- 5-benzo [1, 2,5] thiadiazol-5-yl benzothiazol-5-yl thiazolo- [5,4-b] pyridin-6-yl 3-oxo-3,4-dihydro-2H- pyrido [3,2- / 3] [1,4] thiazin-6-yl 7-chloro-3-oxo-3,4-dihydro-2 / - / - pyrido [3,2-ib] [1 l4] thiazin-6-yl 7-fluoro-3-oxo-3,4-dihydro-2H-pyrido [3,2-6] [1,4] thiazin-6-yl 2-0X0-2, 3-dihydro-1 H-pyrido [3,4-b] [1,4] thiazin-7-yl 6- 0X0-6,7-dihydro-5H-pyridazino [3,4-b] [1,4] thiazin-3-yl 7- 0X0-1, 5,6,7-tetrahydro-1,8-naphthyridin-2-yl 7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1, 4] oxazin-6-yl (3S) -2,3-dihydro [1,4] dioxino [2,3-b] pyridin-3-yl [1, 3] oxathiolo [5,4-c] pyridin-6 3,4-dihydro-2H-pyrano [2,3-c] pyridin-6-yl 5-carbonyl-2,3-dihydro-1,4-benzodioxin-7-yl-2,3-dihydro [1, 4] oxaatino [2,3-c] pyridin-7-yl 5-fluoro-2,3-dihydro-1,4-benzodioxin-7-yl 2,3-dihydro-1-benzofuran-5-yl2 -dihydro [1,4] oxathino [2,3-i] pyridin-7-yl 6,7-dihydro [1,4] oxathiino [3,2-c] pyridazin-3-yl 6,7-dihydro [1] , 4] oxatnno [2,3-c] pindazin-3-yl 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-yl 2,3-dihydrofuro [2,3-c] ] pyridin-5-yl 2,3-dihydro-1 H -pyrido [3,4-b] [1,4] oxazin-7-yl 5-oxo-1, 2,3,5-tetrahydroindolizin-7-yl 6,7-dihydro-5H-pyrano [2,3-c] pyridazin-3-yl 7-hydroxymethyl-6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-yl 5.6- dihydrofuro [2,3-c] pyridazin-3-yl especially 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl 3-oxo-3, 4-dihydro-2H-pyrido [3,2-b] [1,4] thiazin-6-yl 6.7- dih idro [1,4] dioxino [2,3-c] pyridazin-3-yl 6,7-dihydro [1,4] oxathino [2,3-c] pyridazin-3-yl 6,7-dihydro [1] 4] oxaatino [3,2-c] pyridazin-3-yl-2,3-dihydro- [1,4] dioxino [2,3-c] pyridin-7-yl [1, 3] oxathiolo [5.4-] c] pi din-6-yl. When used herein, the term "alkyl" includes groups with straight and branched chains, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, pentyl and hexyl. The terminology "alkenyl" should be interpreted accordingly. Halo or halogen includes fluoro, chlorine, bromine and iodine. The haloalkyl moieties include 1 -3 halogen atoms. The compounds comprised in the invention contain a heterocyclic group and can occur in two or more tautomeric forms depending on the nature of the heterocyclic group; all such tautomeric forms are included within the scope of the invention. Some of the compounds of this invention can be crystallized or recrystallized from solvents such as aqueous and organic solvents. In such cases solvates can be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing varying amounts of water that can be produced by processes such as lyophilization. Furthermore, it should be understood that phrases such as "a compound of formula (I) or a salt thereof and / or one of its pharmaceutically acceptable solvates" are intended to encompass the compound of formula (I), a pharmaceutically acceptable salt of the compound of formula ( I), a solvate of formula (I), or any pharmaceutically acceptable combination thereof. Thus, by way of non-limiting example used herein for illustrative purposes, "a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof" may include a pharmaceutically acceptable salt of the compound of formula (I) which is also present as a solvate Since the compounds of formula (I) are intended to be used in pharmaceutical compositions it will be readily understood that in specific embodiments they are provided in substantially pure form, for example pure by at least 60%, more suitably pure by 75% and particularly pure in at least 85%, especially pure in at least 98% (the percentages expressed are based on weight in weight). The impure preparations of the compounds can be used to prepare the purest forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably 5% and more particularly from 10% to 59% of a compound of formula (I) or one of its salts and / or its pharmaceutically solvates acceptable The specific compounds according to the invention include mentioned in the examples and their pharmaceutically salts and solvates acceptable The pharmaceutically acceptable salts of the compounds of Formula (I) mentioned above include the acid addition or salts of quaternary ammonium, for example its salts with mineral acids for example Hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids, or acids organic, for example acetic acid, fumaric ((2E) -2-butenedioic acid), succinic, maleic, citric, benzoic, p-toluenesulfonic (4-methylbenzene sulphonic), methanesulfonic, naphthalenesulfonic or tartaric acids. The invention covers all these derivatives.

Some of the compounds of formula (I) may exist in the form of optical isomers, eg, diastereoisomers and mixtures of isomers in all relationships, eg, racemic mixtures. The invention includes all these forms, in particular the pure isomeric forms. For example, the invention includes enantiomers and diastereoisomers at the points of 2 3 9 coupling of NR, R and / or R. The different isomeric forms can separate or resolve each other by conventional methods, or any given isomer can be obtained by synthetic methods conventional or by stereospecific or asymmetric synthesis.

In another aspect of the invention there is provided a process for preparing compounds of formula (I) wherein R is H, and salts and / or solvates pharmaceutically acceptable thereof, and such a process comprises cyclizing a compound of formula (HA): (HA) 21 20 5 wherein R is (C 1 6) alkyl as methyl, R is UR or a 2 '2 group convertible thereto and R is R or a group convertible thereto, 1a 1 b 2 5 where A, R, R, R, U and R are as defined in formula (I), to provide a compound of formula (IIB): (IIB) g wherein R is H, and subsequently optionally or as necessary to convert R20 and R2 'in UR5 and R2, interconvert any group variable, and / or form one of its salts and / or one of its solvates pharmaceutically acceptable The cyclization reaction is carried out by treating the compound of formula (NA) with an activating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride or p-toluene sulfonic anhydride and an organic base such as triethylamine or diisopropylethylamine. The mesylate or tosylate preparation takes place under standard conditions and the compound of formula (IIB) is formed in situ. In another aspect of the invention there is provided a process for preparing compounds of formula (I) wherein R is OH, and pharmaceutically acceptable salts and / or solvates thereof and such process comprises cyclizing a compound of formula (IIC): (IIC) 21 wherein R is (C 1 6) alkyl as methyl, R is H or (C-6) alkyl as methyl and R 1a, R 1 b are as defined in formula (I), to provide a compound of formula (IID): (IID) 2 5 and subsequently convert -CO, H to -CH, -A-NR -UR, interconvert any variable group, and / or form one of its salts and / or pharmaceutically acceptable solvates.

The cyclization reaction can be carried out by the treatment of the compound of formula (IIC) with lithium perchlorate in acetonitrile or lithium hydroxide in water to provide the tricyclic hydroxy carboxylic acid (IID). The conversion of -CO2H to -CH2-A-NR -UR can be carried out by methylation using methanol in sulfuric, followed by reduction to diol with sodium borohydride in methanol, and conversion to tosyl derivative with tosyl chloride / dibutyltin oxide. The reaction with 2n 2 '20 20 5 amine HN-A-NR UR R wherein R is UR or a group convertible in this' 2 and R' is R or a group convertible therein provides a compound of formula (IIB) where R is OH. 2 'Conveniently one of R and R is an N-protecting group, as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl. This can be separated by several methods well known to the experts in the technique (for example see "Protective Groups in Organic Synthesis, T.W.

Greene and P. G.M. Wuts, Wiley-lnterscience, 1999), for example acid hydrolysis conventional with, for example, trifluoroacetic acid or hydrochloric acid.

In addition, the invention provides compounds of the formula (IIB) in which R is hydrogen. The free amine of the formula (IIB) in which R is hydrogen 2 5 can be converted to NR UR by conventional means such as formation of 5-amide or sulfonamide with an acyl derivative R COW or R S02W, for compounds in which U is CO or S02 or, when U is CH2, by alkylation with an alkyl halide R CH2-halide in the presence of a base, 5 acylation / reduction with an acyl derivative R COW or reductive alkylation with an aldehyde R CHO under conventional conditions (see for example Smith, M.B .; March, J.M. Advanced Organic Chemistry, Wiley-lnterscience). The 5 appropriate reagents containing the required R group are compounds known or can be prepared analogously to known compounds, see, for example, international publications WO02 / 08224, WO02 / 50061, WO02 / 56882, WO02 / 96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210, WO2004096982, WO2002050036, WO2004058144, WO2004087 45, WO06002047, WO06014580, WO06010040, WO0601 7326, WO06012396, WO06017468, WO06020561 and EP0559285. 5 When R contains an NH group, it can be protected with a N-protecting group suitable as t-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl during coupling of the R5 derivative with the free amine of formula (IIB). The protective group can be removed by means conventional, such as by treatment with trifluoroacetic acid.

Conveniently the resolution of enantiomers at the coupling position G of R is carried out in the compound of formula (IIB), by any conventional method such as high performance liquid chromatography preparatory The compound of formula (NA) can be prepared by following Scheme 1: SCHEME 1 Compounds of general structure (III) can be prepared by 2 'by reaction of acrylate ester (IV) with a compound or HA-N (R) R, as an amino-piperidine protected with Boc, under conventional conditions for additions of Michael (see for example Smith, M.B., March, J.M. Advanced Organic Chemistry, Wiley-Interscience). The reduction of (III) to (NA) happens with the treatment with lithium aluminum hydride in conditions conventional (see for example Smith, M.B .; March, J.M. Advanced Organic Chemistry, Wiley-Interscience).

The compound of formula (IIC) can be prepared by conventional epoxidization of the vinyl ester (IV), for example, by oxidation with m-chloroperbenzoic acid or t-butyl hydroperoxide.

In Scheme 2, a way to reach the intermediary (CH2O) n = paraformaldehyde is shown NBS = N-bromosuccinamide TMSCI = chlorotrimethylsilane BnEtjNCI = benzyltriethylammonium chloride The aniline (XI) is converted into cinnamide (X), which is cycled with aluminum chloride (with loss of the phenyl moiety - See M.C. Elliot et al., S.R.

Inglis et al. J. Med. Chem. 47 (22), 5405-5417 (2004)] Synlett, 5, 898-900 (2004)) to provide (IX). This is selectively O-alkylated with example methyl iodide or dimethisulfate to provide (VIII) and the group methyl is functionalized with N-bromosuccinimide to provide the analogue bromomethyl (VII). This is converted to nitrile (VI) by treatment with KCN, or with NaCN and tetrabutylammonium bromide, which is acid-catalyzed methanolysis (TMS-chloride or HCI in methanol) up to the methyl ester (V), and then vinylation with paraformaldehyde. Something is formed of demethylated material with (V), but this can be methylated again with TMS-diazomethane. This path is particularly suitable for R = F.

In Scheme 3 an alternative way to reach the intermediary (IV): SCHEME 3 Quinolinone (XIV) can be prepared by the reaction of aniline (XVI) commercially available with cinnamoyl chloride to provide (XV) and its subsequent cyclization (for an example of this procedure see Cottet, F.; Marull, M .; Lefebvre, O .; Schlosser, M European Journal of Organic Chemistry (2003), 8, 1559). (XIV) can be converted to bromo quinoline (XIII) under standard conditions (for examples see Smith, M.B., March, J.M. Advanced Organic Chemistry, Wiley-Interscience). Boric acid (XII) can be synthesized from (XIII) under standard conditions (for an example see Li, W., Nelson, D., Jensen, M.

Hoerrner, R .; Cai, D .; Larsen, R .; Reider, P J. Or g. Chem. (2002), 67 (15), 5394). The coupling of (XII) with the known bromo-acrylate, (for synthesis see Rachon, J.; Goedken, V .; Walborsky, H. J. Or g. Chem. (1989), 54 (5), 1006) to provide (IV) can be achieved using a reaction of Suzuki coupling (for conditions see Littke, A.; Dai, C; Fu, G.

J. Am. Chem. Soc. (2000), 122 (17), 4020). This route is particularly suitable for R = H.

In schemes 2 and 3, the RCOCI reagent in the first stage, cinnamoyl chloride, can be replaced by (2E) -3-ethyloxy-2-propenoyl chloride and the subsequent cyclization carried out with trifluoroacetic acid or sulfuric acid instead of aluminum trichloride (E. Bastón et al, European J.

Med. Chem., 2000 35 (10), 931).

An alternative route to the compounds of formula (I) in which A 3 is (a), n is 1 and R is H and U is CH 2, comprises the reaction of a compound of formula (HE): . 1a I b wherein R and R are, as described in formula (I), with a compound RCH2NH2, by reductive alkylation. The compound of formula (ME) can be prepared by the following Scheme 4: SCHEME 4 Reaction of (IV) with a suitable protected cetopiperidine such as 1,4-dioxa-8-azaspiro [4.5] decane followed by reduction of the ester and cyclization with methane sulfonic anhydride provides the tricyclic intermediate. The deprotection of the acetal with hydrochloric acid liberates the ketone.

Another alternative route for the compounds of formula (IIB) in 1a 1 b 9 20 2 '3 which R is F, R is H, R is H, R is H, R is Boc, A is (a), n is 1 and R H (compound 5), comprises Scheme 5A: SCHEME 5A DMSO = dimethylsulfoxide MS2O = methanesulfonic anhydride pyr = pyridine DCE = dichloroethane Diol 3 can be subjected to a desimetrization reaction enzyme to generate the desired E1 enantiomer of compound 4, by treatment with TL lipase and a vinyl ester (such as vinyl or vinyl pivalate), followed by anhydride cyclization methanesulfonic acid, ester hydrolysis with sodium methoxide in methanol and activation of the resulting alcohol in mesylate 4 by methods conventional In Scheme 5B a variant of this process is shown: SCHEME 5B MsOH = methanesulfonic acid MsCl = methanesulfonic chloride 1a 1 b 2 5 The interconversions of R, R, R, A and R are conventional. In compounds containing a hydroxy group optionally protected, conventional hydroxy protecting groups, convenient, that can be eliminated without breaking the rest of the molecule they include acyl and alkylsilyl groups. Protective groups N are eliminated by conventional methods. 1a 1b The interconversion of the R and R groups can be carried out conventionally, in the compounds of formula (I) or (IIB). For example R 1 b 1a 1 b or R methoxy is convertible to R or R hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et al, J. Amer. Chem.

Soc, 1973, 7829) or HBr. Alkylation of the hydroxy group with a suitable alkyl derivative 1 having a leaving group as halide, provides R or 1 b 1a 1a R substituted alkoxy. R halogen is convertible into another R by means conventional, for example in hydroxy, alkylthiol (by means of thiol) and amino using coupling reactions catalyzed with metals, for example using copper as mentioned in Synlett (2003), 1 5, 2428-2439 and in Angewandte Chemie, International Edition, 2003, 42 (44), 5400-5449. R1 b halo as bromine can be introduced by the method of M. A. Alonso et al, Tetrahedron 2003, 59 (16), 2821. R a or R1 b halo as bromine can become cyano through treatment with copper (I) cyanide in N, N-1a 1b dimethylformamide. R or R carboxy can be obtained by conventional 1 a 1 b hydrolysis of R or R cyano, and the carboxy can be converted to hydroxymethyl by conventional reduction. 2 'The compounds of formula HA-N (R) R and (V) are compounds known or can be prepared analogously to known compounds, see, for example, international publications WO2004 / 035569, WO2004 / 089947, WO02 / 08224, WO02 / 50061, WO02 / 56882, WO02 / 96907, WO2003087098, WO2003010138, WO2003064421, WO2003064431, WO2004002992, WO2004002490, WO2004014361, WO2004041210, WO2004096982, WO2002050036, WO2004058144, WO2004087145, WO2003082835, WO2002026723, WO06002047 and WO06014580.

As shown in Scheme 6, the hydroxy-20 4 8 1 aminomethylpyrrolidines of formula (XIII) (HA-NH (R), A is (i), X is CR R, W 2 3 4 7 8 is a bond , W and W are both CH2, R and R are H and R is OH) can be prepare from the doubly protected chiral intermediate (XVI), separated by preparative HPLC. The benzyloxycarbonyl protecting group is eliminated by hydrogenation to provide (XV) and the amino function is converts to a trifluoroacetamide (XIV). The t-butoxycarbonyl protecting group (Boc) is removed with HCI to provide the pyrrolidine hydrochloride salt (III).

SCHEME 6 E1 and E2 (cis) HCI MeOH DCM E1 and E2 (cis) P = 4-dimethylaminopyridine The intermediary (XVI) can be prepared by the general method of Scheme 7: SCHEME 7 3 (XVI) Reagents and conditions: (a) N-hydroxybenzylamine hydrochloride, paraformaldehyde, toluene, EtOH, 80 ° C; (b) Pd (OH) 2, H2 (50psi), MeOH, room temperature; (c) Benzyloxycarbonyl-succinimide, ß?, dichloromethane, room temperature. In Scheme 8 the aminomethylpyrrolidine of formula (XVII) (HA-NH (R2 °), A is (i), X is CR4R8, W1 is a bond, W2 and W3 are both CH2, R4, 7 8 R and R are all H) can be prepared from commercially available Boc protected aminomethylpyrrolidine, and converted to trifluoroacetamide.

SCHEME 8 (XVIII) (XVII) (XIX) DMAP = 4-dimethylaminopyridine The aminomethylmorpholine intermediate of formula (XXI) (HA-NH (R2 °), A is (ii), X is O, w \ W2 and W3 are each CH2) can be prepared from an intermediate chiral dichlorobenzyl (XXIII) (WO2003082835) (Scheme 9) first protecting the amino function with a Boc protecting group (XXII), eliminating the dichlorobenzyl group by hydrogenation to provide (XXI), protecting the N-morpholine atom with a benzyloxycarbonyl group (to allow purification by chromatography) (XX), and hydrogenation to achieve the required morpholine derivative (XXI).

SCHEME 9 In the examples are other details for the preparation of compounds of formula (I). The antibacterial compounds according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials. The pharmaceutical compositions of the invention include those which have a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infections in mammals, including humans. The composition can be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as sterile or oral parenteral solutions or suspensions. The topical formulations of the present invention may be presented as, for example, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated bandages and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist the penetration of the drug and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such vehicles can be present in from about 1% to about 98% of the formulation. More commonly they will constitute up to about 80% of the formulation. Tablets and capsules for oral administration may be in a unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone.; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for the formation of tablets, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrators, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well 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 to be reconstituted with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or edible hydrogenated fats, emulsifying agents, for example lecithin, sorbitan monooleate or gum arabic; 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 sorbic acid, and, if desired, conventional flavoring agents or colorants. The suppositories will contain conventional suppository bases, for example, cocoa butter or other glyceride. For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, with water being preferred. The compound, depending on the vehicle and the concentration used, may be suspended or dissolved in the vehicle. In the preparation of solutions, the compound can be dissolved in water for injection and sterilized by filtration before introducing it into a suitable vial or ampoule and sealing it.

Advantageously, agents such as a local anesthetic, preservatives and buffering agents can be dissolved in the vehicle. To improve stability, the composition can be frozen after filling the vial and removing the water in vacuo. Then, the dry lyophilized powder is sealed in the vial and an attached vial of water for injection can be provided to reconstitute the liquid before use. Parenteral suspensions are prepared in essentially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization can not be effected by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain 0.1% by weight, preferably 10 to 60% by weight, of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will preferably contain 50 to 1000 mg of active ingredient. The dosage used for the treatment of an adult human will preferably be within the range of 100 to 3000 mg daily, for example 1500 mg daily depending on the route and frequency of administration. Such a dose corresponds to 1.5 to 50 mg / kg per day. Suitably the dosage is from 5 mg / kg to 30 mg / kg per day. The compounds of formula (I) may be the only therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a β-lactam then a β-lactamase inhibitor can also be used. The compounds of formula (I) can be used in the treatment of bacterial infections caused by a wide range of organisms, including both Gram-negative and Gram-positive organisms. Some compounds of formula (I) can be active against more than one organism. This can be determined by test methods described herein. All publications, including, but not limited to, patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated by reference herein. as if it were presented in its entirety. The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms.

EXAMPLES AND EXPERIMENTAL PART Generalities Abbreviations used in the examples rt = room temperature MS = mass spectrum ES = mass spectroscopy by electrospray LCMS or LC-MS = mass spectroscopy by liquid chromatography HPLC = high resolution liquid chromatography (Rt refers to retention time) MDAP o Mass-directed autoprep = mass-directed preparative HPLC (using a ZQ mass spectrometer (Waters)) Some reagents are also abbreviated here.

DMF refers to?,? - dimethylformamide, TFA refers to trifluoroacetic acid, THF refers to tetrahydrofuran, Pd / C refers to palladium on carbon catalyst, DCM refers to dichloromethane, Boc refers to tert-Butoxycarbonyl, MeOH it refers to methanol. The proton nuclear magnetic resonance spectra (1H NMR) were recorded at 400 or 250 MHz, and the chemical changes were reported in parts per million (5) down from the internal standard tetramethylsilane (TMS) field. The abbreviations of the NRM data are the following: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, ap = apparent, br = width . CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide and CD3OD is tetradeuteriomethanol. Five mass spectra were obtained using electrospray ionization (ES) techniques. All temperatures are expressed in degrees Celsius. MP-carbonate refers to triethylammonium carbonate and methylpolystyrene (Argonaut Technologies). The Chiralpak AD and AD-H columns comprise silica for preparative columns (particle size for ADI O H 5um and particle size for AD 10um 21 x250mm; particle size for AD 20 um, 101 1 x250 mm) coated with Amilose tris (3,5-dimethylphenylcarbamate) (Chiral Technologies USA). The Chiralpak AS-H column comprises amylose tris [(S) -alpha-methylbenzylcarbamate) coated with 5um silica. The Chiralpak IA column comprises amylose tris (3,5-1,5-dimethylphenylcarbamate) immobilized on 5um silica. The Luna-C18 reverse phase semi-preparative columns comprise silica particles coated at high density with C18 alkyl chains and have good acid stability with a wide pH range (pH 1.5 to pH 10). The SCX column (Stron g Cation eXchange) has benzene sulphonic acid attached or covalently to a silica support and as such strongly retains high organic molecules in pKa (ie basic) such as amines, which can subsequently be released with excess ammonia in a appropriate solvent. The retention times measured depend on the precise conditions of the chromatographic procedures. When cited later in the Examples they are indicative of the order of elution. Reactions involving metal hydrides including lithium hydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium hydride, sodium borohydride and sodium triacetoxyborohydride were carried out under argon.

Differential Scanning Calorimetry (DSC) Method A The DSC is performed in a differential scanning calorimeter of TA Instrument model Q100 Differential Scannin g Calorimeter. The sample is placed and weighed in a dish to the DSC. The saucer is sealed using the manual press provided by the seller. The temperature of the sample rises in ramp from 25 ° C to 300 ° C at 15 ° C / minute.

Method B The DSC is performed on a differential scanning calorimeter of TA instruments Q1000 Differential Scannin g Calorimeter. The sample is weighed and placed in the DSC dish (the sample weights are recorded in the DSC chart). The saucer is sealed by applying manual pressure and pressing and joining each part of the saucer together (loose lid configuration). The temperature of the sample rises from 25 ° C to 350 ° C at 10 ° C / minute.

X-ray powder diffraction (XRPD) Method A PXRD general area detector diffraction system The sample is scanned using the following parameters: Scan interval: 2-40 degrees two teta Generator power: 40 kV, 40 mA Radiation source: Cu Ka Sweep type: Trailed sweep Number of frames: 3 frames Time per frame: 5 min Oscillation of the sample: oscillation of 0.1 -0.5mm depending on the size of the sample Detector distance: 25cm Filter / monochrometer: A single Goebel mirror Detector type: Detector diffraction of general area Method B Difframeter for PXRD PANalvtical X'Pert Pro MPD with Alpha-1 monochrometer The sample is scanned using the following parameters: Scan interval: 2-40 degrees two teta Generator power: 40kV, 45mA Radiation source: Cu Ka Scanning type: Continuous Time per stage: 30 seconds Stage size: 0.017 degrees two tit per stage Sample rotation: revolution time 1 s Incident beam optics: 0.04 radian soller slots, automatic divergence slot, diffracted beam optics: slots automatic (X'celerator module with Alpha-1 monochrometer), 0.04 radian soller slots Detector type: Philips X'Celerator Method C Diffraphrometer for PXRD PANalvtical X'Pert Pro MPD with Alpha monochrometer - The sample is scanned using the following parameters: Scanning interval: 2-40 degrees two teta Generator power: 40 kV, 40 mA Radiation source: Cu Ka Scanning type : Continuous Time per stage: 10 seconds Stage size: 0.017 degrees two tit per stage Sample rotation: revolution time 1 s Incident beam optics: 0.04 radians soller slots, divergence slot at 0.25 degrees, beam mask 10mm, anti-scatter slot at 0.5 degrees Diffraction beam optics: fixed slots (X'celerator module), 0.04 radian soller slots Detector type: Philips X'Celerator RTMS (Multiple real-time slots) As expert chemists can understand, references to preparations carried out in a manner similar to other preparations, or by the general method of other preparations, may encompass variations in routine parameters such as me, temperature, working conditions, minor changes in the quantities of reagents, etc.

EXAMPLE 1 Dihydrochloride of the E2 Enantiomer of 1- (. {4 - [(2,3-dihydrori, 41dioxino [2,3-c1pyridin-7-ylmethyl) amino] -1-piperidinyl} pyrrolo [3.2 , 1-ij1quinolin-4-one (a) (2E) -N- (3-Fluoro-2-methylphenyl) -3-phenyl-2-propenamide A solution of cinnamyl chloride (100 g, 610 mmol) in ethyl acetate (400 ml) was added to a vigorously stirred mixture of 3-fluoro-2-methylaniline (75 g, 600 mmol), saturated aqueous sodium bicarbonate (850 ml), ice (ca 100 g) and ethyl acetate (400 ml) over 2 hours. minutes After 0.25 hours the mixture was filtered, washing it with water, more solids came out of the filtrate and it was filtered again. The resulting solid was dried in vacuo (-160 g, 100%). MS (+ ve ion electrospray) m / z 256 (MH +). (b) 7-Fluoro-8-methyl-2 (1 H) -quinolinone A suspension of (2E) -N- (3-fluoro-2-methylphenyl) -3-phenyl-2-propenamide (75 g, 305 mmol ) in chlorobenzene (400 ml) was treated slowly with aluminum trichloride (163 g, 1.2 moles), with the temperature <; 30 ° C. The reaction was stirred vigorously and heated to 65 ° C (internal temperature) for 1 hour then at 75 ° C (internal temperature) for 0.5 hour. The sample was allowed to cool (ca. 40 ° C), then excess ice was added with vigorous stirring. The resulting precipitate was isolated by filtration and washed with water. Drying in vacuo gave the product (42.5 g, 79%). MS (+ ve ion electrospray) m / z 178 (MH +). (c) crude 7-Fluoro-8-methyl-2- (methyloxy) quinoline 7-fluoro-8-methyl-2 (1 H) -quinolinone (46 g, 260 mmol) was suspended in DMSO (300 mL), it was heated to 35 ° C, then treated with potassium t-butoxide (32 g, 286 mmole), under argon (the internal temperature was raised to 45 ° C). After 15 minutes methyl iodide (21 ml, 48 g, 338 mmol) was added over 2 minutes. (The internal temperature rose to 60 ° C). After 30 minutes the mixture was added to water (2 liters) and extracted with hexane (1.5 liters). The hexane extract was further washed with brine, dried over sodium sulfate, and filtered through a plug of silica, eluting with 1: 1 hexane: dichloromethane (500 ml). Evaporation provided the product (36.8 g, 74%). MS (+ ve ion electrospray) m / z 192 (MH +). (d) 8- (Bromomethyl) -7-fluoro-2- (methyloxy) quinoline A solution of 7-fluoro-8-methyl-2- (methyloxy) quinoline (36.7 g, 192 mmol) in trifluoromethylbenzene (500 ml) ) was treated with N-bromosuccinimide (37.6 g, 21 1 mmol) and benzoyl peroxide (243 mg, 1 mmol) and heated to 70 ° C (oil bath temperature) while it was irradiated with a 120 tungsten lamp. Watts for 1 hour. The cooled mixture was filtered, washed with dichloromethane, and the combined organic fractions were washed with saturated aqueous sodium bicarbonate solution and then dried. The solution was filtered through a plug of silica and evaporated to give a pale yellow solid (51.4 g, 99%). MS (+ ve ion electrospray) m / z 271 (MH +). (e) 7-Fluoro-2- (methyloxy) -8-quinolinellacetonitrile A solution of 8- (bromomethyl) -7-fluoro-2- (methyloxy) quinoline (22.6 g, 84 mmol) in DMF (600 ml) was treated with potassium cyanide (25 g, 385 mmol) and heated at 70 ° C (oil bath temperature) overnight. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried and filtered through a plug of silica and evaporated to give a pale brown solid (1.7 g, 97%). MS (+ ve ion electrospray) m / z 217 (MH +). (f) Methyl 7-fluoro-2- (methyloxy) -8-quinolinyl-1-acetate (i) A solution of [7-fluoro-2- (methyloxy) -8-quinolinyl] acetonitrile (50 g, 0.231 mol) in dry methanol (850 ml) was treated with trimethylsilyl chloride (100 ml, 0.78 moles) and heated at 79 ° C for 2.25 hours. The mixture was evaporated and then partitioned between ethyl acetate (1 L) and water (700 mL). The mixture was filtered to remove methyl (7-fluoro-2-oxo-1,2-dihydro-8-quinolinyl) acetate and the aqueous layer was extracted again with ethyl acetate (2 x 300 mL). The combined organic fraction was washed with 2N sodium hydroxide, water (x 2), dried (sodium sulfate), and evaporated. The reaction was repeated on the same scale, as indicated above. The combined reaction products were chromatographed on silica gel (1.5 kg), eluting with dichloromethane, to provide (83.3 g, 72%).

MS (+ ve ion electrospray) m / z 250 (MH +) (ii) The recovered methyl (7-fluoro-2-oxo-1,2-dihydro-8-quinolinyl) acetate (1 1 g, 46.8 mmol) was suspended in methanol (20 mL), acetonitrile (200 mL) and triethylamine (8 mL, 57 mmol), with stirring together with 2M (trimethylsilyl) diazomethane in hexanes (30 mL, 60 mmol) and the mixture was stirred at room temperature during 3 hours. It was evaporated to dryness and chromatographed on silica gel, eluting with DCM, to give an additional amount of methyl [7-fluoro-2- (methyloxy) -8-quinolinyl] acetate (10.8 g). [Total yield 81%]. (g) 2- [Methyl 7-fluoro-2- (methyloxy) -8-quinolinyl-2-propenoate A mixture of methyl [7-fluoro-2- (methyloxy) -8-quinolinyl] acetate (48 g; 0.193 mol), paraformaldehyde (41 g, 1.37 mol), potassium carbonate (41 g, 0.295 mol) and benzyltriethylammonium chloride (70 g, 0.307 mol) in cyclohexane (1.2 g) was heated at 86 ° C. , with vigorous stirring for 5 hours. The mixture was cooled, water was added and the mixture was extracted with ethyl acetate (x3). The mixture was filtered and extracted again with ethyl acetate (x 3). The combined organic fraction was washed with water (x2), brine, and dried. The reaction was repeated on the same scale, as above, and the products were combined and evaporated to give a solid (97.9 g.; raw yield 97%), sufficiently pure (ca. 90% by NMR) for the next stage. The other 10% of material is mainly initial material. MS (+ ve ion electrospray) m / z 262 (MH +). (h) 3-G4 - ((G (1,1-dimethylethyl) oxycarbonyl} amino) -1-piperidinyl-1-2- [7-fluoro-2- (methyloxy) -8-quinolinyl-1-propanoate methyl A solution of 2 - [7-Fluoro-2- (methyloxy) -8-quinolinyl] -2-methyl propenoate (90% pure, 106 g, equivalent to 0.367 moles), 1,1-dimethylethyl 4-piperidinylcarbamate (80.75 g, 0.404) moles) and 1, 1, 3,3, tetramethylguanidine (13 ml) in dry DMF (1.2 g) was heated at 80 ° C for 2 hours, and then at 50 ° C overnight.The mixture was evaporated until dryness, treated azeotropically with toluene, and chromatographed on silica gel, eluting with hexane and then ethyl acetate-hexane (1: 1), affording the product (1 55.4 g, 92%). MS (ion electrospray + ve) m / z 462 (MH +).

(D (1 - (2-f7-fluoro-2- (methyloxy) -8-quinolinyl-1-3-hydroxypropyl-4-piperidine-1,4-dimethyl-ethylcarbamate A solution of 3- [4- ( { [(1 , 1 -dimethylethyl) oxy] carbonyl} amino) -1-piperidinyl] -2- [7-fluoro-2- (methyloxy) -8-quinolinyl] propanoate methyl (76 g, 0.165 mol) in dry tetrahydrofuran ( 900 ml) at -70 ° C was treated with a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 196 ml, 0.196 mol) and stirred at this temperature for 1 hour, then at 0 ° C-10 ° C. for 1 hour, water (18 ml) followed by aqueous sodium hydroxide solution (2M, 33 ml, 0.196 mol), and water (38 ml) was added.The mixture was stirred for 0.5 hours then ether and sulfate were added Sodium and the mixture was stirred for 0.5 hour, filtered and evaporated, and the residue was recrystallized from ethyl acetate / hexane to give a white solid in two crops (57.7 g, 81%). ions + ve) m / z 434 (MH +). (j) { 1-f (9-fluoro-4-oxo-1,2-dihydro-4H-pyrrolof3,2,1-ylquinolin-1-yl) methyl-1-4-piperidinyl} 1, 1 -dimethylethyl carbamate A solution of (1 -. {2- [7-fluoro-2- (methyloxy) -8-quinolinyl] -3-hydroxypropyl] -4-pipehdinyl) carbamate of 1 , 1-dimethylethyl (67.35 g, 0.156 moles) in chloroform (1 L) was treated with diisopropylethylamine (60 ml, 0.34 moles) and methanesulfonic anhydride (32.6 g, 0.187 moles). The mixture was stirred at room temperature for 0.5 hours, then heated at 65 ° C for 3 hours, and then allowed to cool to room temperature. The mixture was washed with sodium bicarbonate solution (2 x 1 L), brine (1 L), dried and evaporated to give a solid (54.75 g, 88%). MS (+ ve ion electrospray) m / z 402 (MH +). (k) E1 and E2 enantiomers of 1 - [(4-amino-1-piperidinyl) methyl-1-9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-1-quinolin-4-one] Method A It was dissolved. { 1 - [(9-fluoro-4-oxo-1,2-dihydro-4H-pyrrolo [3,2, 1-y] quinolin-1-yl) methyl] -4-piperidinyl} carbamate, 1-dimethylethyl (54.75 g, 0.14 mmol) in dichloromethane (300 ml) and trifluoroacetic acid (100 ml), stirred at room temperature for 3 hours, evaporated to dryness and treated azeotropically with toluene. The residue was triturated with ether to give a pink solid which was filtered, washed with more ether and dried at 35 ° C under vacuum overnight to give a solid (62.35 g, 10% - contains excess TFA). MS (+ ve ion electrospray) m / z 302 (MH +). The racemic material (such as trifluoroacetate salt, 14 g) was separated by preparative chiral hplc in the two enantiomers, E1 and E2, using a 20 um Chiralpak AD column, eluting with 80: 20: 0.1 - CH3CN: CH3OH: lsoprop Roll with Rt for E1 7.2 minutes and Rt for E2 8.3 minutes. The recovery was E1 29.3 g (97.4% ee) and E2 30.2 g (94.4% ee).

Method B { 1 - [(9-Fluoro-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-1-yl) methyl] -4-piperidinyl} 1, 1-dimethylethyl carbamate (92 g, 229 mmol) was treated with concentrated hydrochloric acid (370 ml) and water (300 ml) with external cooling in an ice bath. The mixture was stirred overnight, warming it to room temperature. Then the mixture was concentrated in vacuo to 50 ° C for 3 hours. The resulting anomalous gel was triturated with ethanol (1 liter) and stirred vigorously to give a fine white solid. This was isolated by filtration, washing it with ether (3 x 500 ml). Drying in vacuo at 45 ° C gave a white solid (70.56 g, 82%). 1 - [(4-Amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (racemic, dihydrochloride salt) ( 30 g) was subjected to preparative hplc chromatography on a 20um Chiralpak AD column eluting with 80: 20: 0.1 acetonitrile: methanol: isopropylamine to give the E1 enantiomer (Rt 3.6 minutes) as an almost white solid (9.42 g). Triethylamine can be replaced by isopropylamine in the preparative stage of hplc.

(I) Title compound A mixture of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one (E2 enantiomer, 67 mg, 0.22 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-carboxaldehyde (for the synthesis see International publication WO2004058 44, Example 2 (c)) (37 mg) in dichloromethane / methanol (3 ml / 0.2 ml) was treated with sodium triacetoxyborohydride (141 mg, 0.66 mmol). After stirring overnight the mixture was partitioned between 5% methanol in dichloromethane and aqueous sodium bicarbonate solution. The aqueous phase was extracted several times with 5% methanol in dichloromethane then the combined organic extracts were dried (magnesium sulfate) and evaporated under vacuum. The residue was chromatographed on silica gel, eluting with 0% -20% methanol in DCM, then a gradient of 20% -50% methanol in ethyl acetate gave the free base of the title compound as a yellow oil (71). mg, 71%). 5H (CDCl 3, 250 MHz) 1 .40-1 .55 (2H, m), 1 .80-1 .95 (2H, m), 2.08 (1 H, dt), 2.22 (1 H, dt), 2.45-2.55 (2H, m), 2.75-2.90 (2H, m), 2.95-3.05 (1 H, bd), 3.78 (2H, s), 3.95-4.05 (1 H, m), 4.28-4.35 (4H, m), 4.40-4.50 (2H, m), 6.60 (1 H, d), 6.80-6.90 (2H, m), 7.40 (1 H, dd), 7.65 (1 H, d), 8.10 (1 H, s). MS (+ ve ion electrospray) m / z 451 (MH +). This material was converted to the title compound by adding an excess of hydrogen chloride in ether (86 mg).

EXAMPLE 2 Dihydrochloride of the E1 Enantiomer of 1- (. {4-r (2,3-dihydrori, 41-dioxinor-2,3-clpyridin-7-ylmethyl) aminol-1-piperidinyl}. M pyrrolofS ^ .I-ijlquinolin ^ - ona The free base of the E1 enantiomer (63 mg) was prepared from 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1- ij] quinolin-4-one (E1 enantiomer) (64 mg) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carboxaldehyde (35 mg) by the general method of Example 1 (1) (chromatographed on silica gel, eluting with 0-20% methanol in dichloromethane), and showed the same spectroscopic properties of NMR and MS. The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness and trituration with ether to give a solid (61 mg).

EXAMPLE 3 Dihydrochloride of Diastereomer 1 of 1- ( { (3 / ?, 4S) -4 - [(2,3-dihydrofl-l-dioxin ^^ -pyriridin-y-ilmethi -aminol-S-hydroxy-1-piperidinyl. methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 Tquinolin-4-one dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one This was prepared from 2- [7-fluoro-2- (methyloxy) -8-quinolinyl] -2-propenoate and 1.1 -dimethylethyl [(3f?, 4S) -3-hydroxy-4-piperidinyl] methyl carbamate (for a synthesis, see international publication WO2004058144, Example 34 (a) (cis-1-enantiomer)) according to the general method of Examples 1 (h), 1 (i), 1 (j) and 1 (k) afford the product as a white, racemic solid in the benzylic center. MS (+ ve ion electrospray) m / z 318 (MH +). The material (racemic in the benzylic center) was separated by preparative chiral hplc in the two diastereomers D1 and D2 in a manner similar to Example 1 (k). The stationary phase was Chiralpak AD-H of 5um, eluting with 50: 50: 0.1 - C ^ CN h ^ OH sopropylamine, Rt for D1 3.0 minutes and Rt for D2 27 minutes. Recovery was D1 222 mg (> 99% de) and D2 123 mg (> 99% de) of 400 mg of diastereomeric amine. (b) Title compound A solution of 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (222 mg, 0.7 mmol, diastereomer D1) and 2,3-dihydro [1,4] dioxin [2,3-c] pyridine-7-carboxaldehyde (for a synthesis see international publication WO2004058144, Example 2 (c)) (15 mg, 0.7 mmol) in N, N-dimethylformamide (3 ml) was treated with sodium triacetoxyborohydride (445 mg, 2.1 mmol). After 1 day the mixture was evaporated and the residue was worked up and chromatographed in a manner similar to Example 1 (1) to give the free base of the title compound as a colorless oil (202 mg, 62%). 5H (CDCl 3, 250 MHz) 1 .70-1.80 (2H, m), 2.20-2.30 (2H, m), 2.50-2.65 (2H, m), 2.70-2.95 (3H, m), 3.00-3.10 (1 H, m), 3.85 (2 H, s), 3.95-4.05 (1 H, m), 4.25-4.35 (4H, m), 4.40-4.55 (2H, m), 6.62 (1 H, d), 6.85 (1 H, t), 6.85 (1 H, s), 7.58 (1 H, dd), 7.65 (1 H, m), 8.10 (1 H, s). This material was converted to the title compound (220 mg) by dissolving it in dichloromethane and then adding an excess of hydrogen chloride in ether in a manner similar to Example 1. MS (+ ve ion electrospray) m / z 467 (MH +)..

EXAMPLE 4 Dihydrochloride of diastereomer 2 of 1 - (((3 /? 4S) -4-r (2,3-dihydro-l-dioxino ^ S-clpyridin-y-ilmetillam piperidini ^ metiQ-O-fluoro-l-dihydro ^ H - ^^ The free base of the title compound (93 mg) was prepared from 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (diastereomer D2) (122 mg) and 2,3-dihydro [1,4] dioxin [2] , 3-c] pyridine-7-carboxaldehyde (for a synthesis see international publication WO2004058144, Example 2 (c)) (64 mg) by the general method of Example 3 (chromatographed on silica gel, eluting with 0% methanol). -30% in dichloromethane), providing material with the same NMR and MS spectroscopic data as Example 3. The free base in methanol, was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness, to give a solid (87 mg).

EXAMPLE 5 9-Fluoro-1 - (((3ft, 4S) -3-hydroxy-4-r (H .31-oxatoolor-5,4-c1-pyridin-6-ylmethyl) amino-1-piperidinyl} -methyl-quinolinoline dihydrochloride -4-one The free base of the title compound (41 mg) was prepared from 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-ji] quinolin-4-one diastereomeric and [1, 3] oxathiolo [5,4-c] pyridine-6-carbaldehyde (for a synthesis see international publication WO2004058144, Example 61) with a 55% yield by the general method of Example 3 (b). d? (CDCl 3, 250 MHz) 1 .70-1 .80 (2H, m), 2.20-2.60 (4H, m), 2.70- 3.00 (3H, m), 3.00-3.10 (1H, m), 3.87 (2H , s), 3.95-4.05 (1 H, m), 4.40-4.55 (2H, m), 5.75 (2H, s), 6.62 (1 H, d), 6.85 (1 H, t), 7.25 (1 H , s), 7.58 (1 H, dd), 7.65 (1 H, m), 8.00 (1 H, s). MS (+ ve ion electrospray) m / z 469 (MH +). The free base was converted to the title dihydrochloride salt in a manner similar to Example 1.

EXAMPLE 6 9-Fluoro-1-r ((3ff, 4S) -3-hydroxy-4-f-G (6-γ-6-J-dihydro-pyridazinor-3, 4-6, 41-thiazin-3-yl) methyl-1-dihydrochloride dihydro-4H-pyrrolor3,2,1 - // 1-quinolin-4-one The free base of the title compound (12 mg) was prepared from 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-ji] quinolin-4-one diastereomeric (122 mg) and 6-oxo-6,7-dihydro-5H-pyridazino [3, 4-b] [1,4] thiazine-3-carboxaldehyde (for a synthesis see international publication WO2004058144, Example 58 (d)) (75 mg) with a yield of 6% by the general method of Example 3 (b) . d? (CDCI3, 250 MHz) 1 .70- .80 (2H, m), 2.20-2.60 (4H, m), 2.70- 3.00 (3H, m), 3.00-3.10 (1H, m), 3.78 (2H, s), 3.90-4.00 (1 H, m), 4.05 (2H, s), 4.40-4.55 (2H, m), 6.62 (1 H, d), 6.95 (1 H, t), 7.16 (1 H, s), 7.58 (1 H, dd), 7.90 (1 H, d). MS (+ ve ion electrospray) m / z 497 (MH +). The free base was converted to the title dihydrochloride salt (9 mg) in a manner similar to Example 1 EXAMPLE 7 Dihydrochloride of 1 - (. {(3ff, 4S) -4-r (2,3-dihydro-1 H pyridoi3,4-biri, 41-oxazin-7-ylmethyl) aminol-3-hydroxy-1-piperidinyl.} methyl) -9-fluoro-1,2-dihydro-4H- (a) Acetate of. { 5- ( { R4- (methyloxy) phenylmethoxy} oxy) -4-phenyl (phenylmethyl) oxy] -2-pyridinyl} A solution of thphenylphosphine (39.3 g, 150 mmol) in tetrahydrofuran (600 ml) was treated at 0 ° C with (E) -1,2-diazenedicarboxylic acid bis (1-methylethyl) (30 ml, 152 mmol) . After 10 minutes, [5- ( { [4- (methoxy) phenyl] methyl.} Oxy] -4-oxo-1,4-dihydro-2-pyridinyl] methyl acetate (33.5 g, 1) was added. 10 mmol) (for a synthesis see international publication WO2004058144, Example 60 (c)). After 10 minutes benzyl alcohol (13 g, 120 mmol) was added and the mixture was stirred overnight. Evaporation and chromatography on silica eluting with 20-40% ethyl acetate in hexane provided an oil (26.3 g, 67%) (containing some triphenylphosphine oxide as an impurity). MS (+ ve ion electrospray) m / z 394 (MH +). (b) Acetate of. { 5-hydroxy-4 - [(phenylmethyl) oxy] -2-pyridinyl} methyl. Trifluoroacetate salt A solution of acetate of. { 5- ( { [4- (methyloxy) phenyl] methyl.}. Ox y) -4 - [(phenylmethyl) oxy] -2-pyridinyl} methyl (containing thphenylphosphine oxide as an impurity) (20 g, 50.8 mmol) in dichloromethane (500 ml) was treated with triethylsilane (10 ml, 62.6 mmol). A solution of trifluoroacetic acid (35 ml, 0.45 mol) in dichloromethane (200 ml) was added over 1 hour. After 2 hours the mixture was evaporated and chromatographed on silica gel eluting with 50-100% ethyl acetate -hexane, then with 5-10% methanol -DCM to give a solid, the TFA salt in a mixture 1 : 1 with triphenylphosphine oxide (8.33 g). MS (+ ve ion electrospray) m / z 274 (MH). (c) Acetate of (5- { [2- ( { [(1,1-dimethylethyl) oxylcarbonyl) amino) ethylloxy | -4-. { [(trifluoromethyl) sulfonanoxy} -2-pyridinyl) methyl A solution of thphenylphosphine (24.1 g, 92 mmol) in tetrahydrofuran (600 ml) was treated at 0 ° C with (E) -1,2-diacenedicarboxylate of bis (l -methylethyl) (18.1 ml, 92 mmoles). After 30 minutes a solution of 5-hydroxy-4 - [(phenylmethyl) oxy] -2-pyridinyl acetate trifluoroacetate salt solution was added} methyl as a 1: 1 mixture with thphenylphosphine oxide (23.8 g, 61.3 mmole) and triethylamine (8.6 ml, 61.3 mmole) in tetrahydrofuran (200 ml). After 30 minutes the reaction was warmed to room temperature and allowed to stir for an additional 30 minutes. (1,1-Dimethylethyl) (2- hydroxyethyl) carbamate (9.5 ml, 61.3 mmol) was added and the mixture was stirred overnight. Evaporation and chromatography on silica eluting with 0-100% ethyl acetate in gasoline gave an oil (40.2 g). The oil (40.2 g) was dissolved in EtOH (300 ml) and hydrogenated over 10% palladium in charcoal (20 g) for 16 hours. The mixture was filtered and evaporated to give a yellow oil (44.4 g). A solution of the yellow oil (44.4 g) in dichloromethane (500 ml) was treated with triethylamine (9.41 ml) then with 1, 1-trifluoro-N-phenyl-N - [(trifluoromethyl) sulfonyl] methanesulfonamide (21.9 g ). After 16 hours the mixture was washed with water, dried and evaporated. Chromatography on silica gel, eluting with 0-100% ethyl acetate in petrol gave a colorless oil (19.7 g, 70%). MS (+ ve ion electrospray) m / z 459 (MH +). (d) 7-α (Acetyloxy) methyl-2,3-dihydro-1 H-pyridomer 3,4-b1M, 1,1-dimethylethyl-4-oxazin-1-carboxylate A mixture of (5-) -acetate. [2- ( { [(, 1-dimethyl-ethyl) oxy] carbonyl}. Amino) ethyl] ox ^ pyridinyl) methyl (1.58 g, 3.4 mmol), (+) - 2,2'- bis (diphenylphosphino) -1,1 '-bibphthalene (BINAP) (10 mg, 0.2 mmol), palladium (II) acetate (25 mg, 0.1 mmol) and cesium carbonate (1.57 g, 4.8 mmol) in toluene (20 mL) was heated to 100 ° C under argon for 16 hours then filtered and evaporated. (See S. I. Buchwald, Or g Letts, 1999, 1, 35-37, for the procedure). The residue was chromatographed on silica gel, eluting with 0-100% ethyl acetate in gasoline, to give a white solid (0.84 g, 79%) MS (+ ve ion electrospray) m / z 309 (MH +). (e) 7- (Hydroxymethyl) -2,3-dihydro-1 H-pyrido3,4-b1M, 41-oxazin-1-carboxylate 1,1-dimethylethyl A solution of 7 - [(acetyloxy) methyl] -2,3 -dihydro-1 H -pyrido [3,4-b] [1,4] oxazin-1-carboxylate 1,1-dimethylethyl ester (08.4 g, 2.7 mmol) in dioxane (20 ml) and water (5 ml) were added. treated with 2M sodium hydroxide solution (2.72 ml, 5.4 mmol). After 0.5 hours the mixture was concentrated to a volume of 5 ml and then divided into ethyl acetate and water. The organic extract was dried and evaporated to give a colorless oil (0.78 g, 105%). MS (+ ve ion electrospray) m / z 267 (MH +). (f) 7-Formyl-2,3-dihydro-1 H -pyrido [3,4-b1 [1,4] oxazin-1-carboxylate 1,1-dimethylethyl A solution of 7- (hydroxymethyl) -2,3- Dihydro-1 H -pyrido [3,4-b] [1,4] oxazin-1-carboxylate 1,1-dimethylethyl ester (0.78 g, 2.9 mmol) in dichloromethane (100 ml) was treated with manganese oxide (IV ) (2.02 g, 23.3 mmol) and stirred overnight. Filtration and evaporation gave a white solid (0.62 g, 81%). MS (+ ve ion electrospray) m / z 265 (MH +). (q) 7-r (((3R, 4S) -1 - [(9-Fluoro-4-oxo-1,2-dihydro-4H-pyrrolor3.2.1-lquinolin-1-yl) methyl-1 3-hydroxy-4-piperidinyl.}. Amino) methyl] -2l3-dihydro-1 H-pyridofS ^ -blfl ^ loxazin-l-1,1-dimethylethyl carboxylate A solution of 1 - {[[3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl.}. 9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-ji] quinolin-4-one diastereomeric (50) mg) was reacted with 7-formyl-2,3-dihydro-1 H -pyrido [3,4-b] [1,4] oxazin-1-carboxylate 1,1-dimethylethyl ester (40 mg) by the method Example 3 (b) providing, after chromatography, and eluting with 0-20% methanol in dichloromethane, a white solid (62 mg, 69%) MS (+ ve ion electrospray) m / z 566 ( MH +). (h) Title compound A solution of 7 - [( { (3R, 4S) -1 - [(9-fluoro-4-oxo-1,2-dihydro-4H-pyrrolo [3,2, 1 -ij] quinolin-1-yl) methyl] -3-hydroxy-4-piperidinyl.} Amino) methylene] -2,3-dihydro-1 H -pyrido [3,4-b] [ 1,4] oxazin-1-carboxylate 1,1-dimethylethyl ester (62 mg) in dichloromethane (1.5 ml) was treated with trifluoroacetic acid (1.5 ml). After 1 hour the mixture was evaporated and the residue was treated azeotropically with toluene. The residual trifluoroacetate salt was converted to the crude free base by stirring with an excess of MP-carbonate resin base until pH 7, filtering and evaporating to dryness. Chromatographed on silica gel eluting with 10-40% 2M ammonia / methanol in dichloromethane, followed by further purification in a reverse phase hplc system with mass directed collection (MDAP) (eluent acetonitrile / water / formic acid, monitoring for m / z 466), yielding a white solid (35 mg, 62%). d? (d-6 methanol, 250 MHz) 1.70-1.90 (2H, m), 2.20-2.60 (4H, m), 2.70-3.00 (2H, m), 3.10-3.25 (1H, m), 3.50 (2H, t), 4.00 (2H, s), 4.05 (2H, s), 4.20 (2H, t), 4.40-4.55 (2H, m), 6.60 (1H, d), 6.72 (1H, s), 7.00 (1 H, t), 7.60 (1 H, dd), 7.90 (1 H, d), 7.95 (1 H, d). MS (+ ve ion electrospray) m / z 466 (MH +). The free base was converted to the title dihydrochloride salt (22 mg) in a manner similar to Example 1.

EXAMPLE 8 1 - (((3 4S) -4-f (2,3-Dihydrofuror2,3-c1pyridin-5-ylmethyl) aminol-3-hydroxy-1-piperidinyl} methyl) -9-fluoro- dihydrochloride 1,2-dihydro- ^ pyrrolof3,2,1- / 1-quinolin-4-one (a) (5- ( { [4- (Methyloxy) phenylmethyl} oxy] -4 - [(trimethylsilyl) ethynyl] -2-pyridinyl) methyl acetate (5- ( { [4- (methoxy) phenyl] methyl.} Oxy) -4-. {[[(Thfluoromethyl) sulfonyl] oxy} -2-pyridinyl) methyl (for a synthesis, see WO2004058144 Example 60 (d)) ( 10 g, 23 mmol) in acetonitrile (400 ml) and triethylamine (65 ml) and copper iodide (I) (0.44 g, 2.3 mmol) were added. The mixture was degassed and placed under an argon atmosphere. Trimethylsilylacetylene (10 ml, 69 mmol) and bis (triphenylphosphine) palladium dichloride (11) (0.645 g, 0.9 mmol) were added and the mixture was heated to 45 ° C for 18 hrs. Then the mixture was allowed to cool and filtered. The filtrate was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic layer was separated and dried (sodium sulfate). Chromatography on silica gel, eluting with a gradient of 20-75% ethyl acetate in 40-60 petroleum ether, provided an oil (8.45 g, 96%). MS (+ ve ion electrospray) m / z 384 (MH +). (b) Acetate acetate trifluoroacetate. { 5-hydroxy-4 - [(trimethylsilyl) ethynyl-2-pyridinyl} Methyl acetate acetate was treated. { 5- ( { [4- (Methyloxy) phenyl] methyl.}. Oxy) -4 - [(trimethylsilyl) ethynyl] -2-pyridinyl} methyl (8.45 g, 22 mmol) in dichloromethane (70 ml) with trifluoroacetic acid (9.4 ml) and triethylsilane (3.33 ml) and stirred at room temperature for 18 hours. The mixture was evaporated to dryness and chromatographed on silica gel, eluting with a gradient of 2-8% methanol in dichloromethane. This provided an oil (10 g, 100%). MS (+ ve ion electrospray) m / z 264 (MH +). (c) Furoacetate [2,3-clpindin-5-ylmethyl acetate was dissolved. { 5-hydroxy-4 - [(trimethylsilyl) ethynyl] -2-pyridinylmethyl, trifluoroacetate) (10 g, 22 mmol) in pyridine (200 ml) and treated with copper iodide (1) (5.2 g, 27 mmol), then it was heated under reflux for 18 hours. The mixture was allowed to cool, evaporated to dryness and the residue was partitioned between ethyl acetate and water. This mixture was filtered through kieselguhr to remove copper residues. The organic layer was separated from the filtrate, dried and chromatographed on silica gel, eluting with a gradient of 10% -60% ethyl acetate in 40-60 petroleum ether. This yielded furo [2,3-c] pyridin-5-ylmethyl acetate (1.15 g, 27%) and a less polar product [2- (trimethylsilyl) furo [2,3-c] pyridine acetate. 5-yl] methyl (1.3 g, 23%) as oils. MS (+ ve ion electrospray) m / z 192 (MH +) and MS (+ ve ion electrospray) m / z 264 (MH +). (d) Furo [2,3-c] pyridin-5-ylmethanol A solution of furo [2,3-c] pyridin-5-ylmethyl acetate (1 .15 g) in 1,4-dioxane (30 ml) and water (10 mL) was treated with 2M sodium hydroxide (12 mL) then stirred at room temperature for 18 hours. Then the mixture was partitioned between ethyl acetate and water. The organics were separated and dried, then evaporated to dryness. This provided an oil (0.63 g, 70%). MS (+ ve ion electrospray) m / z 150 (MH +). (e) 2,3-Dihydrofuro [2,3-c1pyridin-5-ylmethanol Furo [2,3-c] pyridin-5-ylmethanol (1.29 g, 8.7 mmol) was dissolved in ethanol (50 ml) and hydrogenated at STP (standard temperature and pressure) over 10% palladium in charcoal pulp for 18 hours. The mixture was filtered through kieselguhr and the filtrate was evaporated to dryness, to provide (1.31 g, 100%). MS (+ ve ion electrospray) m / z 152 (MH +). (f) 2,3-Dihydric acid 2,3-c] pyridine-5-carbaldehyde 2,3-dihydrofuro [2,3-c] pyridin-5-ylmethanol (1.31 g, 8.7 mmol) was dissolved in dichloromethane (100 ml), treated with manganese dioxide (IV) (6 g, 69 mmol) and heated under reflux for 18 hours. Filtration through kieselguhr and evaporation of the filtrate to dryness gave an oil (0.9 g, 70%). MS (+ ve ion electrospray) m / z 150 (MH +). (g) Title compound The free base of the title compound (65 mg) was prepared from 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2, 1 -ij] quinolin-4-one diastereomeric (50 mg) and 2,3-dihydrofuro [2,3-c] pyridin-5- carbaldehyde (23 mg) with a yield of 91% by the general method of Example 3 (b). 5H (d-6 methanol, 250 MHz) 1.70-1.90 (2H, m), 2.20-2.60 (4H, m), 2.70-3.00 (2H, m), 3.10-3.25 (1H, m) , 3.50 (2H, t), 4.10-4.20 (2H, m), 4.30 (2H, s), 4.50 (2H, t), 4.60 (2H, t), 6.60 (1H, d), 7.00 (1H , t), 7.40 (1 H, s), 7.60 (1 H, dd), 7.95 (1 H, d), 8.10 (1 H, s). MS (+ ve ion electrospray) m / z 451 (MH +). The free base was converted to the title dihydrochloride salt (46 mg) in a manner similar to Example 1 EXAMPLE 9 9-Fluoro-1-r ((3?, 4S) -3-hydroxy-4-fr (7-oxo-1, 5,6,7-tetrahydro-1,8-naphthyridin-2-yl) methyl] amino dihydrochloride .}. -1.-Piperidinyl) methyl-1-2.2-dihi 4H-pyrrolo [3,2,1-] quinolin-4-one The free base of the title compound (12 mg) was prepared from 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-ji] quinolin-4-one diastereomeric (50 mg) and 7-oxo-1,5,6,7-tetrahydro-1, 8-naphthyridine-2-carboxaldehyde (for a synthesis, see WO2003087098, Example 307 (f) (synonym 7-oxo-5,6,7,8-tetrahydro- [1,8] naphthyridine-2-carboxaldehyde)) (27) mg), with a yield of 16% by the general method of Example 3 (b). d? (CDCI3, 250 ???) 1 .70-1.90 (2? M), 2.00-2.30 (4? M), 2.40-2.75 (5H, m), 2.80-3.10 (3H, m), 3.95-4.10 (3H, m), 4.45 (2H.m), 6.65 (1H, d), 6.90 (1H, t), 7.00 (1H, dd), 7.35-7.45 (2H, m), 7.68 (1 H, d), 8.30 (H, bs). MS (+ ve ion electrospray) m / z 478 (MH +). The free base was converted to the title dihydrochloride salt (8 mg) in a similar manner to Example 1 EXAMPLE 10A Dihydrochloride of the E1 Enantiomer of 1 - ((4-r (6,7-dihydroyl, 41-dioxinor-2,3-c] pyridazin-3-ylmethyl) aminol-1-piperidinyl} methyl) -9-fluoro-1, 2-dihi pirrolof3,2,1- / y1quinolin-4-one (a) 3,4,6-Trichloropyridazine This was prepared by a slight variation of the Kasnar ef a /, Nucleosides & Nucleotides (1994), 13 (1 -3), 459-79. Hydrazine sulfate salt (51 g) was suspended in water (250 ml), heated to reflux and bromomaleic anhydride (90.38 g) was added dropwise. The mixture was heated to reflux for 4 hours then cooled to room temperature. The reaction was repeated with 29 g of hydrazine sulfate, 53 g of bromomaleic anhydride and 130 ml of water. The precipitates were collected by filtration, washed with water and acetone and dried as a combined batch in vacuo to provide 4-bromo-1., 2-dihydro-3,6-pyridazinedione as a white solid (13 g). The solid in two courses was treated with phosphorus oxychloride (2 x 200 ml) and heated to reflux for 3.5 hours. The mixture was cooled, evaporated and azeotropically treated with toluene. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and extracted with DCM twice more. The organic extracts were dried and evaporated. This residue was redissolved in dichloromethane, and chromatographed on silica gel (300 g) (DCM as eluent) to give a white solid (101.5 g, 87%). (The LC / MS analysis showed ca. 20-30% impurities, bromo-dichloropyridazine isomers). MS (+ ve ion electrospray) m / z 184/185/186 (MH +), trichloropyridazine MS (+ ve ion electrospray) m / z 228/229/231 (MH +), bromo-dichloropyridazine. (b) 2 - [(3,6-Dichloro-4-pyridazinyl) oxyethanol A solution of ethylene glycol (55 ml) in tetrahydrofuran (200 ml) was treated at about 0 ° C (cooling in an ice bath) with sodium hydride. (60% dispersion in oil, 5.9 g) over 40 minutes. After the addition was complete, 3,4,6-trichloropyridazine containing bromo-dichloropyridazine isomers was added as an impurity (27 g) and washed with more dry THF (50 ml) and the mixture was stirred at 0 ° C. ° C for 1 hour, then at room temperature overnight. The mixture was concentrated (to 1/3 volume) then diluted with aqueous sodium bicarbonate solution and extracted with chloroform (5x) and ethyl acetate (3x). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated and the solids were filtered and washed with CHCl3 (x3) and dried under vacuum overnight at 40 ° C to provide a white solid (255 g). , 83%), which contained some bromine derivative (10-15%). MS (+ ve ion electrospray) m / z 209/21 1 (MH +). MS (+ ve ion electrospray) m / z 255/7 (MH +), bromine derivative. (c) 3-Chloro-6,7-dihydro [1,4-dioxinof2,3-clpiridazine A solution of 2 - [(3,6-dichloro-4-pyridazinyl) oxy] ethanol containing some bromine derivative ( 15.46 g, 0.0703 mol) in dry dioxane (1.2 g) was treated with lithium hydride (2.3 g, 0.28 mol) in portions and stirred at room temperature for 1 hour under argon, then heated to 10 ° C. overnight. The reaction mixture was quenched with wet dioxane, then with ice water. The solution was evaporated to half the volume, brought to pH 8 with 5M hydrochloric acid and evaporated to dryness. Water was added and the 5x residue was extracted with chloroform, dried (sodium sulfate) and evaporated to give a white solid (12.4 g, ca.77%) (containing ca. 15% of a bromine species). MS (+ ve ion electrospray) m / z 1 73/5 (Cl MH +); 21 7/9 (Br MH +) (d) 3-Ethenyl-6,7-dihydroH, 41-dioxino [2,3-c1-pyridazine A solution of 3-chloro-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine containing ca. 1 5% of a bromine species (13.6 g, 0.079 moles) in dimethoxyethane (400 ml) was degassed under argon for 10 minutes then tetrakis (triphenylphosphine) palladium (0) (2 g), potassium carbonate (10.33 g) was added. ), 2,4,6-trivinylcyclotriboroxane pyridine complex (11.3 g) and water (55 ml). The mixture was heated at 95 ° C for 48 hours and cooled and evaporated to dryness. The mixture was treated with aqueous sodium bicarbonate solution and extracted (5x) with DCM. The extracts were dried (sodium sulfate), evaporated and the residue chromatographed on silica gel (500 g), eluting with 0-100% ethyl acetate-hexane, affording the product (6.43 g, 50%); [also some impure fractions (1.8 g)] MS (electrospray + ve ion) m / z 165 (MH +). (e) 6,7-Dihydro [1,4] dioxino [2,3-clpiridazin-3-carbaldehyde Method A A solution of 3-ethenyl-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine (1 1 .58 g) in dioxane / water (600 ml / 180 ml) was cooled in ice, treated with an aqueous solution of osmium tetroxide (4% w / v, 25 ml) and sodium periodate (43 g). This mixture was allowed to warm to rt and after 7 hours under stirring the mixture was evaporated to dryness and treated azeotropically with dioxane. Silica gel, dioxane and chloroform were added and the mixture was evaporated to dryness overnight, then added to a silica column (400 g) and chromatographed, eluting with chloroform then with 0-100% ethyl acetate in hexane, to provide a white solid (7.55 g, 64%). MS (+ ve ion electrospray) m / z 167 (MH +).

Method B (i) 6,7-Dihydro [1-Idioxino ^ .S-clpiridazin-S-carboxylic acid] Carbon monoxide was bubbled through a mixture of 3-chloro-6,7-dihydro [1,4] dioxino [ 2,3-c] pyridazine (100 mg, 0.58 mmol) and n-butanol (2.5 mL) for 10 minutes then palladium chloride (II) (5 mg, 0.03 mmole), 1,3-bis (diphenylphosphino) propane (24 mg, 0.06 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.1 ml, 0.64 mmole). The mixture was heated at 100 ° C for 5 hours under a stream of carbon monoxide, allowed to cool and then evaporated. Chromatography eluting with 75% ethyl acetate in hexane gave a slightly impure product (99 mg). This material was taken up in ethyl acetate and filtered to remove a small amount of insoluble yellow solid. Evaporation of the filtrate gave the product (90 mg, 65%). MS (+ ve ion electrospray) m / z 239 (MH +). (ii) 6,7-Dihydro [1,4-dioxoquin [2,3-chlorpyridazine-3-carbaldehyde] A solution of 6,7-dihydro [1,4] dioxino [2,3-c] pyridazine-3-carboxylate of butyl (570 mg, 2.39 mmol) in THF (10 mL) was cooled to about -50 ° C to -40 ° C (solid carbon dioxide / acetonitrile cooling bath) and treated with a solution of toluene hydride of di-isobutylaluminum (1M, 4.6 ml, 4.6 mmol). After 2 hours an aqueous solution of sodium hydroxide (2M, 12 drops) was added followed by DCM (10 mL). The mixture was stirred for 15 minutes at -40 ° C then allowed to warm to its temperature. Sodium sulfate was added and the mixture was stirred for 45 minutes. The mixture was filtered through Kieselguhr by washing three times with 1: 1 THF: DCM and the combined filtrates were evaporated. Chromatography on 10 g of silica eluting with 0% -20% methanol in DCM afforded the product (290 mg, 73%). MS (+ ve ion electrospray) m / z 167 (MH +). An alternative work procedure comprises quenching the reaction with methanol instead of with sodium hydroxide and DCM. The reaction mixture was evaporated to dryness then dissolved in DCM and water was added to form a gel-like precipitate. Concentrated HCl was added and the mixture was stirred and then the phases were separated and separated. Salt was added to the aqueous phase followed by DCM, water and methanol.

After stirring, the layers were separated, the aqueous was extracted with DCM and all the combined organics were dried over magnesium sulfate.

Method C (i) 6,7-Dihydro [1 ^ Idioxino ^. S-cIpiridazin-S-carbonitrile A solution of 3-chloro-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine (2 g , 1.1 mmol) in DMF (40 mL) was degassed under argon for 10 minutes then zinc cyanide (II) (0.82 g, 7 mmol), tris (dibenzylideneacetone) palladium (0) (266 mg) and 1,1 '-bis (diphenylphosphino) ferrocene (322 mg). The mixture was heated at 120 ° C overnight, then evaporated to dryness. The residue was partitioned in saturated aqueous sodium bicarbonate solution and DCM, extracting 3 times with DCM. The DCM phase was dried over sodium sulfate then filtered and evaporated. Chromatography on a 50 g silica column with 0-100% ethyl acetate in hexane afforded the product (1.5 g, 79%). MS (+ ve ion electrospray) m / z 164 (MH). (ii) 6,7-Dihydron, 41dioxino [2,3-c1pyridazin-3-carboxylic acid butyl 6,7-Dihydro [1,4] dioxino [2,3-c] pyridazin-3-carbonitrile (0.5 g, 3.1 mmoles) and cesium carbonate (1.5 g, 4.6 mmol) were suspended in n-butanol (5 mL). After 5 hours of stirring, hydrochloric acid (0.1 M, 15 ml) was added, then 2M hydrochloric acid was added until pH3-3.5 was achieved. After 1 hour (more hydrochloric acid was added until the pH did not rise further) the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted three times with DCM. The combined DCM extracts were dried over sodium sulfate, then evaporated to dryness. Chromatography on a silica column eluting with 0-100% ethyl acetate in hexane gave the product (0.55 g, 77%) MS (+ ve ion electrospray) m / z 239 (MH +). (iii) 6,7-dihydro [1,4-dioxoquin [2,3-c] pyridazin-3-carbaldehyde) 6,7-Dihydro [1,4] dioxino [2,3-c] pyridazine-3-carboxylate was reduced from butyl to the title compound in a manner similar to Method B (ii) above.

Method D 3-Chloro-6,7-dihydro [1,4] dioxino [2,3-c] pyridazine can be converted to morpholine amide by treatment with morpholine and CO, catalyzed with PdCl2 and ligand (such as diphenylphosphinoferrocene) in a suitable solvent such as butyronitrile. The amide is then reduced to carbaldehyde by reduction with di-isobutylaluminum hydride. (f) E1 enantiomer of 1-4-r (6.7-dihydronide .41dioxinor2.3-clpiridazin-3-ylmethyl) aminol-1-piperidinyl) methyl) -9-fluoro-1,2-dihydro-4 / - / -pirrolofS ^. I-Z / lquinolin ^ -one (Method A) A solution of 1 - [(4-amino-1-pipehdinyl) methyl] -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2, 1 -ij] quinolin-4-one (enantiomer E1) (16.5 g, 55 mmol) and 6,7-dihydro [1,4] dioxin [2,3-] c] pyridazin-3-carbaldehyde (10.0 g, 60.3 mmol) in dichloromethane / methanol (220 ml / 60 ml) was cooled in an ice bath and treated with sodium thmacetoxyborohydride (29 g, 135 mmol). The cooling bath was removed. After 3 hours, additional 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-carbaldehyde (1.5 g, 9.1 mmol) was added and stirred overnight. More aldehyde (1.5 g, 9.1 mmol) was added and after 1 hour more sodium thmacetoxyborohydride (2.5 g, 11.8 mmol) was added. After two more hours, the mixture was slowly added to a vigorously stirred sodium bicarbonate solution (250 ml). The phases were separated and the aqueous phase was further extracted with 1% methanol in dichloromethane (2 x 150 mL). The organic extracts were combined, evaporated, and chromatographed on silica gel, eluting with a gradient of 0-25% methanol in dichloromethane, affording the title compound (free base) as a yellow solid (18.1 g, 73% ). d? (d6-DMSO, 250 MHz) 1.20-1.35 (2H, m), 1.75-1.85 (2H, m), 1.92 (1H, t), 2.10 (1H, t ), 2.30-2.40 (1 H, m), 2.52 (1 H, m, partially obscured by the solvent peak), 2.65 (1 H, m), 2.75 (1 H, m), 2.98 (1 H, m ), 3.85 (2H, s), 4.05 (1 H, m), 4.20 (1 H, dd), 4.35 (1 H, dd), 4.40 (2H, (2H, m) 6.50 (1 H, d), 7.00 (1 H, t), 7.60 (1 H, dd), 7.91 (1 H, d) MS (+ ve ion electrospray) m / z 452 (MH +). (q) E1 and E2 enantiomer of 1-g4-r (6.7-dihydrOri. 41dioxinor2.3-clpiridazin-3-ylmethyl) amino1-1-piperidinyl} methyl) -9-fluoro-1, 2-dihydro-4 / - -pyrrolor3,2,1 - // 1-quinolin-4-one (Method B) A solution of 1 - [(4-amino-1-piperidinyl) methyl] ] -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (racemic free base with some TFA salt) (3.5 g, 1 1 .63 mmoles it is assumed to be all free base) and 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-carbaldehyde (1.93 g, 1 1.63 mmol) in DMF (50 ml) is cooled in an ice bath and treated with sodium triacetoxyborohydride (6.1 g, 29 mmol). The cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was treated with aqueous sodium bicarbonate (~20 mL) and water (200 mL), cooled to 0 ° C, and the solid was collected by filtration and dried in vacuo, to give the free base of the racemate as a solid (3.6 g, 69%). This was separated by preparative chiral hplc in two enantiomers, E1 and E2, using a Chiralpak AD column of 20 um, eluting with 80: 20: 0.1 - CH3CN: CH3OH: lsopropylamine with Rt for E1 10.2 min and Rt for E2 12.4 min. The recovery of E1 was 1 .3 g (98% ee), and of E2 it was 1 .3 g (96 % ee). (h) Title Compound The free base of the E1 Enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] - 1-piperidinyl.} Methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one (-100 mg) was converted to the dihydrochloride salt ( 132 mg) in a similar manner to Example 1.

EXAMPLE 10B Monohydrochloride of the E1-enantiomer of 1- (. {4- (6,7-dihydrori, 41-dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9- fluoro-112-dihydro-4H-pyrrolo [3,2,1- / 7] quinolin-4-one Method A The free base of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1 , 4] d -oxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.] Methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - //] quinolin-4-one (55.6 g, 0.123 mol) was suspended in abosolute ethanol (700 ml), and heated to reflux to provide complete dissolution, then cooled to 67 ° C, and hydrochloric acid was added aqueous 6.0 N (20.5 ml, 0.123 moles), in one portion. The solution was maintained for about 2 minutes, then the crystallization began. The suspension was stirred at room temperature for 0.5 hours, then cooled to 3 ° C and stirred for 2 hours. The solid was filtered, washed with cold ethanol (100 ml), and dried at 50 ° C, for 18 hours under high vacuum to provide 57.2 g. 1 M HCl in dioxane can be used instead of aqueous HCl.

Method B The free base of the E1 Enantiomer of 1 - (. {4 - [(6,7-dydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) was suspended. ) am 1, 2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-4-one (3.9 g, 8.64 mmol) for 30 minutes at 25 ° C in acetone (66 ml). To this suspension were added a few crystal germs of the title compound, followed by a solution of 1.0 M HCl in dioxane (8.64 ml, 1.0 equiv). Stirring was continued for 18 hours. The suspension was filtered and the filter cake was washed with cold acetone. The resulting white solid was dried at 0.5 mm, 50 ° C, 4 hours, to provide 4.07 g (96%) of the title compound. Monohydrochloride of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one: fusion start 249 ° C. (DSC Method A).

EXAMPLE 10C 4-Methylbenzene Monosulfonate Salt of the E1 Enantiomer of 1- (. {4- f (6,7-dihydro-1,4,4-dioxinor-2,3-c-pyridazin-3-ylmethyl) amino-1-piperidinyl .}. metM) -9-fluoro-1, 2-dihydro-4H-pyrrolof3,2 - // 1-quinolin-4-one (a) A suspension of the free base of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino ] -1-piperidinyl.} Methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-yl] quinolin-4-one crystalline (244 mg, 0.54 mmol) and acetonitrile (4 mi) was stirred for 30 minutes and then treated with a solution of toluenesulfonic acid in THF (1 M, 0.54 ml, 0.54 mmol) and kept overnight. The solid was filtered to provide 317 mg of the title compound. The solid can be washed with acetonitrile and dried at 50 ° C under a slow stream of nitrogen to give the title compound as a white solid. (b) The free base of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl .) methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1 - / y] quinolin-4-one (1.0 g, 2.21 mmol) was suspended for 30 minutes at 25 minutes. ° C in acetonitrile (15 ml). To this suspension were added a few crystal germs of the title compound, followed by a solution of 1.0 M p-toluenesulfonic acid in THF (2.21 ml, 1.0 equiv). Stirring was continued for 18 hours. The suspension was filtered and the filter cake was washed with cold acetonitrile. The resulting white solid was dried at 0.5 mm, 50 ° C, for 4 hours, to give 1.14 g (83%) of the title compound. Acetone can be used in place of acetonitrile and THF to provide similar product yield. 4-Methylbenzene monosulfonate salt of the E1 enantiomer of 1 - . 1 - ( { 4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.] Methyl) -9- fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 - / y] quinolin-4-one, fusion start 245 ° C. (DSC Method A).

EXAMPLE 10D Monobenzoate salt of the E1 Enantiomer of 1- (. {4 - [(6,7-dihydro [1,4-dioxino [2,3-ctoiridazin-3-ylmethyl)] fluoro-1,2-dihydro-4H- pyrroloi3,2,1 - /] quinolin-4-one Acetonitrile (10mL) was added to the free base 1 of the enantiomer E1 of 1 - ( { 4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-methylmethyl] -1] -piperidinyl} methyl) -9 -fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one crystalline (458.0 mg). To the suspension was added benzoic acid (1.0 equivalent, 1.0 M solution in tetrahydrofuran). The suspension was stirred for 24 hours at room temperature. The solids were then filtered and dried in a vacuum oven at 50 ° C overnight to provide approximately 512.5mg of the title compound. Monobenzoate salt of the E1 Enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl}. m 1, 2-dihydro-4H-pyrrolo [3,2,1 - / y] quinolin-4-one: fusion start 154 ° C. (DSC Method A).

EXAMPLE 10E Mono (2E) -2-butenedioate salt of the E1 Enantiomer of 1 - (. {4-G (6,7-dihydron, 41-dioxino [2,3-clpyridazin-3-ylmethyl) amino-1-piperidinyl} methyl) -9- fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - // lquinolin-4-one (a) Anhydrate I Ethanol (60 ml) was added to the free base of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin- 3-ylmethyl) amino] -1-ptperidinyl.] Methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-yl] quinolin-4-one crystalline (2.052 g). The suspension was heated to 50 ° C for 60 minutes, during which the crystalline free base was completely dissolved in the solvent. To the solution, fumaric acid (1.0 equivalent, 527.5 mg) was added. The solution was again heated to 50 ° C for 10 hours and cooled again to room temperature. The solid was filtered, washed with ethanol and dried in a vacuum oven at 50 ° C with a gentle purging process with nitrogen. The yield of the crystalline fumarate salt anhydrate was 94% (2.4275 g). The fumaric acid can be dissolved in DMSO before the addition, and if crystal germs are added to the free base solution, they are preferably added immediately before the addition of the fumaric acid. Anhydrate I of mono (2E) -2-butenedioate salt of the E1 Enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) ) amino] -1-piperidinyl.} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1 - //] quinolin-4-one: melting start 227 ° C, peak 228aC (DSC Method A). XRPD peaks (values given in degrees two tit): 7.9 ± 0.2 (2T), 8.9 ± 0.2 (2T), 9.5 ± 0.2 (2T), 10.5 ± 0.2 (2T), 1 1 .7 ± 0.2 (2T), 17.5 ± 0.2 (2T), 1 7.8 ± 0.2 (2T). (XRPD Method A). (b) Trihydrate (i) 2,224 g of mono (2E) -2-butenedioate salt of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] were charged. pyridazin-3-ylmethyl) amino] -1-piperidinyl.] methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1- / y] quinolin-4-one in a reactor 50 mi. 9 volumes of acetone and 3 volumes of water were charged into the reactor. The solution was heated to 60 ° C. 4 additional volumes of acetone and 3.6 volumes of water were charged. Dysolution was observed at 60 ° C. It was cooled to 45 ° C. It was maintained at 45 ° C for 1 hour. It was cooled to 0 ° C. The solid was isolated at 0 ° C. The solid was rinsed with acetone. It was dried under vacuum at 30 ° C. (Ü) 65 g of mono (2E) -2-butenedioate salt of the E1 enantiomer of 1 - (. {4 - [(6)] were charged., 7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-4-one in a 1 I reactor. 4 volumes of acetone and 4 volumes of water were charged in the reactor. The solution was heated to 55 ° C. It was cooled to 50 ° C and seeded with 1% (w / w) of trihydrate germs. It was maintained at 50 ° C for 1 hour. From 50 ° C, it was cooled to 40 ° C over 100 minutes. From 40 ° C, it was cooled to 25 ° C over 60 minutes. From 5 ° C, it was cooled to 0 ° C over 30 minutes. 6 volumes of acetone were charged to the suspension, during which time the suspension was heated to 2 ° C. The solid was isolated at 2 ° C. The solid was rinsed with 5 volumes of acetone. It was dried under vacuum at 35 ° C overnight. The final yield was 58 g of trihydrate. Mono (2E) -2-butenedioate salt of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.} Methyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2, 1 - //] quinolin-4-one, trihydrate A broad endothermic fusion / dehydration between 50-1 50 ° C, followed by a sharp melting start 222 ° C (DSC Method A). XRPD peaks (values given in degrees two tit): 5.7 ± 0.2 (2T), 6.7 ± 0.2 (2T), 8.1 ± 0.2 (2T), 9.3 ± 0.2 (2T), 9.9 ± 0.2 (2T), 1 1 .0 ± 0.2 (2T), 1 1 .5 ± 0.2 (2T). (XRPD Method B). (c) Anhydrate II Mono (2E) -2-butenedioate salt trihydrate of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin -3-ylmethyl) amino] -1-piperidinyl.} Methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-] quinolin-4-one, dried in a vacuum oven at 80 ° C to provide the title anhydrate II. Anhydrate II of mono (2E) -2-butenedioate salt of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pihdazin-3-ylmethyl) ) amino] -1-piperidinyl.} methyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2, 1 - / y] quinolin-4-one: fusion start 225 ° C, melting peak 227 ° C AHf 137J / g. (DSC Method B). XRPD peaks (values given in degrees two tit): 6.1 ± 0.2 (2T), 10.5 ± 0.2 (2T), 10.9 ± 0.2 (2T), 16.0 ± 0.2 (2T), 18.3 ± 0.2 (2T), 21 .0 ± 0.2 (2T). (XRPD Method C). (d) Dihydrate Methanol: 5 vol% in water (0.5 ml) was added to the free base of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxin [2,3 -c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.] methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-yl] quinolin-4-one crystalline ( -30 mg). The resulting suspension, under a vortex velocity of 750rpm, was maintained at 40 ° C for 1 hour, then its temperature was cycled from 0-40 ° C for -48 hours (ramp at -1 ° C / minute at 0 ° C. , it was maintained during 1 h, +1 ° C / min up to 40 ° C, it was maintained during 1 h). Finally the temperature of the product was subjected to a ramp of -1 ° C / min up to 23 ° C and was maintained for 1 h at a vortex speed of 500 rpm. The resulting solids and supernatant were removed by filtration at room temperature and placed in a refrigerator and allowed to cool to ~ 4 ° C overnight. The supernatant was allowed to warm to room temperature and allowed to slowly evaporate under ambient laboratory conditions producing therein the solid dihydrate. Mono (2E) -2-butenedioate salt dihydrate of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-//] quinolin-4-one: A broad endothermic fusion / dehydration between 20- 120 ° C, followed by a sudden melting start 1 73 ° C (DSC Method A). XRPD peaks (values given in degrees two teta): 6.1 ± 0.2 (2T), 6.9 ± 0.2 (2T), 7.9 ± 0.2 (2T), 10.6 ± 0.2 (2T), 12.2 ± 0.2 (2T), 12.9 ± 0.2 ( 2T). (XRPD Method A).

EXAMPLE 11 Dihydrochloride of the E2 Enantiomer of 1- (. {4-f (6,7-dihydrori, 41-oxoino [2,3-c1-pyridazin-3-ylmethyl) amino-1-piperidinyl} methyl) -9- fluoro-1, 2-dihyd pirrolor3,2l1 - //] quinolin-4-one A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1, 2-dihydro-4H-pyrrolo [3.2, 1-y] quinolin-4-one (enantiomer E2) ( 100 mg, 0.33 mmol) and 6,7-dihydro [1,4] dioxino [2,3-c] pyridazine-3-carbaldehyde (56 mg, 0.332 mmol) in?,? - dimethylformamide (1.5 mi. ) was treated with sodium triacetoxyborohydride (216 mg, 0.997 mmol) for 16 hours at room temperature. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate, extracted with 10% methanol in dichloromethane and the combined organic extracts were dried (magnesium sulfate) and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate followed by 0-30% methanol in dichloromethane, affording the free base as a white solid (101 mg, 66%). MS (+ ve ion electrospray) m / z 452 (MH +). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness, to give a solid (14 mg).

EXAMPLE 12 Dihydrochloride of the E1 Enantiomer of 9-Fluoro-1- (4. {[[(3-oxo-3,4-dihydro-2H-pyrido [3,2-foH1'41oxaz'n'6-yl] -net-amino) .}. -1. -piperidinyl) methyn- ^ dihydro-4H-pyrrolo [3,2,1- / 7-quinolin-4-one A solution of 1 - [(4-amino-1-pipehdinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one (enantiomer E1) ( 50 mg, 0.17 mmoles) and 3-oxo-3,4-dihydro-2 / - / - pyrido [3,2-α)] [1,4] oxazine-6-carboxaldehyde (for a synthesis, see WO2004058144 Example 1 (1)) (30 mg; 0.17 mmoles) in dichloromethane / methanol (5 ml / 0.5 ml) was treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred at room temperature. After 1 hour an aqueous solution of sodium bicarbonate (10 ml) was added and the mixture was evaporated to a small volume. The resulting solid was collected and washed with water to give the free base (60 mg, 79%). MS (+ ve ion electrospray) m / z 464 (MH +). 5H (CDCl3 / CD3OD, 250 MHz) 1.52 (2H, m), 1.95 (2H, m), 2.10 (1H, t), 2.25 (1H, t), 2.48-2.71 (2H, m ), 2.90 (2H, m), 3.10 (m, partially obscured by the water peak), 3.85 (2H, s), 4.05 (1 H, m), 4.48 (2H, m), 4.62 (2H, s) , 6.63 (1 H, d), 6.90 (2 H, m), 7.22 (1 H, d), 7.42 (1 H, m), 7.75 (1 H, d). The free base in methanol / DCM was converted to the dihydrochloride salt by adding an excess of 4N hydrogen chloride in dioxane, followed by evaporation to dryness, to give a solid (60 mg).

EXAMPLE 13 Dihydrochloride of the E1 Enantiomer of 1- (. {4-r (2,3-dihydron, 41-dioxinof2,3-c] pyridin-7-ylmethyl) amino] -1 ^ iperidium > methyl) -4- oxo-1, 2-dihydro-4H-pyrrolof3,2,1 - // lquinolin-9-carbonitrile (a) (2E) -A / - (3-Bromo-2-methylphen-3-phenyl-2-propenamide) A solution of cinnamyl chloride (89.6 g, 536 mmol) in ethyl acetate (400 ml) was added to a vigorously stirred mixture of 3-bromo-2-methylaniline (99.8 g, 536 mmol), saturated aqueous sodium bicarbonate (850 ml), ice (ca. 100 g) and ethyl acetate (400 ml) After 1 hour The mixture was concentrated (removing most of the ethyl acetate) and filtered The residue was re-suspended in a 5% methanol-water solution (500mL), stirred for 1 hour, filtered and dried in vacuo ( 170 g, 100%). MS (+ ve ion electrospray) m / z 317 (MH +). (b) 7-Bromo-8-methyl-2 (1 / - /) - quinolinone A suspension of (2E) -A / - (3-bromo-2-methylphenyl) -3-phenyl-2-propenamide ( 50 g, 160 mmol) in chlorobenzene (206 ml) was treated slowly with aluminum trichloride (128 g, 960 mmol). The reaction was heated to 125 ° C for 0.5 hours, under argon. The mixture was allowed to cool to room temperature, then added to ice in water (ca. 2L). The mixture was filtered and the resulting solid was washed with water and dried in vacuo to give an almost white solid (59.2 g, qty). MS (+ ve ion electrospray) m / z 239 (MH +). (c) Crude 7-Bromo-8-methyl-2- (methyloxy) quinoline 7-bromo-8-methyl-2 (1 H) -quinolinone (25 g, 105 mmol) was suspended in DMSO (138 mL), then it was treated with potassium t-butoxide (1.1 g, 11.5 mmol), under argon (the internal temperature was stable at 30 ° C). After 10 minutes methyl iodide (8.5 ml, 136 mmol) was added (the internal temperature was raised to 40 ° C and set at 35 ° C after 10 minutes). The reaction mixture was stirred at 35 ° C for 30 minutes. The mixture was added to water (1 L) and extracted twice with hexane (2x300 mL). The hexane extracts were further washed with brine (300 ml), dried over magnesium sulfate, filtered and evaporated under vacuum to give a pale yellow solid (193 g, 73%). MS (+ ve ion electrospray) m / z 253 (MH +). (d) 7-Bromo-8-bromomethyl-2- (methyloxy) quinoline A solution of 7-bromo-8-methyl-2- (methyloxy) quinoline (19.3 g, 76.6 mmol) in trifluoromethylbenzene (292 ml) it was treated with N-bromosuccinimide (27.3 g, 153.2 mmol) and benzoyl peroxide (17 mg) and heated to reflux while irradiated with a tungsten lamp at 100 watts for 2 hours. The cooled mixture was washed with a saturated aqueous solution of sodium bicarbonate and water, then dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica eluting with a gradient of 0-100% dichloromethane in petroleum ether to give a white solid (23.2 g, 91%). MS (+ ve ion electrospray) m / z 332 (MH +). (e) 7-Bromo-2- (methyloxy) -8-quinolinyl-1-acetonitrile A solution of 7-bromo-8-bromomethyl-2- (methyloxy) quinoline (19.3 g, 58.3 mmol) in DMF (345 ml) was treated with cyanide of potassium (15.2 g, 233 mmol) and stirred at 25 ° C overnight. The mixture was evaporated to dryness and the dark residue was partitioned between dichloromethane and water. The aqueous layer was extracted twice more with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with gradient of 0-100% dichloromethane in petroleum ether to give a white solid (128 g, 79%). MS (+ ve ion electrospray) m / z 277 (MH +). (f) [7-Bromo-2- (methoxyl) -8-quinolinyl-1-methyl acetate A solution of 7-bromo-2- (methyloxy) -8-quinolinyl] acetonitrile (12.8 g, 46.2 mmol) in dry methanol (200 ml) was treated with trimethylsilyl chloride (20 ml, 57.1 mmol) and heated at 60 ° C for 3 hours. The methanol was partially evaporated under vacuum. Water (60 ml) was added, then solid potassium carbonate (13 g). The aqueous layer was extracted twice with dichloromethane. The combined organic layers were over magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with dichloromethane to give a white solid (13.1 g, 91%). MS (+ ve ion electrospray) m / z 31 1 (MH +). (g) Methyl 2- [7-Bromo-2- (methyloxy) -8-quinolinyl-2-propenoate A mixture of methyl [7-bromo-2- (methyloxy) -8-quinolinyl] acetate (13.1 g; 42.2 moles), paraformaldehyde (8.8 g, 295 mmole), potassium carbonate (5.8 g, 63 mmole) and benzyltriethylammonium chloride (1 5.4 g, 67.6 mmole) in cyclohexane (275 ml) was heated to 85 ° C, with stirring vigorous for 18 hours. More paraformaldehyde (88 g, 295 mmol), potassium carbonate (2.9 g, 29.5 mmol) and benzyltriethylammonium chloride (7.7 g, 33.8 mmol) were added and the reaction mixture was stirred at 85 ° C for 5 more hours and then at 90 ° C for 18 hours. The mixture was cooled, water (200 ml) was added and the mixture was extracted with ethyl acetate (2 × 200 ml). The combined organic layers were washed with brine (150 ml), dried over magnesium sulfate and evaporated in vacuo to give a white solid (12.4 g, 91%). MS (+ ve ion electrospray) m / z 323 (MH +). (h) 2-r7-Bromo-2- (methyloxy) -8-quinolinyl-3-r4 - ((2,3-dihydrori, 41-dioxino [2,3-clpyridin-7-ylmethyl] ([(1, 1 -dimethylethyl) oxylcarbonyl.} Amino) -1-piperidinylpropanoate methyl A solution of methyl 2- [7-bromo-2- (methyloxy) -8-quinolinyl] -2-propenoate (1 g, 3.1 mmol), (1,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) -4-piperidinylcarbamate 1,1-dimethylethyl ester (for a synthesis, see international publication WO 2004058144 Example 99 (h )) (2.2 g, 6.2 mmoles) and 1, 1, 3.3, tetramethylguanidine (15 drops) in dry DMF (9.5 ml) was heated at 90 ° C for 24 hours then at 100 ° C for 23 hours more. The mixture was evaporated to dryness, and chromatographed on silica gel, eluting with 0-20% methanol in dichloromethane to give a yellow oil (1.7 g, 81%). MS (+ ve ion electrospray) m / z 672 (MH +). (i) (1 - { 2- [7-Bromo-2- (methyloxy) -8-quinolin-3-hydroxypropyl] -4- piperidinyl) (2,3-dihydro [1,41-dioxin] 2,3-c] pyridin-7-ylmethyl) carbamate 1,1-dimethylethyl A solution of 2- [7-bromo-2- (methyloxy) -8-quinolinyl] -3- [4 - ((2,3 -dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl). {[[(1, 1 -dimethylethyl) oxy] carbonyl}. amine) -1-piperidinyl] propanoate methyl (1.7 g, 2.5 mmol) in non-dried tetra break (18.5 ml) at -78 ° C was treated with a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 3 ml, 3 mmol) and stirred at this temperature for 1 hour, then allowed to reach room temperature over 30 minutes. The reaction mixture was again cooled to -78 ° C and a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 3 mL, 3 mmol) was added. The reaction mixture was allowed to reach room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate and filtered. The filtrate was evaporated under vacuum. The residue was redissolved in dichloromethane and chromatographed on silica gel, eluting with a gradient of 1-40% methanol in dichloromethane to give a yellow solid (835 mg, 51%). MS (+ ve ion electrospray) m / z 644 (MH +). (0 (1-r (9-Bromo-4-oxo-1,2-dihydro-4H-pyrrolor3,2.1-//] quinolin-1-yl) methyl-1-4-piperidinyl} (2,3-dihydro) [1,141dioxino [2,3-c1pyridin-7-ylmethyl] carbamic acid 1,1-dimethylethyl ester A solution of (1 -. {2- [7-bromo-2- (methyloxy) -8-quinolinyl] -3- hydroxypropyl] -4-piperidinyl) (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) carbamate 1,1-dimethylethyl ester (835 mg, 1.29 mmol) in chloroform (17 ml), at 0 ° C, under argon, treated with diisopropylethylamine (0.48 ml, 2.85 mmol) and methanesulfonic anhydride (271 mg, 1.55 mmol) in chloroform (3 ml). 60 ° C for 1 hour. The reaction mixture was concentrated to ~10 mL, and chromatographed on silica gel, eluting with a gradient of 0-30% methanol in ethyl acetate, to give a colorless oil (641 mg, 58%). MS (+ ve ion electrospray) m / z 612 (MH +). (k). { 1-r (9-Cyano-4-oxo-1,2-dihydro-4 / - / - pyrrolor3,2,1 - // 1-quinolin-1-yl) methyl] -4-piperidinyl) (2, 1,1-dimethylethyl-3-dihydro [1-l4-dinoxino [2,3-clpyridin-7-ylmethyl) carbamate A mixture of. { 1 - [(9-bromo-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-1-yl) methyl] -4-piperidinyl} (1,3-Dihydro [, 4] dioxino [2,3-c] pyridin-7-methyl) carbamate 1,1-dimethylethyl ester (461 mg, 0.75 mmol) and copper cyanide (1) (16 mg, 1.88 mmoles) in N, N-dimethylformamide (4.2 ml) was heated at 140 ° C for 2 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane / concentrated ammonia / brine. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, and evaporated under vacuum. The brown oil residue was chromatographed on silica gel, eluting with gradient of 0-30% methanol in dichloromethane to give a yellow oil (203 mg, 48%). MS (+ ve ion electrospray) m / z 558 (MH +).

(I) Compound of title A dissolution of. { 1 - [(9-cyano-4-oxo-1,2-dihydro-4 / - / - pyrrolo [3.2, 1 - / y] quinolin-1-yl) methyl] -4-pipehdinil} (1,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) carbamate 1,1-dimethylethyl ester (203 mg, 0.36 mmol) in dichloromethane (9 mL) was treated with trifluoroacetic acid (9 mi). The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The residue was dissolved in a 1: 1 mixture of methanol: dichloromethane (20 ml) and treated with MP-carbonate resin (3 mmol / g). After 30 minutes, the mixture was filtered under vacuum. The filtrate was evaporated to dryness giving the free base as a colorless oil (141 mg, 85%). 5H (CDCl 3, 250 MHz) 1 .40-1 .55 (2H, m), 1 .80-1 .95 (2H, m), 2.1 -2.4 (2H, m), 2.5 (2H, dt), 2.8 (1 H, m), 2.9-3.1 (2H, m), 3.79 (2H, s), 4.00-4.08 (1 H, m), 4.25-4.35 (4H, m), 4.43-4.60 (2H, m) , 6.84 (1 H, d), 7.34-7.36 (2H, d), 7.47-7.51 (1 H, d), 7.71 -7.74 (1 H, d), 8.10 (1 H, s). MS (+ ve ion electrospray) m / z 458 (MH +). The racemic material (as a free base, 200 mg) was separated by preparative chiral hplc in the two enantiomers, E1 and E2, using a Chiralpak AD-H column of 5 um, eluting with 50: 50: 0.1-CH3CN: CH3OH: lsopropylamine with Rt for E1 7min and Rt for E2 13.8 min. The recovery was E1 80 mg (> 99.5% pure) and E2 86 mg (> 99.4 % pure) The E1 enantiomer was converted to the dihydrochloride salt by dissolving the free base in a small amount of methanol and an excess of a 6N hydrochloric acid solution. Then the solution was evaporated under vacuum to provide a solid.

EXAMPLE 14A Dihydrochloride of the E2 Enantiomer of 1- (. {4-r (2,3-dihydro [1,4-dioxinof213-clpyridin-7-ylmethyl) amino-1-piperidinyl}. M-dihydro-4H-pyrrolo [3.2, 1- / lquinolin-4-one (a) 2- [Methyl-7-fluoro-2- (methyloxy) -8-quinolinyl-2-oxiranecarboxylate M-chloroperbenzoic acid (50%, 6.95 g, 0.0201 mol) was added to a 1: 1 mixture solution ( 5.251 g) of methyl 2- [7-fluoro-2- (methyloxy) -8-quinolinyl] -2-propenoate (2.63 g, 0.0101 mol) and [7-fluoro-2- (methyloxy) -8-quinolinyl] methyl acetate in dichloromethane (60 ml) and the mixture was heated at 50 ° C for 6.5 hours and then at 40 ° C for 16 hours. [More acid-chloroperbenzoic acid (3.5 g) was added at 2 hours]. The mixture was cooled, diluted with water and DCM and treated with excess sodium sulfite, followed by aqueous sodium bicarbonate until pH ~ 8, and then extracted (3x more) with dichloromethane. The organic fraction was dried, evaporated and chromatographed on silica gel, eluting with 0-100% ethyl acetate-petroleum ether then with 0-20% methanol-ethyl acetate to provide the product (2614 g; 94% based on methyl 2- [7-fluoro-2- (methyloxy) -8-quinolinyl] -2-propenoate as starting material). (b) 9-Fluoro-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolor3,2,1 - /] quinolin-1-carboxylic acid A mixture of 2- [7-fluoro-2- ( Methyloxy) -8-quinolinyl] -2-oxiranecarboxylic acid methyl ester (3.105 g, 0.012 mol), and lithium perchlorate (2.38 g, 0.0224 mol) in acetonitrile (30 mL) and water (30 mL) were heated to 85 ° C. for 120 hours, it was cooled, and evaporated to dryness. 10% methanol in dichloromethane was added and the resulting solid was collected and dried to provide (1.4 g, 51%). MS (+ ve ion electrospray) m / z 249 (MH +). (c) 9-Fluoro-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolor-3,1,1-methyl-1-quinoline-1-carboxylic acid A solution of 9-fluoro-1-hydroxy 4-Oxo-1,2-dihydro-4 / - / - pyrrolo [3,2,1- //] quinoline-1-carboxylic acid (1.30 g) in methanol (52 ml) was treated with concentrated sulfuric acid ( 0.52 ml) and stirred at room temperature for 1.5 hours. The solution was quenched by stirring with an excess of MP-carbonate resin until pH ~ 7, filtered and evaporated to give a yellow solid (0.855 g, 62%). MS (+ ve ion electrospray) m / z 264 (MH +). (d) Q-Fluoro-l-hydroxy-l-hydroxymethyl-l ^ -dihydro-H-pyrrolofS ^ .I - // 1-quinolin-4-one A solution of 9-fluoro-1-hydroxy-4-oxo-1 , Methyl 2-dihydro-4H-pyrrolo [3,2, 1 - / y] quinoline-1-carboxylate (0.855 g; 3.25 mmole) in methanol (85 ml) was cooled to 0 ° C and sodium borohydride (0.123 g, 3.25 mmol) was added. The mixture was stirred at this temperature for 2 hours. It was quenched with ammonium chloride (5 ml), evaporated to dryness and the residue was treated with methanol and then evaporated again to dryness. Water and dichloromethane were added and the aqueous fraction was evaporated to dryness and again treated with methanol. The resulting solid was filtered and dried (0.765 g), being pure enough for the next reaction. MS (+ ve ion electrospray) m / z 236 (MH +). (e) 9-Fluoro-1 - (hydroxymethyl) -4-oxo-1,2-dihydro-4 / - / - pyrrolo [3,2,1- // 1-quinolin-1-ethyl-4-methylbenzenesulfonate A mixture of 9- fluoro-1-hydroxy-1- (hydroxymethyl) -1,2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one (0.765 g, 3.25 mmol), p-toluenesulfonyl chloride ( 0.62 g, 3.5 mmol) and di-n-butyl (oxo) stannane (40.5 mg, 0.1626 mmol) in dichloromethane (30 ml), tetrahydrofuran (30 ml), DMF (3 ml) and triethylamine (0.68 ml) were stirred at room temperature for 16 hours, then sodium bicarbonate solution was added and the mixture was extracted with 10% methanol-dichloromethane. The organic fraction was dried and evaporated to give a yellow oil which was chromatographed on silica gel, eluting with 0-100% ethyl acetate-petroleum ether followed by 0-20% methanol-ethyl acetate to provide a yellow oil (0.968 g) (77% yield over 2 stages). MS (+ ve ion electrospray) m / z 390 (MH +). (f) (1-f (9-Fluoro-1-hydroxy-4-oxo-, 2-dihydro-4H-pyrrolor3.2.1 - // 1-quinolin-1-yl) methan-4-piperidinyl) carbamate of 1 , 1-dimethylethyl A mixture of 9-fluoro-1- (hydroxymethyl) -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-1-yl-4-methylbenzenesulfonate (0.968 g; 2.49 mmol), 1,1-dimethylethyl 4-piperidinylcarbamate (0.47 g, 2.35 mmol), and anhydrous sodium carbonate (0.746 g, 7.04 mmol), in ethanol (100 ml), was stirred at room temperature for 16 hours. Water was added and the mixture was extracted with 10% methanol-dichloromethane. The organic extracts were dried and evaporated to give a yellow oil (1.038 g, 100%). MS (+ ve ion electrospray) m / z 418 (MH +). (g) 1 -f (4-Amino-1-piperidinyl) methyl-1-9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - / | quinolin-4-one A solution from . { 1 - [(9-fluoro-1-hydroxy-4-oxo-1,2-dihydro-4 / - / - pyrrolo [3,2,1- // Jquinolin-1-yl) methyl] -4-piperidinyl} 1, 1, -dimethylethyl carbamate (1.038 g) in dichloromethane (5 ml) and trifluoroacetic acid (2.5 ml) was stirred at room temperature for 2 hours, during which a further 2 ml of trifluoroacetic acid was added, and evaporated to dryness. The residue was dissolved in 1: 1 dichloromethane / methanol and stirred with an excess of MP-carbonate resin until pH ~ 8, filtered and evaporated to give a yellow oil (0.638 g, 81%). MS (+ ve ion electrospray) m / z 318 (MH +). The racemic material (0.90 g) was separated by preparative chiral hplc in the two enantiomers, E1 and E2, using a Chiralpak AD 10um column (21 x 250 mm), eluting with 80: 20: 0.1 -CH3CN: CH3OH: lsopropylamine ( 20 ml / min) with Rt for E1 5.5 min and Rt for E2 7.0 min. The recovery was E1 379 mg (> 99% ee) and E2 395 mg (> 99% ee). (h) Title Compound An E2 enantiomer solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3, 2 - /)] quinolin-4-one (40 mg, 0.1 3 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carboxaldehyde (for a synthesis see international publication WO2004058144, Example 2 (c)) (20 mg, 0.13 mmol) in DCM (0.5 ml) and methanol (0.10 ml) was stirred at room temperature with sodium triacetoxyborohydride (85 mg, 0.40 mmol) for 4 hours at room temperature. The mixture was treated with aqueous sodium bicarbonate (2 mL) and extracted with 5% methanol in dichloromethane (2 mL) and the organic phase was chromatographed on silica gel, eluting with 0-20% methanol in dichloromethane, affording the free base as a yellow oil (30 mg, 49%). MS (+ ve ion electrospray) m / z 467 (MH +). d? (CD3OD, 400 MHz) 1.13-1.25 (1H, m), 1.40-1.50 (1H, m), 1.70-1.78 (1H, m), 1.85-1.93 (1H, m), 2.18-2.25 (1H, t) , 2.28-2.35 (1H, t), 2.50-2.58 (1H, m), 2.65-2.70 (1H, m), 3.00 (2H, s), 3.10-3.18 (1H, m), 3.80 (2H, s) , 4.20 (1H, d), 4.25-4.30 (2H, m), 4.32-4.38 (2H, m), 4.65 (1H, d), 6.62 (1H, d), 6.95 (1H, s), 7.05 (1H , t), 7.68-7.72 (1H, m), 7.95 (1H, d), 8.00 (1H, s). The free base in methanol-DCM (0.5 ml / 0.5 ml) was converted to the dihydrochloride salt by adding an excess of 1M hydrogen chloride in ether (2 ml), followed by more ether (3 ml), to precipitate a solid. (34 mg).

EXAMPLE 14B Dihydrochloride of 1- (. {4-f (2,3-dihydrori, 41dioxinof2l3-c1pyridin-7-ylmethyl) aminol-1-piperidinyl} methyl) -9-fluoro-pyrrolo [3.2.1 - / 71-quinolin-4-one The title compound was prepared from 9-fluoro-1- (hydroxymethyl) -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-1-yl-4-methylbenzenesulfonate and (1,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) -4-piperidinylcarbamate 1,1-dimethylethyl ester (for a synthesis, see international publication WO2004058144 Example 99 (h )) in a manner similar to the procedures described herein.

EXAMPLE 14C E2 Enantiomer Hydrochloride of 1- (. {4-f (2,3-dihydroxy, 41-dioxino [213-clpyridin- -ylmethyl-O-aminol-l-iperidini-rnetiiyg-fluoro-l-hydroxy-l-dihydro-4H -pyrrolo [312,1 - // 1-quinolin-4-one] The title compound was prepared from 9-fluoro-1- (hydroxymethyl) -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-1-ethyl-4-methylbenzenesulfonate and (1,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) -4-piperidinylcarbamate 1,1-dimethylethyl ester (for a synthesis, see international publication WO2004058144 Example 99 (h )) followed by separation of the enantiomer E2 and preparation of the hydrochloride salt, similarly to the procedures generally described herein.

EXAMPLE 15 Enantiomer dihydrochloride E1 of 1- (. {4 - [(213-dihydrof1, 41-oxathino [2,3-c] pyridin-7-ylmethyl) aminolpiperidin-1-yl] methyl) -9-fluoro- 1-hydroxy-1, 2-dihydro-4H-pyrrolof3,2,1 - // 1-quinolin-4-one An E1 enantiomer solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinoline- 4-one (39 mg, 0.12 mmole) and 2,3-dihydro [1,4] oxatin [2,3-c] pindin-7-carbaldehyde (for a synthesis, see international publication WO2004058144 Example 60 (i )) (22 mg, 0.12 mmol) in N, N-dimethylformamide (1 mL) was treated with sodium triacetoxyborohydride (79 mg, 0.37 mmol) for 18 hours at 60 ° C. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate and extracted with 5% methanol in dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaporated. The residue was chromatographed, twice, on silica gel, eluting with 0-50% methanol in dichloromethane, affording the free base as a colorless oil (56 mg, 94%). MS (+ ve ion electrospray) m / z 483 (MH +). d? (CDCI3, 250 MHz) The first signals are partially obscured by a water peak, 1.40 -1.65 (4H, m), 1.95 (2H, m), 2.35 (1H, t), 2.55 ( 2H, m), 2.82 (1H, d), 3.00 (2H, m), 3.15 (2H, m), 3.35 (2H, d), 3.79 (2H, s), 4.40 (4H, m), 6.62 ( 1 H, d), 6.88 (1 H, t), 7.00 (1 H, s), 7.49 (1 H, dd), 7.69 (1 H, d), 8.03 (1 H, s). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in ether, followed by evaporation to dryness, to give a solid (40 mg).

EXAMPLE 16 9-Fluoro-1-hydroxy-1-r (4-. {F (3-oxo-3,4-dihydro-2H-pyrido [3,2-6iri, 41oxazin-6-yl) methylamino) dihydrochloride .}. - ^ 4H-pyrrolo [3,2,1 - // 1-quinolin-4-one A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - //] quinolin- 4-one (racemic) (44 mg, 0.138 mmol) and 3-oxo-3,4-dihydro-2 / - / - pyrido [3,2-¿> ] [1,4] oxazine-6-carboxaldehyde (for a synthesis, see international publication WO2003087098 Example 31 (e)) (25 mg, 0.138 mmol) in N, N-dimethylformamide (1 ml) was treated with sodium triacetoxyborohydride (87 mg, 0.414 mmol) at room temperature for 16 hours. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate and extracted with 10% methanol in dichloromethane and the combined organic extracts were dried (magnesium sulfate) and evaporated. The residue was chromatographed on silica gel, eluting with 0-30% methanol in dichloromethane, affording the free base as a colorless oil (34 mg, 52%). MS (+ ve ion electrospray) m / z 480 (MH +). 5H (CD3OD, 250 MHz), 1 .10-1.30 (1 H, m), 1.35-1.55 (1 H, m), 1 .70-2.00 (4H, m), 2.15-2.40 (2H, m), 2.50-2.75 (2H, m), 3.00 (2H, m), 3.10- 3.20 (2H, m), 3.30 (1 H, m), 3.81 (2H, s), 4.20 (1 H , d), 4.62 (2H, s), 6.61 (1 H, d), 6.94 (1 H, d), 7.04 (1 H, t), 7.25 (1 H, d), 7.69 (1 H, dd) 7.95 (1 H, d). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness, to give a solid (42 mg).

EXAMPLE 17 Dihydrochloride of the E1-enantiomer of 1- (. {4-f (6,7-dihydro [1,41-oxathi-inof2,3-clpyridazin-3-ylmethyl) amino-1-piperidinyl} -> pyrrolof3,2,1 - //] quinolin-4-one (a) 2-r (3,6-Chloro-4-pyridazinyl) thioethanol A solution of 3,4,6-trichloropyridazine (25 g) in tetrahydrofuran (200 ml) and thethylamine (19 ml) was treated at 0 ° C (cooling ice bath) with 2-mercaptoethanol (8.33 ml) over 5 minutes. After the addition was complete, the mixture was stirred at room temperature for 72 hours. The mixture was stirred with aqueous sodium bicarbonate solution and dichloromethane and the solid was collected, washed with water, ether and pentane and dried in vacuo to give (22.9 g). The combined organic and aqueous fractions were evaporated to half their volume to provide more solid, which was washed and dried as indicated above (5.0 g). The total yield of solid (27.9 g, 91%) contained some bromine analogue (5-10%) by NMR. (b) 3-Chloro-6,7-dihydro [1,4] oxathiino [2,3-c1pyridazine A solution of 2 - [(3,6-chloro-4-pyridazinyl) thio] ethanol (13 g) (previously dried at 50 ° C in vacuo) in dry dioxane (250 ml) was treated with lithium hydride (3 g) in portions and heated at 105-110 ° C for 24 hours. The reaction mixture was cooled and quenched with ice water. The solution was brought to pH 10-1 1 with 5 M hydrochloric acid and evaporated. Water was added and the mixture was extracted 4x with dichloromethane, dried (sodium sulfate), evaporated, and chromatographed on silica gel, eluting with 0-100% ethyl acetate-hexane, to give a white solid (1 .61 g) (containing ca. 10% of the bromine species). MS (+ ve ion electrospray) m / z 189/91 (Cl MH +); 233/5 (Br MH +) d? (CDCl 3, 400 MHz) 3.23 (2H, m), 4.67 (2H, m), 7.26 (1 H, s) (for the main chlorine compound). (c) 3-Ethenyl-6,7-dihydroxy, 41-oxathino [2,3-c-pyridazine] A solution of 3-chloro-6,7-dihydro [1,4] oxathino [2,3-c] pyridazine (1 .0) g) in dimethoxyethane (25 ml) was degassed under argon then tetrakis (triphenylphosphine) palladium (0) (135 mg), potassium carbonate (0.695 g), 2,4,6-trivinylcyclotriboroxane pyridine complex (0.8 g) and water (3.7 mi). The mixture was heated at 105 ° C overnight. More complex 2,4,6-trivinylcyclotriboroxane pyridine (0.4 g) and tetrakis (triphenylphosphine) palladium (0) (30 mg) was added and heating continued for 24 hours. The mixture was cooled, treated with aqueous sodium bicarbonate solution, extracted (4x) with DCM, dried (sodium sulfate), evaporated and chromatographed on silica gel (70 g), eluting with ethyl acetate at 0-100% - hexane, providing a solid (0.56 g) (87% pure by LC-MS). MS (+ ve ion electrospray) m / z 181 (MH +). (d) 6,7-Dihydro [1,41-oxaatino] [2,3-clpiridazine-3-carbaldehyde A solution of 3-ethenyl-6,7-dihydro [, 4] oxathiino [2,3-c] pyridazine (320 mg ) in dioxane / water (20 ml / 5 ml) was treated with an aqueous solution of osmium tetroxide (4% w / v, 2 ml) and sodium periodate (1.08 g), initially stirred in a water bath. ice, then allowed to warm to room temperature. After 2.5 hours the mixture was evaporated to dryness and dissolved in dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (50 g) and chromatographed, eluting with 0-100% ethyl acetate in hexane, to give a white solid (16 mg). , 36%). MS (+ ve ion electrospray) m / z 183 (MH +). (e) Title compound A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4- ona (E1 enantiomer) (40 mg, 0.133 mmol) and 6,7-dihydro [1,4] oxathiino [2,3-c] pi dazin-3-carbaldehyde (24 mg, 0. 1 33 mmol) in dichloromethane / methanol (1 ml / 0.3 ml) was treated with sodium triacetoxyborohydride (93 mg, 0.44 mmol) at room temperature overnight. More 6,7-dihydro [1,4] oxathiino [2,3-c] pyridazin-3-carbaldehyde (8 mg) was added and the mixture was stirred for 1 hour. Added more sodium triacetoxyborohydride (93 mg), and the mixture was stirred at room temperature overnight. Aqueous sodium bicarbonate was added and the mixture was extracted with 10% methanol in dichloromethane (4x). The organic extracts were combined, dried (sodium sulfate), evaporated, and chromatographed on silica gel, eluting with a gradient of 0-20% methanol in dichloromethane, affording the free base of the title compound as a solid. . 5H (CDCl 3, 400 MHz) 1.42 (2H, m), 1.85 (2H, t), 1.98 (2H, br.s), 2.05 (1H, t), 2.23 (1H, t ), 2.45-2.55 (2H, m), 2.75 (1 H, br, d), 2.85 (1 H, dd) 3.00 (1 H, br, d), 3.21 (2H, m), 4.00 (2H, m ), 4.40-4.50 (2H, m), 4.65 (2H, m), 6.60 (1H, d), 6.86 (1H, t), 7.40 (2H, m), 7.67 (1H, d). MS (+ ve ion electrospray) m / z 468 (MH +). The free base in methanol-chloroform was treated with an excess of 4M hydrogen chloride in dioxane, evaporated and triturated with ether to give the title compound as a solid (43 mg).

EXAMPLE 17B E1 Enantiomer Hydrochloride of 1 - (. {4 - [(6,7-dihydro [1,4-oxaatino [2,3-clpyridazin-3-ylmethyl) amino] -1-piperidinyl] methyl) - 9-fluoro-1, 2-dihydro-4H ^ pyrroloi3,2,1 - // lquinolin-4-one A solution of Enantiomer E1 of 1 - (. {4 - [(6,7-dihydro [1,4] oxathino [2,3-c] pyridazin-3-ylmethyl) amino] -1-pipehdinyl}. methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (890 mg, 1.9 mmol) in methanol was treated with 5M hydrochloric acid (0.4 ml, 2 mmol) was evaporated to dryness and triturated with ether to give a white solid (950 mg). MS (+ ve ion electrospray) m / z 468 (MH +).

EXAMPLE 18 Dihydrochloride of 1- (. {4-f (6,7-dihydrori, 41dioxinof2,3-clpiridazin-3-ylmethyl) amino1-1-piperidinyl}. Methyl) -9-fluo pyrrolofS ^ .Iz / lquinolin - ^ ona A solution of 1 - [(4-amino-1-pipe dinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4- ona (racemic) (44 mg, 0.138 mmol) and 6,7-dihydro [1,4] dioxino [2,3-c] pyridazine-3-carbaldehyde (23 mg, 0.138 mmol) in N, N-dimethylformamide (1 mi) was treated with sodium triacetoxyborohydride (87 mg, 0.414 mmol) at room temperature for 20 hours. More 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-carbaldehyde (12.5 mg) and sodium triacetoxyborohydride (43.5 mg) were added and the mixture was stirred at room temperature for 12 more hours The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate and extracted with 10% methanol in dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaporated. The residue was chromatographed on silica gel, eluting with 0-30% methanol in dichloromethane, affording the free base as a colorless oil (25 mg, 40%). MS (+ ve ion electrospray) m / z 468 (MH +). 6H (CD3OD, 250 MHz), 1 .10-1.30 (1 H, m), 1 .30-1.50 (1 H, m), 1 .60-1 .95 (2H, m), 2.15 -2.40 (2H, m), 2.45-2.75 (2H, m), 3.06 (1H, s), 3.14 (1H, m), 3.31 (2H, m), 3.96 (2H, s), 4.20 (1 H, d), 4.30-4.60 (4H, m), 4.66 (1 H, d), 6.62 (1 H, d), 7.02 (1 H, d), 7.06 (1 H, d), 7.69 (1 H , dd), 7.95 (1 H, d). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness, to give a solid.

EXAMPLE 19 1 - ((4-f (2,3-Dihydro-1 H -pyrido3,4-, 4] oxazin-7-ylmethyl) amino] -1-piperidinyl > methyl) -9-fluoro-1 dihydrochloride , 2-dihydro-4H-pyrrolo [3,2,1- /] quinolin-4-one (a) 1-((4-Amino-1-p-pentydinyl) methylene-9-fluoro-1,2-dihydro-4H-pyrrolof3,2,1-inquinolin-4-one It was dissolved. { 1 - [(9-fluoro-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-1-yl) methyl] -4-piperidinyl} 1, 1, -dimethylethyl carbamate (316 mg, 0.79 mmoles) in dichloromethane (2 ml) and trifluoroacetic acid (1 ml), stirred at room temperature for 3 hours then evaporated to dryness and treated azeotropically with chloroform. The residue was dissolved in DCM / methanol (1: 1) and stirred with an excess of MP-carbonate resin until pH7-8. Filtration and evaporation gave a yellow oil (238 mg, 100%). MS (+ ve ion electrospray) m / z 302 (MH +). (b) 7-(((1-((9-Fluoro-4-oxo-1,2-dihydro-4H-pyrrolor3,2,1- // Iquinolin-1-yl) methyl-1-4-piperidinyl}. amino) methyll-2,3-dihydro-1 H-pihdo [3,4-] -1- [4,1-oxazin-1-carboxylate 1,1-dimethylethyl A solution of 1 - [(4-amino-1-piperidinyl ) methyl] -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - //] quinolin-4-one (racemic) (40 mg, 0.132 mmol) and 7-formyl- 2,3-dihydro-1 H -pyrido [3,4-b] [1,4] oxazin-1-carboxylic acid, 1, -dimethylethyl ester (35 mg, 0.132 mmol) in dichloromethane (1.5 ml) and methanol (0.1 ml) was treated with sodium triacetoxyborohydride (84 mg, 0.398 mmol) at room temperature overnight. The mixture was treated with aqueous sodium bicarbonate and extracted with 5% methanol in dichloromethane and the combined organic extracts were dried and evaporated. The residue was chromatographed on silica gel, eluting with 0-30% methanol in dichloromethane to give the free base (82 mg). MS (+ ve ion electrospray) m / z 550 (MH +). (c) Title compound A solution of 7 - [(. {1 - [(9-fluoro-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-1 -yl) methyl] -4-p-peridinyl} amino) methyl] -2,3-dihydro-1 H -pyrido [3,4-o] [1,4] oxazin-1-carboxylic acid 1,1-dimethylethyl ester (82 mg) in dichloromethane (2 ml) treated with trifluoroacetic acid (1 ml). After 3 hours the mixture was evaporated and the residue azeotropically treated with chloroform. The residual trifluoroacetate salt was converted to the crude free base by dissolving in DCM: MeOH (1: 1), stirring with an excess of MP-carbonate resin until pH 7-8, filtering and evaporating to dryness to provide a clear oil. (ca. 44 mg). 5H (CDCl 3, 250 MHz) 1 .30-1 .55 (2H, m), 1 .70-2.00 (2H, m), 2.07 (1 H, m), 2.23 (1 H, m), 2.40-2.70 (2H, m), 2.70-2.90 (2H, m), 2.90-3.10 (1H, m), 3.45 (2H, m), 3.70 (2H, s), 3.90-4.10 (1H, m), 4.1 5-4.30 (2H, m), 4.35-4.55 (2H, m), 4.61 (1 H, s), 6.50 (1 H, s), 6.62 (1 H, d), 6.86 (1 H, t), 7.38 (1 H, dd), 7.66 (1 H, d), 7.90 (1 H, s). MS (+ ve ion electrospray) m / z 450 (MH +). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol (0.3 ml), followed by evaporation to dryness, to give a solid (44 mg).

EXAMPLE 20 Hydrochloride of 1- (. {4 - [(2,3-dihydrof1,41 oxatoinof2,3-dlpyrdin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9-fl ^ / 1-quinolin-4-one (a) ethyl 5 - [(2-hydroxyethyl) thio] -6-oxo-1,6-dihydro-3-pyridinecarboxylate ethyl 5-iodo-6-oxo-1,6-dihydro-3-pyridinecarboxylate (0.59 g, 2.01 mmol) (prepared according to the method of I. Houpis et al, Tet Lett, 1994, 9355) with copper iodide (1) (20 mg, 0.105 mmol), potassium carbonate (0.55 g, 3.96 mmol) , and 2-mercaptoethanol (1 ml, 14.3 mmol) in dry?,? - dimethylformamide (20 ml) were microwaved (150W) to reach a maximum internal temperature of 1 70 ° C, for 20 minutes. The reaction was cooled and combined with the reaction mixture from a second reaction carried out with identical media on the same scale. The solvent was evaporated and the residue was partitioned between water and 10% methanol in dichloromethane. The layers were separated and the aqueous was extracted with 10% methanol in dichloromethane (4x). The combined organics were dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica eluting with 0-10% ethyl acetate in hexane to give a white solid (0.86 g, 88%). MS (ion electrospray -ve) m / z 242 (M-H "). (b) 2,3-Dihydrof1,4loxatiinof2,3-fc) 1-pyridine-7-carboxylic acid ethyl ester Triphenylphosphine (0.796 g, 3.03 mmol) was added to a solution of diisopropyl azodicarboxylate (0.60 ml, 3.05 mmol) in tetrahydrofuran (75 ml). ) at 0 ° C and stirred for 15 minutes. Then ethyl 5 - [(2-hydroxyethyl) thio] -6-OXO-, 6-dihydro-3-pyridinecarboxylate (0.52 g, 2.14 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was chromatographed on silica eluting with 0-100% ethyl acetate in hexane to give a white solid (0.25 g, 52%). MS (+ ve ion electrospray) m / z 226 (MH +). (c) 2,3-Dihydro [1,4] oxathiino [2,3-folpyridin-7-yltrietanol 2,3-Dihydro [1,4] oxathiino [2,3-ib] pyridine-7-carboxylic acid ethyl ester ( 0.25 g, 1.1 mmol) in dry tetrahydrofuran was cooled in ice / water and treated with 1.0 M diisobutylaluminum hydride in tetrahydrofuran (3.75 ml). The mixture was stirred overnight and more diisobutylaluminum hydride solution (2 ml) was added at 0 ° C. After 1 hour the mixture was treated with an aqueous solution of sodium potassium tartrate (25 ml), stirred for 1 hour and then evaporated. The residue was partitioned between water and ethyl acetate and the organic phase was washed with brine and dried. The residue was chromatographed on silica eluting with 1 -100% ethyl acetate in hexane to give a white solid (60 mg, 30%). MS (+ ve ion electrospray) m / z 184 (MH +). (d) 2,3-DihydroH, 41-oxathiino [2,3-i] lp] rdin-7-carbaldehyde 2,3-Dihydro [1,4] oxathiino [2,3-t)] pyridin-7-! L-methanol (0.14 g, 0.765 mmol) in dichloromethane (20 ml) was stirred overnight with manganese (IV) oxide (0.60 g, 3.8 mmol), filtered through kieselguhr and evaporated to give a white solid (100 mg, 72%). MS (+ ve ion electrospray) m / z 182 (MH +). (e) Title compound A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-//] quinolin-4 -one (racemic) (1 50.5 mg, 0.5 mmol) and 2,3-dihydro [1,4] oxathiino [2,3- »] pyridine-7-carbaldehyde (100 mg, 0.55 mmol) in methanol (7 ml ) and acetic acid (3 drops) was treated with (polystyrylmethyl) trimethylammonium cyanoborohydride (0.49 g, 2 mmol) with stirring at room temperature for 6 hours. After allowing to stand at room temperature for 6 days, the mixture was filtered and evaporated to dryness to give an orange oil (282 mg). The residue was chromatographed on silica gel, eluting with 0-10% 2M-methanol / dichloromethane ammonia, affording the free base as a colorless oil (149 mg, 64%). MS (+ ve ion electrospray) m / z 467 (MH +). 5H (CDCl3, 400 MHz) 1.40 (2H, m), 1.88 (2H, t), 2.08 (1H, t), 2.23 (1H, t), 2.50 (2H, m), 2.78 ( 1 H, br, d), 2.85 (1 H, dd), 3.02 (1 H, br, d), 3.12 (2 H, m), 3.70 (2 H, s), 4.0 (1 H, m), 4.45 ( 2H, m), 4.60 (2H, m), 6.60 (1 H, d), 6.85 (1 H, t), 7.38 (1 H, m), 7.42 (1 H, s), 7.65 (1 H, d ), 7.88 (1 H, s). The free base, in dichloromethane, was converted to the dihydrochloride salt by adding one equivalent of a 1 M hydrogen chloride solution in ether, followed by evaporation to dryness, to give a solid (150 mg).

EXAMPLE 21 Dihydrochloride of the E1 Enantiomer of 1 - (. {4-f (2,3-dihydrof1, 41dioxinof2,3-b1pyridin-7-ylmethyl) amino] -1-piperidinyl > methyl) -9-fluoro-1- hydroxydhydro-4H-pyrrolo [3,2,1 - // 1-quinolin-4-one] This was prepared from E1 enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - / and] quinolin-4-one (39 mg, 0.12 mmol) and 2,3-dihydro [1,4] dinoxin [2,3-fc > ] pyridin-7-carbaldehyde (for a synthesis, see international publication WO2003087098 Example 20 (e)) (20 mg, 0.12 mmol) by the general method of Example 15, to provide the free base (22 mg, 38% ). MS (+ ve ion electrospray) m / z 467 (MH +).

The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in ether, followed by evaporation to dryness, to give a solid (21 mg).

EXAMPLE 22 Dihydrochloride of 1 - ((4-f (2,3-dihydron, 41-dioxinor-2,3- 6-pyridin-7-ylmethyl) amino] -1-piperidinyl}. Methyl) -9-fl ^ /] quinoline- 4-one This was prepared from 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - // ] quinolin-4-one (racemic) (200 mg, 0.66 mmol) and 2,3-dihydro [1,4] dioxino [2,3-))] pyridine-7-carbaldehyde (for a synthesis, see international publication WO2003087098 Example 20 (e)) (109.6 mg, 0.66 mmol) by the general method of Example 20 (e) (with the exception that the reaction mixture was filtered after stirring overnight), to provide the free base as a solid (217 mg). MS (+ ve ion electrospray) m / z 451 (MH +). d? (CDCl 3, 400 MHz) 1.40 (2H, m), 1.88 (2H, t), 2.08 (1H, t), 2.23 (1H, t), 2.50 (2H, m), 2.78 (1 H, br, d), 2.85 (1 H, dd), 3.02 (1 H, br, d), 3.72 (2 H, s), 4.0 (1 H, m), 4.23 (2 H, m), 4.40 (4 H , m), 6.60 (1 H, d), 6.85 (1 H, t), 7.21 (1 H, s), 7.38 (1 H, m), 7.68 (1 H, d), 7.74 (1 H, s ). The free base in dichloromethane was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in ether, followed by evaporation to dryness, to give a solid (186 mg).

EXAMPLE 23 1 - ((4-G (1, 2,3-benzothiadiazol-5-ylmethyl) amino-1-piperidinyl} methyl) -9-fluoro-1-hydroxy-1,2-dihydro-4H dihydrochloride -pyrrolof3,2,1 - /] quinolin-4-one A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3.2, 1 - /)] quinolin-4-one (racemic) (48 mg, 0.15 mmole) and 1, 2,3-benzothiadiazole-5-carbaldehyde (prepared by oxidation with manganese (IV) oxide of benzo [1,2] thiadiazol-5-yl-methanol, for a synthesis see international publication WO2003087098 Example 6 (a)) (25 mg, 0.15 mmol) in dichloromethane (3 mL) and methanol (1 mL) was treated with sodium triacetoxyborohydride (95 mg, 0.45 mmol) for 5 hours at room temperature. An excess of sodium bicarbonate solution was added and the mixture was evaporated to dryness. The residue was chromatographed on silica gel, eluting with 0-50% methanol in dichloromethane, affording the free base as an oil (25 mg, 36%). MS (+ ve ion electrospray) m / z 466 (MH +). d? (CDCI3, 250 MHz) 1.51 (2H, m), 1.95-2.25 (m, signals partially obscured by a water peak), 2.38 (1 H, t), 2.55 (1 H, t), 2.65 (2H, m), 2.85 (1H, d), 3.00 (2H, br, d), 3.36 (1H, d), 4.05 (2H, s), 4.40 (2H, m), 6.62 (1H, d), 6.90 (1 H, t), 7.50 (1 H, q), 7.70 (2 H, m), 8.05 (1 H, d), 8.60 (1 H, s). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in ether, followed by evaporation to dryness, to give a solid (30 mg).

EXAMPLE 24 Dihydrochloride of the E2 Enantiomer of 1- (. {4-G (2,3-dihydrori 141dioxinof2,3-clpiridin-7-ylmethyl) amino-1-piperidinyl} methyl) -4-oxo-1, 2 -dihydro-4 / - -pyrrolo [3,2l1 - "] quinoline-9-carbonitrile The E2 enantiomer of Example 13 was converted to the dihydrochloride salt by dissolving the free base in a small amount of methanol and an excess of a 6N hydrochloric acid solution. Then the solution was evaporated under vacuum to provide a solid.

EXAMPLE 25A Dihydrochloride of the E1 Enantiomer of 1 - (. {4 - [(2,3-dihydro [1,41-dioxoquin-2,3-cTpyridin-7-ylmethyl) am fluoro-1-hydroxy-1,2-dihydro-4H- pyrrolor3,211 - / 1-quinolin-4-one A solution of E1 enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1, 2-dihtá ^ (40 mg, 0.12 mmol) and 2.3 -dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (for a synthesis see international publication WO2004058 44, Example 2 (c)) (20 mg, 0.2 mmol) was reacted with triacetoxyborohydride of sodium (85 mg, 0.40 mmol) by the general method described for the E2 enantiomer (Example 14) providing the free base as a yellow oil (36 mg, 60%). MS (+ ve ion electrospray) m / z 467 (MH +). 5H (CD3OD, 400 MHz): NMR identical to that of the E2 enantiomer (Example 14). The free base in methanol-DCM was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in ether, followed by more ether to precipitate a solid (52 mg).

EXAMPLE 25B Hydrochloride of the E1 Enantiomer of 1- (. {4-f (2,3-dihydrof1, 41dioxinof2,3-c] pyridin-7-ylmethyl) amino1-1-piperidinyl}. M dihydro-4H-pyrrolor3, 2.1 - // 1-quinolin-4-one The title compound was prepared from 9-fluoro-1- (hydroxymethyl) -4-oxo-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - / y] quinolin-1 -il4 -methylbenzenesulfonate and 1,1-dimethyl ethyl (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) -4-piperidinylcarbamate (for a synthesis, see international publication WO 2004058144 Example 99 (h)) followed by separation of the E1 enantiomer, in a manner similar to the methods generally described herein.

EXAMPLE 26 9-Fluoro-1 - [(4. {[[(5-oxo-1, 2,3,5-tetrahydro-7- indolizinyl) methylamino] -1- p -peridinyl) methyl-1 hydrochloride 1, 2-dihydro-4H ^ irrolo //] quinolin-4-one (a) 2-Chloro-4 - ((r (, 1 -d-methylethyl) (dimethyl) silillox) methyl) -6- (methyloxy) -pyridine A solution of [2-chloro-6- (methyloxy) ) -4-pyridinyl] methanol (for a synthesis, see Adamczyk, M .; Akireddy, SR; Reddy, Rajarathnam E. Tetrahedron 2002, 58 (34), 6951) (8.02 g, 46.22 mmoles) in dry dimethylformamide (100 ml was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with water, extracted 3x with dichloromethane, dried (magnesium sulfate), evaporated and chromatographed on silica gel (100 g), eluting with 1: 4 ethyl acetate-hexane to provide the desired product (2.38 g, 93%). MS (+ ve ion electrospray) m / z 288/290 (MH +). (b) (2?) - 3-G4 - ((G (1,1-Dimethylethyl) (dimethyl) sililloxy) methyl) -6- (methyloxy) -2-pyridinyl-1-2-butyl propenoate A solution of 2- chloro-4- ( { [(1,1-dimethylethyl) (dirnethyl) silyl] oxy} methyl) -6- (methyloxy) pyridine (9.20 g, 32.01 mmol) in 1,4-dioxane ( 100 ml) was treated with bis (tri-t-butylphosphine) palladium (0) (327 mg, 0.64 mmol), tris (dibenzyldenoacetone) dipalladium (0) (293 mg, 0.32 mmol), dicyclohexylmethylamine (7.53 ml, 35.21 mmol) and butyl acrylate (5.96 ml, 41.62 mmol). The reaction was heated at 120 ° C for 1 h and then treated with water, extracted 3 × with diethyl ether, dried (magnesium sulfate), evaporated and chromatographed on silica gel (250 g), eluting with 1: 4 ethyl acetate-hexane to provide the desired product (8.25 g, 68%). MS (+ ve ion electrospray) m / z 380 (MH +). (c) 3-f4 - ((r (1,1-Dimethylethyl) (dimethyl) silyloxy) methyl) -6- (methyloxy) -2-pyridinyl] butyl propanoate A mixture of butyl (2E) -3- [4 - ( { [(1,1-Dimethyl-ethyl) (dimethyl) silyl] oxy} methyl) -6- (methyloxy) -2-pyridinyl] -2-propenoate (4.84 g, 1249 mmol) and palladium 10% on carbon in methanol (200 ml) was stirred at room temperature for 3 hours. The mixture was filtered through kieselguhr and evaporated to provide the desired product (4.76 g, 98%). MS (+ ve ion electrospray) m / z 382 (MH +). (d) 3-f4 - ((1 (1. 1 -Dimethylethyl) (dimethyl) silyl-oxy) methyl) -6- (methyloxy) -2-pyridinyl-1-propanol A solution of 3- [4- ( { [(1,1-dimethylethyl) (dimethyl) silyl] oxy] methyl] -6- (methyloxy) -2-pi dyl] propanoate (4.76 g, 12.49 mmol) in THF (120 ml) ) was treated with LiAIH4 solution (1 M in THF, 12.49 ml, 12.49 mmol) at -78 ° C. The reaction mixture was allowed to warm to -20 ° C and after stirring at -20 ° C for 15 minutes, the mixture was treated with water (9 ml) and allowed to stir for 1 hour before being filtered and evaporated to give a slightly impure product (3.98 g, 02%). MS (+ ve ion electrospray) m / z 312 (MH +). (e) 7- ( { r (1,1-Dimethylethyl) (dimethyl) siNlloxy.} methyl) -2,3-dihydro-5 (1 H) -indolizinone A solution of 3- [4- (. {([1,1-dimethyl) (dimethyl) silyl] oxy} methyl) -6- (methyloxy) -2-pyridinyl] -1-propanol (5.16 g, 16.59 mmol) in dichloromethane (250 ml) was treated with pyridine (2.94 ml, 36.47 mmol) and trifluoromethanesulfonic anhydride (3.1 ml, 19.88 mmol) and stirred at room temperature for 10 minutes before being treated with tetrabutylammonium iodide (30.61 g, 82.95 mmol) and stirred at room temperature. room temperature for 4 more hours. Then water was added and the mixture was extracted with diethyl ether (x3) and the combined organic extracts were washed again with water. The organic extracts were dried with magnesium sulfate and evaporated. The residue was chromatographed on silica eluting with 0-10% methanol in dichloromethane to provide the desired product (3.93 g, 14.09 mmol). MS (+ ve ion electrospray) m / z 280 (MH +). (f) 7- (hydroxymethyl) -2,3-dihydro-5 (1 / - /) -indolizinone A solution of 7- ( { [(1,1-dimethylethyl) (dimethyl) silyl] oxy}. methyl) -2,3-dihydro-5 (1 / -) -indolizinone (3.93 g, 14.09 mmol) in tetrahydrofuran (100 ml) was treated with acetic acid (1.61 ml, 28.17 mmol) and tetrabutylammonium fluoride (1 ml). M in THF, 21 ml, 21 .13 mmol) and stirred at room temperature for 1 hour before being evaporated. The residue was chromatographed on silica eluting with 0-20% methanol in dichloromethane to provide the desired product (1.87 g, 80%). MS (+ ve ion electrospray) m / z 166 (MH +). (g) 5-Oxo-l, 2,3,5-tetrahydro-7-indolizincarbaldehyde A solution of 7- (hydroxymethyl) -2,3-dihydro-5 (1 / - /) -indolizinone (237 mg, 1. 44 mmol) in acetone (12 ml) was treated with ortho-iodoxybenzoic acid (603 mg, 2.16 mmol) and heated to reflux for 1 hour. The mixture was then evaporated, dissolved in dichloromethane and filtered, redissolved in dichloromethane and filtered again to provide the desired product (238 mg, 101%). MS (+ ve ion electrospray) m / z 164 (MH +). (h) Title compound A mixture of 1 - [(4-amino-1-pipehdinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1 - / y ] quinolin-4-one (racemic) (97 mg, 0.322 mmol), 5-oxo-1, 2,3, 5-tetrahydro-7-indolizincarbaldehyde (52 mg, 0.322 mmol) and 3A molecular sieves in chloroform (5 ml) ) and DMF (0.2 ml) was heated under reflux for 2 hours, cooled to room temperature, and then sodium triacetoxyborohydride (0.137 g, 0.644 mmol) was added and the mixture was heated at 50 ° C for 1.5 hours. The mixture was cooled, filtered, evaporated and chromatographed on silica gel, eluting with 0-20% methanol-DCM to give a white solid (66 mg, 46%). MS (+ ve ion electrospray) m / z 449 (MH +). 5H (CDCI3f 400 MHz) 1.35-1.50 (2H, m), 1.80-2.00 (2H, m), 2.05-2.10 (1 H, m) 2.15-2.25 (3H, m), 2.45- 2.55 (2H, m), 2.73-2.82 (1H, m), 2.83-2.89 (1H, m), 2.98-3.10 (3H, m), 3.57 (2H, s), 3.99-4.07 (1H, m), 4.10-4.1 7 (2H, t), 4.40-4.52 (2H, m), 6.21 (1 H, s), 6.35 (1 H, s), 6.62 (1 H, d), 6.87 (1 H , t), 7.79 (1 H, m), 7.67 (1 H, d). The free base in methanol and chloroform was converted to the dihydrochloride salt by adding an equivalent of a solution of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, to give a solid (50 mg).

EXAMPLE 27 Dihydrochloride of the E2 Enantiomer of 1- (4,4-di (2,3-dihydro [1,4] oxathino [2,3-clpyridin-7-ylmethyl) amino] -1-piperidinyl] methyl) -9-fluoro-1-hydroxy-1 ^ dihydro-H-pyrrolofS ^ .Iz / lquinolin ^ -one E2 Enantiomer of 1 - [(4-Amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - //] quinolin-4-one (39 mg, 0.12 mmol) and 2,3-dihydro [1,4] oxathino [2,3-c] pyridine-7-carbaldehyde (for a synthesis, see international publication WO2004058144 Example 60 (i)) (22 mg , 0.12 mmole) in?,? - dimethylformamide (1 ml) were treated with sodium triacetoxyborohydride (79 mg, 0.37 mmol) at room temperature for 16 hours. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate and extracted with 10% methanol in dichloromethane. The combined organic extracts were dried (magnesium sulfate) and evaporated. The residue was chromatographed on silica gel, eluting with 0-30% methanol in dichloromethane, affording the free base as a colorless oil (48 mg). MS (+ ve ion electrospray) m / z 483 (MH +). d? (CD3OD, 250 MHz) 1.12 (1 H, m), 1.38 (1 H, m), 1.65 (1 H, br.d), 1.80 (1 H, br.d), 2.10-2.45 (3H, m) 2.62 (1 H, br, d), 2.99 (2H, s), 3.08 (1 H, d), 3.20 (2H, m), 3.65 (2H, s), 4.1 7 ( 1 H, d), 4.37 (2 H, m), 4.62 (1 H, d), 6.60 (1 H, d), 7.02 (1 H, t), 7.08 (1 H, s), 7.68 (1 H, dd), 7.84 (1 H, s), 7.92 (1 H, d). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness, to give a cream solid (51 mg, 86%).

EXAMPLE 28 Dihydrochloride of the E2 Enantiomer of 1 - (. {4-f (2,3-dihydrof1, 41dioxinof2l3-blpiridin-7-ylmethyl) amino1-1-p -peridinyl} methyl) -9-fluoro-1 - hydroxy dihydro-4H-pyrrolof3,2,1 - / 1-quinolin-4-one This was prepared from the E2 enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - /) ] quinolin-4-one (39 mg, 0.12 mmol) and 2,3-dihydro [1,4] dioxino [2,3-)]] pyridine-7-carbaldehyde (for a synthesis, see international publication WO2003087098 Example 20 (e)) (20 mg, 0.12 mmol) by the general method of Example 27 to provide, after chromatography, the free base as a yellow oil (40 mg) MS (+ ve ion electrospray) m / z 467 (MH + ). 5H (CD3OD, 250 MHz) 1.20 (1 H, m), 1.45 (1 H, m), 1.75 (1 H, br.d), 1.91 (1 H, br.d) , 2.24 (2H, m) 2.65 (2H, m), 3.1 1 (2H, s), 3.18 (1H, d), 3.80 (2H, s), 4.22 (3H, m), 4.40 (2H, m) , 4.64 (1 H, d), 6.61 (1 H, d), 7.03 (1 H, t), 7.33 (H, d), 7.70 (2 H, m), 7.94 (1 H, d). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in methanol, followed by evaporation to dryness, to give a cream solid (41 mg).

EXAMPLE 29 Dihydrochloride of the E1 Enantiomer of 1- (. {4 - [(6,7-dihydro [1,41-oxa-atinor-2,3- c1-pyridazin-3-ylmethyl) -amino] -1-piperidinyl} methyl) -9-fluoro -1-h dihydro-4H-pyrrolof3l2,1 - // 1-quinolin-4-one A solution of E1 enantiomer of 1 - [(4-amino-1-pipehdinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - /] quinolin-4-one (40 mg, 0.126 mmol) and 6,7-dihydro [1,4] oxathino [2,3-c] pyridazine-3-carbaldehyde (27.5 mg, 0.1 51 mmol) in methanol (0.3 ml) and dichloromethane (100 ml) was treated with sodium thmacetoxyborohydride (95 mg) at room temperature for 18 hours. More 6,7-dihydro [1,4] oxathiino [2,3-c] pyridazin-3-carbaldehyde (10 mg) was added and the mixture was stirred for 1 hour, at which time more sodium thiacetoxyborohydride was added ( 95 mg). The mixture was stirred at room temperature overnight. The mixture was treated with aqueous sodium bicarbonate and extracted (3x) with 10% methanol in dichloromethane. The combined organic extracts were dried (sodium sulfate), evaporated and chromatographed on silica gel, eluting with 0-25% methanol in dichloromethane, affording the free base as a colorless oil. MS (+ ve ion electrospray) m / z 484 (MH +). 5H (CDCl3, 400 MHz) 1.448 (2H, m), 1.91 (2H, br.t), 2.36 (1H, t), 2.51 (1H, t), 2.58 (1H, m) , 2.82 (1 H, d), 2.95 (2H, m), 3.22 (2H, m), 3.32 (1 H, d), 3.97 (2H, s), 4.39 (2H, q), 4.64 (2H, m ), 6.60 (1 H, d), 6.90 (1 H, t), 7.33 (1 H, s), 7.49 (1 H, m), 7.69 (1 H, d). The free base in methanol was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness and trituration with ether to give an almost white solid (34 mg).

EXAMPLE 30 Dihydrochloride of the E1 Enantiomer of 1 - ((4-r (6,7-dihydroH, 41oxatiinor3.2-cte-rridazin-3-ylmethyl) amino] -1 ^ iperidinyl.} M pyrrolor3,2,1- / / 1-quinolin-4-one (a) 3-Chloro-6,7-dihydro [1,41-oxaatinof3,2-c] pihdazine A solution of 2 - [(3,6-dichloro-4-pyridazinyl) thio] ethanol (34 g, 0. 15 moles) in dry dioxane (700 ml) was treated with lithium hydride (1.52 g, 0.18 mol) and heated to reflux overnight. More lithium hydride (1.1 g) was added and the mixture was heated again to reflux overnight. The reaction mixture was cooled, quenched with ice water and filtered. The filtrate was evaporated to one quarter of its volume. Water was added. The aqueous layer was acidified, extracted 4x with dichloromethane, dried (sodium sulfate), evaporated and chromatographed on silica gel eluting with 0-50% ethyl acetate in dichloromethane to give a yellow solid (170 mg, 0.5 %), in the first fractions. Trituration with ethyl acetate-hexane gave the pure product (98 mg). MS (+ ve ion electrospray) m / z 189/91 (MH +). 5H (CDCl 3, 400 MHz) 3.29 (2H, m), 4.51 (2H, m), 6.86 (1 H, s). [Subsequent fractions gave 3-chloro-6,7-dihydro [1,4] oxathino [2,3-c] pyridazine isomeric (4.2 g) - see Example 1 7 (b)] . (b) 3-Ethenyl-6,7-dihydrof1, 4-oxaquino [3,2-c] pyridazine A solution of 3-chloro-6,7-dihydro [1,4] oxathino [3,2-c] pyridazine (450 mg, 2.4 mmol) in dimethoxyethane (12 ml) was treated with tetrakis (triphenylphosphine) palladium (0) (61 mg), potassium carbonate (313 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (375 mg) and water (1.5 mi). The mixture was heated to 96 ° C, overnight. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate solution, extracted (4x) with DCM, dried (sodium sulfate), evaporated and chromatographed on silica gel (50 g), eluting with 1 g. : 1 ethyl acetate-hexane, providing a solid (200 mg, 46%), which contained a slightly impure product. MS (+ ve ion electrospray) m / z 181 (MH +). (c) 6,7-Dihydro [, 41-oxathino] [3,2-c1-pyridazine-3-carbaldehyde A solution of 3-ethenyl-6,7-dihydro [1,4] oxathiino [3,2-c] pyridazine (200 mg 0.1 1 mmol) in dioxane / water (10 ml / 2 ml) was treated with an aqueous solution of osmium tetroxide (4% w / v, 1 ml) and sodium periodate (0.55 g), initially stirred in an ice bath for 1.5 hours, then allowed to warm to room temperature. After 1.5 hours the mixture was treated with sodium bicarbonate solution, evaporated to dryness and dissolved in dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (20 g), and chromatographed, eluting with 0-100% ethyl acetate in hexane, to give a pale yellow solid (63). mg, 31%). MS (+ ve ion electros) m / z 183 (MH +). (d) Title compound An E1 enantiomer solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-//] quinolin-4-one (53 mg, 0.1 76 mmol), 6,7-dihydro [1,4] oxathino [3,2-c] pyridazine-3-carbaldehyde (31 mg, 0.1 7 mmol) in methanol (0.5 ml) ) and dichloromethane (3 mL) was stirred with 3A molecular sieves overnight at room temperature. Sodium triacetoxyborohydride (0.1 13 g, 0.53 mmol) was added and the mixture was stirred at room temperature overnight. Dichloromethane and sodium carbonate were added and the mixture was extracted with 10% methanol in dichloromethane (4x). The extracts were dried with sodium sulfate and evaporated. The residue was chromatographed on silica eluting with 0-20% methanol in dichloromethane to provide the free base as an oil. MS (+ ve ion electrospray) m / z 468 (MH +). d? (CDCl 3, 400 MHz) 1.35-1.50 (2H, m), 1.85-2.05 (4H, m), 2.07 (1 H, m), 2.22 (1 H, m), 2.45-2.60 ( 2H, m), 2.77 (1H, d), 2.84 (1H, m), 3.02 (1H, d), 3.28 (2H, m), 4.02 (2H, s), 4.40-4.55 (4H, m ), 6.62 (1 H, d), 6.86 (1 H, t), 6.91 (1 H, s), 7.39 (1 H, m), 7.67 (1 H, d). The free base in methanol, and chloroform was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness and trituration with ether, to give an almost white solid (60 mg).

EXAMPLE 31 Dihydrochloride of the E1-enantiomer of 1- (. {4-r (6,7-dihydro-5H-pyran [2,3-c1pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyropyrolo [3, 2,1-lquinolin-4-one (a) 4-Bromo-2-. { R4- (R-N-L-oxy) -phenyl-methyl} -6- ( { R4- (methyloxy) pheny1methyl.}. -oxi) -3 (2 / - /) - pyridazinone and 5-bromo-2 - ([4- (methyloxy) phenylmethyl) -6- ((f4- (methyloxy) -phenemetyl] oxy) -3 (2 / - /) - pyridazinone A solution of 4-methoxybenzyl alcohol (6.2 ml, 50 mmol) in dry ether (120 ml) ) was treated dropwise with phosphorus tribromide (2.07 ml, 22 mmol), refluxed for 1 hour, cooled, washed twice with water, dried over magnesium sulfate and the solvent was evaporated. of 4-methoxybenzyl thus produced was added to a mixture of 4-bromo-1,2-dihydro-3,6-pyridazinedione (for a preparation, see Example 10A (a)) (4 g, 21 mmol) and carbonate of potassium (8.28 g, 60 mmol) in dry DMF (60 ml) and stirred overnight at room temperature The mixture was diluted with ethyl acetate, washed 3 times with water, dried over magnesium sulfate and evaporated up to low volume, some solid was filtered and washed with ethyl acetate.The filtrate was evaporated to dryness The residue was chromatographed on silica gel, eluting with 20% ethyl acetate / hexane. This provided the least polar of the two desired products (3.233 g), the more polar of the two desired products (1.626 g) and a mixture of these (1.351 g). Total yield 6.30 g, 70%. MS less polar product (electrospray + ve ion) m / z 431 and 433 (MH +, 15%), 121 (100%). MS more polar product (electrospray + ve ion) m / z 431 and 433 (MH +, 15%), 121 (100%). (b) (2a-3-f2- {4- (Methyloxy) phenylmethyl) -6 - ((r4-fmethyloxy) phenyl-1-methyl) oxy) -3-oxo-2,3-dihydro-4-pyridazinyl] -2 -butylpropenoate and (2E) -3- [2-. { [4- (methyloxy) phenyl] methyl} -6- ( { [4- (methoxy) phenyl] methyl.}. Oxy) -3-oxo-2,3-dihydro-5-pyridazinyl] -2-butyl propenoate Argon was bubbled through a mixture of 4-bromo-2-. { [4- (methyloxy) phenyl] methyl} -6- ( { [4- (methyloxy) phenyl] methyl.}. Oxy) -3 (2 / - /) - pyridazinone and 5-bromo-2-. { [4- (methyloxy) phenyl] methyl} -6- ( { [4- (methyloxy) phenyl] methyl.}. Oxy) -3 (2 / - /) - pyridazinone (1.35 g, 3.14 mmol) in dry dioxane (7.5 ml) for 20 minutes . The solution was then treated with bis (tri-t-butylphosphine) palladium (0) (32 mg, 0.0628 mmole), tris (dibenzylideneacetone) dipalladium (0) (29 mg, 0.0314 mmole), dicyclohexylmethylamine (0.74 mM, 3.45 mmole) and n-butyl acrylate (0.543 mL, 3.78 mmol), was stirred under argon at room temperature for 1 hour and heated at 95 ° C overnight. The mixture was cooled and partitioned between ethyl acetate and water, separated, and the aqueous phase was back extracted with ethyl acetate. The combined organic solution was dried and evaporated and the residue was chromatographed, eluting with 15% ethyl acetate / hexane to obtain the less polar product and 35% ethyl acetate / hexane for the more polar. The less polar product ((2E) -3- [2- { [4- (methyloxy) phenyl] methyl.}. -6- ( { [4- (methyloxy) phenyl] methyl.} Oxy) 3-oxo-2,3-dihydro-4-pyridazinyl] -2-butyl propenoate) (838 mg, 55%). MS (+ ve ion electrospray) m / z 479 (MH +, 70%), 121 (100%) The most polar product ((2E) -3- [2- { [4- (methyloxy) phenyl] methyl.}. -6- ( { [4- (methyloxy) phenyl] methyl.} Oxy) 3-oxo-2,3-dihydro-5-pi dazinyl] -2-butyl propenoate) (580 mg, 39%). MS (+ ve ion electrospray) m / z 479 (MH +, 70%), 121 (100%) (c) 3- (2- { r4- (Methyloxy) phenylmethyl) -3,6-dioxo-1, 2,3,6-tetrahydro-4-pyridazinyl) butyl propanoate A solution of (2E) -3 -[2-. { [4- (methyloxy) phenyl] methyl} -6- ( { [4- (methyloxy) phenyl] methyl.}. Oxy) -3-oxo-2,3-dihydro-4-pyridazinyl] -2-propenoate) butyl (838 mg) in ethanol ( 15 ml) / dioxane (10 ml) was treated with 10% Pd / C (400 mg) and stirred under hydrogen at atmospheric pressure and room temperature for 2 hours. The catalyst was filtered using kieselguhr and the filtrate was evaporated to give the product (0.56 g, 89%). MS (+ ve ion electrospray) m / z 361 (MH \ 60%), 121 (100%) (d) 5- (3-H id roxi pro p i I) - 1 -I G4- (meti loxi) f in i ?? methi l-1,2-dih id ro-3.6-pyridazinedione 3- (2- {[[4- (Methyloxy) phenyl] methyl} -3,6-dioxo-1, 2,3,6-tetrahydro -4-pihdazinyl) butyl propanoate (0.56 g, 1.56 mmol) was dissolved in dioxane and the solution was evaporated to dryness, then redissolved in dry THF (30 mL). The solution, under argon, was cooled to -30 ° C, and treated dropwise with a 1 M solution of lithium aluminum hydride in THF (1.8 ml, 1.8 mmoles), allowed to warm gradually until 0 ° C and stirred in an ice bath for 30 minutes. 2M hydrochloric acid was added until the pH was 3 and the mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted again with ethyl acetate and the combined organic solution was dried and evaporated. Chromatography of the residue, eluting with ethyl acetate, gave the product (300 mg, 67%). MS (+ ve ion electrospray) m / z 291 (MH +, 30%), 121 (100%). (e) 4- (3-Hydroxypropyl) -1,2-dihydro-3,6-pi dazinedione 5- (3-hydroxypropyl) -1- was treated. { [4- (methyloxy) phenyl] methyl} -1,2-dihydro-3,6-pyridazinedione (2.734 g) was treated with anisole (10 ml) and TFA (100 ml) and stirred at 40 ° C overnight. The solution was cooled, evaporated to dryness and kept under high vacuum for 30 minutes. The residue was taken up in methanol (150 ml), refluxed for 12 hours, cooled and evaporated. The residue was kept under high vacuum for 1 hour, triturated under ether and the solid filtered and washed with ether. Drying under vacuum gave the product as a solid (1.48 g, 92%). MS (+ ve ion electrospray) m / z 1 71 (MH +, 100%). (f) 6,7-Dihydro-2H-pyranor2,3-clpiridazin-3 (5H) -one A suspension of 4- (3-hydroxypropyl) -1,2-dihydro-3,6-pyridazinedione (1.48 g) , 8.7 mmole) in THF (105 ml) was kept in an ultrasonic bath for 5 minutes, then cooled under argon in an ice bath. Triphenylphosphine (3.67 g, 14 mmol) was added, followed by diisopropyl azodicarboxylate (2.76 ml, 14 mmol). After 30 minutes the solvent was evaporated and the residue was kept under high vacuum overnight. Chromatography, eluting first with 2.5% methanol / dichloromethane until the triphenylphosphine oxide was removed and then with 5% methanol / dichloromethane, gave the product as an almost white solid (1.049 g, 79%). MS (+ ve ion electrospray) m / z 153 (MH +, 100%) (q) 3- (1 - (r4- (Methyloxy) phenylmethyl) -3,6-dioxo-1, 2,3,6-tetrahydro Butyl-4-pyridazinyl) propane A solution of (2 £) -3- [2-. { [4- (methyloxy) phenyl] methyl} -6- ( { [4- (Methyloxy) phenyl] methyl.}. Oxy) -3-oxo-2,3-dihydro-5-pyridazinyl] -2-propenoate) butyl (580 mg) in Ethanol (15 ml) / dioxane (5 ml) was treated with 10% Pd / C (400 mg) and stirred under hydrogen at atmospheric pressure and room temperature for 2 hours. The catalyst was filtered using kieselguhr and the filtrate was evaporated to provide the product (0.43 g, 98%). MS (+ ve ion electrospray) m / z 361 (MH +, 50%), 121 (100%). (h) 4- (3-Hydroxypropyl) -1 -. { r 4 - (methyloxy) phenylmethyl V 1, 2-dihydro-3,6-pyridazinedione 3- (1 - { [4- (Methyloxy) phenyl] methyl.} -3, Butyl 6-dioxo-1, 2,3,6-tetrahydro-4-pyridazinyl) propanoate (0.43 g, 1.19 mmol) was dissolved in dioxane and the solution was evaporated to dryness, then dissolved again in dry THF (20 g). ml). The solution under argon was cooled to -30 ° C, treated dropwise with a 1 M solution of aluminum hydride and lithium in THF (1.4 ml, 1.4 mmol), allowed to gradually warm to 0 ° C. and stirred in an ice bath for 30 minutes. 2M hydrochloric acid was added until the pH was 3 and the mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted again with ethyl acetate and the combined organic solution was dried and evaporated. The resulting solid was triturated under ethyl acetate, filtered, washed with ethyl acetate and dried under vacuum to provide the product (241 mg, 70%). MS (+ ve ion electrospray) m / z 291 (MH +, 10%), 121 (100%) (i) 2-. { r 4 - (Methyloxy) phenylmethyl) -6,7-dihydro-2 H-pyror-2-3-pyridazin-3 (5H) -one A suspension of 4- (3-hydroxypropyl) -1-. { [4- (methyloxy) phenyl] methyl} -1,2-dihydro-3,6-pyridazinedione (2,624 g, 9.1 mmol) in THF (100 ml) was kept in an ultrasonic bath for 15 minutes, then cooled under argon to -10 ° C. Triphenylphosphine (3.57 g, 13.6 mmol) was added, followed by diisopropyl azodicarboxylate (2.68 mL, 13.6 mmol) and the mixture was allowed to warm gradually to room temperature. After 1 hour the solvent was evaporated. Chromatography on silica gel, eluting first with ethyl acetate to remove the derivatized products and then with 10% ethanol / ethyl acetate, gave the product contaminated with a little triphenylphosphine oxide (2.55 g). MS (+ ve ion electrospray) m / z 273 (MH +, 50%), 121 (100%) (i) 6,7-Dihydro-2H-piranof2,3-clpiridazin-3 (5H) -one It was treated 2-. { [4- (methyloxy) phenyl] methyl} -6,7-dihydro-2H-pyran [2,3-c] pyridazin-3 (5H) -one (2.75 g, 10.1 mmol) with anisole (10 mL) and TFA (100 mL) and warmed to 70 ° C for 24 hours. The solution was cooled and evaporated and the residue was taken up in 2.5% methanol / dichloromethane. This was applied to a column of silica gel and then elution with this solvent mixture followed by 5% methanol / dichloromethane gave the product (1.36 g, 88%). MS (+ ve ion electrospray) m / z 1 53 (MH +, 100%). (k) 6,7-Dihydro-5 / - / - pyran trifluoromethanesulfonate 2,3-clpyridazin-3-yl A solution of 6,7-dihydro-2H-pyran [2,3-c] pyridazin-3 (5H -one (152 mg, 1 mmol) in DMF (2.5 ml) under argon was cooled with ice, treated with sodium hydride (60 mg of 60% dispersion in oil, 1.5 mmol) and stirred for 1 hour, allowing to warm up to room temperature. N-Phenyl-bis (trifluoromethanesulfonimide) (505 mg, 1.4 mmol) was added and stirring continued for 2 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and water (twice), dried over magnesium sulfate and evaporated. Chromatography on silica gel, eluting with 40% ethyl acetate / hexane, gave the product as a white solid (228 mg, 80%). MS (+ ve ion electrospray) m / z 285 (MH +, 100%).

(I) 3-Ethenyl-6,7-dihydro-5 / - / - pyran [2,3-clpi dazine Argon was bubbled for 15 minutes through a solution of trifluoromethanesulfonate of 6,7-dihydro-5 / - - pyrano [2,3-c] pyridazin-3-yl (228 mg, 0.8 mmol) in, 2-dimethoxyethane (6.5 ml). Tetrakis (triphenylphosphine) palladium (0) (50 mg, 0.0475 mmol) was added and the solution was stirred for 20 minutes under argon. The mixture was then treated with potassium carbonate (11.1 mg, 0.8 mmol), water (1.9 ml) and 2,4,6-trivinylcyclotiboroxane: pyridine complex (180 mg, 0.75 mmol) (for a preparation of this reagent see F. Kerins and DF O'Shea, J. Or g.Chem. 2002, 67, 4968-4971). After stirring for 2 hours at 80 ° C, the mixture was cooled and partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were dried and the aqueous fraction was extracted twice with 20% methanol / dichloromethane. The combined organic solution was dried over magnesium sulfate, evaporated and the residue was chromatographed on silica gel, eluting with ethyl acetate to give the product as a white solid (100 mg, 77%). MS (+ ve ion electrospray) m / z 163 (MH +, 100%). (m) 6,7-Dihydro-5H-pyran [2,3-clpi dazin-3-carbaldehyde A solution of 3-ethenyl-6,7-dihydro-5H-pyran [2,3-c] pyridazine (100 mg, 0.61 7 mmol) in dioxane (5.5 ml) / water (1.1 ml) was cooled in ice / water and treated with sodium periodate (306 mg, 1.43 mmol) and an aqueous solution at pH 4. % osmium tetroxide (0.55 ml). The mixture was allowed to warm to room temperature after one hour, and after a total of 4.75 hours of stirring, the solvent was evaporated. Dioxane was added and evaporated, followed by dichloromethane and the mixture briefly maintained in an ultrasonic bath. The entire mixture was applied to a column of silica gel and eluted with ethyl acetate to provide the product (55 mg, 54%). MS (+ ve ion electrospray) m / z 165 (MH +, 100%) (n) Title compound A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1 -ij] quinolin-4- ona (E1 enantiomer) (82 mg, 0.272 mmol) and 6,7-dihydro-5 / - / - pyrano [2,3-c] pihdazin-3-carbaldehyde (50 mg, 0.305 mmol) in chloroform / methanol (1 0.6 ml / 1.6 ml) was heated with 3A molecular sieves at 65 ° C for 5 hours. The mixture was cooled, and treated with sodium t-acetoxyborohydride (15.5 mg, 0.544 mmol), and stirred at room temperature overnight. It was filtered and divided into sodium bicarbonate and 20% methanol-DCM (x3). The organic phase was dried, evaporated and chromatographed on silica gel, eluting with DCM / methanol / 0.88 ammonia (95: 5: 0.5) to provide a white foam (92 mg, 75%) MS (ion electrospray + ve) m / z 450 (MH +, 20%), 226 (100%). 5H (CDCl3, 400 MHz) 1.35-1.50 (2H, m), 1.85-2.00 (2H, m), 2.00-2.15 (3H, m), 2.1 5-2.30 (1H, m) , 2.45-2.65 (2H, m), 2.67 (1H, d), 2.80-2.90 (3H, m), 3.02 (1H, d), 3.95-4.15 (3H, m), 4.35-4.55 (4H, m), 6.62 (1 H, d), 6.86 (1 H, t), 7.30 (1 H, s), 7.39 (1 H, dd), 7.67 (1 H, d). The free base in DCM was converted to the dihydrochloride salt by adding an excess of 1 M hydrogen chloride in ether, followed by evaporation to dryness, to give a pale yellow solid (10 mg). 1 - ( { 4 - [(6,7-Dihydro-5H-pyrano [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.] Methyl) -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3.2, 1 - / y] quinolin-4-one was converted to the hydrochloride salt in a manner similar to the methods described herein.

EXAMPLE 32 9-Fluoro-1-r ((3 /?) - 3-fr (H.31oxatiolor5,4-d / y) quinolin-4-one dihydrochloride (a) (3f?) - 3-. { [(Trifluoroacetyl) amino] meth} -1,1-dimethyl ethyl pyrrolidinecarboxylate To a solution of 1,1-dimethylethyl (3 g) -3- (aminomethyl) -1-pyrrolidinecarboxylate (2 g, 10 mmol), triethylamine (2.9 ml, 21 mmol) ) and dimethylaminopyridine (0.13 g, 1 mmol) in DCM (100 mL) was added trifluoroacetic anhydride (1.5 mL, 10.5 mmol) under argon at room temperature. After 2 hours the mixture was treated with water (150 mL) and extracted with 10% methanol in DCM (3x100 mL), dried, and the solvent was evaporated. The residue was chromatographed on silica gel using gradient of 0% -20% methanol-DCM to provide the desired compound (3.12 g, 105%). 5H (CDCl 3, 400 MHz) 1.5 (9H, s), 1.64 (2H, d), 2.04 (1H, m), 2.48 (1H, m), 3.01 (0.5H, m), 3.10 (0.5H, m), 3.20-3.60 (4H, m), 6.50 (0.5H, bs), 6.80 (0.5H, bs). I 0 (b) 2,2,2-Trifluoro- / V-i (3S) -3-pyrrolidinylmethylacetamide hydrochloride A solution of (3R) -3-. { [(trifluoroacetyl) amino] methyl} -1,1-dimethylethyl pyrrolidinecarboxylate (3.12 g, 10 mmol) in DCM (50 mL) was treated slowly with a solution of 4M HCl in dioxane (25 mL). The reaction was stirred at room temperature for 3 hours. The solvent was then removed to provide a pale yellow oil (2.6 g, 12%). d? (MeOD, 400 MHz) 1.77 (1 H, m), 2.18 (1 H, m), 2.64 (1 H, m), 2.99 (1 H, m), 3.30 (1 H, m), 3.70 ( 5H, m), 9.5 (1 H, bs). (cj 2-r7-Fluoro-2- (methyloxy) -8-quinolinyl-3 - ((3 /?) - 3. {[[(trifluoroacetyl) amino] methyl) -1-pyrrolidinyl-methylpropanoate A solution of 2 - [7-Fluoro-2- (methyloxy) -8-quinolinyl] -2-methyl propenoate (2.4 g, 9.2 mmol), 2,2,2-trifluoro-A / - [(3S) -3- hydrochloride pyrrolidinylmethyl] acetamide (2.4 g, 10.12 mmol) and the thelamine (3.4 mL, 23 mmol) in DMF (30 mL) was stirred and heated at 60 [deg.] C. overnight The solvent was removed in vacuo and the residue was subjected to chromatography on silica gel using gradient of 0% -10% methanol-DCM to give a brown oil (4.2 g, 100%) MS (+ ve ion electrospray) m / z 458 (MH +). (d) methyl 3-r (3f?) - 3- (Aminomethyl) -1-pyrrolidinyl-2-r7-fluoro-2- (methyloxy) -8-quinolinylpropanoate It was treated 2- [7-fluoro-2- ( methyloxy) -8-quinolinyl] -3 - ((3R) -3-. {[[(trifluoroacetyl) amino] methyl} -1- pyrrolidinyl) propanoate methyl (3.4 g, 7.4 mmole) with a 7% solution of potassium carbonate in 2: 5 water: methanol (1 19 ml) for 4 hours. The solvents were evaporated and the residue redissolved in 20% methanol in DCM. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a 0-20% gradient of 2M ammonia-methanol in DCM to provide the desired compound (2.2 g, 82%). MS (+ ve ion electrospray) m / z 362 (MH +). (e) 3 - ((3f?) - 3-r ((1 (1, 1 -Dimethylethyl) oxylcarbonylamino) methyl-1-pyrrolidinyl) -2-f7-fluoro-2- (methyloxy) -8 methyl-3-quinolinylpropanoate A solution of methyl 3 - [(3R) -3- (aminomethyl) -1-pyrrolidinyl] -2- [7-fluoro-2- (methyloxy) -8-quinolinyl] propanoate (2.2 g , 6.1 mmol) and triethylamine (0.86 mL, 6.1 mmol) in DCM (30 mL) was treated with a solution of di-tert-butyl-dicarbonate (1.3 g, 6.1 mmol) in DCM at 0 ° C. stir the mixture at room temperature for 1 hour, water (50 ml) was added and the aqueous fraction was extracted with 20% methanol in DCM (3 × 200 ml) The organic phase was dried and the solvent was evaporated. chromatography on silica gel using gradient 0-10% methanol-DCM to give the desired compound (2.56 g, 87%). MS (+ ve ion electrospray) m / z 462 (MH +). (f) r ((3f?) - 1 - (2-r7-Fluoro-2- (methyloxy) -8-quinolinyl-1-3-hydroxypropyl) -3-pyrrolidinyl) methyl] carbamate of, 1, -dimethylethyl A solution of 3-. { (3R) -3 - [( { [(1,1-dimethylethyl) oxy] carbonyl} amino) methyl] -1-pyrrolidinyl} Methyl -2- [7-fluoro-2- (methyloxy) -8-quinolinyl] propanoate (2.56 g, 5.55 mol) in dry tetrahydrofuran (60 mL) at -78 ° C under argon was treated with a hydride solution of lithium and aluminum in tetrahydrofuran (1 M, 7.2 ml, 7.2 mmol) and then slowly allowed to warm to room temperature. After 0.5 hours, water (0.5 ml) was added followed by aqueous sodium hydroxide solution (2 M, 0.9 ml) and water (1 ml). The mixture was stirred at room temperature for 1 hour. It was filtered and evaporated, and the residue was chromatographed on silica gel using a gradient of 0-20% methanol-DCM to give the desired compound (1.88 g, 78%). MS (+ ve ion electrospray) m / z 434 (MH +). (g) (((3f?) - 1 -r (9-Fluoro-4-oxo-1,2-dihydro-4H-pyrrolor3.2.1 - // 1-quinolin-1-yl) methyl-1-3-pyrrolidinyl}. methyl), 1-dimethylethyl carbamate A solution of [((3f?) - 1 -. {2- [7-fluoro-2- (methyloxy) -8-quinolinyl] -3-hydroxypropyl} -3 1,1-dimethylethyl-pyrrolidinyl) methyl] carbamate (1.88 g, 4.4 mmol) in chloroform (20 mL) was treated with diisopropylethylamine (1.2 mL, 7.04 mmol) and methanesulfonyl chloride (0.45 mL, 5.5 mmoles) at 0 ° C under argon The mixture was stirred at 0 ° C for 0.5 hour, heated to rt and stirred for 1 hour then heated at 45 ° C overnight, and allowed to cool to room temperature. The mixture was diluted with DCM and washed with sodium bicarbonate solution.The aqueous phase was extracted with 10% methanol in DCM (3 x 80 mL) The organic phase was dried and the solvent was evaporated. chromatography on silica gel using 0-10% methanol gradient -DCM to give the desired compound (1.47) g, 84%). MS (+ ve ion electrospray) m / z 402 (MH +). (h) 1 - (1 (3ff) -3- (Aminomethyl) -1-pyrrolidinylmethyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - // 1-quinolin-4-] One was dissolved ( { (3R) -1 - [(9-fluoro-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-1-yl) methyl] 3-1-dimethylethyl-1,3-pyrrolidinyl.] Methyl) carbamate (1.47 g, 3.7 mmol) in dichloromethane (15 ml) and trifluoroacetic acid (15 ml) and stirred at room temperature for 30 minutes, then it evaporated to dryness. The residue was redissolved in methanol and stirred with excess ion exchange resin Amberlyst® A21 (Aldrich: A weakly basic macroreticular resin with alkylamine functionality) for 1 hour and then filtered. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using a 0-20% gradient of 2 M ammonia in methanol-DCM to provide the desired compound (0.75 g, 68%) MS (electrospray ions + ve) m / z 302 (MH +). (i) Title compound A solution of 1 -. { [(3 R) -3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - //] quinolin-4-one (100 mg) and [1, 3] oxatiolo [5,4-c] pyridine-6-carbaldehyde (for a synthesis, see international publication WO2004058144, Example 61) (55 mg) in methanol (4 ml) and chloroform (4 ml) was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (210 mg) was added and the reaction was stirred at room temperature. The solvent was evaporated and the residue was chromatographed on silica gel using a gradient of 0-20% methanol-DCM to give the desired compound (137 mg) as an acetate salt. MS (+ ve ion electrospray) m / z 453 (MH +). d? (CDCl 3, 400 MHz) 1.53 (1 H, m), 2.00 (2H, m), 2.30-3.00 (8H, m), 3.80-4.10 (3H, m), 4.50 (2H, m), 4.88 ( 2H, bs), 5.75 (2H, s), 6.61 (1 H, d), 6.86 (1 H, t), 7.19 (1 H, s), 7.38 (1 H, m), 7.66 (1 H, d ), 8.03 (1 H, d). The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 33 1 - (r (3?) - 3- ( { R (7-Chloro-3-oxo-3,4-dihydro-2H-pyrido3.2-biri, 4] oxazin-6-yl dihydrochloride methylamino.) methyl) -1-pyrrolidininmethyl.}. -9-fluoro-l, 2-dihydro-4H-pyrrolo [3,2,1-quinolin-4-one] This was prepared from 1 -. { [(3f?) - 3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4-one (50 mg) and 7-chloro-3-oxo-3,4-dihydro-2 / - / -pyrid [3,2-t > ] [1,4] oxazine-6-carboxaldehyde (for a synthesis, see international publication WO2003064421 Example 1 (c)) (35.2 mg) by the general method of Example 32 (i). The product was chromatographed on silica gel using a gradient of 0-1 5% methanol-DCM to provide the desired compound (66 mg) as an acetate salt. MS (+ ve ion electrospray) m / z 498 (MH +). d? (CDCl 3, 100 MHz) 1.55 (1 H, m), 2.00 (2H, m), 2.30-3.00 (8H, m), 4.00 (3H, m), 4.50 (2H, m), 4.6 (2H, s), 5.79 (2H, bs), 6.62 (1 H, d), 6.85 (1 H, m), 7.23 (1 H, s), 7.38 (1 H, m), 7.66 (1 H, m). The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 34 9-Fluoro-1- (r (3 /?) - 3 - ((r (3-oxo-3,4-dihydro-2-pyridyl-3-to] [1,4] thiazine-6-dihydrochloride -yl) methyl amino) methyl) -1-pyrrolidinyl] methyl.} -1, 2-dih pyrrolo [3,2,1-] quinolin-4-one This was prepared from 1 -. { [(3 R) -3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - /)] quinolin-4-one (100 mg) and 3-0X0-3, 4-dihydro-2H-pir Do [3, 2- £ > ] [1,4] thiazin-6-carboxaldehyde (for a synthesis, see international publication WO 2004058144A2 Example 7 (d)) (64.5 mg) by the general method of Example 32 (i). The product was chromatographed on silica gel using a gradient of 0-20% methanol-DCM to give the desired compound (127 mg) as an acetate salt. MS (+ ve ion electrospray) m / z 480 (MH +). d? (CDCl 3, 400 MHz) 1.53 (1 H, m), 2.00 (2H, m), 2.30-3.00 (8H, m), 3.15 (1 H, bs), 3.86 (2H, s), 4.00 (1 H, m), 4.49 (2H, m), 6.63 (1 H, m), 6.87 (1 H, m), 6.97 (1 H, d), 7.39 (1 H, m), 7.59 (1 H, d ), 7.67 (1 H, d). The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 35 9-Fluoro-1- (r (3?) - 3- (. {R (3-Oxo-3,4-dihydro-2H-pyrido-2,3-b1f1-l41-oxazin-6-yl) methyl-amino acid dihydrochloride} methyl) -1-pyrrolidininmethyl} -1, 2-dihydro-4 pyrrolor3,2,1- / lquinolin-4-one This was prepared from 1 -. { [(3 R) -3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4-pyrrolo [3,2,1 - /] quinolin-4-one (50 mg) and 3-0X0-3, 4-dihydro-2 / - / - pyrido [3,2- £ > ] [1,4] oxazin-6-carboxaldehyde (for a synthesis, see international publication WO2004058144 Example 1) (30 mg) by the general method of Example 32 (i). The product was chromatographed on silica gel using a gradient of 0-20% methanol-DCM to give the desired compound (63 mg) as an acetate salt. MS (+ ve ion electrospray) m / z 464 (MH +). The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 36 1-R ((3 /?) -3- (r (2,3-dihydroH, 41dioxinof2,3-c1pyridin-7-ylmethyl) amino] methyl} -1-pyrrolidinyl) metin-9 dihydrochloride -fluoro-1, 2-dihydro-4H-pyrrolor3,2,1 - // 1-quinolin-4-one This was prepared from 1 -. { [(3R) -3- (aminomethyl) -1-pyrrolidinium (] methyl.}. -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4-ione (100 mg) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (for a synthesis, see international publication WO2003087098 Example 20 (e)) (54.8 mg) by the general method of Example 32 (i) The product was chromatographed on silica gel using a gradient of 0-20% methanol -DCM to provide the desired compound (140 mg) as an acetate salt.SS (electrospray + ve ion) m / z 451 (MH +) The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 37 9-Fluoro-1 - [(3. {[[[[1, 31-oxatoolor-5,4-c1pyridin-6-ylmethyl) aminolmethyl} -1-pyrrolidinyl) methylene-1 dihydrochloride , 2-dihydro-4H-pyrrolof3,2,1- // lquinolin-4-one This was prepared from 1 -. { [3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - //] quinolin-4-one (prepared from 3- (aminomethyl) -l-pyrrolidinecarboxylate of 1.1 , -dimethylethyl by the general method described for the (R) enantiomer in Example 32) (100 mg) and [1, 3] oxathiolo [5,4-c] pyridin-6-carbaldehyde (for a synthesis, see International Publication WO2004058144, Example 61) (55 mg) by the general method of Example 32 (i). The product was chromatographed on silica gel using a gradient of 0-20% methanol-DCM to give the desired compound (10 mg) as an acetate salt. MS (+ ve ion electrospray) m / z 453 (MH +). The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 38A Dihydrochloride of 1 -. { 3 3 - ((r (7-chloro-3-oxo-3,4-dihydro-2H-pyrido-3,2-b1 [1,4-oxazin-6-yl) -methamino} methyl) -1-pyrrolidinyl] methyl > -9-fluoro-1, 2- dihydro-4H-pyrrolof312.1 - // lquinolin-4-one This was prepared from 1 -. { [3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - //] quinolin-4-one (100 mg) and 7-chloro-3-oxo-3,4-dihydro -2H-pyrido [3,2-i)] [1,4] oxazine-6-carboxaldehyde (for a synthesis, see international publication WO2003064421 Example 15 (c)) (58 mg) by the general method of Example 32 ( i). The product was chromatographed on silica gel using a gradient of 0-20% methanol-DCM to give the desired compound (105 mg) as an acetate salt. MS (+ ve ion electrospray) m / z 498 (MH +). The acetate salt in DCM was converted to the dihydrochloride salt by adding an excess of 4M hydrogen chloride in dioxane, followed by evaporation to dryness, and trituration with ether to give a solid.

EXAMPLE 38B Hydrochloride of Isomers 1, 2, 3 and 4 of 1- (f3 - ((r (7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3Í2-fo1f1141oxazin-6-yl) methyl] amino .). methyl) -1- pyrrolidinyl-1-methyl.}. -9-fluoro-1,2-dihydro Dihydrochloride of 1 -. { [3- ( { [(7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2- £ &]; [1,4] oxazin-6-yl) methyl] amino.} methyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - pyrrolo [3,2,1 - //] quinolin-4-one (40 mg) was subjected to purification by preparative chiral hplc on a Chiralpak AD-H column of 5um eluting with 80: 20: 0.1 acetonitrile: methanol: isopropylamine, providing Isomer 1 (6.0 mg), Isomer 2 (10.0 mg), Isomer 3 (9.0 mg) and Isomer 4 (9.2 mg), all of which with purity > 99.5%. Then, these free bases were converted into the hydrochloride salts.

EXAMPLE 39 Hydrochloride of 1-r (4-. {R (3-oxo-3,4-dihydro-2H-pyridyl) methyl) amino} -1-piperidinyl) methyl] -1,2-dihydro- ^ 4-one (a) (2 £) -A / - (2-Bromophenyl) -3-phenyl-2-propenamide To a solution of 2-bromoaniline (22.27 g, 0.13 mol) and potassium carbonate (26.8 g, 0.13 mol) in acetone (50 ml) and water (65 ml) at 0 ° C cinnamoyl chloride (21.57 g, 0.13 mol) was added in portions over 15 minutes. Then another 150 ml of acetone and water were added to facilitate agitation. The reaction was stirred for 2 hours at 0 ° C before being added to ice water (400 ml). The resulting solid was filtered, washed with water (500 ml) and dried in vacuo. The resulting solid was triturated with hot hexane and dried in vacuo to provide the desired compound as a white solid (29.50 g, 75%). MS (ES +) m / z 303 (MH +, 100%). (b) 8-Bromo-2 (1 H) -quinolonone To a suspension of (2E) -A / - (2-bromophenyl) -3-phenyl-2-propenamide (22.9 g, 76.0 moles) in chlorobenzene (100 ml) under an argon atmosphere at room temperature was added aluminum trichloride (60.78 g, 133.34 mmol). The reaction was heated for 2 hours at 125 ° C after that period of time the reaction mixture was cooled to 50 ° C before being carefully added to ice water (3 I). The resulting solid was filtered and then washed with water (500 ml), then triturated with hot ethanol, filtered and dried in vacuo to provide the desired compound as a white solid (7.39 g, 75%). MS (ES +) m / z 225 (MH +, 100%). (c) 8-Bromo-2- (methyloxy) quinoline To a suspension of 8-bromo-2 (1 / - /) - quinolinone (2.76 g, 12.32 mmole) in N, N-dimethylformamide (40 ml) under one atmosphere of argon at 0 ° C was added potassium carbonate (34 g, 24.63 mmoles). Then the reaction was stirred for 15 minutes before methyl iodide (0.91 ml, 14.78 mmol) was added. The reaction was allowed to warm to room temperature and then stirred for 3 hours. Then the reaction mixture was evaporated and the residue was treated with dichloromethane and water. The aqueous fraction was extracted again with dichloromethane. Then the combined organic fractions were dried (MgSO), the solvent was removed under reduced pressure and then the residue was chromatographed on silica gel using a gradient of methanol-dichloromethane. This provided the desired compound as a yellow solid (2.16 g, 74%). MS (ES +) m / z 239 (MH +, 100%). (d) f2- (Methyloxy) -8-quinolinyl] bico acid According to the literature procedure (Li, W., Nelson, D., Jensen, M .; Hoerrner, R.; Cai, D.; Larsen, R., Reider, P J. Org. Chem. (2002), 67 (15), 5394) a solution of 8-bromo-2- (methyloxy) quinoline (1.95 g, 8.19 mmol) and triisopropylborate (2.30 mi, 9.83 mmoles) in toluene (20 ml) and tetrahydrofuran (5 ml) under an argon atmosphere was cooled to -78 ° C. Then a solution of n-butyllithium (2.5M in hexanes, 3.9 ml, 9.83 mmol) was added dropwise over 20 minutes. The reaction was stirred at -78 ° C for 2 hours and then warmed to -20 ° C. Then the reaction was quenched with 2M HCl solution (10 mL) and treated with dichloromethane. The aqueous fraction was extracted again with dichloromethane. Then the combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was triturated with hexane to provide the desired compound as a yellow solid (453 mg, 40%). MS (ES +) m / z 204 (MH +, 100%). (e) Methyl 2- [2- (methyloxy) -8-quinolinyl-1-2-propenoate To a solution of methyl 2-bromo-2-propenoate (452 mg, 2.74 mmol) (for a synthesis see Rachon, J. Goedken, V., Walborsky, HJ Org. Chem. (1989), 54 (5), 1006) in degassed tetrahydrofuran (10 ml) under an argon atmosphere was added [2- (methyloxy) -8 acid. -quinolinyljorbital (506 mg, 2.49 mmol), bis (tri-1-butylphosphine) palladium (0) (25 mg, 0.05 mmol), bis (dibenzylideneacetone) palladium (0) (23 mg, 0.025 mmol) and potassium fluoride ( 477 mg, 8,217 mmoles). The reaction was heated at 70 ° C for 24 hours and then treated with water and dichloromethane. The aqueous fraction was extracted again with dichloromethane. Then the combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a gradient of ethyl acetate-hexane. This afforded the desired compound as a yellow solid (381 mg, 63%). MS (ES +) m / z 244 (MH +, 100%), 212 (80%). (f) 3-r4- ( { f (1, 1 -Dimethylethyl) oxylcarbonyl) amino) -1-pipe dinin-2-r2- (methyloxy) -8-quinolinylpropanoate methyl To a solution of 2- [2- (Methyloxy) -8-quinolinyl] -2-methyl propenoate (381 mg, 1.57 mmol) in? /,? / '- dimethylformamide (5 mL) and tetramethylguanidine (0.05 mL) was added 4- 1, 1, -dimethylethyl piperidinylcarbamate (345 mg, 1.73 mmol). The reaction mixture was stirred for 12 hours at 60 ° C, after this period of time the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol-dichloromethane. This gave the desired compound as a yellow solid (546 mg, 79%).

MS (ES +) m / z 444 (MH +, 100%). (1,1-dimethylethyl) -1- (3-hydroxy-2- [2- (methyloxy) -8-quinolininpropyl) -4-pperidinyl) carbamate To a solution of 3- [4- ( Methyl {[[(1, 1 -dimethylethyl) oxy} carbonyl} amino) -1-piperidinyl] -2- [2- (methyloxy) -8-quinolinyl] propanoate (546 mg, 1.2 mmoles) in tetrahydrofuran (20 ml) at -78 ° C was added lithium aluminum hydride (1 M in tetrahydrofuran), 1.50 ml, 1.48 mmol). The reaction was then stirred at -78 ° C for 0.5 hour before water (0.2 ml) was added and then a solution of 2M NaOH (0.4 ml) and the mixture was heated to 25 ° C. The mixture was then filtered, dried (MgSO 4) and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol-dichloromethane. This provided the desired compound as a white solid (370 mg, 72%). MS (ES +) m / z 416 (MH +, 100%). (h). { 1-r (4-Oxo-1, 2-dihydro-4 / - / - pyrrolor3l2l1 - // lquinolin-1-yl) methyl-4-piperidinylcarbamate 1,1-dimethylethyl A solution of (1 -. { 3-hydroxy-2- [2- (methyloxy) -8-quinolinyl] propyl] -4-piperidinyl) carbamate 1,1-dimethylethyl ester (370 mg, 0.892 mmol) in chloroform (20 ml) at 0 ° C was added diisopropylethylamine (0.33 ml, 1.96 mmoles) and methanesulfonic anhydride (0.186 g, 1.07 mmoles). Then the reaction was heated at 70 ° C for 5 hours and then treated with dichloromethane and water. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol-dichloromethane to provide the desired compound (0.276 g, 81%). MS (ES +) m / z 384 (MH +, 10%), 284 (100%). (i) 1 - [(4-Amino-1-piperidinyl) methyl-1, 2-dihydro-4 / - / - pyrrolo [3,2,1- // 1-quinolin-4-one dihydrochloride A solution of . { 1 - [(4-Oxo-1,2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-1-yl) methyl] -4-piperidinyl} 1, 1, -dimethylethyl carbamate (276 mg, 0.721 mmol) in chloroform (5 mL) and MeOH (5 mL) was treated with 4M HCl in dioxane (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to provide the desired compound (0.283 g, 10%) as the slightly impure dihydrochloride salt which was used without further purification. MS (ES +) m / z 306 (M + Na, 10%), 284 (MH +, 100%).

(!) Title compound A a solution of the dihydrochloride salt of 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4 / - / - pyrrolo [3,2,1 - / ] quinolin-4-one (32 mg, 0.089 mmol) in methanol (0.1 ml) and dichloromethane (1 ml) was added triethylamine (24 μ ?, 0.178 mmol) and 3-oxo-3,4-dihydro-2 H- pyrido [3,2-i)] [1,4] thiazine-6-carboxaldehyde (for a synthesis, see international publication WO2003087098, Example 301 (d)) (17 mg, 0.089 mmol). This mixture was stirred for 1 hour at room temperature before sodium triacetoxyborohydride (57 mg, 0.178 mmol) was added and the reaction was stirred for an additional 1 hour. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using a gradient of methanol-dichloromethane. This provided the title compound as a yellow solid (39 mg, 95%). MS (ES +) m / z 462 (MH +, 100%). d? (CDCI3, 400 MHz) 1 .66-1 .75 (2H, m), 2.03-2.22 (3H, m), 2.55 (1 H, dd), 2.79 (1 H, dd), 2.81 -2.89 (1 H, m), 2.96-3.1 1 (3 H, m), 3.47 (2 H, s), 3.84-3.89 (1 H, m ), 3.91 (2H, s), 4.28 (1 H, dd), 4.50 (1 H, dd), 6.69 (1 H, t), 7.01 (1 H, d), 7.16 (1 H, t), 7.41 (2H, d,), 7.50 (1 H, br s), 7.60 (1 H, d), 7.72 (1 H, d). This material was converted to the hydrochloride by dissolving it in dichloromethane / methanol and adding 1 equivalent of 1 M HCl / diethyl ether and then evaporating to dryness.

EXAMPLE 40 1- (. {4 - [(2,3-D, Hydro [1,4] dioxino [2,3-clpyridin-7-ylmethyl) amino] -1-piperidinyl} methyl] hydrochloride 1, 2-dih ^^ 4 -one The title compound was synthesized from the dihydrochloride salt of 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4 -one (58 mg, 0.163 mmol) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carboxaldehyde (24 mg, 0.148 mmol) (for a synthesis, see international publication WO2004058144 , Example 2 (c)) by the general method of Example 39 (j), to provide the desired compound (69 mg, 98% yield). MS (ES +) m / z 433 (MH +, 00%), 284 (30%) 5H (CDCl 3, 400 MHz) 1.64-1.75 (2H, m), 2.02-2.18 (3H, m), 2.56. (1 H, dd), 2.73 (1 H, dd), 2.78-2.84 (1 H, m), 2.96-3.1 1 (4H, m), 3.85-3.95 (1 H, m), 4.02 (2H, s ), 4.25-4.35 (4H, m), 4.47-4.53 (1 H, m), 6.68 (1 H, d), 6.94 (1 H, s), 7.16 (1 H, t), 7.41 -7.44 (2H , m), 7.97 (1 H, d), 8.10 (1 H, s) This material was converted to the hydrochloride salt by dissolving it in dichloromethane / methanol and adding 1 equivalent of 1M HCl / diethyl ether and then evaporating to dryness.

EXAMPLE 41 1 - (. {4 - [([1, 3] oxathiolo [5,4-c1pyridin-6-ylmethyl) aminol-1-piperidinyl} methyl) -1,2-dihydro-4H- hydrochloride pyrrolo [3,211 - // lquinolin-4-one] The title compound was synthesized from the dihydrochloride salt of 1 - [(4-amino-1-pipehdinyl) methyl] -1,2-dihydro-4 / - / - pyrrolo [3,2,1- // ] quinolin-4-one and [1, 3] oxathiolo [5,4-c] pi dina-6-carbaldehyde (for a synthesis, see international publication WO2004058144, Example 61) according to the general method of Example 39 ( j), with a yield of 76%. MS (ES +) m / z 435 (MH +, 100%), 284 (40%) d? (CDCI3, 400 MHz) 1.64-1.73 (2H, m), 2.00-2.03 (2H, m), 2.11-2.21 (2H, m), 2.55 (1H, dd), 2.70-2.82 (2H, m), 2.96 -3.11 (2H, m), 3.85-3.89 (1H, m), 4.00 (2H, s), 4.29 (1.H, dd), 4.52 (1H, dd), 5.76 (2H, s), 6.69 (1H , d), 7.16 (1H, t), 7.29 (1H, s), 7.41-7.43 (2H, m), 7.71 (1H, d), 8.00 (1H, s) This material was converted to the hydrochloride by dissolving it in dichloromethane / methanol and adding 1 equivalent of 1M HCl / diethyl ether and then evaporating to dryness.

EXAMPLE 42 1-R Hydrochloride (4-fr (7-chloro-3-oxo-3,4-dihydro-2H-pyrido-3-.2- 14] oxazin-6-yl) methyl-amino} -1-piperidinyl) methyl -1, 2-dihydro-4H-pyrrolo [3,2,1- / 71-quinolin-4-one The title compound was synthesized from the dihydrochloride salt of 1 - [(4-amino-1-piperidinyl) meth] -1, 2-dihydro-4 / - / - pyrrolo [3,2, 1 - / y] quinolin-4-one and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-¿> ] [1,4] oxazin-6-carboxaldehyde (for a synthesis, see international publication WO2003064421, Example 15 (c)) by the general method of Example 39 (j), with a yield of 96%. MS (ES +) m / z 479 (MH +, 00%) d? (CDCl 3, 400 MHz) 1.88-2.27 (5H, m), 2.57 (1 H, dd), 2.78 (1 H, dd), 3.01 -3.14 (4H, m), 3.85-3.92 (1 H, m ), 4.19 (2H, s), 4.30 (1 H, dd), 4.51 (1 H, dd), 4.59 (2 H, s), 6.67 (1 H, d), 7.16 (1 H, t), 7.24 ( 1 H, s), 7.40-7.43 (2H, m), 7.71 (1 H, d) This material was converted to the hydrochloride by dissolving it in dichloromethane / methanol and adding 1 equivalent of 1 M HCl / diethyl ether and then evaporating to dryness .

EXAMPLE 43 ^ - Hydrochloride. { . { 4 - \ ^ 3A-d? DrO'2H '\' rano \ 2,3-c] p r \ d'm-6 ^ ilmethyl) aminol-1-piperidinyl} methyl) -1,2-dihydro-4H-pyrrolor3,2 - // 1-quinolin-4-one The title compound was synthesized from the dihydrochloride salt of 1 - [(4-amino-1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3.2, 1 - /)] quinoline- 4-one and 3,4-dihydro-2 / - / - pyrano [2,3-c] pyridine-6-carbaldehyde (for a synthesis, see international publication WO2004058144, Example 126 (e)) according to the general method of Example 39 (j), with a 100% yield. MS (ES +) m / z 431 (MH +, 100%) d? (CDCl 3, 400 MHz) 1.85-1.88 (2H, m), 1.90-2.21 (4H, m), 2.55 (1H, dd), 2.72 (1H, d), 2.80 (2H, t), 2.94-3.15 (5H, m), 3.84-3.87 (1H, m), 4.02-4.29 (5H, m), 4.46 (1H, dd), 6.67 (1H, d), 7.16 (1 H, t), 7.32 (1 H, s), 7.41 -7.44 (2H, m), 7.72 (1 H, d), 8.06 (1 H, s) This material was converted to the hydrochloride by dissolving it in dichloromethane / methanol and adding 1 equivalent of 1 M HCl / diethyl ether and then evaporating to dryness.

EXAMPLE 44 1-R (3- (r (2,3-dihydron, 41-dioxin-2-2,3-c1-pyridin-7-ylmethyl) aminolmethyl} -1-pyrrolidinyl) methyl-1-9-fluoro-1,2-dihydroxyhydrochloride 4H ^ pyrrolor3,2,1 - //] quinolin-4-one This was prepared from 1 -. { [3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - //] quinolin-4-one and 2,3-dihydro [1,4] dioxin [2,3-c] ] pyridine-7-carbaldehyde (for a synthesis, see international publication WO2003087098 Example 20 (e)) by the general method of Example 36.

EXAMPLE 45 Dihydrochloride of the E2 Enantiomer 1- (. {4-r (6,7-dihydrori.41oxatiinor2.3-c1-pyridazin-3-ylmethyl) amino-1-piperidinyl}. Methyl) -9-fluoro-1-hydroxy -1, 2- dihydro-4H-pyrrolo [3,2,1 - //] quinolin-4-one This was prepared from the E2 enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2, di, and 6,7-dihydro [1,4]. ] oxatun [2,3-c] pyridazin-3-carbaldehyde by the general method of Example 29.

EXAMPLE 46 9-Fluoro-1- (r3 - ((I (3-oxo-3,4-dihydro-2H-pyrido3.2-, 4] thiazin-6-yl) methylamino} methyl] -1,9-dihydrochloride -pyrrolidin-methyl.} -1, 2-dihydro-4H-pyrrolo [3,2,1 - //] quinolin-4-one This was prepared from 1 -. { [3- (aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-4-one and 3-oxo-3,4-dihydro-2H-pyrido [3,2- / b] ] [1,4] thiazin-6-carbaldehyde (for a synthesis, see international publication WO2004058144A2 Example 7 (d)) by the general method of Example 34.

EXAMPLE 47 Hydrochloride of the E1 Enantiomer of 1- (. {4-G (6,7- < ????? G? G1, 4? (?????? 2,3- c1piridazin-3-ilmeti >) amino1-1-piperidinyl.} methyl) -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1- / lquinolin-9-carbonitrile (a) methyl 2-r7-Bromo-2- (methyloxy) -8-quinolinyl-1-3-r4 - ((f (1,1-dimethylethyl) oxy-carbonyl}. amino) -1-piperidinyl-1-propanoate A solution of 2- [Methyl 7-bromo-2- (methyloxy) -8-quinolinyl] -2-propenoate (12.4 g, 38.5 mmol), 1,1-dimethylethyl 4-piperidinylcarbamate (8.5 g, 42.3 mmol) and 1 , 1, 3.3, tetramethylguanidine (10 drops) in dry DMF (120 ml) was heated at 70 ° C for 3 days, and more 1,1-dimethylethyl 4-piperidinylcarbamate (1.5 g) was added and the The mixture was heated at 100 ° C for a further day.The mixture was evaporated and the residue was chromatographed on silica eluting with 2% methanol in dichloromethane to give a pale yellow solid (17.1 g, 85%).

MS (+ ve ion electrospray) m / z 523 (MH +). (b) (1 - { 2- [7-Bromo-2- (methyloxy) -8-quinolinyl-3-hydroxypropyl) -4-piperidine-D-carbamate 1,1-dimethylethyl A solution of 2- [7-bromo] -2- (methyloxy) -8-quinolinyl] -3- [4- ( { [(1,1-dimethylethyl) oxy] carbonyl} amino) -1-piperidinyl] propanoate methyl (1.7 g, 32.5 mmole) in THF (300 ml) at -78 ° C under argon was treated with a solution of lithium aluminum hydride in THF (1 M, 39 ml, 39 mmol). The reaction was stirred at -78 ° C for 1 hour then allowed to stir at room temperature for 2 hours. Water (18 ml) was added followed by aqueous sodium hydroxide solution (2M, 40 ml) and more water (20 ml). Filtration and evaporation provided a solid. This was chromatographed eluting with 0-20% methanol in dichloromethane to give a yellow solid (9.9 g, 61%). MS (+ ve ion electrospray) m / z 495 (MH +). (c). { 1 - [(9-Bromo-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-lquinolin-1-yl] methyl-4-piperidinyl} 1, 1, -dimethylethyl carbamate A solution of (1 -. {2- 2- [7-bromo-2- (methyloxy) -8-quinolinyl] -3-hydroxypropyl} -4-piperidinyl) carbamate of 1, 1-dimethylethyl (9.9 g, 20 mmol), methanesulfonic anhydride (4.2 g, 24 mmol) and diisopropylethylamine (7.7 mL, 44 mmol) in chloroform (260 mL) was heated at 60 ° C (oil bath temperature) for 1 hour, then heated to reflux for 1.5 hours. The mixture was evaporated and the residue was chromatographed eluting with 0-30% methanol ethyl acetate to give a white solid (4.7 g, 51%). MS (+ ve ion electrospray) m / z 463 (MH +). (d) 1, 1, -dimethylethyl (1-r (9-cyano-4-oxo-1,2-dihydro-4H-pyrrolor-3,1,1-l-quinolin-1-yl) methyl-1-4-piperidinyl) carbamate A mix of . { 1 - [(9-bromo-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-1-yl) methyl] -4-pipe dinil} 1, 1, -dimethylethyl carbamate (4.7 g, 10.2 mmol), copper (I) cyanide (3.3 g, 36.6 mmol) and DMF (60 mL) was heated at 135 ° C for 2 hours. The mixture was evaporated to dryness and the residue was partitioned between saturated aqueous ammonia and dichloromethane. The aqueous phase was further extracted with dichloromethane and the combined organic extracts were dried and evaporated (3.2 g). The aqueous phase was further extracted twice with ethyl acetate and these extracts were combined, dried and evaporated (0.5 g). The residues (3.7 g in total) were combined and chromatographed eluting with 0-15% methanol in ethyl acetate to give a white solid (2.7 g, 65%). MS (+ ve ion electrospray) m / z 409 (MH +). . { and} 1 - [(4-Amino-1-p-peridinyl) methyl-4-oxo-1,2-dihydro-4H- ?? p ?? G3,2, 1-ylquinoline-9-carbonitrile A solution of . { 1 - [(9-cyano-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-1-yl) methyl] -4-piperidinyl} carbamate of 1, 1-dimethylethyl (2.65 g, 6.5 mmol) in dichloromethane (50 ml) was treated with TFA (50 ml). After 30 minutes the mixture was evaporated and the residue azeotropically treated twice more with chloroform then triturated with ether (three times). The resulting solid was redissolved in dichloromethane / methanol (60 ml / 120 ml) and treated with MP-carbonate resin (3 mmole of carbonate per gram, 22 g, 66 mmole). The resin was removed by filtration, washing with dichloromethane and methanol. Evaporation of the filtrate gave a white solid (2 g) MS (+ ve ion electrospray) m / z 309 (MH +). (f) Hydrochloride of the E1 enantiomer of 1 - ((4-f (6,7-dihydrofl41-dioxinof2-3-clpyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -4-oxo-1,2-dihydro -4H-pyrrolo [3,2,1-1-quinoline-9-carbonitrile A solution of 1 - [(4-amino-1-piperidinyl) methyl] -4-oxo-1,2-dihydro-4H-pyrrolo [3, 2, 1 -ij] quinoline-9-carbonitrile (200 mg) and 6,7-dihydro [1,4] dioxino [2,3-c] pyridazine-3-carbaldehyde (100 mg) in dichloromethane / methanol (4 ml / 1 mL) was treated with sodium triacetoxyborohydride (400 mg) plus 6,7-dihydro [1,4] dioxino [2,3-c] pyridazine-3-carbaldehyde (100 mg) plus sodium triacetoxyborohydride (200 mg). mg) were added in portions over 6 hours The mixture was treated with saturated aqueous sodium bicarbonate solution A solid was isolated by filtration and then chromatographed eluting with 0-40% methanol in dichloromethane to give a white solid (1 10 mg) d? (CDCl 3, 250 MHz) 1 .38-1 .50 (2H, m), 1 .85-2.00 (2H, m), 2.10-2.22 (1 H, dt), 2.22- 2.35 (1 H, dt), 2.50-2.60 ( 1 H, m), 2.75-2.85 (1 H, m), 2.90-3.10 (2H, m), 4.00 (2H, s), 4.00-4.08 (1 H, m), 4.35-4.40 (2H, m) , 4.45-4.60 (4H, m), 6.82 (1 H, d), 7.08 (1 H, s), 7.38 (1 H, d), 7.55 (1 H, d), 7.78 (1 H, d). This was separated using preparative chiral hplc in the two enantiomers, El and E2, using a Chiralpak AD-H column of 5 um, eluting with 80: 20: 0.1 - CH3CN: CH3OH: lsopropylamine. The fastest moving enantiomer (designated E1) was converted to the title compound by treatment with 1 equivalent of hydrochloric acid to provide a solid (50 mg), > 98% e.e. MS (+ ve ion electrospray) m / z 459 (MH +).

EXAMPLE 48 E2 Enantiomer Hydrochloride of 1- (. {4-r (6J-dihydrori, 4ldiox¡nor2.3-clpiridazin-S-ilmetiQaminol-l-piperidini ^ methyl -oxo-l ^ -dihydro ^ H- pyrrolo [ 3,2,1- /] quinoline-9-carbonitrile The free base of the title compound was prepared by preparative chiral hplc from the racemic material (the enantiomer traveling slower, see Example 47). This material was converted to the title compound with 1 equivalent of hydrochloric acid to give a solid (54 mg), > 98% e.e. MS (+ ve ion electrospray) m / z 459 (MH +).

EXAMPLE 49 Dihydrochloride of 1 - (R / S) -r (4-M3S) -2,3-dihydroM, 41-dioxinor-2,3-6] pyridin-3-ylmethinylamino} -1-piperidinyl) m pyrrolo [3,2,1- / y] quinolin-4-one (a) 3- (1,4-Dioxa-8-azaspiror4.51dec-8-yl) -2- (R / S) -7-fluoro-2- (methyloxy) -8-quinolinylpropanoate methyl A mixture of 2 - [7-Fluoro-2- (methyloxy) -8-quinolinyl] -2-methyl propenoate (10.55 g, 40 mmol), 1,4-dioxa-8-azaspiro [4.5] decane (6.28 g, 44 moles) and 1, 1, 3,3-tetramethylguanidine (2.4 ml) in dimethylformamide (200 ml) was heated under reflux overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and water. The aqueous phase was extracted again with ethyl acetate and the organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-10% methanol / dichloromethane gave the product (11.141 g, 71%). MS (+ ve ion electrospray) m / z 405 (MH +). (b) 3- (1,4-Dioxa-8-azaspiror4.51dec-8-yl) -2- (R / S) -f7-fluoro-2- (methyloxy) -8-quinolin-1-propanol To a solution of 3- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) -2- (R / S) - [7-fluoro-2- (methyloxy) -8-quinolinyl] propanoate of methyl (10.85 g, 27 mmol) in anhydrous THF (130 ml) at -70 ° C was added dropwise a solution of lithium aluminum hydride (2M in THF, 14 ml). The mixture was stirred for 5 h while allowing to warm to -10 ° C. Water (5.5 ml) was added carefully, followed by sodium hydroxide (2M, 6.5 ml), ether (87 ml) and sodium sulfate. After stirring at room temperature, the mixture was filtered through kieselguhr, washed with ethyl acetate, and the filtrate was evaporated to give the crude alcohol (1.1 g). MS (+ ve ion electrospray) m / z 377 (MH +). (c) 1 - (R / SH, 4-Dioxa-8-azaspiror4.51dec-8-ylmethyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2,1- / | quinolin-4-one A crude sample of 3- (1, 4-dioxa-8-azaspiro [4.5] dec-8-yl) -2- (R / S) - [7-fluoro-2- (methyloxy) -8-quinolinyl] -1-propanol (1 1 .25 g) was stirred with methanesulfonic anhydride (5.92 g, 34 mmol) and di-isopropylethylamine (1.1 ml, 67 mmol) in dry chloroform (130 ml) at 70 ° C for three days. The mixture was washed with aqueous sodium bicarbonate, the aqueous phase was extracted with dichloromethane, and the organic fractions were dried and evaporated to give a brown solid (7.70 g). MS (+ ve ion electrospray) m / z 345 (MH +). (d) 9-Fluoro-1 - (R / SH (4-oxo-1-piperidinyl) methyl-1-, 2-dihydro-4 / - / - pyrrolo [3,2,1- // 1-quinolin-4-one] Heated 1 - (R / S) - (1,4-Dioxa-8-azaspiro [4.5] dec-8-ylmethyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1 - /)] quinolin-4-one (7.70 g, 22 mmol) in acetone (600 ml) and 5M hydrochloric acid (300 ml) overnight at 60 ° C. The mixture was basified with sodium bicarbonate and extracted with dichloromethane. The organic extracts were dried and evaporated. Chromatography on silica, eluting with 0-10% methanol / dichloromethane, gave a yellow solid (4.44 g, 67%). MS (+ ve ion electrospray) m / z 301 (MH +). (e) Compound of the title 9-Fluoro-1 - (R / S) - [(4-oxo-1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3.2, 1 - / y] quinolin-4-one (0.10 g, 0.33 mmol) and [(3S) -2,3-dihydro [1,4] dioxino [2,3-o)] pi din-3-ylmethyl] amine (for a preparation see EP0559285A1, Example 5) (0.055 g, 0.33 mmol) were stirred in dry dichloromethane and methanol (5 ml each) with glacial acetic acid (10 drops) and 3A molecular sieves at room temperature for 1 h. Sodium triacetoxyborohydride (0.084 g, 1.33 mmol) was added and the mixture was stirred overnight. Aqueous sodium bicarbonate was added to basify and the phases were separated. The aqueous phase was extracted with 10% methanol / dichloromethane and the organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% methanol / dichloromethane gave the free base of the title compound (0.12 g). d? (CDCl 3, 250 MHz) 1 .40 (2 H, m), 1.86 (2 H, m), 2.09 (1 H, t), 2.23 (1 H, t), 2.50 (2 H, m), 2.78 (1 H, m), 2.85 (1 H, dd), 2.97 (2 H, m), 3.00 (1 H, m), 4.02 (1 H, m), 4.05 (1 H, dd), 4.30 (1 H, dd), 4.45 (3H, m), 6.62 (1 H, d), 6.87 (2H, m), 7.20 (1 H, dd), 7.39 (1 H, dd), 7.67 (1 H, d), 7.82 (1 H , dd). MS (+ ve ion electrospray) m / z 451 (MH +). The free base was treated with hydrogen chloride in 1,4-dioxane (0.4M, 1.33 ml), evaporated and dried under vacuum to provide the dihydrochloride salt (0.12 g).

EXAMPLE 50 Dihydrochloride of the E1 enantiomer of 1- (. {4 - [(6,7-dihydro-5-A-pyran [2,3-c] pyridazin-3-ylmethyl) amino-1-piperidinyl} methyl) - 4-oxo-1,2-dihydro-4-pyrrolor3,2,1 - // 1-quinolin-9-carbonitrile 1 ^ -dihydro ^ H-pyrrolofS ^ .I-ylkyquinolin-g-carbonityl 1 - [(4-Amino-1-piperidinyl) methyl] -4-oxo-1,2-dihydro-4H-pyrrolo [3 , 2,1-ji] racemic quinoline-9-carbonitrile (21 g) by chiral chromatography on a Chiralpak AD-H column of 5um eluting with 95: 5: 0.1 acetonitrile: methanol: isopropylamine, providing E1 enantiomer 750 mg, > 98% ee, then E2 enantiomer, 760 mg, 98% ee. (b) Title compound A solution of enantiomer 1 of 1 - [(4-amino-1-piperidinyl) methyl] -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin -9-carbonitrile (40 mg, 0.13 mmol) and 6,7-dihydro-5 / - / - pyrano [2,3-c] pyridazin-3-carbaldehyde (26.7 mg, 0.167 mmol) in MeOH (1 mL), chloroform (1 ml) with 3A sieves was heated at 65 ° C under Ar for 5 h. It was cooled and sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added and the mixture was stirred at rt overnight. Then the reaction was filtered through kieselguhr, washing with 1: 1 MeOH / DCM. The solvents were evaporated and the residue was partitioned between saturated aqueous NaHCO3 and 20% MeOH in DCM. The aqueous phase was extracted twice more with 20% MeOH in DCM and then the combined organics were dried and evaporated. The residue was subjected to column chromatography on silica gel using gradient DCM, MeOH and aqueous ammonia to give the free base of the title compound (39 mg, 66%). MS (ES +) m / z 457 (MH +). 1 H NMR (400 MHz) or (CDCl 3) 1 .38-1 .52 (2H, m), 1 .83-1 .99 (2H, m), 2.01 -2.1 1 (2H, m), 2.1 1 - 2.21 (1 H, m), 2.22-2.32 (1 H, m), 2.50-2.61 (2H, m), 2.72-2.82 (1 H, m), 2.85-2.91 (2H, m), 2.96 (1 H , m), 3.01 -3.08 (1 H, s), 3.92-4.07 (3H, m), 4.24-4.07 (m, 3H), 4.51 -4.61 (1 H, m), 6.81 (1 H, d, J ), 7.30 (1 H, s), 7.50 (1 H, d,), 7.49 (1 H, d), 7.73 (1 H, d). This material was converted to the hydrochloride by dissolving it in DCM and adding 1 M HCl / diethyl ether then evaporating to dryness.

EXAMPLE 51 Dihydrochloride of the E1 Enantiomer of 1 - (. {4-r (6,7-dihydro-5H-pyranof2,3-c] pyridazin-3-ylmethyl) amino1-1-piperidinyl}. M dihydro-4H- pyrrolo [3,2,1 - / y] quinolin-4-one A solution of E1 enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - // Jquinolin -4-one (40 mg, 0.13 mmol) and 6,7-dihydro-5H-pyran [2,3-c] piñdazin-3-carbaldehyde (25.7 mg, 0.157 mmol) in MeOH (1 mL), chloroform (1 mi) with 3A sieves was heated at 65 ° C under Ar for 5h. It was cooled and sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added and the mixture was stirred at rt overnight. Then the reaction was filtered through kieselguhr, washing with 1: 1 MeOH / DCM. The solvents were evaporated and the residue was partitioned between saturated aqueous NaHCO3 and 20% MeOH in DCM. The aqueous phase was extracted twice more with 20% MeOH in DCM and then the combined organics were dried and evaporated. The residue was subjected to column chromatography on silica gel using gradient DCM, MeOH and aqueous ammonia to give the free base of the title compound (32 mg, 55%). MS (ES +) m / z 466 (MH +). H NMR (400 MHz) 5 (CDCl 3) 1 .41 -1 .91 (3H, m), 1 .91 -2.02 (2H, m), 2.03-2.1 1 (2H, m), 2.31 -2.41 (1 H , m), 2.51 -2.65 (2H, m), 2.78-2.90 (3H, m), 2.92-3.05 (2H, m), 3.56 (1H, d), 4.01 (2H, s), 4.34-4.49 ( 4H, m), 6.63 (1 H, d, J), 6.89-6.93 (1 H, m), 7.28 (1 H), 7.48-7.51 (1 H, m), 7.69 (1 H, d J). This material was converted to the hydrochloride by dissolving it in DCM and adding 1 M HCl / diethyl ether then evaporating to dryness.

EXAMPLE 52 Dihydrochloride of the E1 Enantiomer of 9-Fluoro-1 - [(4- {f (6-oxo-6,7-dihydro-5H-pyridazino [3,4-6-l-1-thiazin-3-yl) -methylamino}. -1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolor3.2.1 - // 1-quinolin-4-one A solution of 1 - [(4-amino-1-pipe dinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (enantiomer E1, 45 mg, 0.15 mmoles) and 6-oxo-6,7-dihydro-5H-pyridazino [3,4-b] [1,4] thiazine-3-carboxaldehyde (for a synthesis see international publication WO 2003087098, Example 312 (d)) (19 mg, 0.1 mmol) in chloroform / methanol (3 ml / 3 ml) was stirred for 6 hours then treated with sodium triacetoxyborohydride. After 72 hours the mixture was divided into water, sodium carbonate and 10% methanol in chloroform. The aqueous phase was extracted 3 more times with 10% methanol in chloroform then the combined organic extracts were dried (sodium sulfate) and evaporated. The residue was chromatographed on silica gel, eluting with a gradient of 0-1 5% methanol in dichloromethane to give the free base of the title compound as a solid. d? (d-6 methanol, 400 MHz) 2.02-2.15 (2H, m), 2.55 (2H, t), 2.70 (1H, t), 2.85 (1H, t), 315 (2H, t), 3. MS (ES +) m / z 481 (MH +). This material was dissolved in methanol / dichloromethane and treated with 4M hydrochloric acid in dioxane. Evaporation afforded the title compound as a gelatinous white solid (28 mg).

EXAMPLES 53 and 54 Hydrochloride of the E1 and E2 Enantiomers of 1- (. {4-G (2,3-dihydro [1,4] dioxino [2,3-c1pyridin-7-ylmethyl) am hydroxy-4-oxo -1, 2-dihydro-4H-pyrrolo [3,2 / 1-quinoline-9-carbonitrile (a) methyl 2-r7-Bromo-2- (methyloxy) -8-quinolinyl-2-oxiranecarboxylate A solution of 2- [7-bromo-2- (methyloxy) -8-quinolinyl] -2- Methyl propenoate (4.9 g, 1 5.2 mmol) in DCM (100 mL) was treated with meta-chloroperbenzoic acid (5.24 g) and heated at 45 ° C for 21 hours. One more equivalent of meta-chloroperbenzoic acid was added and heating was continued for 4 hours. One more equivalent of meta-chloroperbenzoic acid was added and heating continued for 17 hours. Water and DCM were added followed by sodium sulfite and then sodium bicarbonate. The phases were separated and the aqueous phase was further extracted (three times) with 10% methanol in DCM. The organic extracts were dried and evaporated to give a yellow oil. This was chromatographed on silica gel, eluting with a gradient of 0-100% ethyl acetate in hexane to give a pale yellow solid (4.3 g, 84%).

MS (ES +) m / z 339 (MH +). (b) Methyl 9-Bromo-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolof3,2,1-ylquinoline-1-carboxylate A mixture of 2- [7-bromo- Methyl 2- (methyloxy) -8-quinolinyl] -2-oxirancarboxylate (4.3 g, 12.7 mmol), lithium perchlorate (4.06 g, 38 mmol, 3 equivalents), acetonitrile (43 mL) and water (43 mL) were added. stirred at 85 ° C for 17 hours. Additional lithium perchlorate (2 equivalents) was added and the mixture was heated at 85 ° C for 7 hours. Additional lithium perchlorate (2 equivalents) was added and the mixture was heated at 85 ° C for 1 7 hours. The reaction mixture was allowed to cool to room temperature and treated with 10% methanol in DCM. The aqueous phase was further extracted with DCM and the combined organic extracts were dried (MgSO4) and evaporated to give a yellow solid (4.2 g). Chromatography on silica provided a pale yellow solid (3.07 g, 74%). MS (ES +) m / z 327 (MH +). (c) (1 - [(9-bromo-l-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolor-3,2,1-yl] quinolin-1-yl) methyl-1-4-piperidinyl}. (2,3-dihydro [1,4] dioxino [2,3-c1pindin-7-dimethyl-1,1-dimethyl ethyl ester] A solution of 9-bromo-1-hydroxy-4-oxo-1,2-dihydro 4 H-pyrrolo [3.2, 1-yl] quinolin-1-methyl carboxylate (1.56 g, 4.6 mmol) in methanol (50 ml) was treated at 0 ° C with sodium borohydride (528 mg, 13.9 g). mmoles).

After 1 hour the mixture was allowed to warm to room temperature. After 1 hour at room temperature the mixture was heated to 40 ° C for 1 hour. The mixture was allowed to cool to room temperature and more sodium borohydride (528 mg, 13.9 mmol) was added. The mixture was stirred at room temperature overnight, then quenched with aqueous ammonium chloride. The mixture was filtered and the filtrate was dried over magnesium sulfate. The mixture was filtered and evaporated. The residue was chromatographed on silica gel, eluting with a gradient of 10-30% methanol in DCM to give a solid (ca 10 g). This mixture was suspended in 10% methanol in DCM (100 mL) and stirred overnight. Filtration and evaporation afforded a solid (4.2 g) consistent with a mixture of 9-bromo-1-hydroxy-1- (hydroxymethyl) -1,2-dihydro-4H-pyrrolo [3.2, 1-ji] quinolin- 4-one and inorganic. MS (ES +) m / z 297 (MH +). A portion of this material (assumed to be 1.5 millimoles of 9-bromo-1-hydroxy-1- (hydroxymethyl) -1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4 -one) was suspended in DCM (1.7 mL), THF (1.7 mL) and DMF (1.7 mL) then treated with dibutyl (oxo) stannate (19 mg, 0.07 mmol), 4-methylbenzenesulfonyl chloride ( 293 mg, 1.5 mmol) and triethylamine (0.3 ml, 2.3 mmol). After 41 hours chloroform (25 ml), 4-methylbenzenesulfonyl chloride (95 mg) and dibutyl (oxo) stannate (25 mg) were added. After 2 hours the mixture was evaporated on silica and the mixture was chromatographed eluting with a gradient of 0-10% methanol in ethyl acetate to give a white solid (350 mg). This material was consistent with a 2: 1 mixture of 4-methylbenzenesulfonate of (9-bromo-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-1 - il) methyl [MS (ES +) m / z 451 (MH +)] and 9-bromo-1 - (chloromethyl) -1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin -4-one [MS (ES +) m / z 315 (MH +)]. This material (350 mg, estimated 0.9 mmol) was treated with (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) -4-piperidinylcarbamate of 1.1, - dimethylethyl (for a synthesis, see international publication WO 2004058144 Example 99 (h)) (453 mg, 1.3 mmoles), sodium carbonate (318 mg, 3 mmol) and ethanol (10 ml) and heated to 38 ° C. C for 40 hours. The mixture was evaporated and the residue was partitioned between DCM and dilute brine. The organic phase was added on top of a silica column, eluting with a gradient of 0-20% methanol in DCM to provide a white foam (400 mg). MS (ES +) m / z 629 (MH +). (d) (1-f (9-Cyano-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1-i)] quinolin-1-yl) methyl-4-piperidinyl } (2, 1,1-dimethylethyl-3-dihydro [1,4-dioxin [2,3-chlorpyridin-7-ylmethylcarbamate] A mixture of. { 1 - [(9-bromo-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-1-yl) methyl] -4-piperidinyl} (2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) carbamate, 1, -dimethylethyl (400 mg, 0.64 mmol), copper (I) cyanide (200 mg, 2.3 mmol) and DMF (6 ml) was heated at 130 ° C for 16 hours then evaporated to dryness. The residue was partitioned between ethyl acetate / brine / concentrated aqueous ammonia solution. The organic extract was dried and evaporated to give a brown spittle. Chromatography eluting with gradient of 0-30% methanol in DCM provided the product (220 mg, 60%). MS (+ ve ion electrospray) m / z 574 (MhT). (e) Title compounds A dissolution of. { 1 - [(9-cyano-1-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo [3,2, 1 -ij] quinolin-1-yl) methyl] -4-pipehdinil} (1,1-dimethylethyl 2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) carbamate (220 mg, 0.38 mmol) in TFA / DCM (5 ml / 5 ml) was stirred for 45 minutes then evaporated, treated azeotropically with chloroform, then dried in vacuo. The residue was dissolved in DMF / methanol (10 ml / 10 ml) and treated with MP-carbonate resin (3 g, 3 mmole of carbonate per gram, 9 mmole). After 30 minutes the mixture was filtered and evaporated to yield a brown oil which was subjected to chromatography, eluting with a gradient of 0-30% methanol in DCM, which provided the free base of the title compounds as a pale yellow oil (1 10 mg, 61%). 1 H NMR (250 MHz) 5 (CDCl 3) 1 .40-1 .65 (2H, m), 1.90-2.05 (2H, m), 2.35-2.70 (3H, m), 2.85 (1H, d) ), 2.92-3.10 (2H, m), 3.35 (1H, d), 3.80 (2H, s), 4.25-4.35 (4H, m), 4.40-4.50 (2H, m), 6.80-6.88 (2H, m), 7.45 (1 H, d), 7.62 (1 H, d), 7.78 (1 H, d), 8.10 (1 H, s).

MS (+ ve ion electrospray) m / z 474 (MH +). A portion of this material (90 mg) was first partially purified by preparative C18 HPLC using a 1-inch C 8 semi-preparative column, eluting with a solvent system of aqueous ammonium format 50 mmolesar pH 4.0 and acetonitrile. Then the pure racemate (> 99%) was resolved in its two enantiomers by preparative chiral hplc using a 5 um Chiralpak IA column, eluting with 90: 10: 0.1 - CH3CN: CH30H: lsopropylamine, Rt 2.6 minutes for E1 and 3.3 minutes for E2, Both enantiomers were converted to their monohydrochloride salts of the E1 Enantiomer (40 mg) and E2 Enantiomer (39 mg).

EXAMPLE 55 Dihydrochloride of the E1-enantiomer of 1-r (4- {i (7-chloro-3-oxo-3,4-dihydro-1,2-dihydro-4H-pyrrolor3,2,1-ii) quinolin -4-one A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-y] quinolin-4-one (Enantiomer E1, 70 mg, 0.23 mmoles) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-carbaldehyde (for a synthesis see international publication WO 2006010040 , Preparation 6 (h)) (49 mg, 0.23 mmole) in chloroform / methanol (3 ml / 3 ml) was stirred for 2 hours then treated with sodium triacetoxyborohydride (146 mg, 0.65 mmole). After 2 hours the solvents were removed. The residue was chromatographed on silica gel, eluting with a gradient of 0-10% methanol in dichloromethane to give the acetate salt of the free base of the title compound (105 mg). 1 H NMR (400 MHz) 5 (CDCl 3) 1 .55-1.70 (2H, m), 1 .95-2.05 (5H, m), 2.1 5 (1 H, t), 2.25 (1 H, t ), 2.55 (1 H, t), 2.70 (1 H, m), 2.80-2.90 (2H, m), 3.10 (1 H, m), 4.00-4.05 (3H, m), 4.45-4.50 (2H, m), 4.65 (2H, s), 6.65 (2H, m), 6.85 (1H, t), 7.38 (1H, m), 7.68 (1H, d). MS (+ ve ion electrospray) m / z 498 (MH +). This material was converted to the title dihydrochloride salt.

EXAMPLES 56 and 57 Hydrochloride of the E1 and E2 Enantiomers of 1- ( { 4 - [(2,3-D-Hydro [1,4] dioxino [2,3-c1pyridin-7-ylmethyl] am (methyloxy I ^ -dihydro ^ H-pyrrolofS ^ .I-ijlquinolin ^ -ona and Dihydrochloride of the E1 Enantiomer of 1 - (. {4-f (2,3-dihydrori, 41dioxinof2,3-c1piridin-7-Mmetil) aminol-1 -piperidinM.) methyl) -9- (methyl ^ ijlquinolin-4-one) (a) 1-f (4-Amino-1-pperidinyl) methyl-1-9- (methyloxy) -1,2-dihydro-4H-pyrrolof3,2,1-1-quinolin-4-one A solution of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-y] quinolin-4-one dihydrochloride (1.74 g , 4.64 mmol) in methanol (1.7 mL) at room temperature under argon, treated with 25% sodium methoxide in methanol (2.5 mL, 11.5 mmol). Then the reaction was heated to 85 ° C for 2 hours, then an additional addition of 25% sodium methoxide in methanol (5 ml) was added. The reaction was left at 85 ° C overnight (16 hours). A further addition of 25% sodium methoxide in methanol (5 ml) was required in the morning and the reaction was left at 85 ° C for most of the day. The reaction mixture was treated with ammonium chloride (saturated) until the pH reached 8., at which time the solvent was removed under vacuum. The residue was redissolved in 10% methanol in DCM and stirred at room temperature for 1 hour with sodium sulfate. Then this mixture was filtered and the solvent was removed to give a yellow solid (3.81 g). This was purified on a 10 g SCX column eluting with methanol then 2M ammonia in methanol to give a yellow oily solid (0.832, 57%). MS (ES +) m / z 314 (MH +). (b) Compound of the title 1 - [(4-amino-1-piperidinyl) methyl] -9- (methyloxy) -1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (0.108 g, 0.345 mmole) and 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7-carbaldehyde (see international publication WO2004058144, Example 2 (c)) (0.057 g, 0.345 mmole ) was dissolved in chloroform (2.5 ml) and methanol (0.25 ml) at room temperature under argon. Then sodium triacetoxyborohydride (0.219 g, 103 mmol) was added and the reaction was allowed to stir at room temperature for 1 hour. After this, it was purified by chromatography on silica gel (20 g) using a gradient of 0-30% methanol in dichloromethane to give the acetate salt of the free base of the title compound as a clear oil (0.1 75 g. , 100%).

MS (ES +) m / z 463 (MH +). 1 H NMR (250 MHz) 5 (MeOD) 1 .55-1.97 (2H, m), 2.00 (3H, s), 2.05-2.38 (4H, m), 2.49 (1 H, t), 2.90- 3.30 (5H, m), 3.94 (3H, s), 4.19 (2H, s), 4.30-4.38 (6H, m), 6.43 (1H, d), 6.98 (1H, d), 7.03 (1H , s), 7.52 (1 H, d), 7.81 (1 H, d), 8.1 1 (1 H, s). A portion of this material (60 mg) was first purified on a Chiralpak AD-H column of 5 um eluting with 80: 20: 0.1 CH3CN: CH30H: lsopropylamine then finalemtne on a Chiralpak column AS-H of 5 um eluting with providing 90: 10: 0.1 CH3CN: CH30H: lsopropylamine providing the free base of the E1 enantiomer (approximately 10 mg) (Rt 4.8 minutes, 100% ee, 99.5 of chemical purity) then the free base of the enantiomer E2 (approximately 10 mg, Rt 6.9 minutes, 100% ee, 985% purity). Each enantiomer was separately converted into the corresponding hydrochloride salt, by dissolving the free base in methanol and the appropriate amount of 6N HCl was added. The reaction was stirred for about 1 hour and the methanol was removed to leave the remaining mono HCl salts. The enantiomer E1 was also converted to the dihydrochloride salt.

EXAMPLE 58 Dihydrochloride of enantiomer 1 of 1- (. {4 - [(6J-dihydron, 4ldioxinof2,3-c] pyridazin-3-ylmethyl) amino1-1-piperidinyl.} M pyrroloP ^ I-z / lquinolir -one A solution of E1 Enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2, 1-y] quinolin-4-one (0.301) g, 1.0 mmol) in methanol (3mL) at room temperature under argon, treated with 25% sodium methoxide in methanol (0.432 ml, 2.0 mmol), then the reaction was heated to 85 ° C for 2 hours, a further addition of sodium methoxide in methanol (0.432 ml) was added and the reaction was left at 85 ° C overnight (16 hours) Again, a further addition of 25% sodium methoxide in methanol was required. (1.73 ml) and the reaction was left at 85 ° C for a couple of hours.The reaction was cooled to room temperature, then ammonium chloride (saturated) was added until the pH was 8, then the solvent was added. The residue was redissolved in 10% MeOH in DCM and stirred at room temperature for 1 hour, at which time sodium sulfate was added, then this mixture was filtered and the solvent This was removed to give a yellow solid (2.49 g). This was purified on a 10 g SCX column eluting with methanol then 2M ammonia in methanol to give an oily solid (0.693). This material was consistent with a mixture of 1 - [(4-amino-1-piperidinyl) methyl] -9- (methyloxy) -1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4 -one and inorganic material. MS (ES +) m / z 314 (MH +). A portion of this material (108 mg) and 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-carbaldehyde (0.057 g, 0.345 mmol) was dissolved in chloroform (2.5 ml) and methanol (0.25 ml) at room temperature under argon. Then sodium triacetoxyborohydride (0.219 g, 1.03 mmol) was added and the reaction was allowed to stir at room temperature for 16 hours. The reaction was then diluted with 5 ml of sodium bicarbonate (saturated), and the aqueous phase was then separated and further extracted with 10% methanol in DCM (3 < 5 ml). The organic ones were combined, dried (Na2SO4), filtered and the solvent was removed to give a yellow solid (0.120 g). This was then purified by chromatography on silica gel (20 g) using a gradient of 0-30% methanol in dichloromethane to give the free base of the title compound as a clear oil (54 mg). ? ? NMR (250 MHz) 5 (MeOD) 1 .46-1.58 (2H, m), 1.82-2.26 (5H, m), 2.42 (1H, t), 2.49-2.62 (1H, m) , 2.80 (1 H, br d), 2.95 (1 H, dd), 3.19 (1 H, br d), 3.93 (3H, s), 3.97 (1 H, s), 4.28-4.38 (2H, m) , 4.39-4.47 (2H, m), 4.51 -4.62 (2H, m), 6.42 (1 H, d), 6.96 (1 H, d), 7.24 (1 H, s), 7.50 (1 H, d) 7.79 (1 H, d). MS (ES +) m / z 464 (MH +). This material was converted to the dihydrochloride salt by treating a solution in methanol (100 mL) with an excess of 1 M hydrochloric acid in methanol (0.1 mL) followed by evaporation to dryness.

EXAMPLE 59 Dihydrochloride of Diastereomer D1 of 9-Fluoro-1- (r 4 - ((f (7 S) -7- (hydroxymethyl) -6J-dihydro [1141-dioxinor-2,3-clpyridazin-3-inmethyl] -amino) -1-piperidininmethyl .}. -1., 2-Dihydro-4H-pyrrolof3,2,1 - // lquinolin-4-one pyridazine [(4R / S) -2,2-Dimethyl-1,3-dioxolan-4-yl] methanol (3.3 ml) in THF was cooled on ice and sodium hydride (1.2 g, dispersion at 60 ° C) was added. % in oil) 10 ° C below the internal temperature. After 15 minutes 3,4,6-trichloropyridazine (5 g, 27.2 mmol) was added and the mixture was stirred overnight. Ice / water was added and the mixture was evaporated. The residue was diluted with water and extracted with DCM. The extracts were dried and evaporated to give the product (4.78 g, 63% yield). MS (ES +) m / z 280 (MH +). (b) (2R / S) -3-f (3,6-Dichloro-4-pyridazinyl) oxy-1, 2-propanediol A solution of 3,6-dichloro-4- ( { [(4R / S ) -2,2-dimethyl-1,3-dioxolan-4-yl] methyl.} Oxy) pyridazine (4.78 g 17.2 mmol) in methanol (100 ml) and 4M hydrogen chloride in dioxane (100 ml) was stirred for 3h. The reaction mixture was evaporated and azeotropically treated with toluene. The residue was dissolved in 10% methanol in DMC (100 ml) to the residue and treated with MP-carbonate (50 g). More MP-carbonate (50 g and 25 g) was added after 2 h and stirring overnight. After 2h more the mixture was filtered and evaporated. Chromatography on silica gel eluting with 10-20% methanol in DCM gave the product (1.89 g, 46%). MS (ES +) m / z 240 (MH +). (c) f (7R / S) -3-Chloro-6,7-dihydroxy, 41dioxinof2,3-clpyridazin-7-yl-methanol (2R / S) -3 - [(3,6-Dichloro-4- pyridazinyl) oxy] -1, 2-propanediol (1.89 g) was made azeopropic with dioxane (20 ml), then dissolved in dioxane and stirred with lithium hydride for 4 days at 104 ° C, the mixture it was quenched with and acidified to pH 7-8 with 2M hydrochloric acid then evaporated. The residue was extracted with chloroform and the extracts were dried and evaporated. Chromatography on silica gel eluting with 1% -3% methanol in DCM gave the product (47 mg). MS (ES +) m / z 203 (MH +). (d) r (7R / S) -3-Ethenyl-6,7-dihydron, 41-dioxinof2,3-clpyridazin-7-ylmethanol [(7R / S) -3-chloro-6,7-dihydro [1,4] dioxin [2,3-c] pyridazin-7-yl] methanol (147 mg, 0.72 mmol) in 1,2-dimethoxyethane was degassed with a stream of argon. Tetrakis (thphenylphosphine) palladium (0) (18 mg), trietenylboroxin.pyridine (1 10 mg) potassium carbonate (100 mg) and water (1.5 ml) were added and the mixture was heated at 100 ° C overnight . The mixture was evaporated and chromatography on silica gel eluting with ethyl acetate gave the title compound (94 mg, 67% yield). MS (ES +) m / z 195 (MH +). (e) (7R / S) -7- (Hydroxymethyl) -6,7-dihydronide, 41-dioxinor-2,3-c-pyridazine-3-carbaldehyde [(7R / S) -3-Ethenyl-6,7-dihydro [1 4] dioxino [2,3-c] pyridazin-7-yl-methanol (94 mg) in dioxane (4.4 ml) and water (0.85 ml) was stirred with 4M aqueous osmium tetroxide (0.43 ml) and sodium periodate (238 g). mg) for 7 h. The mixture was evaporated and diluted with methanol, ethyl acetate and DCM. Silica was added and the mixture was evaporated and chromatographed on silica eluting with 0-40% methanol in ethyl acetate to provide the product (19 mg, 20% yield).

MS (ES +) m / z 197 (MH +). (f) Title Compound (7R / S) -7- (hydroxymethyl) -6,7-dihydro [1,4] oxoxy [2,3-c] pyridazin-3-carbaldehyde (19 mg , 0.097 mmole) and E1 enantiomer of 1 - [(4-amino-1-pperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3.2 - //] quinolin-4-one (35 mg, 0.1 16 mmol) in methanol (0.5 ml) and chloroform (3 ml) was stirred with 3A sieves for 24 h. Sodium triacetoxyborohydride (62 mg) was added and the mixture was stirred for 72 h with the addition of more sodium triacetoxyborohydride after 8 h. Saturated sodium carbonate (5 drops) was added followed by silica. The mixture was then evaporated and chromatographed on silica eluting with 0-20% methanol in dichloromethane to give the free base of the title compound. H NMR (400 MHz, CDCl 3 + CD 3 OD) 57.82 (1 H, s), 7.51 (1 H, m), 7.21 (1 H, m), 6.97 (1 H, t), 6.63 (1 H, d), 4.60-4.40 (3 H, m), 4.29 (1 H, m), 4.73 (3H, m), 3.92 (2H, m), 3.36 (1H, m), 3.13 (1H, m), 2.91 (2H, m), 2.70 (1H, m), 2.58 ( 1 H, t), 2.27 (1 H, t), 2.14 (1 H, t) 1.56 (2H, m). The free base was dissolved in methanol and DCM, 4M hydrogen chloride in dioxane (0.4 ml) was added and the precipitate was triturated with ether and dried to give the title compound (32 mg) LC / MS (ion electrospray + ve): m / z 482 (MH +).

EXAMPLE 60 Hydrochloride of the E1 Enantiomer of 1- (. {4-R (5,6-dihydrofuro [2,3-c] pyridazin-3-ylmethyl) aminoH-piperidinyl}. M pyrrolo 3.2.1- / ] quinolin-4-one (a) Acid (3,6-dioxo-1, 2,3,6-tetrahydro-4-pyridazinyl) acetic acid A mixture of (2,5-dioxo-2,5-dihydro-3-furanyl) acetic acid (9 g) and hydrazine sulfate (7.2 g) in water was heated to reflux for 4 hours then allowed to cool to room temperature. The precipitate was filtered, washing with water and then acetone. Drying in vacuo gave a white solid (8.04 g, 82%). MS (ES +) m / z 171 (MH +). (b) (methyl 3,6-Dioxo-1, 2,3,6-tetrahydro-4-pyridazinyl) acetate A mixture of (3,6-dioxo-1, 2,3,6-tetrahydro-4) acid pyridazinyl) acetic, (5.0 g), methanol (75 ml) and 4M hydrochloric acid in dioxane (20 ml) was stirred overnight. Evaporation provided a white solid. MS (ES +) m / z 185 (MH +). (c) 4- (2-Hydroxyethyl) -1,2-dihydro-3,6-pyridazinedione A suspension of (3,6-dioxo-1, 2,3,6-tetrahydro-4-pyridazinyl) Methyl acetate (11.1 g, 60.3 mmol) in THF (2 liters) was sonicated to provide a fine dispersion. The mixture was cooled to -1.5 ° C and treated dropwise with a solution of lithium aluminum hydride in THF (1M, 90 mL, 90 mmol). The mixture was stirred at 0 ° C for 2 hours. Sodium hydroxide (2M, 15 mL, 30 mmol) was added, then the mixture was acidified with 5M hydrochloric acid to a pH of about 4-5. The supernatant was decanted and eliminated. The oily residue was extracted with water / methanol (500 ml / 1 liter). This extract was decanted from remaining residue, treated with silica and evaporated. The silica residue was added to the top of a column, eluting with 10-30% methanol in DCM to provide a pale yellow oil (2.7 g). MS (ES +) m / z 157 (MH +). (d) 5,6-Dihydrofuror 2,3-clpiridazin-3 (2H) -one A mixture of 4- (2-hydroxyethyl) -1,2-dihydro-3,6-pyridazinedione (2.7 g) in THF ( 200 ml) was treated with triphenylphosphine (6.6 g) and (E) -1,2-diazenedicarboxylic acid bis (1-methylethyl) (5.0 ml) was heated to 40 ° C. After 3 hours the mixture was evaporated and chromatographed on silica which was added to the top of a column. Chromatography eluting with 0-10% methanol methanol in DCM gave the impure product (420 mg) which was further purified by chromatography in a similar manner to give the product (390 mg). MS (ES +) m / z 139 (MH +). (e) 5,6-Dihydrofuro [2,3-c1-pyridazine-3-N-trifluoromethanesulfonate A solution of 5,6-dihydrofuro [2,3-c] pyridazin-3 (2H) -one (780 mg) in DMF ( 15 ml) was treated with sodium hydride (435 mg) then after 2 hours with N-phenyltrifluoromethanesulfonimide (3.62 g). After 2 hours the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was further extracted (twice) with ethyl acetate and the combined organic extracts were dried and evaporated to give the product (937 mg). MS (ES +) m / z 271 (MH +). (f) 3-Etenyl-516-dydrofuror213-clpiridazine A solution of 5,6-dihydrofuro [2,3-c] pyridazin-3-yl trifluoromethanesulfonate (500 mg, 1.85 mmole) in dimethoxyethane (20 ml) ) was degassed, then treated with tetrakis (triphenylphosphine) palladium (0) (16 mg), potassium carbonate (257 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (416 mg) and water (3.6 ml). The mixture was stirred at 80 ° C for 2 hours then divided into DCM and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with 10% methanol in DCM then the combined organic extracts were dried and evaporated. The residue was chromatographed eluting with ethyl acetate to give a white solid (11.1 mg, 36%). MS (ES +) m / z 149 (MH +). (g) Se-Dihydrofuro ^. S-clpiridazin-S-carbaldehyde A mixture of 3-ethenyl-5,6-dihydrofuro [2,3-c] pyridazine (1 10 mg, 0.74 mmol), 4% osmium tetroxide in water (0.66 ml), sodium periodate (367 mg), dioxane (6.6 ml) and water (1.3 ml) was stirred for 3 hours. The mixture was evaporated and the residue was treated with chloroform and added to the top of a column. Elution with ethyl acetate gave the product (23 mg). MS (ES +) m / z 151 (MH +). (h) Title Compound A solution of E1 Enantiomer of 1 - [(4-amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin -4-one (52 mg, 0.173 mmol) and 5,6-dihydrofuro [2,3-c] pyridazin-3-carbaldehyde (23 mg, 0.153 mmol) in DCM / methanol (3 ml / 0.5 ml) was stirred for the night was then treated with sodium triacetoxyborohydride (97 mg). After 8 hours more sodium triacetoxyborohydride (97 mg) was added and the mixture was stirred overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate solution and 10% methanol in DCM. The extract was dried and evaporated then the residue was chromatographed eluting with 0-20% methanol in DCM to give the free base of the title compound (34 mg). d? (CDCl 3, 250 MHz) 1.35-1.55 (2H, m), 1.80-2.10 (4H, m) 2.20 (1 H, t), 2.40-2.65 (2H, m), 2.75-2.90 ( 2H, m), 2.98-3.08 (1H, m), 3.32 (2H, t), 3.95-4.05 (3H, m), 4.40-4.55 (2H, m), 4.70 (2H, t), 6.65 (1 H, d), 6.85 (1 H, t), 7.35-7.42 (1 H, m), 7.48 (1 H, s), 7.78 (1 H, d). MS (ES +) m / z 436 (MH +). The free base was dissolved in methanol (2 mL) and treated with 0.1M hydrochloric acid (0.8 mL) then evaporated. The residue was dissolved in methanol and added to ether. The resulting solid was isolated by centrifugation and dried in vacuo (26 mg).

EXAMPLE 61 Hydrochloride of the E1 Enantiomer of 1 - (. {4 - [(5,6-dihydrofuro [2,3-c1pyridazin-3-ylmethyl) amino-1-piperidinyl} -me dihydro-4H-pyrrolof3, 2.1 - //] quinolin-4-one A solution of E1 enantiomer of 1 - [(4-amino-1-p -peridinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1- /] quinolin-4-one (48 mg,) and 5,6-dihydrofuro [2,3-c] pyridazin-3-carbaldehyde (20 mg, 0.133 mmol) in DCM / methanol (3 ml / 0.5 ml) was stirred overnight it was then treated with sodium triacetoxyborohydride (85 mg). After 7 hours an additional portion of sodium triacetoxyborohydride (85 mg) was added. After 1.7 hours the mixture was partitioned in saturated aqueous sodium bicarbonate solution and 10% methanol in DCM. The extract was dried and evaporated, then the residue was chromatographed eluting with 0-20% methanol in DCM to give the free base of the title compound (8 mg). d? (CDCl 3, 250 MHz) 1 .40-1 .65 (2H, m), 1 .90-2.70 (5H, m) 2.80 (1 H, d), 2.90-3.05 (2H, m), 3.30-3.40 ( 3H, m), 4.05 (2H, s), 4.30-4.45 (2H, m), 4.70 (2H, t), 6.62 (1H, d), 6.90 (1H, t), 7.45 (1H, s ), 7.50 (1 H, m), 7.70 (1 H, d). MS (ES +) m / z 452 (MH +). This material was converted to the title compound by treating a methanolic solution of hydrochloric acid and evaporating, followed by dissolving the residue in 20% methanol in DCM then precipitating with ether and isolating by centrifugation to give a white solid (4.5 mg).

EXAMPLE 62 Fumarate of (1 ¾ / S) -1-i (4- (r (7S) -6,7-dihydron, 41-dioxin-2-2,3-c1-pyridazin-7-ylmethylamino} -1-piperidinyl) methyl-1-9- fluoro-1, 2-dihydro-4H-pyrrolo [3, ^ // 1-quinolin-4-one (a) SG-Dichloro ^ -I ^ S ^ -oxiranylmethylloxylpyridazine A solution of (2R) -2-oxiranylmethanol (400 mg) in THF (50 ml) was cooled in an ice bath and treated with sodium hydride (dispersion). to 60%, 230 mg). After the addition was complete, 3,4,6-trichloropyridazine (1.0 g) was added in portions and the mixture was stirred at room temperature overnight. The solvent was removed by evaporation and the residue was partitioned between DCM and water. The aqueous phase was further extracted two more times with DCM, then the combined residues were dried and evaporated to give the product (1.1 g). MS (+ ve ion electrospray) m / z 221 (MH +). (b) (2S) -1-Azido-3 - [(3,6-dichloro-4-pyridazinyl) oxyl-2-propanol A mixture of 3,6-dichloro-4-. { [(2S) -2-oxiranylmethyl] oxy} pyridazine (1.1 g) and sodium azide (600 mg) in dioxane / water (25 ml / 5 ml) was heated to reflux for 7 hours then concentrated, diluted with ethyl acetate, washed with brine, dried and evaporated. The residue was chromatographed eluting with hexane then 5% methanol in DCM to provide the product (400 mg). MS (+ ve ion electrospray) m / z 264 (MH +). (cj (7S) -7- (Azidomethyl) -3-chloro-6,7-dihydrof1,4ldioxinor2.3-c] pyridazine A mixture of (2S) -1-azido-3 - [(3,6-dichloro-4- pyridazinyl) oxy] -2-propanol (400 mg) and lithium hydride (200 mg) in dioxane (50 ml) was heated under reflux over the weekend, the mixture was treated with ice then it was brought to a pH of about 7.5 with 5M hydrochloric acid then concentrated to a low volume The mixture was partitioned between water and DCM The aqueous phase was extracted three more times with DCM and the combined extracts were dried and evaporated. Chromatography eluting with 0-10% methanol in DCM gave the product (250 mg) MS (+ ve ion electrospray) m / z 228 (MH +). (d) Hydrochloride of i (7S) -6,7-dihydro [1,4-dioxoinof2,3-c1pyridazin-7-ylmetillamine A solution of (7S) -7- (azidomethyl) -3-chloro-6,7-dihydro [ 1, 4] dioxino [2,3-c] pyridazine (250 mg) in ethanol (15 ml) was hydrogenated over 10% palladium on carbon (120 mg) for 18 hours. The mixture was filtered and evaporated to give the product (220 mg). (e) Title compound A mixture of [(7S) -6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-7-methylmethyl] amine hydrochloride (220 mg), (1 R) / S) -9-fluoro-1 - [(4-oxo-1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one (330 mg) , sodium acetate (540 mg), acetic acid (30 drops) and 3A molecular sieves in methanol / DCM (15 ml / 15 ml) was stirred for 2 hours, then treated with sodium cyanoborohydride (280 mg) and stirred overnight. The mixture was basified and extracted with 10% methanol in DCM followed by drying and evaporation. The residue was chromatographed eluting with 0-50% methanol / DCM to give the free base of the title compound (29 mg). 5H (CDCl 3, 400 MHz), 1.35-1.45 (2H, m), 1.85-1.95 (2H, m), 2.10-2.30 (2H, m), 2.45-2.55 (2H, m ), 2.75-2.80 (1 H, m), 2.88 (1 H, dd), 2.95-3.05 (3H, m), 4.00-4.08 (1 H, m), 4.20-4.55 (5H, m), 6.65 ( 1 H, d), 6.90 (1 H, t), 6.95 (1 H, d), 7.45 (1 H, m), 7.70 (1 H, d), 8.68 (1 H, d). MS (+ ve ion electrospray) m / z 452 (MH +). This material (29 mg) was dissolved in methanol / DCM and treated with a solution of fumaric acid in methanol followed by ether. The resulting precipitate was isolated by centrifugation and then dried in vacuo (13 mg).

Biological Activity Analysis of antimicrobial activity: The antimicrobial activity in whole cells was determined by microdilution of broth using the procedure recommended by Clinical and Laboratory Standards Institute (CLSI), Document M7-A7, "Methods for Dilution Susceptibility Tests for Bacteria that Grow Aerobically".

The compounds were tested in serial double dilutions in a range from 0.016 to 16 mcg / ml. The compounds were evaluated against a panel of organisms Gram positive, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis and Enterococcus faecium. In addition, compounds against a panel of Gram-negative strains were evaluated including Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Legionella pneumophila, Chlamydia pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae and Stenotrophomonas maltophilia. The minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to help determine the MIC end point. Each of Examples 1-61, as identified in the present application, which were tested in at least one exemplified form of salt, had a MIC of = 2ug / ml against a strain of at least one of the organisms listed above. Example 62 had a MIC of < 4ug / mi against a strain of at least one of the organisms listed above.

Claims

NOVELTY OF INVENTION CLAIMS 1 .- A compound of formula (I) or one of its salts and / or one of its pharmaceutically acceptable solvates: (I) wherein: R1 A and R1 d are independently selected from hydrogen; halogen; cyano; alkyl (C ^ .g); alkyl (C- | _6) thio; trifluoromethyl; trifluoromethoxy; carboxy; hydroxy optionally substituted with alkyl (Ci_6) or alkoxy. { C - \ .Q) substituted alkyl (C «| _6); alkoxy (Ci _6) substituted alkyl (C- | _6); hydroxyalkyl (Ci "6); an amino group optionally N-substituted with one or two alkyl (Ci_6), formyl, alkyl (C < 6) carbonyl, or alkyl (C- | 6) sulfonyl; or aminocarbonyl wherein the amino group is optionally substituted by (C 1-4) alkyl; R2 is hydrogen or (C1.4) alkyl, or together with R§ form Y as defined below; A is a group (ia) or (ib): (ia) or (ib) (I) wherein: R3 is as defined for R1 a or R1 ^ or is oxo and n is 1 or 2: or A is a group (ii) (ü) W, W2 and W3 are CR4R8 or W2 and W3 are CR4R8 and W represents a link between W3 and N. X is O, CR4R8, or NR6; an R4 is as defined for R a and Rl b and the remaining ios and R8 are hydrogen or R4 and R8 are together oxo and the rest are hydrogen; R6 is hydrogen or alkyl (C- | _6); or together with R2 forms Y; R7 is hydrogen; halogen; hydroxy optionally substituted with alkyl (C- | .6); or alkyl (C ^); And it is CR R8CH2; CH2CR R8; (C = 0); CR R8; CR4R8 (C = O); or (C = O) CR R8; or when X is CR4R8, R8 and R7 represent together a link; U is selected from CO, and CH2 and R ^ is a ring system optionally substituted bicyclic, carbocyclic or heterocyclic (B): which contains up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic; X1 is C or N when it is part of an aromatic ring, or CR "1 4 when it is part of a non-aromatic ring, X2 is N, NR1 3, O, S (O) x, CO or CR1 4 when it is part of an aromatic or non-aromatic ring, or it may further be CR ^ R ^ when it is part of a non-aromatic ring; X3 and X5 are independently N or C; Y1 is a linking group of 0 to 4 atoms in which each atom is selected of N, NR1 3, O, S (0) x, CO and CR1 4 when it forms part of an aromatic or non-aromatic ring or can additionally be CR1 4R1 5 when it is part of a non-aromatic ring; Y2 is a linking group of 2 to 6 atoms, wherein each Y2 atom is independently selected from N, NR1 3, O, S (O) x, CO, CR when it is part of an aromatic or non-aromatic ring or can additionally be CR1 4R ^ when it forms part of a non-aromatic ring, each of R1 4 and R1 ^ is independently selected from: H; alkyl (C- | _4) thio; halo; alkyl (C- | _4) carboxy; alkyl (C1.4); alkoxy (C < | _4) carb onyl; alkyl (C < | 4) carbonyl; (C 1-4) alkoxy (C 1-4) alkyl; hydroxy; hydroxyalkyl (C1.4); alkoxy (C- | _4); nitro; cyano; carboxy; amine or aminocarbonyl optionally mono or disubstituted by alkyl (C-1.4); or R1 4 and R ^ 5 can together represent oxo; each R1 3 is independently H; trifluoromethyl; (C1.4) alkyl optionally substituted by hydroxy, alkoxy (C † .Q), alkyl (C- |. 6) thio, halo or trifluoromethyl; alkenyl (C2.4); alkoxy (C- | _4) carbonyl; alkyl (C-i _ 4) carbonyl; alkyl (Ci _e) sulfonyl; aminocarbonyl in which the amino group it is optionally mono or disubstituted by (C1.4) alkyl; each x is 9 independently 0, 1 or 2; and R is hydrogen or hydroxy.
2. - The compound according to claim 1, further characterized in that R1a is methoxy, fluoro or cyano and R1b is hydrogen.
3. - The compound according to any of the preceding 2 claims, further characterized in that R is hydrogen.
4. The compound according to any of the preceding claims, further characterized in that R is hydrogen.
5. - The compound in accordance with any of the preceding claims, further characterized in that A is a group 3 (ai), further characterized in that n is 1 and R is hydrogen or hydroxy.
6. - The compound in accordance with any of the claims 1 to 4, further characterized in that A is (ii), W1 is a 2 3 7 link, X, W and W are each CH2 and R is H.
7. - The compound in accordance with any of the preceding claims, further characterized in that U is CH2.
8. - The compound according to any of the preceding claims, further characterized in that R5 is a ring aromatic heterocyclic (B) having 8-1 1 ring atoms including 2-4 13 heteroatoms of which at least one is N or NR, further characterized 2 because Y contains 2-3 heteroatoms, one of which is S and 1 -2 are N, with a N linked to or the heterocyclic ring (B) has an aromatic ring (a) selected from optionally substituted benzo, pyrido and pyridazino and the non-aromatic ring 2 (b) and Y has 3-5 atoms, including at least one heteroatom, with O, S, CH2 or NR13 linked to X5 where R 3 is other than hydrogen, and o either NHCO is linked by means of N to X3, or O, S, CH2 or NH are linked to X3.
9. The compound according to any one of claims 1 to 7, further characterized in that R is selected from: 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin -6-ilo; 3-oxo-3,4-dihydro-2H-pyrido [3,2-fe] [1,4] thiazin-6-yl; 6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-yl; 6,7-dihydro [1,4] oxathino [2,3-c] pyridazin-3-yl; 6,7-dihydro [1,4] oxathino [3,2-c] pyridazin-3-yl; 2,3-dihydro- [1,4] dioxino [2,3-c] pyridin-7-yl; and [1, 3] oxathiolo [5,4-c] pyridin-6-yl.
10. A compound selected from: E2 enantiomer of 1 - (. {4- [2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one; E1 enantiomer of 1 - (. {4- [2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9 - fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one; Diastereomer 1 of 1 - ( { (3R, 4S) -4 - [(2,3-d¡h¡dro [1,4] d¡oxino [2,3-c] p¡nd¡n-7 -ylmethyl) amino] -3-hydroxyl-1-pipendinyl, methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2 - / y] quinolin-4-one; Diastereomer 2 from 1- ( { (3?, 4S) -4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -3-hydroxyl- 1-piperidinyl} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2 ^ / y] quinolin-4-one; 9-Fluoro-1- ( { (3R, 4S) -3-hydroxy-4 - [([1,3] oxathiolo [5,4-c] pyridin-6-methyl) amino] -1-pperidyl, methylene) -1, 2-dihydro-4 - / - pyrrolo [3,2,1- //] quinolin-4-one; 9-Fluoro-1 - [((3f?, 4S) -3-hydroxy-4- { [(6-oxo-6,7-dihydro-5 / - / - pyridazino [3,4-, 4] thiazin-3-yl) methyl] amino.} -1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-4-one; 1 - ( { (3fi, 4S) -4 - [(2,3-D yhydro-1 H -pyrido [3,4-j] [1,4] oxazin-7-methyl] amino ] -3-hydroxy-1-piperidinyl} methyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2,1- / y] quinol -4-one; 1- ( { (3 / ?, 4S) -4 - [(2,3-D-hydrofuro [2,3-c] pyridin-5-ylmethyl) amino] -3- hydroxy-1-piperidinyl] methyl) -9-fluoro-1, 2-hydroxy-4 / - / - pyrrolo [3,2,1 - /] quinolin-4 -one; 9-Fluoro-1 - [((3,4S) -3-hydroxy-4-. {[[(7-oxo-, 5,6,7-tetrahydro-1,8-naphthyridin-2-yl)] methyl] amino.} -1-p -peridinyl) methyl] -1,2-dihydro-4 / - / - pyrrolo [3,2,1- //] quinolin-4-one; E1 enantiomer of 1- ( { 4 - [(6,7-dihydro [1,4] d -oxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-pperiod nil.}. methyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - /)] quinolin-4-one; E2 enantiomer of 1- (. {4 - [(6,7-dithy [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1- p.peridinyl] methyl) -9-fluoro-1,2-dhydro-4-pyrrolo [3,2,1 - /)] quinolin-4-one Enantiomer E1 of 9-Fluoro-1 - [(4- { [(3-oxo-3,4-d.hydro-2H-pyrido [3,2-¿&]; [1,4] oxazin-6-yl) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; E1 enantiomer of 1- (. {4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -4 -oxo-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - /] quinolin-9-carbonitrile; E2 enantiomer of 1- ( { 4- [(2,3-dihydro [1,4] dioxino [2,3-c] pindin-7-ylmethyl) amino] -1-pipendinyl} methyl) -9 -fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3, 2, 1 - / y] quinol-4-one; 1 - ( { 4 - [(2,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl.] Methyl) -9-fluoro- 1-Hydroxy-1,2-dihydro-4H-pyrrolo [3, 2, 1 - //] quinolin-4-one; E1 enantiomer of 1 - ( { 4 - [(2,3-dihydro [1,4] oxathino [2,3-c] pyridin-7-ylmethyl] amino] piperidin-1-yl.] Methyl ) -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3, 2, 1 - /)] quinolin-4-one; 9-Fluoro-1-hydroxy-1 - [(4- {[[3-oxo-3,4-dihydro-2H-pyrido [3,2-fc>] [1,4] oxazin-6- il) methyl] amino.} -1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3.2, 1 - / y] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] oxathino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9 -fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2, 1-//] quinolin-4-one; 1 - ( { 4 - [(6,7-Dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.} Methyl) -9-fluoro- 1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3, 2, 1 - /)] quinolin-4-one; 1 - ( { 4 - [(2,3-Dihydro- / - / - pyrido [3,4-t »] [1,4] oxazin-7-ylmethyl) amino] -1-piperidinyl.} Methyl ) -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 - /)] quinolin-4-one; 1 - ( { 4 - [(2,3-Dihydro [1,4] oxathino [2,3-b] pyridin-7-ylmethyl) amino] -1-piperidinyl] methyl) -9- fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; E1 enantiomer of 1 - ( { 4 - [(2,3-dihydro [1,4] dioxino [2,3-o]] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2, 1 - /] quinolin-4-one; - ( { 4 - [(2,3-Dihydro [1,4] dioxino [2,3-t)] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4-one; 1 - ( { 4 - [(1, 2,3-Benzothiadiazol-5-ylmethyl) amino] -1-piperidinyl.} Methyl) -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3, 2,1 - /] quinolin-4-one; E2 enantiomer of 1 - ( { 4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl.] Methyl) -4 -oxo-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - / y] quinol-9-carbonitrile; E1 enantiomer of 1 - ( { 4 - [(2,3-dihydro [1,4] dioxin [2,3-c] p¡ dn-7-ylmethyl) amino] -1-pipehdin l.) methyl) -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - / y] quinolin-4-one; 9-Fluoro-1 - [(4. {[[(5-oxo-1, 2,3,5-tetrahydro-7-indolizinyl) methyl] amino.} -1-piperidinyl) methyl] -1, 2 -dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; E2 Enantiomer of 1 - (. {4 - [(2,3-dihydro [1,4] oxathiino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9 -fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - / y] quinolin-4-one; E2 Enantiomer of 1 - ( { 4 - [(2,3-Dihydro [1,4] dioxino [2,3- /?] Pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) - 9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3, 2, 1-//] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] oxathino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9 -fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] oxathino [3,2-c] pyridazin-3-ylmethyl) amino] -1-pipehdinyl} methyl) -9-fluoro-1, 2-dihydro-4 - / - pyrrolo [3,2,1 - /)] quinolin-4-one; E1 enantiomer of 1- ( { 4 - [(6,7-dihydro-5H-pyran [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl.} Methyl) -9-fluoro -1, 2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; 9-Fluoro-1 - [((3R) -3-. {[[([1, 3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] methyl.} -1-pyrrolidinyl) methyl ] -1,2-dihydro-4 / - / - pyrrolo [3,2,1 - /] quinolin-4-one; 1 -. { [(3f?) - 3- ( { [(7-Chloro-3-oxo-3,4-dihydro-2 / - / - pyrido [3,2-ib] [1,4] oxazin-6- il) methyl] amino.} methyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2,1 - / y] quinolin-4-one; 9-Fluoro-1 -. { [(3R) -3- ( { [(3-oxo-3,4-dihydro-2 / - / - pyrido [3,2-i)] [1,4] thiazin-6-yl) methyl] Not me} methyl) -1-pyrrolidinyl] methyl} -1, 2-dihydro-4 / - / - pyrrolo [3,2, 1 - /)] quinolin-4-one; 9-Fluoro-1 -. { [(3f?) - 3- ( { [(3-Oxo-3,4-dihydro-2H-pyrido [3,2-t)] [1,4] oxazin-6-yl) methyl] amino} methyl) -1-pyrrolidinyl] methyl} -1, 2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4-one; 1 - [((3R) -3- { [(2l3-Dihydro [1,4] clioxino [2 I3-c] pyridin-7-ylmethyl) amino] methyl.} -1-pyrrolidinyl) methyl] -9 -fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; 9-Fluoro-1 - [(3. {[[([1,3] oxathiolo [5,4-c] pyridin-6-ylmethyl) amino] methyl.} -1-pyrrolidinyl) methyl] -1, 2-dihydro-4H-pyrrolo [3,2, 1 - /] quinolin-4-one; 1 -. { [3- ( { [(7-Chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) methyl] amino.}. methyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4 / - / - pyrrolo [3,2, 1 - /)] quinolin-4-one; Isomer 1, 2, 3 or 4 of 1 -. { [3- ( { [(7-chloro-3-oxo-3,4-dihydro-2H-pyrida [3,2-a]] [1,4] oxazin-6-yl) methyl] amino } metN) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2, 1 - /] quinolin-4-one; 1 - [(4- { [(3-Oxo-3,4-dihydro-2H-pyrido [3,2-a]] [1,4] thiazin-6-yl) methyl ] amin.} -1-piperidinyl) methyl] -1,2-dihydro-4H-pyrrolo [3,2,1- / y] quinolin-4-one; 1 - ( { 4 - [(2,3-Dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl. methyl) -1,2-dihydro-4H-pyrrolo [3,2,1- / y] quinolin-4-one; 1 - ( { 4 - [([1, 3] Oxathiolo [5,4-c] pyridn-6-ylmethyl) amino] -1-pipendinyl.] Methyl) -1 , 2-dihydro-4H-pyrrolo [3,2, 1-//] quinolin-4-one; 1 - [(4- { [(7-Chloro-3-oxo-3,4-d -hydro-2H-pyrido [3,2-¿&] [1,4] oxazin-6-yl) methylene] amino] -1, -1-piperidinyl) methyl] -1,2-dihydro-4-pyrrolo [3,2,1 - / y] quinolin-4-one; 1 - ( { 4 - [(3,4-D yhydro-2 - / - p-pyrano [2,3-c] pyridin-6-ylmethyl) amino] -1-pyridine Nyl, methylene) -1, 2-d, 4-dr-4 / - / - pyrrolo [3,2, 1 - / y] quinolin-4-one; 1 - [(3-. {[[(2,3-D yhydro [1,4] dioxino [2,3-c] pyridin-7-methyl) amino] methyl.} -1 - pyrrolidinyl) methyl] -9-fluoro-1,2-d, 4-dH-pyrrolo [3,2 - / y] quinolin-4-one; E2 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] oxathi [3, 3-c] pindazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1-hydroxy-1,2-dihydro-4H-pyrrolo [3,2,1 - / y] quinolin-4-one; 9-Fluoro-1 -. { [3- ( { [(3-oxo-3,4-d¡h¡dro-2H-pyrido [3,2-)]] [1,4] thiazin-6-ll) meth l] amino} methylene) -1-pyrrolidinyl] m-4-one; 1 - ( { 4 - [(6,7-Dihydro [1,4] dioxyl [2,3-c] pyridazin-3-ylmethyl) amino] -1-pyridinyl} methyl ) -4-oxo-1,2-dihydro-4H-pyrrolo [3,2- /)] quinol-9-carbontril (enantiomer E1); 1- ( { 4 - [(6,7-Dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-p.peridinyl. Meth. ) -4-oxo-, 2-dihydro-4 / - / - pyrrolo [3.2, 1 - / yjquinolin-9-carbonitrile (enantiomer E2); 1- (R / S) - [(4- { [(3S) -2,3-D yhydro [1,4] dioxino [2,3- / 5] pi d¡n-3-ilmet l] amino.} -1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1- / y] quinolin-4-one; E1 enantiomer of 1- ( { 4 - [(6,7-dihydro-5H-pyran [2,3-c] pihdazin-3-ylmethyl) amino] -1-piperidinyl.} Methyl) -4 -oxo-1, 2-dihydro-4 - / - pyrrolo [3,2,1 - /] quinolin-9-carbonitrile; E1 enantiomer of 1- ( { 4 - [(6,7-dihydro-5 / - / - pyrano [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) - 9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1-//] quinolin-4-one; E1 Enantiomer of 9-Fluoro-1 - [(4- {[[(6-oxo-6,7-dihydro-5H-pyridazino [3,4- £)] [1,4] thiazin-3-yl) methyl] amino} -1-piperidinyl) methyl] -1,2-dihydro-4 / - / - pyrrolo [3,2,1 - /] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1 -hydroxy-4-oxo-1,2-dihydro-4 / - / - pyrrolo [3,2,1-//] quinoline-9-carbonitrile; E2 enantiomer of 1- (. {4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -1 -hydroxy-4-oxo-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - /)] quinoline-9-carbonitrile; E1 enantiomer of 1 - [(4- {[[7] -chloro-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) methyl] amino.} -1-piperidinyl) methyl] -9- fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one; E1 enantiomer of 1- (. {4 - [(2,3-dihydro [1,4] dioxin] [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9- (methyloxy) -1,2-dihydro-4H-pyrrolo [3,2,1-ij ] quinolin-4-one; E2 enantiomer of 1- (. {4 - [(2,3-dihydro [1,4] dioxino [2,3-c] pyridin-7-ylmethyl) amino] -1-piperidinyl} methyl) -9- (methyloxy) -1,2-dihydro-4H-pyrrolo [3,2,1-ij] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9 - (methyloxy) -l, 2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; Diastereomer D1 of 9-Fluoro-1 -. { [4- ( { [(7R S) -7- (hydroxymethyl) -67-dihydro [1,4] dioxino [2,3-c] pyridazin-3-yl] methyl.} Amino) -1 - piperidinyl] methyl} -1, 2-dihydro-4H-pyrrolo [3,2- / y] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(5,6-dihydrofuro [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl}. Methyl) -9-fluoro-1, 2 -dihydro-4 / - -pyrrolo [3,2,1 - /)] quinolin-4-one; E1 enantiomer of 1 - (. {4 - [(5,6-dihydrofuro [2,3-c] pihdazin-3-ylmethyl) amino] -1-piperidinyl}. Methyl) -9-fluoro-1-hydroxy -1, 2-dihydro-4H-pyrrolo [3,2,1-//] quinolin-4-one; and (1 RS) -1 - [(4- { [(7S) -6,7-Dihydro [1,4] dioxino [2,3-c] pyridazin-7-ylmethyl] amino.} -1 -piperidinyl) methyl] -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2,1- //] quinolin-4-one; or one of its salts and / or one of its pharmaceutically acceptable solvates. 1 1 .- A compound selected from: 4-methylbenzene monosulfonate salt of the E1 Enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin- 3-ylmethyl) amino] -1-piperidinyl.] Methyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - / y] quinolin-4-one; mono (2E) -2-butenodiate salt of the E1 Enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3-c] pyridazin-3-ylmethyl) amino] -1-piperidinyl} methyl) -9-fluoro-1,2-dihydro-4 / - / - pyrrolo [3,2,1-//] quinolin-4-one; anhydrate I of mono (2E) -2-butenediotate salt of the E1 enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dinoxino [2,3-c] pyridazin-3) -ylmethyl) amino] -1-piperidinyl.} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - / y] quinolin-4-one; and mono (2E) -2-butenedioate salt trihydrate of the E1 Enantiomer of 1 - (. {4 - [(6,7-dihydro [1,4] dioxino [2,3- c] pindazin-3-ylmethyl] ) amino] -1-phenylenyl} methyl) -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 - /] quinolin-4-one; 12. The use of a compound as claimed in claim 1, in the manufacture of a medicament useful in the treatment of bacterial infections in mammals. 13. - A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmaceutically acceptable carrier. 14. - A compound of formula (IIB): where R is hydrogen. 15. The compound according to claim 14, further characterized in that it is selected from: E1 enantiomer of 1 - [(4-Amino-1-piperidinyl) methyl] -9-fluoro-1,2-dihydro-4H -pyrrolo [3,2,1 -ij] quinolin-4-one; E2 enantiomer of 1 - [(4-Amino-1-pipe dinyl) methyl] -9-fluoro-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one; 1 -. { [(3R, 4S) -4-amino-3-hydroxy-1-piperidinyl] methyl} -9-fluoro-, 2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one; 1 - [(4-Amino-1-p -peridinyl) methyl] -9-fluoro-1-hydroxy-1,2-dihydro-4 / - / - pyrrolo [3,2,1 - /)] quinolin-4 -one; 1 -. { [(3f?) - 3- (Aminomethyl) -1-pyrrolidinyl] methyl} -9-fluoro-1, 2-dihydro-4H-pyrrolo [3,2,1 - / y] quinolin-4-one; 1 - [(4-Amino-1-piperidinyl) methyl] -1,2-dihydro-4 / - / - pyrrolo [3,2,1 - / y] quinolin-4-one; 1- (4-Amino-1-piperidinyl) methyl] -4-oxo-1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinoline-9-carbonitrile; and 1 - [(4-Amino-1-piperidinyl) methyl] -9- (methyloxy) -1,2-dihydro-4H-pyrrolo [3,2,1 -ij] quinolin-4-one. 16.- 6,7-Dihydro [1,4] dioxino [2,3-c] pyridazin-3-carbaldehyde.