AU2007331247A1 - 2-quinolinone and 2-quinoxalinone- derivatives and their use as antibacterial agents - Google Patents

Description

WO 2008/071961 PCT/GB2007/004766 2-QUINOLINONE AND 2-QUINOXALINONE- DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS Field of Invention The present invention relates to novel piperidines, pharmaceutical compositions thereof, and methods of use. In addition, the present invention relates to therapeutic methods for the treatment of bacterial infections. Background The international health community continues to express serious concern that the evolution of antibacterial resistance will result in strains against which currently available antibacterial agents will be ineffective. For example, resistant strains of Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium are both difficult to treat and difficult to eradicate. Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups. Summary In accordance with the present invention, the applicants have hereby discovered compounds that possess the ability to act as antimicrobials. Accordingly, the present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, their use as medicaments, and their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. Accordingly the present invention provides a compound of Formula (I): R 8 H E_ R 9 R N O b N A R Nol6 ( R Formula (1) WO 2008/071961 PCT/GB2007/004766 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is substantially free of a cis (±) mixture of its enantiomers, and wherein A is selected from CH and N; D is selected from C-R 7 and N; wherein at least one of A and D is carbon; E is selected from 0, NH, and S, wherein: i) E is NH if R 8 and R 9 together from =0; and ii) E is O or S if R 8 and R9 are each H; G is selected from 0 and S; J is selected from C-R4 and N; R1 is selected from H, halo, cyano, CI.

6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl, ORi, and -N(Ria)2, wherein said C1- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R Ria in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI.

6 alkyl is optionally substituted with one or more R20; R2 is selected from H, halo, cyano, C1.6alkyl, C 2

-

6 alkenyl, C2-0alkynyl, -OR 2 a, and -N(R 2a)2 wherein said C 1

.

6 alkyl, C 2

.

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R20 R 2 in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI.

6 alkyl are optionally substituted with one or more R20;

R

3 is selected from H, halo, cyano, Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl, -OR 3 a, and

-N(R

3a )2, wherein said C 1

.

6 alkyl, C 2

.

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R"; R3 in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI.

6 alkyl is optionally substituted with one or more R30; RW is selected from H, halo, -CO 2 H, cyano, CI.

6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl, wherein said CI- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R4; R6 is selected from fluoro, CI- 6 alkyl, C 2

-

6 alkenyl, C 2

.

6 alkynyl, -OR a, wherein said Ci- 6 alkyl,

C

2

.

6 alkenyl, and C 2

.

6 alkynyl are optionally substituted with one or more R60; R6' in each occurrence is independently selected from H and CI.

6 alkyl, wherein said Ci- 6 alkyl are optionally substituted with one or more R6 0 ; 2 WO 2008/071961 PCT/GB2007/004766 R7 is selected from H, halo, cyano, CI- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl, wherein said Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R'7; R8 and R9 are each hydrogen, or R8 and R 9 together form =0; and 10 20 30 4 070 R , R , R, R40, R60, and R in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO 2 H, Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

.

6 alkynyl. In another aspect, the present invention provides a compound of Formula (II):

R

8 H E R 9 R N Q bN AZt 2 aG R N 0 D R 3 Formula (II) or a pharmaceutically acceptable salt thereof, wherein the R6 group on carbon "a" and the -NH- group on carbon "b" are in a trans relationship to each other, and wherein A is selected from CH and N; D is selected from C-R 7 and N; wherein at least one of A and D is carbon; E is selected from 0, NH, and S, wherein: i) E is NH if R 8 and R 9 together from =0; and ii) E is O or S if R 8 and R 9 are each H; G is selected from 0 and S; J is selected from C-R 4 and N; R1 is selected from H, halo, cyano, Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2 -6alkynyl, ORIa, and -N(R'a)2, wherein said CI- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R10; Ra in each occurrence is independently selected from H and CI- 6 alkyl, wherein said C 1

.

6 alkyl is optionally substituted with one or more R20 R2 is selected from H, halo, cyano, CI- 6 alkyl, C 2

-

6 alkenyl, C 2

-

6 alkynyl, -OR 2 a, and -N(R 2 a) 2 wherein said CI- 6 alkyl, C 2

.

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R 2 0 ; 3 WO 2008/071961 PCT/GB2007/004766 R2' in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said Ci- 6 alkyl are optionally substituted with one or more R20 3 3a R3 is selected from H, halo, cyano, Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl, -OR , and

-N(R

3 a) 2 , wherein said Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R30;

R

3 ' in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said Ci- 6 alkyl is optionally substituted with one or more R30;

R

4 is selected from H, halo, -CO 2 H, cyano, Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl, wherein said Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R40 6 6, R' is selected from fluoro, Ci- 6 alkyl, C 2

-

6 alkenyl, C 2

-

6 alkynyl, -OR a, wherein said Ci- 6 alkyl,

C

2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more R6 R' in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said C1.

6 alkyl are optionally substituted with one or more R6

R

7 is selected from H, halo, cyano, CI- 6 alkyl, C 2

-

6 alkenyl, and C 2

.

6 alkynyl, wherein said C1 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl are optionally substituted with one or more Ri 0 ; R8 and R! are each hydrogen, or R8 and R 9 together form =0; and R1 0 , R 20 , R 3 0 , R 4 0 , R 60 , and R'" in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO 2 H, Ci- 6 alkyl, C 2

-

6 alkenyl, and C 2

-

6 alkynyl. The compounds of Formulas (I) and (1I) and pharmaceutically acceptable salts thereof are believed to be effective in treating bacterial infections. Accordingly, the present invention relates to compounds of Formulas (I) and (II) that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, methods for their us in the treatment of bacterial infections, their use as medicaments for the treatment of bacterial infections, and their use in the manufacture of such medicaments. Detailed Description of the Invention In this specification the prefix C,-y as used in terms such as C.yalkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, Ci-4alkyl includes Cialkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl (propyl and isopropyl) and C 4 alkyl (butyl, 1 -methylpropyl, 2-methylpropyl, and t-butyl). 4 WO 2008/071961 PCT/GB2007/004766 As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. The term "alkenyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C 2 -salkenyl" includes, but is not limited to, groups such as C 2

-

6 alkenyl, C2Aalkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, and 2-methyl-i -heptenyl. The term "alkynyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C 2 -salkynyl" includes, but is not limited to, groups such as C 2

-

6 alkynyl, C 24 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 2-heptynyl, and 4-methyl-5-heptynyl. The term "halo" refers to fluoro, chloro, and bromo. In one aspect, "halo" may refer to fluoro. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. The term "carbocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3-12 ring atoms, wherein one or more -CH 2 - groups can optionally be replaced by a corresponding number of -C(O)- groups. In one aspect, the term "carbocyclyl" may refer to a monocyclic ring containing 3 to 6 ring atoms or a bicyclic ring containing 9 or 10 atoms. In another aspect, the term "carbocyclyl" may refer to a monocyclic ring containing 5 or 6 atoms. Illustrative examples of "carbocyclyl" include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1-oxocyclopentyl, phenyl, naphthyl, tetralinyl, indanyl or 5 WO 2008/071961 PCT/GB2007/004766 1 -oxoindanyl. A particular example of a "carbocyclyl" group is phenyl. The term "heterocyclyl" refers to a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolone, isothiazolyl, isoxazolyl, morpholino, 2-oxopyrrolidinyl, 2-oxo-1,3-thiazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridone, quinolyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thienyl, thiomorpholino, thiophenyl, pyridine-N-oxide and quinoline-N-oxide. In one aspect of the invention the term "heterocyclyl" may refer to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur, and oxygen, and may, unless otherwise specified, be carbon or nitrogen linked, and a ring nitrogen atom may be optionally oxidized to form an N-oxide. The symbol "(±)" is intended to signify a racemic mixture; i.e. an optically inactive mixture of equal amounts of (+) and (-) enantiomers of the indicated compound. When a compound or mixture is designated as being "cis (±)" or "trans (±)," it should be understood that the cis or trans relationship indicated therein pertains to the relationship between the group on carbon "a" and the -NH- group on carbon "b." Where a particular R group is present in a compound of Formulas (I) or (II) more than once, it is intended that each selection for that R group is independent at each occurrence. Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl. The term "substantially free" is intended to indicate that the specified entity is present in an amount less than 10%, more particularly less than 5%, in particular less than 2%, more 6 WO 2008/071961 PCT/GB2007/004766 particularly less than 1%, in particular less then 0.5%, particularly less than 0.2%. As used herein, the term "optionally substituted," indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound which exhibits an antibacterial effect. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. Compounds and substituent definitions of the present invention have been named with the aid of ACD/Name by ACD/Labs@. Compounds of Formulas (I) and (1I) and pharmaceutically acceptable salts thereof may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods well-known in the art. 7 WO 2008/071961 PCT/GB2007/004766 A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. The compounds of Formulas (I) and (II) have two chiral carbons on the central piperidine ring, carbon "a" and carbon "b." Additionally, the compounds of Formulas (I) and (II) may have other chiral centers and/or geometric isomeric centers (E- and Z- isomers) It is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess antibacterial activity. The invention further relates to any and all tautomeric forms of the compounds of Formula (I) and (II) and pharmaceutically acceptable salts thereof that possess antibacterial activity. It is also to be understood that certain compounds of Formulas (I) and (1I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity. Additional embodiments of the invention are as follows. Unless otherwise indicated, these additional embodiments relate to both compounds of Formulas (I) and (II), and to pharmaceutically acceptable salts thereof. The specific substituents and stereochemical relationships may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter. Carbon "a"l and Carbon "b" In one aspect, the R 6 group on carbon "a" and the -NH- group on carbon "b" of the compounds of Formula (I) are in a cis (+) relationship to each other, wherein the compound of 8 WO 2008/071961 PCT/GB2007/004766 Formula (1) is substantially free of a cis (±) mixture of its enantiomers. In another aspect, the R6 group on carbon "a" and the -NH- group on carbon "b" of the compounds of Formula (I) are in a cis (-) relationship to each other, the compound of Formula (I) is substantially free of a cis (±) mixture of its enantiomers. In still another aspect, the R 6 group on carbon "a" and the -NH- group on carbon "b" of the compounds of Formula (1) are in a trans (+) relationship to each other. In still another aspect, the R6 group on carbon "a" and the -NH- group on carbon "b" of the compounds of Formula (I) are in a trans (-) relationship to each other. A In one aspect, A is N. In another aspect, A is CH. D In one aspect, D is N. In another aspect, D is CH. In still another aspect, D is selected from N and CH. A and D In one aspect, A is N; and D is CH. In another aspect, A is CH; and D is N. 9 WO 2008/071961 PCT/GB2007/004766 E, G, R', and R' In one aspect, E and G are each 0; and R8 and R 9 are each H. In another aspect, E is NH; G is selected from 0 and S; and R8 and R9 together form =0; In still another aspect, E is NH; G is S; and RW and R! together form=0. In yet another aspect, E is NH; G is 0; and R8 and R9 together form =0. In one aspect, J is N. In another aspect, J is CH. In still another aspect, J is selected from N and CH. In yet another aspect, J is selected from N and C-R 4 ; and

R

4 is selected from H and CI.

6 alkyl. In a further aspect, J is selected from N and C-R 4 ; and

R

4 is selected from H and methyl. In still a further aspect, J is selected from C-R 4 ; and R is selected from H and methyl. A, D, E, G, R , and R9 In one aspect, A, D, E, G, R8, and R 9 , together with the ring atoms to which they are attached, form a group selected from: 10 WO 2008/071961 PCT/GB2007/004766 H 0 N X0

N

N and In another aspect, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form: 0 N In still another aspect, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form: H 0 N X 0 In yet another aspect, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form:

H

0 N S In a further aspect, A, D, E, G, R , and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 0N N NN , and 11 WO 2008/071961 PCT/GB2007/004766 R1 In one aspect, R' is H. R2 In one aspect, R2 is selected from cyano and -OR 2 a; and R2' is C1.

6 alkyl. In another aspect, R2 is selected from cyano and methoxy. In still another aspect, R 2 is cyano. In yet another aspect, R 2 is -OR 2 a; and R2' is C1.

6 alkyl. In a further aspect, R2 is methoxy. R3 R6 In one aspect, R' is selected from fluoro and -OR 6 a; and R6a is selected from H and Ci- 6 alkyl. In another aspect, R 6 is selected from fluoro, hydroxy, and methoxy. In still another aspect, R6 is fluoro. In yet another aspect, R6 is hydroxy. In a further aspect, R6 is methoxy. 12 WO 2008/071961 PCT/GB2007/004766 R', R2, R, R , R , R , A, D, E, G, and J Formula (1) 1) In one aspect, the compound of Formula (1), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ia): 0 H N RN N N J R3 Formula (la) 1 2 3 6 or a pharmaceutically acceptable salt thereof, wherein R , R2, R , R6, G, and J are as defined hereinabove, and wherein the compound of Formula (Ia) is substantially free of a cis (+) mixture of its enantiomers. 1.1) In one aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, G is selected from 0 and S; J is selected from N and CH;

R

1 is H; R2 is selected from cyano and -OR 2 a

R

2 a is Ci- 6 alkyl;

R

3 is H;

R

6 is selected from fluoro and -OR 6 a; and R6a is selected from H and Ci- 6 alkyl. 1.2) In another aspect of the compound of Formula (1a), or a pharmaceutically acceptable salt thereof, G is selected from 0 and S; J is selected from N and CH; R1 is H; 13 WO 2008/071961 PCT/GB2007/004766

R

2 is selected from cyano and methoxy;

R

3 is H; and

R

6 is selected from fluoro, hydroxy, and methoxy. 1.3) In still another aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, G is selected from 0 and S; J is selected from N and C-R 4 ; R1 is H;

R

2 is selected from cyano and -OR2a

R

2 a is CI- 6 alkyl;

R

3 is H; Ri is selected from H and CI.

6 alkyl; R' is selected from fluoro and -OR 6a; and

R

6 a is selected from H and CI.

6 alkyl. 1.4) In yet another aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, G is selected from 0 and S; J is selected from N and C-R 4 ; R, is H;

R

2 is selected from cyano and -OR2a R2' is methyl; Ris H;

R

4 is selected from H and methyl; R1 is selected from fluoro and -OR 6 a; and

R

6 a is selected from H and methyl. 2) In another aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (Ib): 14 WO 2008/071961 PCT/GB2007/004766 N H 0 b N o a 0 6 R2 | R O J R 3 Formula (Ib) 1 2 3 6 or a pharmaceutically acceptable salt thereof, wherein R , R, R3, R , and J are as defined hereinabove, wherein the compound of Formula (Ib) is substantially free of a cis (±) mixture of its enantiomers. 2.1) In one aspect of the compound of Formula (Ib), J is selected from N and CH; R1 is H; R2 is selected from cyano and -OR2a R2' is Ci.

6 alkyl; R1 is H; R1 is selected from fluoro and -OR6a ; and R6a is selected from H and Ci- 6 alkyl. 2.2) In another aspect of the compound of Formula (Ib), J is selected from N and CH; R' is H; R2 is selected from cyano and methoxy;

R

3 is H; and R6 is selected from fluoro, hydroxy, and methoxy. 2.3) In still another aspect of the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, J is selected from N and CH;

R

1 is H; R2 is selected from cyano and -OR 2 a; 15 WO 2008/071961 PCT/GB2007/004766

R

2 a is Ci- 6 alkyl;

R

3 is H;

R

6 is selected from fluoro and -OR 6a; and

R

6 a is selected from H and C1.

6 alkyl. 2.4) In yet another aspect of the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, J is selected from N and CH; R' is H;

R

2 is selected from cyano and methoxy; R is H; and R6 is selected from fluoro, hydroxy, and methoxy. 3) In still another aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ic): R 8 H E R9 RiN b N A: R N 0 6 D R2 R NROD0R

R

3 Formula (Ic) 1 2 3 6 8 9 or a pharmaceutically acceptable salt thereof, wherein R , R2, 3, R, R e, R9, A, D, E, G, and J are as defined hereinabove, wherein the compound of Formula (Ic) is substantially free of a cis (±) mixture of its enantiomers. 3.1) In one aspect of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R, and R, together with the ring atoms to which they are attached form, a group selected from: 16 WO 2008/071961 PCT/GB2007/004766 H 0 0 N N_ N and J is selected from N and CR 4 ; R' is H; R2 is selected from cyano and -OR2a

R

2 a is CI 6 alkyl; R1 is H;

R

4 is selected from H and C 16 alkyl; R6 is selected from fluoro and -OR6a; and

R

6 a is selected from H and Ci 6 alkyl. 3.2) In another aspect of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R', and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 N N , and J is selected from N and CR4; R1 is H; R2 is selected from cyano and -OR 2 a; R2a is Ci- 6 alkyl;

R

3 is H; R is selected from H and C- 6 alkyl; R' is selected from fluoro and -OR 6a; and R"a is selected from H and C- 6 alkyl. 3.3) In still another aspect of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, e, and R, together with the ring atoms to which they are attached, form 17 WO 2008/071961 PCT/GB2007/004766 a group selected from:

H

0 0 N N and J is selected from N and CR 4 ; R' is H; R2 is selected from cyano and -OR 2 a; R2' is methyl; RW is H;

R

4 is selected from H and methyl; R is selected from fluoro and -OR 6a; and R6a is selected from H and methyl. 3.4) In yet another aspect of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R 9 , together with the ring atoms to which they are attached, form a group selected from: H

H

0 N_ oN N NN ,and J is selected from N and CR4; R' is H; R2 is selected from cyano and -OR2a. R2a is methyl; R3 is H; R4 is selected from H and methyl; R6 is selected from fluoro and -OR6a; and R6a is selected from H and methyl. 4) In a further aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Id): 18 WO 2008/071961 PCT/GB2007/004766

R

8 2R N A R6 R R D R3 Formula (Id) or a pharmaceutically acceptable salt thereof, wherein R , R , R , R6, R', R , A, D, E, G, and J are as defined hereinabove, and wherein the compound of Formula (Id) is substantially free of a cis (±) mixture of its enantiomers. 4.1) In one aspect of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 0 N N_ N and J is selected from N and CR4; R' is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is CI.

6 alkyl;

R

3 is H; R4 is selected from H and CI 6 alkyl; R' is selected from fluoro and -OR 6 a; and R6' is selected from H and CI- 6 alkyl. 4.2) In another aspect of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R, together with the ring atoms to which they are attached, form a group selected from: 19 WO 2008/071961 PCT/GB2007/004766

H

0 H 0 N N NN N and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is CI.

6 alkyl; R is H; Ri is selected from H and C.

6 alkyl; R is selected from fluoro and -OR 6 a; and

R

6 a is selected from H and C.

6 alkyl. 4.3) In still another aspect of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, A, D, E, G, R, and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 0 N N_ N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and -OR 2 a; R2' is methyl; R is H;

R

4 is selected from H and methyl; RW is selected from fluoro and -OR 6 a; and R6a is selected from H and methyl. 4.4) In yet another aspect of the compound of Formula (Id), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form 20 WO 2008/071961 PCT/GB2007/004766 a group selected from: H H 0 N N NN N and J is selected from N and CR;

R

1 is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is methyl;

R

3 is H;

R

4 is selected from H and methyl; R6 is selected from fluoro and -OR 6 a; and

R

6 a is selected from H and methyl. 5) In still a further aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (le): R 8 H E R9 R N N R 2 a \K\ _ R N 0 F D R 3 Formula (le) or a pharmaceutically acceptable salt thereof, wherein R1, R2, RW, R6, R, R, A, D, E, G, and J are as defined hereinabove, and wherein the compound of Formula (le) is substantially free of a cis (+) mixture of its enantiomers. 5.1) In one aspect of the compound of Formula (le), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R9, together with the ring atoms to which they are attached, form a group selected from: 21 WO 2008/071961 PCT/GB2007/004766 H 0 N N_ N and J is selected from N and CR4; R' is H;

R

2 is selected from cyano and -OR2a

R

2 a is Ci 6 alkyl;

R

3 is H; and

R

4 is selected from H and Ci 6 alkyl. 5.2) In another aspect of the compound of Formula (le), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 0N N NN , and J is selected from N and CR;

R

1 is H; R2 is selected from cyano and -OR2a

R

2 a is CI- 6 alkyl;

R

3 is H; and R4 is selected from H and CI- 6 alkyl. 5.3) In still another aspect of the compound of Formula (le), or a pharmaceutically acceptable salt thereof, A, D, E, G, RN, and R9, together with the ring atoms to which they are attached, form a group selected from: 22 WO 2008/071961 PCT/GB2007/004766 H 0 N N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is selected from H and methyl. 5.4) In yet another aspect of the compound of Formula (Le), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 N N 0N-

N

N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and Ri is selected from H and methyl. 6) In yet a further aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (If): 23 WO 2008/071961 PCT/GB2007/004766 Ra8 H E R9 RN N A b 2 a \/G R N 0 F D J R 3 Formula (If) or a pharmaceutically acceptable salt thereof, wherein R , R 2, R3, R8, R9, A, D, E, G, and J are as defined hereinabove, wherein the fluoro group on carbon "a" and the -NH- group on carbon "b" are in a cis relationship to each other, and wherein the compound of Formula (If) is substantially free of a cis (±) mixture of its enantiomers. 6.1) In one aspect of the compound of Formula (If), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 N N and J is selected from N and CR4; R' is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is C 1

.

6 alkyl;

R

3 is H; and R4 is selected from H and C1.

6 alkyl. 6.2) In another aspect of the compound of Formula (If), or a pharmaceutically acceptable salt thereof, A, D, E, G, R, and R', together with the ring atoms to which they are attached, form a group selected from: 24 WO 2008/071961 PCT/GB2007/004766 H

H

0 0 N N , and J is selected from N and CR4; R' is H;

R

2 is selected from cyano and -OR2a

R

2 ' is CI.

6 alkyl;

R

3 is H; and RW is selected from H and C 16 alkyl. 6.3) In still another aspect of the compound of Formula (If), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R', together with the ring atoms to which they are attached, form a group selected from: H 0 0 N N and J is selected from N and CR; R1 is H;

R

2 is selected from cyano and methoxy; RW is H; and

R

4 is selected from H and methyl. 6.4) In yet another aspect of the compound of Formula (If), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: 25 WO 2008/071961 PCT/GB2007/004766

H

0 H 0)NN N N NN and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and RW is selected from H and methyl. 7) In one aspect, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ig): R 8 HE R R NA R N 0 F D J R3 Formula (Ig) 1 2 3 8 9 or a pharmaceutically acceptable salt thereof, wherein R , R2, R , Re, R9, A, D, E, G, and J are as defined hereinabove, wherein the compound of Formula (Ig) is substantially free of a cis (±) mixture of its enantiomers. 7.1) In one aspect of the compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R9, together with the ring atoms to which they are attached, form a group selected from: 26 WO 2008/071961 PCT/GB2007/004766 H 0 N N_ N and J is selected from N and CR 4 ;

R

1 is H; R2 is selected from cyano and -OR 2 a;

R

2 a is C 1

.

6 alkyl; R is H; and R is selected from H and C.

6 alkyl. 7.2) In another aspect of the compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, A, D, E, G, R', and R', together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 N N NN and J is selected from N and CR4; R1 is H; R2 is selected from cyano and -ORa R22 is Ci- 6 alkyl; R is H; and R4 is selected from H and C.

6 alkyl. 7.3) In still another aspect of the compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: 27 WO 2008/071961 PCT/GB2007/004766 H 0 N N and J is selected from N and CR4; R1 is H; R2 is selected from cyano and methoxy; R3 is H; and

R

4 is selected from H and methyl. 7.4) In yet another aspect of the compound of Formula (Ig), or a pharmaceutically acceptable salt thereof A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: H 0H 0 N N 0)N-

N

N and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and methoxy; R is H; and R4 is selected from H and methyl. 8) In another aspect, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ih): 28 WO 2008/071961 PCT/GB2007/004766 R 8 H E R9 RN N R 2 t R N 0 F D J R 3 Formula (1h) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R3, R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, wherein the compound of Formula (Ii) is substantially free of a cis (±) mixture of its enantiomers. 8.1) In one aspect of the compound of Formula (Ih), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R, together with the ring atoms to which they are attached, form a group selected from: H 0 0 N

N

N and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and -OR-a

R

2 a is C 1

-

6 alkyl;

R

3 is H; and

R

4 is selected from H and C1.

6 alkyl. 8.2) In another aspect of the compound of Formula (1h), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R 9 , together with the ring atoms to which they are attached, form a group selected from: 29 WO 2008/071961 PCT/GB2007/004766 H 0 H0 N N NNN and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and -OR 2 a; R a is CI- 6 alkyl;

R

3 is H; and RW is selected from H and C1 6 alkyl. 8.3) In still another aspect of the compound of Formula (Ih), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R, together with the ring atoms to which they are attached, form a group selected from: H 0 N N_ N and J is selected from N and CR 4 ;

R

1 is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is selected from H and methyl. 8.4) In yet another aspect of the compound of Formula (Ih), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R9, together with the ring atoms to which they are attached, form a group selected from: 30 WO 2008/071961 PCT/GB2007/004766

H

0

H

0 N O\/ N, and J is selected from N and CR; R' is H; R2 is selected from cyano and methoxy;

R

3 is H; and R4 is selected from H and methyl. Formula (II) 1.1 In one aspect of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R', together with the ring atoms to which they are attached, form a group selected from: H 0 0 N 0 0 N and J is selected from N and CR; R' is H;

R

2 is selected from cyano and -OR2a R a is C 1

.

6 alkyl; W is H;

R

4 is selected from H and C- 6 alkyl; R6 is selected from fluoro and -OR 6 a; and Ra is selected from H and C1 6 alkyl. 1.2) In another aspect of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R9, together with the ring atoms to which they are attached, form a group selected from: 31 WO 2008/071961 PCT/GB2007/004766 H 0 H0 N N N_ N_ N and J is selected from N and CR 4 ; R' is H; R2 is selected from cyano and -OR2a R 2 is Ci- 6 alkyl; RW is H;

R

4 is selected from H and C 1 6 alkyl; R6 is selected from fluoro and -OR 6a; and

R

6 a is selected from H and Ci- 6 alkyl. 1.3) In still another aspect of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R', together with the ring atoms to which they are attached, form a group selected from: H O N N and J is selected from N and CR ; R1 is H; R2 is selected from cyano and -OR 2 a;

R

2 a is methyl;

R

3 is H;

R

4 is selected from H and methyl; R6 is selected from fluoro and -OR a; and R6' is selected from H and methyl. 1.4) In yet another aspect of the compound of Formula (1I), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R 9 , together with the ring atoms to which they are attached, form 32 WO 2008/071961 PCT/GB2007/004766 a group selected from: H 0 N 60

N

N and J is selected from N and CR4; R1 is H; R2 is selected from cyano and -OR2a

R

2 a is methyl; RW is H; R4 is H; R6 is selected from fluoro and -OR 6 a; and R6a is selected from H and methyl. 1.5) In a further aspect of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 N N N_ N_ N and J is selected from N and CR 4 ; R' is H; R2 is selected from cyano and -OR 2 a; R2' is methyl;

R

3 is H; R4 is selected from H and methyl; RW is selected from fluoro and -OR 6 a; and R6' is selected from H and methyl. 2) In one aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ila): 33 WO 2008/071961 PCT/GB2007/004766

R

8 H E R 9 RN W.N

A

2 RD R N 0 R 6 / G K- T

R

3 Formula (Ila) or a pharmaceutically acceptable salt thereof, wherein R', R2, R3, R6, R 8 , R 9 , A, D, E, G, and J are as defined hereinabove. 2.1) In one aspect of the compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 0N N NN , and J is selected from N and CR; R' is H; R2 is selected from cyano and -OR 2 a; R2' is Ci- 6 alkyl; RW is H; R4 is selected from H and C 1

-

6 alkyl;

R

6 is selected from fluoro and -OR 6 a; and R' is selected from H and CI.

6 alkyl. 2.2) In another aspect of the compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: 34 WO 2008/071961 PCT/GB2007/004766

H

0 o N N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and -OR2a

R

2 a is C1.

6 alkyl;

R

3 is H;

R

4 is selected from H and C 16 alkyl; R is selected from fluoro and -OR6a; and R6' is selected from H and Ci- 6 alkyl. 2.3) In still another aspect of the compound of Formula (Ha), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and RW, together with the ring atoms to which they are attached, form a group selected from: H 0 N N_ N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is C 1

-

6 alkyl;

R

3 is H;

R

4 is H; R is selected from fluoro and -OR 6 a; and R6' is selected from H and C 16 alkyl. 2.4) In yet another aspect of the compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R 9 , together with the ring atoms to which they are attached, form 35 WO 2008/071961 PCT/GB2007/004766 a group selected from: H 0 0 0 N and J is selected from N and CR4; R' is H;

R

2 is selected from cyano and -OR2a R2a is methyl;

R

3 is H; R4 is selected from H and methyl;

R

6 is selected from fluoro and -OR 6 a; and R6' is selected from H and methyl. 2.5) In a further aspect of the compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 0 N 0 0 N and J is selected from N and CR 4 ; R, is H; R2 is selected from cyano and -OR2a

R

2 a is methyl;

R

3 is H;

R

4 is H; R6 is selected from fluoro and -OR6a; and R6' is selected from H and methyl. 36 WO 2008/071961 PCT/GB2007/004766 3) In another aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ilb):

R

8 H E

R

9 R N N A R 2 a. 6 \ /X G. R N xO R D

R

3 Formula (Ilb) or a pharmaceutically acceptable salt thereof, wherein R , R2, R3, R6, R8, R, A, D, E, G, and J are as defined hereinabove. 3.1) In one aspect of the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R!, together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 N N , and J is selected from N and CR4; RI is H;

R

2 is selected from cyano and -OR~a R2a is CI- 6 alkyl; is H;

R

4 is selected from H and C 1

.

6 alkyl; R6 is selected from fluoro and -OR 6a; and

R

6 a is selected from H and C 1

.

6 alkyl. 3.2) In another aspect of the compound of Formula (Ilb), or a pharmaceutically acceptable salt thereof, A, D, E, G, R, and R', together with the ring atoms to which they are attached, form 37 WO 2008/071961 PCT/GB2007/004766 a group selected from: H O o N N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and -OR2a R2' is C,- 6 alkyl; W is H;

R

4 is selected from H and CI.

6 alkyl; R is selected from fluoro and -OR a; and

R

6 a is selected from H and C I 6 alkyl. 3.3) In still another aspect of the compound of Formula (Ilb), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: .H 0 o N N and J is selected from N and CR;

R

1 is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is C 1

.

6 alkyl; R is H;

R

4 is selected from H;

R

6 is selected from fluoro and -OR 6 a; and R6' is selected from H and CI.

6 alkyl. 38 WO 2008/071961 PCT/GB2007/004766 3.4) In yet another aspect of the compound of Formula (1Ib), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 0N N and J is selected from N and CR; R1 is H;

R

2 is selected from cyano and -OR2a R2' is methyl;

R

3 is H;

R

4 is selected from H and methyl; R is selected from fluoro and -OR 6a; and

R

6 a is selected from H and methyl. 3.5) In a further aspect of the compound of Formula (Ilb), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R!, together with the ring atoms to which they are attached, form a group selected from: H 0 o N N and J is selected from N and CR; R' is H; R2 is selected from cyano and -OR 2 a;

R

2 a is methyl;

R

3 is H;

R

4 is H; 39 WO 2008/071961 PCT/GB2007/004766

R

6 is selected from fluoro and -OR 6 a; and R6' is selected from H and methyl. 4) In still another aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (1Ic) R 8 H E R RN N R R N 0 F D R3 Formula (I1c) or a pharmaceutically acceptable salt thereof, wherein R', R2, R , R , R , A, D, E, G, and J are as defined hereinabove, and wherein the fluoro group on carbon "a" and the -NH- group on carbon "b" are in a trans relationship to each other. 4.1) In one aspect of the compound of Formula (I1c), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and RW, together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 N N -N 00 S N, and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and -OR2a R2, is CI- 6 alkyl;

R

3 is H; and

R

4 is selected from H and Ci.

6 alkyl. 40 WO 2008/071961 PCT/GB2007/004766 4.2) In another aspect of the compound of Formula (1Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 N N and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and -OR2a

R

2 a is CI.

6 alkyl;

R

3 is H; and R4 is selected from H and C1.

6 alkyl. 4.3) In still another aspect of the compound of Formula (1Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R8, and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 NO N and J is selected from N and CR; R' is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is CI 6 alkyl; R3 is H; and W is H. 41 WO 2008/071961 PCT/GB2007/004766 4.4) In yet another aspect of the compound of Formula (1Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R', and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 O 0 N N and J is selected from N and CR; R1 is H; R2 is selected from cyano and methoxy;

R

3 is H; and R4 is selected from H and methyl. 4.5) In a further aspect of the compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, E, G, R, and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 o N N and J is selected from N and CR 4 ; R1 is H; R2 is selected from cyano and methoxy; R is H; and R' is H. 5) In yet another aspect, the compound of Formula (1I), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ild): 42 WO 2008/071961 PCT/GB2007/004766 R 8 H E R9 R N A 2 a- \/G R N 0 F D R 3 Formula (Ild) or a pharmaceutically acceptable salt thereof, wherein R , R2, R , R , R , A, D, E, G, and J are as defined hereinabove. 5.1) In one aspect of the compound of Formula (Ild), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 0- -N N NNN ,and J is selected from N and CR;

R

1 is H; R2 is selected from cyano and -OR 2 a; R2' is C 1

-

6 alkyl;

R

3 is H; and

R

4 is selected from H and Ci- 6 alkyl. 5.2) In another aspect of the compound of Formula (Ild), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R, together with the ring atoms to which they are attached, form a group selected from: 43 WO 2008/071961 PCT/GB2007/004766 H 0 N NN and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and -OR2a

R

2 ' is CI- 6 alkl;

R

3 is H; and

R

4 is selected from H and Ci- 6 alkyl. 5.3) In still another aspect of the compound of Formula (Ild), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 N N and J is selected from N and CR ; R' is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is C 1

-

6 alkl;

R

3 is H; and W is H. 5.4) In yet another aspect of the compound of Formula (Ild), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R 9 , together with the ring atoms to which they are attached, form a group selected from: 44 WO 2008/071961 PCT/GB2007/004766 H 0 o N 0-)

N

N and J is selected from N and CR;

R

1 is H; R2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is selected from H and methyl. 5.5) In a further aspect of the compound of Formula (Ild), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 0 N 0-

N

N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and W is H. 6) In a further aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (Ile): 45 WO 2008/071961 PCT/GB2007/004766

R

8 HE R R- N .. G1 2 C a X Z R N 0 F D J

R

3 Formula (Ile) or a pharmaceutically acceptable salt thereof, wherein R', R , R , R , R , A, D, E, G, and J are as defined hereinabove. 6.1) In one aspect of the compound of Formula (Ile), or a pharmaceutically acceptable salt thereof, A, D, E, G, R , and R , together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 0N N ON- N \0 \0 \S N and J is selected from N and CR ; R' is H;

R

2 is selected from cyano and -OR 2 a

R

2 a is C 1

-

6 alkyl;

R

3 is H; and

R

4 is selected from H and C1.

6 alkyl. 6.2) In another aspect of the compound of Formula (Ile), or a pharmaceutically acceptable salt thereof, A, D, E, G, R, and R!, together with the ring atoms to which they are attached, form a group selected from: 46 WO 2008/071961 PCT/GB2007/004766 H 0 N N and J is selected from N and CR4; R1 is H;

R

2 is selected from cyano and -OR 2 a;

R

2 a is C 1

.

6 al 1; R is H; and

R

4 is selected from H and C 16 alkyl. 6.3) In still another aspect of the compound of Formula (Ile), or a pharmaceutically acceptable salt thereof, A, D, E, G, R", and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 N 0 0 N and J is selected from N and CR4; R' is H;

R

2 is selected from cyano and -OR2a

R

2 ' is CI- 6 alkyl; RW is H; and

R

4 is H. 6.4) In yet another aspect of the compound of Formula (Ile), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: 47 WO 2008/071961 PCT/GB2007/004766 H 0 N 0N N and J is selected from N and CR 4 ; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is selected from H and methyl. 6.5) In a further aspect of the compound of Formula (Ile), or a pharmaceutically acceptable salt thereof, A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: H 0 0 N

N

N and J is selected from N and CR4; R' is H; R2 is selected from cyano and methoxy; R is H; and R is methyl. 7) In still a further aspect, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (If): O H N R N O F

R

3 Formula (Ilf) 48 WO 2008/071961 PCT/GB2007/004766 or a pharmaceutically acceptable salt thereof, wherein RI, R2, R 3 , and J are as defined hereinabove, and wherein the fluoro group on carbon "a" and the -NH- group on carbon "b" are in a trans relationship to each other. 7.1) In one aspect of the compound of Formula (If), or a pharmaceutically acceptable salt thereof, J is selected from N and CR4; R' is H; R2 is selected from cyano and -OR2a; R2a is CI- 6 alkyl; R is H; and R4 is selected from H and C1.

6 alkyl. 7.2) In another aspect of the compound of Formula (Hf), or a pharmaceutically acceptable salt thereof, J is selected from N and CR 4 ; R1 is H; R2 is selected from cyano and -OR 2 a; R2a is CI- 6 alkyl;

R

3 is H; and R4 is H. 7.3) In still another aspect of the compound of Formula (If), or a pharmaceutically acceptable salt thereof, J is selected from N and CR ; R' is H; R2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is selected from H and methyl. 7.4) In yet another aspect of the compound of Formula (f), or a pharmaceutically acceptable salt thereof, 49 WO 2008/071961 PCT/GB2007/004766 J is selected from N and CR4; R' is H;

R

2 is selected from cyano and methoxy; Ri is H; and

R

4 is H. 8) In yet a further aspect, the compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, may be a compound of Formula (I1g): H N N __ ) R 1 b R2R N O F N J R3 Formula (I1g) or a pharmaceutically acceptable salt thereof, wherein R , R 2 , R 3 , and J are as defined hereinabove, and wherein the fluoro group on carbon "a" and the -NH- group on carbon "b" are in a trans relationship to each other. 8.1) In one aspect of the compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, J is selected from N and CR4;

R

1 is H; R2 is selected from cyano and -OR 2 a; R2a is C 1

-

6 alkyl;

R

3 is H; and

R

4 is selected from H and C1.

6 alkyl. 8.2) In another aspect of the compound of Formula (ig), or a pharmaceutically acceptable salt thereof, J is selected from N and CR; R1 is H;

R

2 is selected from cyano and -OR 2 a; 50 WO 2008/071961 PCT/GB2007/004766 R2' is C1.

6 alkyl;

R

3 is H; and

R

4 is H. 8.3) In still another aspect of the compound of Formula (ig), or a pharmaceutically acceptable salt thereof, J is selected from N and CR4; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is selected from H and methyl. 8.4) In yet another aspect of the compound of Formula (ig), or a pharmaceutically acceptable salt thereof, J is selected from N and CR4; R' is H;

R

2 is selected from cyano and methoxy;

R

3 is H; and

R

4 is H. In another aspect, the present invention provides compounds of Formulas (I) and (II) and pharmaceutically acceptable salts thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention. Biological Activity The compounds of Formulas (I) (II) and pharmaceutically acceptable salts thereof are of interest due to their antibacterial effects. The ability of the invention compounds disclosed herein to achieve an antibacterial effect may be demonstrated by the following tests. Bacterial Susceptibility Testing Methods I Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media in a 96 well format. Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay may be 51 WO 2008/071961 PCT/GB2007/004766 grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension may be adjusted to be equal to a 0.5 McFarland and a further 1 in 10 dilution may be made into the same liquid medium to prepare the final organism suspension in 100 pL. Plates may be incubated under appropriate conditions at 37 'C for 24 hours prior to reading. The Minimum Inhibitory Concentration (MIC) was determined as the lowest drug concentration able to reduce growth by 80% or more. Compounds were evaluated against a panel of Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium. In addition, compounds were evaluated against a panel of Gram negative species including Haemophilus influenzae, Escherichia coli and Moraxella catarrhalis. Compounds of the present invention and pharmaceutically acceptable salts thereof are believed to generally have MIC's less than or equal to 8 Rg/ml versus one or more of the organisms named above. The compound of Example 2 had an MIC of 0.25 (mg/L) against Staphylococcus aureus and an MIC of 0.5 (mg/L) against Escherichia coli. Bacterial Susceptibility Testing Methods 2 Compounds may be tested for antimicrobial activity by susceptibility testing using microbroth dilution methods recommended by CSLI. Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays such that the final dimethylsulfoxide concentration in the assay is 2% (v/v). The Staphylococcus aureus (Sau) 516 cells used in the assay may be grown overnight on appropriate agar media and then suspended in the NCCLS-recommended liquid susceptibility-testing media. The turbidity of each suspension may be adjusted to be equal to a 0.5 McFarland standard, and a further 1-in 200 dilution may be made into the same liquid medium to prepare the final organism suspension, and 100 pL of this suspension may be added to each well of a microtiter plate containing compound dissolved in 2 pL of dimethylsulfoxide. Plates may be incubated under appropriate conditions of atmosphere and temperature and for times according to NCCLS standard methods prior to being read. As used in Table 1 below, the term "inhibition" refers to the percentage of Staphylococcus aureus 516 cell growth that is suppressed (compared to 52 WO 2008/071961 PCT/GB2007/004766 an untreated sample) by the compound of the indicated example number. When tested in the above in-vitro assay, the compounds and salts of the example numbers listed below were tested at the indicated concentrations, providing the indicated inhibitions. In most instances, the highest concentrations at which the compounds were tested was 8 pg/mL. In some instances, however, compounds were tested at concentrations higher than 8 pg/mL, typically when the concentration was first measured in PM and was subsequently converted to ptg/mL. In those cases in which compounds were tested at more than one concentration higher than 8 ttg/mL, the concentration closest to 8 ptg/mL is provided below. TABLE 1 Example Tested Inhibition Number Concentration (%) (ptg/mL) 1 8 100 2 8 100 3 8 99 4 8 100 5 8 100 6 8 99 7 8 100 8 8 99 9 8 100 10 8 100 Examples 11 to 20 11 8 100 12 8 100 13 8 100 14 8 100 15 8 97 16 8 97 17 8 99 53 WO 2008/071961 PCT/GB2007/004766 18 8 95 19 8 100 20 8 100 Examples 21 to 30 21 8 100 22 8 100 23 8 100 24 8 100 25 8 98 26 8 98 27 8 87 28 8 98 29 8 84 30 8 98 Examples 31 to 40 31 8 87 32 8 98 33 13 96 34 12 91 35 14 100 36 12 90 37 13 100 38 12 100 39 14 100 40 12 100 54 WO 2008/071961 PCT/GB2007/004766 Examples 41-52 41 8 100 42 8 100 43 4 100* 44 8 100 45 8 97 46 8 100 47 8 100 50 14 100 51 9 100 52 13 100 *The inhibition for the compound of Example 43 at a concentration of 8 pg/mL was 12%, though it is believed that the 12% figure is erroneous. Thus, in one aspect there is provided a compound of Formula (I) or (11), or a pharmaceutically acceptable salt thereof, for use as a medicament. In still another aspect, there is provided the use a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man. In yet another aspect, there is provided the use of a compound of Formula (I) or (1I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas 55 WO 2008/071961 PCT/GB2007/004766 aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man. In a further aspect, there is provided the use of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man. In still a further aspect, there is provided the use of a compound of Formula (I) or (1I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man. In another aspect, there is provided a method for treating a bacterial infection in a warm blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (1) or (II), or a pharmaceutically acceptable salt thereof. In still another aspect, there is provided a method for treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, 56 WO 2008/071961 PCT/GB2007/004766 Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I) or (1I), or a pharmaceutically acceptable salt thereof. In yet another aspect, there is provided a method for treating a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I) or (11), or a pharmaceutically acceptable salt thereof. In a further aspect, there is provided a method for treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (1) or (IL), or a pharmaceutically acceptable salt thereof. 57 WO 2008/071961 PCT/GB2007/004766 In still a further aspect, there is provided a compound of Formula (I) or (11), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a warm blooded animal, such as man. In another aspect, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man. In still another aspect, there is provided a compound of Formula (I) or (11), or a pharmaceutically acceptable salt thereof, for use in treating infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man. In yet another aspect, there is provided a compound of Formula (I) or (11), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, 58 WO 2008/071961 PCT/GB2007/004766 Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, and Munnheimia, in a warm-blooded animal such as man. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Acinetobacter baumanii. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Aeromis hydrophila. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Bacillus anthracis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Bacteroidesfragilis. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Bordatella pertussis. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Burkholderia cepacia. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Chlamyida pneumoniae. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Citrobacter freundii. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Clostridium difficile. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterobacter cloacae. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterococcusfaecalis. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterococcusfaecium. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterobacter aerogenes. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Escherichia coli. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Fusobacterium necrophorum. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Haemophilus influenzae. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Haemophilus parainfluenzae. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Haemophilus somnus. In a further aspect, the terms "infection" and 59 WO 2008/071961 PCT/GB2007/004766 "bacterial infection" may refer to a bacterial infection caused by Klebsiella oxytoca. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Klebsiella pneumoniae. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Legionella pneumophila. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Listeria monocytogenes. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Moraxella catarrhalis. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Morganella morganii. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Mycoplasma pneumoniae. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Neisseria gonorrhoeae. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Neisseria meningitidis. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Pasteurella multocida. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Proteus mirabilis. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Proteus vulgaris. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Pseudomonas aeruginosa. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Salmonella typhi. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Salmonella typhimurium. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Serratia marcesens. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Shigella flexneria. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Shigella dysenteriae. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus aureus. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus epidermidis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus haemolyticus. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus intermedius. In still a further aspect, the terms "infection" and "bacterial infection" may refer 60 WO 2008/071961 PCT/GB2007/004766 to a bacterial infection caused by Staphylococcus saprophyticus. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Stenotrophomonas maltophila. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus agalactiae. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus mutans. In a still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus pneumoniae. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus pyrogenes. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Aeromonas. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Acinetobacter. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Bacillus. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Bacteroides. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Bordetella. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Burkholderia. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Chlamydophila. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Citrobacter. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Clostridium. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Enterobacter. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Enterococcus. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Escherichia. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Flavobacterium. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Fusobacterium. In one aspect, the terms "infection and 61 WO 2008/071961 PCT/GB2007/004766 "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Haemophilus. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Klebsiella. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Legionella. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Listeria. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Morganella. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Moraxella. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Mycoplasma. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Neisseria. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Pasteurella. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Peptococci. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Peptostreptococci. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Prevotella. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Proteus. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Pseudomonas. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Salmonella. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Serratia. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Shigella. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Staphylococcus. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Stenotrophomonas. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Streptococcus. 62 WO 2008/071961 PCT/GB2007/004766 In one aspect, the terms "infection" and "bacterial infection" may refer to a gynecological infection. In another aspect the terms "infection" and "bacterial infection" may refer to a respiratory tract infection (RTI). In still another, the terms "infection" and "bacterial infection" may refer to a sexually transmitted disease. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a urinary tract infection. In a further aspect, the terms "infection" and "bacterial infection" may refer to acute exacerbation of chronic bronchitis (ACEB). In yet a further aspect, the terms "infection" and "bacterial infection" may refer to acute otitis media. In one aspect, the terms "infection" and "bacterial infection" may refer to acute sinusitis. In another aspect, the terms "infection" and "bacterial infection" may refer to an infection caused by drug resistant bacteria. In still another aspect, the terms "infection" and "bacterial infection" may refer to catheter-related sepsis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to chancroid. In a further aspect, the terms "infection" and "bacterial infection" may refer to chlamydia. In still a further aspect, the terms "infection" and "bacterial infection". may refer to community acquired pneumonia (CAP). In yet a further aspect, the terms "infection" and "bacterial infection" may refer to complicated skin and skin structure infection. In one aspect, the terms "infection" and "bacterial infection" may refer to uncomplicated skin and skin structure infection. In another aspect, the terms "infection" and "bacterial infection" may refer to endocarditis. In still another aspect, the terms "infection" and "bacterial infection" may refer to febrile neutropenia. In yet another aspect, the terms "infection" and "bacterial infection" may refer to gonococcal cervicitis. In a further aspect, the terms "infection" and "bacterial infection" may refer to gonococcal urethritis. In still a further aspect, the terms "infection" and "bacterial infection" may refer to hospital-acquired pneumonia (HAP). In yet another aspect, the terms "infection" and "bacterial infection" may refer to osteomyelitis. In a further aspect, the terms "infection" and "bacterial infection" may refer to sepsis. In still a further aspect, the terms "infection" and "bacterial infection" may refer to syphilis. In a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically 63 WO 2008/071961 PCT/GB2007/004766 acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In still a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In yet a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Id), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (le), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (If), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (1h), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. 64 WO 2008/071961 PCT/GB2007/004766 In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ila), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ilb), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ile), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (If), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect, there is provided a pharmaceutical composition comprising a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). 65 WO 2008/071961 PCT/GB2007/004766 The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived 66 WO 2008/071961 PCT/GB2007/004766 from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more 67 WO 2008/071961 PCT/GB2007/004766 of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful classes of antibacterial agents (for example, macrolides, quinolones, B-lactams or aminoglycosides) and/or other anti infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with 68 WO 2008/071961 PCT/GB2007/004766 bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents. As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient. In addition to its use in therapeutic medicine, the compound of Formulas (I) and its pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of antibacterial effects in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant invention, any of the alternate embodiments of the compounds of the invention described herein also apply. Process If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples. It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5 1h Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents. 69 WO 2008/071961 PCT/GB2007/004766 It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991). Examples of suitable protecting groups for a hydroxy group are, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon. A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another 70 WO 2008/071961 PCT/GB2007/004766 suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up. In one aspect, the present invention provides a process for preparing a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of Formula (AA):

R

6 R (N

NH

2 R2 N 0

R

3 Formula (AA) with a compound of Formula (AB): G Formula (AB) in the presence of a suitable reducing agent, and thereafter if necessary: i) converting the compound of Formula (I) or Formula (11) into another compound of Formula (I) or Formula (1I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt. The compound of Formula (AA) may be reacted with the compound of Formula (AB) under typical reductive amination conditions. The first step of the reaction, the imine-formation, typically takes place in the presence of a dehydrating agent such as molecular sieves (MS 71 WO 2008/071961 PCT/GB2007/004766 3A), though the reaction will generally proceed without a dehydrating agent. A suitable solvent is methanol or methanol/chloroform mixtures. The imine intermediate is typically not isolated; rather, the reducing agent is generally added to the reaction mixture after imine formation. Suitable reducing agents for the second (reduction) step of the process include boron reducing agents such as NaB(OAc) 3 H or NaBH 3 CN. In another aspect, the present invention provides a process for preparing a compound of Formula (I) or (II) in which R6 is F, or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of Formula (AC): F 2 R' (N NH 2 R N 0

R

3 Formula (AC) with a compound of Formula (AB): 0 Formula (AB) in the presence of a suitable reducing agent, and thereafter if necessary: i) converting the compound of Formula (I) or (II) into another compound of Formula (I) or (II); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt. The reaction conditions for the reaction of a compound of Formula (AC) with a compound of Formula (AB) are as described above for the reaction of a compound of Formula (AA) with a compound of Formula (AB). 72 WO 2008/071961 PCT/GB2007/004766 In still another aspect, the present invention provides a process for preparing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of Formula (BI): R R N N A -E R8 2 Ri (NQ NyA J<R R N 0 D G

R

3 Formula (BI) with a suitable reducing agent, and thereafter if necessary: i. converting the compound of Formula (I) or (II) into another compound of Formula (I) or (II); ii. removing any protecting groups; and/or iii. forming a pharmaceutically acceptable salt. Suitable reducing agents for the reduction of the compound of Formula (BI) include boron reducing agents such as NaB(OAc) 3 H or NaBH 3 CN. A suitable solvent is methanol or methanol/chloroform mixtures Compounds of Formula (AA) may be prepared as shown in Scheme 1. 73 WO 2008/071961 PCT/GB2007/004766 Scheme 1

R

6 R N Base r + L NGs N 0 3 1 XI N -N'PG iI

R

3 Formula (AD) Formula (AE) Formula (AF) deprotection

R

6 R N NH 2

R

3 Formula (AA) Reaction of a compound of Formula (AD) with a compound of Formula (AE) in the presence of a base such as sodium hydride may be used to obtain a compound of Formula (AF). Deprotection provides a compound of Formula (AA). Suitable leaving groups include leaving groups such as mesylate, chloro, bromo, and iodo. Suitable protecting groups include alkoxycarbonyl groups such as t-butoxycarbonyl, which may be deprotected using acids such as HCI. Another method that may be used to prepare compounds of Formula (AA) is shown in Scheme 2. 74 WO 2008/071961 PCT/GB2007/004766 Scheme 2

R

6 H R, diisopropylazodicarboxylate Ri N - PG R N 0 trphenyl phosphine R Ra Ra Ra H Formula (AF) Formula (AD) PG Formula (AG) deprotection

R

6 R N

NH

2 Ra R 3 Formula (AA) Reaction of a compound of Formula (AD) under Mitsunobu conditions with a compound of Formula (AG) may be used to obtain a compound of Formula (AF). Deprotection provides a compound of Formula (AA). . Suitable protecting groups include alkoxycarbonyls such as t butoxycarbonyl, which may be removed using acids such as HCI. Scheme 3 depicts another method for preparing compounds of Formula (AA). 75 WO 2008/071961 PCT/GB2007/004766 Scheme 3 0 2 R H 1)Base 1 R H R N' 0 ~2) Alkylating agent 2Rr P 3) SwemO oxidation 2R N: 0 + HN RR Ha Formula (AD) R Formula (Al) (AD) Formula (AH) reducing agent RR R 6 R rN NH 22 R -N , PG R N deprotection R2 N 0R

R

3 Formula (AF) Formula (AA) A compound of Formula (AD) may be reacted with a base such as NaH, followed by reaction with bromo- or chloroethanol or bromo-or chloro acetaldehyde, or with a protected derivative thereof, (followed by deprotection and oxidation in case of an alcohol derivative), providing a compound of Formula (AH). The compound of Formula (AH) may be reacted with the compound of Formula (Al) under typical reductive amination conditions. As noted above for the reaction of the compound of Formula (AA) with the compound of Formula (AB), the imine-formation typically takes place in the presence of a dehydrating agent such as molecular sieves (MS 3A), though the reaction will generally proceed just as well without a dehydrating agent. A suitable solvent is tetrahydrofuran, dichloromethane or chloroform/methanol mixtures. The imine intermediate is typically not isolated; rather, the reducing agent is generally added to the reaction mixture after imine formation. Suitable reducing agents for the second step of the reaction (the reduction) include boron reducing agents such as NaB(OAc) 3 H or NaBH 3 CN. Deprotection of the compound of Formula (AF) provides a compound of Formula (AA). Suitable protecting groups for the amino group 76 WO 2008/071961 PCT/GB2007/004766 substituent on the piperidine ring of the compound of Formula (Al) include alkoxycarbonyls such as t-butoxycarbonyl, which may be removed using acids such as HCI; and azides, which may be converted to the amine reductively, either with triphenyl phosphine (Staudinger Reaction) or by hydrogenation. Compounds of Formula (AL), which are compounds of Formula (AE) in which the leaving group is a mesylate leaving group, may be prepared according to Scheme 4. Scheme 4 HN PG HN PG HN PG R6

R

6 R6 2-Bromoethanol MsCI N NEt 3 N NEta N H Formula (Al) OH OS 2 Me Formula (AG) Formula (AL) A compound of Formula (AL) may be prepared by reaction of a compound of Formula (AI) with bromoethanol or a derivative thereof in the presence of a base such as triethylamine, providing a compound of Formula (AG). The compound of Formula (AG) may be reacted with mesyl chloride, in the presence of a base, such as trialkyl amine or an immobilized version thereof on a resin, providing a compound of Formula (AL). The compound of Formula (AL) is potentially unstable, and may be present as part of a mixture with the corresponding chloride (arising from attack of chloride on the mesyl group) and needs to be prepared fresh under careful controlled conditions. 77 WO 2008/071961 PCT/GB2007/004766 A compound of Formula (AO), which is a compound of Formula (AD) in which J is CH, may be prepared according to Scheme 5. Scheme 5 R cinnamoyl- R R R NH 2 chloride R 2 H R2 N AIC1 3 R 2,6-Lutidine

R

3 33 Formula (AM) Formula (AO) Formula (AN) As shown in Scheme 5, a compound of Formula (AO) may be prepared from commercially available compounds of Formula (AM) by reaction with cinnamoylchloride in the presence of a suitable base such as 2,6-lutidine, followed by cyclization with aluminum trichloride. In similar manner, cinnamoyl chloride may be replaced with E-ethoxyacryloyl chloride and cyclization of the intermediate E-ethoxyacryloylamides affected with sulfuric acid instead of aluminium trichloride (E. Baston et al, European Journal of Medicinal Chemistry 35 (2000) 931). Unsymmetrical substituted anilines generally lead to regioisomeric quinolin-2(1H)-one derivatives, which may be difficult to separate by chromatography due to limited solubility. Such mixtures may be separated either by crystallization or may be converted to the corresponding 2-chloroquinoline derivatives (for example with phosphorusIll oxychloride), which may be separated by chromatography or by crystallization and can then be hydrolyzed back with refluxing hydrochloride acid to the single regioisomers of the compound of Formula (AO). 78 WO 2008/071961 PCT/GB2007/004766 A compound of Formula (AO) may also be prepared according to Scheme 6. Scheme 6 R R 12 R'1 H R2 NO methylacrylate R 2 NO 1. Zn R N 0 R Pd-catalyst 3 O OMe 2. uv light 3 30 Formula (AP) Formula (AQ) Formula (AO) Zinc Sonogashira R Lindlar reduction R 2 NO20 R NO 2 o R3 O 0 Formula (AS) Formula (AR) A compound of Formula (AO) may be prepared from a compound of Formula (AP) by forming a carbon-carbon bond, followed by intramolecular amide bond formation of an appropriately set up cis unsaturated system. The isomerization of a trans double bond may be performed thermically or photochemically under uv light. Alternatively, the carbon-carbon bond formation may be performed as a Sonogashira Coupling to an alkyne intermediate, which may be partially hydrogenated to a cis double bond under Lindlar conditions. A compound of Formula (AO) may also be prepared according to Scheme 7. 79 WO 2008/071961 PCT/GB2007/004766 Scheme 7 0 3 Diethyl Oxalate 0 NaBH 4 R 3 NO 2 2 % w/w NaOEt in ethanol Acetonitie Ethanol 0N 400C overnight O NO 2 OOC 1 3 R Water, conc HCI R 0 NO 2 R2 R R3- R 2 R R Formula (BE) Formula (BF) 2 R3 DBU R 3 Formula (BG) Fe/ AcOH OH acetonitrile 600C 800C R N 0 2 /N R N 0 R R1 Formula (BH) Formula (AO) A compound of the Formula (AO) may be prepared from a compound of Formula (BE) by deprotonation with a base such as sodium ethoxide, followed by reaction with diethyl oxalate to form a compounds of the Formula (BF). This intermediate may then be reduced with a suitable reducing agent such as sodium borohydride, providing a compound of Formula (BG). The compound of Formula (BG) may then be cyclized to a compound of Formula (BH), after reduction of the nitro group with a suitable reducing agent such as iron in acetic acid or tin dichloride. Finally, elimination with a base such as DBU, provides a compound of Formula (AO). A compound of Formula (AU), which is a compound of Formula (AD) in which J is N, may be prepared according to Scheme 8. Scheme 8 R 2 NH ethylglyoxalate 2 H 2H R N OT

NH

2 N R R 3 Formula (AT) Formula (AU) 80 WO 2008/071961 PCT/GB2007/004766 Regioisomeric mixtures of the compound of Formula (AU) may be separated by the methods described above for Scheme 5. Scheme 9 depicts another method for preparing compound of Formula (AU). Scheme 9 RI R2

-NO

2

R

3 0 Formula (AW) Pd/C H2 ethyl bromoacetate R2 R H R N 0 R NO 2 R NilT o H 2 0 2 IN NI r NN

NH

2 R3 H R3

R

3 Formula (AX) Formula (AV) Formula (AU) PdC ethyl glyoxylate H 2 R R2

NO

2

R

3 0 Formula (AY) A compound of Formula (AU) may be obtained by oxidation of a compound of Formula (AX) with oxidants such as hydrogen peroxide. The compound of Formula (AX) may be obtained by reacting a compound a compound of Formula (AV) with bromoacetic acid esters, or with ethylgloxylate, followed by reduction of the nitro group and spontaneous cyclization. Suitable reducing agents include Pd/C and 12, iron in acetic acid, and tin chloride. 81 WO 2008/071961 PCT/GB2007/004766 A compound of Formula (AZ), which is a compound of Formula (AG) in which the protecting group is t-butoxycarbonyl, may be prepared according to scheme 10. Scheme 10 RPG R 6 HN N /Formula (BB) PG-O N N CsCO 3 Formula (BA) Formula (BC) I deprotection R 1) H 2 , Pd(OH) 2

R

6 N -N )fO0-t-Bu 2) di-t-butyl dicarbonate N O Formula (AZ) Formula (BD) A compound of Formula (BA) may be reacted with a compound of Formula (BB) in the presence of a base providing a compound of Formula (BC). Examples of Cs 2

CO

3 , NaH,

K

2 C0 3 or Na 2

CO

3 . Suitable leaving groups for this reaction include mesylate and halo groups such as chloro and bromo. Suitable protecting groups for this reaction include silyl protecting groups such as t-butyl-dimethylsilyl. The protecting group of the compound of Formula (BC) may be removed using t-butylammonium fluoride, providing a compound of Formula (BD). The compound of Formula (BD) may be deprotected by hydrogenation. Examples of suitable catalysts for such a reaction include Pd(OH) 2 , Platinum black, and PtO 2 , followed by reaction with di-t-butylcarbonate, providing a compound of Formula (AZ). When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure enantiomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final products or chiral intermediates using a standard procedure. The resolution of enantiomers may be achieved by 82 WO 2008/071961 PCT/GB2007/004766 chromatography on a chiral stationary phase, such as a Chiralpak AD column. Consideration has to be given to solubility as well as resolution. Alternatively, resolution may be obtained by preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphersulfonic acid. Alternatively, a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protection group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence. Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure. The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials and products. Examples The invention is now illustrated by but not limited to the following Examples, for which, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) temperatures are quoted as 'C; operations were carried out at room temperature, that is typically in the range 18-26 0 C and without the exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) in general, the course of reactions was followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable; 83 WO 2008/071961 PCT/GB2007/004766 (v) the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques. Proton magnetic resonance spectra were generally determined in DMSO-d 6 unless otherwise stated, using a Bruker DRX-300 spectrometer or a Bruker DRX-400 spectrometer, operating at a field strength of 300 MHz, or 400 MHz, respectively. In cases where the NMR spectrum is complex, only diagnostic signals are reported. Chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (5 scale) and peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; din, doublet of multiplets; t, triplet, m, multiplet; br, broad. Fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1100 series LC/MSD equipped with Sedex 75ELSD, and where appropriate, either positive ion data or negative ion data were collected. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). Reverse Phase HPLC was carried out using YMC Pack ODS-AQ (100x20 mmID, S-5pt particle size, 12 nm pore size) on Agilent instruments; (vi) each intermediate was purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; and (vii) the following abbreviations may be used: TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; DMSO is dimethylsulfoxide; CDCl 3 is deuterated chloroform; MeOD is deuterated methanol, i.e. D 3 COD; MS is mass spectroscopy; ESP (or ES) is electrospray; El is electron impact; APCI is atmospheric pressure chemical ionization; THF is tetrahydrofuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC/MS is liquid chromatography/mass spectrometry; h is hour(s); min is minute(s); d is day(s); MTBD is N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; TFA is trifluoroacetic acid; v/v is 84 WO 2008/071961 PCT/GB2007/004766 ratio of volume/volume; Boc denotes t-butoxycarbonyl; Cbz denotes benzyloxycarbonyl; Bz denotes benzoyl; atm denotes atmospheric pressure; rt denotes room temperature; mg denotes milligram; g denotes gram; ptL denotes microliter; mL denotes milliliter; L denotes liter; pM denotes micromolar; mM denotes millimolar; M denotes molar; N denotes normal; nm denotes nanometer. Intermediate 1 1- {2-r(3R,4S)-4-Amino-3 -hydroxypiperidin- 1 -yll ethyl -2-oxo- 1,2-dihydroquinoline-7 carbonitrile and Intermediate 2 1- {2-r(3S,4R)-4-Amino-3-hydroxvpiperidin- 1 -yllethyl I -2-oxo- 1,2-dihydroquinoline-7 carbonitrile A mixture of 1-[2- cis(+) (4-azido-3-hydroxypiperidin-1-yl)ethyl]-2-oxo-1,2 dihydroquinoline-7-carbonitrile (Intermediate 3) (0.545g, 1.61 mmol) and triphenylphophine (0.507 g, 1.93 mmol) in acetonitrile/ water (9:1, 50 mL) was stirred at room temperature for 6 days. The reaction mixture was concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (6:1, containing 0.2% ammonium hydroxide) gave the racemic mixture of Intermediate 1 and 2 as a colorless hard foam, 0.452 g (90%). MS (ESP): 313 (MH*) for C 17

H

20

N

4 0 2 'H-NMR (DMSO-d6) 5: 1.48 (in, 2H); 2.20-2.40 (in, 2H); 2.45-2.61 (in, 4H); 2.72 (in, 1H); 3.44 (in, 1H); 4.35 (dd, 2H); 6.78 (d, 1H); 7.64 (d, 1H); 7.90 (d, 1H); 8.00 (d, 1H); 8.08 (d, IH). (OH and NH 2 protons were exchanged with methanol). The racemic mixture was separated on a Chiralpak AD column (250 x 20 mm, 10 micron) with 60% hexanes and 40% ethanol! methanol (1:1), containing 0.1% diethyl amine. Intermediate 2 was eluting first, [a]D =+ 45.5, followed by Intermediate 1, []D =-45.9 (in methanol/ chloroform 1:1, c = 1). Intermediate 3 1-2- Cis(±) (4-azido-3-hydroxypiperidin-1-yl)ethyll-2-oxo-1,2.-dihydroquinoline-7 85 WO 2008/071961 PCT/GB2007/004766 carbonitrile A solution of 1-[2- cis± (4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)ethyl]-2 oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 4) (0.724 g, 1.6 mmol) in THF (5 mL) was treated dropwise at room temperature with a solution of tetrabutyl ammonium fluoride in THF (LM, 2.2 mL). After one hour saturated aqueous sodium hydrogencarbonate solution (10 mL) was added and THF was removed under reduced pressure. It was extracted with dichloromethane/ ether (1:1, -200 mL). The organic phase, containing some insoluble product was separated, the aqueous phase was back extracted with dichloromethane (100 mL) and the combined organic phases were concentrated to dryness under reduced pressure and dried under high vacuum to give the product as a colorless solid, 0.545 g (quant.). 1 H-NMR (DMSO-d,) 6: 1.56 (in, lH); 1.71 (in, 1H); 2.25-2.63 (in, 6H); 3.67 (in, 2H); 4.35 (dd, 2H); 5.06 (in, 1H); 6.78 (d, IH); 7.64 (dd, 1H); 7.90 (d, 1H); 8.00 (d, 1H); 8.08 (brs, 1H). Intermediate 4 1-2- Cis(+) (4-azido-3- { [tert-butyl(dimethyl)silylloxLy piperidin- 1 -yl)ethyll-2-oxo- 1,2 dihydroquinoline-7-carbonitrile A suspension of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5) (0.51 g, 3.0 mmol) in DMF (15 mL) was treated at 0"C with sodium hydride (in oil, 60%, 132 mg). It was stirred for 2 hours, then a solution of 2- cis± (4-azido-3-{[tert butyl(dimethyl)silyl]oxy}piperidin-1-yl)ethyl methanesulfonate (Intermediate 6) (3 mmol) in DMF (7 mL) was added via syringe. The cooling was removed and it was stirred over night at room temperature. DMF was removed under reduced pressure, the residue was taken up in dichloromethane (- 200 mL) and saturated aqueous sodium hydrogencarbonate solution (20 mL, pH adjusted to pH10 with 1M NaOH solution). The aqueous phase was back-extracted two times with dichloromethane (2X 100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with hexanes/ acetone (4:1) gave the product as a hard foam, 0.724 g (53%). MS (ESP): 453 (MH*) for C 23

H

32

N

6

O

2 Si 'H-NMR (DMSO-d 6 ) 8: 0.00 and 0.03 (2xs, 6H); 0.80 (s, 9H); 1.59 (in, 1H); 1.70 (m, 1H); 2.30-2.65 (in, 6H); 3.69 (m, 1H); 3.80 (in, 1H); 4.29 (in, 1H); 4.42 (m,1H); 6.77 (d, 1H); 7.63 (d, 1H); 7.90 (d, 1 H); 7.99 (d, 1H); 8.08 (s, 1H). 86 WO 2008/071961 PCT/GB2007/004766 Intermediate 5 2-Oxo- 1,2-dihydroquinoline-7-carbonitrile 7-Bromoquinolin-2(lH)-one (Intermediate 46) (9.21 g, 41 mmol) and copper (I) cyanide (4.05 g) were heated in N-methylpyrrolidone (50 mL) at 160 0 C for 16 hours. It was cooled to room temperature, an aqueous solution of ethylenediamine tetra acetate (2M, pH 8.3, 100 mL) was added and the mixture was stirred at room temperature and open to air for 5 days. The precipitate was collected by filtration through a 0.45 pm membrane, washed with water and ethyl acetate and recrystallized from DMF/ water to give the product as a brown solid, 90% purity, which was used without further purification, 4.72 g (60%). MS (ESP): 171 (MH*) for C 1 0

H

6

N

2 0 'H-NMR (DMSO-d6) 5: 6.66 (d, lH); 7.55 (d, 1H); 7.61 (s, 1H); 7.85 (d, 1H); 7.99 (d, 1 H); 12.01 (s, 1H). Alternate Procedure for the synthesis of Intermediate 5 A mixture of 3-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile (Intermediate 66, 15.51 g, 82.42 mmol) and 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) in acetonitrile (155 mL) was heated at 75 *C for 2.5 hours. The reaction mixture was cooled to room temperature and a precipitate was collected by filtration, washed with water (77 mL) and with methanol (77 mL) and dried under reduced pressure to give the product as an off-white solid, 9.71 g (68%). Mp > 250 0 C MS (ESP): 171 (MH*) for CioH 6

N

2 0 1 H-NMR (DMSO-d 6 ) 5 ppm 6.67 (d, 1H); 7.48-7.68 (in, 2H); 7.85 (d, 1H); 7.98 (d, 1H); 12.01 (s, 1H). Intermediate 6 2-(Cis(±))-(4-Azido-3- { rtert-butyl(dimethyl)silylloxylpiperidin-1-yl)ethyl methanesulfonate A mixture of 2-(cis±)-(4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)ethanol (Intermediate 7, 1.8 g, 6 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.18 mL, 8.4 mmol) was treated at 0C with methanesulfonyl chloride (0.556 mL, 7.2 mmol). After 90 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf -0.9). Potassium phosphate buffer (pH 7, 1M, 15 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice-cold ether (100 mL). The aqueous phase 87 WO 2008/071961 PCT/GB2007/004766 was back-extracted once with ether (50 mL) and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was taken up in DMF (10 mL). This crude preparation of the mesylate was used without delay for the next step. MS (ESP): 379 (MH) for C 14

H

36

N

4 0 4 SSi Intermediate 7 2- (Cis(±))-(4-Azido-3-{[tert-butyl(dimethyl)silylloxylpiperidin-1-yl)ethanol A mixture of (cis±)-4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine (Intermediate 8) (1.625 g, 6.34 mmol), N,N-diisopropylethylamine (1.65 mL, 9.5 mmol and 2-bromoethanol (0.584 mL, 8.25 mmol) in dry acetonitrile (17 mL) was heated in the microwave at 70"C for two hours. The solvent was removed under reduced pressure, the residue taken up in ethyl acetate (~150 mL) and washed with saturated aqueous sodium hydrogencarbonate solution (-25 mL). The aqueous phase was back-extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/ methanol (20:1) gave 1.80 g (95%) of product as a colorless oil. MS (ESP): 301 (MH*) for C 13

H

28

N

4 0 2 Si 'H-NMR (DMSO-d) 8: 0.08 (s, 6H); 0.87 (s, 9H); 1.65 (m, 2H); 2.18 (in, 1H); 2.25-2.60 (in, 5H); 3.44 (in, 2H); 3.73 (m, 1H); 3.91 (in, 1H); 4.35 (in, 1H). Intermediate 8 (Cis(±))-4-azido-3-Itert-butyl(dimethyl)silylloxylpiperidine A solution of tert-butyl (cis±)- 4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1 carboxylate (Intermediate 9) (2.3 g, 6.45 mmol) in dichloromethane (50 mL) was treated at 0*C with trifluoroacetic acid (5 mL). After 3 hours the mixture was concentrated under reduced pressure and the residue was codistilled twice with dichloromethane. The residue was taken up in dichloromethane (100 mL) and washed with saturated aqueous sodium hydrogencarbonate solution (30 mL). The aqueous phase was back extracted once with dichloromethane (100 mL) and the combined organic phases were dried over sodium sulfate to give the product as a slightly yellow oil, 1.625 g (98%). 'H-NMR (DMSO-d 6 ) 6: 0.07 and 0.09 (2xs, 6H); 0.88 (s, 9H); 1.49-1.73 (m, 2H); 2.45 (in, 1H); 2.56-2.69 (in, 3H); 3.65 (m, 1H); 3.79 (in, 1H). 88 WO 2008/071961 PCT/GB2007/004766 Intermediate 9 tert-Butyl (cis(+) )-4-azido-3-{ [tert-butyl(dimethyl)silyl]oxylpiperidine-1-carboxylate A mixture of tert-butyl (cis±)-4-azido-3-hydroxypiperidine-l-carboxylate (Intermediate 10) (1.76 g, 7.25 mmol) and imidazole (0.74 g, 10.9 mmol) in DMF (7 mL) at 0C was treated with tert-butyl dimethylsilyl chloride (1.3 g, 8.7 mmol). Cooling was removed and the mixture was stirred over night at room temperature. It was cooled to 0"C and quenched with phosphate buffer (LM, pH 7, 20 mL). After 15 minutes, the mixture was diluted with ethyl acetate (100 mL), the organic phase was washed with water (2x 50 mL) and dried over sodium sulfate. Chromatography on silica gel with hexanes/ ethyl acetate (9:1) gave the product as a colorless oil, 2.3 g (89%). 'H-NMR (DMSO-d6) 6: 0.10 (s, 6H); 0.87 (s, 9H); 1.37 (s, 9H); 1.56-1.80 (in, 2H); 3.09 3.30 (m, 2H); 3.46 (in, 2H); 3.62 (in, IH); 3.88 (in, 1H). Intermediate 10 tert-Butyl (cis(±))-4-azido-3-hydroxypiperidine-1-carboxylate To a mixture of (cis±)-4-azidopiperidin-3-ol (prepared following the procedure described in WO 2005/066176 for the chiral material) (2.1 g, 14.8 mmol) and potassium hydroxide (2.5 g, 44 mmol) in isopropanol (20 mL) and dichloromethane (25 mL) was added at 0 0 C a solution of di-tert-butyl dicarbonate (3.9 g, 17.7 mmol) in dichloromethane (10 mL). The cooling was removed and it was stirred 2 hours at room temperature. It was quenched with water (50 mL) and isopropanol and dichloromethane were removed under reduced pressure. It was neutralized with potassium phosphate buffer (I M, pH 7, 100 mL), extracted with ethyl acetate twice (2x 300 mL) and the combined organic phases were dried over sodium sulfate. Solvent was removed under reduced pressure and the residue was titurated from hexanes (~20 mL) to give 0.966 g of product as a colorless solid. Chromatography of the mother liquors with hexanes/ ethyl acetate (5:1) afforded 0.353 g of product (35 %). MS (ESP): 265.2 (MNa*) for CioH 18

N

4 0 3 'H-NMR (DMSO-d 6 ) 6: 1.39 (s, 9H); 1.58 (in, 1H); 1.74 (in, LH); 3.20-3.40 (in, 4H); 3.69 (in, 2H); 5.40 (d, 1H). 89 WO 2008/071961 PCT/GB2007/004766 Intermediate 11 1- {2-r(3R,4S)-4-Amino-3-hydroxypiperidin- 1 -yllethyl } -7-methoxyquinoxalin-2(l H1)-one and Intermediate 12 1- {2-r(3S,4R)-4-Amino-3-hydroxypiperidin- 1 -yllethyl I -7-methoxyquinoxalin-2(l H)-one A mixture of 1-[2-{(cis±)- (4-azido-3-hydroxypiperidin-1-yl)}ethyl]-7-methoxyquinoxalin 2(1H)-one (Intermediate 13) (0.507 g, 1.47 mmol) and triphenylphophine (0.463 g, 1.77 mmol) in acetonitrile/ water (9:1, 20 mL) was stirred at room temperature for 5 days. The reaction mixture was concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (5 mL) and chromatographed on silica gel with dichloromethane/ methanol (6:1, containing 0.2% ammonium hydroxide) to give the racemic mixture of Intermediate 11 and 12 as a colorless hard foam (0.422 g, 90%). MS (ESP): 319 (MH*) for C 16

H

22

N

4 0 3 1 H-NMR (DMSO-d 6 ) 6: 1.48 (m, 2H); 1.89 (m, 1H); 2.28 (m, 1H); 2.37 (dd, 1H); 2.54 2.62 (m, 3H); 2.71 (m, 1H); 3.45 (m, 1H); 3.91 (s, 3H); 4.30 (dd, 2H); 6.96-7.00 (m, 2H); 7.73 (d, 1H); 8.03 (s, lH). (OH and NH 2 protons were exchanged with methanol). The racemic mixture was separated on a Chiralpak AD column (250 x 20 mm, 10 micron) with ethanol/ methanol (1:1), containing 0.1% diethyl amine. Intermediate 12 was eluting first, [aID = + 45.5, followed by Intermediate 11, [a]D =-44.7 (in methanol/ chloroform 1:1, c= 1). Intermediate 13 1-r2-{(Cis(±))- (4-azido-3-hydroxypiperidin- 1 -yl) } ethyl]-7-methoxyquinoxalin-2(l H)-one A solution of 1-[2-(cis±)-4-azido-3-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)ethyl]-7 methoxyquinoxalin-2(lH)-one (Intermediate 14, 0.721 g, 1.57 mmol) in THF (5 mL) was treated dropwise at room temperature with a solution of tetrabutyl ammonium fluoride in THF (IM, 2.2 mL). After one hour saturated aqueous sodium hydrogencarbonate solution (10 mL) was added and THF was removed under reduced pressure. It was extracted with dichloromethane/ ether (1:1, ~200 mL). The aqueous phase was back extracted with dichloromethane (100 mL) and the combined organic phases were dried over sodium sulfate. 90 WO 2008/071961 PCT/GB2007/004766 Chromatography on silica gel with hexanes/ acetone (1:1) gave the product as a colorless hard foam, 0.507 g (94%). MS (ESP): 345 (MH*) for C 16 H2 0

N

6 0 3 'H-NMR (DMSO-d 6 8: 1.58 (in, 1H); 1.70 (in, 1H); 2.25-2.65 (m, 6H); 3.67 (m, 2H); 3.90 (s, 3H); 4.31 (dd, 2H); 5.11 (in, 1H); 6.97-7.00 (in, 2H); 7.73 (d, 1H); 8.03 (s, 1H). Intermediate 14 1-[2-(Cis(±))-4-azido-3-{ [tert-butyl(dimethyl)silylloxylpiperidin-1-yl)ethyll-7 methoxyquinoxalin-2(1H)-one 7-Methoxyquinoxalin-2(lH)-one (Intermediate 15, 0.528 g, 3.0 mmol) was treated with sodium hydride (in oil, 60%, 132 mg) and 2- cis± (4-azido-3-{[tert butyl(dimethyl)silyl]oxy}piperidin-1-yl)ethyl methanesulfonate (Intermediate 6, 3 mmol) using a procedure similar to the one described for the synthesis of Intermediate 4 to give the product as a hard foam, 0.721 g (52%). MS (ESP): 459 (MH*) for C 22

H

34

N

6

O

3 Si 'H-NMR (DMSO-d 6 ) 6: 0.03 and 0.05 (2xs, 6H); 0.82 (s, 9H); 1.65 (in, 2H); 2.25-2.70 (in, 6H); 3.70 (in, 1H); 3.90 (s, 3H); 3.83 (in, 1H); 4.24 (in, 1H); 4.39 (in, 1H); 6.96-7.00 (in, 2H); 7.73 (in, 1H); 8.02 (s, 111). Intermediate 15 7-Methoxyquinoxalin-2(1H)-one To a solution of 8% aqueous sodium hydroxide (1.32 L) was added 7-methoxy-3,4 dihydroquinoxalin-2(lH)-one (Intermediate 16, 100 g) followed by a solution of 3 wt% hydrogen peroxide in water (1.17 L). The reaction mixture was slowly heated to 80 "C and maintained at this temperature for 4 hours. Then the heating source was removed and acetic acid (150 mL) was added dropwise. The suspension was stirred overnight at room temperature and the precipitated solid was collected by filtration to afford the product as a tan solid (90 g). MS (ESP): 177 (MH*) for C 9

H

8

N

2 0 2 'H-NMR (DMSO-d 6 ) 5: 3.83 (s, 3H); 6.76 (d, 1H); 6.90 (dd, 1H); 7.67 (d, 1H); 7.97 (s, lH); 12.32 (brs, 1H). 91 WO 2008/071961 PCT/GB2007/004766 Intermediate 16 7-Methoxy-3,4-dihydroquinoxalin-2(lH)-one In a 18-L Parr apparatus a suspension of ethyl [(4-methoxy-2-nitrophenyl)imino]acetate (Intermediate 17) was hydrogenated at 55 psi in the presence of 20 wt% Pd/C (100 g, containing ~ 50 wt% water) until no hydrogen was consumed. (Note: The reaction was strongly exothermic and the temperature should be controlled at around 60 "C by adjusting the rate of recharging hydrogen and by a cooling system). The reaction mixture was discharged, filtered over a celite cake, and evaporated under reduced pressure to give a crude solid that was triturated with MTBE (6 L) to give the product as a tan solid (400 g). MS (ESP): 179 (MH*) for C 9 HioN 2 0 2 'H-NMR (DMSO-d 6 ) 6: 3.61 (in, 5H); 5.57 (in, lH); 6.35-6.40 (in, 2H); 6.60 (m, 1H); 10.13 (brs, 1H). Alternative procedure for Intermediate 16 Ethyl N-(4-methoxy-2-nitrophenyl)glycinate (Intermediate 18, 15.8 g crude) was taken up in 200 mL of 1:1 methanol/acetic acid, treated with 10% palladium on carbon (2 g), and stirred in an atmosphere of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness giving 10.6 g of the crude product as a tan solid. This was used without further purification. MS (ESP): 179 (MH*) for C 9

HION

2 0 2 Intermediate 17 Ethyl [(4-methoxy-2-nitrophenyl)iminolacetate A solution of 4-methoxy-2-nitroaniline (1 kg, 5.95 mol) and ethyl glyoxylate (1180 mL, 50 wt% in toluene, 5.95 mol) in toluene (10 L) was refluxed in a Dean-Stark apparatus for 48 hours and evaporated under reduced pressure to give the crude product as a dark brown oil, which was used without further purification. Intermediate 18 Ethyl N-(4-methoxy-2-nitrophenyl)jlycinate A mixture of 4-methoxy-2-nitroaniline (25.0 g, 0.15 mol), ethyl bromoacetate (200 mL, 1.8 mol) and potassium carbonate (31.1 g, 0.23 mol) was heated at 150 0 C for 4.5 hours. After cooling to room temperature aqueous sodium hydroxide solution (IM, 600 mL) was added. 92 WO 2008/071961 PCT/GB2007/004766 This mixture was extracted with ethyl acetate (2x500 mL). The combined organic phases were dried over magnesium sulfate and concentrated to dryness. Chromatography on silica gel with 25-50% acetone in hexanes gave 22.1 g of the crude product as a red solid. 'H NMR revealed the presence of -20% dialkylated product. This material was used without further purification. 'H NMR (DMSO-d 6 ) 6: 1.18-1.23 (t, 3H); 3.74 (s, 3H); 4.12-4.18 (q, 2H); 4.23-4.25 (d, 2H); 6.90 - 6.93 (d, 1H); 7.25-7.29 (dd, IH); 7.51-7.52 (d, IH); 8.23-8.27 (t, 1H). Intermediate 19 Cis(±) 1-[2-(4-amino-3-fluoropiperidin-1-yl)ethyll-2-oxo-1,2-dihydroquinoline-7-carbonitrile A solution of cis(±) tert-butyl {l-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]-3 fluoropiperidin-4-yl}carbamate (Intermediate 20, 397 mg, 0.95 mmol) in chloroform (8 mL) was treated at 0 0 C with 30% trifluoroacetic acid in chloroform (5 mL). After 5 hours at room temperature the solvent was removed under reduced pressure to give the trifluoroacetate salt of the product, which was taken to the next step without further purification. MS (ESP): 315 (MH*) for C1 7 H1 9

FN

4 0 Intermediate 20 Cis(±) tert-butyl { 1-[2-(7-cyano-2-oxoquinolin- 1(2H)-yl)ethyll-3-fluoropiperidin-4 yllcarbamate A suspension of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5, 0.3 g, 1.7 mmol) in DMF (10 mL) was treated at room temperature with sodium hydride and cis(±) 2- {4-[(tert butoxycarbonyl)amino]-3-fluoropiperidin- 1-yl} ethyl methanesulfonate (Intermediate 21, -1.7 mmol) as described for Intermediate 4. Chromatography on silica gel with hexanes/ethyl acetate (2:3), gave the product as a solid, 397 mg (73%). MS (ESP): 415 (MH*) for C22H 27

FN

4 03 'H-NMR (DMSO-d6) 6: 1.37 (s, 9H); 1.48 (m, 1H); 1.67 (in, 1H); 2.27 (m, 2H); 2.56 (m, 2H); 2.96 (in, 1H); 3.15 (in, 1H); 3.46 (in, 1H); 4.34 (in, 2H); 4.60 (m, 1H); 6.77 (in, 1H); 6.91 (m, 1H); 7.64 (in, 1H); 7.90 (m, 1H); 7.99 (in, 1H); 8.07 (s, 1H). 93 WO 2008/071961 PCT/GB2007/004766 Intermediate 21 Cis(±) 2-{4-[(tert-butoxycarbonyl)aminol-3-fluoropiperidin- 1-yl ethyl methanesulfonate Cis(±) tert-butyl [3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]carbamate (Intermediate 22, 314 mg, 1.2 mmol) was reacted with mesyl chloride in the presence of triethyl amine using a procedure similar to the one described for the synthesis of Intermediate 6. The crude mesylate was used without delay for the next step. Intermediate 22 Cis(±) tert-butyl [3-fluoro-1-(2-hydroxyethyl)piperidin-4-yllcarbamate To a solution of cis(±) tert-butyl [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3 fluoropiperidin-4-yl]carbamate (Intermediate 23, 530 mg, 1.4 mmol) in tetrahydrofuran (10 mL) at O'C was added tetrabutylammonium fluoride (LM in THF, 2.8 mL). After 30 minutes the reaction was quenched with saturated sodium bicarbonate and extracted twice with ethyl acetate, dried over magnesium sulfate and concentrated. Silica gel chromatography with 2.5% methanol in ethyl acetate afforded the product as a colorless solid, 314 mg (85%). 'H-NMR (CDCl 3 -d) 6: 1.43 (s, 9H); 1.81 (m, 2H); 2.30 (m, 1H); 2.36 (m, lH); 2.59 (m, 2H); 2.75 (m, lH); 2.95 (m, 1H); 3.24 (m, 1H); 3.61 (m, 2H); 3.71 (m, 1H); 4.68 (m, 1H); 4.85 (m, 1H). Intermediate 23 Cis(±) tert-butyl r1-(2-{[tert-butyl(dimethyl)silylloxylethyl)-3-fluoropiperidin-4 yllcarbamate Cis(±) 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-fluoropiperidin-4-amine (Intermediate 24, 2.8 g, 10.4 mmol) and di-tert-butyl dicarbonate (3.4 g, 15.6 mmol) were combined in tetrahydrofuran (50 mL) at room temperature. After 90 minutes the reaction mixture was concentrated under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded the product as a colorless oil, 3.2 g (82%). H-NMR (CDCl 3 -d) 6: 0.03 (s, 6H); 0.86 (s, 9H); 1.43 (s, 9H); 1.77 (m, 2H); 2.25 (m, I H); 2.37 (m, 1H); 2.58 (m, 2H); 2.95 (m, 1H); 3.26 (m, 1H); 3.62 (m, 1H); 3.74 (m, 2H); 4.65 (m, 1H); 4.83 (m, IH). 94 WO 2008/071961 PCT/GB2007/004766 Intermediate 24 Cis(±) 1-(2-{rtert-butyl(dimethyl)silylloxylethyl)-3-fluoropiperidin-4-amine Cis(±) benzyl benzyl[ 1 -(2- {[tert-butyl(dimethyl)silyl]oxy} ethyl)-3-fluoropiperidin-4 yl]carbamate (Intermediate 25, 5.2 g, 10.4 mmol) was hydrogenated in anhydrous methanol (15 mL) on palladium hydroxide 20 wt. % on carbon (31 mg) for 24 hours, then filtered through celite and concentrated under reduced pressure to give the product as a colorless oil, 2.8 g. Intermediate 25 Cis(±) benzyl benzyl[ 1-(2- { rtert-butyl(dimethyl)silylloxyl ethyl)-3-fluoropiperidin-4 yllcarbamate A mixture of cis(±) benzyl benzyl(3-fluoropiperidin-4-yl)carbamate hydrochloride (Intermediate 26, 4.3 g, 6.1 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (9.8 mL, 45.7 mmol) and cesium carbonate (9.9 g, 30.4 mmol) in acetonitrile (150 mL) was heated at 60"C overnight. The reaction mixture was filtered and concentrated under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded the product as a colorless oil, 5.2 g (91%). MS (ESP): 501 (MH+) for C 28 H4 1

FN

2

O

3 Si Intermediate 26 Cis(±) benzyl benzyl(3-fluoropiperidin-4-yl)carbamate To a solution of cis(±) tert-butyl 4-{benzyl[(benzyloxy)carbonyl]amino}-3-fluoropiperidine 1-carboxylate (Intermediate 27, 6 g, 13.5 mmol) in dichloromethane (50 mL) at 0 0 C was added 4N HCl in dioxane (6.8 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration to afford the product as a colorless solid, 4.4 g (86%). MS (ESP): 343 (MH*) for C 20

H

23

FN

2 0 2 Intermediate 27 Cis(±) tert-butyl 4- {benzyl[(benzyloxy)carbonyllamino } -3-fluoropiperidine- 1 -carboxylate To a mixture of cis(±) tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate (Intermediate 28, 1.1 g, 3.6 mmol) in dioxane (20 mL) and saturated sodium carbonate (10 95 WO 2008/071961 PCT/GB2007/004766 mL) at 0"C was added dropwise benzyl chloroformate (0.76 mL, 5.4 mmol) and the reaction mixture was stirred at 0"C for 1 hour. Ethyl acetate (~20 mL) and brine (~20 mL) were added and the layers were separated. The aqueous phase was extracted once with ethyl acetate and the combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to give the product as a colorless solid, 1.4 g (89%). MS (ESP): 343 (-BOC, MH*) for C 25

H

31

FN

2 0 4 'H-NMR (CDCl 3 A- 6: 1.46 (s, 9H); 1.46 (m, IH); 2.00 (m, 1H); 2.91 (m, 2H); 4.33 (m, 4H); 4.86 (m, 2H); 5.16 (m, 2H); 7.28 (m, 10H). Intermediate 28 Cis(±) tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate A mixture of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (Intermediate 29, 8.1 g, 37.3 mmol), benzylamine (4.5 mL, 41 mmol) and 3A molecular sieves in dichloromethane (150 mL) was treated at 0"C with sodium triacetoxyborohydride (11.8 g, 56 mmol) in portions. The reaction mixture was stirred at room temperature for 30 minutes and then filtered. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded the product as an off-white solid, 6.9 g (60%). MS (ESP): 309 (MH*) for C 17

H

25

FN

2 0 2 Intermediate 29 tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate A solution of tert-butyl 4-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 30, 14 g, 51 mmol) in acetonitrile (200 mL) was treated at O'C with

SELECTFLUOR

TM (20 g, 57 mmol) in portions. The reaction mixture was stirred at 0"C for 30 minutes, then diluted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate and concentrated. Silica gel chromatography with hexanes/ ethyl acetate (3:2) afforded the product as a colorless oil, 8.1 g (72%). 'H-NMR (CDCl-d) 5: 1.48 (s, 9H); 2.56 (m, 2H); 3.22 (m, 2H); 4.18 (m, 1H); 4.45 (m, 1H); 4.72 (m, IH). 96 WO 2008/071961 PCT/GB2007/004766 Intermediate 30 tert-Butyl 4-[(trimethylsilyl)oxyl-3,6-dihydropyridine-1(2H)-carboxylate A mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (11 g, 55 mmol) and triethylamine (18.5 mL, 132 mmol) in DMF (40 mL) was treated dropwise at 0"C with chlorotrimethylsilane (8.4 mL, 66 mmol). The reaction mixture was heated at 80"C overnight, and then cooled to room temperature. Saturated sodium bicarbonate was added and the product was extracted twice with hexanes. The combined organic extracts were dried over magnesium sulfate and concentrated to give 14 g (93%) of product as a yellow oil. 'H-NMR (CDCly) 6: 0.18 (s, 9H); 1.45 (s, 9H); 2.09 (m, 2H); 3.51 (m, 2H); 3.86 (m, 2H); 4.78 (m, I H). Intermediate 31 1- {2-r(3S,4R)-4-Amino-3-methoxypiperidin- 1 -yllethyl} -7-methoxyquinoxalin-2(l H)-one A solution of tert-butyl {(3S,4R)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H1) yl)ethyl]piperidin-4-yl}carbamate (Intermediate 32, 420 mg, 0.97 mmol) in dichloromethane (50 mL) and treated with trifluoroacetic acid (10 mL). After 1 hour, the reaction was concentrated to dryness. The residue was taken up in 15% methanol in chloroform (30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was re-extracted with 15% methanoL/chloroform (4 x 30 mL). The combined organic phases were dried over magnesium sulfate and concentrated to dryness giving 310 mg (97%) of the crude product as an oil. MS (ESP): 333 (MH*) for C 1 7

H

24

N

4 0 3 Intermediate 32 tert-Butyl {(3S,4R)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yl carbamate A solution of 7-methoxyquinoxalin-2(1H)-one (Intermediate 15, 320 mg, 1.79 mmol) in dry DMF (10 mL) was cooled in an ice bath under nitrogen and treated with sodium hydride (60% in oil, 86 mg, 2.15 mmol). The reaction was stirred at room temperature for -90 min. The reaction was again cooled in an ice bath and treated with a solution of 2-{(3S,4R)-4-[(tert butoxycarbonyl)amino]-3-methoxypiperidin- I -yl} ethyl methanesulfonate in dry DMF (Intermediate 33, -0.20 mmol/mL, 1.97 mmol). The reaction was stirred at room temperature overnight, then concentrated to dryness under reduced pressure. The residue was 97 WO 2008/071961 PCT/GB2007/004766 partitioned between ethyl acetate and water. The aqueous phase was re-extracted 2x with ethyl acetate. The combined organic layers were dried over magnesium sulfate. Chromatography on silica gel with a gradient of 15-25% acetone in hexanes gave 420 mg (55%) of the product as a colorless solid. MS (ESP): 433 (MH*) for C2 2

H

3 2N 4 0 5 'H NMR (DMSO-d 6 ) 6: 1.38 (s, 9H); 1.43-1.51 (m, 1H); 1.57-1.72 (m, 1H); 2.20-2.40 (m, 2H); 2.55-2.66 (m, 2H); 2.67-2.78 (m, lH); 2.80-2.93 (m, 1H); 3.18 (s, 3H); 3.29 (s, 1H); 3.51-3.65 (m, 1H); 3.92 (s, 3H); 4.24-4.43 (m, 2H); 6.40 (d, lH); 6.96-7.05 (m, 2H); 7.75 (d, 1H); 8.04 (s, 1H). Intermediate 33 2- {(3S,4R)-4-[(tert-Butoxycarbonyl)aminol-3-methoxypiperidin- 1-yll ethyl methanesulfonate A solution of tert-butyl [(3S,4R)-1-(2-hydroxyethyl)-3-methoxypiperidin-4-yl]carbamate (Intermediate 34, 540 mg, 1.97 mmol) in dry dichloromethane (20 mL) at 0"C was treated with triethylamine (0.38 mL, 2.76 mmol) followed by methanesulfonyl chloride (0.18 mL, 2.36 mmol). After 15 min, TLC revealed complete disappearance of starting material. The reaction was quenched with potassium phosphate buffer (1M, pH 7). The aqueous phase was re-extracted (lx) with dichloromethane. Ethyl acetate was added to the combined organic phases. Dichloromethane was removed under reduced pressure leaving behind the product in solution in ethyl acetate. This organic phase was washed with water to remove any remaining salts. The aqueous phase was re-extracted (lx) with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. Dry DMF (10 mL) was added to the filtrate. Ethyl acetate was removed under reduced pressure leaving behind the product in DMF, which was used directly in the next step without further purification. Intermediate 34 tert-Butyl r(3S,4R)-1-(2-hydroxyethyl)-3-methoxypiperidin-4-yllcarbamate A solution of 2-[(3S,4R)-4-(dibenzylamino)-3-methoxypiperidin- 1 -yl]ethanol (Intermediate 35, 940 mg, 2.66 mmol) and di-tert-butyl dicarbonate (0.67 mL, 2.92 mmol) in methanol (100 mL) was hydrogenated over 20% palladium hydroxide on carbon (240 mg) overnight. The reaction mixture was filtered through celite and concentrated to dryness under reduced pressure. Chromatography on silica gel with 2-10% methanol in chloroform gave 540 mg (74%) of the product as a colorless oil. 98 WO 2008/071961 PCT/GB2007/004766 'H NMR (DMSO-d6) 6: 1.38 (s, 9H); 1.43-1.50 (m, 1H); 1.58-1.73 (m, 1H); 2.15 (d, 2H); 2.37 (t, 2H); 2.54-2.64 (m, 1H); 2.75-2.88 (m, 1H); 3.22 (s, 3H); 3.27-3.32 (m, 1H); 3.41 3.59 (in, 3H); 4.37 (t, IH); 6.35 (d, 1H). Intermediate 35 2-[(3S,4R)-4-(Dibenzylamino)-3 -methoxypiperidin- 1 -yllethanol and Intermediate 36 2-[(3R,4S)-4-(Dibenzylamino)-3-methoxypiperidin- 1 -yllethanol A mixture of cis(±)NN-dibenzyl-3-methoxypiperidin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (0.5 mL, 7.1 mmol), and NN-diisopropylethylamine (1.4 mL, 8.3 mmol) were reacted like described for Intermediate 7, but heating for one hour at 70 0 C. Chromatography on silica gel with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 1.3 g (68%) of the cis-racemic product as a colorless solid. MS (ESP): 355 (MH*) for C 22

H

30

N

2 0 2 'H NMR (DMSO-d6) 5: 1.44 - 1.58 (m, 1H); 1.64 (d, 111); 1.79 - 2.08 (m, 2H); 2.32 (t, 2H); 2.36 - 2.45 (m, 1H); 2.88 (d, 111); 3.13 (d, 1H); 3.30 (s, 3H); 3.40 - 3.49 (in, 2H); 3.56 (s, 1H); 3.59 - 3.87 (m, 4H); 4.34 (s, 1H); 7.11 - 7.24 (m, 2H); 7.24 - 7.40 (m, 8 H). The enantiomers were separated by chiral chromatography on a chiral cell OJ column (250x20 mm, 10 micron) eluting with 1:1 methanol/ ethanol and 0.1% diethylamine at 10 mL/min flow rate. The (-) isomer (Intermediate 36) eluted first followed by the (+) isomer (Intermediate 35). Intermediate 37 1- {2-[(3R,4S)-4-Amino-3 -methoxypiperidin- 1 -yllethyl } -7-methoxyquinoxalin-2(l H)-one tert-Butyl {(3R,4S)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate (Intermediate 38, 100 mg, 0.23 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 31 to give 70 mg (9 1%) of the crude product as an oil. MS (ESP): 333 (MH*) for C 17

H

24

N

4 0 3 99 WO 2008/071961 PCT/GB2007/004766 Intermediate 38 tert-Butyl {(3R,4S)-3-methoxy- 1-[2-(7-methoxy-2-oxoquinoxalin- l(2H)-yl)ethyllpiperidin-4 ylcarbamate 7-Methoxyquinoxalin-2(lH)-one (Intermediate 15, 530 mg, 3.00 mmol), 2-{(3R,4S)-4-[(tert butoxycarbonyl)amino]-3-methoxypiperidin- 1-yl} ethyl methanesulfonate (Intermediate 39, -0.33 mmol/mL, 3.30 mmol), and sodium hydride (60% in oil, 140 mg, 3.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 32. The crude product was purified by flash chromatography eluting with 25% acetone in hexanes to give 540 mg (42%) of the product as an off white solid. MS (ESP): 433 (MH*) for C 22

H

32

N

4 0 5 'H NMR (DMSO-d6) 6: 1.38 (s, 9H); 1.42-1.50 (in, 1H); 1.57-1.72 (in, 1H); 2.20-2.38 (in, 2H); 2.60 (t, 2H); 2.68-2.78 (in, lH); 2.79-2.93 (in, 1H); 3.18 (s, 3H); 3.25-3.31 (in, 1H); 3.50-3.67 (in, 111); 3.92 (s, 3H); 4.23-4.42 (in, 2H); 6.41 (d, 111); 6.96-7.07 (in, 2H); 7.75 (d, 1H); 8.04 (s, 1H). Intermediate 39 2-{ (3R,4S)-4-[(tert-Butoxycarbonyl)aminol-3-methoxypiperidin- 1-yllethyl methanesulfonate tert-Butyl [(3R,4S)-1-(2-hydroxyethyl)-3-methoxypiperidin-4-yl]carbamate (Intermediate 40, 0.91 g, 3.3 mmol), triethylamine (0.64 mL, 4.62 mmol), and methanesulfonyl chloride (0.31 mL, 3.99 mmol) were reacted as described for Intermediate 33. The crude product was used directly in the next step without further purification. Intermediate 40 tert-Butyl [(3R,4S)-1-(2-hydroxyethyl)-3-methoxypiperidin-4-yllcarbamate 2-[(3R,4S)-4-(Dibenzylamino)-3-methoxypiperidin- 1 -yl]ethanol (Intermediate 36, 3.2 g, 9.0 mmol) was reacted using a procedure similar to the one described for the synthesis of Intermediate 34 to give 1.7 g (68%) of the product as a colorless oil. 'H NMR (DMSO-d 6 ) 5: 1.38 (s, 9H); 1.42-1.50 (in, 1H); 1.58-1.73 (in, 1H); 2.11-2.21 (in, 2H); 2.38 (t, 2H); 2.55-2.66 (in, 1H); 2.77-2.89 (in, 1H); 3.23 (s, 3H); 3.28-3.33 (in, 1H); 3.41-3.59 (in, 3H); 4.38 (s, 1H); 6.36 (d, 1H). 100 WO 2008/071961 PCT/GB2007/004766 Intermediate 41 1-{ 2-[(3S,4R)-4-Amino-3-methoxypiperidin- I -yllethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile tert-Butyl {(3S,4R)-1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4 yl}carbamate (Intermediate 42, 370 mg, 0.87 mmol) was reacted with trifluoroacetic acid in dichloromethane using a procedure similar to the one described for the synthesis of Intermediate 31 to give 300 mg (quant.) of the crude product as an oil. MS (ESP): 327 (MH*) for CisH22N 4 02 Intermediate 42 tert-Butyl {(3S,4R)-1-[2-(7-Cyano-2-oxoquinolin-1(2H)-yl)ethyll-3-methoxypiperidin-4 yllcarbamate 2-Oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5, 370 mg, 2.20 mmol), 2 {(3S,4R)-4-[(tert-butoxycarbonyl)amino]-3-methoxypiperidin-1 -yl} ethyl methanesulfonate (Intermediate 33, ~0.24 mmol/mL, 2.40 mmol), and sodium hydride (60% in oil, 110 mg, 2.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 32. Chromatography on silica gel with 25-35% acetone in hexanes giving 370 mg (39%) of the product as an off white solid. MS (ESP): 427 (MH*) for C 23

H

30

N

4 0 4 'H NMR (DMSO-d 6 ) : 1.38 (s, 9H); 1.42-1.51 (in, 1H); 1.57-1.71 (in, IH); 2.18-2.40 (in, 2H); 2.56 (t, 2H); 2.65-2.76 (in, 1H); 2.78-2.90 (in, 111); 3.18 (s, 3H); 3.27 (s, 1H); 3.58 (s, 1H); 4.30-4.46 (in, 2H); 6.37 (d, 1H); 6.78 (d, 1H); 7.66 (dd, 1H); 7.91 (d, lH); 8.01 (d, 1H); 8.09 (s, 1H). Intermediate 43 1- 12-[(3R,4S)-4-Amino-3-methoxypiperidin- 1 -yllethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile tert-Butyl {(3R,4S)-I-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4 yl}carbamate (Intermediate 44, 320 mg, 0.75 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 31 to give 250 ing (quant.) of the crude product as an oil. MS (ESP): 327 (MH*) for Ci 8

H

22

N

4 0 2 101 WO 2008/071961 PCT/GB2007/004766 Intermediate 44 tert-Butyl {(3R,4S)-1-r2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyll-3-methoxypiperidin-4 ylcarbamate A mixture of tert-butyl {(3R,4S)-1-[2-(7-bromo-2-oxoquinolin-l(2H)-yl)ethyl]-3 methoxypiperidin-4-yl}carbamate (Intermediate 45, 460 mg, 0.98 mmol) and potassium cyanide (96 mg, 1.5 mmol) in acetonitrile (10 mL) was degassed and purged with nitrogen (3 times). A solution of tributyl tin chloride (14 iL/mL in heptane, 0.90 p.L, 0.003 mmol), 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg, 0.005 mmol), and tris(dibenzylideneacetone)dipalladium (0) (5 mg, 0.005 mmol) was added. The mixture was degassed 3x and stirred at room temperature for 30 min. The mixture was degassed once more then heated to 80 CC overnight. LC/MS revealed incomplete conversion to product. More tributyl tin chloride (14 iL/mL in heptane, 0.90 pL, 0.003 mmol), 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg, 0.005 mmol), and tris(dibenzylideneacetone)dipalladium (0) (5 mg, 0.005 mmol) was added. The reaction was stirred again overnight resulting in complete conversion to product. The reaction was diluted with dichloromethane. The organic phase was washed with water. The aqueous phase was re-extracted 4x with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated to. Chromatography on silica gel with 25-35% acetone in hexanes gave 320 mg (76%) of the product as a yellow solid. MS (ESP): 427 (MH*) for C 23

H

30

N

4 0 4 'H NMR (DMSO-d6) 8: 1.33-1.41 (m, 9H); 1.42-1.50 (in, 1H); 1.56-1.73 (m, 1H); 2.17 2.41 (in, 2H); 2.57 (t, 2H); 2.64-2.76 (m, 1H); 2.78-2.91 (in, 1H); 3.13-3.22 (in, 3H); 3.25 3.30 (in, 1H); 3.52-3.66 (in, 1H); 4.29-4.44 (in, 2H); 6.38 (d, 1H); 6.79 (d, 1H); 7.65 (dd, 1H); 7.92 (d, 1H); 8.01 (d, 1H); 8.09 (d, 1H). Intermediate 45 tert-Butyl {(3R,4S)-1-[2-(7-bromo-2-oxoquinolin-1(2H)-yl)ethyll-3-methoxypiperidin-4 yllcarbamate 7-Bromoquinolin-2(lH)-one (Intermediate 46, 450 mg, 2.00 mmol), 2-{(3R,4S)-4-[(tert butoxycarbonyl)amino]-3-methoxypiperidin-1 -yl} ethyl methanesulfonate (Intermediate 39, -0.23 mmol/mL, 2.30 mmol), and sodium hydride (60% in oil, 100 mg, 2.61 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 32. The crude product was purified by flash chromatography eluting with a gradient of 15-30% 102 WO 2008/071961 PCT/GB2007/004766 acetone in hexanes giving 460 mg (48%) of the product as an off white solid. MS (ESP): 480/ 482 (MH+) for C22H 3 oBrN 3 04 H NMR (DMSO-d 6 ) 8: 1.36-1.41 (in, 9H); 1.43-1.52 (in, 1H); 1.59-1.75 (in, 1H); 2.20 2.38 (m, 2H); 2.54 (t, 2H); 2.63-2.75 (in, 111); 2.77-2.89 (in, 1H); 3.16-3.23 (in, 3H); 3.26 3.32 (in, 1H); 3.52-3.68 (in, 1H); 4.33 (t, 2H); 6.40 (d, 1H); 6.64 (d, 1H); 7.44 (dd, 1H); 7.68 (d, 1H); 7.73-7.78 (in, 1H); 7.91 (d, 1H). Intermediate 46 7-Bromoquinolin-2(1H)-one (2E)-N-(3-bromophenyl)-3-phenylacrylamide (Intermediate 47, 16 g, 53 mmol) and aluminium trichloride (31.8 g, 238 mmol) were heated in chlorobenzene (100 mL) at 90"C bath temperature for one hour. The reaction mixture was cooled to room temperature and poured onto ice. It was stirred until the ice had completely molten, the mixture was filtered and washed with water and ethyl acetate to give the crude product as slightly brown solid in a mixture with the minor product 5-bromoquinolin-2(H)-one (- 3:2), 8.8 g (70%). This mixture could not be separated. The mixture was heated in phosphoroxychloride (50 mL) at 65*C for one hour. The reaction mixture was cooled to room temperature and poured onto ice. It was carefully neutralized at 0C with sodium carbonate, extracted into ethyl acetate (300 mL), washed with brine, dried over sodium sulfate and concentrated to give the crude mixture of 7-bromo-2-chloroquinoline and 5-bromo-2-chloroquinoline. The mixture was taken up in dichloromethane (100 mL), treated with silica gel (- 20 g), filtered and the filter cake was washed with dichloromethane. Filtrate and wash were combined and concentrated. The residue was crystallized from toluene/ hexanes (-70 mL, 1:1) to provide pure 7-bromo-2 chloroquinoline, 3.74 g as a colorless solid mp 113 0 C. H-NMR (DMSO-d 6 ) 6: 7.63 (d, J 8.4 Hz, 1H); 7.81 (dd, J 8.4, 1.6 Hz, 1H); 8.03 (d, J 8.4 Hz, 1H); 8.18 (d, J 1.6 Hz, 1H); 8.48 (d, J 8.4 Hz, 111). MS (ESP): 242/244/246 (MH*) for C 9

H

5 BrClN This chloride was heated in 5M HCI (100 mL) and dioxane (10 mL) for 1 hour at reflux. It was cooled, filtered and washed with water to give the title compound, 2.89 g, as a colorless solid, mp 295"C. MS (ESP): 224.13/226.13 (MH*) for C 9

H

6 BrNO H-NMR (DMSO-d 6 ) 6: 6.51 (d, J 9.6 Hz, 1H); 7.32 (dd, J 8.6, 1.6 Hz, 1H); 7.46 (d, J 1.6 103 WO 2008/071961 PCT/GB2007/004766 Hz, IH); 7.61 (d, J 8.6 Hz, IH); 7.88 (d, J 9.6 Hz, IH); 11.80 (brs, 1H). Intermediate 47 (2E)-N-(3-Bromophenyl)-3-phenylacrylamide To a solution of 3-bromoaniline (13.1 mL, 120 mmol) in dichloromethane (100 mL) and 2,6 lutidine (21 mL, 180 mmol) at 0"C was added a solution of cinnamoylchloride (20 g, 120 mmol) in dichloromethane (50 mL) dropwise. The reaction mixture was allowed to reach room temperature and stirred for 2 hours. It was quenched with potassium phosphate buffer (100 mL, IM, pH 7) and stirred for 15 minutes. Dichloromethane was removed under reduced pressure and it was extracted with ethyl acetate. The organic phase was washed with phosphate buffer (like above, 200 mL), dried over sodium sulfate and concentrated to dryness. The residue was crystallized from toluene/ hexanes to give the product as colorless solid (33.4 g, 92%). MS (ESP): 302/304 (MH*) for C 1 5

H

1 2 BrNO 'H-NMR (DMSO-d6) 8: 6.79 (d, 1H); 7.23-7.70 (m, 9H); 8.07 (s, LH); 10.38 (s, IH). Intermediate 48 1- 12-[(3S,4S)-4-Amino-3-methoxypiperidin- 1 -yllethyl} -7-methoxyquinoxalin-2(l H)-one tert-Butyl {(3S,4S)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate, (-) trans enantiomer (Intermediate 49, 190 mg, 0.44 mmol) was reacted with trifluoroacetic as described for Intermediate 31 to give 140 mg (93%) of the crude product as an oil. MS (ESP): 333 (MH*) for C 1 7

H

24

N

4 0 3 Intermediate 49 tert-Butyl {(3S,4S)-3-methoxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yl I carbamate, (-) trans enantiomer and 104 WO 2008/071961 PCT/GB2007/004766 Intermediate 50 tert-Butyl {(3R,4R)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-vl)ethyllpiperidin-4 yllcarbamate, (+) trans enantiomer 7-Methoxyquinoxalin-2(1IH)-one (Intermediate 15, 430 mg, 2.45 mmol), 2-{trans(±)-4 [(tert-butoxycarbonyl)amino]-3-methoxypiperidin-1-yl} ethyl methanesulfonate (Intermediate 51, ~0.27 mmol/mL, 2.70 mmol), and sodium hydride (60% in oil, 110 mg, 2.70 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 32. The crude product was purified by flash chromatography eluting with a gradient of 15-35% acetone/ hexanes to give 490 mg (45%) of the racemic mixture of the products as an off white solid. MS (ESP): 433 (MH*) for C 22

H

32

N

4 0 5 'H NMR (DMSO-d6 6: 1.21-1.33 (in, 1H); 1.37 (s, 9H); 1.63-1.74 (in, 1H); 1.78 (t, 1H); 2.01 (t, lH); 2.62 (t, 2H); 2.80-2.90 (in, 1H); 2.96-3.06 (in, 1H); 3.07-3.18 (in, 1H); 3.22 3.29 (in, 4H); 3.93 (s, 3H); 4.27-4.43 (in, 2H); 6.78 (d, LH); 6.96-7.06 (m, 2H); 7.75 (d, I1H); 8.05 (s, I1H). The mixture of enantiomers was separated by supercritical fluid chromatography on a Chiralpak AD-H column (250 x 21 mm, 5 micron) eluting with an isocratic gradient of 20% isopropanol/0. 1% dimethylethylamine at a flow rate of 60 mL/min. This gave 190 mg of tert butyl {(3S,4S)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate (Intermediate 49) (first eluting compound, (-) trans enantiomer) and 190 mg of tert-butyl {(3R,4R)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate (Intermediate 50) (second eluting compound, (+) trans enantiomer). Intermediate 51 2- {trans(±)-4-[(tert-Butoxycarbonyl)aminol-3-methoxypiperidin- 1 -yll ethyl methanesulfonate tert-Butyl [trans(±)-1-(2-hydroxyethyl)-3-methoxypiperidin-4-yl]carbamate (Intermediate 52, 0.74 g, 2.7 mmol), triethylamine (0.53 mL, 3.78 mmol), and methanesulfonyl chloride (0.25 mL, 3.24 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 33. The crude product was used directly in the next step without further purification. 105 WO 2008/071961 PCT/GB2007/004766 Intermediate 52 tert-Butyl rtrans(±)-1-(2-hydroxyethyl)-3-methoxypiperidin-4-yllcarbamate tert-Butyl [trans(±)-3-methoxypiperidin-4-yl]carbamate (Intermediate 53, 1.1 g, 4.8 mmol), 2-bromoethanol (0.44 mL, 6.2 mmol), and ethyl(diisopropyl)amine (1.25 mL, 7.2 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7 to give 0.74 g (57%) of the product as a colorless oil. 1 H NMR (DMSO-d 6 ) 6: 1.24-1.34 (in, 1H); 1.38 (s, 9H); 1.62-1.77 (in, 2H); 1.82-1.97 (in, 111); 2.38 (t, 2H); 2.73 (d, 1H); 2.98-3.18 (in, 3H); 3.27 (s, 3H); 3.46 (q, 2H); 4.39 (t, 1H); 6.78 (d, 1H). Intermediate 53 tert-Butyl rtrans(±)-3-methoxvpiperidin-4-yllcarbamate Benzyl trans(±)-4-[(tert-butoxycarbonyl)amino]-3-methoxypiperidine- 1 -carboxylate (Intermediate 54, 0.98 g, 2.69 mmol) was hydrogenated in methanol (50 mL) over 10% Pd/C (400 mg) at normal pressure. After 1 hour the reaction mixture was filtered through celite. The filtrate was concentrated to dryness giving 0.61 g (98%) of the product as a colorless oil. 'H NMR (DMSO-d6) S: 1.14-1.29 (m, 1H); 1.34-1.42 (in, 9H); 1.68 (d, 1H); 2.11 (dd, 1H); 2.26-2.38 (in, 1H); 2.71-2.82 (in, 1H); 2.86-2.98 (in, 1H); 3.14-3.21 (in, 3H); 3.26 (s, 3H); 6.75-6.86 (in, 1H). Intermediate 54 Benzyl trans(±)-4-[(tert-butoxycarbonyl)aminol-3-methoxypiperidine- 1 -carboxylate Benzyl trans(±)-4-[(tert-butoxycarbonyl)amino]-3-hydroxypiperidine-1-carboxylate (Intermediate 55, 1.0 g, 2.86 mmol) was suspended in 10 mL of toluene and treated with a 50 wt% solution of aqueous sodium hydroxide (6 mL) followed by dimethylsulfate (0.33 mL, 3.43 mmol) and benzyl triethylammonium chloride (catalytic amount). The reaction was stirred vigorously for one hour. The reaction was quenched with ice. The phases were separated. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness. Chromatography on silica gel with 25-50% acetone in hexanes gave 0.78 g (78%) of the product as a colorless oil. MS (ESP): 365 (MH*) for C 19

H

28

N

2 0 5 '1H NMR (DMSO-d6) 6: 0.55-0.68 (in, 1011); 1.04-1.19 (in, 1H); 2.17-2.46 (in, 2H); 2.55 2.64 (in, 2H); 2.67-2.80 (in, 1H); 2.85-3.07 (in, 1H); 3.10-3.31 (in, 1H); 4.09 (s, 3H); 4.32 106 WO 2008/071961 PCT/GB2007/004766 (s, 2H); 6.45-6.61 (in, 5H). Intermediate 55 Benzyl trans(±)-4-[(tert-butoxycarbonyl)aminol-3-hydroxypiperidine- 1 -carboxylate A mixture of benzyl trans(±)-4-amino-3-hydroxypiperidine-1-carboxylate (WO 2005/066176, 3.0 g, 12.0 mmol), di-tert-butyl dicarbonate (2.9 g, 13.2 mmol) and sodium bicarbonate (3.0 g, 36.0 mmol) in ethyl acetate/water (1:1, 100 mL) was stirred vigorously overnight. The biphasic mixture was separated. The aqueous phase was re-extracted Ix with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness giving 4.2 g of the product as a colorless solid. This material was used without further purification. H NMR (DMSO-dy) 6: 1.15-1.32 (in, IH); 1.35-1.42 (in, 9H); 1.71-1.83 (in, 1H); 2.60 2.79 (in, 1H); 2.82-2.98 (in, 1H); 3.15-3.29 (in, 2H); 3.74-3.86 (in, 1H); 3.88-3.98 (in, 1H); 5.00 (d, 1H); 5.04-5.08 (in, 211); 6.73 (d, 1H); 7.25-7.42 (in, 5H). Intermediate 56 1-{2-r(3R,4R)-4-Amino-3-methoxypiperidin-1-yllethyll-7-methoxyquinoxalin-2(1H)-one tert-Butyl {(3R,4R)-3-methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate, (+) trans enantiomer (Intermediate 50, 190 mg, 0.44 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 31 to give 150 ing (quant.) of the crude product as an oil. MS (ESP): 333 (MH*) for C 17

H

24

N

4 0 3 Intermediate 57 1- 2-[(4-Amino-3-hydroxypiperidin- 1 -yllethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer A tert-Butyl {(3-hydroxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate, trans enantiomer A (Intermediate 58, 130 mg, 0.31 mmol) was reacted with trifluoroacetic acid as described for Intermediate 31 to give 78 mg (79%) of the crude product as an oil. MS (ESP): 319 (MH*) for C 1 6

H

22

N

4 0 3 107 WO 2008/071961 PCT/GB2007/004766 Intermediate 58 tert-Butyl {3-hydroxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 vlIcarbamate, trans enantiomer A and Intermediate 59 tert-Butyl {3-hydroxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yl carbamate, trans enantiomer B A solution of tert-butyl {trans(±)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-[2-(7-methoxy-2 oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 60, 0.60 g, 1.13 mmol) in THF (20 mL ) was treated at 0 0 C with a solution of tetrabutylammonium fluoride in THF (IM, 2.2 mL). The reaction was stirred at room temperature for 2 hours, then concentrated to dryness under reduced pressure. The crude residue was taken up in ethyl acetate. The organic phase was washed with water. The aqueous phase was re-extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to. Chromatography on silica gel with 0-5% methanol in dichloromethane gave 0.27 g of the desired product and 0.12 g of an 0-acetylated side product. The side product was taken up in methanol and treated with a catalytic amount of potassium carbonate. This was stirred at room temperature for one hour resulting in complete conversion to the alcohol. The reaction mixture was concentrated to dryness. The residue was partitioned between aqueous potassium phosphate buffer (pH = 7) and ethyl acetate. The aqueous phase was re extracted 2x with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to dryness giving an additional 100 mg of the desired (79% total) of product. MS (ESP): 419 (MH+) for C 21

H

30

N

4 0 5 'H NMR (DMSO-d 6 ) 6: 1.18-1.33 (m, 1H); 1.38 (s, 9H); 1.63-1.77 (m, 1H); 1.86 (t, 1H); 1.97 (t, 1H); 2.54-2.64 (m, 2H); 2.80-2.93 (m, 1H); 2.96-3.09 (m, 211); 3.23 (dd, 1H); 3.92 (s, 3H); 4.32 (t, 2H); 4.67 (d, 1H); 6.62 (d, 1H); 6.94-7.06 (m, 2H); 7.69-7.79 (m, 1H); 8.04 (s, IH). The mixture of enantiomers was separated by supercritical fluid chromatography on a Chiralpak AD-H column (250 x 21 mm, 5 micron) eluting with an isocratic gradient of 25% 108 WO 2008/071961 PCT/GB2007/004766 isopropanol/0. 1% dimethylethylamine at a flow rate of 60 mL/min. This gave 130 mg of tert butyl {3-hydroxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate, trans enantiomer A (Intermediate 58, first eluting enantiomer) and 130 mg of tert-butyl {(3 hydroxy- 1 -[2-(7-methoxy-2-oxoquinoxalin- 1(2H)-yl)ethyl]piperidin-4-yl} carbamate, trans enantiomer B (Intermediate 59, second eluting enantiomer). Intermediate 60 tert-Butyl {trans(±)-3-{[tert-butyl(dimethyl)silylloxy}-1-[2-(7-methoxy-2-oxoquinoxalin 1(2H)-yl)ethyl1piperidin-4-yl I carbamate 7-Methoxyquinoxalin-2(1IH)-one (Intermediate 15, 430 mg, 2.43 mmol), 2-(trans(±)-4-[(tert butoxycarbonyl)amino]-3-{ [tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)ethyl methanesulfonate (Intermediate 61, ~0.27 mmol/mL, 2.70 mmol), and sodium hydride (60% in oil, 110 mg, 2.70 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 32. The crude product was purified by flash chromatography eluting with a gradient of 10-25% acetone/hexanes giving 600 mg (46%) of the product as an off white solid. MS (ESP): 533 (MH*) for C 27 H44N 4 0 5 Si 'H NMR (DMSO-d 6 ) : 0.00 (s, 6H); 0.79 (s, 9H); 1.33 (s, 9H); 1.37-1.47 (m, 1H); 1.49 1.59 (m, 1H); 1.87 (t, 1H); 1.95-2.07 (m, 1H); 2.55-2.66 (m, 2H); 2.77-2.89 (m, 1H); 2.92 3.02 (m, 1H); 3.11 (s, 1H); 3.30 - 3.40 (m, 1H); 3.89 (s, 3H); 4.17-4.41 (m, 211); 6.57 (d, 1H); 6.91-7.04 (m, 2H); 7.72 (d, 1H); 8.01 (s, 1H). Intermediate 61 2-(trans(±)-4-r(tert-Butoxycarbonyl)aminol-3-{[tert-butyl(dimethyl)silylloxylpiperidin-1 yl)ethyl methanesulfonate tert-Butyl [trans(±)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-(2-hydroxyethyl)piperidin-4 yl]carbamate (Intermediate 62, 1.0 g, 2.7 mmol), triethylamine (0.52 mL, 3.74 mmol), and methanesulfonyl chloride (0.25 mL, 3.21 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 33. The crude product was used directly in the next step without further purification. 109 WO 2008/071961 PCT/GB2007/004766 Intermediate 62 tert-Butyl [trans(±)-3-{[tert-butyl(dimethyl)silylloxy}-1-(2-hydroxyethyl)piperidin-4 yllcarbamate tert-Butyl (trans(±)-3 -{ [tert-butyl(dimethyl)silyl]oxy} piperidin-4-yl)carbamate (Intermediate 63, 1.3 g, 3.9 mmol), 2-bromoethanol (0.36 mL, 5.1 mmol), and ethyl(diisopropyl)amine (1.0 mL, 5.9 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 7 to give 1.0 g (67%) of the desired product. 'H NMR (DMSO-d 6 ) 6: 0.00 (s, 6H); 0.79 (s, 9H); 1.33 (s, 9H); 1.39 (dd, 1H); 1.46-1.58 (in, LH); 1.71-1.82 (in, 1H); 1.82-1.93 (in, lH); 2.33 (t, 2H); 2.72 (d, 111); 2.80-2.90 (m, 1H); 2.99-3.16 (in, 1H); 3.32-3.47 (in, 3H); 4.36 (t, 1H); 6.56 (d, 1H). Intermediate 63 tert-Butyl (trans(±)-3- { [tert-butyl(dimethyl)silylloxyl piperidin-4-yl)carbamate Benzyl trans(±)-4-[(tert-butoxycarbonyl)amino]-3- {[tert-butyl(dimethyl)silyl]oxy} piperidine-1-carboxylate (Intermediate 64, 1.8 g, 3.9 mmol) was hydrogenated in methanol (50 mL) over 10% palladium on carbon (-400 mg) at normal pressure for one hour. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give 1.3 g (quant.) of the product as a colorless solid. H NMR (DMSO-dr) 6: 0.00 (s, 6H); 0.80 (s, 9H); 1.20-1.30 (m, 1H); 1.33 (s, 9H); 1.53 (d, 1H); 2.15 (dd, 1H); 2.23-2.39 (in, 1H); 2.74 (d, 1H); 2.88 (dd, 1H); 3.20 - 3.30 (m, 2H); 4.08 (s, 1H); 6.58 (d, 1H). Intermediate 64 Benzyl trans(±)-4-r(tert-butoxycarbonyl)aminol-3- rtert-butyl(dimethyl)silylloxyl piperidine 1-carboxylate A mixture of benzyl trans(±)-4-[(tert-butoxycarbonyl)amino]-3-hydroxypiperidine-1 carboxylate (Intermediate 55, 2.0 g, 5.7 mmol), imidazole (0.58 g, 8.6 mmol) and tert butyl(chloro)dimethylsilane (1.0 g, 6.9 mmol) in DMF (15 mL) was stirred at room temperature under nitrogen overnight. Water (50 mL) was added to the reaction and the mixture was extracted 2x with ether. The combined organic phases were dried over sodium sulfate and concentrated to dryness. Chromatography on silica gel with 10-25% acetone in hexanes giving 1.8 g (69%) of the product as a colorless solid. 'H NMR (DMSO-d6) 6: 0.00 (s, 6H); 0.80 (s, 9H); 1.27-1.41 (in, 10H); 1.61-1.72 (in, 1H); 110 WO 2008/071961 PCT/GB2007/004766 2.59-3.05 (in, 2H); 3.30 - 3.40 (in, 2H); 3.69-3.95 (in, 2H); 4.92-5.14 (in, 2H); 6.68 (d, 1H); 7.24-7.40 (in, 5H). Intermediate 65 1- {2-r4-Amino-3-hydroxypiperidin- I -yllethyl } -7-methoxyquinoxalin-2(l H)-one, trans enantiomer B tert-Butyl {3-hydroxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl] piperidin-4-yl}carbamate trans enantiomer B (Intermediate 59, 130 mg, 0.31 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 31 to give 84 mg (85%) of the crude product as an off white foam. MS (ESP): 319 (MH*) for C 16 H22N 4 0 3 Intermediate 66 3-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile Ethyl 3-(4-cyano-2-nitrophenyl)-2-oxopropanoate (6.5 kg, 24.8 mol) and acetonitrile (21 L) was stirred at 22'C, sodium borohydride (0.30 kg, 7.9 mol) was added in portions, the mixture was then stirred for 1 hour at 24 0 C. Acetic acid (65 L) was charged to the solution and the internal temperature was raised to 65'C. Iron (3.3 kg) was added to the solution in portions (6 x 0.5 kg) over 1 hour. After a further 1 hour the product was isolated by filtration, washed sequentially with water (3 x 25L) and ethanol (29 L) and dried under reduced pressure to give the product as a beige solid, 3.07 kg (66%). Mp >250'C MS (ESP): 189 (MH*) for C 10

H

8

N

2 0 2 'H-NMR (DMSO-d 6 ) 8 ppm: 2.90 - 3.20 (in, 2H); 4.10 - 4.20 (in, 1H); 5.65 (d, 1H) 7.15 (s, 1H) 7.35 - 7.45 (in, 2H); 10.38 (s, lH). Intermediate 67 1- {2-r-4-Amino-3-fluoropiperidin- 1-yllethyl} -2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A To a solution of tert-butyl {l-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]-3-fluoropiperidin-4 yl}carbamate, trans enantiomer A (Intermediate 68, 0.30 g, 0.72 mmol) in dichloromethane (20 mL), was added trifluoroacetic acid (4 mL) with cooling in an ice bath. The reaction mixture was allowed to warm to room temperature. TLC revealed clean but incomplete 111 WO 2008/071961 PCT/GB2007/004766 conversion after ~ 30 min (15% methanol/dichloromethane containing 0.5% ammonium hydroxide as eluent). Another 4 mL of trifluoroacetic acid was added. After 30 min the reaction was concentrated to dryness. The crude residue was partitioned between 15% methanol/dichloromethane and saturated sodium bicarbonate. The aqueous phase was adjusted to pH - 10 with saturated sodium carbonate solution. The layers were separated. The aqueous phase was re-extracted 2x with 15% methanol/dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated to dryness giving 0.30 g of the crude product as an oil. MS (ESP): 315 (MH+) for C 17

H

19

FN

4 0 5 Intermediate 68 tert-Butyl {1-r2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyll-3-fluoropiperidin-4-yl carbamate, trans enantiomer A A solution of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5, 500 mg, 2.94 mmol) in dry DMF (10 mL) was treated at 0C with sodium hydride (60% in oil, 153 mg, 3.82 mmol). Cooling was removed and the reaction was stirred at room temperature for 90 min. The reaction was again cooled in an ice bath and treated with a solution of 2-{(3R,4R) 4-[(tert-butoxycarbonyl)amino]-3-fluoropiperidin- 1 -yl} ethyl methanesulfonate, trans enantiomer A (Intermediate 69, -0.38 mmol/mL, 3.82 mmol), in dry DMF. The reaction was stirred at room temperature overnight. It was quenched with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel with a gradient of 10-50% acetone in hexanes gave 680 mg (56%) of the product as an off white solid. 'H NMR (DMSO-d 6 ) 8 ppm: 1.25-1.43 (m, 1IH); 1.67-1.78 (m, 1H); 2.04-2.17 (m, 2H); 2.57 2.68 (in, 2H); 2.80-2.89 (in, 1H); 3.25-3.32 (m, 1H); 4.27-4.47 (m, 2H); 4.30 (m, 1H) 6.78 (d, 1H); 6.99 (d, 1H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, 1H); 8.09 (s, 1H). MS (ESP): 415 (MH) for C 22

H

27

FN

4 0 3 112 WO 2008/071961 PCT/GB2007/004766 Intermediate 69 2- 4-r(tert-Butoxycarbonyl)aminol-3-fluoropiperidin- 1 -yl ethyl methanesulfonate, trans enantiomer A A solution of tert-butyl [3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]carbamate, trans enantiomer A (Intermediate 70, 2.0 g, 7.62 mmol) in dry dichloromethane (50 mL) at 0"C was treated with triethylamine (1.5 mL, 10.7 mmol) followed by methanesulfonyl chloride (0.71 mL, 9.15 mmol). After 15 min, the reaction was quenched with potassium phosphate buffer (IM, pH 7). The aqueous phase was extracted once with dichloromethane. Ethyl acetate was added to the combined organic phases. Dichloromethane was removed under reduced pressure leaving behind the product in solution in ethyl acetate. This organic phase was washed with water to remove any remaining salts. The aqueous phase was re-extracted (lx) with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. Dry DMF (20 mL) was added to the filtrate. Ethyl acetate was removed under reduced pressure leaving behind the product in DMF, which was used without delay in the next step without further purification. Intermediate 70 tert-Butyl [3 -fluoro- 1 -(2-hydroxyethyl)piperidin-4-yllcarbamate, trans enantiomer A To a solution of benzyl benzyl[3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]carbamate, trans enantiomer A (Intermediate 71, 5.6 g, 14.5 mmol) in ethanol (100 mL) was added 20% palladium hydroxide on carbon (1.5 g). The reaction was stirred under an atmosphere of hydrogen overnight. TLC revealed complete disappearance of starting material (15% methanol/dichloromethane containing 0.5% ammonium hydroxide as eluent). The reaction mixture was then treated with di-tert-butyl dicarbonate (4.0 mL, 17.4 mmol) and stirred under nitrogen for 1 hour. TLC revealed complete disappearance of starting material. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness and subjected to chromatography on silica gel eluting with a gradient of 0-5% methanol/dichloromethane followed by an isocratic gradient of 5% methanol/dichloromethane containing 0.25% ammonium hydroxide to give 2.86 g (75%) of the product as a yellow oil. 'H NMR (DMSO-d 6 ) 8 ppm: 1.29-1.45 (in, 1 1H); 1.65-1.79 (in, 1H); 1.93-2.08 (in, 2H); 2.38 2.46 (in, 2H); 2.69-2.79 (in, IH); 3.10-3.21 (in, IH); 3.47 (q, 2H); 4.26 (in, IH) 4.44 (t, IH); 6.99 (d, 1H). 113 WO 2008/071961 PCT/GB2007/004766 Intermediate 71 Benzyl benzyl-r3-fluoro-1-(2-hydroxyethyl)piperidin-4-yllcarbamate, trans enantiomer A and Intermediate 72 Benzyl benzyl-[3-fluoro-1-(2-hydroxyethyl)piperidin-4-yllcarbamate, trans enantiomer B A solution of tetrabutylammonium fluoride in tetrahydrofuran (IM, 21.3 mL, 21.3 mmol) was added to trans (±) benzyl benzyl[l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3 fluoropiperidin-4-yl]carbamate (Intermediate 73, 8.9 g, 17.8 mmol) in tetrahydrofuran (20 mL) at 0 0 C. The solution was allowed to warm to room temperature and stirred for one hour. The mixture was then cooled to 0"C and quenched with water. The mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica with 40% acetone in hexanes gave the product as an oil (5.1 g, 74%). 1 H NMR (DMSO-d 6 ) 8 ppm: 1.55 (in, 1H); 1.67 (in, 1H); 2.02 (in, 2H); 2.40 (in, 2H); 2.74 (in, 1H); 3.14 - 3.28 (in, 2H); 3.43 (in, 2H); 3.93 (in, 1H); 4.40 (t, 2H); 4.50 (in, 1H); 5.06 (in, 2H); 7.15 (in, 1H); 7.20 - 7.31 (in, 8H); 7.36 (in, 1H). MS (ESP): 387.25 (MH+) for C 22 H27FN 2

O

3 The racemic mixture was separated on a Chiralpak AD column (500 x 20 mm, 20micron) with ethanol/ methanol (1:1), containing 0.1% diethyl amine. Trans enantiomer A (Intermediate 71) was eluted first, followed by trans enantiomer B (Intermediate 72). The chiral purity (using an analytical method equivalent to the preparative method described above) was determined to be >98% e.e. for both enantiomers. Intermediate 73 Trans (±) benzyl benzyl- 1-(2- rtert-butyl(dimethyl)silylloxyl ethyl)-3-fluoropiperidin-4 yllcarbamate A mixture of trans (+) benzyl benzyl(3-fluoropiperidin-4-yl)carbamate hydrochloride (Intermediate 74, 7.98 g, 21.1 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (6.85 g, 27.5 mmol) and cesium carbonate (17.9 g, 55.0 mmol) in acetonitrile (60 mL) was heated to 114 WO 2008/071961 PCT/GB2007/004766 60"C for twelve hours. The reaction mixture cooled to room temperature and concentrated under reduced pressure to near dryness. The residue was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica with 10% acetone in hexanes gave the product as oil (8.9 g, 84%). 1H NMR (chloroform-d3) 6 ppm: 0.04 - 0.07 (s, 6H); 0.77 - 0.88 (s, 9H); 1.58 - 1.74 (m, 2H); 2.05 - 2.20 (m, 2H); 2.44 - 2.58 (in, 2H); 2.69 - 2.84 (m, 1H); 3.24 (in, 1H); 3.65 (s, 2H); 4.44 - 4.59 (m, 3H); 5.11 (s, 2H); 7.13 - 7.28 (in, 9H); 7.34 (in, 2H). MS (ESP): 501.28 (MH*) for C 28

H

41

FN

2

O

3 Si Intermediate 74 Trans (W) benzyl benzyl(3-fluoropiperidin-4-vl)carbamate hydrochloride To a solution of trans (+) tert-butyl 4-{benzyl[(benzyloxy)carbonyl]amino}-3 fluoropiperidine-l-carboxylate (Intermediate 75, 12.05 g, 28.2 mmol) in dichloromethane (50 mL) at 0"C was added hydrogen chloride (lM in diethyl ether, 56.5 mL, 56.5 mmol). The solution was allowed to stir for one hour. The solid was filtered, and the filter cake washed with diethyl ether to give the mono hydrochloride salt of the product (10.1 g, 95%). 1 H NMR (DMSO-d) 6 ppm: 1.68 (in, 1H); 2.00 - 2.15 (m, 1H); 3.08 (m, 1H); 3.18 (m, 1H); 3.34 (m, 2H); 3.50(m, 1H); 4.34-4.49 (m, 2H); 4.65 (m, 1H); 5.02 (s, 111); 5.14 (d, J=19.40 Hz, 2H); 7.15 - 7.30 (in, 8H); 7.32 (in, 2H). MS (ESP): 343.19 (MH*) for C 20

H

23

FN

2 0 2 Intermediate 75 Trans () tert-butyl-4-{benzylr(benzyloxy)carbonyllamino}-3-fluoropiperidine-1-carboxylate To a solution of trans (+) tert-butyl (4-benzylamino)-3-fluoropiperidine-1-carboxylate (Intermediate 76, 10.3 g, 33.4 mmol) in 1,4-dioxane (100 mL) and sodium carbonate (5.31 g, 50.1 mmol) in water (20 mL) was added benzyl chloroformate (5.89 nL, 41.8 mmol) dropwise at 0 0 C. The mixture was allowed to warm to room temperature and stirred for two hours. The reaction mixture was then concentrated to near dryness and diluted with ethyl acetate. The organic phase was washed with water and brine, then dried over sodium sulfate. Chromatography on silica with 20% ethyl acetate in hexanes gave the product as a solid (12.5 g, 94%). MS (ESP): 343.18 (MH+ minus BOC) for C 25 H3 1

FN

2 0 4 115 WO 2008/071961 PCT/GB2007/004766 1H NMR (chloroform-d 3 ) 6-ppm: 1.45 (s, 9H); 1.67 (d, J=8.67 Hz, 2H); 1.84 (m, IH); 2.59 2.75 (m, 2H); 3.91-4.07 (m, 2H); 4.48 (d, J=16 Hz, 2H); 4.63 (d, J=16 Hz, 1H); 5.18 (s, 2H); 7.20 - 7.34 (m, 1OH). Intermediate 76 Trans (+) tert-butyl (4-benzylamino)-3-fluoropiperidine-I-carboxylate The title compound was prepared as described by Monique B. van Neil et al, J. Med. Chem., 1999, 42, 2087-2104 and the references therein. 'H NMR (DMSO-d 6 ) 6 ppM: 1.32 (m, 1H); 1.39 (s, 9H); 1.79 (m, 1H); 2.38 (m, 1H); 2.73 (m, 1H); 3.18 (m, 1H); 3.31 (m, 1H); 3.46 (m, 1H); 3.60-3.80 (m, 3H); 4.39 (m, 1H); 7.20-7.38 (m, 5H). Intermediate 77 1- {2-[4-Amino-3-fluoropiperidin- 1 -yll ethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer A tert-Butyl {3-fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate, trans enantiomer A (Intermediate 78, 0.30 g, 0.71 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 67 to give 0.25 g of the crude product as an oil. MS (ESP): 321 (MH*) for C 16

H

21

FN

4 0 2 Intermediate 78 tert-Butyl f3-fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 ylI carbamate, trans enantiomer A 7-Methoxyquinoxalin-2(LH)-one (Intermediate 15, 0.52 g, 2.95 mmol), 2-{4-[(tert butoxycarbonyl)amino]-3-fluoropiperidin- 1 -yl} ethyl methanesulfonate, trans enantiomer A (Intermediate 69, -0.38 mmol/mL, 3.82 mmol), and sodium hydride (60% in oil, 153 mg, 3.82 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 68. Chromatography on silica gel with a gradient of 10-50% acetone in hexanes gave 0.83 g (67%) of the product as an off white solid. 'H NMR (DMSO-d 6 ) 6 ppm: 1.23-1.45 (m, 11H); 1.64-1.80 (m, IH); 2.04-2.19 (m, 2H); 2.61 2.71 (m, 2H); 2.84 (d, 1H); 3.25-3.33 (m, 1H); 3.92 (s, 3H); 4.27-4.43 (m, 2H); 4.28 (m, 1H); 16.94-7.05 (m, 3H); 7.75 (d, 1H); 8.04 (s, 1H). 116 WO 2008/071961 PCT/GB2007/004766 MS (ESP): 421 (MH*) for C 2 1

H

29

FN

4 0 4 Intermediate 79 1- {2-[4-Amino-3-fluoropiperidin- I -yllethyl} -2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B tert-Butyl {1 -[2-(7-cyano-2-oxoquinolin- 1 (2H)-yl)ethyl]-3-fluoropiperidin-4-yl}carbamate, trans enantiomer B (Intermediate 80, 0.30 g, 0.72 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 67 to give 0.25 g of the crude product as an oil. MS (ESP): 315 (MH*) for C, 7

H

1 9

FN

4 0 Intermediate 80 tert-Butyl { 1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyll-3-fluoropiperidin-4-ylIcarbamate, trans enantiomer B 2-Oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5, 0.50 g, 2.94 mmol), 2-{4-[(tert butoxycarbonyl)amino]-3-fluoropiperidin- l-yl} ethyl methanesulfonate, trans enantiomer B (Intermediate 81, ~0.38 mmol/mL, 3.82 mmol), and sodium hydride (60% in oil, 153 mg, 3.82 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 68. Chromatography on silica gel with a gradient of 10-50% acetone in hexanes gave 0.64 g (53%) of the product as an off-white solid. MS (ESP): 415 (MH*) for C 2 2

H

27

FN

4 0 3 'H NMR (DMSO-d 6 ) 6 ppm: 1.25-1.43 (in, 11H); 1.67-1.78 (in, 1H); 2.04-2.17 (in, 2H); 2.57 2.68 (in, 2H); 2.80-2.89 (in, 1H); 3.25-3.32 (in, 1H); 4.27-4.47 (in, 2H); 4.30 (in, lH); 6.78 (d, 1H); 6.99 (d, 1H); 7.66 (dd, IH); 7.91 (d, 1H); 8.01 (d, 1H); 8.09 (s, IH). Intermediate 81 2- {4-[(tert-Butoxycarbonyl)aminol-3-fluoropiperidin- 1 -Y1l ethyl methanesulfonate, trans enantiomer B tert-Butyl [3-fluoro- 1 -(2-hydroxyethyl)piperidin-4-yl]carbamate, trans enantiomer B (Intermediate 82, 2.0 g, 7.62 mmol), triethylamine (1.5 mL, 10.7 mmol), and methanesulfonyl chloride (0.71 mL, 9.15 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 69. The crude product was used directly in the next step without further purification. 117 WO 2008/071961 PCT/GB2007/004766 Intermediate 82 tert-Butyl r3-fluoro-1-(2-hydroxyethyl)piperidin-4-yllcarbamate, trans enantiomer B Benzyl benzyl[3-fluoro-1-(2-hydroxyethyl)piperidin-4-yl]carbamate, trans enantiomer B (Intermediate 72, 5.6 g, 14.4 mmol), 20% palladium hydroxide on carbon (0.5 g), and di tert-butyl dicarbonate (3.5 g, 15.8 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 70. Chromatography on silica gel eluting with 10% methanol (0.1% ammonium hydroxide) in ethyl acetate gave 2.9 g (76 %) of product as an oil. 1H NMR (CDCl 3 ) 6 ppm 1.36-1.55 (m, 10H); 2.02-2.31 (m, 3H); 2.52-2.64 (m, 2H); 2.72 2.82 (m, 2H); 3.09-3.20 (m, 1H); 3.60 (t, 3H); 4.31 (m, 1H); 4.80 (d, 1H) Intermediate 83 1- {2-r4-Amino-3-fluoropiperidin- 1 -yllethyl } -7-methoxyquinoxalin-2(l H)-one, trans enantiomer B tert-Butyl {3-fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}carbamate, trans enantiomer B (Intermediate 84, 0.33 g, 0.78 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 67 to give 0.27 g of the crude product as an oil. MS (ESP): 321 (MH*) for C 16

H

21

FN

4 0 2 Intermediate 84 tert-Butyl {3-fluoro-1-r2-(7-methoxy-2-oxocuinoxalin-1(2H)-yl)ethyllpiperidin-4 yllcarbamate, trans enantiomer B 7-Methoxyquinoxalin-2(lH)-one (Intermediate 15, 0.52 g, 2.95 mmol), 2-{4-[(tert butoxycarbonyl)amino]-3-fluoropiperidin- 1 -yl} ethyl methanesulfonate, trans enantiomer B (Intermediate 81, ~0.38 mmol/mL, 3.82 mmol), and sodium hydride (60% in oil, 153 mg, 3.82 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 68. Chromatography on silica gel with a gradient of 10-50% acetone in hexanes gave 0.93 g (78%) of the product as an off white solid. MS (ESP): 421 (MH*) for C 21

H

29

FN

4 0 4 'H NMR (DMSO-d 6 ) 6 ppm: 1.23-1.45 (m, 1 H); 1.64-1.80 (m, IH); 2.04-2.19 (m, 2H); 2.61 2.71 (m, 2H); 2.84 (d, IH); 3.25-3.33 (m, 1H); 3.92 (s, 3H); 4.27-4.43 (m, 2H); 4.28 (m, 1H); 118 WO 2008/071961 PCT/GB2007/004766 16.94-7.05 (m, 3H); 7.75 (d, 1H); 8.04 (s, 1H). Intermediate 85 1-{2-r(3R,4R)-4-Amino-3-methoxypiperidin- 1-yllethyll -2-oxo-1,2-dihydroquinoline-7 carbonitrile A solution of tert-butyl {(3R,4R)- 1-[2-(7-cyano-2-oxoquinolin- 1(2H)-yl)ethyl]-3 methoxypiperidin-4-yl}carbamate (Intermediate 86, 280 mg, 0.66 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (10 mL). After 1 hour, the reaction was concentrated to dryness. The residue was taken up in 15% methanol in chloroform (30 mL) and washed with saturated sodium bicarbonate solution. The aqueous layer was adjusted to pH - 10 with saturated sodium carbonate solution, and re-extracted with 15% methanol/chloroform (3 x 30 mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness giving 240 mg of the crude product as an oil. MS (ESP): 327 (MH*) for Ci 8 H22N402 Intermediate 86 tert-Butyl {(3R,4R)-1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyll-3-methoxypiperidin-4 yllcarbamate and Intermediate 87 tert-Butyl {(3S,4S)-1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyll-3-methoxypiperidin-4 yllcarbamate A mixture of tert-butyl [trans(±)-3-methoxypiperidin-4-yl]carbamate (Intermediate 53, 0.63 g, 2.7 mmol) and 2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-7-carbonitrile (Intermediate 88, 0.57 g, 2.7 mmol) in 1:1 dry methanol/chloroform (30 mL) was heated to 70 0 C for 2 hours. The reaction was cooled to room temperature, treated with sodium triacetoxy borohydride (1.7 g, 8.1 mmol) and stirred at room temperature for 2 hours. The reaction was filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous phase was re-extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. 119 WO 2008/071961 PCT/GB2007/004766 Chromatography on silica gel with 25-50% acetone in hexanes gave 0.74 g (62%) of the racemic mixture of the products. MS (ESP): 427 (MH+) for C2 3

H

30

N

4 0 4 'H NMR (DMSO-d 6 ) ppM: 1.19 - 1.33 (in, 1H); 1.37 (s, 9H); 1.64 - 1.73 (m, 1H); 1.77 (in, 1H); 1.99 (in, 1H); 2.59 (in, 2H); 2.79 - 2.87 (in, 1H); 2.93 - 3.04 (in, 1H); 3.05 - 3.15 (in, 1H); 3.23 - 3.30 (in, 1H); 3.28 (s, 3H); 4.30 - 4.47 (in, 2H); 6.79 (d, 2H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, 1H); 8.09 (s, 1H). The mixture of enantiomers was separated by HPLC on a Chiralpak AD column (20 x 250 mm, 10 micron) with an isocratic gradient of 80% hexanes, 20% 1:1 ethanol/methanol, 0.1% diethylamine at a flow rate of 20 mL/min. This gave 0.28 g of tert-butyl {(3R,4R)-1-[2-(7 cyano-2-oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}carbamate (Intermediate 86, second eluting peak, (+) isomer) and 0.32 g of tert-butyl {(3S,4S)-1-[2-(7-cyano-2 oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}carbamate (Intermediate 87, first eluting peak, (-) isomer). Intermediate 88 2-Oxo- I -(2-oxoethyl)- 1,2-dihydroquinoline-7-carbonitrile To a solution of 1-(2,2-diethoxyethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile (Intermediate 89, 21.5 g, 75.1 mmol) in acetonitrile (230 mL) was added concentrated hydrochloric acid (2 eq., 12.5 mL). After 1 hour, the resulting precipitate was collected by filtration. This gave 16 g (100%) of the product as a colorless solid after drying, which was used without further purification. MS (ESP): 213 (MH*) for C 12

H

8

N

2 0 2 H NMR (DMSO-dr) 8 pom: 5.25 - 5.38 (in, 2H); 6.82 (d, 1H); 7.67 (d, 1H); 7.95 (d, 1H); 8.02 - 8.14 (in, 2H); 9.64 - 9.74 (in, 1H). Intermediate 89 1-(2,2-Diethoxyethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile A mixture of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5, 35.0 g, 201 mmol), 2-bromo-1,1-diethoxyethane (44.1 mL, 281 mmol) and cesium carbonate (78.5 g, 241 mmol) in dry NMP (200 mL) was stirred at 70 0 C overnight. The reaction mixture was diluted with water (350 mL) and extracted with butyl acetate (2x 350 mL). The combined organic phases 120 WO 2008/071961 PCT/GB2007/004766 were filtered through celite and washed with water (lx 175 mL). The butyl acetate solution was concentrated to 140 mL and diluted with iso-hexane 525 ml. The precipitate was isolated by filtration and washed with iso-hexane 70 ml. This gave 34 g (60%) of the product as a colorless solid after drying, which was used without further purification. MS (ESP): 309 (MNa*) for C 1 6

H

1 8

N

2 0 3 'H-NMR (DMSO-d 6 ) 5 ppm: 0.96 (t, 6H); 3.34 - 3.47 (in, 2H); 3.56 - 3.73 (in, 2H); 4.39 (d, 2H); 4.72 (t, 1H); 6.80 (d, IH); 7.62 (d, 1H); 7.89 (d, IH); 8.02 (d, 1H); 8.13 - 8.22 (in, 1H). Intermediate 90 1-{2-[(3S,4S)-4-Amino-3-methoxypiperidin-1-yllethyll-2-oxo-1,2-dihydroquinoline-7 carbonitrile tert-Butyl {(3S,4S)-1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4 yl}carbamate (Intermediate 87, 0.32 g, 0.75 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 85 to give 0.24 g of the crude product as an oil. MS (ESP): 327 (MH*) for C 18

H

22

N

4 0 2 Intermediate 91 Cis(±) 1-[2-(4-amino-3-fluoropiperidin-1-yl)ethyll-7-methoxyquinoxalin-2(lH)-one, trifluoroacetic acid salt To a solution of cis(±) tert-butyl {3-fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H) yl)ethyl]piperidin-4-yl}carbamate (Intermediate 92, 222 mg, 0.53 mmol), in chloroform (10 mL) at 0 0 C, was added 30% trifluoroacetic acid in chloroform (6 mL). After 3 hours at room temperature the solvent was removed under reduced pressure, providing the title compound, which was used in the next step without purification. The title compound may be present in the form of a bis-trifluoroacetic acid salt. MS (ESP): 321 (MH*) for C 16

H

2 1

FN

4 0 Intermediate 92 Cis(±) tert-butyl {3-fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 ylIcarbamate 7-Methoxyquinoxalin-2(1H-one (Intermediate 15, 181 mg, 1 mmol) and cis(±) 2-{4-[(tert 121 WO 2008/071961 PCT/GB2007/004766 butoxycarbonyl)amino]-3-fluoropiperidin- 1-yl} ethyl methanesulfonate (Intermediate 21, ~1 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 20. Chromatography on silica gel with hexanes/ethyl acetate (2:3) gave 222 mg (51%) product as a solid. MS (ESP): 421 (MH*) for C 21 H2 9

FN

4 0 4 'H-NMR (CDCl 3 d 5: 1.44 (s, 9H); 1.86 (in, 2H); 2.40 (in, 2H); 2.80 (in, 2H); 3.15 (in, 1H); 3.41 (in, 1H); 3.70 (in, 1H); 3.94 (s, 3H); 4.42 (in, 2H); 4.70 (in, 2H); 6.93 (in, 2H); 7.77 (in, IH); 8.11 (s, 1H). Intermediate 93 1-{ 2-[(3R,4S)-4-Amino-3-methoxypiperidin-1-yllethyll-4-methyl-2-oxo-1,2 dihydroquinoline-7-carbonitrile, trifluoroacetic acid salt Tert-butyl {(3R,4S)-1-[2-(7-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl]-3 methoxypiperidin-4-yl}carbamate (Intermediate 94, 360 mg, 0.81 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 91, providing the title compound. The title compound may be present in the form of a bis trifluoroacetic acid salt. MS (ESP): 341 (MH*) for C 19

H

24

N

4 0 2 Intermediate 94 tert-Butyl {(3R,4S)-1-[2-(7-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)ethyll-3 methoxypiperidin-4-yl Icarbamate To a solution of 4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile (V. N. Gogte, S.B. Kulkarni and B.D. Tilak, Indian Journal of Chemistry, 15B , 769-773 (1977)) (368 mg, 2 mmol) in anhydrous DMF (20 mL) was added sodium hydride (120 mg, 60% in oil, 3 mmol). The mixture was stirred for 1 hour at room temperature. A solution of 2-{(3R,4S)-4-[(tert butoxycarbonyl)amino]-3-methoxypiperidin- 1 -yl} ethyl methanesulfonate (Intermediate 39, -2 mmol) in DMF was then added at 0*C. The reaction mixture was stirred overnight at room temperature, and was then diluted with water and extracted three times with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated. Silica gel chromatography with hexanes/ethyl acetate (3:2) afforded 360 mg of a 3:1 mixture of the title compound and the 0-alkylation product. MS (ESP): 441 (MH*) for C 24

H

32

N

4 0 4 122 WO 2008/071961 PCT/GB2007/004766 Intermediate 95 Cis (±)1-[2-(4-amino-3-fluoropiperidin-1-yl)ethyll-4-methyl-2-oxo-1,2-dihydroquinoline-7 carbonitrile, trifluoroacetic acid salt Cis(±) tert-butyl {l-[2-(7-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl]-3-fluoropiperidin-4 yl}carbamate (Intermediate 96, 269 mg, 0.63 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 91 to give the crude product (200 mg). The title compound may be present in the form of a bis trifluoroacetic acid salt. MS (ESP): 329 (MH*) for C 18

H

2 1

FN

4 0 Intermediate 96 Cis(±) tert-butyl {l -[2-(7-cyano-4-methyl-2-oxoquinolin- 1(2H)-yl)ethyll-3-fluoropiperidin-4 yllcarbamate To a mixture of 4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile (V. N. Gogte, S.B. Kulkarni and B.D. Tilak, Indian Journal of Chemistry, 15B, 769-773 (1977)) (350 mg, 1.9 mmol) in anhydrous DMF (20 mL) was added sodium hydride (90 mg, 60% in oil, 2.2 mmol). The mixture was stirred for 1 hour at room temperature. A solution of cis(±) 2- {4-[(tert butoxycarbonyl)amino]-3-fluoropiperidin-1 -yl} ethyl methanesulfonate (Intermediate 21, -1.9 mmol) in DMF was then added at 0 0 C. The reaction mixture was stirred overnight at room temperature, and was then diluted with water and extracted three times with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated. Silica gel chromatography with hexanes/ethyl acetate (1:1) afforded 269 mg (33%) of the product as a tan solid. MS (ESP): 428 (MH*) for C 23

H

29

FN

4 0 3 Intermediate 97 1-(2-((3S,4R)-4-Amino-3-fluoropiperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7 carbonitrile, trifluoroacetic acid salt tert-Butyl (3S,4R)-1-(2-(7-cyano-2-oxoquinolin-l(2H)-yl)ethyl)-3-fluoropiperidin-4 ylcarbamate (Intermediate 98, 0.5 g, 1.21 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 91 to give the crude product in quantitative yield, which was used directly for next step. The title compound 123 WO 2008/071961 PCT/GB2007/004766 may be present in the form of a bis-trifluoroacetic acid salt. MS (ESP): 315 (MH*) for C 17

H

1 9

FN

4 0 Intermediate 98 tert-Butyl (3S,4R)-1-(2-(7-cyano-2-oxoquinolin-l(2H)-yl)ethyl)-3-fluoropiperidin-4 ylcarbamate A mixture of 2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 5, 0.5 g, 2.94 mmol) and 60 wt. % sodium hydride in mineral oil (0.176 g, 4.41 mmol) in DMF (50 mL) was stirred at room temperature under nitrogen for 1 hour. The solution was cooled to 0 'C and a solution of 2-((3S,4R)-4-(tert-butoxycarbonylamino)-3-fluoropiperidin-1 yl)ethylmethanesulfonate (Intermediate 99, 1 g, 2.94 mmol) in DMF (10 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. Silica gel chromatography (0% 75% ethyl acetate in hexanes) afforded the title compound as a tan solid, 0.55 g (45%). [a]D =+0.063 (c=0.2, DMSO). MS (ESP): 415 (MH*) for C 22

H

27

FN

4 0 3 Intermediate 99 2-((3S,4R)-4-(tert-Butoxycarbonylamino)-3-fluoropiperidin-1-yl)ethylmethanesulfonate The title compound was prepared from (3S,4R)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-3 fluoropiperidin-4-amine (Intermediate 100) using a procedure similar to the one described for the synthesis of Intermediate 21 from Intermediate 24. MS (ESP): 341 (MH*) for C 13

H

2 5

FN

2 0 5 S Intermediate 100 (3S,4R)-1-(2-tert-Butyldimethylsilyloxy)ethyl)-3-fluoropiperidin-4-amine A solution of benzyl (3S,4R)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-fluoropiperidin-4 ylcarbamate (Intermediate 101, 8 g, 19.48 mmol) in ethanol (100 ml) was hydrogenated on palladium on carbon (10%, activated, 1.037g) under normal pressure at room temperature overnight. The reaction mixture was filtered through a 0.45 pm membrane and solvent was evaporated under reduced pressure to afford the title compound as an oil (5g, 93%). MS (ESP): 277 (MH*) for C 13

H

29

FN

2 OSi 124 WO 2008/071961 PCT/GB2007/004766 1 H-NMR (CDCl 3 -d 6: 0.04 (s, 6H); 0.87 (s, 9H); 1.75 (in, 4H); 2.35 (in, 2H); 2.56 (in, 2H); 2.81 (in, 2H); 3.15 (in, 1H); 3.74 (in, 2H); 4.57 (in, 1 H). Intermediate 101 Benzyl (3S,4R)-1-(2-tert-butyldimethylsilyloxy)ethyl)-3-fluoropiperidin-4-ylcarbamate To a stirred mixture of benzyl (3S,4R)-3-fluoropiperidin-4-ylcarbamate hydrochloride (Intermediate 102, 5.9 g, 20.43 mmol) and cesium carbonate (33.3 g, 102.17 mmol) in acetonitrile (300 mL) at room temperature was added (2-bromoethoxy)(tert butyl)dimethylsilane (21.92 mL, 102.17 mmol). The reaction was stirred at 60 "C overnight. The reaction mixture was filtered through a fritted funnel and concentrated. Silica gel chromatography (0%-50% ethyl acetate in hexanes) afforded the title compound as a yellow oil, 8 g (95%). MS (ESP): 411 (MH*) for C 21

H

35

FN

2

O

3 Si Intermediate 102 Benzyl (3S,4R)-3-fluoropiperidin-4-ylcarbamate, hydrochloride salt To solution of (3S,4R)-tert-butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine- 1 carboxylate (Intermediate 103, 8 g, 22.7 mmol) in dichloromethane (200 mL) at 0 *C was added 4M hydrogen chloride in dioxane (11.35 mL, 45.4 mmol). The reaction mixture was allowed to warm to room temperature and stir overnight. Another equivalent of 4M hydrogen chloride in dioxane was added and the reaction was stirred for another 4 hours. The resulting white precipitate was collected by filtration and dried under reduced pressure to give the title compound (5.9 g, 90%). MS (ESP): 253 (MH*) for C 13

H

1 7

FN

2 0 2 Intermediate 103 (3S,4R)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate To a mixture of (3S,4R)-tert-butyl 4-amino-3-fluoropiperidine-l-carboxylate (prepared using the procedures described in PCT Pub. Nos. WO 2006087543 and W02007071965) (5.1 g, 23.37 mmol) in dioxane (150 ml) and saturated sodium carbonate (50 mL) at 0 *C was added benzyl chloroformate (5.00 ml, 35.05 mmol). After 15 minutes, the reaction mixture was diluted with ethyl acetate and saturated sodium chloride. The layers were separated and the organic extracts were dried over magnesium sulfate, filtered and evaporated. Silica gel 125 WO 2008/071961 PCT/GB2007/004766 chromatography (0%-50% ethyl acetate in hexanes) afforded the title compound as an off white solid, 8 g (97%). MS (ESP): 353 (MH) for C 18 H2 5

FN

2 0 4 'H-NMR (CDC1-d) 6: 1.44 (m, 9H); 1.73 (in, 2H); 2.80 (in, 2H); 3.60 (in, 1H); 4.30 (in, 2H); 4.65 (in, 1H); 5.06 (in, 1H); 5.09 (s, 2H); 7.34 (in, 5H). Intermediate 104 1- {2-[(3S,4R)-4-Amino-3-methoxypiperidin- 1 -yllethyl I -4-methyl-2-oxo- 1,2 dihydrocuinoline-7-carbonitrile, trifluoroacetic acid salt tert-Butyl {(3S,4R)-1-[2-(7-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl]-3 methoxypiperidin-4-yl}carbamate (Intermediate 105, 191 mg, 0.43 mmol) was reacted with trifluoroacetic acid using a procedure similar to the one described for the synthesis of Intermediate 91 to give the crude title compound in quantitative yield, which was used directly for next step. The title compound may be present in the form of the bis trifluoroacetic acid salt. MS (ESP): 341 (MH+) for C 19

H

24

N

4 0 2 Intermediate 105 tert-Butyl f(3S,4R)-1-[2-(7-cyano-4-methyl-2-oxoquinolin-1(2H)-yl)ethyll-3 methoxypiperidin-4-yllcarbamate To a solution of 4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile (V. N. Gogte, S.B. Kulkami and B.D. Tilak, Indian Journal of Chemistry, 15B_, 769-773 (1977)) (435 mg, 2.36 mmol) in anhydrous DMF (20 mL) was added sodium hydride (142 mg, 60% in oil, 3.54 mmol). The mixture was stirred for 1 hour at room temperature. A solution of 2- {(3S,4R)-4 [(tert-butoxycarbonyl)amino]-3-methoxypiperidin-1-yl} ethyl methanesulfonate (Intermediate 33, -2.8 mmol) in DMF was then added at 0 0 C. The reaction mixture was stirred overnight at room temperature, and was then diluted with water, and extracted three times with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated. Reverse phase chromatography with acetonitrile/water/ammonium acetate afforded the title compound as a light yellow solid after lyophilization (191 mg, 18%). MS (ESP): 441 (MH*) for C 24

H

32

N

4 0 4 126 WO 2008/071961 PCT/GB2007/004766 Intermediate 106 1-(2-((3R,4S)-4-Amino-3-fluoropiperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7 carbonitrile trifluoroacetate The title compound was prepared from tert-butyl (3R,4S)-4-(benzylamino)-3 fluoropiperidine-l-carboxylate (W02007071965 and W02006087543) by a process analogous to the sequence described for the racemic material (Intermediate 19), except for the following modification in the final step: The crude trifluoroacetic acid salt of the title compound was taken up in dichloromethane (100 mL) and washed once with saturated sodium bicarbonate (20 mL). The aqueous wash was adjusted to pH = 10 with 20% sodium hydroxide and extracted three times with dichloromethane (100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness to afford the title compound as an off-white solid, 352 mg (81%). MS (ESP): 315 (MH*) for C 1 7

H

1 9

FN

4 0 Example 1 1-(2-{(3R,4S)-4-r(2,3-Dihydror1,4]dioxinor2,3-clpyridin-7-ylmethyl)aminol-3 hydroxypiperidin- 1 -yll ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt A mixture of 1-f{2-[(3R,4S)-4-amino-3-hydroxypiperidin- 1 -yl]ethyl} -2-oxo- 1,2 dihydroquinoline-7-carbonitrile (Intermediate 1, 74 mg, 0.24 mmol) and 2,3 dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (39 mg, 0.24 mmol) was heated over freshly activated 3 A molecular sieves at 70 0 C for 3 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxy borohydride (150 mg, 0.75 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 pm membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (8:1 to 4:1). Fractions containing product were pooled and concentrated to dryness. The residue was taken up in dichloromethane/ diethyl ether (1:2, 10 mL) and HCl in diethyl ether (2M, ~0. 15 mL) was added. The mixture was concentrated to dryness under reduced pressure, codistilled two times with dichloromethane (2x 15 mL) and titurated from ether to give the title composition as a colorless solid, 91 mg (72%), mp >2 10 0 C. MS (ESP): 462 (MH*) for C 25

H

27

N

5 0 4 'H-NMR (DMSO-d 6 ) 5: 2.18 (m, 2H); 3.15 (in, 1H); 3.25-3.36 (in, 4H); 3.69 (in, 2H); 127 WO 2008/071961 PCT/GB2007/004766 4.10-4.49 (m, 7H); 4.61 (dd, 2H); 6.64 (brs, 1H); 6.83 (d, IH); 7.30 (s, 1H); 7.72 (d, 1H); 7.97 (d, 1H); 8.08 (d, 1H); 8.22 (m, 2H); 9.45 (brs, 2H); 10.00 (brs, 1H). Example 2 1-[2-((3R,4S)-3-Hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-bl[1,4]oxazin-6 yl)methyllamino}piperidin-1-yl)ethyll-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and Intermediate 1 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. 'H NMR (D 2 0) 6: (D 2 0) 2.28 (m, 2H); 3.15 (ddd, 1H); 3.26 (m, 1H); 3.40-3.72 (m, 4H); 3.91 (m, 1H); 4.28 (s, 2H); 4.52 (m, 1H); 4.61 (m, 1H); 4.71 (s, 2H); 4.80 (m, 1 H); 6.65 (d, 1H); 7.08 (d, 1H); 7.35 (d, 1H); 7.66 (d, 1H); 7.87 (d, 1H); 7.96 (s, 1H); 8.02 (d, 1H). ES (MH)*: 475 Example 3 1-r2-((3R,4S)-3-Hydroxy-4- { r(3-oxo-3,4-dihydro-2H-pyrido[3,2-bl[1,41thiazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) and Intermediate 1 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. 'H NMR (D 2 0) 5: (D 2 0) 2.31 (m, 2H); 3.20 (ddd, 1H); 3.31 (m, 1H); 3.40-3.80 (m, 4H); 3.55 (s, 2H); 3.95 (m, 1H); 4.34 (s, 2H); 4.55-4.70 (m, 2H); 4.82 (m, 1H); 6.84 (d, 1H); 7.11 (d, 1H); 7.66 (d, 1H); 7.80 (d, 1H); 7.87 (d, 1H); 7.96 (s, 1H); 8.03 (d, 1H). ES (MH)*: 491 Example 4 1-(2- f(3S,4R)-4-r(2,3-Dihydror 1,41dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 hydroxypiperidin-1-vlethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 2,3-Dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde and Intermediate 2 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the 128 WO 2008/071961 PCT/GB2007/004766 title composition. H NMR (DMSO-d 6 ) 6: 2.17 (m, 2H); 3.14 (m, 11H); 3.25-3.38 (m, 4H); 3.69 (m, 2H); 4.00-4.49 (m, 7H); 4.61 (dd, 2H); 6.62(brs, 1H); 6.83 (d, 1H); 7.25 (s, 1H); 7.72 (d, 1H); 7.97 (d, 1H); 8.06 (d, 1H); 8.20 (m, 2H); 9.39 (brs, 2H); 9.93 (brs, 1H). ES (MH)*: 462 Example 5 1-r2-((3S,4R)-3-Hydroxy-4-{f(3-oxo-3,4-dihydro-2H-pyridor3,2-bl[1,41oxazin-6 yl)methyllamino I piperidin- I -yl)ethyll-2-oxo- 1 2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde and Intermediate 2 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. H NMR (DMSO-d 6 ) : 2.20 (m, 2H); 3.19 (m, 1H); 3.25-3.48 (m, 4H); 3.71 (m, 2H); 4.19 (m, 2H); 4.55-4.65 (m, 3H); 4.69 (s, 2H); 6.63 (brs, 1H); 6.83 (d, 1H); 7.26 (d, 1H); 7.44 (d, 1H); 7.73 (d, 1H); 7.97 (d, 1H); 8.07 (d, 111); 8.24 (brs, 1H); 9.28 (m, 1H); 9.58 (m, 1H); 10.07 (m, 1H); 11.40 (m, 1H). ES (MH)*: 475 Example 6 I-[2-((3S,4R)-3-Hydroxy-4-{ [(3-oxo-3,4-dihydro-2H-pyrido[3,2-blr1,4]thiazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde and Intermediate 2 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. 'H NMR (DMSO-d6) 6: 2.21 (m, 2H); 3.20 m, 1H); 3.30-3.76 (m, 6H); 3.60 (s, 2H); 4.24 (m, 2H); 4.57-4.67 (m, 3H); 6.62 (d, 1H); 6.83 (d, 1H); 7.27 (d, 1H); 7.73 (d, 1H); 7.89 (d, 1H); 7.98 (d, 1H); 8.07 (d, 1H); 8.24 (m, 1H); 9.34 (m, 1H); 9.61 (m, 1H); 10.04 (m, 1H); 11.08 (s, 1H). ES (MH)*: 491 129 WO 2008/071961 PCT/GB2007/004766 Example 7 1-(2-{(3R,4S)-4-[(2,3-Dihydro[ 1,41dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 hydroxypiperidin-1-ylethyl)-7-methoxyquinoxalin-2(lH)-one, bis hydrochloride salt 2,3-Dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde and Intermediate 11 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. H NMR (D 2 O) 6: 2.28 (m, 2H); 3.20 (ddd, 111); 3.31 (m, 1H); 3.45-3.76 (m, 4H); 3.92 (s, 3H); 3.99 (m, 1H); 4.29-4.62 (m, 8H); 4.83 (m, 1H); 6.93 (m, 1H); 7.12 (m, 1H); 7.22 (d, 1H); 7.81 (dd, 1H); 8.06 (d, 1H); 8.19 (d, 1H). ES (MH)*: 468 Example 8 6-[({(3R,4S)-3-Hydroxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 ylamino)methyll-2H-pyridor3,2-bl[1,41oxazin-3(4H)-one, bis hydrochloride salt 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde and Intermediate 11 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. 'H NMR (DMSO-d 6 ) 5: 2.19 (m, 2H); 3.19 (m, 1H); 3.30-3.48 (m, 4H); 3.62-3.83 (m, 2H): 3.96 (s, 3H); 4.18 (m, 2H); 4.54-4.76 (m, 3H); 4.69 (s, 2H); 6.54 (m, 1H); 7.04 (dd, 1H); 7.21 (d, 1H); 7.26 (d, 1H); 7.44 (d, 1H); 7.79 (d, 1H); 8.09 (s, 1H); 9.28 (m, 1H); 9.61 (m, I1H); 10.26 (m, I1H); 11.41 (s, I1H). ES (MH)*: 481 Example 9 6-[({(3R,4S)-3-Hydroxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 ylamino)methyll-2H-pyrido[3,2-b][1,41thiazin-3(4H)-one, bis hydrochloride salt 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde and Intermediate 11 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. 'H NMR (DMSO-d 6 ) 8: 2.19 (m, 2H); 3.17 (m, 1H); 3.25-3.70 (m, 6H); 3.59 (s, 2H); 3.96 (s, 3H); 4.23 (m, 2H); 4.55-4.67 (m, 3H); 6.53 (d, 111); 7.04 (dd, 1H); 7.20 (d, 1H); 7.27 (d, 1H); 7.79 (d, 111); 7.90 (d, 1H); 8.09 (s, 1H); 9.30 (m, 1H); 9.60 (m, 1H); 10.21 (m, I1H); 11.08 (s, I H). 130 WO 2008/071961 PCT/GB2007/004766 ES (MH)*: 497 Example 10 1-(2-{(3S,4R)-4-r(2,3-Dihydror 1,4]dioxinor2,3-clpyridin-7-ylmethyl)aminol-3 hydroxypiperidin- 1 -yll ethyl)-7-methoxyquinoxalin-2(l H)-one, bis hydrochloride salt 2,3-Dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde and Intermediate 12 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. 'H NMR (DMSO-d 6 ) 6: 2.18 (in, 2H); 3.16 (m, 1H); 3.26-3.40 (in, 4H); 3.65-3.74 (in, 2H); 3.96 (s, 3H); 4.26-4.43 (in, 7H); 4.62 (dd, 2H); 6.55 (in, 1H); 7.04 (dd, 1H); 7.19 (d, 1H); 7.36 (s, 1H); 7.79 (d, 1H); 8.08 (s, 1H); 8.26 (s, 1H); 9.51 (m, 2H); 10.18 (in, 1H). ES (MH)*: 468 Example 11 6-(({(3S,4R)-3-Hydroxy-1-[2-(7-methoxy-2-oxoguinoxalin-1(2H)-yl)ethyllpiperidin-4 yl}amino)methyll-2H-pyrido(3,2-blr1,41oxazin-3(4H)-one, bis hydrochloride salt 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde and Intermediate 12 were reacted using a procedure similar to the one described for the synthesis of Example 1, providing the title composition. ' H NMR (D2O) 6: 2.28 (in, 2H); 3.17 (ddd, 1H); 3.27 (in, 111); 3.51-3.75 (m, 4H); 3.91 (s, 3H); 3.99 (in, 1H); 4.28 (in, 2H); 4.50-4.62 (m, 2H); 4.71 (s, 2H); 4.80 (m, 1H); 6.90 (d, 1H); 7.08 (d, 1H); 7.11 (dd, IH); 7.34 (d, 1H); 7.79 (d, 1H); 8.05 (s, 1H). ES (MH)*: 481 Example 12 1-(2-{(3S,4R)-4-[(2,3-Dihydrof l,41dioxinor2,3-clpyridin-7-ylmethyl)aminol-3 fluoropiperidin- 1-yl} ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, monoacetic acid salt and 131 WO 2008/071961 PCT/GB2007/004766 Example 13 1-(2-f(3R,4S)-4-[(2,3-Dihydro[1,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 fluoropiperidin- 1 -ylI ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, monoacetic acid salt Cis(±) 1-[2-(4-amino-3-fluoropiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile (Intermediate 19, 0.95 mmol) was suspended in chloroform/methanol (1:1, 20 mL) and free based by dropwise addition of NN-diisopropylethylamine until all material was solubilized. This was then subjected to reductive amination with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine 7-carbaldehyde (160 mg, 0.95 mmol) and sodium triacetoxyborohydride (600 mg, 2.8 mmol) using a procedure similar to the one described for the synthesis of Example 1. The residue obtained after filtration was taken up in dichloromethane and saturated sodium bicarbonate. The pH of the aqueous phase was adjusted to pH-10 with 1M sodium hydroxide solution. The aqueous phase was back extracted with dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated. Reverse phase chromatography with water/acetonitrile/ammonium acetate afforded the product as a tan foam, 276 mg (62%). 'H-NMR (CDCl-d) 5: 1.86 (m, 2H); 2.34 (m, 3H); 2.71 (m, 2H); 2.82 (m, 1H); 3.03 (m, 1H); 3.30 (m, 1H); 3.93 (m, 2H); 4.30 (m, 4H); 4.42 (m, 2H); 4.90 (m, 1H); 6.80 (d, 1H); 6.90 (s, 1H); 7.45 (d, 1H); 7.65 (m, 2H); 7.78 (s, 1H); 8.09 (s, 1H). MS (ESP): 464 (MH+) for C 25

H

2 6

FN

5 0 3 The racemic mixture was separated on a Chiralpak AD, 250 x 20mm, 10p column (50% methanol, 50% ethanol, 0.1% diethylamine). Example 12 eluted first, [a]D = + 14.3 (c=0.3, methanol) (89 mg), followed by Example 13, [a]D = -11.6 (c=0.328, methanol) (80 mg). Example 14 1-(2- f(3S,4R)-4-r(2,3-Dihydro[ 1,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 methoxypiperidin-1-yllethyl)-7-methoxyquinoxalin-2(lH)-one, bis-hydrochloride salt A mixture of 1- {2-[(3S,4R)-4-amino-3-methoxypiperidin- I -yl]ethyl } -7-methoxyquinoxalin 2(1H)-one (Intermediate 31, 160 mg crude, 0.48 mmol) and 2,3-dihydro[1,4]dioxino[2,3 c]pyridine-7-carbaldehyde (80 mg, 0.48 mmol) in dry methanol/chloroform (1:1, 10 mL) was heated under nitrogen over 3 A molecular sieves for one hour at 70 "C. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (310 mg, 1.44 mmol) was added. After 30 min, the reaction was filtered through celite. The filtrate was concentrated to dryness, taken up in 15% methanol in chloroform, and washed with saturated 132 WO 2008/071961 PCT/GB2007/004766 sodium bicarbonate solution. The aqueous phase was re-extracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel with a gradient of 2-5% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 160 mg (70%) of the free base of the title composition as an oil. This was taken up in dichloromethane/ diethyl ether (1:1, 5 mL) and treated with 2.0 M HCl in ether (-2 eq). The resulting precipitate was collected by filtration, reconstituted in water and lyophilized to give 148 mg of the of the title composition as a solid. 'H NMR (D 2 0) 5: 2.04-2.33 (in, 2H); 3.05-3.25 (in, 2H); 3.44 (s, 3H); 3.50-3.71 (in, 3H); 3.87 (s, 3H); 4.04 (s, 1H); 4.21 (d, 3H); 4.26-4.32 (in, 3H); 4.33-4.40 (in, 2H); 4.45-4.58 (in, 1H); 4.74-4.87 (in, 1H); 6.82-6.92 (in, 1H); 7.02-7.12 (in, 2H); 7.75 (d, 1H); 8.01 (s, 1H); 8.09 (s, 1H). MS (ESP): 482 (MH*) for C 25

H

31

N

5 0 5 Example 15 6-[({(3S,4R)-3-Methoxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yllamino)methyll-2H-pyridor3,2-blr1,41oxazin-3(4H)-one 1- {2-[(3S,4R)-4-amino-3-methoxypiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one (Intermediate 31, 160 mg crude, 0.48 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (85 ing, 0.48 mmol) and sodium triacetoxy borohydride (310 mg, 1.44 mmol) were reacted as described for Example 14 (except for the hydrochloride salt preparation) to give 139 mg (58%) of the title composition. 'H NMR (DMSO-d 6 ) 6: 1.36-1.53 (in, 1H); 1.59-1.77 (in, 1H); 2.24-2.37 (in, 1H); 2.40 2.46 (in, 1H); 2.60 (t, 2H); 2.65-2.84 (in, 2H); 3.14-3.21 (in, 3H); 3.30 - 3.34 (in, 2H); 3.67 (q, 2H); 3.92 (s, 3H); 4.22-4.45 (in, 2H); 4.61 (s, 2H); 6.92-7.10 (in, 3H); 7.30 (d, 111); 7.75 (d, 1H); 8.04 (s, 1H); 11.15-11.27 (in, 1H). MS (ESP): 495 (MH+) for C 25

H

30

N

6 0 5 Example 16 1-(2- f(3R,4S)-4-[(2,3-Dihydro[ 1,41dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 methoxypiperidin-1-yllethyl)-7-methoxyquinoxalin-2(lH1)-one, bis-hydrochloride salt 1- {2-[(3R,4S)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2( 1H)-one (Intermediate 37, 37 mg, 0.11 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7 133 WO 2008/071961 PCT/GB2007/004766 carbaldehyde (WO 2004/058144) (18 mg, 0.11 mmol) and sodium triacetoxy borohydride (70 mg, 0.33 mmol) were reacted as described according to Example 14 to give 29 mg of the title composition as a colorless solid. 1H NMR (D 2 0) 6: 2.17-2.30 (in, 2H); 3.12-3.24 (m, 2H); 3.49 (s, 3H); 3.56-3.75 (in, 3H); 3.92 (s, 3H); 4.09 (s, 1H); 4.25 (d, 2H); 4.34 (dd, 2H); 4.41 (dd, 2H); 4.52-4.70 (m, 2H); 4.79-4.93 (m, 2H); 6.93 (d, 1H); 7.08-7.16 (m, 2H); 7.82 (d, 1H); 8.07 (s, 1H); 8.13 (s, 1H). MS (ESP): 482 (MH) for C 25

H

31

N

5 0 5 Example 17 6-[({(3R,4S)-3-Methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyllpiperidin-4 yllamino)methyll-2H-pyrido[3,2-blrl,41oxazin-3(4H)-one 1- {2-[(3R,4S)-4-Amino-3-methoxypiperidin- I -yl]ethyl } -7-methoxyquinoxalin-2(l H)-one (Intermediate 37, 37 mg crude, 0.11 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (20 mg, 0.11 mmol) and sodium triacetoxy borohydride (70 mg, 0.33 mmol) were reacted as described for Example 14 (except for the hydrochloride salt preparation) to give 34 ing (63%) of the title composition. 1H NMR (DMSO-d6) 6: 1.39-1.53 (m, 1H); 1.59-1.77 (m, 1H); 2.29 (d, 1H); 2.38-2.47 (m, 1H); 2.60 (t, 2H); 2.65-2.85 (in, 3H); 3.13-3.22 (m, 3H); 3.30 - 3.34 (in, 2H); 3.58-3.78 (in, 2H); 3.92 (s, 3H); 4.24-4.44 (m, 2H); 4.61 (s, 2H); 6.93-7.07 (in, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.04 (s, 1H); 11.20 (s, 1H). MS (ESP): 495 (MH) for C 25

H

30

N

6 0 5 Example 18 6-f({(3R,4S)-3-Methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yllethyllpiperidin-4 yl amino)methyll-2H-pyrido[3,2-blr1,41thiazin-3(4H)-one, bis-hydrochloride salt 1- {2-[(3R,4S)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one (Intermediate 37, 70 mg crude, 0.21 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (40 mg, 0.21 mmol) and sodium triacetoxy borohydride (130 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 to give 73 mg of the title composition as an off-white solid. 'H NMR (D2O) 8: 2.13-2.28 (in, 2H); 3.03-3.21 (m, 2H); 3.41-3.46 (m, 3H); 3.50 (s, 2H); 134 WO 2008/071961 PCT/GB2007/004766 3.52-3.72 (m, 4H); 3.86 (s, 3H); 4.08 (s, 1H); 4.19-4.35 (m, 3H); 4.44-4.59 (m, 1H); 4.74 4.88 (m, 1H); 6.86 (d, 1 H); 7.01-7.10 (m, 2H); 7.70-7.79 (m, 2H); 8.01 (s, 1H). MS (ESP): 511 (MH*) for C 25

H

30

N

6 0 4 S Example 19 1-(2-{(3S,4R)-4-r(2,3-Dihydro[1,4]dioxinor2,3-clpyridin-7-ylmethyl)aminol-3 methoxypiperidin-1-ylethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis-hydrochloride salt 1- {2-[(3S,4R)-4-amino-3-methoxypiperidin- I -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile (Intermediate 41, 93 mg, 0.29 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7 carbaldehyde (WO 2004/058144) (47 mg, 0.29 mmol) and sodium triacetoxy borohydride (180 mg, 0.86 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 to give 95 mg of the title composition as a colorless solid. H NMR (D2O) 6: 2.14-2.33 (m, 2H); 3.12-3.27 (m, 2H); 3.42-3.49 (m, 3H); 3.54-3.62 (m, 2H); 3.63-3.76 (m, 2H); 4.09 (s, 1H); 4.25 (d, 1H); 4.32-4.39 (m, 4H); 4.43-4.50 (m, 2H); 4.50-4.65 (m, 1H); 4.83 (d, 1H); 6.80 (d, 1H); 7.29 (s, 1H); 7.61 (dd, 1H); 7.82 (d, 1H); 7.91 (s, 1H); 7.97 (d, 1H); 8.22 (s, 1H). MS (ESP): 476 (MH*) for C 26

H

29

N

5 0 4 Example 20 1-r2-((3S,4R)-3-Methoxy-4-{r(3-oxo-3,4-dihydro-2H-pyridor3,2-blr1,4]oxazin-6 yl)methyllaminoIpiperidin-1-yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile 1- {2-[(3S,4R)-4-amino-3-methoxypiperidin- 1 -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile (Intermediate 41, 93 mg, 0.29 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (51 mg, 0.29 mmol) and sodium triacetoxy borohydride (180 mg, 0.86 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 (except for the hydrochloride salt preparation) to give 80 mg (57%) of the title compound as an off white solid. 'H NMR (DMSO-d6) 8: 1.36-1.51 (m, 1H); 1.59-1.75 (m, 1H); 2.23-2.37 (m, 1H); 2.56 (t, 2H); 2.60-2.80 (m, 3H); 3.17 (s, 3H); 3.26-3.32 (m, 2H); 3.68 (q, 2H); 4.25-4.45 (m, 2H); 4.61 (s, 2H); 6.78 (d, 1H); 6.99 (d, I H); 7.29 (d, 1H); 7.65 (dd, 1H); 7.91 (d, 1H); 8.00 (d, 1H); 8.10 (s, 1H); 11.20 (s, 1H). MS (ESP): 489 (MH*) for C 26

H

28

N

6 0 4 135 WO 2008/071961 PCT/GB2007/004766 Example 21 1-[2-((3S,4R)-3-Methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyridor3,2-blr1,4]thiazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll -2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 1-{2-[(3S,4R)-4-Amino-3-methoxypiperidin-1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 carbonitrile (Intermediate 41, 93 mg, 0.29 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (55 mg, 0.29 mmol) and sodium triacetoxy borohydride (180 mg, 0.86 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 to give 68 mg of the title composition as a yellow solid. 'H NMR (D 2 0) 6: 2.14-2.27 (in, 2H); 3.00-3.15 (in, 2H); 3.44 (s, 3H); 3.47-3.53 (in, 4H); 3.57-3.70 (in, 2H); 4.05 (s, 1H); 4.12-4.21 (in, 1H); 4.27 (d, 2H); 4.47-4.64 (in, 1H); 4.72 4.86 (in, IH); 6.80 (d, 1H); 7.05 (d, 1H); 7.61 (dd, lH); 7.75 (d, lH); 7.82 (d, lH); 7.91 (s, 1H); 7.97 (d, lH). MS (ESP): 505 (MH*) for C 26

H

28

N

6 0 3 S Example 22 1-(2-{(3R,4S)-4-[(2,3-Dihydror 1,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 methoxypiperidin- 1 -yll ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis-hydrochloride salt 1- {2-[(3R,4S)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile (Intermediate 43, 80 mg, 0.25 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7 carbaldehyde (WO 2004/058144) (41 mg, 0.25 mmol) and sodium triacetoxy borohydride (160 mg, 0.74 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 to give 69 mg of the title composition as an off-white solid. 'H NMR (DO) 6: 2.14-2.30 (m, 2H); 3.12-3.25 (in, 2H); 3.41-3.48 (in, 3H); 3.54-3.62 (m, 2H); 3.63-3.74 (in, 2H); 4.08 (s, 1H); 4.26 (s, 1H); 4.30-4.38 (in, 4H); 4.40-4.47 (in, 2H); 4.53-4.66 (in, 1H); 4.75-4.90 (in, 1H); 6.80 (d, 1H); 7.24 (s, 1H); 7.62 (dd, IH); 7.83 (d, 1 H); 7.92 (s, 1H); 7.98 (d, 1H); 8.19 (s, 1H). MS (ESP): 476 (MH*) for C 26

H

29

N

5 0 4 136 WO 2008/071961 PCT/GB2007/004766 Example 23 1-[2-((3R,4S)-3-Methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,41oxazin-6 yl)methyllamino I piperidin- 1 -yl)ethyll -2-oxo- 1,2-dihydroquinoline-7-carbonitrile 1-{2-[(3R,4S)-4-Amino-3-methoxypiperidin-1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 carbonitrile (Intermediate 43, 80 mg, 0.25 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (45 mg, 0.25 mmol) and sodium triacetoxy borohydride (160 mg, 0.74 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 (except for the hydrochloride salt preparation) to give 62 mg (55% yield) of the title compound as an off white solid. 1 H NMR (DMSO-d6) 8: 1.36-1.51 (m, 1H); 1.61-1.74 (m, 1H); 2.23-2.36 (m, 1H); 2.58 (t, 2H); 2.61-2.85 (m, 3H); 3.13-3.21 (m, 3H); 3.26-3.32 (m, 2H); 3.58-3.78 (m, 2H); 4.30 4.45 (m, 2H); 4.61 (s, 2H); 6.78 (d, LH); 7.00 (d, 1H); 7.30 (d, 1H); 7.65 (dd, 1H); 7.91 (d, 1H); 8.00 (d, 1H); 8.07-8.13 (m, 1H); 11.21 (s, 1H). MS (ESP): 489 (MH*) for C 26

H

28

N

6 0 4 Example 24 1-[2-((3R,4S)-3-Methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b]l 1,41thiazin-6 yl)methyllaminolpiperidin-1-yl)ethyll-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 1-{2-[(3R,4S)-4-Amino-3-methoxypiperidin-1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 carbonitrile (Intermediate 43, 80 mg, 0.25 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (48 mg, 0.25 mmol) and sodium triacetoxy borohydride (160 mg, 0.74 mmol) were reacted as described for Example 14 to give 56 mg of the title composition as an off white solid. 'H NMR (D 2 0) 6: 2.10-2.24 (m, 2H); 2.89-3.13 (m, 2H); 3.38-3.46 (m, 5H); 3.48-3.52 (m, 2H); 3.53-3.68 (m, 2H); 4.04 (s, 1H); 4.11 (d, 1H); 4.27 (d, 2H); 4.49-4.62 (m, 1H); 4.73 4.84 (m, 1H); 6.79 (d, lH); 7.05 (d, 1H); 7.61 (dd, IH); 7.75 (d, I H); 7.82 (d, 1H); 7.91 (s, 1H); 7.97 (d, IH). MS (ESP): 505 (MH*) for C 26

H

28

N

6 0 3 S 137 WO 2008/071961 PCT/GB2007/004766 Example 25 1-(2- f(3S,4S)-4-r(2,3-Dihydror 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)aminol-3 methoxypiperidin-1-yl ethyl)-7-methoxyquinoxalin-2(111)-one, bis-hydrochloride salt 1- {2-[(3S,4S)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one (Intermediate 48, 70 mg, 0.21 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7 carbaldehyde (WO 2004/058144) (35 mg, 0.21 mmol) and sodium triacetoxy borohydride (130 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 14 to give 61 mg of the title composition as a yellow solid. 'H NMR (D2O) 6: 1.83-2.02 (in, 1H); 2.37-2.50 (in, LH); 2.90-3.06 (in, lH); 3.08-3.23 (in, 1H); 3.33-3.48 (in, 4H); 3.55-3.70 (in, 3H); 3.73-3.81 (in, LH); 3.87 (s, 3H); 4.16-4.26 (in, 1H); 4.32-4.39 (in, 4H); 4.43-4.51 (in, 2H); 4.60 - 4.80 (in, 2H); 6.87 (d, 1H); 7.07 (dd, 1H); 7.27 (s, 1H); 7.76 (d, IH); 8.01 (s, 1H); 8.20 (s, 1H). MS (ESP): 482 (MH*) for C 25

H

31

N

5 0 5 Example 26 6-[({(3S,4S)-3-Methoxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 ylPamino)methyll-2H-pyridor3,2-br1,4]oxazin-3(4H)-one 1-{2-[(3S,4S)-4-Amino-3-methoxypiperidin-1-yl]ethyl}-7-methoxyquinoxalin-2(lH)-one (Intermediate 48, 70 mg, 0.21 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6 carbaldehyde (WO 2004/058144) (37 mg, 0.21 mmol) and sodium triacetoxy borohydride (130 mg, 0.63 mmol) were reacted as described for Example 14 (except for the hydrochloride salt preparation). The crude product was subjected to flash chromatography eluting with a gradient of 0-10% methanol/dichloromethane to give 62 mg (62%) of the title compound, [cC]D = -19.5 (methanol, c=0.58). H NMR (DMSO-d 6 ) 6: 1.04-1.23 (in, 1H); 1.76 (t, 1H); 1.81-1.91 (in, 1H); 1.93-2.07 (in, 1H); 2.18-2.42 (in, 1H); 2.61 (t, 2H); 2.79-2.99 (in, 2H); 3.20 - 3.30 (in, 4H); 3.54-3.75 (in, 2H); 3.91 (s, 3H); 4.25-4.43 (in, 2H); 4.59 (s, 2H); 6.90-7.06 (in, 3H); 7.27 (d, 1H); 7.74 (d, 1H); 8.02-8.06 (in, 1H); 11.18 (s, 1H). MS (ESP): 495 (MH*) for C 25

H

30

N

6 0 5 138 WO 2008/071961 PCT/GB2007/004766 Example 27 1-(2-{(3R,4R)-4-[(2,3-Dihydro[1,4]dioxinor2,3-clpyridin-7-ylmethyl)aminol-3 methoxypiperidin-1-yl ethyl)-7-methoxyquinoxalin-2(lH)-one, bis-hydrochloride salt 1-{2-[(3R,4R)-4-Amino-3 -methoxypiperidin- 1 -yl]ethyl } -7-methoxyquinoxalin-2(l H)-one (Intermediate 56, 75 mg, 0.23 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7 carbaldehyde (WO 2004/058144) (37 mg, 0.23 mmol) and sodium triacetoxy borohydride (150 mg, 0.69 mmol) were reacted as described for Example 14 to give the title composition (63 mg) as a yellow solid. 'H NMR (DQ) 8: 1.81-2.02 (m, 1H); 2.34-2.52 (m, 1H); 2.92-3.05 (m, 1H); 3.10-3.23 (m, 1H); 3.37-3.49 (m, 4H); 3.54-3.72 (m, 3H); 3.73-3.82 (m, 1H); 3.85-3.90 (m, 3H); 4.22 (d, 1H); 4.29-4.41 (m, 4H); 4.43-4.51 (m, 2H); 4.60 - 4.80 (m, 2H); 6.83-6.91 (m, 1H); 7.07 (dd, 1H); 7.26-7.31 (m, 1H); 7.74 (d, 1H); 7.97-8.03 (m, 1H); 8.17-8.26 (m, 1H). MS (ESP): 482 (MH*) for C 25

H

31

N

5 0 5 Example 28 6-[({(3R,4R)-3-Methoxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yl amino)methyll-2H-pyrido[3,2-b]r1,4]oxazin-3(4H)-one 1- {2-[(3R,4R)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one (Intermediate 56, 75 mg, 0.23 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6 carbaldehyde (WO 2004/058144) (40 mg, 0.23 mmol) and sodium triacetoxy borohydride (150 mg, 0.69 mmol) were reacted as described for Example 14 (except for the hydrochloride salt preparation) to give 73 mg (66%) of the title compound, [a]D = +17.5 (methanol, c=0.56). 'H NMR (DMSO-d6) 8: 1.04-1.22 (m, 1H); 1.78 (t, 1H); 1.83-1.93 (m, 1H); 2.00 (m, 1H); 2.22-2.35 (m, IH); 2.62 (t, 2H); 2.81-3.00 (m, 2H); 3.20 - 3.30 (m, 4H); 3.56-3.78 (m, 2H); 3.92 (s, 3H); 4.26-4.44 (m, 2H); 4.61 (s, 2H); 6.92-7.08 (m, 3H); 7.29 (d, 1H); 7.75 (d, 1H); 8.05 (s, 1H); 11.21 (s, 1H). MS (ESP): 495 (MH*) for C 25

H

30

N

6 0 5 Example 29 1-(2- 4-[(2,3-Dihydro[ 1,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3-hydroxypiperidin- 1 yllethyl)-7-methoxyquinoxalin-2(lH)-one, trans enantiomer A, bis hydrochloride salt 1-{2-[4-Amino-3-hydroxypiperidin-1-yl]ethyl}-7-methoxyquinoxalin-2(1H)-one, trans 139 WO 2008/071961 PCT/GB2007/004766 enantiomer A (Intermediate 57, 39 mg, 0.12 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine 7-carbaldehyde (WO 2004/058144) (20 mg, 0.12 mmol) and sodium triacetoxy borohydride (76 mg, 0.36 mmol) were reacted as described for Example 14 to give the title composition as a yellow solid (39 mg). 'H NMR (D2O) 6: 1.82-2.00 (m, 1H); 2.48 (dd, 1H); 3.01 (t, 1H); 3.08-3.21 (in, 1H); 3.30 3.44 (m, 1H); 3.58 (t, 2H); 3.79-3.95 (in, 5H); 3.97-4.09 (m, 1H); 4.30-4.50 (m, 6H); 4.65 (t, 2H); 6.87 (d, 1H); 7.07 (dd, 1H); 7.28 (s, IH); 7.76 (d, 1H); 8.01 (s, IH); 8.20 (s, 1H). MS (ESP): 468 (MH) for C 24 11 29

N

5 0 5 Example 30 6-[ (3-Hydroxy- 1 -r2-(7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)ethyllpiperidin-4 yllamino)methyll-2H-pyridor3,2-b]r1,4]oxazin-3(4H)-one, trans enantiomer A 1-{2-[4-amino-3-hydroxypiperidin-1-yl]ethyl}-7-methoxyquinoxalin-2(1H)-one, trans enantiomer A (Intermediate 57, 39 mg, 0.12 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (21 mg, 0.12 mmol) and sodium triacetoxy borohydride (76 mg, 0.36 mmol) were reacted as described for Example 14 (except for the hydrochloride salt preparation) to give 49 mg (84%) of the title compound. 'H NMR (DMSO-d6) 6: 1.09-1.26 (m, 1H); 1.94 (t, 2H); 2.04 (t, 1H); 2.20 - 2.35 (m, 1H); 2.64 (t, 2H); 2.88-3.10 (m, 2H); 3.18-3.32 (in, 111); 3.63-3.87 (in, 2H); 3.98 (s, 3H); 4.39 (t, 211); 4.67 (s, 2H); 4.90 (d, 1H); 6.99-7.11 (m, 3H); 7.36 (d, 1H); 7.81 (d, 111); 8.10 (s, IH); 11.27 (s, 1H). MS (ESP): 481 (MH*) for C 24

H

28

N

6 0 5 Example 31 1-(2-{4-[(2,3-dihydro[1,41dioxinor2,3-cpyridin-7-ylmethyllaminol-3-hydroxypiperidin-1 yllethyl)-7-methoxyguinoxalin-2(1H)-one, trans enantiomer B, bis-hydrochloride salt 1- {2-[4-amino-3-hydroxypiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer (Intermediate 65, 42 mg, 0.13 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7 carbaldehyde (WO 2004/058144) (22 mg, 0.13 mmol) and sodium triacetoxy borohydride (83 mg, 0.39 mmol) were reacted as described for Example 14 to give 45 mg of the title composition as a yellow solid. 'H NMR (D 2 O) 6: 1.82-1.99 (m, 1H); 2.42-2.53 (in, 1H); 3.01 (t, 1H); 3.08-3.20 (in, 1H); 3.32-3.44 (in, 1H); 3.58 (t, 2H); 3.80-3.95 (m, 5H); 3.96-4.09 (m, 1H); 4.32-4.50 (in, 6H); 140 WO 2008/071961 PCT/GB2007/004766 4.65 (t, 211); 6.87 (d, 1H); 7.07 (dd, 1H); 7.29 (s, 1H); 7.76 (d, 1H); 8.00 (s, 111); 8.21 (s, 1H). MS (ESP): 467 (MH*) for C2 4

H

29

N

5 0 5 Example 32 6-[({3-Hydroxy-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yliamino)methyll-2H-pyridor3,2-blr1,4]oxazin-3(4H)-one, trans enantiomer B 1- {2-[4-Amino-3-hydroxypiperidin- I -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer (Intermediate 65, 42 mg, 0.13 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (24 mg, 0.13 mmol) and sodium triacetoxy borohydride (83 mg, 0.39 mmol) were reacted as described for Example 14 (except for the hydrochloride salt preparation) to give 42 mg (68% yield) of the title compound. 'H NMR (DMSO-d6j 5: 1.02-1.21 (in, 111); 1.88 (t, 2H); 1.98 (t, 1H); 2.15-2.31 (in, 11-1); 2.59 (t, 2H); 2.84-3.03 (in, 2H); 3.13-3.25 (in, 1H); 3.58-3.80 (in, 2H); 3.92 (s, 3H); 4.32 (t, 2H); 4.61 (s, 2H); 4.84 (d, 1H); 6.94-7.05 (in, 3H); 7.30 (d, LH); 7.68-7.79 (in, 1H); 8.04 (s, IH); 11.16-11.29 (m, 1H). MS (ESP): 481 (MH*) for C 24

H

28

N

6 0 5 Example 33 1-(2- {4-r(2,3-Dihydro[1,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3-fluoropiperidin- 1 ylI ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A, bis-hydrochloride salt A mixture of 1-{2-[4-amino-3-fluoropiperidin-1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 carbonitrile, trans enantiomer A (Intermediate 67, crude, 150 mg, 0.48 mmol) and 2,3 dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (80 mg, 0.48 mmol) in dry methanol/chloroform (1:1, 20 mL) was heated under nitrogen over 3 A molecular sieves for one hour at 70 "C. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (300 mg, 1.43 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness. The crude product was taken up in 15% methanol/chloroform and washed with saturated sodium bicarbonate solution. The aqueous phase was re-extracted once with 15% methanol/chloroform. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel with 141 WO 2008/071961 PCT/GB2007/004766 a gradient of 0-5% methanol in dichloromethane gave 66 mg (26%) of the free base of the title composition as an oil. This was taken up in 1:1 dichloromethane/diethyl ether (5 mL) and treated with 1.0 M HC1 in ether (-2 eq) resulting in a precipitate. This mixture was concentrated to dryness. The resulting solid was reconstituted in water and lyophilized to give 66 mg of the title composition. IH NMR (D20) 6 ppm: 1.81-1.94 (m, 1H); 2.30-2.43 (m, 1H); 3.13-3.26 (m, 1H); 3.32-3.42 (m, 1H); 3.42-3.50 (m, 1H); 3.53 (t, 2H); 3.57-3.66 (m, 1H); 3.79-3.93 (m, 1H); 4.11-4.27 (m, 2H); 4.38-4.43 (m, 2H); 4.50-4.56 (m, 2H); 4.62-4.75 (m, 1H); 4.80-4.88 (m, 1H); 4.85 (m, 1H) 6.85 (d, 1H); 7.25 (s, 1H); 7.68 (dd, 1H); 7.89 (d, 1H); 7.98 (s, 1H); 8.03 (d, 1H); 8.20 (s, IH). MS (ESP): 464 (MH*) for C2 5

H

26

FN

5 0 3 Example 34 1-[2-((3-Fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-bl[1,4]oxazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A 1- {2-[4-Amino-3-fluoropiperidin- 1 -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A (Intermediate 67, 150 mg, 0.48 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (85 mg, 0.48 mmol), and sodium triacetoxyborohydride (300 mg, 1.43 mmol) were reacted as described for Example 33 (except for the hydrochloride salt preparation) to give 70 mg (30%) the title composition. [a]D = -12.4 (methanol, c=0.5). 'H NMR (DMSO-d 6 ) 8 ppm: 1.21 (m, 1H); 1.84-1.95 (m, 1H); 2.04-2.21 (m, 2H); 2.30-2.41 (m, 1H); 2.57-2.67 (m, 2H); 2.78-2.87 (m, 1H); 3.18-3.29 (m, LH); 3.73 (s, 2H); 4.29 (m, 1H); 4.29-4.46 (m, 2H); 4.61 (s, 2H); 6.78 (d, 1H); 7.01 (d, 1H); 7.30 (d, 1H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, 1H); 8.11 (s, 1H); 11.19 (s, 1H). MS (ESP): 477 (MH*) for C 25

H

25

FN

6 0 3 Examples 35 to 40 were purified by reverse phase HPLC on a Waters XBridge C-18 column eluting with 5-50% water/acetonitrile with ammonium acetate buffer (pH = 8). 142 WO 2008/071961 PCT/GB2007/004766 Example 35 1-(2-{4-r(2,3-Dihydro[1,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3-fluoropiperidin- 1 ylIethyl)-7-methoxyquinoxalin-2(1H)-one, trans enantiomer A, bis hydrochloride salt 2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridine-7-carbaldehyde and 1- {2-[4-Amino-3 fluoropiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(1H)-one, trans enantiomer A (Intermediate 77) were reacted using a procedure similar to the one described for the synthesis of Example 33, providing the title composition. 'H NMR (D2O) 6 ppm: 1.81-1.97 (m, 1H); 2.32-2.45 (m, 1H); 3.20-3.32 (m, 1H); 3.35-3.44 (m, 1H); 3.52-3.72 (m, 4H); 3.91 (s, 3H); 3.85 - 3.95 (m, 1H); 4.13-4.28 (m, 2H); 4.37-4.43 (m, 2H); 4.51-4.56 (m, 2H); 4.57-4.73 (m, 2H); 4.94 (m, 1H); 6.90 (d, 1H); 7.10 (dd, 1H); 7.30 (s, 1H); 7.78 (d, 1H); 8.03 (s, 1H); 8.22 (s, 1H). ES (MH)* 470 Example 36 6-r({3-Fluoro-1-r2-(7-methoxy-2-oxoquinoxalin- 1(2H)-yl)ethyllpiperidin-4 yllamino)methyll-2H-pyridor3,2-b[1 ,4]oxazin-3(4H)-one, trans enantiomer A 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazine-6-carbaldehyde and 1-{2-[4-Amino-3 fluoropiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer A (Intermediate 77) were reacted using a procedure similar to the one described for the synthesis of Example 33 (except for the hydrochloride salt preparation), providing the title compound. IH NMR (DMSO-d) ppm: 1.14-1.29 (m, IH); 1.82-1.95 (m, 1H); 2.04-2.20 (m, 2H); 2.52 2.61 (m, 1H); 2.60-2.70 (m, 2H); 2.78-2.89 (m, 1H); 3.16-3.27 (m, 1H); 3.67-3.80 (m, 2H); 3.88-3.96 (m, 3H); 4.29-4.43 (m, 2H); 4.30 (m, 1H); 4.61 (s, 2H); 6.96-7.06 (m, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.00-8.09 (m, 1H); 11.19 (s, 1H). ES (MH)* 483 Example 37 1-(2-{ 4-[(2,3-Dihydror,4]dioxino[2,3-clpyridin-7-ylmethyl)aminol-3-fluoropiperidin-1 vl Iethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B, bis-hydrochloride salt 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde and 1-{2-[4-Amino-3-fluoropiperidin 1-yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B (Intermediate 79) 143 WO 2008/071961 PCT/GB2007/004766 were reacted using a procedure similar to the one described for the synthesis of Example 33, providing the title composition. 1 H NMR (D2O) 5 ppm: 1.81-1.94 (m, 1H); 2.30-2.43 (m, 1H); 3.13-3.26 (m, 1H); 3.32-3.42 (m, 1H); 3.42-3.50 (m, 1H); 3.53 (t, 2H); 3.57-3.66 (m, 111); 3.79-3.93 (m, 1H); 4.11-4.27 (m, 2H); 4.38-4.43 (m, 2H); 4.50-4.56 (m, 2H); 4.62-4.75 (m, 1H); 4.80-4.88 (m, 1H); 4.85 (m, 1H) 6.85 (d, 1H); 7.25 (s, 1H); 7.68 (dd, 1H); 7.89 (d, 1H); 7.98 (s, 1H); 8.03 (d, 1H); 8.20 (s, 1H) ES (MH)* 464 Example 38 1-2-(3-Fluoro-4- {[(3-oxo-3,4-dihydro-2H-pyrido[3,2-blr,41oxazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde and 1-{2-[4-Amino-3 fluoropiperidin- 1 -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B (Intermediate 79) were reacted using a procedure similar to the one described for the synthesis of Example 33 (except for the hydrochloride salt preparation), providing the title compound. 'H NMR (DMSO-d 6 ) 5 ppm: 1.21 (m, 1H) 1.84-1.95 (m, 111); 2.04-2.21 (m, 2H); 2.30-2.41 (m, 1H); 2.57-2.67 (m, 2H); 2.78-2.87 (m, 1H); 3.18-3.29 (m, 1H); 3.73 (s, 2H); 4.29 (m, 1H) 4.29-4.46 (m, 2H); 4.61 (s, 2H); 6.78 (d, 1H); 7.01 (d, 1H); 7.30 (d, 1H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, 1H); 8.11 (s, 1H); 11.19 (s, 1H) ES (MH)* 477 [c]D = +19.8 (methanol, c=0.46) Example 39 1-(2-{4-[(2,3-Dihydro[ 1,4]dioxinor2,3-clpyridin-7-ylmethyl)aminol-3-fluoropiperidin- 1 yl I ethyl)-7-methoxyquinoxalin-2(IH)-one, trans enantiomer B, bis-hydrochloride salt 2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridine-7-carbaldehyde and 1-{2-[4-Amino-3 fluoropiperidin- I -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer B (Intermediate 83) were reacted using a procedure similar to the one described for the synthesis of Example 33, providing the title composition. IH NMR (D 2 0) 6 ppm: 1.81-1.97 (m, 1H); 2.32-2.45 (m, 1H); 3.20-3.32 (m, 1H); 3.35-3.44 (m, 1H); 3.52-3.72 (m, 4H); 3.91 (s, 3H); 3.85 - 3.95 (m, 1H); 4.13-4.28 (m, 2H); 4.37-4.43 144 WO 2008/071961 PCT/GB2007/004766 (in, 2H); 4.51-4.56 (in, 2H); 4.57-4.73 (m, 2H); 4.94 (in, 1H); 6.90 (d, 1H); 7.10 (dd, 1H); 7.30 (s, 1H); 7.78 (d, 1H); 8.03 (s, IH); 8.22 (s, 1H). ES (MH)* 470 Example 40 6-r({3-Fluoro-1-r2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 yl amino)methyll-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, trans enantiomer B 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde and 1-{2-[4-Amino-3 fluoropiperidin- 1 -yl]ethyl} -7-methoxyquinoxalin-2(l H)-one, trans enantiomer B (Intermediate 83) were reacted using a procedure similar to the one described for the synthesis of Example 33 (except for the hydrochloride salt preparation), providing the title compound. 'H NMR (DMSO-d) 6 ppm: 1.14-1.29 (in, IH); 1.82-1.95 (in, 1H); 2.04-2.20 (in, 2H); 2.52 2.61 (in, 1H); 2.60-2.70 (m, 2H); 2.78-2.89 (in, 1H); 3.16-3.27 (m, 1H); 3.67-3.80 (in, 2H); 3.88-3.96 (in, 3H); 4.29-4.43 (in, 2H); 4.30 (in, 1H); 4.61 (s, 2H); 6.96-7.06 (in, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.00-8.09 (in, 1H); 11.19 (s, 1H) ES (MH)* 483 Example 41 1-(2- {(3R,4R)-4-r(2,3-dihydror 1,4]dioxinor2,3-clpyridin-7-vlmethyl)aminol-3 methoxypiperidin-1-yl ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt A mixture of 1- {2-[(3R,4R)-4-amino-3-methoxypiperidin- 1 -yl]ethyl} -2-oxo- 1,2 dihydroquinoline-7-carbonitrile (Intermediate 85, 105 mg crude, 0.32 mmol) and 2,3 dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (53 mg, 0.32 mmol) in dry methanol/chloroforn (1:1, 10 mL) was heated under a nitrogen atmosphere over 3 A molecular sieves for three hours at 70 "C. The reaction was allowed to cool to room temperature and sodium triacetoxy borohydride (205 mg, 0.97 mmol) was added. The reaction was stirred at room temperature overnight, and then filtered through celite. The filtrate was concentrated to dryness, taken up in 15% methanol in chloroform, and washed with saturated sodium bicarbonate solution. The aqueous phase was re-extracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography on silica gel 145 WO 2008/071961 PCT/GB2007/004766 with a gradient of 2-10% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 61 mg (40%) of the free base of the title composition as an oil. This was taken up in 1:1 dichloromethane/diethyl ether (5 mL) and treated with 1.0 M HCl in ether (-2 eq). The resulting precipitate was collected by filtration, reconstituted in water and lyophilized to give 63 mg of the title composition as a solid. MS (ESP): 476 (MH*) for C 26

H

29

N

5 0 4 H NMR (D 2 0) 8 ppm: 1.84 - 2.00 (in, 1H); 2.37 - 2.49 (in, LH); 2.93 - 3.06 (in, 1H); 3.10 3.23 (in, 1H); 3.33 - 3.44 (in, 4H); 3.53 - 3.80 (in, 4H); 4.19 (d, IH); 4.27 - 4.40 (in, 4H); 4.40 - 4.48 (in, 2H); 4.62 - 4.76 (in, 2H); 6.79 (d, 1H); 7.22 (s, 1H); 7.62 (dd, 1H); 7.83 (d, 1H); 7.91 (s, lH); 7.97 (d, 1H); 8.14 - 8.20 (in, 1H). Example 42 1-[2-((3R,4R)-3-methoxy-4- { r(3-oxo-3,4-dihydro-2H-pyridor3,2-blr1,4]oxazin-6 yl)methyllamino Ipiperidin- I -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile 1- {2-[(3R,4R)-4-Amino-3 -methoxypiperidin- 1 -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile (Intermediate 85, 105 mg, 0.32 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (57 mg, 0.32 mmol) and sodium triacetoxy borohydride (205 mg, 0.97 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 41 (except for the hydrochloride salt preparation). Chromatography on silica gel with a gradient of 2-10% methanol in dichloromethane containing 0.25% ammonium hydroxide gave 88 mg (56%) of the title compound as an off white solid. MS (ESP): 489 (MH*) for C 26

H

28

N

6 0 4 'H NMR (DMSO-d6) 6 ppm: 1.00 - 1.15 (in, 1H); 1.76 (in, 111); 1.87 (d, 1H); 1.99 (in, 1H); 2.22 - 2.34 (in, 1H); 2.59 (in, 2H); 2.78 - 2.96 (in, 2H); 3.25 - 3.33 (in, 2H); 3.30 (s, 3H); 3.55 - 3.77 (in, 2H); 4.30 - 4.50 (in, 2H); 4.61 (s, 2H); 6.79 (d, 1H); 6.97 (d, 1H); 7.28 (d, 1H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, 1H); 8.12 (s, IH); 11.21 (s, 1H). Example 43 1-(2-{(3S,4S)-4-[(2,3-Dihydro[ 1,41dioxino[2,3-clpyridin-7-ylmethyl)aminol-3 methoxypiperidin-1-ylethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 1-{2-[(3S,4S)-4-Amino-3-methoxypiperidin-1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 146 WO 2008/071961 PCT/GB2007/004766 carbonitrile (Intermediate 90, 120 mg, 0.37 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine 7-carbaldehyde (WO 2004/058144) (61 mg, 0.37 mmol) and sodium triacetoxy borohydride (234 mg, 1.10 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 41, providing the title composition (54 mg). MS (ESP): 476 (MH+) for C 2 6

H

29

N

5 0 4 IH NMR (D 2 0) 5 ppm 1.84 - 2.00 (in, 1H); 2.37 - 2.49 (in, 1H); 2.93 - 3.06 (in, 1H); 3.10 3.23 (in, 1H); 3.33 - 3.44 (in, 4H); 3.53 - 3.80 (in, 4H); 4.19 (d, 1H); 4.27 - 4.40 (in, 4H); 4.40 - 4.48 (in, 2H); 4.62 - 4.76 (in, 2H); 6.79 (d, 1H); 7.22 (s, 1H); 7.62 (dd, 1H); 7.83 (d, 1H); 7.91 (s, 1H); 7.97 (d, 1H); 8.14 - 8.20 (in, 1H). Example 44 1-[2-((3SAS)-3-Methoxy-4- {[(3-oxo-3,4-dihydro-2H-pyrido[3,2-blr1,4]oxazin-6 yl)methyllaminohpiperidin-1-yl)ethyll-2-oxo-1,2-dihydroquinoline-7-carbonitrile 1- {2-[(3S,4S)-4-Amino-3-methoxypiperidin- 1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 carbonitrile (Intermediate 90, 120 mg, 0.37 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (61 mg, 0.37 mmol) and sodium triacetoxy borohydride (234 mg, 1.10 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 41 (except for the hydrochloride salt preparation), providing the title compound. MS (ESP): 489 (MH*) for C 26

H

28

N

6 0 4 1H NMR (DMSO-d) 8 ppm 1.00 - 1.15 (m, 1H); 1.76 (in, 1H); 1.87 (d, 1H); 1.99 (m, 1H); 2.22 - 2.34 (in, 1H); 2.59 (in, 2H); 2.78 - 2.96 (in, 2H); 3.25 - 3.33 (in, 2H); 3.30 (s, 3H); 3.55 - 3.77 (in, 2H); 4.30 - 4.50 (m, 2H); 4.61 (s, 2H); 6.79 (d, 1H); 6.97 (d, 1H); 7.28 (d, 1H); 7.66 (dd, 1H); 7.91 (d, 111); 8.01 (d, 1H); 8.12 (s, 1H); 11.21 (s, 1H). Example 45 6-r({(3S,4R)-3-Fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyllpiperidin-4 ylamino)methyll-2H-pyrido[3,2-blr1,4]oxazin-3(4H)-one, bis hydrochloride salt and 147 WO 2008/071961 PCT/GB2007/004766 Example 46 6-r({ (3R,4S)-3-Fluoro- 1 -[2-(7-methoxy-2-oxoquinoxalin- 1(2H)-yl)ethyllpiperidin-4 ylamino)methyll-2H-pyrido[3,2-b [1,41oxazin-3(4H)-one, bis hydrochloride salt A solution of cis(±) 1-[2-(4-amino-3-fluoropiperidin-1-yl)ethyl]-7-methoxyquinoxalin 2(lH)-one, trifluoroacetic acid salt (Intermediate 91, ~0.53 mmol) in dichloroethane/methanol (1:1, 20 mL) was neutralized with NN-diisopropylethylamine. 3 oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (113 mg, 0.63. mmol) was added and the reaction was stirred at reflux over 3 A molecular sieves overnight. The reaction mixture was cooled to 0 0 C, and sodium cyanoborohydride (40 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then filtered through a fitted funnel and concentrated. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate followed by saturated sodium chloride. The organic extracts were dried over magnesium sulfate and concentrated. Reverse phase chromatography with water/methanol/trifluoroacetic acid yielded the product as trifluoroacetic acid salt. The salt was dissolved in water and chloroform and basified with saturated sodium carbonate. The layers were separated and the aqueous was extracted with chloroform. The organic extracts were dried over magnesium sulfate and concentrated to give a racemic mixture of the free bases of the title compositions as a solid, 26 mg (10%). MS (ESP): 483 (MH*) for C 24

H

27

FN

6 0 4 'H-NMR (CDCI-d) 8: 1.70 (m, 4H); 2.35 (m, 2H); 2.64 (m, lH); 2.73 (m, 2H); 3.04 (m, 1H); 3.31 (in, 1H); 3.86 (s, 2H); 3.92 (s, 3H); 4.35 (in, 2H); 4.63 (s, 2H); 4.83 (in, 1H); 6.86 (in, 1H); 6.92 (in, 1H); 6.98 (in, lH); 7.21 (in, 1H); 7.77 (in, 1H); 8.11 (s, 1H). The racemic mixture was separated by chiral chromatography (HPLC, Chiralcel OJ, 250 x 20mm, lO mobile phase: 50% hexane, 25% ethanol, 25% methanol, 0.1% diethylamine). The free base of Example 45 eluted first, followed by the free base of Example 46. The hydrochloride salts were prepared by dissolving the free bases in dichloromethane (2 mL) and adding 2.2 equivalents of 4N HCl in dioxane. The resulting colorless precipitates were collected by filtration to yield 48 mg and 46 mg of Example 45 and 46, respectively. 148 WO 2008/071961 PCT/GB2007/004766 Example 47 1-[2-((3R,4S)-3-Methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyridor3,2-b1[1,4]oxazin-6 yl)methyllamino} piperidin- 1 -yl)ethyll-4-methyl-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis-hydrochloride salt 1- {2-[(3R,4S)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -4-methyl-2-oxo- 1,2 dihydroquinoline-7-carbonitrile (Intermediate 93, -0.81 mmol) was suspended in chloroform/methanol (1:1, 20 mL) and NN-diisopropylethylamine was added dropwise until solid went into solution. 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (210 mg, 1.2 mmol) was added and the reaction was refluxed over 3 A molecular sieves for 5 hours. Sodium triacetoxyborohydride (340 mg, 1.6 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 2 hours then filtered through a 0.45 ptm membrane and concentrated. The residue was taken up in dichloromethane and saturated sodium bicarbonate. The pH of the aqueous phase was adjusted to pH-10 with IM sodium hydroxide solution. The aqueous phase was back extracted with dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated. Reverse phase chromatography with water/acetonitrile/ammonium acetate afforded the free base of the title composition as a tan foam, 144 mg (36%). The bis-hydrochloride salt was prepared using a procedure similar to the one described for the synthesis of Example 45. MS (ESP): 503 (MH*) for C 27

H

30

N

6 0 4 'H-NMR (DMSO-d 6 ) 6: 1.41 (in, 1H); 1.75 (in, 2H); 2.28 (in, 1H); 2.44 (s, 3H); 2.53 (in, 2H); 2.70 (in, 2H); 3.16 (s, 3H); 3.31 (in, 2H); 3.64 (in, 2H); 4.35 (in, 2H); 4.59 (s, 2H); 6.68 (s, 1H); 6.97 (d, 1H); 7.27 (d, 1H); 7.66 (d, 1H); 7.92 (d, 1H); 8.08 (s, 1H); 8.31 (s, 1H); 11. 19 (s, I1H). Example 48 1-[2-((3S,4R)-3-Fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-blr,41oxazin-6 yl)methyllaminol piperidin- 1 -yl)ethyll-4-methyl-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt and 149 WO 2008/071961 PCT/GB2007/004766 Example 49 1-r2-((3R,4S)-3-Fluoro-4- { r(3-oxo-3,4-dihydro-2H-pyridor3,2-blrl,4]oxazin-6 yllmethyllamino Ipiperidin-1-yl)ethyll-4-methyl-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt, bis hydrochloride salt Cis (±)1-[2-(4-amino-3-fluoropiperidin-1-yl)ethyl]-4-methyl-2-oxo-1,2-dihydroquinoline-7 carbonitrile (Intermediate 95, 200 mg, 0.63 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2 b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (170 mg, 0.94 mmol) and sodium triacetoxyborohydride (260 mg, 1.26 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 47. Reverse phase chromatography with water/acetonitrile/TFA provided a racemic mixture of the title compounds as a dry film, 80 mg. The racemic mixture was separated by chiral chromatography (SFC, Chiralpak AD-H, 250 x 21mm, 5p; 50% methanol, 0.1% dimethylethylamine. The free base of Example 48 eluted first, followed by the free base of Example 49. The bis-hydrochloride salts were prepared using a procedure similar to the one described for the synthesis of Example 45, providing the title compounds as colorless solids (6 mg and 4 mg, respectively). MS (ESP): 491 (MH*) for C 26

H

27

FN

6 0 3 'H-NMR (DMSO-d 6 ) 6: 1.60 (in, 2H); 2.12 (in, 4H); 2.44 (s, 3H); 2.54 (in, 2H); 2.91 (in, 1H); 3.12 (in, 1H); 3.71 (m, 2H); 4.34 (in, 2H); 4.59 (s, 2H); 4.70 (m, 1H); 6.68 (s, 1H); 7.01 (d, 1H); 7.28 (d, 1H); 7.66 (in, 1H); 7.92 (d, IH); 8.07 (s, IH); 11.18 (s, IH). Example 50 1-[2-((3S,4R)-3-Fluoro-4- { r(3-oxo-3,4-dihydro-2H-pyridor3,2-blr1,4]oxazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 1-{2-[(3S,4R)-4-amino-3-fluoropiperidin-1-yl]ethyl}-2-oxo-1,2-dihydroquinoline-7 carbonitrile trifluoroacetate (Intermediate 97, 1.2 mmol) was suspended in chloroform/methanol (1:2, 30 mL) and neutralized by dropwise addition of NN diisopropylethylamine. 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (258 mg, 1.45 mmol) was added and the reaction was refluxed over 3 A molecular sieves for 5 hours. Sodium triacetoxyborohydride (512 mg, 2.42 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 30 minutes then filtered 150 WO 2008/071961 PCT/GB2007/004766 through a fitted funnel and concentrated. The residue was taken up in dichloromethane and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over magnesium sulfate and concentrated. Reverse phase chromatography with water/acetonitrile/ammonium acetate afforded a product as an off-white solid after lyophilization. The hydrochloride salt was prepared by dissolving the lyopholization product in dichloromethane (5 mL) and adding 2.2 equivalents of 4N HCI in dioxane to afford the title composition as a colorless solid, 154 mg (26%). MS (ESP): 477 (MH*) for C 25

H

25

FN

6 0 3 'H-NMR (DMSO-d6) 6: 1.61 (m, 2H); 2.20 (m, 2H); 2.52 (m, 4H); 3.04 (m, 2H); 3.72 (s, 2H); 4.34 (m, 2H); 4.59 (s, 2H); 4.82 (m, 1H); 6.67 (d, 1H); 7.01 (d, 1H); 7.28 (d, 1H); 7.64 (d, 1H); 7.89 (d, 1H); 8.00 (d, 1H); 8.09 (s, 1H); 11.19 (s, 1H). Example 51 1-[2-((3S,4R)-3-Methoxy-4-{ {(3-oxo-3,4-dihydro-2H-pyridor3,2-b][1,4]oxazin-6 yl)methyllamino Ipiperidin- 1 -yl)ethyll-4-methyl-2-oxo- 1,2-dihydroquinoline-7-carbonitrile bis-trifluoroacetic acid salt I - {2-[(3S,4R)-4-Amino-3-methoxypiperidin- 1 -yl]ethyl} -4-methyl-2-oxo- 1,2 dihydroquinoline-7-carbonitrile, trifluoroacetate, (Intermediate 104, -0.52 mmol) was suspended in chloroform/methanol (1:2, 15 mL) and neutralized by dropwise addition of NN diisopropylethylamine. 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (93 mg, 0.52 mmol) was added and the reaction was refluxed over 3 A molecular sieves overnight. Sodium triacetoxyborohydride (138 mg, 0.65 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 5 hours then filtered through a fritted funnel and concentrated. The residue was taken up in dichloromethane and washed with saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over magnesium sulfate and concentrated. Reverse phase chromatography with water/acetonitrile/trifluoroacetic acid afforded title composition as a white solid after lyophilization, 108 mg (34%). MS (ESP): 503 (MH*) for C 27

H

30

N

6 0 4 H-NMR (DO-da) : 2.26 (m, 2H); 2.49 (s, 3H); 3.20 (m, 2H); 3.48 (s, 3H); 3.64 (m, 4H); 4.18 (m, 4H); 4.70 (m, 6H); 6.75 (s, 1H); 7.06 (d, 1H); 7.35 (d, 1H); 7.69 (m, 1H); 7.94 (s, 1H); 8.01 (d, 1H). 151 WO 2008/071961 PCT/GB2007/004766 Example 52 1-[2-((3R,4S)-3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b]r1,4]oxazin-6 yl)methyllamino I piperidin- 1 -yl)ethyll-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt 1- {2-[(3R,4S)-4-amino-3-fluoropiperidin- 1 -yl]ethyl} -2-oxo- 1,2-dihydroquinoline-7 carbonitrile (Intermediate 106, 352 mg, 1.12 mmol) was suspended in chloroform/methanol (1:1, 30 mL). 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (299 mg, 1.68 mmol) was added and the reaction was refluxed over 3 A molecular sieves overnight. Sodium triacetoxyborohydride (356 mg, 1.68 mmol) was added at 0"C. The reaction mixture was stirred at room temperature for 5 hours then filtered through a fritted funnel and concentrated. The residue was taken up in dichloromethane and washed with saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate and concentrated. Reverse phase chromatography with water/acetonitrile/ammonium acetate afforded the acetic acid salt of the title compound as an off-white solid after lyophilization. The bis-HCl salt was prepared from a solution of the acetic acid salt in dichloromethane (5 mL), by adding 2.2 equivalents of 4N HCl in dioxane. Filtration and drying under vacuum afforded the desired compound as a colorless solid, 154 mg (26%). MS (ESP): 477 (MH*) for C 25

H

25

FN

6 0 3 1 H-NMR (DMSO-d6 S: 1.57 (in, 2H); 2.37 (in, 2H); 2.58 (in, 4H); 2.91 (in, 2H); 3.71 (s, 2H); 4.34 (in, 2H); 4.59 (s, 2H); 4.70 (in, 1H); 6.76 (d, 1H); 7.00 (d, 1H); 7.28 (d, 1H); 7.63 (d, IH); 7.89 (d, lH); 7.98 (d, 1H); 8.08 (s, IH). 152

Claims (32)

1. A compound of Formula (I): R 8 E R R 9 H Rb _G 2 a R N R 6 D R 3 Formula (1) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is substantially free of a cis (+) mixture of its enantiomers, and wherein A is selected from CH and N; D is selected from C-R 7 and N; wherein at least one of A and D is carbon; E is selected from 0, NH, and S, wherein: i) E is NH if R 8 and R 9 together from =0; and ii) E is O or S if R 8 and R 9 are each H; G is selected from 0 and S; J is selected from C-R 4 and N; R' is selected from H, halo, cyano, Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, ORIa, and -N(Ria)2, wherein said Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 10 ; Rla in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said Ci- 6 alkyl is optionally substituted with one or more R20; R 2 is selected from halo, cyano, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -OR 2 a, and -N(R 2 a) 2 wherein said Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 2 0 ; R2' in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI- 6 alkyl are optionally substituted with one or more R20; 153 WO 2008/071961 PCT/GB2007/004766 R 3 is selected from H, halo, cyano, CI. 6 alkyl, C 2 - 6 alkenyl, and C 2 . 6 alkynyl, -OR 3 a, and -N(R 3 a) 2 , wherein said CI- 6 alkyl, C 2 - 6 alkenyl, and C 2 . 6 alkynyl are optionally substituted with one or more R30; R in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said Ci- 6 alkyl is optionally substituted with one or more R30; R 4 is selected from H, halo, cyano, -CO 2 H, Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, wherein said Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R40 R6 is selected from fluoro, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -OR 6 a, wherein said Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 6 R6' in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI- 6 alkyl are optionally substituted with one or more R 6 R 7 is selected from H, halo, cyano, Ci- 6 alkyl, C 2 . 6 alkenyl, and C 2 - 6 alkynyl, wherein said C1. 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R70; R8 and R9 are each hydrogen, or R8 and R 9 together form =0; and R10, R 20, R, RO , R6, and R70 in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO 2 H, Ci- 6 alkyl, C 2 . 6 alkenyl, and C 2 - 6 alkynyl.

2. The compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R 1 is H.

3. The compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein: R 2 is selected from cyano and -OR 2 a; and R2' is selected from Ci- 6 alkyl.

4. The compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein R 3 is H.

5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims I to 4, wherein: R6 is selected from fluoro and -OR6a ; and R' is selected from H and Ci- 6 alkyl. 154 WO 2008/071961 PCT/GB2007/004766

6. The compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein: J is selected from C-R 4 and N; and R 4 is selected from H and C 1 . 6 alkyl.

7. The compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 O O X0 N N NNN ,and

8. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein J is selected from N and C-R 4 ; A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 H 0 0 N- N-'N XO OC N and R 1 is H; R 2 is selected from cyano and methoxy; R 3 is H; Ri is selected from H and methyl; and R' is selected from fluoro, hydroxy, and methoxy.

9. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, wherein the R 6 group on carbon "a" and the -NH group on carbon "b" of the compounds of Formula (I) are in a cis (+) relationship to each other. 155 WO 2008/071961 PCT/GB2007/004766

10. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, wherein the R6 group on carbon "a" and the -NH group on carbon "b" of the compounds of Formula (1) are in a cis (-) relationship to each other.

11. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, selected from: 1-[2-((3R,4S)-3-Hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino} piperidin- 1 -yl)ethyl]-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt; 6-[({(3R,4S)-3-Hydroxy- 1-[2-(7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)ethyl]piperidin 4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, bis hydrochloride salt; 1-(2-{(3R,4S)-4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, monoacetic acid salt; 1-(2-f{(3S,4R)-4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 methoxypiperidin- 1-yl} ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt; 1-(2- {(3R,4R)-4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 methoxypiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one, bis-hydrochloride salt; 1-[2-((3-Fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A; 1-[2-((3R,4R)-3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile; 1-[2-((3S,4R)-3-Fluoro-4-{ [(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino}piperidin- 1-yl)ethyl]-4-methyl-2-oxo- 1,2-dihydroquinoline-7 carbonitrile, bis hydrochloride salt; and 1-[2-((3R,4S)-3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino } piperidin- 1 -yl)ethyl]-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt. 156 WO 2008/071961 PCT/GB2007/004766

12. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, said process comprising reacting a compound of Formula (AA): R 6 R N 0 R 3 Formula (AA) with a compound of Formula (AB): D G) Formula (AB) in the presence of a suitable reducing agent, and thereafter if necessary: i. converting the compound of Formula (I) into another compound of Formula (I); ii. removing any protecting groups; and/or iii. forming a pharmaceutically acceptable salt.

13. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, said process comprising reacting a compound of Formula (BI): R 6 R NA N A8 R2' N "Io D G ) R 3 Formula (BI) 157 WO 2008/071961 PCT/GB2007/004766 with a suitable reducing agent, and thereafter if necessary: i. converting the compound of Formula (I) into another compound of Formula (I); ii. removing any protecting groups; and/or iii. forming a pharmaceutically acceptable salt.

14. The use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, for the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as man.

15. A method for treating a bacterial infection in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims I to 11.

16. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, for use in treating a bacterial infection in a warm-blooded animal such as man.

17. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

18. A compound of Formula (II): Ra H E R9 2 N NA G R N O R6 D J R 3 Formula (II) 158 WO 2008/071961 PCT/GB2007/004766 or a pharmaceutically acceptable salt thereof, wherein the R6 group on carbon "a" and the -NH- group on carbon "b" are in a trans relationship to each other, and wherein A is selected from CH and N; D is selected from C-R 7 and N; wherein at least one of A and D is carbon; E is selected from 0, NH, and S, wherein: i. E is NH if R 8 and R 9 together from =0; and ii. E is O or S if R 8 and R 9 are each H; G is selected from 0 and S; J is selected from C-R 4 and N; R' is selected from H, halo, cyano, Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, ORia, and -N(Rla) 2 , wherein said CI. 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more Ri; Ria in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI. 6 alkyl is optionally substituted with one or more R20 R 2 is selected from H, halo, cyano, CI 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -OR 2 a, and -N(R 2 a) 2 wherein said C 1 . 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R20 R2' in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said CI- 6 alkyl are optionally substituted with one or more R20 33a RW is selected from H, halo, cyano, C1.6alkyl, C2-6alkenyl, and C2-6alkynyl, -OR a, and -N(R 3a)2, wherein said CI- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R'O; R 3 " in each occurrence is independently selected from H and Ci- 6 alkyl, wherein said Ci- 6 alkyl is optionally substituted with one or more R30; R 4 is selected from H, halo, -CO 2 H, cyano, Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, wherein said C 1 . 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R. R is selected from fluoro, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, -OR 6 a, wherein said C 1 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 60 ; Ra in each occurrence is independently selected from H and CI. 6 alkyl, wherein said CI. 6 alkyl are optionally substituted with one or more R60. 159 WO 2008/071961 PCT/GB2007/004766 R 7 is selected from H, halo, cyano, CI- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl, wherein said Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 70-; R 8 and R9 are each hydrogen, or R 8 and R9 together form =0; and 10 20 3004 R , R , R, R40, R 60 , and R 7 0 in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO 2 H, CI- 6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl.

19. The compound of Formula (1I), or a pharmaceutically acceptable salt thereof, as claimed in claim 18, wherein R' is H.

20. The compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in claim 18 or 19, wherein: R 2 is selected from cyano and -OR 2 a; and R 2 is selected from CI- 6 alkyl.

21. The compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 20, wherein R 3 is H.

22. The compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 21, wherein: R is selected from fluoro and -OR6a; and R6' is selected from H and CI- 6 alkyl.

23. The compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 22, wherein: J is selected from C-R 4 and N; and R4 is selected from H and Ci- 6 alkyl.

24. The compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 23, wherein A, D, E, G, R 8 , and R9, together with the ring atoms to which they are attached, form a group selected from: 160 WO 2008/071961 PCT/GB2007/004766 H 0 H 0 O N -0) N- N N_ 0 0 S ,and

25. The compound of Formula (11), or a pharmaceutically acceptable salt thereof, as claimed in claim 18, wherein: J is selected from C-R 4 and N; A, D, E, G, R 8 , and R 9 , together with the ring atoms to which they are attached, form a group selected from: H 0 0 N N and R is H; R 2 is selected from cyano and -OR 2 a; R 2 a is selected from methyl; R 3 is H; and R 4 is selected from H and methyl.

26. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 18, selected from: 1-(2-{(3S,4S)-4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 methoxypiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(lH)-one, bis-hydrochloride salt; 6-[({(3S,4S)-3-Methoxy- 1-[2-(7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)ethyl]piperidin 4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 1-(2-{(3R,4R)-4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 methoxypiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one, bis-hydrochloride salt; 6-[({ (3R,4R)-3-Methoxy- 1-[2-(7-methoxy-2-oxoquinoxalin- 1(2H)-yl)ethyl]piperidin 4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 161 WO 2008/071961 PCT/GB2007/004766 1-(2- {4-[(2,3-Dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 hydroxypiperidin- 1-yl} ethyl)-7-methoxyquinoxalin-2(l H)-one, trans enantiomer A, bis hydrochloride salt; 6-[({3-Hydroxy- 1-[2-(7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)ethyl]piperidin-4 yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, trans enantiomer A; 1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 hydroxypiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one, trans enantiomer B, bis-hydrochloride salt; 6-[({3-Hydroxy-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, trans enantiomer B; 1-(2- {4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A, bis-hydrochloride salt; 1-[2-((3-Fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino} piperidin- 1 -yl)ethyl]-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer A; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 fluoropiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one, trans enantiomer A, bis hydrochloride salt; 6-[({3-Fluoro-1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4 yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, trans enantiomer A; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B, bis-hydrochloride salt; 1-[2-(3-Fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl] amino} piperidin- 1 -yl)ethyl]-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, trans enantiomer B; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 fluoropiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one, trans enantiomer B, bis hydrochloride salt 6-[({3-Fluoro- 1 -[2-(7-methoxy-2-oxoquinoxalin- 1 (2H)-yl)ethyl]piperidin-4 yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, trans enantiomer B; 162 WO 2008/071961 PCT/GB2007/004766 1-(2-{(3R,4R)-4-[(2,3-dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 methoxypiperidin- 1-yl} ethyl)-2-oxo- 1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt; 1-[2-((3R,4R)-3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino} piperidin- 1 -yl)ethyl]-2-oxo- 1,2-dihydroquinoline-7-carbonitrile; 1-(2- {(3S,4S)-4-[(2,3-Dihydro[ 1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3 methoxypiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile, bis hydrochloride salt; and 1-[2-((3S,4S)-3-Methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6 yl)methyl]amino } piperidin- 1 -yl)ethyl] -2-oxo- 1,2-dihydroquinoline-7-carbonitrile.

27. A process for preparing a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 26, said process comprising reacting a compound of Formula (AA): R 6 RI <NO NH 2 R N 0 R 3 Formula (AA) with a compound of Formula (AB): 0 Formula (AB) in the presence of a suitable reducing agent, and thereafter if necessary: i. converting the compound of Formula (II) into another compound of Formula (II); ii. removing any protecting groups; and/or iii. forming a pharmaceutically acceptable salt. 163 WO 2008/071961 PCT/GB2007/004766

28. A process for preparing a compound of Formula (1), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 26, said process comprising reacting a compound of Formula (BI): R 6 R N N A E R8 R2 N O D / W R 3 Formula (BI) with a suitable reducing agent, and thereafter if necessary: i. converting the compound of Formula (II) into another compound of Formula (II); ii. removing any protecting groups; and/or iii. forming a pharmaceutically acceptable salt.

29. The use of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 26, for the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as man.

30. A method for treating a bacterial infection in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 26.

31. A compound of Formula (IL), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 26, for use in treating a bacterial infection in a warm blooded animal such as man.

32. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 18 to 26, and at least one pharmaceutically acceptable carrier, diluent, or excipient. 164