WO2006002047A2

WO2006002047A2 - Antibacterial agents

Info

Publication number: WO2006002047A2
Application number: PCT/US2005/020950
Authority: WO
Inventors: William Henry Miller; Israil Pendrak; Mark Andrew Seefeld
Original assignee: Glaxo Group Limited
Priority date: 2004-06-15
Filing date: 2005-06-15
Publication date: 2006-01-05
Also published as: JP2008502689A; US20070287701A1; WO2006002047A3; US7691850B2; EP1796466A2; EP1796466A4

Abstract

Naphthalene, quinoline, quinoxaline and naphthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.

Description

TITLE ANTIBACTERIAL AGENTS

FIELD OF THE INVENTION This invention relates to novel compounds, compositions containing them and their use as antibacterials.

BACKGROUND OF THE INVENTION The emergence of pathogens resistant to known antibiotic therapy is becoming a serious global healthcare problem (Chu, et al_M (1996) J. Med. Chem., 39: 3853-3874). Thus, there is a need to discover new broad spectrum antibiotics useful in combating multidrug- resistant organisms. Importantly, it has now been discovered that certain compounds have antibacterial activity, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in humans.

SUMMARY OF THE INVENTION This invention comprises compounds of the formula (I), as described hereinafter, which are useful in the treatment of bacterial infections. This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. This invention is also processes for the preparation of compounds of formula (I)₁ as well as processes for the preparation of intermediates useful in the synthesis of compounds of formula (I). This invention is also a method of treating bacterial infections in mammals, particularly in humans.

DETAILED DESCRIPTION OF THE INVENTION This invention provides a compound of formula (1) or a pharmaceutically acceptable salt, solvate or derivative thereof:

(I) wherein:

13 Z₁, Z₃, and Z₄ are each independently N or CR ;

Z₂, Z₅ and Z₆ are each CR 1^ηa^a.;

Ri and R^1a are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (Ci_6)alkoxy unsubstituted or substituted by (C-_|_g)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any of which is unsubstitued or N-substituted by one or two (C^ _ e)alkyl, acyl, (C^alkylsulphonyl, CONH2, hydroxy, (C-i_6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C-_|_6)alkylsulphonyloxy; (C^. g)alkyl; (Ci__β)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C-i_β)alkylsulphonyl; (Ci_β)alkylsulphoxide; arylsulphonyl; arylsulphoxide; or an amino, piperidyl, guanidino or amidino group unsubstituted or N-substituted by one or two (C-j_β)alkyl, acyl or (C^alkylsulphonyl groups; or R₁ and R^1a of Z₂ or R₁ and R^1a of Z₁ together form ethylenedioxy;

A is CR₂R₃;

R₂ is hydrogen; halogen; hydroxy; acyloxy; or (C_1-6)alkoxy; and R₃ is hydrogen;

W₁ is CR₄R₅;

R₄ is hydrogen; halogen; hydroxy; (C_1-6)alkyl; (C_1-6)hydroxyalkyl; C(=O)-NR^1dR1^d'; (C_1- ₆)alkoxy; NR^1bR^1b'or acyloxy; and R₅ is hydrogen or (C_1-6)alkyl; or R₄ and R₅ together are =N-OH;

R^1b and R^1b' are each independently hydrogen; acyl; (C_1-6)alkyl; aryl; heteroaryl; or together with the nitrogen they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring is optionally substituted with 1 to 3 substitutents selected from halogen, (C₁.₆)alkyl, hydroxy or aryl);

W₂ is CR₆; R₆ is hydrogen; halogen; hydroxy; (C_1-6)alkyl; NR^1cR^1c'; acyloxy; or (Ci_-6)alkoxy;

R^1c and R^1c' are each independently hydrogen; (Ci.₆)alkyl; aryi; heteroaryl; or together with the nitrogen they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring is optionally substituted with 1 to 3 substitutents selected from halogen, (C_1-6)alkyl, hydroxy or aryl);

R^1d and R^1d' are each independently hydrogen or (C_1-6)alkyl;

B is CR₇R₈ or a bond;

R₇ and R₈ are each independently hydrogen or (C_1-6)alkyl;

R₉ is hydrogen; aryl; heteroaryl; (C-|_g)alkyl unsubstituted or substituted by one or two (C^_6)alkoxy, acyloxy, carboxy, hydroxy, amino, piperidyl, piperazinyl, morpholino, guanidino, or amidino, any of which is unsubstituted or N-substituted by one or two aryl, heteroaryl, halogen, unsubstituted (C<|_6)alkyl, acyl, (C<|_6)alkylsulphonyl, arylsulphonyl, hydroxy, (C-]__β)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy, or (C^_6)alkylsulphonyloxy, so long as the substitution does not lead to an unstable compound; (Ci_6)alkylcarbonyl; or (C2_6)alkenylcarbonyl;

Rio is a group -U-R₁₁ where R₁₁ is a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system (A):

containing up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic; X is C or N when part of an aromatic ring or CR₁₂ when part of a non aromatic ring; X^z is N, NR₁₃, O, S(O)_x, CO or CR₁₂ when part of an aromatic or non- aromatic ring or may in addition be CR₁₄Ri₅ when part of a non aromatic ring; 3 5 X and X are independently N or C; Y is a 0 to 4 atom linker group each atom of which is independently selected from N, NR₁₃, O, S(O)_x, CO and CR₁₂ when part of an aromatic or non- aromatic ring or may additionally be CR₁₄Ri₅ when part of a non aromatic ring, Y is a 2 to 6 atom linker group, each atom of Y being independently selected from N, NR₁₃, O, S(O)_x, CO and CR₁₂ when part of an aromatic or non- aromatic ring or may additionally be CR₁₄R₁₅ when part of a non aromatic ring; R₁₂, Ru and Ri₅ are at each occurrence independently selected from: H; (C^ _ 4)alkylthio; halo; (C-j_4)alkyl; (C2-4)alkenyl; hydroxy; hydroxy^ _4)alkyl; mercapto(Ci_4)alkyl; (C-_|_4)alkoxy; trifluoromethoxy; nitro; cyano; carboxy; amino or aminocarbonyl unsubstituted or substituted by (C-|_4)alkyl;

Ri₃ is at each occurrence independently hydrogen; trifluoromethyl; (C-). 4)alkyl unsubstituted or substituted by hydroxy, carboxy, (C<i_4)alkoxy, (C-j_ 6)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; or aminocarbonyl wherein the amino group is optionally substituted with (C-]_4)alkyl;

each x is independently O, 1 or 2;

U is C(=O); SO₂; or CRt₆Ri₇; and

Ri₆ and R₁₇ are independently selected from H; aryl; heteroaryl; (C-). 6)alkyl; (Ci_e)alkyl substituted by (C-|_6)alkoxy, hydroxy, amino, piperidyl, piperazinyl, morpholino, guanidino, or amidino, any of which is substituted or N- substituted by one or two hydrogen, aryl, heteroaryl, halogen, cyano, CF3, (C-] _ 6)alkyl, acyl, (C^._βjalkylsulphonyl, arylsulphonyl, hydroxy, (C-|_g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy, or (C-). g)alkylsulphonyloxy, so long as the substitution does not lead to an unstable compound; (C-|_g)alkoxy-substituted(Ci_g)alkyl; hydroxy-substituted(Ci_g)alkyl; amino-substituted(C-|_6)alkyl, which is N-substituted by one or two (C-|_g)alkyl, acyl, (Ci_6)alkylsulphonyl, or arylsulphonyl; (C-_j_e)alkylcarbonyl; (C2- 6)alkenylcarbonyl; (Ci_e)alkoxycarbonyl; CO2H; or CF3; or a pharmaceutically acceptable salt or solvate thereof. In some aspects, this invention describes compounds of formula I wherein Z₁, Z₃ and Z₄ are CR^1a. In other aspects, this invention describes compounds of formula I wherein Zi and Z₄ are N and Z₃ is CR^1a. In some embodiments, this invention describes compounds of formula I wherein Z₁ and Z₃ are N and Z₄ is CR^1a. In yet other embodiments, this invention describes compounds of formula I ' wherein Z₁ and Z₃ are CR^1a and Z₄ is N. In certain aspects, this invention describes a compound of formula I wherein R₁ is OCH₃. 1a In other aspects, this invention describes compounds of formula I wherein R is at each occurrence independently hydrogen; halogen; or cyano. In certain embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a and R^1a of Z₂, Z₃ and Z₅ are each hydrogen; R^1a of Z₆ is hydrogen, halogen or cyano; and R₁ is OCH₃. In other embodiments, this invention describes compounds of formula I wherein Z₁ and Z₃ are CR^1a; Z₄ is N; R^1a of Z₂ and Z₅ are each hydrogen; R^1a of Z₃ is hydrogen or halogen; R^1a of Z₆ is hydrogen, halogen or cyano; and R₁ is OCH₃. In certain aspects, this invention describes compounds of formula I wherein Ri and R^1a of Z₂ together form ethylenedioxy. In some embodiments, this invention describes compounds of formula I wherein R₁ and R^1a of Z₁ together form ethylenedioxy. In other aspects, this invention describes compounds of formula I wherein R₂ is hydrogen or hydroxy. In some aspects, this invention describes compounds of formula I wherein R₂ is hydrogen. In some embodiments, this invention describes compounds of formula I wherein R₄ is hydrogen; halogen; hydroxy; (C_1-6)alkyl; (C₁.₆)hydroxyalkyl; C(=O)-NR^1dR1^d'; and R₅ is hydrogen or (C_1-6)alkyl or R₄ and R₅ together are =N-OH. In other embodiments, this invention describes compounds of formula I wherein R₄ is hydroxy; and R₅ is hydrogen. In some embodiments, this invention describes a compound of formula I wherein R₄ is C(=O)-NH₂ and R₅ is hydrogen. In certain embodiments, this invention describes compounds of formula I wherein R₆ is hydrogen; hydroxy; halogen; or (C_1-6)alkyl. In some embodiments, this invention describes a compound of formula I wherein B is CH₂. In certain other embodiments, this invention describes compounds of formula I wherein R₉ is hydrogen or (Chalky!. In still other embodiments, this invention describes compounds of formula I wherein Rg is hydrogen. In further embodiments, this invention describes compounds of formula I wherein U is CH₂; SO₂; or C(=O). In yet further embodiments, this invention describes compounds of formula I wherein U is CH₂. In some embodiments, this invention describes compounds of formula I wherein the (a) and (b) rings of R₁₁ are both aromatic as demonstrated by the following non- limiting examples: 1 H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl, 3H- imidazo[4,5-b]-pyrid-2-yl, 3H-quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo[1 ,2,3]- thiadiazol-5-yl, benzo[1 ,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[1 ,2-a]pyridin-2-yl, imidazo-[1 ,2-a]-pyrimidin-2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1 ,8]-naphthyridine-3- yl, oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl, 1,3-dioxo-isoindol-2yl, benzimidazol-2-yl, benzothiophen-2-yl, 1H- benzotriazol-5-yl, 1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione-6- yl, 3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl, 4-oxo- 4H-pyrido[1 ,2-a]pyrimidin-3-yl, benzo[1 ,2,3]thiadiazol-6-yl, benzo[1 ,2,5]thiadiazol-5-yl, benzo[1 ,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl, imidazo[1 ,2-a]pyridazin-2-yl, imidazo[1 ,2-b]pyridazin-2-yl, pyrazolo[1 ,5-a]pyrazin-2-yl, pyrazolo[1 ,5-a]pyridin-2-yl, pyrazolo[1 ,5-a]pyrimidin-6-yl, pyrazolo[5,1-c][1,2,4]triazin-3-yl, pyrido[1 ,2-a]pyrimdin-4-one-2-yl, pyrido[1 ,2-a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yl, thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl, thieno[3,2- b]pyridin-6-yl, thiazolo[5,4-b]pyridin-6-yl, 4-oxo-4H-pyrido[1 ,2-a]pyrimidin-2-yl, 1-oxo-1 ,2- dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl, [1 ,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl. In yet other embodiments, R₁-_I is defined by a non-aromatic (a) ring and aromatic (b) ring as illustrated by the following non-limiting examples:_(2S)-2,3-dihydro-1H-indol-2- yl, (2S)-2,3-dihydro-benzo[1 ,4]dioxine-2-yl, 3-(R,S)-3,4-dihydro-2H-benzo[1 ,4]thiazin-3-yl, 3-(R)-2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-3-yl, 3-(S)-2,3-dihydro-[1 ,4]dioxino[2,3- b]pyridin-3-yl, 2,3-dihydro-benzo[1 ,4]dioxan-2-yl, 3-substituted-3H-quinazolin-4-one-2-yl, 2,3-dihydro-benzo[1 ,4]dioxan-2-yl, 1-oxo-i ,3,4,5-tetrahydrobenzo[c]azepin-2-yl. In still other embodiments, R₁₁ is defined by an aromatic (a) ring and a non aromatic (b) ring as illustrated by the following non-limiting examples: 1,1,3-trioxo-1, 2,3,4- tetrahydro-1 f-benzo[1 ,4] thiazin-6-yl, benzo[1 ,3]dioxol-5-yl, 2,3-dihydro-benzo[1 ,4]dioxin- 6-yl, 2-oxo-2,3-dihydro-benzooxazol-6-yl, 4H-benzo[1 ,4]oxazin-3-one-6-yl (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl), 4H-benzo[1 ,4]thiazin-3-one-6-yl (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]thiazin-6-yl), 4H-benzo[1 ,4]oxazin-3-one-7-yl, 4-oxo-2,3,4,5-tetrahydro- benzo[b][1 ,4]thiazepine-7-yl, 5-oxo-2,3-dihydro-5H-thiazolo[3,2~a]pyrimidin-6-yl, benzo[1 ,3]dioxol-5-yl, 2-oxo-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]thiazin-7-yl, 2-oxo-2,3- dihydro-1 H-pyrido[3,4-b][1 ,4]thiazin-7-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazin-6- yl, 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl, 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-7-yl, 6,7-dihydro-[1 ,4]dioxino[2,3-d]pyrimidin-2-yl, 3- oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazin-6-yl, 2-oxo-2,3-dihydro-1 H-pyrido[3,4- b][1 ,4]oxazin-7-yl, 2-oxo-2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl, 6-oxo-6,7-dihydro- 5H-8-thia-1 ,2,5-triaza-naphthalen-3-yl, 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl, 3- substituted-3H-benzooxazol-2-one-6-yl, 3-substituted-3H-benzooxazole-2-thione-6-yl, 3- substituted-3H-benzothiazol-2-one-6-yl, 2,3-dihydro-1 H-pyrido[2,3-b][1 ,4]thiazin-7-yl, 3,4- dihydro-2H-benzo[1 ,4]thiazin-6-yl, 3,4-dihydro-1 H-quinolin-2-one-7-yl, 3,4-dihydro-1 H- quinoxalin-2-one-7-yl, 6,7-dihydro-4H-pyrazolo[1 ,5-a]pyrimidin-5-one-2-yl, 5,6,7,8- tetrahydro-[1 ,8]naphthyridin-2-yl, 2-oxo-3,4-dihydro-1 H-[1 ,8]naphthyridin-6-yl, 3,4-dihydro- 2H-pyrido[3,2-b][1 ,4]thiazin-6-yl. In some aspects, this invention describes compounds of formula I wherein Rn is 4H-Pyrido[3,2-b][1,4]thiazin~3-oxo-6-yl; 2,3-Dihydro-benzo[1 ,4]dioxin-6-yl; 4H-Pyrido[3,2- jb][1 ,4]oxazin-3-oxo-6-yl; 4/-/-benzo[1 ,4]thiazin-3-oxo-6-yl; 2,3-Dihydro-furo[2,3-c]pyridin-5- yl; 7-Chloro-4H-pyrido[3,2-jb]oxazin-3-oxo-6-yl; 2,3-Dihydro-[1 ,4]dioxino[2,3-c]-pyridin-6-yl; 2,3-Dihydro-benzofuran-7-carbonitrile-5-yl; 7-Methyl-4H-pyrido[3,2-ό][1 ,4]thiazin-3-oxo-6- yl; 3-Oxa-1-thia-5-aza-indan-5-yl; 5-Methyl-2,3-dihydro-benzo[1 ,4]dioxin-6-yl; 6-Fluoro- 2,3-dihydro[1 ,4]dioxin-7-yl; 2,3-Dihydro-benzofuran-5-yl; 7-Fluoro-4H-benzo[1 ,4]thiazin-3- oxo-6-yl; 4H-Benzo[1 ,4]thiazin-3-oxo-6-yl; or 8-Methyl-2,3-dihydro-benzo[1 ,4]dioxin-6-yl. In other aspects, this invention describes a compound of formula I wherein R₁₁ is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl. In yet other aspects, this invention describes a compound of formula I wherein R₁₁ is 4H-Pyrido[3,2-ό][1 ,4]oxazin-3-oxo-6-yl. In some embodiments, this invention describes compounds of formula I wherein R₁ is OMe; R^1a of Z₂ and Z₅ are hydrogen; R^1a of Z₆ is fluoro; R₂ is hydrogen; R₄ is hydroxy; R₅ is hydrogen; R₆ is hydrogen; R₇ and R₈ are hydrogen; R₉ is hydrogen; U is CH₂; Rn is 4H-Pyrido[3,2-b][1,4]thia2in-3-oxo-6-yl or 4/-/-Pyrido[3,2-6][1 ,4]oxazin-3-oxo-6- yl. In some aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano. In other aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is fluoro or cyano. In yet other aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; and R₂ is hydrogen or hydroxy. In some embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; and R₂ is hydrogen. In certain aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a Of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; and R₅ is hydrogen or methyl. In other aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydroxy and R₅ is hydrogen. In some embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; and R₆ is hydrogen; hydroxy; fluoro; or methyl. In yet other embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; and R₆ is hydrogen. In still yet other embodiments, this invention describes compounds of formula I wherein Z-i and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; and R₇ and R₈ are independently hydrogen or methyl. In further embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; and R₇ and R₈ are hydrogen. In some aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R₇ and R₈ are independently hydrogen or methyl; and R₉ is hydrogen or methyl. In yet other aspects, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R₇ and R₈ are independently hydrogen or methyl; and R₉ is hydrogen. In certain embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R₇ and R₈ are independently hydrogen or methyl; R₉ is hydrogen or methyl and U is CH₂; SO₂ or S(=0). In still other embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R₇ and R₈ are independently hydrogen or methyl; R₉ is hydrogen or methyl and U is CH₂. In some embodiments, this invention describes compounds of formula I wherein Z-i and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R₇ and R₈ are independently hydrogen or methyl; R₉ is hydrogen or methyl; U is CH₂; SO₂ or S(=0); and R₁₁ is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl. In yet other embodiments, this invention describes compounds of formula I wherein Zi and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R7 and R₈ are independently hydrogen or methyl; R₉ is hydrogen or methyl; U is CH₂; SO₂ or S(=O); and R₁₁ is R₁₁ is 4/-/-Pyrido[3,2-b]oxazin-3-oxo-6-yl. In still other embodiments, this invention describes compounds of formula I wherein Z₁ and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a Of Z₂, Z₃ and Z₅ are hydrogen; and R^1a of Z₆ is hydrogen, fluoro, chloro, or cyano; R₂ is hydrogen or hydroxy; R₄ is hydrogen, hydroxy, fluoro, methyl, or methoxy; R₅ is hydrogen or methyl; R₆ is hydrogen; hydroxy; fluoro; or methyl; R₇ and R₈ are independently hydrogen or methyl; R₉ is hydrogen or methyl; U is CH₂; SO₂ or S(=O); and R₁₁ is 2,3-Dihydro-benzo[1 ,4]dioxin-6-yl; AH- benzo[1 ,4]thiazin-3-oxo-6-yl; 2,3-Dihydro-furo[2,3-c]pyridin-5-yl; 4H-Pyrido[3,2-b]oxazin-3- oxo-6-yl; 7-Chloro-4H-pyrido[3,2-jb]oxazin-3-oxo-6-yl; 2,3-Dihydro-[1 ,4]dioxino[2,3-c]- pyridin-6-yl; 2,3-Dihydro-benzofuran-7-carbonitrile-5-yl;7-Methyl-4H-pyrido[3,2- ό][1 ,4]thiazin-3-oxo~6-yl; 3-Oxa-1-thia-5-aza-indan-5-yl; 5-Methyl-2,3-dihydro- benzo[1 ,4]dioxin-6-yl; 6-Fluoro-2,3-dihydro[1 ,4]dioxin-7-yl; 2,3-Dihydro-benzofuran-5-yl; 7- Fluoro-4H-benzo[1 ,4]thiazin-3-oxo-6-yl; 4H-Benzo[1 ,4]thiazin-3-oxo-6-yl; or 8-Methyl-2,3- dihydro-benzo[1 ,4]dioxin-6-yl. In some embodiments, this invention describes compounds of formula I wherein Zi and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; R^1a of Z₆ is fluoro or cyano; R₂ is hydrogen; R₄ is hydroxy; R₅ is hydrogen; R₆ is hydrogen; R₇ and R₈ are hydrogen; R₉ is hydrogen; R₁₁ is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl or 4H-Pyrido[3,2- b]oxazin-3-oxo-6-yl. In still other embodiments, this invention describes compounds of formula I wherein Zi and Z₄ are N; Z₃ is CR^1a; R₁ is OMe; R^1a of Z₂, Z₃ and Z₅ are hydrogen; R^1a of Z₆ is fluoro or cyano; R₂ is hydrogen; R₄ is hydroxy; R₅ is hydrogen; R_g is hydrogen; Rn is 4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl or 4H-Pyrido[3,2-b]oxazin-3-oxo-6-yl; and R₄ and B are cis. In some aspects, this invention describes compounds of formula I wherein Z₁ and Z₃ are CR^1a; Z₄ is N; R₁ is OMe; R^1a of Zi, Z₂ and Z₅ are hydrogen; R^1a of Z₃ is hydrogen or fluoro; R^1a of Z₆ is hydrogen, fluoro or cyano; and R₂ is hydrogen. In further aspects, this invention describes compounds of formula I wherein Z₁ and Z₃ are CR^1a; Z₄ is N; R₁ is OMe; R^1a of Z₁, Z₂ and Z₅ are hydrogen; R^1a of Z₃ is hydrogen or fluoro; R^1a of Z₆ is hydrogen, fluoro or cyano; R₂ is hydrogen; R₄ is hydrogen or hydroxy; R₅ is hydrogen; R₆ is hydrogen or methyl; R₇ and R₈ are hydrogen; R₉ is hydrogen; and U is CH₂ or SO₂. In still further aspects, this invention describes compounds of formula 1 wherein Z₁ and Z₃ are CR^1a; Z₄ is N; R₁ is OMe; R^1a of Z₁, Z₂ and Z₅ are hydrogen; R^1a of Z₃ is hydrogen or fluoro; R^1a of Z₆ is hydrogen, fluoro or cyano; R₂ is hydrogen; R₄ is hydrogen or hydroxy; R₅ is hydrogen; R₆ is hydrogen or methyl; R₇ and R₈ are hydrogen; R₉ is hydrogen; U is CH₂ or SO₂; and R₁₁ is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-one-6-yl; AH- Pyrido[3,2-b]oxazin-3-one-6-yl; 3-Oxa-1-thia-5-aza-indan-5-yl; or 4H-benzo[1 ,4]thiazin-3- one-6-yl. In some embodiments, this invention describes compounds of formula I wherein Z₁ and Z₃ are CR^1a; Z₄ is N; R₁ is OMe; R^1a of Z₁, Z₂ and Z₅ are hydrogen; R^1a of Z₃ is hydrogen or fluoro; R^1a of Z₆ is fluoro or cyano; R₂ is hydrogen; R₄ is hydroxy; R₅ is hydrogen; R₆ is hydrogen; R₇ and R₈ are hydrogen; R₉ is hydrogen; U is CH₂; and. Ri₁ is 4H-Pyrido[3,2-b][1 ,4]thiazin-3-one-6-yl or 4H-Pyrido[3,2-b]oxazin-3-one-6-yl. In still other embodiments, this invention describes compounds of formula I wherein Z₁ and Z₃ are CR^1a; Z₄ is N; R₁ is OMe; R^1a of Z₁, Z₂ and Z₅ are hydrogen; R^1a of Z₃ is hydrogen or fluoro; R^1a of Z₆ is fluoro or cyano; R₂ is hydrogen; R₄ is hydroxy; R₅ is hydrogen; R₆ is hydrogen; R₇ and R₈ are hydrogen; R₉ is hydrogen; U is CH₂^R₁₁ is 4H- Pyrido[3,2-b][1 ,4]thiazin-3-one-6-yl or 4H-Pyrido[3,2-b]oxazin-3-one-6-yl; and R₄ and B are cis. In some aspects, this invention describes compounds of formula (I) wherein the compound is 6-({[((3S)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one; 6-({[((3f?)-1-{2- [3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)- 2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one; (2,3-dihydro-1-benzofuran-5-ylmethyl)[((3S)-1-{2- [3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; [(7-fluoro- 2,3-dihydro-1 ,4-benzodioxin-6-yl)methyl][((3S)~1 -{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine;(2,3-dihydro-1,4-benzodioxin-6- ylmethyl)[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine;6-({[((3R)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1,4]thiazin-3(4W)-one;6-({[((3S)-1-{2-[3- fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2- ό][1,4]thiazin-3(4f/)-one;6-({[((3S)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ύ][1 ,4]oxazin-3(4H)-one;5-({[((3S)-1-{2-[3- fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2,3- dihydro-1-benzofuran-7-carbonitrile;7-chloro-6-({[((3/?)-1-{2-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ό][1 ,4]oxazin- 3(4H)-one;7-fluoro-6-({[((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethy!}-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-1,4-benzothiazin-3(4/^)-one;(2,3-dihydrofuro[2,3- c]pyridin-5-ylmethyl)[((3S)-1-{2-[3-f!uoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine;6-(methyloxy)-4-{2-[(3S)-3-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1 ,4]thiazin-6-yl)methyl]amino}methyl)-1 -pyrrolidinyl]ethyl}-3-quinolinecarbonitrile; 6-(methyloxy)-4-[2-((3S)-3-{[([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]methyl}-1- pyrrolidinyl)ethyl]-3-quinolinecarbonitrile;6-(methyloxy)-4-{2-[(3S)-3-({[(3-oxo-3,4-dihydro- 2H-pyrido[3,2-/?][1 ,4]oxazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-3- quinolinecarbonitrile;6-(methyloxy)-4-{2-[(3S)-3-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1,4]thiazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-1 ,5-naphthyridine-3- carbonitrile;1-[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl][(5-methyl-2,3-dihydro-1 ,4-benzodioxin-6-yl)methyl]amine;1-((3S)-1-{2- [3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-Λ/-[(8-methyl-2,3- dihydro-1 ,4-benzodioxin-6-yl)methyl]methanamine; 6-({[((3S)-1-{2-[3-chloro-6- (methyloxy)-i ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H- pyrido[3,2-ύ][1 ,4]thiazin-3(4H)-one; 6-({[((3S)-1-{2-[3-chloro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2Ay-pyrido[3,2-/?][1,4]oxazin- 3(4H)-one;[((3S)-1-{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amine; 6-({[((3S)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]oxazin-3(4H)-one; 6-({[((3S)-1 -{2- [S.δ-difluoro-e-CmethyloxyJ^-quinolinylJethylJ-S-pyrrolidinyOmethylJaminolmethyO^W- pyrido[3,2-/)][1 ,4]thiazin-3(4H)-one; [((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amine; 7-chloro-6- ({[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; 6-({[((3S)-1 -{2- [3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)- 2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; 6-({[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-o][1 ,4]thiazin-3(4H)-one;(2,3- dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; 6-({[((3S)-1-{2-[3-fluoro-6-(methyloxy)- 1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-7-methyl-2H-pyrido[3,2- /?][1 ,4]thiazin-3(4H)-one; 6-({[((3S)-1-{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}tnethyl)-2/-/-pyrido[3,2-ifj][1,4]thiazin-3(4H)-one; 6-({[((3S)-1-{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; 6-({[((3R)-1- {(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4-y!]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ύ][1 ,4]oxazin-3(4H)-one; 6-({[((3R)-1- {(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one; 6-({[((3S)-1 - {(2R)-2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-2-hydroxyethyl}-3- pyrrolidinyl)methyl]amino}methyl)~2W-pyrido[3,2-6][1 ,4]thiazin-3(4H)-one; Λ/-[((3S)-1 -{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro- 2/7-1 ,4-benzothiazine-6-sulfonamide; Λ/-[((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H-1 ,4-benzothiazine-6- sulfonamide; Λ/-[((3R)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]-2,3-dihydro-1 ,4-benzodioxin-6-sulfonamide; Λ/-[((3R)-1-{2-[3-fluoro-6- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2W-1,4- benzothiazine-6-sulfonamide; Λ/-[((3R)-1 -{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}- 3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H-1 ,4-benzothiazine-6-sulfonamide; Λ/-[((3R)-1 - {2-[3-cyano-6-(methyloxy)-4-quinolinyl]ethy[}-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H- 1 ,4-benzothiazine-6-sulfonamide; (±)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-^jb][1 ,4]thiazin-3(4fO- one; (+)-6-({[(frans-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-jb][1 ,4]thiazin-3(4/-/)-one; 6- ({[(frans-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4/-0-one; 6-{{[{trans-3,4)- 1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-6][1 ,4]thiazin-3(4H)-one; (±)-6-({[(frans- 3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ύ][1,4]oxazin-3(4/7)-one; 6-({[(trans-3,4)- 1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3₎2-ύ][1 ,4]oxazin-3(4H)-one; 6-{{[(trans-3,4)~ 1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4/-0-one; (±)-6-({[((cis- 3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][1 ,4]thiazin-3(4H)-one; 6-({[((3S,4S)-1- {2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-o][1 ,4]thiazin-3(4/V)-one;6-({[((3R,4R)-1 - {2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidiriyl)methyl]amino}methyl)-2H-pyrido[3,2-o][1 ,4]thiazin-3(4H)-one;6-({[((3S,4S)-1- {2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ύ][1_l4]oxa2in-3(4H)-one; 6-({[((3R,4R)-H2-[3-fluoro^-(methyloxy)-1 ,5-naphthyridin^yl]ethyl}^hydroxy-^- pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-jb][1 ,4]oxa2in-3(4H)-one; (±)-7-chloro-6-({[((cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-d][1 ,4]oxazin-3(4H)-one; 7-chloro-6-({[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy- 3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]oxazin-3(4/-/)-one; 7-chloro-6- ({[((3/?,4/^:?)-1-{2-[3-fluoro-6-(methyloxy)-1 _J5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ib][1 ,4]oxazin-3(4H)-one; (±)- (cis-3,4)-4- {[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-1-{2-[3-fluoro-6- (methy!oxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol; (3S,4S)-4-{[(2,3- dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol; (3R,4R)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3- c]pyridin-7-ylmethyl)amino]methy!}-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yllethyl^S-pyrrolidinol-.δ-fluoro-θ-^ICCSS^SJ-i^-tS-fluoro-^β-CmethyloxyJ-i .δ-naphthyridin- 4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-1 ,4-benzoxazin-3(4/-0-one; 6-({[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-4-quino!inyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one; 6-({[((3S,4S)-1- {2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ib][1_l4]oxazin-3(4/-/)-one; (±)-6-({[((cis- 3,4)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-/?][1,4]thiazin-3(4H)-one; 6-({[((3S,4S)-4- hydroxy-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyI)-2H-pyrido[3,2-Jb][1 ,4]thiazin-3(4H)-one; (±)-6-({[((cis- 3,4)-4-hydroxy-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; 6-({[((3S,4S)-1 - {2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]oxazin-3(4H)-one; 6-({[((3S,4S)-1- {2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-it>][1 ,4]thiazin-3(4W)-one; (3S,4S)-1-{2-[3- chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin- 7-ylmethyl)amino]methyl}-3-pyrrolidinol; (+)-6-[({[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin^-yOethylJ^-^ethyloxyJ-S-pyrrolidinylJmethylJaminoJmethyl^W-pyridoCS^- b]{\ ,4]thiazin-3(4H)-one; (±)-6-[({[(cis-3,4)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- ylJethylH-Cmethylbxyi-S-pyrrolidihyllmethylJaminoJmethyll-ΣW-pyridoCS^-όJCI.^oxazin- 3(4H)-one; (±)-6-({[(3-fluoro-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-d][1 ,4]thiazin-3(4H)-one; (±)-(2,3- dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)[(3-fluoro-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]annine; (±)-6-({[((3S,4f?)-4-fluoro-1 -{2-[3- fluoro-θ-CmethyloxyJ-i .δ-naphthyridin^-yllethylϊ-S-pyrrolidinyOmethyπaminoJmethyO^H- pyrido[3,2-ύ][1 ,4]thiazin-3(4H)-one; (+)-6-({[((3S,4S)-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)- 1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2- jb][1 ,4]thiazin-3(4H)-one; (+)-6-({[(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 4-hydroxy-3-methyl-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-Jb][1 ,4]thiazin- 3(4H)-one; (±)-6-({[(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- methyl-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][1 ,4]thiazin-3(4H)-one; (±)-6- ({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-4-methyl-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4AV)-one; (±)-6-({[(1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-4-methyl-3- pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-/)][1 ,4]thiazin-3(4H)-one; (±)-6-({[(1 -{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-methyl-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; (+)-6-({[(1 -{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-methyl-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]oxazin-3(4H)-one; (+)- [(1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-methyl-3- pyrrolidinyl)methyl]([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amine; (±)-(2,3- dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]amine; (+)-4-{2-[3-methyl-3-({[(3- oxo-3,4-dihydro-2W-pyrido[3,2-jfc)][1 ,4]thiazin-6-yl)methyl]amino}methyl)-1- pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile; (±)-4-[2-(3-methyl-3- {[([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]methyl}-1-pyrrolidinyl)ethyl]-6-(methyloxy)- 3-quinolinecarbonitrile; 6-({[1-((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)-1-methylethyl]amino}methyl)-2H-pyrido[3,2-6][1 ,4]thiazin-3(4H)- one; Λ/-(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)-2-((3R)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-2-propanamine; Λ/-[((3S)-1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro- 2H-pyrido[3,2-jb][1 ,4]thiazine-6-carboxamide; Λ/-[((3S)-1-{2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2- ό][1 ,4]thiazine-6-carboxamide; Λ/-[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1 ,4]thiazine-6-carboxamide; (+)-Λ/-[((cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-Λ/-methyl-3-oxo-3,4-dihydro-2W- pyrido[3,2-/?][1 ,4]thiazine-6-carboxamide; (±)-Λ/-[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]-Λ/-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2- 6][1 ,4]thiazine-6-carboxamide; (3S,4S)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol; 6-({[((3S,4S)-1-{2-[8-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-o][1 ,4]thiazin-3(4H)-one; 6-({[((3S,4S)-1- {2-[8-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]oxazin-3(4/V)-one; 6-({[((3S,4S)-1 - {2-[6-fluoro-5-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-ϋ][1_l4]oxazin-3(4H)-one; 6-({[((3S,4S)-1- {2-[6-fluoro-5-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; 6-({[((3S,4S)-1 - {2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ύ][1 _J4]oxazin-3(4H)-one; 6-({[((3S,4S)-1- {2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4AV)-one; 6-{[({(3S,4S)-1- [2-(9-chloro-2,3-dihydro[1 ,4]dioxino[2,3-/]quinolin-10-yl)ethyl]-4-hydroxy-3- pyrrolidinyl}methyl)amino]methyl}-2Ay-pyrido[3_J2-ib]t1_>4]thiazin-3(4W)-one; 6-{[({(3S,4S)-1- ^-(θ-chloro^.S-dihydroti ^ldioxinoP.S-flquinolin-IO-ylJethyll^-hydroxy-S- pyrrolidinyl}methyl)amino]methyl}-2H-pyrido[3,2-ό][1 ,4]oxazin-3(4H)-one; 6-{[({(3S,4S)-1- [2-(2,3-dihydro[1 ,4]dioxino[2,3-/]quinolin-10-yl)ethyl]-4-hydroxy-3- pyrrolidinyl}methyl)amino]methyl}-2/-/-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; 6-({[((3S,4S)-4- hydroxy-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-o][1 ,4]oxazin-3(4W)-one; (3S,4S)-1-{2-[6- (methyloxy)-1 _I5-naphthyridin-4-yl]ethyl}-4-{[([1 ,3]oxathiolo[5,4-c]pyridin-6- ylmethyl)amino]methyl}-3-pyrrolidinol; 7-chloro-6-({[((3S,4S)-4-hydroxy-1-{2-[6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H- pyrido[3,2-b][1 ,4]oxazin-3(4H)-one; (3S,4S)-4-({[(7-fluoro-2,3-dihydro-1 ,4-benzodioxin-6- yl)methyl]amino}methyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol; (3S,4S)-4-({[(7-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)methyl]amino}methyl)-1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol; 7-fluoro-6-({[((3S,4S)-4- hydroxy-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-1 ,4-benzothiazin-3(4H)-one; 6-({[((3S,4S)-4- hydroxy-1-{2-[6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2Λ/- pyrido[3,2πb][1 ,4]thiazin-3(4H)-one; 6-({[((3S,4S)-4-hydroxy-1 -{2-[6-(methyloxy)-4- quinolinyl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ib][1,4]oxazin-3(4H)- one; (3S,4S)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)annino]methyl}-1 -{2-[6- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol; N-[((3R,4Sy\ -{2-[3-fluoro-6-(methyloxy)-1 , 5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2/-/-1 ,4- benzothiazine-6-sulfonamide; Λ/-[((3S,4S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-/)][1,4]oxazine- 6-carboxamide; (±)-6-[({[(3R,4S;/(f3S,4R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2- b][1 ,4]thiazin-3(4H)-one; (±)-6-[({[(3R, 4S)/(3S, 4R)-A -{2-[3-fluoro-6-(methy!oxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2H- pyrido[3,2-/?][1 ,4]thiazin-3(4H)-one; 6-[({[(3f?,4S>-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2/-/- pyrido[3,2-ib][1 ,4]thiazin-3(4H)-one; (±)-6-[({[(3S,4Ry('3S_;4R)-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2H- pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; (±H(3R4Syf3S,4R)--4-{[(2,3-dihydro[1 ,4]dioxino[2,3- c]pyridin-7-ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yllethyl^S-pyrrolidinylJmethanolj β-røCSR^ZJ-i^-CS-fluoro-θ-Cmethyloxy)-! ^- naphthyridin-4-yl]ethyl}-4-(hydroxyimino)-3-pyrrolidinyl]methyl}amino)methyl]-2/-/- pyrido[3,2-ib][1 ,4]thiazin-3(4H)~one; 6-[({[(3f?,4Z)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-(hydroxyimino)-3-pyrrolidinyl]methyl}annino)methyl]-2W- pyrido[3,2-/)][1 ,4]oxazin-3(4H)-one; (3Z,4R)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinone oxime; (±)-(3S,4S)/(3R,4R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- ylJethylH-^fCS-oxo-S^-dihydro^H-pyridofS^-jbJfi^Jthiazin-θ-yOmethyllaminoymethyO-S- pyrrolidinecarboxamide; (±J-CSS^SVCSR^RJ-i^-tS-fluoro-θ-CmethyloxyJ-I .S- naphthyridin-4-yl]ethyl}-4-({[(3-oxo-3,4-dihydro-2/-/-pyrido[3,2-6][1 ,4]oxazin-6- yl)methyl]amino}methyl)-3-pyrrolidinecarboxamide; (±)-(3S,4S)/(3R,4R)-4-{[(2,3- dihydroli ^ldioxinop.S-clpyridin-y-ylmethyOaminoJmethylJ-i^-tS-fluoro-θ-Cmethyloxy)- 1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinecarboxamide; 4-{2-[(3S,4S)-3-hydroxy-4-({[(3-oxo- 3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]thiazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-6- (methyloxy)-1 ,5-naphthyridine-3-carbonitrile; 4-{2-[(3S,4S)-3-hydroxy-4-({[(3-oxo-3,4- dihydro-2/-/-pyrido[3,2-ύ][1 ,4]oxazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-6- (methyloxy)-i ,5-naphthyridine-3-carbonitrile; 4-[2-((3S,4S)-3-{[(2,3- dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylnnethyl)amino]methyl}-4-hydroxy-1-pyrrolidinyl)ethyl]- 6-(methyloxy)-1 ,5-naphthyridine-3-carbonitrile; (±)-6-{[((3S,4R)/(3R,4S)-4-hydroxy-1-{2-[6- (methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)amino]methyl}-2/-/-pyrido[3,2- b\[\ ,4]thiazin-3(4H)-one; (±)-6-{[((3S,4f?j/f3R,4S)-1-{2-[3-f!uoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)amino]methyl}-2H-pyrido[3,2- b][1 ,4]thiazin-3(4f/)~one;or a pharmaceutically acceptable salt or solvate thereof. In certain aspects, this invention describes a process for preparing an intermediate useful in the synthesis of a compound of formula (I), a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative of a compound of formula (I), which process comprises: (1) reacting a compound of formula (a) with a compound of formula (b) to form a compound of formula (c):

(a) (b) (°)

wherein: Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, Ri, W₁, W₂, A, B and R₉ are as defined in formula (I); X is oxirane, CH=CH₂, or CH₂CH₂-L; L is a leaving group; P is hydrogen, a suitable protecting group or R₁₀; and

(2) optionally forming a pharmaceutically acceptable salt, solvate or derivative thereof. In some embodiments of the processes of this invention, R₄ Of W₁ is OH and R₅ is H. In some aspects, this invention describes a process for preparing intermediates useful in the preparation of compounds of formula (1), and compounds of formula (I) wherein R₄ of W₁ is OH and R₅ is H comprising the: (1) reaction of a compound of formula (d) with a compound of formula (e) to form a compound of formula (f); and (2) cleavage of the N-O bond with: (a) retention of P; or (b) cleavage of P and subsequent reintroduction of P; and (3) removal of P₁ to form the compound of formula (a)

^(d) <^e> (f) (g)

wherein P is at each occurrence an independently selected protecting group. In other aspects of this invention, a process is described for preparing a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, which process comprises: (1) reacting a compound of formula (c), wherein P is hydrogen, with a compound of formula (h): L₁-U-R₁₁ (h) wherein: U and R₁₁ are as previously defined; L₁ is a leaving group; or reacting a compound of formula (c), wherein P is hydrogen, with a compound of formula (h_a): CHO-R₁₁ (h_a) and reducing the resulting imine; and (2) optionally forming a pharmaceutically acceptable salt, solvate or derivative thereof. In some embodiments of the immediately preceding process, R₄ Of W₁ is OH and R₅ is H. In some aspects, this invention describes a process for preparing a compound of formula (I) or a useful intermediate in the preparation of a compound of formula (I), said process comprising: (1) reacting a compound of formula (i) with CN or CH₃NO₂ to yield a compound of formula Q):

wherein: P₂ is a protecting group; Z is CN or CH₂NO₂; and (2) reducing Z to CH₂NH₂ to form a compound of formula (k); and (3) converting CH₂NH₂ to CH₂NHP₃ or CH₂NHR₁₀, to form a compound of formula (I); and (4) removing protecting group P₂ to generate a compound of formula (m); and (5) reacting said compound of formula (m) with a compound of formula (a) to generate a compound of formula (n)

(n)

In another embodiment of this invention the compound of formula (j), (k), (I), (m) or (n) is reacted with a trialkyl- or triarylphosphine and a dialkyldiazodicarboxylate in the presence of an organic acid optionally followed by cleavage of the resultant ester to form the corresponding 3,4-(cis)-substituted compounds of formula (o), (p), (q), (r) or (s):

(S)

or wherein a compound of formula (j), (I), (m) or (n) is: (1) reacted with an alkyl- or haloalkyl sulfonylhalide or an arylsulfonyl halide (said aryl group optionally substituted with from 1-3 substituents selected from halogen, CN, NO₂, CF₃, and (C_1-6)alkyl); and (2) reacted with MOP₄ to form the compound of structural formula (t), (u), (v), or (W)

(W)

wherein M is a metal; P₄ is hydrogen, (C_1-6)alkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substitutents independently selected from halogen, (C_1-6)alkyl, NO₂, CN and CF₃); and (3) optionally treated under conditions suitable for removal of P₄; and (4) optionally forming a pharmaceutically acceptable salt, solvate or derivative thereof.

In some embodiments, this invention describes a composition comprising a compound of formula I or any of its described embodiments or aspects and a pharmacutically acceptable excipient. In yet other embodiments, this invention describes a method of treating bacterial infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound according to formula I. It is to be appreciated that this invention includes all possible combinations of the described embodiments. Furthermore, this invention is not to be limited to any of the illustrated examples or any particular embodiments or aspects of the invention as described herein. Unless otherwise defined, the term "alkyl" when used alone or when forming part of other groups (such as the 'alkoxy' group) includes substituted or unsubstituted, straight or branched chain alkyl groups containing the specified range of carbon atoms. For example, the term "(Ci_-6)alkyl" include methyl, ethyl, propyl, butyl, iso-propyle, sec-butyl, tert-butyl, iso-pentyl, and the like. The term "alkenyl" means a substituted or unsubstituted alkyl group of the specified range of carbon atoms, wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond. For example, the term "(C_{2 6})alkenyl" include ethylene, 1- propene, 2-propene, 1-butene, 2-butene, and isobutene, and the like. Both cis and trans isomers are included. The term "cycloalkyl" refers to subsituted or unsubstituted carbocyclic system of the specifed range of carbon atoms, which may contain up to two unsaturated carbon- carbon bonds. For example, the term "(C_{3 7})cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl. The term "alkoxy" refers to an O-alkyl radical where the alkyl group contains the specified range of carbon atoms and is as defined herein. The term "acyl" refers to a C(=O)alkyl or a C(=O)aryl radical. In some embodiments, the alkyl group contains 13 or less carbons; in some embodiments 10 or less carbon atoms; in some embodiments 6 or less carbon atoms; and is as otherwise defined. Aryl is as defined herein. The term "alkylsulphonyl" refers to a SO₂alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein. The term "alkylthio" refers to a Salkyl the alkyl group contains the specified range of carbon atoms and is as defined herein. The term "heterocyclylthio" refers to a S-heterocyclyl radical wherein the heterocyclyl moiety is as defined herein. The term "heterocyclyloxy" refers to an O-heterocyclyl radical wherein heterocyclyl is as defined herein. The term "arylthio" refers to an S-aryl radical wherein aryl is as defined herein. The term "aryloxy" refers to an O-aryl radical wherein aryl is as defined herein. The term "acylthio" refers to a S-acyl radical wherein acyl is as defined herein. The term "acyloxy" refers to an O-acyl radical wherein acyl is as defined herein. The term "alkoxycarbonyl" refers to a CO₂alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein. The term "alkylsulphonyloxy" refers to an O-SO₂alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein. The term "arylsulphonyl" refers to a SO₂aryl radical wherein aryl is as herein defined. The term "arylsulphoxide" refers to a SOaryl radical wherein aryl is as defined herein. Unless otherwise defined, suitable substituents for any alkyl, alkoxy, alkenyl, and cycloalkyl groups includes up to three substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, carboxy, amino, amidino, sulphonamido, unsubstituted (Ci_3)alkoxy, trifluromethyl, and acyloxy. Halo or halogen includes fluoro, chloro, bromo and iodo. The term "haloalkyl" refers to an alkyl radical containing the specified range of carbon atoms and is as otherwise defined herein, which is further substituted with 1-3 halogen atoms. The term "haloalkoxy" refers to an alkoxy radical of the specified range and as defined herein, which is further substituted with 1-3 halogen atoms. The term "hydroxyalkyl" refers to an alkyl group as defined herein, further substituted with a hydroxy group. Unless otherwise defined, the term "heterocyclic" as used herein includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (C^alkylthio; halo; (C_{1 4})haloalkoxy; (C^haloalkyl; (C₁ ₄)alkyl; (C₂₄)alkenyl; hydroxy; hydroxy, (C_{1 4})alkyl; (C-|_4)thioalkyl; (C_{1 4})alkoxy; nitro; cyano, carboxy; (C_{1 4})alkylsulphonyl; (C₂₄)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (C^alkyl or (C₂₄)alkenyl. Each heterocyclic ring suitably has from 3 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention. Where an amino group forms part of a single or fused non-aromatic heterocyclic ring as defined above suitable optional substituents in such substituted amino groups include hydrogen; trifluoromethyl; (C^alkyl optionally substituted by hydroxy, (C₁ ₄)alkoxy, (C_{1 4})alkylthio, halo or trifluoromethyl; and (C_{2 4})alkenyl. When used herein the term "aryl", includes optionally substituted phenyl and naphthyl. Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (C_{1 4})alkylthio; halo; (C_{1 4})haloalkoxy; (C₁ Jhaloalkyl; (C_{1 4})alkyl; (C₂ ₄)alkenyl; hydroxy; (C^hydroxyalkyl; (C_{1 4})alkylthio; (C_{1 4})alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted by (C_{1 4})alkyl; (C_{1 4})alkylsulphonyl; (C₂ ₄)alkenylsulphonyl. Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Furthermore, it will be understood that phrases such as "a compound of Formula I or a pharmaceutically acceptable salt, solvate or derivative thereof" are intended to encompass the compound of Formula I, a derivative of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a solvate of formula (I), or any pharmaceutically acceptable combination of these. Thus by way of non-limiting example used here for illustrative purpose, "a compound of Formula I or a pharmaceutically acceptable salt, solvate or derivative thereof" may include a pharmaceutically acceptable salt of a compound of formula (I) that is further present as a solvate. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable salts of the above-mentioned compounds of formula (I) include the free base form or their acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p- toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids. Compounds of formula (I) may also be prepared as the N-oxide. Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester. The invention extends to all such derivatives. One of skill in the art will recognize that where compounds of the invention contain multiple basic sites, a compound of the invention maybe present as a salt complexed with more than one equivalent of a corresponding acid or mixture of acids. Pharmaceutically acceptable derivatives refers to compounds of formula (I) that have been covalently modifed with a group that undergoes at least some in vivo cleavage to a compound of formula (I). Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt. Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v): R^a (i) — CH-O.CO.R⁰

R^c- N< R^e (ϋ)

R^a

CHOCO

wherein R^a is hydrogen, (C_{1 6}) alkyl, (C₃₇) cycloalkyl, methyl, or phenyl, R is (C₁

₆) alkyl, (C_{1 6})alkoxy, phenyl, benzyl, (C_{3 7})cycloalkyl, (C_{3 7})cycloalkyloxy, (C_{1 6})alkyl(C_{3 7})

cycloalkyl, 1-amino(C_{1 6})alkyl, or a b 1-(C_{1 g} alkyOamino^ ₆) alkyl; or R and R together form a 1 ,2-phenylene group

optionally substituted by one or two methoxy groups; R represents (C_{1 6})alkylene

optionally substituted with a methyl or ethyl group and R and R independently represent f g (C_{1 6}) alkyl; R represents (C_{1 6}) alkyl; R represents hydrogen or phenyl optionally

substituted by up to three groups selected from halogen, (C_{1 6}) alkyl, or (C_{1 6}) alkoxy; Q is

oxygen or NH; R is hydrogen or

(C_1-6) alkyl; R' ΪS hydrogen, (C_{1 6}) alkyl optionally substituted by halogen, (C_{2 6})

alkenyl, (C_{1 6})alkoxycarbonyl, aryl or heteroaryl; or R and R¹ together form

(C_{1 6}) alkylene; R represents hydrogen, (C_{1 6}) alkyl or (C_{1 6})alkoxycarbonyl; k and R represents (C_{1 8})alkyl, (C_{1 8})alkoxy, (C₁ ^aIkOXy(C_{1 6})alkoxy or aryl. Examples of suitable in vivo hydrolysable ester groups include, for example, 8CyIoXy(C_{1 6})alkyl groups such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (i-aminoethyl)carbonyloxymethyl; (C_{1 6})alkoxycarbonyloxy(C_{1 6})alkyl groups, such as ethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; CJi(C_1- ₆)alkylamino(C_{1 6})alkyl especially di(C₁ ^alkylamino^ ₄)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(C_{1 6})alkoxycarbonyl)-2-(C_{2 6})alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl. A further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:

k wherein R is hydrogen, C_{1 6} alkyl or phenyl. R is preferably hydrogen. Compounds of formula (I) may also be prepared as the corresponding N-oxides. Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such form, including pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. For purposes of the processes of this invention, one of skill in the art will recognize that use of the term CN as a reagent in a reaction refers to any method of delivering a CN group. The particular CN containing reagent will, of course, depend upon the particular reaction contemplated. For example, in some embodiments of this invention, the CN maybe bonded to a triaklyl silane such as TMS-CN, and the like. In other variations, HCN itself could be used. In other embodiments, the CN maybe delivered as an inorganic salt, such as NaCN, KCN, etc. In such case, it is sometimes preferred to use a phase transfer reagent to increase the solubilty of the CN ion in an organic solvent. In such cases, for example, a quaternary ammonium salt wherein the CN functions as a counterion maybe utilized. For purposes of the processes of this invention, one of skill in the art will recognize that the use of the reagent CH₃NO₂, as for example, a nucleophile, may require the coadministration of a base in order to at least partially deprotonate the CH₃NO₂ in order to increase its nucleophilicity. Alternatively, the reagent maybe deprotonated prior to the reaction where the reagent is introduced as a metal salt. One of skill in the readily appreciates that optimization for a given reaction may require some routine variation in reaction parmeters such as reaction time, temperature, energy source, pressure, light, pressure, solvent or solvents used, co-reagents, catalysts, and the like. Protective groups wherever found herein maybe designated by their specific formula or alternatively, maybe referred to generically by P or P_n (wherein n is an integer). It is to be appreciated that where generic descriptors are used, that such descriptors are at each occurrence independent from each other. Thus, a compound with more than one of the same generic descriptors (e.g. P) does not indicate that each P is the same protective group, they maybe the same or different, so long as the group is suitable to the chemistry being employed. Where protection or deprotection is generically referred to, one of ordinary skill in the art will understand this to mean that suitable conditions are employed that will allow for the removal of the protecting group to be removed while minimizing reaction at other positions of the molecule, unless otherwise indicated. May protective groups and protective group strategies are known to those of skill in the art in maybe found in numerous references including, Greene, et al. "Protective Groups in Organic Synthesis" (Published by Wiley-lnterscience), which is herein incorporated by reference in its entirety. Leaving groups wherever found herein maybe designated by a specific chemical formula, or alternatively, maybe generically referred to as L or Ln (wherein n is an integer). It is to be appreciated that where a generic descriptor is used, that such descriptors are at each occurrence independent from each other. Leaving groups can be single atoms such as Cl, Br, or I, or maybe a group such as OSO₂CH₃, OC(=O)CH₃, 0(C=O)CF₃, OSO₂CF₃, and the like. One skilled in the art will readily ascertained that leaving groups generally refer to atoms or groups which can be eliminated, substituted or otherwise dissociate during the course of the reaction. The antibacterial compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials. The pharmaceutical compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans. The composition may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents. Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day. No toxicological effects are indicated when a compound of formula (I) or a pharmaceutically acceptable derivative thereof is administered in the above-mentioned dosage range. The compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a β-lactam then a β-lactamase inhibitor may also be employed. Compounds of formula (I) are active against a wide range of organisms including both Gram-negative and Gram-positive organisms. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference (whether specifically stated to be so or not) as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms. The compounds of the present invention were prepared by the methods illustrated in Schemes I through XX.

Scheme I

I-4 I-3

I-5 I-6

Reagents and conditions: (a) Cbz-succinimide, Et₃N, DMF, RT; (b) TFA, CH2CI2, RT; (C) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, EtOH, 80 ⁰C; (d) Pd/C, H₂ (1 atm), MeOH, RT; (e) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)₃.

Pyrrolidine 1-1 was reacted with a suitable electrophile such as Cbz-CI or Cbz- succinimide to afford carbamate 1-2. Selective removal of the Boc group afforded 1-3 and was achieved with TFA in methylene chloride. Other acids (HCI, HF, etc.) can be used to remove this protecting group. Amine 1-3 was then heated with a vinyl naphthyridine either neat or in a suitable solvent (dioxane, DMF) generating the product 1-4. Deprotection of the benzyl carbamate functionality was performed under hydrogenolysis conditions. The use of protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes and maybe used for the preparation of compounds of the present invention wherever appropriate, such as those detailed in Greene, "Protective Groups in Organic Synthesis" (published by Wiley- Interscience) citep previously, herein. The primary amine derivative I-5 is then converted to a secondary amine 1-6 by reaction with an aldehyde and a suitable reducing agent. For example, [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine is subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBH3CN in solvent. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Many additional methods for reductive aminations are known and maybe used to help prepare compounds of the present invention wherever appropriate, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience) which is herein incorporated by reference.

Scheme Il

II-3 II-2

1-6 I-5 Reagents and conditions: (a) (CF3CO)2θ, RT; (b) TFA, CH2CI2, RT; (c) 8-ethenyl-2- (methyloxy)-i ,5-naphthyridine, DMF, 100 ⁰C; (d) K₂CO₃, H₂O, THF, RT; (e) 3-oxo-3,4- dihydro-2W-pyrido[1 ,4]thiazine-6~carboxaldehyde, CH₂CI₂, EtOH; then NaBH₄, EtOH.

Pyrrolidine 1-1 was reacted with a suitable electrophile such as trifluoroacetic anhydride or ethyl trifluoroacetate to afford carbamate 11-1. Selective removal of the Boc group afforded II-2 and was achieved with TFA in methylene chloride. Other acids (HCI, HF, etc.) can be used to remove this protecting group. Amine II-2 was then heated with a vinyl naphthyrine either neat or in a suitable solvent (dioxane, DMF) generating the product 11-3. Deprotection of the ethyl carbamate functionality was performed under basic aqueous conditions. The base used could be (KOH, NaOH, LiOH, K₂CO₃) or another similar base. The primary amine derivative 11-4 is then converted to a secondary amine II- 5 by reaction with an aldehyde and a suitable reducing agent. For example, 1-((3S)-1-{2- [6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methanamine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH₂CI₂, EtOH or CH₃CN. The imine is subsequently or simultaneously reacted with a suitable reducing agent such as NaBH₄, NaBH(OAc)₃ or NaBH₃CN in solvent. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et₃N), diisopropylethylamine ((J-Pr)₂NEt), or K₂CO₃, may be used.

Scheme III

1-5, R = H, R1 = H III-2, R = H, R1 + H 111-1, R = CH₃, R1 = H HI-3, R = CH₃, R1 = H IH-4, R = H, R1 = OH Hl-5, R = H, R1 = OH III-6, R = CH₃, R1 = OH HI-7, R = CH₃, R1 = OH

Reagents and conditions: (a) EDC, HOBt, (/-Pr)₂NEt, DMF, 3-oxo-3,4-dihydro-2Λ/- pyrido[3,2-jfc>][1 ,4]thiazine-6-carboxylic acid. A suitable carboxylic acid, for instance 3-oxo-3,4-dihydro-2H-pyrido[3,2- b][\ ,4]thiazine-6-carboxylic acid, is converted to an activated form using, for example, EDC and HOBt, or SOCI2, and the activated form is subsequently reacted with an appropriate amine, for instance amine I-5, in a suitable solvent such as DMF, CH2CI2, or CH3CN, to afford III-2. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et^N), diisopropylethylamine ((/-Pr)₂NEt), or pyridine, may be used. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag) which is herein incorporated by reference.

Scheme IV

IV-1 I-3

IV-2 IV-3

Reagents and conditions: (a) 2-(methyloxy)-8-[(2S)-2-oxiranyl]-1 ,5-naphthyridine, DMF, 100 ⁰C; (b) Pd/C, H₂ (1 atm), MeOH, RT; (c) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6- carboxaldehyde, CH₂CI₂, EtOH; then NaBH₄, EtOH. Amine 1-3 was reacted with an electophilic epoxide such as 2-(methyloxy)-8-[(2S)- 2-oxiranyl]-1 ,5-naphthyridine to give alcohol IV-1. Deprotection of IV-1 under hydrogenolysis conditions using Pd in an alcoholic solvent under a H2 atmosphere provided the primary amine IV-2. The primary amine derivative IV-2 was then converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBH^CN in solvent to give amine IV-3. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used.

Scheme V

V-5 V-6

Reagents and conditions: (a) NaHSO₃, KCN, THF, H₂O₁ 0 ⁰C; (b) LiAIH₄, THF, RT, 20 h; (c) (BoC)₂O, MeOH, RT; (d) Pd/C, H₂ (1 atm), EtOH, RT; (e) 8-ethenyl-7-fluoro-2- (methyloxy)-i ,5-naphthyridine, DMF, 85 ⁰C; (f) TFA, DCM, RT; (g) 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH₄, EtOH.

Pyrrolidinone V-1 was converted to cyanohydrin V-2 using NaHSO₃ in aqueous THF at O ⁰C (J. Med. Chem. 1993, 36, 2292-2299). LiAIH₄ was used to reduce V-2 to the corresponding amino alcohol V-3. The amine functionality of V-3 was protected using Boc anhydride to give V-4. The benzyl carbamate protecting group was then removed under hydrogenolysis conditions using a palladium catalyst in alcohol to give the amine V-5. The secondary amine V-5 was the heated together with a vinyl electrophile either under neat conditions or in an appropriate solvent such as DMF, dioxane or DME to give the product compound V-6. The Boc protecting group was removed under acidic conditions using TFA in methylene chloride at RT. The resulting primary amine derivative was subsequently converted to a secondary amine V-7 by reaction with an aldehyde and a suitable reducing agent. For example, 3-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH₂CI₂, EtOH or CH₃CN. The imine is subsequently or simultaneously reacted with a suitable reducing agent such as NaBH₄, NaBH(OAc)₃ or NaBH₃CN in solvent. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et₃N), diisopropylethylamine ((J-Pr)₂NEt), or K₂CO₃, may be used. Scheme Vl

VM VI-2

Vl-3 VI-4

Reagents and conditions: (a) MCPBA, DCM, RT, 2 days; (b) TMSCN, Et₂AICI, DCM, RT, 24 h; (c) LiAIH₄, THF, RT, 20 h; (d) Cbz-succinimide, Et₃N, DMF, RT; (e) TFA, CH2CI2, RT; (f) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, EtOH, 85 ⁰C; (g) Pd/C, H₂ (1 atm), MeOH, RT; (h) 3-oxo-3,4-dihydro-2W-pyrido[1 ,4]thiazine-6- carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)3. Alkene VI-1 was converted to an epoxide VI-2 using a suitable oxidizing reagent such as MCPBA or other peracids. The epoxide was opened under nucleophilic conditions aided by a Lewis acid to give the silyl protected hydroxy nitrile VI-3 in a trans relative configuration. The nitrile functionality was reduced and the TMS group cleaved simultaneously using IJAIH4 as a reducing agent in a polar aprotic solvent. The resulting amino alcohol VI-4 was reacted with Cbz-succinamide to protect the primary amine and afford compound VI-5. Deprotection of the Boc-amine was achieved with TFA in DCM to give secondary amine VI-6. The amine was then reacted with a electrophilic vinyl compound either neat or in a small amount of solvent providing VI-7. Removal of the Cbz- group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent in an atmosphere of hydrogen. The primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBH3CN in solvent to give the amine VI-8. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Scheme VII

VII-2 VII-3

VII-4 VII-5

VII-6

Reagents and conditions: (a) Λ/-Hydroxybenzylamine hydrochloride, toluene, EtOH, 8O⁰C; (b) Pd(OH)₂, H₂ (50psi), EtOH₁ RT; (c) Cbz-succinimide, Et₃N, DMF, RT; (d) TFA, CH₂CI₂, RT; then MP-carbonate resin, DCM, RT; (e) 8-ethenyl-7-fluoro-2-(methyloxy)- 1 ,5-naphthyridine, EtOH, 80 ⁰C; (f) Pd(OH)₂, MeOH, H₂ (1 atm), RT; (g) 3-oxo-3,4- dihydro-2A/-pyrido[1 ,4]thiazine-6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)₃. The alkene VI-1 was reacted with an appropriate electron-rich cycloaddition reagent to give the cis-adduct VIM . The benzyl functionality was removed and the N-O bond cleaved simultaneously under hydrogenolysis conditions using Pd(OH)2 in a polar protic solvent under an atmosphere of hydrogen. The resulting amino alcohol VII-2 was reacted with Cbz-succinamide to protect the primary amine and afford compound Vll-3. Deprotection of the Boc-amine was achieved with TFA in DCM to give secondary amine VII-4. The secondary amine was then reacted with an electrophilic vinyl compound either neat or in a small amount of solvent providing VII-5. Removal of the Cbz-group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBI-14, NaBH(OAc)3 or NaBH3CN in solvent to give the amine VII-6. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et^N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Scheme VIII

VII-3 VIIM

VIH-2 VIII-3

VIII-4

Reagents and conditions: (a) BnNEt3CI, toluene, (CH3)2SO4, RT; (b) TFA, CH2CI2, RT; then MP-carbonate resin, DCM, RT; (c) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5- naphthyridine, EtOH, 80 ⁰C; (d) Pd(OH)₂, MeOH, H₂ (1 atm), RT; (e) 3-oxo-3,4-dihydro- 2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)3.

Alcohol VII-3 was converted to an ether using dimethylsulfate as the alkylating reagent with the aid of a phase transfer catalyst in toluene. Deprotection of the Boc-amine Vlll-1 was achieved with TFA in DCM to give secondary amine Vlll-2. The secondary amine was then reacted with an electrophilic vinyl compound either neat or in a small amount of solvent providing Vlll-3. Removal of the Cbz-group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBH4, NaBH(OAc)3 or NaBH3CN in solvent to give the amine VIII-4. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Scheme IX

IX-3 IX-4

Reagents and conditions: (a) NaHSO3, KCN, THF, H₂O, 0 ⁰C; (b) DAST₁ DCM, -78° C; (c) LiAIH₄, THF, RT, 20 h; (c) (Boc)₂O, MeOH, RT; (d) Pd/C, H₂ (1 atm), EtOH, RT; (e) 8- ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, DMF, 85 ⁰C; (f) TFA, DCM, RT; (g) 3- oxo-3,4-dihydro-2W-pyrido[1,4]thiazine-6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)₃.

Cyanohydrin V-2 was converted to fluoride IX-1 using an DAST as a fluorinating reagent in a polar aprotic solvent such as DCM at low temperature. The nitrile functionality was subsequently reduced to the corresponding amine using LiAIH₄ in THF at 0 C and the primary amine immediately protected using Boc anhydride in THF. Removal of the Cbz-group of IX-2 was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The secondary amine XI-3 was then reacted with an electrophilic vinyl compound either neat or in a small amount of solvent providing IX-4. Deprotection of the Boc-amine was achieved with TFA in DCM after which the resulting primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvent such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBHsCN in solvent to give the amine lX-5. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used.

Scheme X

VI-3 X-1

X-2 X-3

X-4

Reagents and conditions: (a) TBAF, THF, 0 ⁰C; (b) DAST, DCM -78°C; (c) LiAIH₄, THF₁ RT; (d) Cbz-succinimide, Et_βN, DMF, RT; (e) TFA, CH₂CI₂, RT; then MP-carbonate resin, DCM, RT; (f) 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine, EtOH, 80 ⁰C; (g) Pd(OH)₂, MeOH, H₂ (1 atm), RT; (h) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6- carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)3.

SiIyI ether VI-3 was deprotected to a secondary alcohol using TBAF in THF. The resulting alcohol was converted to fluoride X-1 using DAST as a nucleophilic fluorinating reagent in a polar aprotic solvent such as DCM at low temperature. The nitrile functionality was subsequently reduced to the corresponding amine using LiAIH₄ in THF at 0 C and the primary amine subsequently protected using Cbz succinamide in DMF to give X-2. Deprotection of the Boc-amine was achieved with TFA in DCM giving secondary amine X- 3. The secondary amine was then reacted with an electrophilic vinyl compound either neat or in a small amount of solvent providing X-4. Removal of the Cbz group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The resulting primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvent such as DMF, CH₂CI₂, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBH₄, NaBH(OAc)3 or NaBHβCN in solvent to give the amine X-5. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et^N), diisopropylethylamine ((J-Pr)₂NEt), or K₂Cθ3, may be used. Scheme Xl

VII-3 XM

XI-2 XI-3

XI-4

Reagents and conditions: (a) DAST, DCM -78°C; (b) TFA, CH2CI2, RT; then MP- carbonate resin, DCM, RT; (c) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, EtOH₁ 80 ⁰C; (d) Pd(OH)₂, MeOH, H₂ (1 atm), RT; (e) 3-oxo-3,4-dihydro-2W-pyrido[1 ,4]thiazine- 6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH(OAc)₃.

The alcohol VII-3 was converted to fluoride XI-1 using DAST as a nucleophilic fluorinating reagent in a polar aprotic solvent such as DCM at low temperature. Deprotection of the Boc-amine was achieved with TFA in DCM giving secondary amine XI-2. The secondary amine was then reacted with an electrophilic vinyl compound either neat or in a small amount of solvent providing XI-3. Removal of the Cbz group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The resulting primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvent such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBh^, NaBH(OAc)3 or NaBH3CN in solvent to give the amine XI-4. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Scheme XII

XIM XII-2 XII-3

XII-4 XII-5 XII-6

XII-7 XII-3

Reagents and conditions: (a) K₂CO₃, MeI, acetone, reflux (b) NaBH₄, EtOH, 0⁰C (c) LiAIH₄, THF, 0°C (d) N-(benzyloxycarbonyloxy)succinimide, DCM, O⁰C (e) 4M HCI in dioxane, MeOH, 25⁰C (f) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, EtOH, 85°C (g) Pd(OH)₂, EtOH, 50 psi (h) 3-oxo-3,4-dihydro-2W-pyrido[3,2-6][1,4]thiazine-6- carbaldehyde, Na₂SO₄, DCM-EtOH, 25°C then NaBH(OAc)₃

Alkylation of commercially available cyano-ketone (XII-1) provided methylpyrrolidine (XII-2). A two step reduction, first on the ketone then the nitrile provided the amine (XII-3), which was protected as the Z-carbamate (XII-5). The Boc group was removed using the standard methods as described by references such as Kocienski and Greene, previously cited herein. The resulting amine (Xlf-6) underwent Michael addition into an appropriate napthyridine yielding the adduct (XII-7). The Z-carbamate was subsequently removed through standard hydrogenolysis and the primary amine underwent reductive amination with an appropriate aldehyde generating analog (XII-9).

Scheme XIII

XIII-1 XIII-2 XIII-3

XIII-7 XIIl-S

Reagents and conditions: (a) N-(benzyloxycarbonyloxy)succinimide, DCM, 0°C (b) SOg-pyr, DMSO, Et₃N, 0-25⁰C (c) MeMgBr, THF-toluene, 0-25⁰C (d) 4M HCI in dioxane, MeOH, 25°C (e) 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine, EtOH, 85⁰C (g) Pd(OH)₂, EtOH, 50 psi (h) 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][1 ,4]thiazine-6- carbaldehyde, Na₂SO₄, DCM-EtOH, 25°C then NaBH(OAc)₃

The amine (XIII-1) [prepared according to Hong, C-Y. J. Med. Chem. 1997, 40, 3584.] was protected as the Z-carbamate (XIII-2). The alcohol was oxidized and the resulting ketone (XIII-3) was reduced using an alkyl-Grignard to the tertiary alcohol (XIII- 4). The Boc group on the pyrrolidine ring was removed using standard procedures such as those described by protecting group references like Kocienski or Greene, cited previously herein. The free amine (XIII-S) underwent Michael addition into an appropriate napthyridine generating adduct (XIII-6). The Z-carbamate was removed through hydrogenolysis and the resulting primary amine (XIII-7) underwent reductive amination with an appropriate aldehyde generating analog (XIII-8).

Scheme XIV

XIV-3 ^XIV-⁴

Reagents and conditions: (a) (BOC)₂O, Et₃N, CH₂CI₂, RT; (b) 10% Pd-C, H₂, MeOH, 50 psi; (c) 4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile, DMF, 90 ⁰C; (d) 4M HCI- dioxane, CH₂CI₂, RT; (e) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, NaHCO₃, CH₂CI₂, MeOH; then NaBH₄.

Pyrrolidine XIV-1, prepared according to the procedure of Hagen (J. Med Chem., 1990, 33, 849 - 854), was reacted with a suitable electrophile such as BOC-anhydride to afford the protected carbamate XIV-2. Selective removal of the N-benzyl group afforded XII-3 and was achieved via catalytic hydrogenation using Pd-C catalyst in methanol and a H₂ atmosphere. Amine XIV-3 was then heated with a vinyl naphthyrine or quinoline, either neat or in a suitable solvent (dioxane, DMF), generating the product XIV-4. In this example 4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile was utilized and the reaction was carried out at an elevated temperature. Deprotection of the t-butyl carbamate functionality was performed under acidic conditions using HCI in dioxane, however, alternative acids such as trifluoroacetic acid could be used. The primary amine derivative XIV-5, here isolated as a HCI salt, was then converted to a secondary amine XIV-6 by reaction with an aldehyde and a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBH3CN. This transformation may be carried out using the free base form of the amine or, as in this example, a salt form. If a salt-from of the amine is used, then the reaction is carried out in the presence of a base such as NaHCθ3, triethylamine (Et3N), diisopropylethylamine ((i- Pr)₂NEt), or K₂CO₃.

Scheme XV

Reagents and conditions: (a) 2M MeNH₂, DCM-MeOH₁ NaHCO3, then NaBH^ ; (b) 3- oxo-3,4-dihydro-2j^L/-pyrido[3,2-ό][1 ,4]thiazine-6-carboxylic acid, DPPA, Et₃N, DMF, RT; (c) ) 4M HCI-dioxane, CH₂CI₂, RT; (d) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine, diisopropylethylamine, DMF, 90 ⁰C. The pyrrolidine aldehyde XV-1 (CB Research) was reacted with methylamine and the resulting imine was reduced with NaBH4 to provide N-methylaminomethylpyrrolidine XV-2. This reductive amination process may be carried out using any number of methods that are well known in the art. The amine XV-2 was reacted with an appropriate carboxylic acid, in this example 3-oxo-3,4-dihydro-2H-pyrido[3,2-Jb][1 ,4]thiazine-6- carboxylic acid was used, in the presence of an activating agent such as DPPA to provide the amide XV-3. The BOC protecting group was removed via standard treatment with acid, in this example HCI in dioxane was used, to provide the pyrrolidine XV-4 as an HCI salt. The secondary amine XV-4 was heated together with a vinyl electrophile such as 8- ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine either under neat conditions or in an appropriate solvent such as DMF, dioxane or DME to give the product XV-5. If the amine exists as a salt, the free base is generated by the addition of a suitable base such as Et3N, diisopropylethylamine or NaHCC>3.

Scheme XVI

VII-3 XVI-1

XVI-5 XVI-4 Reagents and conditions: (a) PCC, DCM, RT; (b) Hydroxlamine hydrochloride, NaOAc; (c) HCI/dioxane, RT; (d) 8-ethenyl-7-f[uoro-2-(methyloxy)-1 ,5-naphthyridine, DMF, TEA, 90 ⁰C; (e) 10% Pd/C, H₂ (50psi), EtOH, THF, RT; (f) 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde, CH₂CI₂, EtOH; then NaBH4.

Alcohol VII-3 was oxidized to the corresponding ketone using an appropriate chromium-based oxidant such as PCC or PDC to give ketone IM. The ketone functionality was converted to an oxime XVI-2 by reaction with hydroxylamine in dry solvent. Deprotection of the Boc-amine was achieved with HCI in dioxane to give the secondary amine XVI-3. The secondary amine was then reacted with an electrophilic vinyl compound either neat or in a small amount of polar solvent providing XVI-4. Removal of the Cbz-group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH₂CI₂, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBH_βCN in solvent to give the amine XVI-5. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((J-Pr)₂NEt), or K₂Cθ3, may be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience). Scheme XVII

XV1I-2

Reagents and conditions: (a) EDC, HOBt, (/-Pr^NEt, DMF, 3-oxo-3,4-dihydro-2H- pyrido[3,2-jb][1 ,4]oxazine-6-carboxylic acid; (b) 3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6- sulfonyl chloride, Et₃N, DCM.

A suitable carboxylic acid, for instance 3-oxo-3,4-dihydro-2/-/-pyrido[3,2- b][\ ,4]oxazine-6-carboxyIic acid, is converted to an activated form using, for example, EDC and HOBt, or SOCI2, and the activated form is subsequently reacted with an appropriate amine, for instance amine III-4, in a suitable solvent such as DMF, CH2CI2, or CH3CN, to afford XVII-1. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((/-Pr^NEt), or pyridine, may be used. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag). A sulfonyl halide, in conjunction with a suitable base such as triethylamine, will react with III-4 to give the corresponding sulfonamide XVII-2. Scheme XVlII

XVIIM XVIII-2

XVIII-3

Reagents and conditions: (a) K₂OsO₂(OH)₂ , t-BuOCI, n-PrOH, NaOH, (BoC)₂O; (b) Pd/C, H₂, EtOH; (c) 8-ethenyl-2-(methyloxy)-1,5-naphthyridine, EtOH, 85 ⁰C; (d) TFA, DCM, RT, 2 h; (e) 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, CH2CI2, EtOH; then NaBH(OAc)₃.

Alkene XVIH-1 was converted to a Boc-protected syn-vicinal aminoalcohol using K₂OsO₂(OH)₂ , t-BuOCI, NaOH, and (Boc)₂0. Removal of the Cbz-group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The secondary amine XVIII-3 was then reacted with a electrophilic vinyl compound, such as 8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine, either neat or in a small amount of solvent providing XVIII-4. Deprotection of the Boc-amine was achieved with TFA in DCM to give a primary amine. The primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBH^., NaBH(OAc)3 or NaBH3CN in solvent to give the amine XVIII-5. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience).

Scheme XIX

XIX-1 XIX-2

XIX-3 XIX-4

XIX-5 XIX-6

Reagents and conditions: (a) NMM, isobutylchloroformate, NH₃, THF; (b) NiCI₂, NaBH₄, MeOH; (c) (BoC)₂O, DCM, Et₃N; (d) Pd(OH)₂, H₂, MeOH; (e) 8-ethenyl-7-fluoro-2- (methyloxy)-1 ,5-naphthyridine, EtOH, 85 ⁰C; (f) TFA, DCM, RT; (g) 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde, NaHCO₃, MeOH-DCM; then NaBH₄.

The racemic carboxylic acid XIX-1 (prepared by the base hydrolysis of the commercially available ethyl ester (Asta Tech)) was reacted with a hindered chloroformate to produce a mixed anhydride. Ammonia was reacted with the anhydride in situ to provide amide XIX-2. The Cyano functionality of XIX-2 was selectively reduced with NiCI₂ in combination with NaBH₄ giving amine XIX-3. The primary amine was protected with Boc anhydride and the secondary amine subsequently unmasked by removal of a benzyl group under hydrogenolysis conditions using Pd/C in a polar protic solvent under H₂. The resulting secondary amine XIX-4 was heated together with a vinyl electrophile such as 8- ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine either under neat conditions or in an appropriate solvent such as DMF, dioxane or DME to give the product XIX-5. The BOC protecting group was removed via treatment with acid, in this example TFA in DCM was used, to provide the primary amine. The primary amine derivative was then converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBHφ NaBH(OAc)3 or NaBH3CN in solvent to give the amine XIX-6. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Many additional methods for reductive animations are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley-lnterscience). Scheme XX

Reagents and conditions: (a) KCN₁ HCI, HCOH; THF, (b) Ethyl-cis-beta- cyanoacrylate, AgF; CH CN, (c) LiAIH , THF; O⁰C; d) Boc^A Et N, CHdCI₂- e) H₃ 10%Pd/C CH OH; f) DMF, 90⁰C; (f) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5- naphthyridine, EtOH, 85 ⁰C; (g) 4N HCI /dioxane, DCM; (h) 3-oxo-3,4-dihydro-2W- pyrido[1 ,4]thiazine-6-carboxaldehyde, NaHCO , MeOH-DCM; then NaBH .

Amine XX-1 was reacted with KCN and formaldehyde under acidic conditions to give the acetonitrile derivative XX-2. Reaction of XX-2 with AgF and an appropriate cyano acrylate will provide the pyrrolidine XX-3. Simultaneous reduction of both the ester and cyano functionality of XX-3 with a strong reduding agent such as LiAIH , provided amino alcohol XX-4. Protection of the amine and alcohol groups was performed with Boc anhydride in DCM with the addition of a base such as Et N. Removal of the benzyl group was achieved under hydrogenolysis conditions using a palladium catalyst in an alcoholic solvent under an atmosphere of hydrogen. The secondary amine XX-6 was then reacted with a electrophilic vinyl compound, such as 8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine, either neat or in a small amount of solvent providing XX-7. Deprotection of the Boc-amine and Boc-protected alcohol was achieved with HCI in dioxane/DCM to give the primary amine XX-8. The primary amine derivative was converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH2CI2, EtOH or CH3CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBH4, NaBH(OAc)3 or NaBH3CN in solvent to give the amine XX-9. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or K2CO3, may be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as "Compendium of Organic Synthetic Methods", Vol. I - Vl (published by Wiley- Interscience).

Experimentals General

Proton nuclear magnetic resonance 0 H NMR) spectra were recorded at 400 MHz, and chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Mass spectra were obtained using electrospray (ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, NJ. Melting points were obtained on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius. E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical HPLC was performed on Beckman chromatography systems. Preparative HPLC was performed using Gilson chromatography systems. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada. Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado. Nomenclature of base structures was generally provided by the ACD program used as a plug-in for the structure drawing program ISIS. Racemic compounds with more than one stereocenter which are present as a single, or essentially single diastereomer, are generally referred to by indicating that the compound is racemic via f±) and the relative stereochemistry of the diastereomers indicated by the R₁S designations of each center, or by their relative orientations (cis or trans)

Preparation 1

Preparation of 4-chloro-6-(methyloxy)-3-quinolinecarbonitrile

a) Diethyl ({[4-(methyloxy)phenyl]amino}methylidene)propanedioate To a solution of 4-aminoanisole (50 g, 0.406 mol) in EtOH (500 mL) was added diethyl ethoxymethylenemalonate (81 mL, 0.406 mol). The reaction solution was refluxed for 4 h; LCMS showed complete reaction. The reaction solution was concentrated under reduced pressure to give the desired product (118 g, 100%) as a crystalline solid.

b) Ethyl 4-hydroxy-6-(methyloxy)-3-quinolinecarboxylate Diethyl ({[4-(methyloxy)phenyl]amino}methylidene)propanedioate (100 g, 0.34 mol) was taken up in Dowtherm (500 mL) and heated at 250 ⁰C for 1.5 h; 75% conversion. The reaction solution was cooled, treated with hexanes (750 mL) and cooled to 0 ⁰C in ice bath. The brown solid was filtered off and washed with hexanes (2X) and dried under vacuum to give 60 g (71%). c) Ethyl 4-bromo-6-(methyloxy)-3-quinolinecarboxylate To a vigorously stirred solution of ethyl 4-bromo-6-(methyloxy)-3- quinolinecarboxylate (10 g, 40.5 mmol) in DMF (40 mL) was added PBr3 (4.4 ml_, 42.5 mmol) via dropwise addition over 15 min at rt. The reaction was allowed to stir at ambient temperature for 45 min after which was added water (150 mL). The reaction was neutralized with aq. NaHCC>3. The solid was collected by filtration and washed with water and dried under vacuum to give the desired product (12 g, 95%).

d) 4-Bromo-6-(methyloxy)-3-quinolinecarboxylic acid To a solution of the ethyl 4-bromo-6-(methyloxy)-3-quinolinecarboxylate (12 g, 38.7 mmol) in THF (120 mL) was added 2N NaOH (45 mL, 90 mmol) dropwise over 15 min. The reaction solution was stirred for 24 h and then neutralized with 2N HCI (pH 6). The THF was removed in vacuo and the resulting aqueous solution was acidified to pH 2. The product was collected by filtration and washed with water and fully dried under vacuum (48 h). Isolated 10.8 g (100%).

e) 4-Chloro-6-(methyloxy)-3-quinolinecarboxamide To a suspension of dried 4-bromo-6-(methyloxy)-3-quinolinecarboxylic acid (1.4 g, 5 mmol) in CH2CI2 (20 mL) at 0 ⁰C was added oxalyl chloride (2M in CH2CI2, 5.0 mL, 10 mmol). After 1 h, an aliquot was quenched with NH4OH and LCMS indicated desired product was formed. Excess NH4OH (2 mL) was slowly added to the reaction solution, maintained at 0 ⁰C (very exothermic), and the reaction was stirred an additional 2 h. The product was isolated via filtration to give 1.0 g (83%).

f) 4-Chloro-6-(methyloxy)~3-quinolinecarbonitrile To a suspension of 4-chloro-6-(methyloxy)-3-quinolinecarboxamide (0.92 g, 3.9 mmol) in CH2CI2 (8 mL) and Et₃H (4 mL) at 0 ⁰C was added TFAA (2.0 mL, 14 mmol) over 5 min. The reaction was warmed to rt and then stirred at this temperature for 2 h (complete by LCMS). The reaction solution was partitioned between water and CH2CI2 and the organic phase was collected. The aqueous phase was further extracted with CH2CI2. The organic layers were combined and washed with brine and dried over MgSOφ The solution was filtered and the solvent was removed in vacuo. The resulting material was redissolved in EtOAc and the product was precipitated via the addition of hexane. The solid material was collected by filtration and washed with cold hexanes and water to remove remaining Et^N. Isolated 580 mg (65%) of pure product as an off-white solid: LC/MS (ES) m/e 219 (M+H)⁺.

Preparation 2

Preparation of 4-bromo-6-(methyloxy)-3-quinolinecarbonitrile a) Methyl 2-{[(1 £)-(dimethylamino)methylidene]amino}-5-(methyloxy)benzoate

A suspension of 5-hydroxy-anthrilinic acid (2.5 g, 16.4 mmol, 1 eq) and dimethylforrnamide-dimethylacetal (7 mL, 52.6 mmol, 3.2 eq) in DMF (15 mL) was heated at 150 °C for 1 h, while methanol was distilled off through a short distillation apparatus. An additional dimethylformamide-dimethylacetal (4 mL) was added and heating resumed for another hour. The reaction mixture was concentrated under vacuum to remove excess DMF and DMF-DMA. The residue was partitioned between saturated NaHCO solution and DCM. The combined extracts were dried and evaporated to give the titled compound (3.6 g, 93% yield) as dark-grey oil, which was used for the next reaction without purification.

b) 4-Hydroxy-6~(methyloxy)-3-quinolinecarbonitrile To a cold solution of acetonitrile (2 mL, 38 mmol, 2.8 eq) in THF (30 mL) at -72 ⁰C (Dry-ice/IPA) was added dropwise nBuLi (12 mL, 30 mmol, 2.2 eq) under argon atmosphere. The reaction mixture became an orange suspension after 1 h. A solution of methyl 2-{[(1/Ξ)-(dimethylamino)methylidene]amino}-5-(methyloxy)benzoate (3.2 g, 13.6 mmol, 1 eq) in THF (30 mL) was then added dropwise while the internal temperature was maintained at -72 ⁰C. The resulting mixture was slowly warmed to RT overnight. To the resulting light-brown suspension was added glacial acetic acid (6 mL) with slight cooling. After stirring for 1 h, the suspension was then quenched with water (60 mL) and filtered to give the titled compound (2.3 g, 85 % yield).

c) 4-Bromo-6-(methyloxy)-3-quinolinecarbonitrile To a suspension of 4-hydroxy-6-(methyloxy)-3-quinolinecarbonitrile (2.19 g, 10.9 mmol, 1 eq) in DMF (20 ml_) at 0 ⁰C was added dropwise PBr (1.1 ml_, 11.6 mmol, 1.06 eq) with efficient stirring. After stirring for 1 h, the suspension was then quenched with NaOH (2.5 N, 200 ml_) and filtered to give the titled compound (2.6 g, 90 % yield) as an off-white solid: LC/MS (ES) m/e 264 (M+H)⁺.

Preparation 3

Preparation of 4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile To a solution of 4-chloro-6-(methyloxy)-3-quinolinecarbonitrile (1.1 g, 5.03 mmol), potassium carbonate (0.76 g, 5.53 mmol), tetrakis-triphenylphosphine (120 mg, 0.10 mmol) in DME (30 ml_) and H2O (10 ml.) was added 2,4,6-trivinylcycloborane-pyridine complex (1.33 g, 5.53 mmol). After stirring for 5 hours at 85°C the reaction contents was concentrated and the product purified by chromatography on silica gel (hexanes/EtOAc, 4:1) to give a light brown solid (0.9 g, 86%): LC/MS (ES) m/e 211 (M+H)⁺.

Preparation 4

Preparation of 4-ethenyl-6-(methyloxy)-1 ,5-naphthyridine-3-carbonitrile a) (2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester A solution of 5-amino-2-methoxypyridine (Aldrich, 10Og, 0.806 mole) and diethyl ethoxymethylenemalonate (Aldrich, 163 ml_, 0.806 mole) in EtOH (1 L) was heated at reflux for 4 hours, then was cooled to RT. Concentration to dryness gave the title compound (238 g, quantitative).

b) 6-Methoxy-4-oxo-1 ,4-dihvdro-ri ,51naphthyridine-3-carboxylic acid ethyl ester Dowtherm A (Fluka, 500 mL) was brought to boiling (250 ⁰C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).

c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).

d) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid 2 N NaOH (300 mL, 600 mmole) was added dropwise over 30 min to a stirred solution of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (83.56 g, 268 mmole) in THF (835 mL). Stirring was continued overnight, at which time LC/MS showed that the saponification was complete. 2 N HCI was added to pH 6 and the THF was removed in vacuo. 2 N HCI was added to pH 2, then water (250 mL) was added, and the mixture was cooled thoroughly in ice. The solid was collected by suction filtration, washed with water and dried (first using a rotary evaporator at 50 ⁰C and then under high vacuum at 50 ⁰C overnight) to give the title compound (76.7 g, slightly over quantitative). This material was used without further purification.

(e) 4-Chloro-6-(methyloxy)-1 ,5-naphthyridine-3-carboxamide To a solution of 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (840 mg, 3.0 mmol) in toluene (10 mL) was added thionyl chloride (3 mL) as one portion under N2 protection. After refluxing at 100 ⁰C for 2h, the mixture was concentrated and azotropically dried with toluene to afford a yellow solid, which was dissolved in anhydrous DCM (3 mL). The resulting solution was cooled down to 0 ⁰C and treated with NH solution (5 ml_, 50% in water). After stirring at 0 ⁰C for 30 min, the reaction mixture was warmed up to 25 ⁰C and stirred for 12h. DCM was removed, and the solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (648 mg, 91%).

(T) 4-Chloro-6-(methyloxy)-1 ,5-naphthyridine-3-carbonitrile To a solution of 4-chloro-6-(methyloxy)-1 ,5-naphthyridine-3-carboxamide (647 mg, 2.7 mmol) in anhydrous DCM (2 ml.) with triethyamine (2 ml_) at 0 ⁰C was added trifluororacetic anhydride (1 ml_) slowly. The resulting solution was warmed up to 25 ⁰C and stirred for 1 h. The mixture was partitioned between CHCI and H^D. The aqueous layer was extracted several times with CHCI . The organic fractions were combined, concentrated and purified with column chromatography (silica, 0-25% ethyl acetate/hexane) affording the title compound as an off-white solid (540 mg, 91%): LC/MS (ES) m/e 220 (M+H)⁺.

(g) 4-Ethenyl-6-(methyloxy)-1 ,5-naphthyridine-3-carbonitrile To a solution of 4-chloro-6-(methyloxy)-1 ,5-naphthyridine-3-carbonitrile (280 mg, 1.28 mmol), potassium carbonate (885 mg, 6.4 mmole), tetrakis-triphenylphosphine (30 mg, 0.026 mmole) in DME/H2O (20 ml_, 3:1) was added 2,4,6-trivinylcycloborane- pyridine complex (154 mg, 0.64 mmole). After stirring for 1 h at 90 ⁰C, another batch of tetrakis-triphenylphosphine (30 mg, 0.026 mmol) was added. After refluxing for another 1.5 h, the mixture contents were cooled down to room temperature and extrated with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ehtyl acetate in hexane) to give the title compound as a light yellow solid (176 mg, 65%): LC/MS (ES) m/e 212 (M+H)⁺.

Preparation 5

Preparation of 7-chloro-8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine (a) 3-Chloro-6-methoxy-quinolin-4-ol 6-Methoxy-quinolin-4-ol (18.5 g) in acetic acid (750 ml_) was treated with N- chlorosuccinimide (15.52 g) and the mixture was heated at 6O⁰C for 4.5 hr, cooled, and evaporated. Excess sodium bicarbonate solution was added and the solid collected and washed with water and dried in vacuo at 4O⁰C overnight, to give a yellow solid (21.3 g). MS (ES) m/z 210/212 (M + H)⁺.

(b) 4-Bromo-3-chloro-6-methoxy-quinoline 3-Chloro-6-methoxy-quinolin-4-ol from above in dry DMF (80 mL) was cooled in ice and phosphorus tribromide (15.6 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 3.5 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (13.2 g). MS (ES) m/z 272/274/276 (M + H)⁺.

(c) 7-Chloro-2-methoxy-8-vinyl-quinoline 4-Bromo-3-chloro-6-methoxy-quinoline (0.5 g) in DME (14 mL) under argon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.104 g) and the mixture stirred at room temperature for 20 minutes. Anhydrous potassium carbonate (0.25 g), water (4 mL), and vinylborane:pyridine complex was added and the mixture was heated at 100⁰C for 1 hr. It was cooled, diluted with water and extracted with ether, dried (sodium sulfate) and evaporated to dryness. As starting material (4b) was still present the crude reaction product was reacted again, as above, and heated for a further 6 hours. After work-up the product was chromatographed on silica gel, eluting with DCM to afford a white solid (0.35 g): MS (ES) m/z 220/222 (M + H)⁺.

Preparation 6

8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine a) (2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester A solution of 5-amino-2-methoxypyridine (Aldrich, 100 g, 0.806 mole) and diethyl ethoxymethylenemalonate (Aldrich, 163 mL, 0.806 mole) in EtOH (1 L) was heated at reflux for 4 h, then was cooled to RT. Concentration to dryness gave the title compound (238 g, quantitative).

(b) 6-Methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester Dowtherm A (Fluka, 500 ml_) was brought to boiling (250 ⁰C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to room temperature and diluted with hexane (750 mL). The mixture was cooled in ice for 1 h, then the brown solid was filtered off, washed with hexane, and dried under vacuum to afford the title compound (61.72g, 73%).

(c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately room temperature - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).

(d) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid 2 N NaOH (300 mL, 600 mmol) was added dropwise over 30 min to a stirred solution of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (83.56 g, 268 mmol) in THF (835 mL). Stirring was continued overnight, at which time LC/MS showed that the saponification was complete. 2 N HCI was added to pH 6 and the THF was removed in vacuo. 2 N HCI was added to pH 2, then water (250 mL) was added, and the mixture was cooled thoroughly in ice. The solid was collected by suction filtration, washed with water and dried (first using a rotary evaporator at 50 ⁰C and then under high vacuum at 50 ⁰C overnight) to give the title compound (76.7 g, slightly over quantitative). This material was used without further purification.

(e) 4-Bromo-6-methoxy-[1 ,5]naphthyridin-3-ylamine A suspension of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid (50 g, 177 mmol) in dry DMF (600 mL) was treated with triethylamine (222.5 ml_, 1.60 mole), te/f-butanol (265 mL, 2.77 mole) and diphenylphosphoryl azide (41.75 mL, 194 mmol). The reaction was stirred under argon at 100 ⁰C for 1 h, then was cooled to room temperature and concentrated to low volume. Ethyl acetate and excess aqueous sodium bicarbonate solution were added, the mixture was shaken, and some insoluble solid was filtered off. The layers were separated and the organic phase was washed with water (2x) and dried (MgSθ4). Concentration to dryness gave a crude mixture of 4-bromo-6- methoxy-[1 ,5]naphthyridin-3-ylamine (minor product) and (4-bromo-6-methoxy- [1 ,5]naphthyridin-3-ylamine)carbamic acid terf-butyl ester (major product) along with impurities. Without further purification, this mixture was dissolved in CH2CI2 (150 mL) and treated with trifluoroacetic acid (100 mL). The reaction was stirred for 3 h then was concentrated to dryness. The residue was partitioned between CHCI3 and saturated sodium bicarbonate solution and the layers were separated. The aqueous phase was extracted with CHCI3, and the combined organic fractions were dried (MgSC>4) and concentrated to low volume. The solid was collected by suction filtration, washed with a small volume of CHCI3 and dried under vacuum to afford a first crop of the title compound (31.14 g). The filtrate was purified by flash chromatography on silica gel (30% EtOAc in CHCI3) to afford further material (2.93 g, total = 34.07 g, 76%). Alternatively, the filtrate was left at room temperature overnight and then filtered to give a second crop of the title compound (2.5 g).

(f) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-diazonium tetrafluoroborate A solution of 4-bromo-6-methoxy-[1 ,5]naphthyridin-3-ylamine (25.2 g, 99.2 mmol) in dry THF (400 mL) was maintained at -5°C while nitrosonium tetrafluoroborate (12.9 g, 110 mmol) was added portionwise over 30 min (approximately 2 g portions). The reaction was continued for an additional 1 h at -5 ⁰C, at which time TLC* and LC/MS indicated that the reaction was complete. The orange solid was collected by suction filtration, washed with ice-cold THF and dried under vacuum to provide the title compound (31.42 g, 90%).

(g) 4~Bromo-3-fluoro-6-methoxy-[1 ,5]naphthyridine A suspension of 4-bromo-6-methoxy-[1 ,5]naphthyridine-3-diazonium tetrafluoroborate (31.42 g, 89.0 mmol) in decalin (mixed isomers, 500 mL) in a 2 L flask* was heated to 180 ⁰C and held at this temperature for 5 min. The mixture was cooled and diluted with CHCI3 (500 ml_, to keep the product in solution), and the resulting mixture was stirred vigorously for 30 min to break up a black solid byproduct. The mixture was then poured onto a column of silica gel and the column was eluted with CHCI3 to remove decalin and then with 3% EtOAc/CHCl3 to afford the title compound (9.16 g, 40%).

(h) 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine To a solution of 8-bromo-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (2.0 g, 7.81 mmol), potassium carbonate (1.08 g, 7.81 mmol), tetrakis-triphenylphosphine (90 mg, 0.08 mmol) in DME (60 mL) and H2O (20 ml_) was added 2,4,6-trivinylcycloborane- pyridine complex (0.94 g, 3.91 mmol). After stirring for 10 h at 85 ⁰C the reaction contents were concentrated and the product purified by chromatography (silica, 25% EtOAc in hexane) to give the title compound as a low melting solid (1.43 g, 90%): MS (ES) m/z 206 (M + H)⁺. Preparation 7

Preparation of 4-ethenyl-3,8-difluoro-6-(methoxy)quinoline

a) 3-fluoro-4-nitrophenyl methyl ether A solution of 3-fluoro-4-nitrophenol (25 g, 0.159 mmol) in acetonitrile (500 mL) and methanol (500 mL) was treated with diisopropyl ethylamine (28 mL). The reaction mixture was cooled in an ice-bath and after 30 minutes, trimethylsilyldiazomethane was added dropwise. The mixture was stirred at room temperature for 18 hours then evaporated under vacuum to afford the product as an oil (29.4 g, 100%). MS (+ve ion electrospray) m/z 172 (MH+).

b) 2-fluoro-4-(methoxy)aniline A solution of 3-fluoro-4-nitrophenyl methyl ether (28.1 g, 164 mmol) in ethanol (200 mL) was hydrogenated with palladium on charcoal. The reaction mixture was filtered through Kieselguhr and evaporated under vacuum to afford the product as an oil (22.8 g, 98%); MS (+ve ion electrospray) m/z 141 (MH+).

c) ethyl 8-fluoro-6-(methoxy)-4-oxo-1 ,4-dihydro-3-quinolinecarboxylate A mixture of aniline 2-fluoro-4-(methoxy)aniline (22.8 g, 162 mmol) and diethyl [(ethyloxy)methylidene]propanedioate (32.6 mL) were heated to reflux in Dowtherm A under a flow of argon. After 15 minutes (when all ethanol was removed), the mixture was allowed to cool down and was diluted with pentane. A precipitate was formed which was triturated with pentane, filtered and dried under vacuum to afford the product as an oil (33.06 g, 77%); MS (+ve ion electrospray) m/z 265 (M+H)+.

d) ethyl 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylate To a solution of ethyl 8-fluoro-6-(methoxy)-4-oxo-1 ,4-dihydro-3- quinolinecarboxylate (12 g, 45 mmol) in DMF (56 ml) was added dropwise phosphorus tribromide (4.5 ml, 47 mmol) over fifteen minutes (slightly exothermic). The reaction was held at O⁰C, with an ice bath, for one hour and allowed to warm to room temperature then stirred for a further 2 hours. The mixture was then diluted with water (400 mL). A solution of sodium bicarbonate was added to reach pH 7. The reaction mixture was stirred for one hour at O⁰C then filtered. The precipitate was washed with water and dried in vacuo to afford the product as a yellow solid (12.2 g, 82%). MS (+ve ion electrospray) m/z 329 (MH+).

e) 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylic acid A solution of ethyl 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylate (12.2 g, 37.3 mmol) in tetrahydrofuran (450 mL) was diluted by addition of a solution of sodium hydroxide 2N (27 mL) in water (75 mL). The reaction mixture was stirred overnight at room temperature then acidified to pH 3 with a solution of hydrogen chloride 5N. The solvents were evaporated to half the volume in vacuo. The reaction mixture was acidified to pH 1 by further addition of hydrogen chloride 5N, cooled to 4⁰C for 30 minutes then filtered. The precipitate was dried in vacuo to afford the product as a white solid (10.1 g, 90%); MS (+ve ion electrospray) m/z 301 (MH+).

f) 1 ,1-dimethylethyl [4-bromo-8-fluoro-6-(methoxy)-3-quinolinyl]carbamate A solution of 4-bromo-8-fluoro-6-(methoxy)-3-quinolinecarboxylic acid (7.5 g, 25 mmol) in butanol (40 mL) and DMF (88 mL) was treated with triethylamine (30 mL) then diphenylphosphoryl azide (5.8 mL, 27.5 mmol). The reaction mixture was heated at 100⁰C for two hours under argon atmosphere. The mixture was then cooled down to room temperature and evaporated to half the volume in vacuo. Water (100 mL) was added to the mixture under vigorous stirring. A precipitate was formed, filtered and dried in vacuo. This crude product was chromatographed on silica gel eluting with 10% methanol in dichloromethane to afford the product as a white solid (6.4 g, 69%). MS (+ve ion electrospray) m/z 372 (MH+).

g) 4-bromo-8-fluoro-6-(methoxy)-3-quinolinamine 1 ,1-Dimethylethyl [4-bromo-8-fluoro-6-(methoxy)-3-quinolinyl]carbamate (6.4 g, 17.3 mmol)) was treated with trifluoroacetic acid (50 ml) in dichloromethane (50 ml) at room temperature for two hours then evaporated to dryness. The residue was basified with sodium bicarbonate. A precipitate was formed which was filtered and dried in vacuo to afford the product as a white solid (4.7 g, 100%). MS (+ve ion electrospray) m/z 272 (MH+).

h) 4-bromo-6-methoxy-8-fluoroquinolin-3-yl-diazonium tetrafluoroborate A solution of 4-bromo-8-fluoro-6-(methoxy)-3-quinolinamine (3 g, 11.1 mmol) in anhydrous THF (40 mL) cooled down to -9⁰C, with an ethanol/ice bath, was treated with nitrosonium tetrafluoroborate (1.4 g, 12.2 mmol) added portionwise over 20 minutes. The reaction mixture was stirred for 30 minutes at -2⁰C under argon atmosphere. A precipitate was formed which was filtered, washed with cold THF and dried in vacuo overnight to afford the product as a yellow solid (3.2 g, 79%). MS (+ve ion electrospray) m/z 370 (MH+).

i) 4-bromo-3,8-difluoro-6-(methoxy)quinoline 4-Bromo-6-methoxy-8-fluoroquinolin-3-yl-diazonium tetrafluoroborate (2.4 g, 6.5 mmol) was added to hot Decalin ® (45 mL). The reaction mixture was maintained at 17O⁰C for 5 minutes. Cold Decalin® (20 mL) was added and the reaction mixture was cooled down with an ice bath. The Decalin ® layer was decanted off the dark residue and washed with a solution of sodium bicarbonate, brine and water. The organic layer was dried over magnesium sulfate. Solvents from the work-up were evaporated under vacuum and and the Decalin® layer was cooled down to 4⁰C. A precipitate was formed (product) which was filtered off. The decalin filtrate and the dark residue obtained before work-up were combined and chromatographed eluting with dichloromethane to afford the further product as a white solid (combined yield, 0.75 g, 42%). MS (+ve ion electrospray) m/z 275 (MH+).

j) 4-ethenyl-3,8-difluoro-6-(methoxy)quinoline 4-Bromo-3,8-difluoro-6-(methoxy)quinoline (0.63 g, 2.3 mmol) in DME (26 mL) under argon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) and the mixture stirred at room temperature for 20 minutes. Anhydrous potassium carbonate (0.32 g, 2.3 mmol), water (7 mL), and vinylborane:pyridine complex (see F. i Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and the mixture was heated at 100⁰C for 2 hr. It was cooled, diluted with water and extracted with ether, dried over magnesium sulfate and evaporated to dryness. After work-up the product was chromatographed on silica gel, eluting with 10 %methanol in DCM to afford a white solid (0.46g, 90%). MS (+ve ion electrospray) m/z 221 (MH+).

Preparation 8

Preparation of (S)-2-(6-Methoxy-H ,51-naphthyridin-4-yl)oxirane

a) 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%). The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%)

b) Bromomethyl-(6-methoxy-[1 ,5]-naphthyridin-4-yl)-ketone 4-Hydroxy-6-methoxy-[1,5]-naphthyridine (10g, 0.057mol) in dichloromethane (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml, 0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane). The triflate (13.2g, 0.044mol) in DMF (200ml) with triethylamine (12ml, 0.086mol) butyl vinyl ether (22ml, 0.17mol), palladium (II) acetate (0.97g, 0.0044mol) and 1 ,3- bis(diphenylphosphino)propane (1.77g, 0.0044mol) was heated at 6O⁰C for 3 hours then evaporated and chromatographed on silica gel (dichloromethane) to give a yellow solid (10.7g, 95%). This was dissolved in THF (250ml), water (40ml) and treated with N- bromosuccinimide (7.4g.0.042 mol) for 1 hour, then evaporated and chromatographed on silica gel (dichloromethane) to give the ketone (10.42g, 98%).

c) (R)-2-Bromo-1-(6-methoxy-[1 ,5]-naphthyridin-4-yl)ethanol Bromomethyl-(6-methoxy-[1 ,5]-naphthyridin-4-yl)-ketone (6.6g, 0.023mol) in toluene was treated with (+)-B-chlorodiisopinocamphenylborane ((+)-DIP-chloride) (12g, 0.037mol) and stirred overnight, then diethanolamine (15g, 0.14mol) added and the mixture stirred for 3 hours, filtered and evaporated. Chromatography on silica gel (ethyl acetate-hexane )gave a white solid (4.73g, 73%).

d) (f?)-2-(6-Methoxy-[1 ,5]-naphthyridin-4-yl)oxirane (R)-2-Bromo-1-(6-methoxy-[1 ,5]-naphthyridin-4-yl)ethanol (4.8g, 0.017mol) in methanol (20ml) was stirred with potassium carbonate (2.6g, 0.019 mol) for 1 hour, then evaporated and chromatographed on silica gel (ethyl acetate-hexane-dichloromethane) to give a solid (3.14g, 92%), (91% ee by chiral HPLC). MS (+ve ion electrospray) m/z 203 (M+H+).

Preparation 9

Preparation of 8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine To a solution of 6-(methyloxy)-1 ,5-naphthyridin-4-yl trifluoromethanesulfonate (from Prep. 5b) (5.0 g, 16.23 mmole) in DME (80 ml.) and H2O (40 mL) was added trivinyl boronate (1.96 g, 8.1 mmole), K2CO3 (2.23 g, 16.23 mmole) and Pd(PPh3)4 (0.19 g, 0.16 mmole). After 3 h at 90° C under N2, the reaction solution was concentrated under vacuum and purified on silica (hexanes, EtOAc, 4:1) to give a yellow oil (2.44 g, 81%): LC- MS (m/z) (ES) 187 (M+H)⁺.

Preparation 10

Preparation of 4-ethenyl-3-fluoro-6-(methyloxy)quinoline

a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A).

b) 4-Bromo-6-methoxy-quinoline-3-carboxylic acid ethyl ester PBr3 (64.5 g, 22.5 mL, 0.239 mole) was added dropwise to a stirred, ice cold suspension of 4-hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester (59 g, 0.239 mole) in DMF (750 mL); the temperature rose to 15-20 ⁰C for 30 min and then dropped to ca. 5 °C (the starting material dissolved fairly quickly and a new solid precipitated out). After 3 hr the solid was collected, washed sequentially with cold DMF, hexane, and water, then was dried at 40 ⁰C in vacuo overnight to give the title compound (41 g, 78%): LC/MS (ES) m/e 310/312 (M + H)⁺. c) 4-Bromo-6-methoxyquinoline-3-carboxylic acid 4-Bromo-6-methoxy-quinoline-3-carboxylic acid ethyl ester (41 g, 0.132 mole), partially dissolved in THF (600 ml_), was treated dropwise with aqueous 2 M sodium hydroxide (198.4 mL, 0.396 mole). After 24 hr, the reaction was complete by TLC (2% MeOH/CH2Cl2). The mixture was neutralized with 5 M HCI then the THF was removed in vacuo. The residue was dissolved in water and acidified with 5 M HCI. The solid product was collected under suction, washed well with water, and dried in vacuo to give the title compound (34 g, 91%) as a white solid: MS (ES) m/e 282/284 (M + H)⁺.

d) (4-Bromo-6-methoxy-quinolin-3-yl)-carbamic acid fert-butyl ester To a solution of 4-Bromo-6-methoxyquinoline-3-carboxylic acid (34 g, 0.121 mole), triethylamine (141 mL) and terf-butanol (181 mL) in dry DMF (400 mL) was added diphenylphosphoryl azide (36.6 g, 28.6 mL, 0.133 mole). The mixture was heated at 100 ⁰C for 1h (see Note), then cooled and concentrated. The residue was dissolved in CH2CI2 and washed with water (some insoluble material was removed by filtration). The aqueous phase was extracted with dichloromethane and the combined organics were dried (Na2SO4) and concentrated. Chromatography on silica gel (1 kg, 1 :1 ether/light

petroleum ether) gave the carbamate (22.7 g, 53 %): MS (ES) m/e 309/311 (M + H)⁺, 354/6. Further elution with ether gave several mixed fractions then pure 3-amino-4-bromo-6- methoxyquinoline (2.0 g, 6.5%): MS (ES) m/e 309/311 (M + H)⁺, 254/6.

e) 3-Amino-4-bromo-6-methoxyquinoline (4-Bromo-6-methoxy-quinolin-3-yl)-carbamic acid terf-butyl ester (22.7 g, 0.0643 mole) was dissolved in CH2CI2 (200 mL) and treated with trifluoroacetic acid (100 mL). After 3.5 hr at RT, the mixture was concentrated and the residue was dissolved in water. The solution was made basic with aqueous sodium carbonate. The precipitate was filtered off, washed with water, and dried at 40 °C in vacuo overnight, to give the title compound ( 16.46 g, 101%) as a white solid: MS (ES) m/e 254/256 (M + H)⁺.

f) 4-Bromo-3-methoxyquinolin-3-yl-diazonium tetrafluoroborate 3-Amino-4-bromo-6-methoxyquinoline (18.4 g, 0.0727 mole) was dissolved in dry THF (250 mL) and the solution was cooled to -8 ⁰C (EtOH-ice bath). Nitrosonium tetrafluoroborate (9.34 g, 0.08 mole) was added in portions over 10 min, keeping the temperature less than -2 °C. The mixture was stirred at -5 to 0 ⁰C for 30 min, then the yellow precipitate was filtered off and washed sequentially with cold THF and hexane. Drying in vacuo gave the title compound (19.4 g, 76%) an insoluble orange-yellow solid.

g) 4-Bromo-3-fluoro-6-methoxyquinoline A well stirred solution of decahydronaphthalene (mixed isomers, 120 mL) was heated to ca. 167-170 ⁰C (internal temperature) and the diazonium tetrafluoroborate salt (6.0 g) was added portionwise over 30 sec, when the solid turned black. The reaction mixture was immediately cooled and the decahydronaphthalene was filtered off. The filtrate was saved for further processing. The residue was extracted with dichloromethane (3x). Some insoluble material remained. The solution was concentrated and the residue was chromatographed on silica gel (CH2CI2 then CHCI3) to give the title compound (1.1

g) as a white solid: MS (ES) m/e 256/258 (M + H)⁺, Rt = 2.65 min. About 4% of a dibromo impurity was present: MS (ES) m/e 316/318/320 (M + H)⁺ Rt = 2.94 min.

The decahydronaphthalene solution was treated with excess ethereal HCI and the solid hydrochloride salt was collected and washed with hexane. This was converted to the free base by reaction with aqueous sodium carbonate followed by extraction with CH2CI2. This gave additional title compound (0.87 g; total yield = 1.97 g, 45%).

h) 4-ethenyl-3-fluoro-6-(methyloxy)quinoline 4-Bromo-3,fluoro-6-(methoxy)quinoline (2,3 mmol) in DME (26 mL) under argon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) and the mixture stirred at room temperature for 20 minutes. Anhydrous potassium carbonate (0.32 g, 2.3 mmol), water (7 mL), and vinylborane:pyridine complex (see F. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and the mixture was heated at 100⁰C for 2 hr. It was cooled, diluted with water and extracted with ether, dried over magnesium sulfate and evaporated to dryness. After work-up the product was chromatographed on silica gel, eluting with 10 %methanol in DCM to afford a white solid (0.44g, 90%). MS (+ve ion electrospray) m/z 203 (MH+). Preparation 10a

Preparation of 4-ethenyl-6-(methyloxy)quinoline

a) 4-bromo-6-methoxy quinoline To a stirred solution of 4-hydroxy-6-methoxyquinoline (1.20 g, 70.5 mmole) in DMF (60 ml_) at RT was added PBr₃ (8.0 mL, 84.6 mmole) dropwise. After 2h, the reaction contents were poured onto H2O (300 mL) and the product filtered and washed with H2O to give, after drying under high vacuum, the title compound (14.3 g, 87%) as a light yellow solid: LC-MS (ES) m/e 233 (M+H)⁺.

b) 4-ethenyl-6-(methyloxy)quinoline To a solution of 6-(methyloxy)-1 ,5-naphthyridin-4-yl trifluoromethanesulfonate (5.0 g, 16.23 mmol) in DME (80 mL) and H2O (40 mL) was added trivinyl boronate (1.96 g, 8.1 mmol), K₂CO₃ (2.23 g, 16.23 mmol) and Pd(PPh₃)₄ (0.19 g, 0.16 mmol). After 3 h at 90 ⁰C under N₂, the reaction solution was concentrated under vacuum and purified on silica (hexane/EtOAc, 4:1) to give the title compound as a yellow oil (2.44 g, 81%): LC/MS (m/z) (ES) 186 (M+H)⁺.

Preparation 10b

Preparation of 4-ethenyl-8-fluoro-6-(methyloxy)quinoline

a) 8-Fluoro-6-methoxy-quinolin-4-ol 2-Fluoro-4-methoxyphenylamine (3.8Og, 26.7 mmole) and methyl propiolate (2.37ml, 0.267 mole) in methanol (100ml) was stirred for 72 hours at room temperature, then heated at 5O⁰C for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66g), a portion of which was recrystallised from dichloromethane-hexane. The unsaturated ester (0.96g) in warm Dowtherm A (5ml) was added over 3 minutes to refluxing Dowtherm A (15ml), and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipate was filtered to give the title compound (0.50 g, 61%). MS (ES) m/e 196 (M+H)⁺.

b) 1 ,1 ,1 -Trif luoromethanesulfonic acid 8-fluoro-6-methoxy-quinolin-4-yl ester 8-Fluoro-6-methoxyquinolin-4-ol (0.48 g, 2.46 mmole) and dimethylaminopyridine (0.03 g) in dichloromethane (20 ml_) and 2,6-lutidine (0.48 ml.) was treated dropwise with triflic anhydride (0.48 ml) and the mixture was stirred at room temperature for 4 hours. It was washed with saturated ammonium chloride, dried, evaporated, and chromatographed on silica gel (dichloromethane) to afford a yellow solid (0.69 g, 86%). MS (ES) m/e 326 (M+H)⁺.

c) 4-ethenyl-8-fluoro-6-(methyloxy)quinoline To a solution of 1 ,1 ,1 -trifluoromethanesulfonic acid 8-fluoro-6-methoxy-quinolin-4- yl ester (1.0g, 3.1 mmol), potassium carbonate (1.28 g, 9.3 mmole), tetrakis- triphenylphosphine (350 mg, 0.3 mmole) in DME/H2O (20 ml_, 3:1) was added 2,4,6- trivinylcycloborane-pyridine complex (460 mg, 1.5 mmole). After stirring for 3h at 90 ⁰C, the mixture contents were cooled to room temperature and extracted with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ehtyl acetate in hexane) to give the title compound as a light yellow solid (428 mg, 65%): LC/MS (ES) m/e 212 (M+H)⁺.

Preparation 10c

Preparation of 4-ethenyl-6-fluoro-5-(methyloxy)quinoline

a) 4-bromo-2-fluorophenyl ethyl carbamate A solution of 4-bromo-2-fluorophenol (25 g, 130 mmol) and triethyl amine (21.6, 155 mmoles) in DCM (120 mL) at 0 C was treated with a solution of ethylchlororformate (14.8 mL, 155 mmol) in DCM (40 mL) dropwise. The reaction mixture was stirred at 0 C for 1 h and allowed to reach room temperature. The reaction mixture was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under vacuum to afford the title comound (32 g, 93%) as a colorless oil. LC-MS (ES) (M+H)⁺ m/z = 263.

b) 4-bromo-2-fluoro-5-nitrophenyl ethyl carbonate To a solution of 4-bromo~2-fluorophenyl ethyl carbamate (32 g, 130 mmol) in concentrated sulfuric acid (55 ml_) at 10 C, was added fuming nitric acid (8.5 ml_, 195 mmol) dropwise. After 2h, the reaction mixture was poured onto ice-water and extracted several times with ethyl acetate. The combined organics were dried over magnesium sulfate and evaporate under vacuum to afford the title compound (35g, 92%) as a yellow oil. LC-MS (ES) (M+H)⁺ m/z = 309.

c) 4-bromo-2-fluoro-5-nitrophenol A solution of 4-bromo-2-fluoro-5-nitrophenyl ethyl carbonate (35 g, 113 mmole) in MeOH (200 mL) was treated with sodium bicarbonate (19 g, 227 mmole). The reaction mixture was stirred at 60 C for 4 hours. The methanol was evaporated under vacuum. Water (55 mL) was added to the residue and the aqueous layer was acidified to pH=5 by addition of a solution of 6N hydrogen chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (25g, 93%) as a yellow solid. LC- MS (ES) (M+H)⁺ m/z = 237.

d) 4-bromo~2-fluoro-5-nitrophenyl methyl ether

A solution of 4-bromo-2-fluoro-5-nitrophenol (25 g, 106 mmol) in DMF (200 mL) was treated with potassium carbonate (28.9 g, 212 mmol) and methyl iodide (12.8 mL, 212 mmol). The reaction mixture was stirred at 60 C for 5 hours and evaporated in vacuo. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under vacuum to afford the product (25.6 g, 97%) as a yellow solid. LC-MS (ES) (M+H)⁺ m/z = 251.

e) 2-bromo-4-fluoro-(methyloxy)aniline A mixture of 4-bromo-2-fluoro-5-nitrophenyl methyl ether (25.5 g, 102 mmol), acetic acid (250 mL), ethanol (250 mL) and iron powder (22.7 g, 408 mmol) was heated to 100 C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralised by addition of potassium carbonate and filtered through Celite. The aqueous layer was extracted thrice with DCM. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (15 g, 67%) as a white solid. LC-MS (ES) (M+H)⁺ m/z = 220.

f) 5-({[2-bromo-4-fluoro-5-(methyloxy)phenyl]amino}methylidene)-2,2-dimethyl-1 ,3- dioxane-4,6-dione A mixture of 2-bromo-4-fluoro-(methyloxy)aniline (15g, 68 mmol), 2,2-dimethyl- [1 ,3]dioxane-4,6-dione (11.8 g, 82 mmol) and trimethylorthoformate (13.6 mL) in ethanol (70 mL) was refluxed for 3 hours. After cooling, the solid was filtered off, washed with ethanol and air dried. To give the product (23.3 g, 92%) as a white solid. LC-MS (ES) (M+H)⁺ m/z = 374.

g) 8-bromo-6-fluoro-5-(methyloxy)-4-(1 H)-quinilone Intermediate 5-({[2-bromo-4-fluoro-5-(methyloxy)phenyl]amino}methylidene)-2,2- dimethyl-1 ,3-dioxane-4,6-dione (13 g, 34.8 mmol) was slowly added over five minutes to refluxing Dowtherm A (40 mL). After an additional five minutes at reflux, the mixture was allowed to cool to room temperature and ether was added. The product was filtered off, thoroughly washed with ether and then dried to afford the title compound (5.4 g, 57%) as a gold colored solid. LC-MS (ES) (M+H)⁺ m/z = 273.

h) 6-fluoro-5-(methyoxy)-4(1 H)-quinilinone A suspension of 8-bromo-6-fluoro-5-(methyloxy)-4-(1 H)-quinilone (3.5 g, 12.8 mmol) in dioxane/water (300/100 mL) was treated with a solution of sodium hydroxide 1 N (12.8 mL, 12.8 mmol). The solution was hydrogenated with palladium on charcoal. The reaction mixture was filtered through Kieselguhr, acidified by addition of a solution of hydrogen bromide and evaporated to dryness. The residue was treated with water (30 mL), filtered and dried in vacuo to afford the product (3.0 g, 60%) as a white solid. LC-MS (ES) (M+H)⁺ m/z = 194.

i) 4-bromo-5-fluoro-6-methyloxy)quinoline To a solution of 6-fluoro-5-(methyoxy)-4(1 H)-quinilinone (2 g, 10 mmole) in DMF (13 mL) was added dropwise phosphorus tribromide (1.2 mL, 12.4 mmol) over 5 minutes. The reaction was allowed to cool to room temperature and was then diluted with ice-water and stirred 1hour, then diluted with additional water. The product was filtered, washed with water and dried in vacuo to afford the product (1.8 g, 71%) as a white solid. LC-MS (ES) (M+H)⁺ m/z = 257.

j) 4-ethenyl-6-fluoro-5-(methyloxy)quinoline To a solution of 4-bromo-5-fluoro-6-(methyloxy)quinoline (0.80 g, 3.1 mmol), potassium carbonate (1.28 g, 9.3 mmole), tetrakis-triphenylphosphine (350 mg, 0.3 mmole) in DME/H2O (20 mL, 3:1) was added 2,4,6-trivinylcycloborane-pyridine complex (460 mg, 1.5 mmole). After stirring for 3h at 90 ⁰C, the mixture contents were cooled to room temperature and extracted with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ethyl acetate in hexane) to give the title compound as a light yellow solid (0.41 g, 65%): LC/MS (ES) m/e 205 (M+H)⁺.

Preparation 10d

Preparation of 9-Chloro-10-vinyl-2,3-dihydro-[1 ,4]dioxino[2,3-f|quinoline

a) 7-Bromo-2,3-dihydro-benzo[1 ,4]dioxin-6-ylamine

A solution of 2,3-dihydro-benzo[1 ,4]dioxin-6-ylamine (80 g, 530 mmol, 1 eq) in tetrahydrofuran (1000 mL) at -78⁰C was treated with concentrated sulfuric acid (50 drops) then N-bromosuccinimide (94.2 g, 530 mmol, 1 eq) was added over 0.5 hour. After the addition the mixture was stirred at -78⁰C for 1 hour then treated with solid sodium carbonate (12 g, 113 mmol, 0.21 eq). The mixture was evaporated and the residue partitioned between ether and water. The organic extract was dried, filtered and evaporated to give to oil that was chromatographed on silica gel eluting with dichloromethane to afford oil (141 g, 92%). LC/MS (ES) m/z 230 (MH⁺ 91%); 1 H-NMR (400 MHz₁ d6- DMSO), 6.85 (1 H, s, CHCNH2 ), 6.34 (1 H₁S₁CHCBr), 4.79 (2H₁ s, NH2), 4.16 (4H, dd, J = 16, 2 x (CH2O)) b) 5-[(7-Bromo-2,3-dihydro-benzo[1 ,4]dioxin-6-ylamino)-methylene]-2,2-climethyl- [1 ,3]dioxane-4,6-dione

A mixture of 7-Bromo-2,3-dihydro-benzo[1 ,4]dioxin-6-ylamine (14.8 g, 64.3 mmol, 1 eq), triethyl orthoformate (12.7 cm3, 77.2 mmol, 1.2 eq) and 2,2-dimethyl-[1 ,3]dioxane- 4,6-dione (Meldrum's acid) (11.1 g, 77.2 mmol, 1.2 eq) in ethanol (70 ml_) was heated to reflux. After 1 hour the mixture was allowed to cool to room temperature then filtered, washing with ethanol then ether, to afford a white solid (22.9 g, 93%). LC/MS (ES) m/z 384 (MH⁺ 100%); 1 H-NMR (400 MHz, d4-DMSO), 11.43 (1 H, br d, J = 20, NH), 8.6 (1 H, d, J = 12, NCH=C), 7.49 (1H, s, CHCBr), 7.28 (1H, s, CHCN), 4.30-4.27 (4H, m, 2 x (CH2O)), 1.68 (6H, s, (CH3)2C)

c) 6-Bromo-2,3-dihydro-7H-[1 ,4]dioxino[2,3-/]quinolin-10-one

5-[(7-Bromo-2,3-dihydro-benzo[1 ,4]dioxin-6-ylamino)-methylene]-2,2-dimethyl- [1 ,3]dioxane-4,6-dione (22.9 g, 59.6 mmol) was added portionwise to refluxing Dowtherm A ®(45 ml_) over 3 minutes. After a further 3 minutes at reflux the mixture was cooled to room temperature. Ethyl acetate/hexane (10 mL/20 ml_) was added and a black solid isolated by filtration. This residue was dissolved in hot methanol (400 mL) and filtered through Keiselguhr. Water (800 mL) was added and the mixture stored at 5⁰C overnight. Filtration and drying afforded a pale yellow solid (10.3 g, 61%). MS (APCI-) m/z 281 [M-H]" M H-NMR (400 MHz, c/6-DMSO), 10.61 (1 H, br s, NH), 7.64 (1 H₁ d, J = 8, CHNHC), 7.48 (1 H, s, CHCBr), 5.88 (1 H, br d, J = 7.04, CH=CO), 4.28-4.27 (4H, br m, 2 x (CH2O)).

d) 2,3-Dihydro-7H-[1 ,4]dioxino[2,3-/]quinolin-10-one

A suspension of 6-bromo-2,3-dihydro-7H-[1 ,4]dioxino[2,3-/]quinolin-10-one (3.4 g, 12 mmol) in water/dioxane (150 mL /80 ml_) was treated with 1 M aqueous sodium hydroxide solution then hydrogenated over 10% palladium on charcoal (1.5 g) for 20 hours. The mixture was filtered then acidified with 5M aqueous hydrochloric acid. On concentrating to ca 100 mL, a solid began to crystallise out. The mixture was stored at 5⁰C overnight. Filtration and drying afforded a pale yellow solid (2.8 g, 100%). LC/MS (ES) m/z 203 (MH⁺ 92%); 1 H-NMR (400 MHz, c/6-DMSO), 11.4 (1 H, s, NH), 7.64 (1 H, d, J = 7.2, CHNHC), 7.15 (1 H, d, J = 9.2, CHCO), 6.95 (1 H, d, J = 8.8, CHCN), 5.80 (1 H₁ d, J = 7.2, CH=CO), 4.26-4.27 (4H, m, 2 X (CH2O)).

e) 9-Chloro-2,3-dihydro-[1 ,4]dioxino[2,3-/]quinolin-10-ol

2,3-Dihydro-7H-[1,4]dioxino[2,3-/]quinolin-10-one (6.93 g, 34.1 mmol, 1 eq) in acetic acid (95.9 mL) was sonicated and warmed until all had dissolved, and then it was treated with N-chlorosuccinimide (5.01 g, 37.5 mmol, 1.1 eq) and the mixture was heated at 35⁰C for 18 hr, cooled and the solid collected and washed with acetic acid and dried in vacuo at 40oC overnight, to give a white solid (5.93 g, 73%). LC/MS (ES) m/z 237 (MH⁺ 84%); ¹H-NMR (400 MHz, c/6-DMSO), 8.17 (1 H, d, J = 6.28, CHNHC), 7.21 (1 H, d, J=8.96 Hz, CHCO), 7.01 (1 H, d, J = 9, CHCN), 4.29-4.25 (4H, m, 2 x (CH2O)).

f) 10-Bromo-9-chloro-2,3-dihydro-[1 ,4]dioxino[2,3-/]quinoline

9-Chloro-2,3-dihydro-[1 ,4]dioxino[2,3-f]quinolin-10-ol (3.12 g, 13.1 mmol) in dry DMF (16.7 mL) was cooled in ice and phosphorus tribromide (4.78 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 2 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (3.55 g, 90%). LC/MS (ES) m/z 300 (MH⁺ 100%); 1H- NMR (400 MHz, DMSO), 8.73 (1 H, s, CHNHC), 7.62 (1 H, d, J = 9.12, CHCOCH2), 7.47 (1H, d, J = 9.08, CHCN), 4.43 (4H, m, 2 x (CH2O)).

g) 9-Chloro-10-vinyl-2,3-dihydro-[1 ,4]dioxino[2,3-/]quinoline

To a solution of 10-Bromo-9-chloro-2,3-dihydro-[1 ,4]dioxino[2,3-f]quinoline (-] ^ 5 g_ 38.4 mmol, 1 eq) in DME (425 ml_, degassed with Argon), was added Pd(PPh3)4 the reaction was stirred under Argon for 20mins. Water (122 ml_), K2CO3 (5.32 g, 38.4 mmol, 1 eq) and the 2,4,6-trivinylcyclotriboroxane-pyridine complex (2.49 g, 15.4 mmol, 0.4 eq) were added, the mixture was then heated to reflux at 100° C overnight. The reaction was then cooled, the product was extracted with water and DCM, dried over Na^O^ filtered and evaporated to dryness. The solid obtained was the passed through silica with as a pale yellow solid (5.5 g, 58%).LC/MS (ES) m/z 247 (MH⁺ 100%); 1 H-NMR (400 MHz, CDCI ), 8.69 (1 H, s, CHNHC), 7.59 (1H, d, J = 9.2, CHCO), 7.18 (1H, dd, J = 18, 12, CCH=C), 5.68 (1 H, dd, J = 12, 1 , Hcis of CH2=C), 5.49 (1 H, dd, J = 18, 1 , H trans of CH2=C), 4.37-4.339 (4H, m, 2 x (CH2O)).

Preparation 10e

Preparation of 10-vinyl-2,3-dihydro-[1 ,4]dioxino[2,3-/]quinoline

a) 10-Bromo-2,3-dihydro-[1 ,4]dioxino[2,3-/]quinoline 2,3-dihydro-[1 ,4]dioxino[2,3-f]quinolin-10-ol (2.8 g) in dry DMF (8 ml.) was cooled in ice and phosphorus tribromide (0.7 ml_) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 2 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (1.65 g, 90%). LC/MS (ES) m/z 267.

b) 10-vinyl-2,3-dihydro-[1 ,4]dioxino[2,3-f]quinoline To a solution of 10-Bromo-2,3-dihydro-[1 ,4]dioxino[2,3-f]quinoline (Q.8 g, 38.4 mmol, 1 eq) in toluene (15 mL) was added vinyltributyl tin (1.05 ml_) and Pd(PPh3)4 (i73 _mg) The reaction was stirred under Argon for 18hours at 130 C. The reaction was then cooled and evaporated to dryness. The solid obtained was passed through silica gel to obtain the title compound with as a pale yellow solid (0.50 g, 64%). LC/MS (ES) m/z 214.

Preparation 11

Preparation of 7-fluoro-2-(methyloxy)-8-f(2S)-2-oxiranvn-1 ,5-naphthyridine (a) 1-[3-fluoro-6-(methoxy)-1 ,5-naphthyridin-4-yl]-1 ,2-ethanediol To a solution of AD-mixβ (50 g) in terf-butanol/water (200 mL/200 mL), cooled in an ice-bath for 30 minutes, 8-ethenyl-7-fluoro~2-(methyloxy)-1 ,5-naphthyridine (Preparation 6) (8 g, 39.2 mmol) was added and the reaction mixture was stirred at room temperature for 48 hours. Sodium sulfite (75 g) was added and the mixture was stirred for a further 30 minutes. It was extracted with diethyl ether then several times with 10% methanol in chloroform. The organic extract was evaporated under vacuum to afford the desired product as an oil (8.93 g, 96%). MS (+ve ion electrospray) m/z 239 (MH+); enantiomeric excess = 44%, as determined by chiral analytical HPLC.

(b) 2-[3-fluoro-6-(methoxy)-1 ,5-naphthyridin-4-yl]-2-hydroxyethyl 4-methylbenzenesulfonate To a solution of 1-[3-fluoro-6-(methoxy)-1 ,5-naphthyridin-4-yl]-1 ,2-ethanediol (16.5g, 71 mmol)) in dichloromethane (200 mL), triethylamine (10 mL) and dibutyltin oxide (350 mg) was added tosyl chloride (13.2g). After 3 hours, the mixture was diluted with water/sodium bicarbonate and extracted several times with chloroform. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 20-30% ethyl acetate in chloroform to afford the desired product (20.3 g, 75%). MS (+ve ion electrospray) m/z 393 (M + H)⁺.

(c) 7-fluoro-2-(methoxy)-8-(2-oxiranyl)-1 ,5-naphthyridine To a suspension of 2-[3-fluoro-6-(methoxy)-1 ,5-naphthyridin-4-yl]-2-hydroxyethyl 4-methylbenzenesulfonate (10.5 g, 26.7 mmol) in anhydrous methanol (160 mL), cooled in an ice-bath, potassium carbonate (7.03 g, 50.9 mmol) was added. After 15 minutes with cooling, the mixture was stirred at room temperature for a further 1.75 hours. It was then diluted with water, extracted several times with dichloromethane, dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with dichloromethane, chloroform then 20% ethyl acetate in chloroform to afford the title product as an oil (5.55 g, 94%). MS (+ve ion electrospray) m/z 221 (M + H)⁺.

Preparation 12

Preparation of 7-methyl-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ibiri ,41thiazine-6-carbaldehvde a) Methyl 7-bromo-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-lb][1 ,4]thiazine-6-carboxylate A solution of ethyl 2-mercaptoacetate (18.4 ml) in DMF (650 ml) was ice-cooled and treated with sodium hydride (6.78 g of a 60% dispersion in oil). After 1 hour methyl 6-amino-3,5-dibromopyridine-2-carboxylate (50 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was partitioned between EtOAc and water(2 litres each), shaken, separated and the EtOAc along with solid that crystallised out washed with water (2 x 1 litre). The EtOAc was evaporated to low volume, solid filtered, washed with water and EtOAc and dried. The filtrate was separated, EtOAc dried and evaporated. The residue was taken up in AcOH and heated to 100⁰C overnight, then evaporated. The white solid was triturated uder EtOAc, filtered off, washed with a little EtOAc and dried (Na2SO₄). Combining the 2 batches of ester gave 33.35g (70%). MS (APCI^") m/z 223

([M-H]-, 100%).

b) Methyl 7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-ib][1 ,4]thiazine-6-carboxylate Methyl 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-6][1 ,4]thiazine-6-carboxylate (1.44 g, 4.75 mmol) was dissolved in DMF (20 mL) and treated with PdCl2(PPh3)2 (167 mg, 0.238 mmol), LiCI (604 mg, 14.2 mmol) and Me₄Sn (0.66 mL, 4.75 mmol). The reaction was heated at 100 ⁰C for 30 min, at which point the reaction was no longer proceeding. An additional 0.25 mL of Me₄Sn was added and the reaction was heated for an additional 4 h. After cooling, the reaction was diluted with DCM and water. The product was extracted into DCM and the combined extract was dried (Na2SO₄) and filtered and the concentrated in vacuo. Purification provided product (500 mg).

c) 6-(Hydroxymethyl)-7-methyl-2H-pyrido[3,2-jb][1,4]thiazin-3(4H)-one Methyl 7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-ιb][1 ,4]thiazine-6-carboxylate (54 mg, 0.195 mmol) was dissolved in THF (5 mL), cooled to -10 ⁰C and treated with 1.0M LiH3-3NMe2 (0.42 mL, 0.42 mmol). The reaction was maintained at -10 ⁰C for 1 h and then quenched with 6N HCI. The reaction solution was diluted with EtOAc and water and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na2SO₄), filtered and concentrated. The crude product (30.3 mg) was used directly in the next step without further purification.

d) 7-Methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazine-6-carbaldehyde To a solution of 6-(hydroxymethyl)-7-methyl-2/-/-pyrido[3,2-/)][1 ,4]thiazin-3(4H)-one (290 mg, 1.38 mmol) in MeCl2 (20 mL) and was added MnO2 (1.2 g, 13.8 mmol). The reaction was vigorously stirred at RT for 12 h and then filtered and the solvent was removed at reduced pressure. Purification provided 176 mg of the desired aldehyde: MS (ES) m/z 209 (M + H)⁺. Preparation 13

Preparation of 8-methyl-2,3-dihydro-1 ,4-benzodioxin-6-carbaldehvde (a) (a) 3-Bromo-4-hydroxy-5-methoxybenzaldehyde To a solution of vanillin (30.40 g, 0.20 mol) in glacial acetic acid (200 ml_) was added bromine (46.79g, 0.29 mol) in glacial acetic acid (20 ml_) at 10° over a period of 1h. Additional acetic acid (10OmL) was added to the thickening mixture and the reaction was stirred for 24h at ambient temperature. The reaction was diluted with ice/water (300 ml_); the precipitate was filtered and washed well with water. A light beige solid (40.69g, 89%) was obtained after vacuum drying: MS (ES) m/z 230.0. (M+H)⁺.

(b) 3-Bromo-4,5-dihydoxybenzaldehyde To a solution of the compound of Example (a) (12.1g, 0.52 mol) in CH2CI2 (200 ml.) was added 1.0 M boron tribromide in CH2CI2 (2.2 eq, 115 ml.) at 0°. The reaction was stirred at 0° for 20 min, then at ambient temperature for 2.5h. The reaction was then cooled to 0°, and quenched by the slow addition of methanol. The solvents were removed under reduced pressure and the trimethyl borate was removed by azeotropation with added methanol. Vacuum drying yielded a dark green-brown solid (11.51 g, 100%) which was used without further purification: MS (ES) m/z 217.2. (M+H)⁺.

(c) 8-Bromo-2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde To a solution of the compound of Example (c) (11.5g, 0.52 mol) in DMF (220 ml_) was added cesium carbonate (50.7g, 1.56 mol). The mixture was stirred at ambient temperature for 30 min, then 1 ,2-dibromoethane (12.76g, 0.68 mol) were added. After heating at 80° for 4h, the DMF was removed under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with brine and dried (MgSθ4). The crude product was purified by flash column chromatography (silica gel, 4:1 hexane:ethyl acetate) to give an off-white solid (9.57g,75%): MS (ES) m/z 243.2 (M + H)⁺. (d) 8-methyl-2,3-dihydro-1 ,4-benzodioxin-δ-carbaldehyde To a solution of 8-bromo-2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde (240 mg, 0.987 mmol) in DMF (5 ml_) were added LiCL (126 mg, 2.96 mmol), Me Sn (0.137 ml_, 0.987 mmol) and PdCL^PPh )₂(35 mg, 0.049 mmol). After heated at 70 ⁰C for 12 hr, the mixture was cooled down to room temperature and diluted with aqueous KF solution. The resulting solution was extracted several times with DCM. The organic patrts were comboined, concentrated and purified with column chromatography (silica, 10-40% Ethyl acetate in hexane) affording the title compound as an off-white solid (145 mg, 83%): MS (ES) m/z 179 (M + H)⁺ .

Preparation 14

Preparation of 5-methyl-2,3-dihvdro-1 ,4-benzodioxin-6-carbaldehvde To a solution of N,N,N'-trimethylethylenediamine (3.3 g, 32.3 mmol) in THF (100 mL) at -15 ⁰C was dropwise added π-BuLi (19.2 mL, 30.5 mmol, 1.6 M in THF). After stirring at -15 ⁰C for 15 minutes, a solution of solution of 1 ,4-benzodioxane-6-aldehyde (5.0 g, 30.5 mmol) in THF (10 mL). After 20 minutes, another batch of π-BuLi (5 mL, 3.1 mmol, 1.6 M in THF) was added and stirred for 3 h. The resulting solution was cooled down to -72 ⁰C and the mixture was treated with MeI (25.9 g, 182.5 mmol) slowly. After stirring at -72 ⁰C for 3 h, the mixture was diluted with HCI solution (1 M in water). The aqueous layer was extracted several times with diethyl ether. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5-40% ethyl acetate in hexane) to provide the title compound as an off-white compound (1.0 g, 18%): %): MS (ES) m/z 179 (M + H)⁺ .

Preparation 15

Preparation of fi .SIOxathiolofδ^-clpyricline-β-carbaldehvde

a) 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1H)-pyrone To a solution of Kojic acid (50 g, 0.352 mol) in DMF (650 ml_) under an argon atmosphere, cooled to O⁰C, was added a solution of potassium t-butoxide (39.5 g, 0.352 mol) in DMF (100 ml_) and the resultant suspension was vigourously stirred (overhead stirring) for 1 hour at 5-1O⁰C. 4-methoxybenzyl chloride was added dropwise and the mixture was heated to 5O⁰C for 30 hours, followed by 9O⁰C for 5 hours, after which the mixture was evaporated to a minimum volume of DMF. 750 mL of distilled water was added and the mixture refridgerated overnight. The resultant solid was collected by filtration and dried in vacuo at 5O⁰C to afford the product as a light brown solid (85 g, 64%); MS (+ve ion electrospray) m/z 263 (M+H+).

b) 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1H)-pyridinone

To a suspension of 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1 H)- pyrone (40 g, 153 mmol) in ethanol (105 mL) was added concentrated aqueous ammonia (295 mL) and refluxed for 18 hours. The mixture was cooled, then refrigerated for 3 hours, and cooled in an ice-bath for 45 minutes. The solid was filtered off, washed with cold ethanol, follwed by cold petroleum ether and dried in vacuo to afford the product as brown solid (26.21 g, 66%).

c) [5-({[4-(methoxy)phenyl]methyl}oxy)-4-oxo-1 ,4-dihydro-2-pyridinyl]methyl acetate

A solution of 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1H)- pyridinone (26 g, 0.1 mol) in pyridine (150 mL) was cooled to 5⁰C and treated with acetyl chloride (10.48 ml, 0.149 mol). The reaction mixture was stirred and allowed to warm to room temperature then heated at 6O⁰C for 18 hours. Pyridine was evaporated under vacuum and the residue was triturated with water (250 mL), cooled in an ice-bath for 30 minutes. The solid formed was filtered off , washed with cold water and dried in vacuo to afford the product as a solid (15.7 g, 50%); MS (+ve ion electrospray) m/z 304(MH+).

d) (5-({[4-(methoxy)phenyl]methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate

[5-({[4-(methoxy)phenyl]methyl}oxy)-4-oxo-1 ,4-dihydro-2-pyridinyl]methyl acetate (25g, 82 mmol) was dissolved in dry dichloromethane (600 mL). Triethylamine (23 mL, 164 mmol) was added and the reaction cooled to 0⁰C. Trifluoromethane sulfonic anhydride (21 ml_, 123 mmol) was added dropwise and the reaction left to stir at room temperature overnight. The reaction was poured into water, the organic layer collected and dried (Mg SO4) . The crude product was chromatographed on silica eluting with 10- 20% Ethyl acetate in hexane . Product containing fractions were combined and dried to afford the product as a solid (24.95g, 70%); MS (+ve ion electrospray) m/z 436(MH+).

e) [4-[(1 ,1-dimethylethyl)thio]-5-({[4-(methoxy)phenyl]methyl}oxy)-2-pyridinyl]methyl acetate To a solution of (5-({[4-(methoxy)phenyl]methyl}oxy)-4- {[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (10 g, 23 mmol) in anhydrous toluene, (R)-(+)-2,2 bis(diphenylphosphino)-1 ,1-binaphthyl (312 mg, 0.4 mmol) was added. The reaction mixture was degassed before adding palladium acetate (103 mg, 0.4 mmol). Sodium 2-methyl-2-propanethiolate was added, the system degassed again and the reaction mixture was strirred at 6O⁰C for 3 hours, under argon atmosphere then at 70oC for a further 18 hours. The reaction mixture was filtered and the filtrate was evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 20-35% ethyl acetate in hexane to afford the product as an oil (9.1 g, 100%); MS (+ve ion electrospray) m/z 376(MH+).

f) {4-[(1 , 1 -dimethylethyl)thio]-5-hydroxy-2-pyridinyl}methyl acetate

A solution of [4-[(1,1-dimethylethyl)thio]-5-({[4-(methoxy)phenyl]methyl}oxy)-2- pyridinyl]methyl acetate (9 g, 24 mmol) in dichloromethane (100 mL) was treated with triethylsilane (3.86 mL, 24 mmol). The reaction mixture was stirred for 10 minutes before adding trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 3 hours under argon atmosphere. The solvents were evaporated under vacuum. The residue was taken up in dichloromethane and chromatographed on silica gel eluting with 10%-30% ethyl acetate in hexane to afford the product as an oil (5.1 g, 83%); MS (+ve ion electrospray) m/z 256(MH+).

g) 6-(hydroxymethyl)-4~mercapto-3-pyridinol {4-[(1,1-dimethylethyl)thio]-5-hydroxy-2-pyridinyl}methyl acetate (2.5 g, 9.8 mmol) was dissolved in concentrated HCI and the mixture was heated at 8O⁰C for 18 hours. The solvent was evaporated under vacuum and the residue was triturated with diethyl ether to afford the product as a solid (1.35 g, 88%); MS (+ve ion electrospray) m/z 158(MH+).

h) [1 ,3]oxathiolo[5,4-c]pyridine-6-methanol

To a solution of 6-(hydroxymethyl)-4~mercapto-3-pyridinol (500 mg, 3.2 mmol) in anhydrous DMF, potassium carbonate was added. The reaction mixture was stirred for 10 minutes and dibromomethane (0.44 mL, 6.4 mmol) was added. The reaction mixture was stirred at 7O⁰C for 18 hours under an argon atmosphere. DMF was removed in vacuo and the residue was partitioned between 5%MeOH in dichloromethane and water. The aqueous layer was extracted several times with 5% methanol in dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 3-5% methanol in dichloromethane to afford the product as a solid (381 mg, 70%); MS (+ve ion electrospray) m/z 170(MH+).

i) [1 ,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde

[1 ,3]oxathiolo[5,4-c]pyridine-6-methanol (0.92g, 5.44 mmole) was treated with manganese (IV) oxide (3.83 g, 44 mmole) at RT in DCM (50 mL) to afford the aldehyde (567 mg, 62%) as a solid; MS (+ve ion electrospray) m/z 168 (MH+).

Preparation 16

Preparation of 3-Oxo-3,4-dihvdro-2/-/-pyridor3,2-jb1H ,41oxazine-6-carboxaldehyde

a) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 °C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 ⁰C for 30 min, then was quenched with glacial AcOH (2.5 ml_). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z 219.0 (M + H)⁺.

b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate 2-Bromo-5-hydroxy-6-nitropyridine (30 g, 0.14 mole) was suspended in acetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added, followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated at reflux for 10 hr, then was cooled to room temperature and diluted with Et2θ. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford material (38 g, 89%), which was used without further purification; MS (ES) m/z 305.0 (M + H)⁺.

c) 6-Bromo-4/-/-pyrido[3,2-b][1 ,4]oxazin-3-one Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 ml_), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 °C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%); MS (ES) m/z 229.0 (M + H)⁺.

d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1 ,4]oxazin-3-one 6-Bromo-4H-pyrido[3,2-b][1 ,4]oxazin-3-one (6.0 g, 26.3 mmole) and trans-2- phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1 ,4-dioxane (150 mL) and the solution was degassed with argon. (Phi3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl3) to afford a solid (2.5 g, 38%). MS (ES) m/z 253.0 (M + H)⁺.

e) 3-Oxo-3,4-dihydro-2/-/-pyrido[3,2-/j][1,4]oxazine-6-carboxaldehyde 6-((£)-Styryl)-4H-pyrido[3,2-jb][1,4]oxazin-3-one (1.2 g, 4.8 mmole) was dissolved in CH2CI2 (200 ml.) and the solution was cooled to -78 ⁰C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (1.76 ml_, 24 mmole) was added to the solution, and the reaction was stirred at -78 ⁰C for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et2θ (50 ml_). The collected solid was washed with additional Et2θ and dried to afford a solid (700 mg, 82%). MS (ES) m/z 179.0 (M + H)⁺.

Preparation 17

OHC^^^O. TT I

Preparation of 2,3-Dihydro-π ,41dioxinor2,3-c1pyridine-7-carboxaldehvde

a) 5-Benzyloxy-2-hydroxymethyl-1 H-pyridin-4-one A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojic acid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40 mmol), concentrated aqueous (880) ammonia (100 ml_), and ethanol (20 ml_) was heated to reflux overnight. The mixture was allowed to cool to room temperature then filtered. The resultant solid was washed with ether and dried in vacuo (5.9 g); MS (APCI+) m/z 232 (MH+).

b) (2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridin-7-yl)-methanol A solution of 5-Benzyloxy-2-hydroxymethyl-1 f/-pyridin-4-one (2 g, 8.7 mmol) in water (220 ml_) containing sodium hydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1 g) for 4 hours. The mixture was filtered and evaporated to give a white solid. This solid was dissolved in N,N-dimethylformamide (8 mL) then treated with potassium carbonate (2.9 g) and 1 ,2-dibromoethane (0.6 mL, 7 mmol). The mixture was heated at 85⁰C overnight. The cooled mixture was evaporated onto silica and chromatographed eluting with 10-30% methanol in ethyl acetate affording a white solid (250 mg, 21 %); MS (APCl+) m/z 168 (MH+).

c) 2,3-Dihydro-[1 ,4]dioxino[2,3-c]pyridine-7-carboxaldehyde A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%); MS (APCI+) m/z 166 (MH+).

Preparation 18

Preparation of 3-Oxo-3,4-dihvdro-2/-7-pyrido[3,2-/?1f 1 ,41thiazine-6-carboxaldehyde

a) Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-jfc>][1 ,4]thiazine-6-carboxylate A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) was ice-cooled and treated with sodium hydride (540 mg of a 60% dispersion in oil). After 1 hour methyl δ-amino-δ-bromopyridine^-carboxylate (3 g) (T.R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was diluted with EtOAc (1 litre), washed with water (3 x 300 mL), dried and evaporated to about 10 mL. The white solid was filtered off and washed with a little EtOAc to give the ester (0.95g); MS (APCI^") m/z 223 ([M-H]", 100%).

b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazine-6-carboxylic acid A solution of Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazine-6-carboxylate (788 mg) in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 hours with 0.5M NaOH solution (8 mL) and stirred overnight. After evaporation to approx. 3 ml, water (5 mL) was added and 2M HCI to pH4. The precipitated solid was filtered off, washed with a small volume of water and dried under vacuum to give a solid (636 mg); MS (APCI") m/z 209 ([M-H]^", 5%), 165([M-COOH]^", 100%).

c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ό][1 ,4]thiazine A solution of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazine-6-carboxylic acid (500mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to -10°C and isobutyl chloroformate (0.339ml) added. After 20 minutes the suspension was filtered through kieselguhr into an tee-cooled solution of sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes and the pH reduced to 7 with dilute HCI. The solvent was evaporated and the residue triturated under water. The product was filtered and dried under vacuum to give a white solid (346mg); MS (APCI") m/z 195 ([M-H]-, 50%), 165(100%).

d) 3-Oxo-3,4-dihydro-2A/-pyrido[3,2-ib][1,4]thiazine-6-carboxaldehyde A solution of 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazine (330 mg) in dichloromethane (30 mL)/THF (30 mL) was treated with manganese dioxide (730 mg) and stirred at room temperature. Further manganese dioxide was added after 1 hour (730 mg) and 16 hours (300 mg). After a total of 20 hours the mixture was filtered through kieselguhr and the filtrate evaporated. The product was triturated with EtOAc/hexane (1 :1) and collected to give a solid (180mg); MS (APCI") m/z 195 ([M-H]", 95%), 165 (100%). Preparation 19

Preparation of S-oxo-SAdihvdro^H-pyridorS^-ifrlH ^ithiazine-δ-carboxylic acid

This acid was prepared from 3-Oxo-3,4-dihydro-2H-pyrido[3,2-/?][1 ,4]thiazine-6- carboxaldehyde (890 mg) by oxidation with Oxone (potassium peroxymonosulphate) (3.1g) in a DMF solution (50 mL). After 1.5 hours at room temperature, dilution with water (50 mL) filtration and drying in vacuo afforded the acid as a white solid (750 mg, 77%).

Preparation 19a

Preparation of 3-oxo-3,4-dihydro-2H-pyridof3,2-ibiri ,41oxazine-6-carboxylic acid

a) 2-Bromo-5-hydroxy-6-nitropyridine 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 ⁰C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 ⁰C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z 219.0 (M + H)⁺.

c) 6-Bromo-4/-/-pyrido[3,2-b][1 ,4]oxazin-3-one Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 ⁰C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%); MS (ES) m/z 229.0 (M + H)⁺.

d) 6-((£)-Styryl)-4H-pyrido[3,2-ό][1 ,4]oxazin-3-one 6-Bromo~4/-/-pyrido[3,2-b][1,4]oxazin-3-one (6.0 g, 26.3 mmole) and trans-2- phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1 ,4-dioxane (150 mL) and the solution was degassed with argon. (Ph3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl3) to afford a solid (2.5

g, 38%): LCMS (ES) m/z 253.0 (M + H)⁺.

e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]oxazine-6-carboxaldehyde 6-((£)-Styryl)-4/-/-pyrido[3,2-/)][1 ,4]oxazin-3-one (1.2 g, 4.8 mmole) was dissolved in CH2CI2 (200 mL) and the solution was cooled to -78 ⁰C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (1.76 mL, 24 mmole) was added to the solution, and the reaction was stirred at -78 ⁰C for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et^O (50 mL). The collected solid was washed with additional Et^O and dried to afford a solid (700 mg, 82%). MS (ES) m/z 179.0 (M + H)⁺.

f) 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ύ][1 ,4]oxazine-6-carboxylic acid This acid was prepared from 3-Oxo-3,4-dihydro-2H-pyrido[3,2-(b][1 ,4]oxazine-6- carboxaldehyde (900 mg) by oxidation with Oxone (potassium peroxymonosulphate) (3.7g) in a DMF solution (50 mL). After 1.5 hours at room temperature, dilution with water (50 mL) filtration and drying in vacuo afforded the acid as an off-white solid (687 mg, 70%): LCMS (ES) m/e 195 (M+H)⁺; ¹H NMR δ 7.81 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 4.77 (s, 2H).

Preparation 19b

Preparation of 3-oxo-3,4-dihvdro-2H-1 ,4-benzothiazine-6-sulfonyl chloride

To an ice-cold solution of chlorosulfonic acid (22 mL, 33.1 mmol) was added the benzothiazinone (6 g, 36.3 mmol) portion-wise. The dark blue solution was warmed to 25 ⁰C over 1 h, then heated at 45 ⁰C for 2 h. After cooling, addition of the solution to ice- water resulted in the formation of a white precipitate. The solid was filtered, washed with H2O / hexane and dried affording the title compound as a white solid (8.46 g, 88%); MS (APCI+) m/z 246 (M+H)⁺.

Preparation 20

Preparation of 7-Fluoro-3-oxo-3,4-dihvdro-2H-pyrido[3,2-άiπ ,41thiazine-6-carboxaldehyde

a) Methyl 6-amino-5-bromo-3-fluoropyridine-2-carboxylate A mixture of methyl e-amino-δ-bromopyridine^-carboxylate (19.8 g) (T. R. Kelly and F. Lang, J. Org. Chem.61, 1996, 4623-4633) and 1-chloromethyl-4-fluoro-1 ,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (34.3 g) in acetonitrile (340 ml_) under argon was heated to 40⁰C for 1 hour, 6O⁰C for 1 hour and then 8O⁰C overnight. After partitioning between EtOAc and water (50OmL each) the aqueous fraction was re- extracted with EtOAc (300 mL) and the combined organic solution dried with MgSθ4 and evaporated. Chromatography (20% then 30% EtOAc in hexane) separated various byproducts from the required ester (2.09 g); MS (+ve ion electrospray) m/z 249 and 251 (MH⁺, 100%)

b) Methyl δ-amino-δ-ethoxycarbonylmethylthio-S-fluoropyridine^-carboxylate A solution of ethyl mercaptoacetate (1.15 mL) in DMF (40 mL) was ice-cooled under argon, treated with sodium hydride (420 mg of a 60% dispersion in oil) and stirred until all was in solution (about 1 hour). The ester (308a) (2.48g) was added, the mixture allowed to warm to room temp, and stirred overnight. EtOAc (150 mL) was added, the solution washed with water (3x 150 mL), dried and evaporated. Chromatography of the residue (30 then 40% EtOAc in hexane) gave the product as an oil (1.7 g). MS (+ve ion electrospray) m/z 289 (MH⁺, 100%)

c) Methyl 7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-ύ][1 ,4]thiazine-6-carboxylate A solution of the fluoropyridine (13b) (1.7 g) in acetic acid (100 mL) was heated at 110⁰C overnight, evaporated and dried under vacuum to give the product as a white solid (1.55 g, containing 0.33 equivalent of acetic acid); MS (+ve ion electrospray) m/z 243 (MH⁺, 85%), 211 (100%) d) 7-Fluoro-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-jb][1 ,4]thiazine-6-carboxylic acid This compound was prepared from methyl 7-fluoro-3-oxo-3,4-dihydro-2H- pyrido[3,2-ό][1 ,4]thiazine-6-carboxylate by the method of Preparation 9b (86%).

e) 7-Fluoro-6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazine This compound was prepared from 7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1 ,4]thiazine-6-carboxylic acid by the method of Preparation 9c (73%); MS (-ve ion electrospray) m/z 213 ([M-H]^", 100%)

f) 7-Fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]thiazine-6-carboxaldehyde A mixture of the 7-fluoro-pyridothiazinone (13e) (971 mg), manganese dioxide (3.72 g), THF (70 ml_) and 1 ,2-dichloroethane (70 mL) was heated at 60⁰C under argon for 20 hours. Filtration through kieselguhr and evaporation of solvent gave a solid which was triturated under EtOAc/hexane 1 :3 and collected (608 mg); MS (+ve ion electrospray) m/z 213 (MH⁺, 100%).

Preparation 21

Preparation of 7-chloro-3-oxo-3,4-dihydro-2H-1 ,4-benzoxazine-6-carbaldehvde

b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate The hydroxypyridine (30 g, 0.14 mole) was suspended in acetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added, followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated at reflux for 10 hr, then was cooled to room temperature and diluted with Et^O. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford material (38 g, 89%), which was used without further purification. MS (ES) m/z 305.0 (M + H)⁺.

c) 6-Bromo-4/-/-pyrido[3,2-b][1 ,4]oxazin-3-one The nitropyridine (38 g, 0.125 mole) was dissolved in glacial AcOH (150 ml_), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 °C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 ml_). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%). MS (ES) m/z 229.0 (M + H)⁺.

d) 6-((£)-Styryl)-4H-pyrido[3,2-ό][1 ,4]oxazin-3-one The bromopyridine (10c) (6.0 g, 26.3 mmole) and frans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1 ,4-dioxane (150 mL) and the solution was degassed with argon. (Ph3P)4Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H2O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl3) to afford a solid (2.5 g, 38%).

MS (ES) m/z 253.0 (M + H)⁺.

e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]oxazine-6-carboxaldehyde The pyridine (1Od) (1.2 g, 4.8 mmole) was dissolved in CH2CI2 (200 mL) and the solution was cooled to -78 ⁰C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (1.76 mL, 24 mmole) was added to the solution, and the reaction was stirred at -78 °C for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et^O (50 mL). The collected solid was washed with additional Et2θ and dried to afford a solid

(700 mg, 82%); MS (ES) m/z 179.0 (M + H)⁺.

f) 6-Bromo-7-chloro-4H-pyrido[3,2-b][1 ,4]oxazin-3-one 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (2Og, 87.7 mmole) was dissolved in DMF (175 mL) and cooled in an ice bath. Chlorine gas was then slowly bubbled in for 45 minutes, and then the saturated solution was stirred in the ice bath for 2 hours. The mixture was purged with nitrogen and slowly added with stirring to 1 L of ice water which contained 100g of Na^SO , making sure to keep the temperature <15 ⁰C. After stirring 30 minutes the product was filtered, washed thoroughly with water and dried to afford (22.5g, 98%) of a white solid. ¹H NMR (400 MHz, DMSO-c/6): 4.76 (2H, S₁), 7.78 (1 H, s),11.71 (1 H, s).

' g) 7-Chloro-6-((£)-styryl)-4H-pyrido[3,2-ό][1 ,4]oxazin-3-one 6-Bromo-7-chloro-4H-pyrido[3,2-b][1 ,4]oxazin-3-one (22 g, 83.7 mmole) and trans- 2-phenylvinylboronic acid (17.33 g, 117 mmole) were dissolved in 1 ,4-dioxane (300 mL) and the solution was degassed with argon. (Ph3P)4Pd (1.9 g, 2 mole %) was added, followed by a solution of potassium hydrogen carbonate (21 g, 210 mmole) in H2O (100 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with ethyl acetate (1 L). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The residue was slurried with chloroform (120 mL), then diluted with diethyl ether (100 mL). The precipitated product was collected by filtration and washed with ether to provide the product (16.4 g, 68%) as an off-white solid. ¹H NMR (400 MHz, DMSO-c/6): 4.71 (2H, s), 7.32-7.46 (3H, m), 7.54-7.74 (4H, m), 11.6 (1H, s).

h) 7-Chloro-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ό][1 ,4]oxazine-6-carboxaldehyde 7-Chloro-6-((£)-styryl)-4/-/-pyrido[3,2-jb][1 ,4]oxazin-3-one (8.0 g, 27.9 mmole) was dissolved in a mixture of DMF (400 mL) and methanol (40 mL), and the solution was cooled to -78 ⁰C. Ozone was bubbled through the solution with stirring for 45 minutes, then the excess ozone was removed by bubbling oxygen through the solution for 30 min. Dimethylsulfide (21 mL, 279 mmole) was added to the solution, and the reaction was stirred at -78 ⁰C for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et2θ (150 ml_). The collected solid was washed with additional Et2<D and dried to afford a white solid (4 g, 68%). ¹H NMR (400 MHz, DMSO-c/6): 4.86 (2H, m), 7.73 (1 H, s); 10.05 (1 H, s), 11.84 (1 H, s).

Preparation 22

Preparation of 7-fluoro-2,3-dihvdrobenzori ,4ldioxine-6-carboxaldehyde

7-Fluoro-2,3-dihydrobenzo[1 ,4]dioxine-6-carboxaldehyde was prepared from 6- fluoro-2,3-dihydrobenzo[1 ,4]dioxine [V. Daukas et al Chemija, 1999, 10 (1), 59] by reaction of dichloromethyl methyl ether and titanium tetrachloride: LC-MS (ES) m/e 155 (M+H)⁺. Preparation 23

Preparation of phenylmethyl f(3f?)-3-pyrrolidinylmethvncarbamate

a) 1 ,1-dimethylethyl (3S)-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate To a solution of (S)-3-(aminomethyl)-1-Λ/-Boc-pyrrolidine (3.0 g, 14.98 mmole) in DMF (40 mL) was added triethylamine (2.5 ml_, 17.94 mmole) and N- (benzyloxycarbonyloxy)succinimide (4.46 g, 17.90 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in diethyl ether (250 mL). The organic solution was washed with H2O (2 x 150 mL), brine (100 mL) and dried over Na2SO4 and concentrated. The remaining residue was purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (4.46 g, 91%) as a light yellow oil:

LC-MS (ES) m/e 335 (M + H)⁺. b) phenylmethyl [(3R)-3-pyrrolidihylrhethyl]carbamate To a solution of 1,1-dimethylethyl (3S)-3-[({[(phenylmethyl)oxy]carbonyl} amino)methyl]-1-pyrrolidinecarboxylate in DCM (100 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (2.93 g, 94%) as a

light yellow oil: LC-MS (ES) m/e 235 (M + H)⁺.

Preparation 24

Preparation of (±)-phenylmethyl {[c/s-4-hvdroxy-3-pyrrolidinvnmethyl)carbamate

a) (±)-1 , 1 -dimethylethyl-2-(phenylmethyl)hexahydro-5fy-pyrrolo[3,4-c/]isoxazole-5- carboxylate

To a solution of 1 ,1-dimethylethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (10.0 g, 59.1 mmole) in toluene (300 mL) and EtOH (100 mL) was added paraformaldehyde (8.87 g, 295.5 mmole), Λ/-hydroxybenzylamine hydrochloride (13.92 g, 88.65 mmole) and triethylamine (12.4 mL, 88.65 mmole). After 24 hours at 8O⁰C, the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 1 :1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 1 :1) to give the title compound (15.27 g, 85%) as a colorless oil: LC-MS (ES) m/e 305 (M+H)⁺.

b) (±)-1 ,1-dimethylethyl-c/s-3-(aminomethyl)-4-hydroxy-1-pyrrolidinecarboxylate

To a solution of (±)-1,1-dimethylethyl-2-(phenylmethyl)hexahydro-5H-pyrrolo[3,4- d]isoxazole-5-carboxylate (14.0 g, 46.0 mmole) in EtOH (100 ml_) in a Parr flask was added Pd(OH)2 (~ 400 mg). The reaction contents were shaken under 50 psi of H2

overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (10.Og, 99%) as a low melting white solid: LC-MS (ES) m/e 217 (M+H)⁺.

c) (±)-1 ,1-dimethylethyl c/s-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate

To a solution of (±)-1 ,1-dimethylethyl c/s-3-(aminomethyI)-4-hydroxy-1- pyrrolidinecarboxylate (10.0 g, 46.0 mmole) in DMF (50 ml_) at RT was added Et3N (8.4 ml_, 60.0 mmole) and Λ/-(benzyloxycarbonyloxy)succinimide (14.95 g, 60.0 mmole). After 18 h, the DMF was removed under vacuum and the residue purified on silica (25-50% DCM/EtOAc) to give the title compound (15.3 g, 95%) as a white foam: LC-MS (ES) m/e 351 (M+H)⁺; and a small amount of an Λ/-methylated byproduct [1 ,1-dimethylethyl (3S,4S)-3-hydroxy-4-[(methyl{[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate ] (0.33 g, 2%): LC-MS (ES) m/e 365 (M+H)⁺. The racemic title compound was separated into its chiral constituents via preparative chiral column chromatography. The first eluting enantiomer (E1 , [α]rj = +17.7°, c=0.5, MeOH) and second eluting enantiomer (E2, [α]p = -16.7°, c=0.5, MeOH) were then used directly. (see below)

(3S,4S) = (EΙ)-enantiomer (3R,4R) = (E2)-enantiomer The absolute stereochemistries of the intermediates above were determined by vibrational circular dichroism.

d) (±)-phenylmethyl {[c/s-4-hydroxy-3-pyrrolidinyl]methyl}carbamate

To a solution of (±)-1 ,1-dimethylethyl c/s-3-hydroxy-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (15.3 g, 43.7 mmole) in DCM (150 ml_) at RT was added TFA (50 ml_). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (175 mmole, 65 g) was added with vigorous stirring at RT. After 4h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (10.38 g, 95%) as a white foam: LC-MS (ES) m/e 251 (M+H)⁺. Example 1

Preparation of 6-({f((3S)-1-(2-r6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-3- PVrrolidinyl)methvnamino)methyπ-2/-/-pyridoF3,2-ά1[1 ,41thiazin-3(4/-/)-one

a) 1 ,1-dimethylethyl (SSJ-S-^trifluoroacetyOaminoJmethylJ-i-pyrrolidinecarboxylate To a stirred solution of (S)-3-(aminomethyl)-1-Λ/-Boc-pyrrolidine (2.0 g, 10.0 mmole), in dry CH2CI2 (50 mL) at RT was added diisopropylethyl amine (2.6 mL, 15.0 mmole) and trifluoroacetic anhydride (1.39 mL, 10.0 mmole). After 3h at RT, the reaction contents were concentrated under vacuum. Purification on silica (EtOAc) afforded the title compound (2.96 g, 99%) as an off-white solid: LC-MS (ES) m/e 297 (M+H)⁺. b) 2,2,2-trifluoro-Λ/-[(3ft)-3-pyrrolidinylmethyl]acetamide To a stirred solution of 1 ,1-dimethylethyl (3S)-3{[(trifluoroacetyl)amino]methyl}-1- pyrrolidinecarboxylate (2.96 g, 10.0 mmole), in CH2CI2 (50 mL) at RT was added TFA (25 mL). After 2h, the reaction contents were concentrated under vacuum. The remaining residue was dissolved in (CHCl3//-PrOH, 10:1) and washed with saturated aqueous NaHCC>3. The organic phase was separated and dried over Na2SC>4. Concentration under vacuum afforded the title compound (1.86 g, 95%) as a yellow oil: LC-MS (ES) m/e 197 (M + H)⁺.

c) ethyl [((3S)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]carbamate To a stirred solution of 2,2,2-trifluoro-Λ/-[(3f?)-3-pyrrolidinylmethyl]acetamide (1.0 g, 5.1 mmole), in DMF (20 mL) was added 8-ethenyl-2-(methyloxy)-1,5-naphthyridine (1.41 g, 7.65 mmole). After 24h at 100 ⁰C, the reaction contents were concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title

compound (1.42 g, 73%) as yellow oil: LC-MS (ES) m/e 383 (M + H)⁺.

d) [((3S)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine To a stirred solution of ethyl [((3S)-1-{2-[6-(methyIoxy)-1 ,5-naphthyridin-4~yl]ethyl}- 3-pyrrolidinyl)methyl]carbamate (0.80 g, 2.09 mmole) in MeOH (30 mL) and H2O (15 mL) at RT was added potassium carbonate (1.44 g, 10.5 mmole). After 18 h, the reaction contents were concentrated under reduced pressure and filtered through celite (EtOH) to give the title compound (0.59 g, 99 %) as a light brown oil: LC-MS (ES) m/e 289 (M + H)⁺.

e) 6-({[((3S)-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4/^)-one To a stirred solution of [((3S)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine (0.22 g, 0.77 mmole) in dry CH2CI2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde (0.15 g, 0.77 mmole). After 24h, at RT was added NaBH4 (0.03 g, 0.85 mmole). After 24h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHC^/MeOH, 9:1 containing 5% NH4OH)

afforded the title compound (0.25 g, 70%) as light yellow solid: ¹ H NMR (400 MHz, CD₃OD) 5 8.78 (d, J = 4.5 Hz, 1 H)₁ ^' 8.29 (d, J = 9.1 Hz, 1 H), 7.85 (m, 2H), 7.36 (d, J = 9.1 Hz, 1 H), 7.15 (d, J = 5.8 Hz, 1 H), 4.38 (s, 2H), 4.19 (s, 3H), 3.91 (m, 2H), 3.82 (m, 4H), 3.67 (s, 2H), 3.31 (m, 2H), 3.18 (m, 1 H), 2.55 (m, 2H), 2.10 (m, 2H). LC-MS (ES) m/e 465 (M + H)⁺.

This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 2

Preparation of 6-({[((3R)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3- Pyrrolidinyl)methyllamino)methyl)-2/-/-pyrido[3,2-ibiri ,41thiazin-3(4/-/)-one

Prepared essentially according to the procedure of Example 1 , except substituting [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.30 g, 1.0 mmole) for [((3S)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine, the title compound (0.33 g, 70 %) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1, containing 5%

NH₄OH): ¹ H NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 8.30 (d, J = 9.1 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.29 (d, J = 9.1 Hz, 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 4.37 (m, 2H), 4.20 (s, 3H), 3.98 (m, 2H), 3.75 (m, 5H), 3.61 (m, 2H), 3.13 (m, 2H), 2.50 (m, 2H), 2.04 (m, 2H). LC-MS (ES) m/e 483 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 3

Preparation of (2,3-dihvdro-1 -benzofuran-5-ylmethvnr((3S)-142-r3-fluoro-6-(methyloxy^')- 1 ,5-naphthyridin-4-vπethylV3-pyrrolidinv0methyl1amine

a) phenylmethyl [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]carbamate To a solution of phenylmethyl [(3S)-3-pyrrolidinylmethyl]carbamate (127 mg, 0.54 mmole) in DMF (1 ml_) was added 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.10 g, 0.49 mmole). After 24 h at 100 °C, the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1 , containing 5% NH4OH) to afford the title compound (0.16 g, 77

%) as a light yellow oil: LC-MS (ES) m/e 439 (M + H)⁺.

b) [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine To a solution of phenylmethyl [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.13 g, 0.29 mmole) in MeOH (50 mL) was added Pd(OH)2 (100 mg). The reaction contents were placed under a balloon of H2 and stirred for 18 hours. The reaction contents were filtered through Celite (MeOH) and concentrated under vacuum to give the title compound (66 mg, 76%) as a light yellow oil: LC-MS (ES) m/e 305 (M + H)⁺.

c) (2,3-dihydrofuro[2,3-c]pyridin-5-ylmethyl)[((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine To a stirred solution of [((3S)-1-{2-[3-fluoro-6-(methyloxy)~1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amine (66 mg, 0.22 mmole) in dry CH2CI2 (25 mL) and dry EtOH (20 mL) at RT was added 2,3-dihydro-1-benzofuran-5-carbaldehyde (37 mg, 0.25 mmole). After 24h, at RT was added NaBH4 (11 mg, 0.29 mmole). After 2h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded

the title compound (58 mg, 60 %) as light yellow solid: ¹H NMR (400 MHz, CDCI₃) δ 8.61 (S₁ 1 H), 8.16 (m, 1 H), 8.02 (s, 1 H), 7.16 (s, 1 H)₁ 7.06 (m, 1H)₁ 7.03 (d, 1 H), 6.73 (m, 2H), 4.56 (m, 2H)₁ 4.08 (s, 3H), 3.72 (s, 2H), 3.41 (m, 2H)₁ 3.19 (m, 2H), 2.92 (m, 21H)₁ 2.70- 2.90 (m, 3H)₁ 2.55-2.68 (m, 3H), 2.31-2.48 (m, 2H), 2.04 (m, 1 H), 1.51 (m, 1 H). LC-MS (ES) m/e 437 (M + H)⁺.

Example 4

Preparation of r(7-fluoro-2.3-dihvdro-1.4-benzodioxin-6-yl)methylir((3S)-1-(2-r3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-vnethyl)-3-pyrrolidinyl)methyllamine Prepared essentially according to the procedure for Example 3, except substituting 7-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde (57 mg, 0.31 mmole) for 2,3- dihydro-1-benzofuran-5-carbaldehyde, the title compound (74 mg, 50 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 8.59 (s, 1 H), 8.15 (d, J= 6.2Hz₁ 1 H), 7.13 (d, J= 5.8Hz, 1H), 6.83 (d, J= 6.7Hz, 1 H), 6.56 (d, J= 10.5Hz, 1 H)₁ 4.19 (s, 4H), 4.07 (S₁ 3H)₁ 3.66 (S₁ 2H)₁ 3.39 (m, 2H), 2.94 (m, 1 H)₁ 2.70-2.89 (m, 3H), 2.65 (m, 1 H), 2.56 (d, 2H), 2.30-2.46 (m, 2H),2.03 (m, 1 H), 1.49 (m, 1 H). LC-MS (ES) m/e 471 (M + H)⁺. This material, as a solution in MeOH₁ was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 5

Preparation of (2,3-dihvdro-1 ,4-benzodioxin-6-ylmethyl)r((3S)-1-(2-f3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yllethyl)-3-pyrrolidinvπmethvnamine

Prepared essentially according to the procedure for Example 3, except substituting 2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde (45 mg, 0.27 mmole) for 2,3-dihydro-1- benzofuran-5-carbaldehyde, the title compound (50 mg, 40 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 8.60 (s, 1 H), 8.16 (d, J= 9.1 Hz, 1H), 7.14 (d, J= 9.1Hz, 1H), 6.80 (s, 1H), 6.75 (s, 2H), 4.20 (s, 4H), 4.08 (s, 3H), 3.62 (s, 2H), 3.41 (m, 2H), 2.94 (m, 1 H), 2.69-2.89 (m, 3H), 2.64 (m, 1 H), 2.54 (m, 2H), 2.31-2.44 (m, 2H), 2.03 (m, 1 H), 1.48 (m, 1 H). LC-MS (ES) m/e 453 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 6

Preparation of 6-((IT(3f?)-1 -l2-r3.8-difluoro-6-(methyloxy)-4-αuinolinvHethyl)-3- pyrrolidinyl)methyllamino)methyl)-2H-pyridor3₁2-ibiri ,41thiazin-3(4/-/)-one Prepared essentially according to the procedure for Example 3, except substituting 3-0X0-3, 4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde (0.15 g, 0.78 mmole) for 2,3- dihydro-1-benzofuran-5-carbaldehyde, and substituting [((3R)-1-{2-[3,8-difluoro-6- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]amine (0.25 g, 0.78 mmole) for [((3S)- 1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (375 mg, 75 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.61 (s, 1 H), 7.56 (d, J= 7.80Hz, 1 H), 7.02-7.07 (m, 2H), 6.95 (d, J= 7.8 Hz, 1 H), 3.93 (s, 3H), 3.81 (s, 2H), 3.46 (s, 2H), 3.23 (m, 2H), 2.91 (m, 1 H), 2.58-2.81 (m, 6H), 2.35-2.49 (m, 2H), 2.06 (m, 1 H), 1.52 (m, 1H). LC-MS (ES) m/e 500 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 7

Preparation of 6-(([((3SVI -f2-r3-fluoro-6-(methyloxy)-4-quinolinvnethyl}-3- pyrrolidinyl)methvnamino)methyl)-2/-/-pyridor3,2-ib1[1 ,41thiazin-3(4/-/)-one Prepared essentially according to the procedure for Example 3, except substituting 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde (34 mg, 0.17 mmole) for 2,3- dihydro-1-benzofuran-5-carbaldehyde, and substituting [((3S)-1-{2-[3-fluoro-6- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]amine (53 mg, 0.17 mmole) for [((3S)- 1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (38 mg, 45 %) was prepared as a light yellow solid: ^ H NMR (400 MHz, CD₃OD) δ 8.54 (d, J=1.2 Hz, 1 H), 7.92 (d, J= 9.1 Hz, 1 H), 7.66 (d, J= 7.8 Hz, 1 H), 7.31- 7.38 (m, 2H), 7.00 (d, J= 7.8 Hz, 1 H), 3.97 (s, 3H), 3.78 (s, 2H), 3.50 (s, 2H), 3.28 (m, 2H), 2.92 (m, 1H), 2.65-2.79 (m, 4H), 2.62 (m, 2H), 2.40-2.47 (m, 2H), 2.17 (m, 1 H), 1.54 (m, 1 H). LC-MS (ES) m/e 482 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 8

Preparation of 6-(fl((3S)-1 -{2-r3-fluoro-6-(methyloxy)-4-quinolinvnethyl>-3- pyrrolidinyl)methyllamino|methvπ-2H-pyridor3,2-ibiri ,41oxazin-3(4H)-one Prepared essentially according to the procedure for Example 3, except substituting 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]oxazine-6-carboxaldehyde (28 mg, 0.16 mmole) for 2,3- dihydro-1-benzofuran-5-carbaldehyde, and substituting [((3S)-1-{2-[3-fluoro-6- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinyl)methyl]amine (48 mg, 0.16 mmole) for [((3S)- 1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (42 mg, 57 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 7.90 (d, J= 9.1 Hz, 1H), 7.22-7.34 (m, 2H), 6.94 (d, J= 8.0 Hz, 1 H), 4.61 (s, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.24 (m, 2H), 2.91 (m, 1 H), 2.56-2.80 (m, 6H), 2.57 (m, 1H), 2.35-2.49 (m, 2H), 2.07 (m, 1H), 1.52 (m, 1 H). LC-MS (ES) m/e 466 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 9

Preparation of 7-chloro-6-(M(3f?)-1-(2-r3-fluoro-6-(methyloxyV1.5-naphthyridin-4-vnethylV 3-pyrrolidinyl)methyl1amino)methyl)-2/-/-pyridor3.2-άiπ ,41oxazin-3(4/-/)-one Prepared essentially according to the procedure for Example 3, except substituting 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]oxazine-6-carbaldehyde (170 mg, 0.79 mmole) for 2,3-dihydro-1-benzofuran-5-carbaldehyde, and substituting [((3R)-1-{2-[3- fluoro-6-(methyloxy)-4-naphthyridyl]ethyl}-3-pyrrolidinyl)methyl]amine (240 mg, 0.79 mmole) for [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine, the title compound (250 mg, 64 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.52 (s, 1 H), 8.11 (d, J = 9.1 Hz, 1H), 7.14 (s, 1 H), 6.98 (d, J = 9.1 Hz, 1 H), 4.52 (m, 2H), 4.00 (s, 3H), 3.85 (m, 2H), 3.39 (m, 2H), 2.99 (m, 1 H), 2.84 (m, 3H), 2.76 (m, 3H), 2.46 (m, 2H), 2.02 (m, 1 H), 1.46 (m, 1 H). LC-MS (ES) m/e 501 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 10

Preparation of 7-fluoro-6-(ffl(3R)-1-{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vπethyl)- 3-pyrrolidinvπmethyl1amino)methyl)-2H-1 ,4-benzothiazin-3(4H)-one Prepared essentially according to the procedure for Example 3, except substituting 7-fluoro-3-oxo-3,4-dihydro-2/-/-1 ,4-benzothiazine-6-carbaldehyde (165 mg, 0.78 mmole) for 2,3-dihydro-1-benzofuran-5-carbaldehyde, and substituting [((3f?)-1-{2-[3-fluoro-6- (methyloxy)-4-naphthyridyl]ethyl}-3-pyrrolidinyl)methyl]amine (240 mg, 0.79 mmole) for [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (240 mg, 62 %) was prepared as a light yellow solid: ^'Η NMR (400 MHz, CDCI₃) δ 8.57 (s, 1 H), 8.15 (d, J = 9.1 Hz, 1 H), 7.04 (d, J = 9.1 Hz, 1 H), 6.96 (d, J = 9.2 Hz, 1 H), 6.87 (d, J = 6.4 Hz, 1H), 4.05 (s, 3H), 3.75 (m, 2H), 3.39 (m, 4H), 2.71-2.92 (m, 7H), 2.43 (m, 2H), 2.02 (m, 1 H), 1.48 (m, 1 H). LC-MS (ES) m/e 500 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 11

Preparation of 5-(H(OSVI -f2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethylV-3- pyrrolidinvDmethyliaminoTmethvD^.S-dihydro-i-benzofuran^-carbonitrile

Prepared essentially according to the procedure of example 3 except substituting 5-formyl-2,3-dihydro-1-benzofuran-7-carbonitrile (85 mg, 0.53 mmole) for 2,3-dihydro-1- benzofuran-5-carboxaldehyde, the title compound (0.17 g, 70 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 8.79 (s, 1 H), 8.16 (d, J = 9.0 Hz, 1 H), 7.60 (s, 1 H), 7.50 (s, 1 H), 7.21 (d, J = 9.0 Hz, 1 H), 4.67 (t, J = 8.2 Hz, 2H), 4.11 (s, 2H), 4.07 (s, 3H), 3.85 (m, 2H), 3.61 (m, 4H), 3.33 (m, 2H), 3.25 (m, 4H), 2.35 (m, 2H), 1.97 (m, 1 H). LC-MS (ES) m/e 462 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title - compound.

Example 12

Preparation of (2,3-dihvdrofuror2.3-clpyridin-5-ylmethyl)r((3S)-1 -(2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-vnethyl)-3-pyrrolidinyl)methvπamine

Prepared essentially according to the procedure for Example 3, except substituting 2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde (188 mg, 0.62 mmole) for 2,3-dihydro-1- benzofuran-5-carboxaldehyde, the title compound (223 mg, 82 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.61 (1 H, s), 8.16 (1 H, d), 8.02 (1 H, s), 7.16 (1 H, s), 7.06 (1H, d), 7.03 (1 H, d), 6.73 (2H, d), 4.56 (2H, t), 4.08 (3H, s), 3.72 (2H, s), 3.41 (2H, t), 3.19 (2H, t), 2.92 (21 H, m), 2.70-2.90 (3H, m), 2.55-2.68 (3H, m), 2.31-2.48 (2H, m), 2.04 (1H, m), 1.51 (1H, m). LC-MS (ES) m/e 438 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 13

Preparation of 6-(methyloxy)-442-r(3S)-3-((r(3-oxo-3,4-dihvdro-2H- pyridor3,2-biri,41thiazin-6-yl)methyl1amino)methyl)-1-pyrrolidinvnethyl>-3- quinolinecarbonitrile Prepared essentially according to the procedure of Example 3 except substituting 4-{2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (100 mg, 0.32 mmol) for [((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine, and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2- 6][1 ,4]thiazine-6-carboxaldehyde (60 mg, 0.32 mmol) for 2,3-dihydro-1-benzofuran-5- carboxaldehyde , the title compound (10 mg, 60 %) was prepared as light yellow solid: LC/MS (ES) m/e 489 (M+H)⁺; ¹ H NMR (CD₃OD, 400 MHz) δ 9.07 (s, 1H), 8.08 (d, J = 9.1 Hz, 1H) ), 7.71 (d, J = 8.1 Hz, 1 H), 7.4 (s, 1 H), 7.36(d, J = 5.1 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1 H), 4.45 (s, 2H), 4.35 (s, 2H), 4.15 (s, 4H), 3.95 (m, 4H), 3.6 (m, 4H), 3.4 (m, 1H), 3.35 (m, 2H), 2.9-3.1 (m, 1 H), 2.4-2.6 (m, 1H), 1.9-2.1 (m, 1H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 14

Preparation of 6-(methyloxy)-4-r2-((3SV3-(f(f1 ,31oxathiolor5,4-cl pyridin-6- Vlmethyl)amino1methyl>-1-pyrrolidinyl)ethyll-3-quinolinecarbonitrile

Prepared essentially according to the procedure for Example 3, except substituting [1 ,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (50 mg, 0.29 mmol) for 2,3-dihydro-1- benzofuran-5-carbaldehyde and substituting 4-{2-[(3S)-3-(aminomethyl)-1- pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (100 mg, 0.32 mmol) for [((3S)-I- {2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine. The title compound (100 mg, 75%) was obtained as a yellow solid: LC/MS (ES) m/e 462 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) 6 9.07 (s, 1 H), 8.10 (d, J = 9.6 Hz, 1H) ), 8.0 (s, 1 H), 7.8 (s, 1 H), 7.7 (d, J = 5.1 Hz, 1 H), 7.55 (d, J = 6.6 Hz, 1H),6.1 (s, 2H), 5.95(s, 2H), 5.45 (S, 1H), 4.8 (s, 2H), 4.35 (s, 2H), 4.15 (s, 3H), 3.95 (m, 4H), 3.6 (m, 4H), 3.4 (m, 1 H), 3.35 (m, 2H), 2.9-3.1 (m, 1 H), 2.4-2.6 (m, 1H), 1.9-2.1 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound. Example 15

Preparation of 6-(methyloxy)-4-(2-r(3S)-3-(lf(3-oxo-3,4-dihydro-2f/-pyridor3,2-ibiri .41 oxazin-θ-vOmethynaminolmethvD-i-pyrrolidinvnethylVS-quinolinecarbonitrile

Prepared essentially according to the procedure for Example 3, except substituting 3-oxo-3,4-dihydro-2f/-pyrido[3,2-jb][1 ,4]oxazine-6-carbaldehyde (55 mg, 0.32 mmol) for 2,3-dihydro-1-benzofuran-5-carbaldehyde, and substituting 4-{2-[(3S)-3-(aminomethyl)-1- pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile (100 mg, 0.32 mmol) for [((3S)-I- {2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine. The title compound (100 mg, 33%) was obtained as a light yellow solid: LC/MS (ES) m/e 473 (M+H)⁺; ¹H NMR (CD₃OD, 400 MHz) δ 8.91 (s, 1H), 8.07 (d, J = 9.3 Hz, 1H) ), 7.64 (d, J = 7.6 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 7.1 (d, J = 8.1 Hz, 1 H)₁ 4.65 (s, 2H), 4.3 (s, 2H), 4.1 (S, 3H), 3.95 (m, 4H), 3.65 (s, 2H), 3.55 (m, 4H), 3.35 (m, 4H), 2.9-3.1 (m, 1H), 2.4-2.6 (m, 1H), 1.9-2.1 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound.

Example 16

Preparation of 6-(methyloxy)-4-(2-f(3S)-3-((r(3-oxo-3,4-dihvdro-2H-pyridor3,2-b1 ri ,41thiazin-6-yl)methyl1amino)methyl)-1-pyrrolidinvnethyl}-1 ,5-naphthyridine- 3-carbonitrile

Prepared essentially according to the procedure for Example 3, except substituting 4-ethenyl-6-(methyloxy)-1 ,5-naphthyridine-3-carbonitrile (100 mg, 0.32 mmol) for [((3S)-I- {2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-ib][1,4]thia2ine-6-carbaldehyde (62 mg, 0.32 mmol) for 2,3-dihydro-1-benzofuran-5-carbaldehyde, the title compound (20 mg) was obtained as an off-white solid: LC/MS (ES) m/e 490 (M + H)⁺; ¹ H NMR (400 MHz, CD₃OD) δ 8.84 (s, 1 H), 8.15 (d, J = 9.10 Hz, 1 H), 7.65 (d, J = 7.85 Hz, 1 H), 7.22 (d, J = 9.08 Hz, 1 H), 7.02 (d, J = 7.89 Hz, 1 H), 3.96 (m, 2H), 3.90 (s, 3H), 3.63 (m, 1H), 3.52 (m, 2H), 3.30 (s, 2H), 3.29, (M, 1 H), 3.01 (m, 2H), 2.74 (m, 1 H), 2.10 (m, 1H), 1.98 (M, 1H), 2.61 (M, 1 H), 2.58 (M, 2H), 1.77 (m, 1H), 1.60 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 17

Preparation of 1-((3S)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vπethyl)-3- PVrrolidinyl)-Λ/-r(5-methyl-2,3-dihvdro-1,4-benzodioxin-6-yl)methvπmethanamine

Prepared essentially according to the procedure for Example 3, except substituting 5-methyl-2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde (44 mg) for 2,3-dihydro-1- benzofuran-5-carbaldehyde, the title compound (63 mg) was obtained as an off-white solid: LC/MS (ES) m/e 467 (M+H)⁺; ¹H NMR (400 MHz, CDCI3) δ 8.53 (s, 1H), 8.08 (d, J = 9.04 Hz, 1H), 6.98 (d, J = 9.04 Hz, 1H), 6.67 (d, J = 8.30, 1 H) 6.60 (d, J = 8.28 Hz, 2H), 4.19 (m, 2H), 4.14 (m, 2H), 4.01 (s, 3H), 3.62 (s, 2H), 3.33 (t, J = 7.58 Hz, 2H), 2.84 (m,1 H), 2.74 (m, 1H), 2.67 (M, 2H), 2.58 (M, 1 H), 2.56 (M, 2H), 2.30 (M, 2H), 2.12 (S, 3H), 1.95 (m, 1H), 1.44 (m, 1H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 18

Preparation of 1-((3S)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-3- Pyrrolidinvn-A/-r(8-methyl-2,3-dihvdro-1 ,4-benzodioxin-6-yl)methvnmethanamine

Prepared essentially according to the procedure for Example 3, except substituting 8-methyl-2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde (37 mg) for 2,3-dihydro-1- benzofuran-5-carbaldehyde, the title compound (51 mg) was obtained as an off-white solid: LC/MS (ES) m/e 467 (M+H)⁺; ¹ H NMR (400 MHz, CDCI3) δ 8.53 (s, 1 H), 8.08 (d, J = 9.0 Hz, 1 H), 6.98 (d, J = 9.03 Hz, 1H), 6.58 (d, J = 2.3 Hz, 2H), 4.19 (m, 2H), 4.15 (m, 2H), 4.01 (s, 3H), 3.57 (s, 2H), 3.33 (t, J = 7.81 Hz, 2H), 2.74 (m, 1 H), 2.67 (M, 2H), 2.54 (M, 1 H), 2.54 (M, 2H), 2.29 (M, 2H), 2.11 (S, 3H), 1.94 (m, 1 H), 1.44 (m, 1H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 19

Preparation of 6-αr((3S)-1-(2-r3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-3- pyrrolidinyl)methyl1amino)methvπ-2H-pyridor3,2-άiπ ,41thiazin-3(4H)-one

a) Phenylmethyl [((3S)-1-{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]carbamate

To a solution of 7-chloro-8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine (1.68 g, 7.6 mmol)in DMF (5 ml_) was added phenylmethyl [(3R)-3-pyrrolidinylmethyl]carbamate hydrochloride (2.1 g, 7.6 mmol) and diisopropylethylamine (3.9 mL, 22.8 mmol)). The reaction was heated at 100 ⁰C for 18 h. Upon cooling to room temperature, the crude reaction mixture was directly added to a silica gel column and purified to give a light brown oil (1.3 g): LC/MS (ES) m/e 455 (M + H)⁺.

b) [((3S)-1 -{2-[3-Chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine

A solution of phenylmethyl [((3S)-1-{2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (1.0 g, 2.2 mmol) in MeOH (30 mL) was treated with 40% KOH (15 mL, 107 mmol) and heated at 100 ⁰C for 3 h. The MeOH was stripped off at reduced pressure and the residue was treated with water. The product was extracted into CHCI3 and the combined organic phases were dried (K2CO3) and filtered. Purification of silica gel provided the product as a light brown oil (0.36 g, 51%): LC/MS (ES) m/e 321 (M + H)⁺.

c) 6-({[((3S)-1 -{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one

To a stirred solution of [((3S)-1 -{2-[3-Chloro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amine (100 mg, 0.31 mmol) in dry CH2CI2 (5 mL) and dry EtOH (5 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-ibJ[1 ,4]thiazine-6- carboxaldehyde (67 mg, 0.34 mmol) along with a small amount of Na2SC>4 and NaHCθ3. After 24h at RT, NaBH4 (12 mg, 0.32 mmol) was added. After 2h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica gel afforded the title compound as a light yellow solid(15 mg, 9.4%): LC/MS (ES) m/e 499/501 (M + H)⁺; ^"I H NMR (CD₃OD, 400 MHz) δ 8.78 (s, 1H), 8.25 (d, J = 9.1 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 1 H), 4.35 (s, 2H), 4.1 (s, 3H), 3.9 (m, 4H), 3.66 (s, 4H), 3.5 (m, 4H), 3.3 (m, 2H), 2.9-3.0 (m, 1 H), 2.2-2.3 (m, 1 H), 1.95-2.05 (m, 1 H). This material, as a solution in MeOH, was treated with 3 equivalents of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound. Example 20

Preparation of 6-((r((3S)-1-{2-r3-chloro-6-(methyloxy')-1 ,5-naphthyridin-4-yl1ethyl>- 3-pyrrolidinyl)methvnamino)methyl)-2/-/-pyridor3,2-άiπ ,41oxazin-3(4H)-one

Prepared essentially according to the procedure for Example 19, except substituting 3~oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]oxazine-6-carbaldehyde (61 mg, 0.34 mmol) for 3-oxo-3,4-dihydro-2H-pyrido[3,2-/)][1 ,4]thiazine-6-carboxaldehyde. The title compound (150 mg, 92%) was obtained as a light yellow solid: LC/MS (ES) m/e 483/485 (M + H)⁺; ¹ H NMR (CD₃OD, 400 MHz) δ 8.78 (s, 1 H), 8.25 (d, J = 9.1 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 7.11 (d, J = 8.1 Hz, 1 H), 4.7 (s, 2H), 4.3 (s, 2H)₁ 4.2 (s, 3H), 3.9 (m, 4H), 3.66 (s, 4H), 3.5 (m, 4H), 3.3 (m, 2H), 3.0 (m, 1 H), 2.2-2.3 (m, 1 H), 1.95-2.05 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound. Example 21

Preparation of f((3S)-1-(2-f3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyll-3- pyrrolidinvπmethylKflSioxathiolorδ^-cipyridin-β-ylmethvDamine

Prepared essentially according to the procedure for Example 19, except substituting [1 ,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (57 mg, 0.34 mmol) for 3-oxo- 3,4-dihydro-2H-pyrido[3,2-ιb][1 ,4]thiazine-6-carboxaldehyde. The title compound (140 mg) was obtained as a light yellow solid: LC/MS (ES) m/e 472/474 (M + H)⁺; ¹H NMR (CD₃OD₁ 400 MHz) δ 8.85 (s, 1 H), 8.22 (d, J = 9.1 Hz, 1 H), 8.08 (d, J = 3.0 Hz, 1 H), 7.71 (d, J = 6.8 Hz, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 5.94 (bs, 2H), 5.4 (s, 1 H), 4.35 (s, 2H), 4.11 (s, 3H), 3.85 (m, 4H), 3.52 (m, 4H), 3.25 (m, 3H), 3.0 (m, 1 H), 2.3-2.5 (m, 1 H), 1.8-2.0 (m, I H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound. Example 22

Preparation of 6-(CT((3S)-1 -(2-r3,8-difluoro-6-(methyloxy)-4-quinolinyllethyl>-3- PVrrolidinyl)methyllamino)methyl)-2/-/-pyridor3,2-άiri,41oxazin-3(4/-/)-one

a) 1 , 1 -dimethylethyl (3S)-3-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-/)][1 ,4]thiazin-6- yl)methyl]amino}methyl)-1-pyrrolidinecarboxylate To a solution of 1 ,1 -dimethylethyl (3S)-3-(aminomethyl)-1-pyrrolidinecarboxylate (0.41 g, 2.07 mmole) in dry CH2CI2 (25 mL) and dry EtOH (20 ml_) at RT was added 3- όxo-3,4-dihydro-2/-/-pyrido[3,2-ιb][1,4]oxazine-6-carbaldehyde (0.36 g, 2.07 mmole). After 24h, at RT was added NaBH4 (79 mg, 2.08 mmole). After 2h, silica gel (5g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) afforded the title

compound (0.40 g, 53%) as light yellow solid: LC-MS (ES) m/e 363 (M + H)⁺.

b) 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-ib][1,4]thia2in-3(4H)-one To a stirred solution of 1 ,1-dimethylethyl (3S)-3-({[(3-oxo-3,4-dihydro-2H- pyrido[3,2-ό][1 ,4]oxazin-6-yl)methyl]amino}methyl)-1-pyrrolidinecarboxylate (0.40 g, 1.10 mmole) in DCM (10 ml_) was added 4M HCI (2mL, 4M in dioxane). After 3 h at RT, the suspension was concentrated under vacuum and purified on silica (CHCtø/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (282 mg, 98 %) as light yellow solid:

LC-MS (ES) m/e 263 (M + H)⁺.

c) 6-({[((3S)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ύ][1 ,4]oxazin-3(4/-0-one To a stirred solution of 8-ethenyl-4,7-difluoro-2-(methyloxy)-1,5-naphthyridine (0.27 g, 1.10 mmole) in DMF (2 mL) was added 6-({[(3S)-3- pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one (0.29 g, 1.1 mmole). After 24 h at 90 ⁰C, the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (96 mg, 18%) as a light yellow

solid: ¹H NMR (400 MHz, CDCI₃) δ 8.60 (s, 1 H), 7.18 (d, J= 8.0 Hz, 1H), 7.01-7.06 (m, 2H), 6.91 (d, J= 8.0 Hz, 1 H), 4.62 (s, 2H), 3.92 (s, 3H), 3.80 (s, 2H), 3.23 (t, 2H), 2.75 (m, 1H), 2.54-2.82 (m, 6H), 2.32-2.49 (m, 2H), 2.06 (m, 1H), 1.52 (m, 1H). LC-MS (ES) m/e 484 (M+H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 23

Preparation of 6-((F(OSVI -(2-r3,8-difluoro-6-(methyloxy)-4-quinolinvnethyl)-3- PVrrolidinyl)methvnamino>methyl)-2H-pyridor3,2-ibiri,41thiazin-3(4f/)-one Prepared essentially according to the procedure for Example 22, except substituting 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]thiazin- 3(4H)-one (266 mg, 0.95 mmole) for 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2/-/- pyrido[3,2-ib][1 ,4]oxazin-3(4H)-one, the title compound (220 mg, 46%) was prepared as a light yellow solid: ¹H NMR (400 MHz, CDCI₃) δ 8.61 (s, 1H), 7.56 (d, J= 7.8Hz, 1H), 7.02- 7.07 (m, 2H), 6.95 (d, J= 7.8Hz, 1H), 3.93 (s, 3H), 3.81 (s, 2H), 3.46 (s, 2H), 3.23 (m 2H), 2.91 (m, 1 H), 2.58-2.81 (m, 6H), 2.35-2.49 (m, 2H), 2.06 (m, 1 H), 1.52 (m, 1H). LC-MS (ES) m/e 500 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 24

Preparation of f((3S)-1-(2-r3-fluoro-6-(methyloxyV1 ,5-naphthyridin-4-vπethyl)-3- pyrrolidinyl)methylKπ ,31oxathiolor5,4-c1pyridin-6-ylmethyl)amine Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (110 mg, 0.54 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1 ,5-naphthyridine, and substituting ([1,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)[(3S)-3-pyrrolidinylmethyl]amine (68 mg, 0.27 mmole) for 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4A7)- one, the title compound (56 mg, 44 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.61 (s, 1 H), 8.16 (d, J= 9.0 Hz, 1H), 8.02 (s, 1 H), 7.19 (s, 1 H), 7.06 (d, J = 9.0 Hz, 1H), 5.73 (s, 2H), 4.08 (s, 3H), 3.80 (s, 2H), 3.41 (t, 2H), 2.92 (m, 1 H), 2.68-2.88 (m, 3H), 2.57-2.67 (m, 3H), 2.33-2.44 (m, 2H), 2.03 (m, 1 H), 1.52 (m, 1 H). LC-MS (ES) m/e 456 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 25

Preparation of 7-chloro-6-((IY(3S)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)- 3-pyrrolidinyl)methyl1amino|methyl)-2/-/-pyrido[3₁2-άiri ,41oxazin-3(4H)-one Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (100 mg, 0.49 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1 ,5-naphthyridine, and substituting 7-chloro-6-({[(3S)- 3-pyrrolidinylmethyl]amino}methyl)-2W-pyrido[3,2-ό][1,4]oxazin-3(4H)-one (129 mg, 0.43 mmole) for 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-ύ][1 ,4]oxazin-3(4H)- one, the title compound (31 mg, 4 %) was prepared as a light yellow solid: ^"Η NMR (400 MHz, CDCI₃) δ 8.58 (s, 1H), 8.14 (d, J= 9.0Hz, 1H), 7.22 (s, 1 H), 7.04 (d, J= 9.0Hz, 1H), 4.61 (s, 2H), 4.06 (s, 3H), 3.89 (s, 2H), 3.49 (s, 1H), 3.40 (m, 2H), 2.95 (m, 1 H), 2.76-2.91 (m, 4H), 2.79 (m, 2H), 2.42 (m, 2H), 2.04 (m, 2H), 1.51 (m, 2H). LC-MS (ES) m/e 501 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 26

Preparation of 6-(ff((3SM42-F3-fluoro-6-nτ)ethyloxy>1 ,5-naphthyridin-4-vπethyl)-3- Pyrrolidinyl)methyl1amino}methyl)-2f/-pyridof3.2-ib1f1,41oxazin-3(4/-/)-one

Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (143 mg, 0.70 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1 ,5-naphthyridine, the title compound (32 mg, 10 %) was prepared as a light yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1 H), 8.06 (d, J = 9.1 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.54 (s, 3H), 4.00 (s, 3H), 3.87 (s, 2H), 3.37 (m, 2H), 2.70-3.05 (m, 8H), 2.57 (m, 1 H), 2.48 (m, 1 H), 2.07 (m, 1 H), 1.56 (m, 1 H). MS (ES) m/e 467 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 27

Preparation of 6-(ff((3S)-1-(2-f3-fluoro-6-(methyloxy)-1.δ-naphthyridin^-vπethvD-S- pyrrolidinyl)methvπamino>methyl)-2H-pyridof3,2-ibiπ ,41thiazin-3(4/-y)-one

Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (143 mg, 0.70 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1 ,5-naphthyridine, and substituting 6-({[(3S)-3- pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4H)-one, (195 mg, 0.70 mmole) for 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2f/-pyrido[3,2- 6][1 ,4]oxazin- 3(4H)-one, the title compound (124 mg, 37 %) was prepared as a light yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.75 (d, J= 7.8 Hz, 1H), 7.21 (d, J= 9.1 Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1H), 4.13 (s, 3H), 4.00 (s, 2H), 3.55 (s, 2H), 3.53 (m, 2H), 3.08 (m, 3H), 2.96 (m, 2H), 2.86 (m, 2H), 2.69 (m, 1H), 2.56 (m, 1H), 2.16 (m, 1H), 1.65 (m, 1H). LC-MS (ES) m/e 483 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 28

Preparation of (2,3-dihvdroH ,41dioxinor2,3-c1pyridin-7-ylmethvflr((3SV1-(2-r3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yllethylV3-pyrrolidinvnmethvnamine

Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (143 mg, 0.70 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1 ,5-naphthyridine, and substituting 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (115 mg, 0.70 mmole) for 6-({[(3S)-3- pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2- b][1 ,4]oxazin-3(4H)-one, the title compound was prepared as an orange hygroscopic solid: LC/MS (ES) m/e 454 (M+H)⁺; ¹H NMR (DMSO, 400 MHz) δ 9.8 (bs, 1H), 8.85 (s, 1 H), 8.4 (d, J = 5.6 Hz, 1 H), 8.33 (d, J = 9.1 Hz, 1 H), 7.51 (d, J = 11.6 Hz, 1 H), 7.29 (d, J = 9.1 Hz, 1 H), 4.5 (m, 3H), 4.25 (s, 2H), 4.1 (s, 3H), 3.8 (m, 1H), 3.7 (m, 2H), 3.6 (m, 2H), 3.5(m, 2H), 3.25 (m, 2H), 3.1 (s, 2H), 2.85 (m, 2H), 2.25 (m, 1 H), 1.8 (m, 1 H), 1.3 (s, 1 H), 0.8 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound.

Example 29

Preparation of 6-({IY(3S)-1-{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-3- pyrrolidinyl)methvnamino)methyl)-7-methyl-2H-pyridor3,2-ά1f1,41thiazin-3(4H)-one

Prepared essentially according to the procedure for Example 22, except substituting 7-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-ib][1 ,4]thiazine-6-carbaldehyde (75 mg, 0.25 mmol) for 2,3-dihydro-1-benzofuran-5-carbaldehyde, and substituting substituting 8-ethenyl-7-fluorό-2-(methyloxy)-1 ,5-naphthyridine (43 mg, 0.25 mmole) for 8- ethenyl-4,7-difluoro-2-(methyloxy)-1 ,5-naphthyridine, the title compound was obtained as an off-white solid (66 mg, 53%): LC/MS (ES) m/e 497 (M+H)⁺; ¹H NMR (400 MHz, CDCI3) δ 8.52 (s, 1 H), 8.09 (d, J = 9.04 Hz, 1H), 7.27 (s, 1 H), 6.97 (d, J = 9.04 Hz, 1 H), 4.00 (s, 3H), 3.71 (s, 2H), 3.34 (s, 2H), 3.32, (M, 1H), 2.86 (m,1H), 2.77 (m, 1H), 2.70 (M, 2H), 2.61 (M, 1 H), 2.58 (M, 2H), 2.36 (M, 2H), 2.15 (S, 3H), 1.98 (m, 1 H), 1.47 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 30

Preparation of 6-({f((3S)-1-((2S)-2-hvdroxy-2-r6-(methyloxy)-1.5-naphthyridin-4-vnethyl>-3- PVrrolidinvπmethyllamino)methyl)-2/-/-pyridor3,2-άiπ,41thiazin-3(4fy)-one

a) phenylmethyl [((3S)-1-{(2S)-2-hydroxy-2~[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]carbamate To a solution of phenylmethyl [(3S)-3-pyrrolidinylmethyl]carbamate (0.53 g, 2.27 mmole) and UCIO4 (0.24 g, 2.27 mmole) in DMF (1 mL) was added 2-(methyloxy)-8- [(2S)-2-oxiranyl]-1 ,5-naphthyridine (0.45 g, 2.25 mmole). After 24 h at 80 ⁰C, the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1 , containing 5% NH4OH) to afford

the title compound (0.24 g, 25 %) as a light yellow oil: LC-MS (ES) m/e 437 (M + H)⁺.

b) (1 S)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[6-(methyloxy)-1 ,5-naphthyridin-4- yljethanol To a solution of phenylmethyl [((3S)-1-{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.24 g, 0.56 mmole) in MeOH (50 mL) was added Pd(OH)2 (100 mg). The reaction contents were placed under a balloon of H2 and stirred for 18 hours. The reaction contents were filtered through Celite (MeOH) and concentrated under vacuum to give the title compound (0.16 g, 98%) as a light yellow oil: LC-MS (ES) m/e 303 (M + H)⁺.

c) 6-({[((3S)-1 -{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]thiazin-3(4/-0-one To a stirred solution of (1 S)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[6- (methyloxy)-1,5-naphthyridin-4-yl]ethanol (72 mg, 0.24 mmole) in dry CH2CI2 (25 ml.) and dry EtOH (20 ml.) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]thiazine-6- carbaldehyde (47mg, 0.24 mmole). After 24h at RT₁ was added NaBH4 (10 mg, 0.26 mmole). After 2h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCI_β/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (61 mg, 54 %) as light yellow solid:

¹ H NMR (400 MHz, CDCI₃) δ 8.81 (d, J= 4.5 Hz, 1 H), 8.23 (d, J= 9.1 Hz, 1 H), 7.84 (d, J= 4.5 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1 H), 7.12 (d, J= 9.1 Hz, 1 H), 6.92 (d, J= 8.0 Hz, 1 H), 5.74 (m, 1 H), 4.04 (s, 3H), 3.82 (s, 2H), 3.46 (s, 2H), 3.00-3.11 (m, 1 H), 2.58-2.83 (m, 6H), 2.33-2.58 (m, 1H), 2.01 (m, 2H), 1.65 (m, 1 H). LC-MS (ES) m/e 481 (M + H)⁺.

Example 31

Preparation of 6-((r((3S)-1-((2S)-2-hvdroxy-2-f6-(methyloxy)-1.S-naphthyridin^-yllethyll-S- pyrrolidinyl)methyllamino)methyl)-2H-pyridor3,2-άiri .41oxazin-3(4H)-one Prepared essentially according to the procedure for Example 30, except substituting 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ό][1,4]oxazine-6-carbaldehyde (51 mg, 0.29 mmole) for 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ό][1 ,4]thiazine-6-carbaldehyde, The title compound (79 mg, 67 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) 5 8.80 (cl, J= 4.5 Hz, 1 H), 8.23 (d, J= 9.1 Hz, 1 H), 7.80 (d, J= 4.5 Hz, 1 H), 7.17 (d, J= 8.0 Hz, 1H), 7.10 (d, J= 9.1 Hz, 1 H), 6.87 (d, J= 8.0 Hz, 1 H), 5.73 (m, 1H), 4.62 (s, 2H), 4.02 (s, 3H), 3.81 (s, 2H), 3.11-2.94 (m, 2H)₁ 2.51-2.86 (m, 6H), 2.33-2.51 (m, 1 H), 2.02 (m, 1 H), 1.62 (m, 1 H). LC-MS (ES) m/e 465 (M + H)⁺.

This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 32

Preparation of 6-((F(QR)-I -((2S)-2-hvdroxy-2-r6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3- pyrrolidinyl)methvnamino|methyl)-2/-/-pyridor3,2-άiri ,41oxazin-3(4H)-one Prepared essentially according to the procedure for Example 30, except substituting 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ό][1 ,4]oxazine-6-carbaldehyde (71 mg, 0.40 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[3,2-6][1,4]thiazine-6-carbaldehyde, and substituting (1 S)-2-[(3R)-3-(aminomethyl)-1 -pyrrolidinyl]-1 -[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethanol (0.12 g, 0.41 mmole) for (1 S)-2-[(3S)-3-(aminomethyl)-1- pyrrolidinyl]-1-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethanol, the title compound (100 mg, 53 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.80 (d, J= 4.5 Hz, 1 H), 8.24 (d, J= 9.1 Hz, 1 H), 7.80 (d, J= 4.5 Hz, 1 H), 7.18 (d, J= 8.0 Hz, 1 H), 7.10 (d, J= 9.1 Hz, 1 H), 6.87 (d, J= 8.0 Hz, 1 H), 5.73 (m, 1H), 4.63 (s, 2H), 4.01 (s, 3H), 3.80 (s, 2H), 3.11-2.95 (m, 2H), 2.84 (m, 1H), 2.49-2.79 (m, 5H), 2.40 (m, 1H), 2.04 (m, 1H), 1.62 (m, 1 H). LC-MS (ES) m/e 465 (M + H)⁺.

This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 33

Preparation of 6-((r((3R)-1-((2SV2-hvdroxy-2-f6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl>-3- pyrrolidinyl)methyllamino>methvπ-2H-pyridor3,2-άiri ,41thiazin-3(4H)-one

Prepared essentially according to the procedure for Example 30, except substituting (1 S)-2-[(3R)-3-(aminomethyl)-1-pyrrolidinyl]-1-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethanol (102 mg, 0.34 mmole) for (1 S)-2-[(3S)-3-(aminomethyl)-1 - pyrrolidinyl]-1-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethanol, the title compound (80 mg, 49%) was prepared as a light yellow solid: 1 H NMR (400 MHz, CDCI₃) δ 8.80 (d, J= 4.5 Hz, 1 H), 8.24 (d, J= 9.1 Hz, 1 H), 7.83 (d, J= 4.4 Hz, 1H), 7.56 (d, J= 7.8 Hz, 1 H), 7.11 (d, J= 9.1 Hz, 1 H), 6.92 (d, J= 7.8 Hz, 1 H), 5.72 (dd, 1 H), 4.03 (s, 3H), 3.83 (s, 2H), 3.47 (s, 2H), 2.98-3.12 (m, 1 H), 2.58-2.87 (m, 4H)₁ 2.48-2.58 (m, 2H), 2.38 (m, 1 H), 2.05 (m, 1 H), 1.63 (m, 1H). LC-MS (ES) m/e 481 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 34

Preparation of 6-(H(QS)-I -((2R)-2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yll-2- hvdroxyethyl)-3-pyrrolidinyl)methyllamino)methyl)-2/-/-pyridof3,2-ά1f1,41thiazin-3(4H)-one

(a) phenylmethyl [((3S)-1-{(2R)-2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-2- hydroxyethyl}-3-pyrrolidinyl)methyl]carbamate

To a solution of 7-fluoro-2-(methyloxy)-8-[(2S)-2-oxiranyl]-1 ,5-naphthyridine (220 mg, 1.0 mmol) in acetonitrile (5 ml_) were added phenylmethyl [(3R)-3- pyrrolidinylmethyl]carbamate (235 mg, 1.0 mmol) followed by Lithium perchlorate (106 mg, 1.0 mmol). After heated at 43 ⁰C for 48 h, the resulting mixture was cooled down to room temperature, concentrated and purified with column chromatograhy (silica, 1- 5% methanol in DCM (1% NH₄OH)) to provide the tilte compound as an off-hwite solid (250 mg, 55%): : LC/MS (ES) m/e 455 (M+H)⁺.

(b) (1R)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethanol

To a solution of phenylmethyl [((3S)-1-{(2f?)-2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]-2-hydroxyethyl}-3-pyrrolidinyl)methyl]carbamate (250 mg, 0.55 mmol) in EtOH (5 ml_) was added Pd(OH)₂ (20 mg). The suspension was hydrogenated at 1atm of H₂ using a balloon. After 12 h, the mixture was filtered and washed several times with MeOH. The filtrate was concentrated to afford the title compound (175 mg, 100%) as an off-white foam, which was used without further purification: LC/MS (ES) m/e 321 (M+H)⁺.

(c) 6-({[((3S)-1-{(2R)-2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-2-hydroxyethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-;b][1 ,4]thiazin-3(4H)-one

To a stirred solution of (1R)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethanol (90 mg, 0.28 mmol) in dry CH2CI2 (2 mL) and dry EtOH (2 mL) was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-ύ][1,4]thiazine-6- carboxaldehyde (55 mg, 0.28 mmol) along with Na2SC>4 (350 mg, 2.46 mmol). After 18h at room temperature, NaBH4 (24 mg, 0.56 mmol) was added. After 2h, the solution wa partitioned between ethyl acetate and the aqueous solution of sodium bicarbonate. The aqueous solution was extreacted several times with ethyl acetate. The organic fraction were pooled, concentrated and purified with column chromatography (silica, 0-8% MeOH in DCM (1% NH₄OH)) affording a light yellow solid, which was completed with chiral purification. The title compound (5 mg, 3.6%) was provided as a white solid: LC/MS (ES) m/e 499 (M + H)⁺; ¹ H NMR (400 MHz, CD₃OD): δ 8.56 (s, 1 H), 8.14 (d, J = 9.0 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.10 (d, J = 9.2 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 5.82-5.84 (m, 1 H), 4.03 (S, 3H), 3.64 (s, 2H), 3.39-3.41 (m, 1 H), 3.09-3.12 (m, 1 H), 2.87-3.07 (m, 2H), 2.59-2.67 (m, 2H), 2.48-2.52 (m, 2H), 2.28-2.36 (m, 2H), 1.86-1.97 (m, 1 H), 1.37-1.46 (m, 1 H), 1.16-1.18 (m, 1 H). This material, as a solution in MeOH, was treated with 3 equivalents of 4M HCI in dioxane and evaporated to dryness to provide the hydrochloride salt of the title compound.

Example 35

Preparation of Λ/-r((3S)-1-f2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vπethyl}-3- pyrrolidinyl)methyl1-3-oxo-3,4-dihvdro-2/-/-1 ,4-benzothiazine-6-sulfonamide

To a stirred solution of [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.50 g, 1.65 mmole) in dry CH2CI2 (25 mL) at RT was added triethylamine (0.34 mL, 2.48 mmole) and 3-oxo-3,4-dihydro-2H-1 ,4- benzothiazine-6-sulfonyl chloride (0.47 g, 1.80 mmole). After 24h, the reaction solution was concentrated under vacuum. Purification on silica (CHC^/MeOH, 9:1 containing 5%

NH4OH) afforded the title compound (0.80 g, 91%) as light yellow solid: ¹H NMR (400 MHz, CDCI₃) δ 8.59 (s, 1 H), 8.16 (d, J = 9.0 Hz, 1H), 7.34 (m, 3H), 7.03 (d, J = 9.0 Hz, 1 H), 4.04 (s, 3H), 3.47 (s, 2H), 3.34 (m, 2H), 2.95 (m, 3H), 2.79 (m, 2H), 2.61 (m, 1H), 2.52 (m, 2H), 2.34 (m, 1H), 1.97 (m, 1 H), 1.55 (m, 1 H). LC-MS (ES) m/e 532 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 36

Preparation of Λ/-f((3ffl-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3- pyrrolidinyl)methyll-3-oxo-3,4-dihvdro-2H-1 ,4-benzothiazine-6-sulfonamide

Prepared essentially according to the procedure for Example 35, except substituting [((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine (164 mg, 0.54 mmole) for [((3R)-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (376 mg, 70 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 9.39 (br, 1 H), 8.63 (s, 1 H), 8.19 (d, J=9.04Hz, 1 H), 7.31-7.38 (m, 2H), 7.25 (d, J=6.23Hz, 1 H), 7.07 (d, J=9.05Hz, 1 H), 4.07 (s, 3H), 3.46 (s, 2H), 3.38 (t, 2H), 2.71-3.06 (br m, 5H), 2.56 (d, 2H), 2.40 (m, 2H), 2.00 (m, 1H), 1.56 (m, 1 H). LC-MS (ES) m/e 532(M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 37

Preparation of Λ/-r((3R)-1-f243-flύoro-6-(methyloxy)-1 ,5-naphthyridin-4-y[lethylV3- PVrrolidinvnmethyll-2,3-dihydro-1 ,4-benzodioxin-6-sulfonamide

Prepared essentially according to the procedure for Example 35, except substituting 2,3-dihydro-1 ,4-benzodioxin-6-sulfonyl chloride (94 mg, 0.40 mmole) for 3- oxo-3,4-dihydro-2H-1 ,4-benzothiazine-6-sulfonyl chloride, and substituting [((3S)-1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (150 mg, 0.50 mmole) for [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine, the title compound (200 mg, 99%) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.64 (s, 1 H)₁ 8.18 (d, J=9.01 Hz, 1 H), 7.24-7.30 (m, 2H), 7.08 (d, J=9.04Hz, 1H), 6.91 (d, J=8.49Hz, 1H), 4.28 (m, 4H), 4.09 (s, 3H), 3.37 (t, 2H), 2.96 (m, 3H), 2.80 (m, 2H), 2.54 (m, 2H), 2.30-2.46 (m, 2H), 1.99 (m, 1 H), 1.54 (m, 1 H). LC-MS (ES) m/e 503 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 38

Preparation of Λ/-IY(3f?)-1 -{2-r3-fluoro-6-(methyloxy)-4-quinolinyllethyl)-3- PVrrolidinyl)methvn-3-oxo-3,4-dihydro-2H-1 ,4-benzothiazine-6-sulfonamide

Prepared essentially according to the procedure for Example 35, except substituting [((3S)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amine (108 mg, 0.35 mmole) for [((3R)-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (100 mg, 55 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 9.53 (br s, 1 H), 8.60 (s, 1 H), 7.96 (d, J=9.20Hz, 1 H), 7.24-7.41 (m, 4H), 7.15 (d, J=2.59Hz, 1H), 3.94 (s, 3H), 3.46 (s, 2H), 3.18 (m, 2H), 2.94 (m, 3H), 3.72 (m, 2H), 2.31-2.68 (m, 4H), 2.01 (m, 1 H), 1.56 (m, 1 H). LC-MS (ES) m/e 531 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 39

Preparation of A/-F((3R)-1-(2-f3, 8-difluoro-6-(methyloxy V4-αuinolinyllethyl)-3- PVrrolidinyl)methvn-3-oxo-3.4-dihvdro-2/-/-1₁4-benzothiazine-6-sulfonamide

Prepared essentially according to the procedure for Example 35, except substituting [((3S)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amine (96 mg, 0.30 mmole) for [((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (57 mg, 35 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.60 (s, 1 H)₁ 7.37 (s, 1 H), 7.34 (s, 1 H), 6.98-7.05 (m, 2H), 3.94 (s, 3H), 3.46 (s, 2H), 3.18 (m, 2H), 2.94 (d, 2H), 3.87 (m, 1 H), 2.45-2.82 (br m, 5H), 2.41 (m, 1 H), 2.00 (m, 1H), 1.53 (m, 1 H). LC-MS (ES) m/e 549 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 40

Preparation of Λ/-lT(3ffl-1 -(2-r3-cvano-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl>-3- Pyrrolidinyl)methyll-3-oxo-3,4-dihydro-2/-/-1.4-benzothiazine-6-sulfonamide

Prepared essentially according to the procedure for Example 35, except substituting 4-{2-[(3S)-3-(aminomethyl)-1 -pyrrolidinyl]ethyl}-6-(methyloxy)-1 ,5- naphthyridine-3-carbonitrile (10 mg, 0.03 mmole) for [((3f?)-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine, the title compound (10 mg, 62 %) was prepared as a light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.87 (s, 1H), 8.82 (m, 1 H), 8.24 (d, J=9.08Hz, 1 H), 7.41 (s, 1 H), 7.36 (s, 1 H), 7.24 (s, 1 H), 4.10 (s, 3H), 3.68 (m, 1 H), 3.44-3.54 (m, 3H), 3.16 (m, 1 H), 2.94 (m, 2H), 2.86 (m, 1 H), 2.65 (m, 1 H), 2.51 (m, 1 H), 2.28-2.43 (m, 2H), 2.04 (m, 1 H), 1.58 (m, 1 H), 0.85 (m, 1 H). LC-MS (ES) m/e 539 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 41

Preparation of (±)-6-({r(1-{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl>-3-hydroxy- 3-pyrrolidinyl)methyllamino)methyl)-2H-pyridof3,2-άiπ ,41thiazin-3(4H)-one

a) (±)-phenylmethyl S-cyano-S-hydroxy-i-pyrrolidinecarboxylate To a stirred solution of phenylmethyl 3-oxo-i-pyrrolidinecarboxylate (1.0 g, 4.56 mmole) and KCN (0.81 g, 12.54 mmole) in THF (5 ml_) and H₂O (15 mL) at 0⁰C was added NaHSO₃ (1.14 g, 10.9 mmole) in H₂O (5.0 mL). After 3h, the reaction contents were concentrated in vacuo, extracted with CHCI₃ (2 x 100 mL), and the organics dried over Na₂SO^ Purification on silica (hexanes/EtOAc, 1 :1) afforded the title compound

(0.92 g, 82%) as a light yellow oil: LC-MS (ES) m/e 247 (M+H)⁺. b) (±)-phenylmethyl 3-(aminomethyl)-3-hydroxy-1 -pyrrolidinecarboxylate To a stirred solution of phenylmethyl 3-cyano-3-hydroxy-1 -pyrrolidinecarboxylate (0.92 g, 3.74 mmole), in THF (50 mL) at RT was added LiAIH₄ (3.75 ml_, 1M in THF). After 24h, the reaction was quenched with H2O (0.15 mL), 20% NaOH (0.30 mL) and then H2O (0.35 mL).The reaction contents were filtered through a scinter-glass funnel and concentrated under vacuum to afford the title compound (0.50 g, 79%) as a yellow oil: LC- MS (ES) m/e 250 (M + H)⁺.

c) (±)-phenylmethyl 3-[({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-hydroxy-1- pyrrolidinecarboxylate

To a stirred solution of phenylmethyl 3-(aminomethyl)-3-hydroxy-1 - pyrrolidinecarboxylate (0.5 g, 2.33 mmole) at RT in EtOH (50 mL) was added Boc anhydride (1.09 g, 5.0 mmole). After 24h, the reaction contents were concentrated under vacuum and purified on silica (hexanes/EtOAc, 1 :1) to give the title compound (0.81 g, 99%) as yellow oil: LC-MS (ES) m/e 351 (M + H)⁺.

d) (±)-1 ,1-dimethylethyl [(3-hydroxy-3-pyrrolidinyl)methyl]carbamate To a stirred solution of phenylmethyl 3-[({[(1 ,1-dimethylethyl)oxy]carbonyl} amino)methyl]-3-hydroxy-1 -pyrrolidinecarboxylate (0.81 g, 2.31 mmole) in MeOH (30 mL) at RT was added Pd(OH)2 (100 mg). After 18 h under H2 (1 atm) with stirring, the reaction contents were filtered through Celite (MeOH) and concentrated under reduced pressure to give the title compound (0.47 g, 95%) as a light yellow oil: LC-MS (ES) m/e 217 (M + H)⁺.

e) (±)~3-(aminomethyl)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol hydrochloride salt To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.12 g, 0.60 mmole) in EtOH (10 mL) was added 1 ,1-dimethylethyl [(3-hydroxy-3- pyrrolidinyl)methyl]carbamate (0.13 g, 0.60 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) affording 1 ,1- dimethylethyl [(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3- pyrrolidinyl)metHyl]carbamate (90 mg, 36%) as light yellow solid: LC-MS (ES) m/e 421 (M+H)⁺. The material was dissolved in dioxane (5 ml_) and treated with 4M HCI in dioxane (10 ml_) for 2 hours at RT. The solvent was removed under vacuum to give the title compound as a light yellow solid: LC-MS (ES) m/e 321 (M+H-HCI)⁺.

f) (±)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one To a stirred solution of 3-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol hydrochloride salt (0.21 mmole) in dry CH2CI2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2W-pyrido[1 ,4]thiazine-6- carboxaldehyde (0.04g, 0.21 mmole) and Et3N (0.06 mL, 0.42 mmole). After 24h at RT was added NaBH4 (0.01 g, 0.23mmole). After 2h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCtø/MeOH, 9:1 containing 5% NH4OH) afforded the title

compound (0.075 g, 72%) as light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.51 (s, 1H), 8.08 (d, J = 9.0 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.00 (d, J = 9.0 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 4.38 (s, 2H), 4.03 (s, 3H), 3.81 (m, 2H), 3.37 (m, 4H), 3.12 (m, 4H), 2.72 (m, 2H), 2.54 (m, 2H), 1.92 (m, 2H). LC-MS (ES) m/e 499 (M + H)⁺.

Example 42

Preparation of (±)-6-({f(fra/7s-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-4- hvdroxy-3-pyrrolidinyl)methvnamino)methyl)-2Ay-pyridof3,2-/7if1 ,41thiazin-3(4H)-one a) 1 ,1-dimethylethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate To a stirred solution of 1 ,1-dimethylethyl 2,5-dihydro-1f/-pyrrole-1-carboxylate (5.0 g, 29.55 mmole) in DCM (200 mL) at RT was added MCPBA (7.65 g, 44.3 mmole). After 24 h, the reaction contents were washed with 10% aqueous NaHCC>3 and dried over Na2SC>4. Purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (4.5 g,

82%) as a yellow oil: LC-MS (ES) m/e 186 (M+H)⁺.

b) (±)-1 , 1 -dimethylethykrans-3-cyano-4-[(trimethylsilyl)oxy]-1 -pyrrolidinecarboxylate To a stirred solution of diethyl aluminum chloride (0.65 mL, 1M in heptane) and TMS nitrile (3.13 g, 31.6 mmole) at RT was added 1 ,1-dimethylethyl 6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylate (4.5 g, 24.3 mmole) in CH2CI2 (15 mL) over 20 minutes. After 24h, H2O (0.1 mL) and EtOAc (100 mL) were added and the reaction contents were filtered through a scinter-glass funnel and concentrated under vaccuum. Purification on silica (hexanes/EtOAc, 1 :1) afforded the title compound (6.14 g, 89%) as an light yellow low-melting solid: LC-MS (ES) m/e 285 (M+H)⁺.

c) (+)-1 , 1 -dimethylethyl-£rans-3-(aminomethyl)-4-hydroxy-1 -pyrrolidinecarboxylate To a stirred solution of (±)-1,1-dimethylethyl-fray?s-3-cyano-4-[(trimethylsilyl)oxy]-1- pyrrolidine carboxylate (4.67 g, 16.5 mmole), in THF (100 mL) at RT was added LiAIH4 (33 mL, 1M in THF). After 24h, the reaction was quenched with H2O (1.32 mL), 20% NaOH (1.0 mL) and then H2O (4.6 mL).The reaction contents were filtered through a scinter-glass funnel and concentrated under vacuum to afford the title compound (3.0 g, 84%) as a yellow oil: LC-MS (ES) m/e 217 (M + H)⁺.

d) (±)-1 ,1-dimethylethyl frans-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]- 1 -pyrrolidinecarboxylate

To a solution of (±)-1,1-dimethylethyl-fra/7s-3-(aminomethyl)-4-hydroxy-1- pyrrolidinecarboxylate (6.0 g, 23.0 mmole) in DMF (50 mL) at RT was added EtβN (5.0 mL, 36.1 mmole) and Λ/-(benzyloxycarbonyloxy)succinimide (9.0 g, 36.1 mmole). After 18 h, the DMF was removed under vacuum and the residue purified on silica (25-50% DCM/EtOAc) to give the title compound (8.76 g, 90%) as a white foam: LC-MS (ES) m/e 351 (M+H)⁺.

e) (±)-phenylmethyl {[frans-4-hydroxy-3-pyrrolidinyl]methyl}carbamate

To a stirred solution of (±)-1 ,1-dimethylethyl fra/?s-3-hydroxy-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (4.44 g, 12.7 mmole) in DCM (75 ml_) was added TFA (25 ml_). After stirring for 2 h, the reaction contents were concentrated under vacuum and the residue dissolved in DCM (15OmL). MP-carbonate resin (18.8g, 50.8 mmole) was added and the reaction contents were stirred vigorously overnight. The reaction contents were filtered through a scinter-glass funnel and the resin washed with MeOH. The filtrate was concentrated and dried under vacuum to give an off-white foam: LC-MS (ES) m/e 251 (M + H)⁺.

f) (±)-phenylmethyl [((rans-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]carbamate

To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (2.55 g, 12.5 mmole) in EtOH (10 mL) was added phenylmethyl (±)-{[fra/?s-4-hydroxy-3- pyrrolidinyl]methyl}carbamate (3.12 g, 12.5 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHCIβ/MeOH, 9:1 containing 5% NH4OH) affording the

title compound (5.56 g, 98%) as a light yellow foam: LC-MS (ES) m/e 455 (M+H)⁺.

g) (+)-7ra/7s-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol

To a solution of (±)-phenylmethyl [(frans-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]carbamate (1.8 g, 3.96 mmole) in MeOH (100 ml_) in a round bottom flask was added Pd(OH)2 (~ 100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were

filtered through Celite® (MeOH) and concentrated to give the title compound (1.3 g, quant.) as a light yellow foam: LC-MS (ES) m/e 321 (M+H)⁺.

h) (±)-6-({[(fra/7S-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4W)-one To a stirred solution of (±)-£rans-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.62 g, 1.94 mmole) in dry CH2CI2 (25 ml_) and dry EtOH (10 ml_) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6- carboxaldehyde (0.38 g, 1.94 mmole). After 24h, at RT was added NaBH(OAc)3 (0.61 g, 2.91 mmole). After 2h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.60 g,

62%) as light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.60 (s, 1 H), 8.15 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 6.94 (d, J = 7.8 Hz₁ 1 H), 4.11 (s, 3H), 4.05 (m, 4H), 3.52 (m, 4H), 3.42 (s, 2H), 3.19 (m, 2H), 2.98 (m, 2H), 2.70 (m, 2H). LC-MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. The racemic title compound above was separated into its enentiomerically pure constituents using chiral chromatography to give:

42 E1 : 6-({[(fr-ans-1-{2-[3~fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ϋ][1 ,4]thiazin-3(4H)-one : ¹ H NMR (400 MHz, CDCI₃) δ 8.60 (S, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 4.11 (s, 3H), 4.05 (m, 4H), 3.52 (m, 4H), 3.42 (s, 2H), 3.19 (m, 2H), 2.98 (m, 2H), 2.70 (m, 2H). LC-MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. 42 E2: 6-({[(frc?ns-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one: ¹ H NMR (400 MHz,), 8.15 (d, J = 9.0 CDCI₃) δ 8.60 (s, 1 H Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1H), 4.11 (s, 3H), 4.05 (m, 4H), 3.52 (m, 4H), 3.42 (s, 2H), 3.19 (m, 2H)₁ 2.98 (m, 2H), 2.70 (m, 2H). LC-MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 43

Preparation of (±)-6-({f(frans-1-{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl)-4- hvdroxy-3-pyrrolidinyl)methvnamino>methyl)-2H-pyridof3,2-άiπ ,41oxazin-3(4/-/)-one

Prepared essentially according to the procedure of Example 42, except substituting 3-oxo-3,4-dihydro-2H-pyrido[1,4]oxazine-6-carboxaldehyde (0.34 g, 1.94 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (0.60 g, 64%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 , containing 5% NH4OH): ¹ H NMR (400 MHz, CDCI₃) δ 8.51 (s, 1 H), 8.07 (d, J = 9.0 Hz, 1 H)₁ 7.15 (d, J = 8.0 Hz₁ 1 H)₁ 6.98 (d, J = 9.0 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 4.50 (s, 2H), 4.09 (s, 3H), 3.67 (m, 2H), 3.49 (m, 4H), 3.21 (m, 2H), 2.85 (m, 4H), 2.43 (m, 2H). LC-MS (ES) m/e 483 (M + H)^+'. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. The racemic title compound above was separated into its enentiomerically pure constituents using chiral chromatography to give: Example 43 E1 : 6-({[(fraπs-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3_l2-/)][1 _I4]oxazin-3(4H)- one: ¹H NMR (400 MHz, CDCI₃) δ 8.51 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 8.0 Hz₁ 1 H), 4.50 (s, 2H), 4.09 (s, 3H), 3.67 (m, 2H), 3.49 (m, 4H), 3.21 (m, 2H), 2.85 (m, 4H), 2.43 (m, 2H). LC-MS (ES) m/e 483 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 43 E2: 6-({[(frans-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]oxazin-3(4/-/)- one: ¹ H NMR (400 MHz, CDCI₃) δ 8.51 (s, 1 H), 8.07 (d, J = 9.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 6.98 (d, J = 9.0 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 4.50 (s, 2H), 4.09 (s, 3H), 3.67 (m, 2H), 3.49 (m, 4H), 3.21 (m, 2H), 2.85 (m, 4H), 2.43 (m, 2H). LC-MS (ES) m/e 483 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 44

Preparation of (±V6-({r(c/s-142-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-4- hvdroxy-3-pyrrolidinyl)methyllamino)methyl)-2H-pyridor3,2-ibiπ ,41thiazin-3(4/-/)-one a) (±)-phenylmethyl [(c/s-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]carbamate

To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.73 g, 3.60 mmole) in EtOH (5 ml_) was added (±)-phenylmethyl {[c/s-4-hydroxy-3- pyrrolidinyl]methyl}carbamate (0.90 g, 3.60 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHCtø/MeOH, 9:1 containing 5% NH4OH) affording the

title compound (1.57 g, 96%) as a light yellow foam: LC-MS (ES) m/e 455 (M+H)⁺.

b) (±)-c/s-4-(aminomethyl)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol

To a solution of phenylmethyl (±)-[(c/s-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]carbamate (1.57 g, 3.46 mmole) in MeOH (100 ml.) in a round bottom flask was added Pd(OH)2 (~ 100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were

filtered through Celite® (MeOH) and concentrated to give the title compound (1.11 g, quant.) as a light yellow foam: LC-MS (ES) m/e 321 (M+H)⁺.

c) (±)-6-({[(C/s-1 -{2-[3-fluoro~6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1,4]thiazin-3(4/-/)-one To a stirred solution of (+)-c/s-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.23g, 0.72 mmole) in dry CH2CI2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6- carboxaldehyde (0.14 g, 0.72 mmole). After 24h, at RT was added NaBH(OAc)3 (0.23 g, 1.08 mmole). After 2h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.24 g,

66%) as light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1 H), 8.19 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 4.21 (s, 2H), 4.12 (S, 3H), 3.52 (m, 4H), 3.33 (s, 4H), 3.21 (m, 2H), 3.09 (m, 2H), 2.98 (m, 2H). LC- MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 45

Preparation of 6-((K(3S,4S)-1 -(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl}-4- hydroxy-3-pyrrolidinyl)methvnamino)methyl)-2H-pyridor3,2-/3iπ ,41thiazin-3(4H)-one

Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (0.60 g, 1.87 mmole) for (+)-4-(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.42 g, 45%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 , containing 5% NH₄OH): ¹ H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1 H), 8.19 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 7.8 Hz₁ 1H), 7.17 (d, J = 9.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1 H), 4.21 (s, 2H), 4.12 (s, 3H), 3.52 (m, 4H), 3.33 (s, 4H), 3.21 (m, 2H), 3.09 (m, 2H), 2.98 (m, 2H). LC-MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 46

Preparation of 6-({r((3S,4S)-1-f2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl)-4- hvdroxy-3-pyrrolidinyl)methvnamino)methyl)-2/-/-pyrido[3.2-/3lf1 ,4lthiazin-3(4/-/)-one Prepared essentially according to the procedure of Example 44, except substituting (3/R_l4R)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (0.60 g, 1.87 mmole) for (±)-4-(aminomethyl)-1-{2-[3~fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.57 g, 61%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 , containing 5% NH₄OH): ¹ H NMR (400 MHz, CD₃OD) δ 8.65 (s, 1 H)₁ 8.19 (d, J = 9.0 Hz, 1 H)₁ 7.77 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 9.0 Hz₁ 1 H)₁ 7.11 (d, J = 8.0 Hz, 1 H), 4.21 (s, 2H), 4.12 (s, 3H), 3.52 (m, 4H), 3.33 (s, 4H), 3.21 (m, 2H), 3.09 (m, 2H)₁ 2.98 (m, 2H). LC-MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 47

Preparation of 6-({r((3S,4S)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl1ethyl)-4- hvdroxy-3-pyrrolidinyl)methvnamino)methyl)-2H-pyridor3,2-άiπ ,41oxazin-3(4/-/)-one

Prepared essentially according to the procedure of Example 44, except substituting 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]oxazine-6-carboxaldehyde (0.28 g, 1.56 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, and substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol (0.50 g, 1.56 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.45 g, 60%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃ZMeOH, 9:1 ,

containing 5% NH₄OH): ¹H NMR (400 MHz₁ CD₃OD) δ 8.67 (s, 1H), 8.20 (d, J = 9.0 Hz, 1 H), 7.35 (d, J = 7.9 Hz₁ 1 H)₁ 7.19 (d, J = 9.0 Hz₁ 1H)₁ 7.11 (d, J = 8.0 Hz, 1H), 4.68 (app s, 2H), 4.27 (S₁ 2H)₁ 4.15 (s, 3H)₁ 3.60 (m, 2H)₁ 3.47 (m, 4H)₁ 3.31 (m, 2H), 3.25 (m, 2H). LC-MS (ES) m/e 483 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 48

Preparation of 6-(ir((3S,4S)-1-(2-r3-fluoro-6-(methyloxy)-1.5-naphthyridin-4-vnethyl)-4- hvdroxy-3-pyrrolidinyl)methvnamino}methyl)-2H-pyridor3,2-it)iπ ,41oxazin-3(4H)-one

Prepared essentially according to the procedure of Example 44, except substituting 3-oxo-3,4-dihydro-2W-pyrido[1,4]oxazine-6-carboxaldehyde (0.22 g, 1.25 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, and substituting (3y^c?,4f?)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidin (0.40 g, 1.25 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.21 g, 35%) was prepared as an off-white solid following flash chromatography on silica gel (CHCtø/MeOH, 9:1,

containing 5% NH₄OH): ¹H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.20 (d, J = 9.0 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1 H)₁ 7.11 (ύ, J = 8.0 Hz, 1H), 4.68 (app s, 2H), 4.27 (s, 2H), 4.15 (s, 3H), 3.60 (m, 2H), 3.47 (m, 4H), 3.31 (m, 2H)₁ 3.25 (m, 2H). LC-MS (ES) m/e 483 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 49

Preparation of (±)-7-chloro-6-((r(c/s-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl1ethylM-hvdroxy-3-pyrrolidinyl)methyl1arrιino)methyl)-2/-/-Pyridof3,2-άiri ,41oxazin-3(4H)- one Prepared essentially according to the procedure of Example 44, except substituting 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]oxazine-6-carbaldehyde (0.20 g, 0.93 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (0.43 g, 89%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 , containing 5% NH4OH): ¹ H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.48 (s, 1H)₁ 7.19 (d, J = 9.0 Hz, 1 H), 4.72 (app s, 2H), 4.27 (s, 2H), 4.14 (s, 3H), 3.57 (m, 2H), 3.38 (m, 5H), 3.20 (m, 4H)₁ 3.81 (m, 1 H). LC-MS (ES) m/e 517 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 50

Preparation of 7-chloro-6-({r((3S,4S)-1-{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- vnethyl>-4-hvdroxy-3-pyrrolidinyl)methyllamino|methyl)-2H-pyridor3,2-ibiri .41oxazin-3(4H)- one Prepared essentially according to the procedure of Example 44, except substituting 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]oxazine-6-carbaldehyde (0.33 g, 1.56 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde, and substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (0.50 g, 1.56 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.48 g, 59%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 , containing 5% NH₄OH): ¹H NMR (400 MHz₁ CD₃OD) δ 8.67 (s, 1H), 8.20 (d, J = 9.0 Hz₁ 1 H), 7.48 (s, 1H), 7.19 (d, J = 9.0 Hz, 1 H), 4.72 (app s, 2H), 4.27 (s, 2H)₁ 4.14 (s, 3H), 3:57 (m, 2H), 3.38 (m, 5H), 3.20 (m, 4H), 3.81 (m, 1 H). LC-MS (ES) m/e 517 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 51

Preparation of 7-chloro-6-αr((3S,4S^')-1-{2-[3-fluoro-6-(methyloxy^')-1 ,5-naphthyridin-4- yl1ethyl)-4-hvdroxy-3-pyrrolidinyl)methyl1amino|methyl)-2H-pyrido[3,2-άiri ,4loxazin-3(4/-/)- one

Prepared essentially according to the procedure of Example 44, except substituting 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-/)][1 ,4Joxazine-6-carbaldehyde (0.26 g, 1.25 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, and substituting (3R,4f?)-4-(aminomethyl)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (0.40 g, 1.25 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.21 g, 32%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 , containing 5% NH₄OH): ¹ H NMR (400 MHz, CD₃OD) δ 8.67 (s, 1 H), 8.20 (d, J = 9.0 Hz, 1H), 7.48 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.72 (app s, 2H), 4.27 (s, 2H), 4.14 (s, 3H), 3.57 (m, 2H), 3.38 (m, 5H), 3.20 (m, 4H), 3.81 (m, 1 H). LC-MS (ES) m/e 517 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 52

Preparation of (+)-c/s-4-(f(2.3-dihydroπ .41dioxinor2,3-c1pyridin-7-ylmethyl)amino1methyl)- 1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3-pyrrolidinol

Prepared essentially according to the procedure of Example 44, except substituting 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.12 g, 0.72 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (0.19 g, 55%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1, containing 5% NH₄OH): ¹H NMR (400 MHz, CDCI₃) δ 8.52 (s, 1H), 8.09 (d, J=9.05Hz, 1 H), 8.03 (s, 1 H), 7.00 (d, J=9.04Hz, 1 H), 6.68 (s, 1 H), 4.42 (m, 1 H), 4.24 (m, 4H), 4.02 (s, 3H), 3.70 (m, 2H), 3.33 (m, 2H), 3.04 (m, 1 H), 2.78 (m, 5H), 2.64 (m, 1 H), 2.46 (m, 1 H), 2.44 (m, 1 H). LC-MS (ES) m/e 470 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 53

Preparation of (3S,4S)-4-{r(2.3-dihvdroM ,41dioxinor2,3-c1pyridin-7-ylmethyl)amino1methyl)- 1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3-pyrrolidinol

Prepared essentially according to the procedure of Example 44, except substituting 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (259 mg, 1.57 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, and substituting (3S,4S)- 4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.48 g, 1.50 mmole) for (+)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol,the title compound (411 mg, 56%) was prepared as an όff-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 ,

containing 5% NH₄OH): ^"Η NMR (400 MHz₁ CDCI₃) δ 8.52 (s, 1H), 8.09 (d, J=9.05Hz, 1 H), 8.03 (s, 1 H), 7.00 (d, J=9.04Hz, 1 H), 6.68 (s, 1 H), 4.42 (m, 1 H), 4.24 (m, 4H), 4.02 (s, 3H), 3.70 (m, 2H), 3.33 (m, 2H), 3.04 (m, 1 H), 2.78 (m, 5H), 2.64 (m, 1H), 2.46 (m, 1 H), 2.44 (m, 1 H). LC-MS (ES) m/e 470 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 54

Preparation of (3S,4S)-4-(r(2,3-dihvdroH ,41dioxinor2,3-c1pyridin-7-ylmethyl)amino1methyl}- 1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3-pyrrolidinol

Prepared essentially according to the procedure of Example 44, except substituting 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (248 g, 1.50 mmole) for 3-0X0-3, 4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, and substituting {3R,4R)-4- (aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.50 g, 1.58 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol,the title compound (306 mg, 44%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃ZMeOH, 9:1 , containing 5%

NH₄OH): ¹ H NMR (400 MHz, CDCI₃) δ 8.52 (s, 1H), 8.09 (d, J=9.05Hz, 1H), 8.03 (s, 1 H), 7.00 (d, J=9.04Hz, 1H), 6.68 (s, 1H), 4.42 (m, 1H), 4.24 (m, 4H), 4.02 (s, 3H), 3.70 (m, 2H), 3.33 (m, 2H), 3.04 (m, 1H), 2.78 (m, 5H), 2.64 (m, 1 H), 2.46 (m, 1 H), 2.44 (m, 1 H). LC-MS (ES) m/e 470 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Preparation of 8-fluoro-6-((f((3S,4SV1-f2-r3-fluoro-6-(methyloxyV1 ,5-naphthyridin-4- yllethylM-hvdroxy-3-pyrrolidinyl)methvπamino)methvO-2H-1 ,4-benzoxazin-3(4H)-one

Prepared essentially according to the procedure of Example 44, except substituting 8-fluoro-3-oxo-3,4-dihydro-2/-/-1 ,4-benzoxazine-6-carbaldehyde (104 g, 0.53 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, and substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol (168 mg, 0.53 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (70 mg, 27%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 ,

containing 5% NH₄OH): ¹H NMR (400 MHz, CDCI₃) δ 8.56 (s, 1 H), 8.15 (d, J=9.05Hz, 1H), 7.06 (d, J=9.04Hz, 1H), 6.66 (d, J=10.65Hz, 1H), 6.55 (s, 1H), 4.59 (q, 2H), 4.48 (m, 1 H), 4.06 (s, 2H), 3.61 (m, 2H), 3.50 (s, 3H), 3.37 (m, 2H), 3.05 (m, 1 H), 2.69-2.95 (m, 6H), 2.74 (m, 1 H), 2.68 (m, 1 H), 2.45 (m, 1 H). LC-MS (ES) m/e 500 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 56

Preparation of 6-({r((3S₁4S)-1-f2-r3-fluoro-6-(methyloxy)-4-quinolinyllethyl)-4-hvdroxy-3- pyrrolidinyl)methyl1amino)methyl)-2/-/-pyrido[3,2-ά1f1 ,41thiazin-3(4/-/)-one

Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinol (0.55 g, 1.72 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.57 g, 66%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 ,

containing 5% NH₄OH): ¹ H NMR (400 MHz, CDCI3) δ 8.58 (s, 1 H), 8.00 (d, J=9.20Hz, 1H)₁ 7.57 (d, J=7.79Hz, 1H), 7.32 (d, J=9.18Hz, 1H), 7.24 (s, 1H), 6.89 (d, J=7.82Hz, 1H), 4.53 (m, 1H), 3.97 (s, 3H)₁ 3.86 (q, 2H)₁ 3.50 (s, 2H), 3.45 (s, 2H), 3.28 (m, 2H), 3.05 (m, 1 H), 2.83-2.96 (m, 6H)₁ 2.69 (m, 1 H)₁ 2.53 (m, 1H). LC-MS (ES) m/e 498 (M + H)⁺. This material, as a solution in MeOH₁ was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 57

Preparation of 6-((f((3S.4S)-1 -(2-f3-fluoro-6-(methyloxy)-4-quinolinyllethyl)-4-hvdroxy-3- pyrrolidinyl)methvnamino)methyl)-2Ay-pyridof3,2-ib]f1 ,41oxazin-3(4H)-one

Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinol (0.52 g, 1.61mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol,, and substituting 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]oxazine-6-carboxaldehyde (0.29 g, 1.62 mmole) for 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (0.41 g, 53%) was prepared as an off-white solid following flash chromatography on silica gel (CHCtø/MeOH, 9:1,

containing 5% NH₄OH): ¹H NMR (400 MHz, CDCI₃) δ 8.59 (s, 1H)₁ 8.01 (d, J=9.19Hz, 1H), 7.33 (d, J=9.19Hz, 1H), 7.22 (d, J=9.22Hz, 1H), 6.86 (d, J=8.05Hz, 1H)₁ 4.62 (s, 2H), 4.54 (m, 1H), 3.97 (s, 3H), 3.85 (m, 2H), 3.28 (m, 2H), 3.04 (m, 1H), 2.78-3.00 (m, 6H), 2.66 (m, 1 H), 2.55 (m, 1H). LC-MS (ES) m/e 482 (M + H)⁺. This material, as a solution in MeOH₁ was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 58

Preparation of (±)-6-({r(c/s-4-hvdroxy-1-f2-r6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl)-3- pyrrolidinvπmethvπamino)methyl)-2H-pyrido[3,2-feiri ,41thiazin-3(4H)-one

Prepared essentially according to the procedure of Example 44, except substituting (±)-4-(aminomethyl)-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol (0.35 g, 1.16 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (0.39 g, 70%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 ,

containing 5% NH₄OH): ¹H NMR (400 MHz, CD₃OD) δ 9.06 (m, 1H), 8.52 (d, J = 9.0 Hz, 1 H), 8.38 (m, 1 H), 7.83 (d, J = 7.8 Hz, 1 H)₁ 7.65 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.41 (s, 2H), 4.39 (s, 3H), 3.95 (m, 4H), 3.88 (m, 2H), 3.75 (m, 2H), 3.53 (m, 4H), 3.37 (m, 2H). LC-MS (ES) m/e 481 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 59

Preparation of 6-((r((3S,4S)-4-hvdroxy-1-{2-r6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl>-3- pyrrolidinyl^')methyllamino>methvn-2H-pyridor3,2-άiri ,41thiazin-3(4/-/)-one

Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4-(aminomethyl)-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol (0.63 g, 2.07 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinoϊ, the title compound (0.62 g, 62%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1,

containing 5% NH₄OH): ¹H NMR (400 MHz₁ CD₃OD) δ 9.06 (m, 1H), 8.52 (d, J = 9.0 Hz, 1 H)₁ 8.38 (m, 1 H), 7.83 (d, J = 7.8 Hz₁ 1 H), 7.65 (d, J = 9.0 Hz₁ 1 H), 7.17 (d, J = 7.8 Hz, 1 H)₁ 4.41 (s, 2H), 4.39 (s, 3H), 3.95 (m, 4H), 3.88 (m, 2H)₁ 3.75 (m, 2H)₁ 3.53 (m, 4H), 3.37 (m, 2H). LC-MS (ES) m/e 481 (M + H)⁺. This material, as a solution in MeOH₁ was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 60

Preparation of (±)-6-({r(c/^'s-4-hvdroxy-1-{2-r6-(methyloxy)-1 ,5-naphthyridin-4-yl1ethyl)-3- pyrrolidinyl)methvnamino>methyl)-2/-/-pyrido[3,2-άiπ ,41oxazin-3(4/-A-one

Prepared essentially according to the procedure of Example 44, except substituting (±)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethy!}-3- pyrrolidinol (0.35 g, 1.16 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6~(methyloxy)-1,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol, and substituting 3-oxo-3,4-dihydro-2H- pyrido[1 ,4]oxazine-6-carboxaldehyde (0.21 g, 1.16 mmole) for 3-oxo-3,4-dihydro-2H- pyrido[1,4]thiazine-6-carboxaldehyde, the title compound (0.32 g, 59%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1,

containing 5% NH₄OH): ¹H NMR (400 MHz₁ CD₃OD) δ 9.06 (m, 1 H), 8.52 (d, J = 9.0 Hz, 1H), 8.36 (m, 1H), 7.65 (d, J = 9.0 Hz₁ 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.71 (s, 2H), 4.34 (s, 3H), 4.11 (m, 2H), 3.95 (m, 4H), 3.79 (m, 2H)₁ 3.50 (m, 4H), 3.21 (m, 2H). LC-MS (ES) m/e 465 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCl in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 61

Preparation of 6-({lY(3S,4S)-1-(2-r3-chloro-6-(methyloxy)-1.5-naphthyridin-4-yllethyll4- hvdroxy-3-pyrrolidinvπmethyllaιτιino}rrιethyl)-2H-pyrido[3.2-άiri .41oxazin-3(4H)-one

Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (74 mg, 0.22 mmole) for (+)-4-(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-i ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, and substituting 3-oxo-3,4-dihydro- 2H-pyrido[1,4]oxazine-6-carboxaldehyde (39 mg, 0.22 mmole) for 3-oxo-3,4-dihydro-2/-/- pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (94 mg, 85%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 ,

containing 5% NH₄OH): ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1 H), 8.12 (d, J=9.03Hz, 1 H), 7.13 (d, J=8.02Hz, 1 H), 7.04 (d, J=9.02Hz, 1 H), 6.82 (d, J=8.04Hz, 1H), 4.54 (s, 2H), 4.49 (m, 1H), 4.04 (s, 3H), 3.78 (m, 2H), 3.51 (m, 2H), 3.07 (m, 1 H), 2.75-2.91 (m, 6H), 2.63 (m, 1H), 2.51 (m, 1H). LC-MS (ES) m/e 499 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 62

Preparation of 6-((r((3S,4S)-1-(2-r3-chloro-6-(methyloxyV1 ,5-naphthyridin-4-yllethyl>-4- hvdroxy-3-pyrrolidinyl)methvnamino)methyl)-2H-pyridor3,2-iblf1 ,41thiazin-3(4/-/)-one Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (74 mg, 0.22 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, the title compound (107 mg, 94%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 , containing 5% NH₄OH): ¹ H NMR (400 MHz, CDCI₃) δ 8.64 (s, 1 H), 8.15 (d, J=9.02Hz, 1 H), 7.54 (d, J=7.78Hz, 1 H), 7.08 (d, J=9.01 Hz, 1 H), 6.88 (d, J=7.81Hz, 1H), 4.49 (m, 1H), 4.07 (s, 3H), 3.80 (m, 2H), 3.53 (m, 2H), 3.43 (s, 2H), 3.05 (m, 1H), 2.80-2.90 (m, 6H), 2.62 (m, 1H), 2.46 (m, 1H). LC-MS (ES) m/e 515 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 63

Preparation of (3S,4S)-1-f2-f3-chloro-6-(methyloxy)-1.5-naphthyridin-4-vnethyl)-4-(r(2.3- dihvdrori .41dioxinor2,3-clpyridin-7-ylmethyl)aminolmethyl>-3-pyrrolidinol

Prepared essentially according to the procedure of Example 44, except substituting (3S,4S)-4~(aminomethyl)-1-{2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol (74 mg, 0.22 mmole) for (±)-4-(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, and substituting 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (36 mg, 0.22 mmole) for 3-oxo-3,4- dihydro-2H-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (57 mg, 53%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl₃/MeOH,

9:1 , containing 5% NH₄OH): ¹ H NMR (400 MHz, CDCI₃) δ 8.64 (s, 1 H), 8.14 (d, J=9.02Hz, 1 H), 8.10 (s, 1H), 7.09 (d, J=9.01 Hz, 1H), 6.73 (s, 1 H), 4.51 (m, 1 H), 4.30 (m, 4H), 4.08 (s, 3H), 3.77 (m, 2H), 3.54 (m, 2H), 3.12 (m, 1H), 2.70-2.89 (m, 6H), 2.53 (m, 1 H), 2.42 (m, 1 H). LC-MS (ES) m/e 486 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 64

Preparation of (±)-6-r((f(cis-3,4)-1 -{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-4- (methyloxy)-3-pyrrolidinyllmethyl)amino)methyll-2/-/-pyridor3,2-άiri,41thiazin-3(4H)-one

a) (±)-1 , 1 -dimethylethyl (cis-3,4)-3-(methyloxy)-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate

To a solution of 1 ,1 -dimethylethyl (cis-3,4)-3-hydroxy-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (3.9 g, 11.1 mmole) in toluene at RT was added caustic (14.5 ml_), benzyltriethylamine chloride (25 mg, 0.11 mmole) and dimethyl sulfate (1.26 mL, 13.32 mmole). After stirring for 3h, the reaction solution was diluted with H₂O (100 mL) and EtOAc (200 mL). the layers were separated and the organic layer dried over Na₂SO₄. Concentration under vacuum and purification on silica (hexanes/EtOAc, 1 :1) afforded the title compound (2.9 g, 72%) as a colorless oil: LC-MS (ES) m/e 365 (M + H)⁺.

b) (±)-phenylmethyl {[(cis-3,4)-4-(methyloxy)-3-pyrrolidinyl]methyl}carbamate

To a solution of (±)-1 ,1-dimethylethyl c/s-3-hydroxy-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (1.6 g, 4.39 mmole) in DCM (150 mL) at RT was added TFA (50 ml_). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (17.6 mmole, 6.5 g) was added with vigorous stirring at RT. After 4h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.89 g, 100%) as a white foam: LC-MS (ES) m/e 265 (M+H)⁺.

c) (±)-phenylmethyl {[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- (methyloxy)-3-pyrrolidinyl]methyl}carbamate

To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.89 g, 4.39 mmole) in EtOH (5 mL) was added (±)-phenylmethyl {[(cis-3,4)-4-(methyloxy)-3- pyrrolidinyl]methyl}carbamate (1.16 g, 4.39 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) affording the

title compound (1.62 g, 72%) as a light yellow foam: LC-MS (ES) m/e 469 (M+H)⁺.

d) (±)-{[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-(methyloxy)-3- pyrrolidinyl]methyl}amine

To a solution of (±)-phenylmethyl {[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-(methyloxy)-3-pyrrolidinyl]methyl}carbamate (1.78 g, 3.5 mmole) in MeOH (100 ml.) in a round bottom flask was added Pd(OH)2 (~ 100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were

filtered through Celite® (MeOH) and concentrated to give the title compound (1.17 g, quant.) as a light yellow foam: LC-MS (ES) m/e 335 (M+H)⁺.

e) (±)-6-[({[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-(methyloxy)- 3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2-b][1 ,4]thiazin-3(4/-0-one To a stirred solution of (±)-{[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethyl}-4-(methyloxy)-3-pyrrolidinyl]methyl}amine (0.7Og₁ 2.1 mmole) in dry CH2CI2 (25 ml_) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine- 6-carboxaldehyde (0.41 g, 2.1 mmole). After 24h, at RT was added NaBH(OAc)3 (0.67 g, 3.15 mmole). After 2h, the reaction solution was concentrated under vacuum and purified on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.70 g,

65%) as light yellow solid: ¹ H NMR (400 MHz, CD₃OD) D 9.01 (s, 1 H), 8.37 (d, J = 9.0 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.42 (d, J = 9.0 Hz, 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 4.39 (s, 2H), 4.23 (s, 3H), 4.20 (m, 2H), 3.82 (m, 4H), 3.75 (m, 2H), 3.59 (s, 2H), 3.48 (m, 3H), 3.43 (s, 3H), 2.95 (m, 1H). LC-MS (ES) m/e 513 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCl in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 65

Preparation of (±)-6-f((r(cis-3.4)-1 -(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-4- (methyloxy)-3-pyrrolidinvnmethyl)amino)methyll-2/-/-pyridor3,2-)biri ,41oxazin-3(4H)-one - Prepared essentially according to the procedure of Example 64, except substituting 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]oxazine-6-carboxaldehyde (0.37 g, 2.10 mmole) for 3-oxo-3,4-dihydro-2/-/-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (0.72 g, 69%) was prepared as an off-white solid following flash chromatography on silica gel (CHCl3/MeOH, 9:1 , containing 5% NH4OH): ¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 1 H), 8.30 (d, J = 9.0 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 4.73 (s, 2H), 4.43 (s, 3H), 4.35 (m, 4H), 4.15 (m, 1H), 3.74 (m, 4H), 3.48 (m, 2H), 3.45 (s, 3H), 3.32 (s, 2H), 2.95 (m, 1 H). LC-MS (ES) m/e 497 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 66

Preparation of (±)-6-({[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2/V-pyrido[3,2-/b][1 ,4]thiazin-3(4/-/)-one a) (±)-phenylmethyl 3-cyano-3-hydroxy-1-pyrrolidinecarboxylate To a stirred solution of phenylmethyl 3-oxo-1-pyrrolidinecarboxylate (1.0 g, 4.56 mmole) and KCN (0.81 g, 12.54 mmole) in THF (5 mL) and H₂O (15 mL) at 0⁰C was added NaHSOβ (1.14 g, 10.9 mmole) in H₂O (5.0 mL). After 3h, the reaction contents were concentrated in vacuo, extracted with CHCI3 (2 x 100 mL), and the organics dried over Na₂Sθ4. Purification on silica (hexanes/EtOAc, 1:1) afforded the title compound

(0.92 g, 82%) as a light yellow oil: LC-MS (ES) m/e 247 (M+H)⁺.

b) (±)-phenylmethyl S-cyano-S-fluoro-i-pyrrolidinecarboxylate

To a stirred solution of phenylmethyl S-cyano-S-hydroxy-i-pyrrolidinecarboxylate (1.8 g, 7.31 mmole), in DCM (50 mL) at -78 ⁰C was added DAST dropwise (0.98 mL, 8.04 mmole). After 2h, Aqueous Na2CC>3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1 :1) provided the title compound (1.0 g, 55%) as a light orange oil: LC-MS (ES) m/e 249 (M+H)⁺.

c) (±)-phenylmethyl 3-[({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-fluoro-1- pyrrolidinecarboxylate

To a stirred solution of (±)-phenylmethyl 3-cyano-3-fluoro-1-pyrrolidinecarboxylate (1.0 g, 4.03 mmole), in THF (50 mL) at 0 ⁰C was added B₂H₆ (12.1 mL, 1M in THF). After 24h, the reaction was quenched with 6N HCI (5 mL) and stirred for 1 h at RT.The reaction solution was made basic (pH=8) with 6N NaOH and the solution was concentrated to a solid under vacuum. The reaction contents were extracted with EtOAc (100 mL) and THF (100 mL) and then concentrated under vacuum. The residue was dissolved in THF (75 mL) and (BoC)₂O (0.94 g, 4.28 mmole) in THF (15 mL) was added to the solution. After 12 hr at RT, the reaction solution was concentrated and purified on silica (hexanes/EtOAc, 1:1) to afford the title compound (1.0 g, 70%) as a colorless oil: LC-MS (ES) m/e 353 (M + H)⁺.

d) (+)-1 ,1-dimethylethyl [(3-fluoro-3-pyrrolidinyl)methyl]carbamate

To a stirred solution of phenylmethyl 3-[({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)methyl]-3-fluoro-1-pyrrolidinecarboxylate (0.90 g, 2.56 mmole) in MeOH (30 mL) at RT was added Pd(OH)₂ (100 mg). After 18 h under H₂ (1 atm) with stirring, the reaction contents were filtered through Celite (MeOH) and concentrated under reduced pressure to give the title compound (0.54 g, 98%) as an off- white solid: LC-MS (ES) m/e 219 (M + H)⁺.

e) (±)-1 ,1-dimethylethyl [(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 3-pyrrolidinyl)methyl]carbamate

To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.51g, 2.50 mmole) in EtOH (5mL) was added 1 ,1-dimethylethyl [(3-fluoro-3- pyrrolidinyl)methyl]carbamate (0.53 g, 2.50 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the

title compound (0.90 g, 85%) as light yellow solid: LC-MS (ES) m/e 423 (M+H)⁺.

f) (±)-6-({[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ύ][1 ,4]thiazin-3(4H)-one

To a stirred solution of 1,1-dimethylethyl [(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.85 g, 2.0 mmole) in dioxane (50 mL) was added 4M HCI in dioxane (2OmL). After 4h at RT, the reaction solution was concentrated to dryness under vacuum. To the amine hydrochloride salt in dry CH2CI2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine- 6-carboxaldehyde (0.39 g, 2.0 mmole) and Et^N (0.84 mL, 6.0 mmole). After 24h at RT₁ NaBH4 (0.01 g, 0.23mmole) was added. After 2h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) afforded

the title compound (0.67 g, 67%) as light yellow solid: ¹H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.15 (m, 2H), 4.31 (s, 2H), 4.13 (s, 3H), 3.75 (m, 2H), 3.64 (m, 2H), 3.60 (m, 4H), 3.57 (m, 4H), 2.54 (m, 2H). LC-MS (ES) m/e 501 (M + H)⁺. The material was dissolved in dioxane (5 mL) and treated with 4M HCI in dioxane (10 mL) for 2 hours at RT. The solvent was removed under vacuum to give the title compound as a light yellow solid. Example 67

Preparation of (±)-(2,3-dihydrori ,41dioxinor2,3-c1pyriclin-7-ylmethyl)f(3-fluoro-1-(2-f3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3-pyrrolidinyl)methyl1amine

Prepared essentially according to the procedure of Example 66, except substituting 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.15 g, 0.93 mmole) for 3-oxo-3,4-dihydro-2W-pyrido[1 ,4]thiazine-6-carboxaldehyde, the title compound (0.26 g, 59%) was prepared as an off-white solid following flash chromatography on silica gel (CHCI₃/MeOH, 9:1 , containing 5% NH₄OH): ¹ H NMR (400 MHz₁ CD₃OD) δ 8.74 (s, 1 H), -8.35 (s, 1H), 8.25 (d, J = 9.0 Hz, 1 H), 7.39 (s, 1 H), 7.23 (d, J = 9.0 Hz, 1 H), 4.65 (m, 2H), 4.49 (m, 2H), 4.43 (s, 2H), 4.19 (s, 3H), 3.75 (m, 8H), 2.65 (m, 2H). LC-MS (ES) m/e 472 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 68

Preparation of (±y6-({r(frans-4-fluoro-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- vnethylV3-pyrrolidinvπmethvnamino)methyl)-2f/-pyridor3.2-άiπ .41thiazin-3(4f/)-one

a) (±)-1 ,1-dimethylethyl (3f?,4S)-3-fluoro-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]- 1 -pyrrolidinecarboxylate

To a stirred solution of (±)-1 ,1-dimethylethyl c/s-3-hydroxy-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.8 g, 2.29 mmole), in DCM (50 mL) at -78 ⁰C was added DAST dropwise (0.59 ml_, 4.80 mmole). After 2h, Aqueous Na2CC>3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SC>4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (0.68 g, 85%) as a colorless oil: LC-MS (ES) m/e 353 (M+H)⁺.

b) (±)-phenylmethyl {[c/s-4-fluoro-3-pyrrolidinyl]methyl}carbamate

To a solution of (±)-1 ,1-dimethylethyl /ra/?s-3-fluoro-4- [({[(phenylmethyl)oxy]carbonyl}amino)rnethyl]-1 -pyrrolidinecarboxylate (1.0 g, 2.84 mmole) in DCM (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (11.4 mmole, 4.2g) was added with vigorous stirring at RT. After 4h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.54 g, 75%) as a light orange oil: LC-MS (ES) m/e 253 (M+H)⁺.

c) (±)-phenylmethyl [(fra/7s-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]carbamate

To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.44 g, 2.14 mmole) in EtOH (5 ml.) was added (±)-phenylmethyl {[frans-4-fluoro-3- pyrrolidinyl]methyl}carbamate (0.54 g, 2.14 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the

title compound (0.90 g, 92%) as a light yellow foam: LC-MS (ES) m/e 457 (M+H)⁺.

d) (±)-[(^ans-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine

To a solution of (±)-phenylmethyl [(fra/7s-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]carbamate (0.40 g, 0.88 mmole) in MeOH (100 m L) in a round bottom flask was added Pd(OH)2 (~ 100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were

filtered through Celite® (MeOH) and concentrated to give the title compound (0.25 g, 88%) as a colorless oil: LC-MS (ES) m/e 323 (M+H)⁺.

e) (±)-6-({[(fr-a/7s-4-fluoro-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thia2in-3(4H)-one To a stirred solution of (±)-[(fra/is-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.25 g, 0.77 mmole) in dry CH2CI2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine- 6-carboxaldehyde (0.15 g, 0.77 mmole). After 24h, at RT was added NaBH(OAc)3 (0.24 g, 1.15 mmole). After 2h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.23 g, 60%) as light yellow solid: ¹H NMR (400 MHz, CD₃OD) δ 8.75 (s, 1H), 8.25 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H)₁ 7.15 (d, J= 7.8 Hz, 1H), 4.43 (S₁ 2H)₁ 4.19 (s, 3H)₁ 3.90 (m, 2H), 3.77 (m, 4H), 3.65 (m, 4H)₁ 3.57 (m, 2H)₁ 3.32 (app s, 2H). LC-MS (ES) m/e 501 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 69

Preparation of (±)-6-((f(c/s-4-fluoro-1-(2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yllethyl)-3-pyrrolidinyl^')methyl1amino>methyl)-2/-/-pyridor3,2-iblfl41thiazin-3(4H)-one

a) (±)-1 ,1-dimethylethyl c/s-S-cyano^-fluoro-i-pyrrolidinecarboxylate

To a stirred solution of (±)-1 ,1-dimethylethyl fra/7s-3-cyano-4-[(trimethylsilyl)oxy]-1- pyrrolidinecarboxylate (1.0 g, 3.52 mmole), in DCM (50 mL) at -78 ⁰C was added DAST dropwise (0.90 mL, 7.40 mmole). After 3h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (0.51 g, 67%) as a colorless oil: LC-MS (ES) m/e 215 (M+H)⁺.

b) (±)-1 ,1-dimethylethyl c/s-3-fluoro-4~[({[(phenylmethyl)oxy]carbonyl}amino)rnethyl]-1- pyrrolidinecarboxylate

To a stirred solution of (±)-1 ,1-dimethylethyl c/s-3-cyano-4-fluoro-1- pyrrolidinecarboxylate (0.51 g, 2.38 mmole), in THF (50 ml_) at RT was added UAIH4 (2.4 ml_, 1M in THF). After 24h, the reaction was quenched with H2O (0.096 mL), 20% NaOH (0.072 mL) and then H2O (0.34 mL).The reaction contents were filtered through a scinter- glass funnel and concentrated under vacuum to afford the title compound as a yellow oil which was used directly: LC-MS (ES) m/e 219 (M + H)⁺. To the crude amine in DMF (50 mL) at RT was added Et^N (0.42 mL, 3.0 mmole) and Λ/-(benzyloxycarbonyloxy)succinimide (0.75 g, 3.0 mmole). After 18 h, the DMF was removed under vacuum and the residue purified on silica (25-50% DCM/EtOAc) to give the title compound (0.47 g, 56%) as a colorless oil: LC-MS (ES) m/e 353 (M+H)⁺.

b) (±)-phenylmethyl {[c/s-4-fluoro-3-pyrrolidinyl]methyl}carbamate

To a solution of (±)-1 ,1-dimethylethyl c/s-3-fluoro-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.45 g, 1.28 mmole) in DCM (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (5.12 mmole, 1.9 g) was added with vigorous stirring at RT. After 4h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.32 g, 99%) as a light orange oil: LC-MS (ES) m/e 253 (M+H)⁺.

c) (±)-phenylmethyl [(c/s-4-fluoro-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 3-pyrrolidinyl)methyl]carbamate

To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.26 g, 1.28 mmole) in EtOH (5 ml_) was added (±)-phenyl methyl {[c/s-4-fluoro-3- pyrrolidinyl]methyl}carbamate (0.32 g, 1.28 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the

title compound (0.20 g, 34%) as a light yellow foam: LC-MS (ES) m/e 457 (M+H)⁺.

d) (±)-[(c/s-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine

To a solution of (±)-phenylmethyl [(c/s-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]carbamate (0.20 g, 0.44 mmole) in MeOH (100 mL) in a round bottom flask was added Pd(OH)2 (~ 100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were

filtered through Celite® (MeOH) and concentrated to give the title compound (0.15 g, 99%) as a colorless oil: LC-MS (ES) m/e 323 (M+H)⁺.

e) (±)-6-({[(c/s-4-fluoro-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one To a stirred solution of (±)-[(c/s-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine (0.15 g, 0.46 mmole) in dry CH2CI2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1 ,4]thiazine- 6-carboxaldehyde (0.077 g, 0.46 mmole). After 24h, at RT was added NaBH(OAc)3 (0.15 g, 0.69 mmole). After 2h, the reaction solution was concentrated under vacuum and purified on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) to afford the title compound

(0.1O g, 46%) as light yellow solid: ¹ H NMR (400 MHz, CDCI₃) δ 8.67 (s, 1H), 8.21 (d, J = 9.1 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.10 (m, 2H), 4.13 (s, 2H), 4.10 (s, 3H), 3.62 (m, 2H), 3.49-3.43 (m, 6H), 3.21 (m, 2H), 2.99 (m, 2H), 2.32 (app s, 2H). LC-MS (ES) m/e 501 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 70 D1

Preparation of (±)-6-({|^"(1-(2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl)-4-hvdroxy- 3-methyl-3-pyrrolidinyl)methyllamino>methyl)-2H-pyridor3,2-άiπ.41thiazin-3(4H)-one-D1

a) 1 , 1 -dimethylethyl 3-cyano-3-methyl-4-oxo-1 -pyrrolidinecarboxylate

To a solution of 1 ,1 -dimethylethyl 3-cyano-4-oxo-1-pyrrolidinecarboxylate (3.9 g, 18,6 mmol) in acetone (185 mL) were added K₂CO₃ (3.07 g, 22.3 mmol) and MeI (1.39 mL, 22.3 mmol). After 12h at reflux, the solution was cooled and the solid precipitate filtered. The filtrate was then concentrated and the residue purified by column chromatography (silica, 0.5% MeOH in DCM (1% NH₄OH)) affording the title compound (2.3 g, 55%) as a yellow oil: LCMS (ES) m/e 225 (M+H)⁺.

b) 1 , 1 -dimethylethyl 3-cyano-4-hydroxy-1 -pyrrolidinecarboxylate

NBoc^" To a solution of 1,1-dimethylethyl S-cyano-S-methyM-oxo-i-pyrrolidinecarboxylate (2.3 g, 10.2 mmol) in EtOH (100 mL) at 0⁰C was added NaBH₄ (775 mg, 20.5 mmol) portion-wise. After 30 min., the solution was concentrated and the residue partitioned between H₂O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na₂SO₄), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH₄OH)) affording the title compound as a yellow oil: LCMS (ES) m/e 227 (M+H)⁺.

c) 1 ,1 -dimethylethyl 4-hydroxy-3-methyl-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]- 1-pyrrolidinecarboxylate

To a solution of the nitrile (1.6 g, 7.08 mmol) in THF (70 mL) at 0⁰C was added dropwise a solution of LAH in THF (14 mL, 14.16 mmol, 1M in THF). After 1h, the solution was quenched by dropwise addition of a saturated solution of potassium sodium tartrate. The aqueous phase was back-extracted several times with DCM and the combined organic fractions were dried (Na₂SO₄), concentrated and the resulting crude residue was used directly: LCMS (ES) m/e 231 (M+H)⁺. To the crude amine in DCM (70 mL) at 0⁰C was added portion-wise N- (benzyloxycarbonyloxy)succinimide (1.94 g, 7.23 mmol). After 1h, the solution was partitioned between DCM-H₂O. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na₂SO₄), concentrated and the resulting diastereomers were separated by column chromatography (silica, 1 % MeOH in DCM (1 % NH₄OH)) yielding the higher eluting D1 diastereoemer (660 mg, 26%) and the D2 diastereomer (610 mg, 24%) as yellow oils: LCMS (ES) m/e 365 (M+H)⁺.

d) (±)-phenylmethyl [(4-hydroxy-3-methyl-3-pyrrolidinyl)methyl]carbamate (D1 diastereomer)

To a solution of the Boc-amine (660 mg, 1.81 mmol, D1 diastereomer) in MeOH (18 mL) at 25°C was added dropwise a solution of HCI in dioxane (3.2 ml_, 12.7 mmol, 4M in dioxane). After 12h, the solution was concentrated and then neutralized by addition of excess DIPEA to the salt in DCM. The residue was then purified through a pad of silica (90:10:1 MeOH, DCM and NH₄OH) yielding the title compound (360 mg, 75%) as a yellow oil: LCMS (ES) m/e 265 (M+H)⁺.

e) (±)-phenylmethyl [(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy- 3-methyl-3-pyrrolidinyl)methyl]carbamate (D1 diastereomer)

A solution of the pyrrolidine (360 mg, 1.36 mmol, D1 diastereomer) and 8-ethenyl- 7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (278 mg, 1.36 mmol) in EtOH (1 mL) was heated to 85⁰C. After 12h, the solution was concentrated and the residue purified by column chromatography (silica, 2% MeOH in DCM (1%NH₄OH)) yielding the title compound as an orange oil: LCMS (ES) m/e 469 (M+H)⁺.

f) (±)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-methyl- 3-pyrrolidinol (D1 diastereomer)

A solution of the Z-carbamate (340 mg, 468 mmol) and Pd(OH)₂ (170 mg, 50wt%) in EtOH (7 mL) was hydrogenated at 50 psi using a Parr-Shaker. After 2h, the solution was filtered through Celite^®, concentrated and used directly in the reductive amination: LCMS (ES) m/e 335 (M+H)⁺. h) (±)-6-({[(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3-methy!-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyriclo[3_l2-jb][1 _l4]thia2in-3(4H)-one-(D1

diastereomer)

A solution of the amine (80 mg, 0.240 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2- ύ][1,4]thiazine-6-carbaldehyde (47 mg, 0.240 mmol) and Na₂SO₄ (51 mg, 0.359 mmol) in DCM-EtOH (2 mL, 1 :1) was stirred at 25⁰C. After 2h, NaBH(OAc)₃ (76 mg, 0.359 mmol) was added and the reaction stirred an additional 1 h, was concentrated and purified via column chromatography (silica, 2% MeOH in DCM (1% NH₄OH)) yielding the title compound (38 mg, 31%) as a yellow foam: LCMS (ES) m/e 513 (M+H)+; ¹H NMR (400 MHz, CD₃OD) δ 8.74 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 7.78 (d , J = 7.8 Hz, 1H), 7.28 (d, J = 9.1 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 4.24 (s, 3H), 4.07-4.09 (m, 1H), 3.85 (s, 2H), 3.66 (S, 2H), 3.55-3.61 (m, 2H), 3.31-3.35 (m, 1 H), 2.87-2.91 (m, 3H)₁ 2.82-2.86 (m, 2H)₁ 2.71- 2.79 (d, J = 11.6 Hz, 1 H), 2.59-2.65 (d, J = 9.5 Hz, 1H)₁ 1.49 (s, 3H).

This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 70 D2

Preparation of (±)-6-((r(1-(2-r3-fluoro-6-(methyloxyV1 ,5-naphthyridin-4-yllethyl>-4-hvdroxy- 3-methyl-3-pyrrolidinvπmethvnamino)methyl)-2H-pyridor3,2-/?iπ ,41thiazin-3(4H)-one (D2- diastereomer)

The title compound (142 mg, 74%) was prepared as a yellow foam prepared essentially according to Example 70 D1 , except substituting the D2 diastereomer of 1 ,1- dimethylethyl 4-hydroxy-3-methyl-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate (610 mg, 1.68 mmol) for the D1 diastereomer: LCMS (ES) m/e 513 (M+H) ; H NMR (400 MHz, CD OD) δ 8.77 (s, 1H), 8.36 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1 H), 7.32 (d, J = 9.3 Hz, 1 H), 7.14 (d, J = 7.8 Hz₁ 1 H), 4.22 (s, 3H), 2.93-2.95 (m, 1 H), 3.62 (s, 2H), 3.52 (s, 2H), 3.49-3.50 (m, 2H), 3.34-3.40 (m, 1 H), 2.85-3.01 (m, 3H), 2.49-2.55 (m, 4H), 1.02 (s, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 71 D1/D2

Preparation of (±)-6-((f(1-(2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-vπethyl)-4-hvdroxy- 4-methyl-3-pyrrolidinyl)methvnamino)methyl)-2H-pyridor3,2-ib1f1 ,41thiazin-3(4/-/)-one (D1 Diastereomer) a) 1 ,1-dimethylethyl 3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate

To a solution of 1 ,1-dimethylethyl 3-(aminomethyl)-4-hydroxy-1- pyrrolidinecarboxylate (3g, 13.9 mmol) [Prepared according to Hong, C-Y. J. Med. Chem. 1997, 40, 3584.] in DCM (100 mL) at O⁰C was added N- (benzyloxycarbonyloxy)succinimide (3.8 g, 15.3 mmol) portion-wise. After 1h, the reaction was partitioned between H O-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na SO ), concentrated and purified by column chromatography (silica, 3% MeOH in DCM (1% NH OH)) yielding the title compound (4.8g, quant.) as a clear oil: LCMS (ES) m/e 351 (M+H) .

b) 1 ,1 -dimethylethyl 3-oxo-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1 - pyrrolidinecarboxylate

v /-^NHz NBoc A solution of the alcohol (1g, 2.88 mmol) in DMSO (4 mL) and Et N (1.2 mL) was cooled briefly in an ice-bath. SO -pyr. (819 mg, 5.14 mmol) was added portion-wise and the solution warmed to 25⁰C. After 2h, the reaction was partitioned between H O-EtOAc and the aqueous phase was back-extracted several times with EtOAc. The combined organic fractions were dried (Na SO ), concentrated and purified via column chromatography (silica, 0.5-1% MeOH in DCM (1% NH OH)) yielding the title compound (2.38 g, 63%) as a yellow oil: LCMS (ES) m/e 349 (M+H) .

c) 1 ,1 -dimethylethyl 3-hydroxy-3-methyl-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]- 1 -pyrrolidinecarboxylate

To a solution of the pyrrolidinone (1 g, 2.87 mmol) in toluene-THF (3:1 , 14 mL) at 0⁰C was added dropwise a solution of MeMgBr (8.2 mL, 1.4 M in toluene-THF) in toluene-THF (14 mL). The solution warmed to 25°C over 12h and was partitioned between brine-DCM. The aqueous phase was back-extracted several times with DCM and the combined organic fractions were dried (Na SO ), concentrated and purified by column chromatography (silica, 2% MeOH in DCM (1% NH OH)) yielding the title compound (450 mg, 43%) as an inseparable mixture of diastereomers (3.5:1): LCMS (ES) m/e 365 (M+H) .

d) (+)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-4-methyl-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one: (D1 and D2 Diastereomers)

The title compounds D1 (higher eluting diastereomer, 69 mg, 17%) and D2 (247 mg, 60%) were prepared as yellow foams according to Example 1 , except substituting 1 ,1 -dimethylethyl 3-hydroxy-3-methyl-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate (450 mg, 1.24 mmol, diastereomeric mixture) for 1 ,1 -dimethylethyl 4-hydroxy-3-methyl-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate (D1 diastereomer). (D1): D1 LCMS (ES) m/e 513 (M+H) ; H NMR (400 MHz, CD OD) δ 8.61 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1 H), 4.11 (s, 3H), 3.76 (s, 2H), 3.50 (s, 2H), 3.39-3.43 (m, 2H), 3.04-3.08 (m, 1H), 2.82-2.92 (m, 4H), 2.71-2.73 (m, 1H), 2.58-2.67 (m, 2H), 2.13-2.15 (m, 1H), 1.36 (s, 3H). (D2): D2 LCMS (ES) m/e 513 (M+H) ; H NMR (400 MHz, CD OD) δ 8.66 (s, 1H), 8.22 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1 H), 7.02 (d, J = 7.7 Hz, 1H), 4.13 (s, 3H), 3.80 (s, 2H), 3.52 (s, 2H), 3.44-3.47 (m, 2H), 3.27-3.29 (m, 1 H), 3.01 (d, J = 9.8 Hz, 1H), 2.79-2.93 (m, 3H), 2.63 (d, J = 10.1 Hz, 1H), 2.47-2.52 (m, 2H), 2.29-2.39 (m, 1H), 1.22 (s, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compounds.

Example 72

Preparation of (+)-6-((r(1-f2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vHethyl)-3-rnethyl- 3-pyrrolidinvπmethyllamino>methvπ-2/-/-pyridor3,2-6iπ ,41thiazin-3(4f/)-one

(a) (±)-1 , 1 -Dimethylethyl {[3-methyl~1 -(phenylmethyl)-3-pyrrolidinyl]methyl}carbamate

To a solution of (±)-{[3-methyl-1-(phenylmethyl)-3-pyrrolidinyl]methyl}amine (1.35 g, 6.6 mmol) in DCM (10 mL) was added Bis(1,1 -dimethylethyl) dicarbonate (1.73 g, 7.9 mmol) and triethylamine (2.3 mL). After stirring at 25 ⁰C for 18 h, the solution was partitioned between DCM and H O. The aqueous layer was extracted several times with DCM. The organic fractions were combined, dried over MgSO , concentrated and purified by column chromatography (silica, 30-50% ethyl acetate in hexane) to afford the title compound as a brown oil (2.0 g, quantitive): LC/MS m/z 305 (M + H)⁺.

(b) (±)-1 ,1 -Dimethylethyl [(3-methyl-3-pyrrolidinyl)methyl]carbamate

To a solution of (±)-1 ,1-dimethylethyl {[3-methyl-1-(phenylmethyl)-3- pyrrolidinyl]methyl}carbamate (2.0 g, 6.6 mmol) in MeOH (50 mL) was added Pd/C (1.3 g, 10 wet%). The suspension was hydrogenated at 50 psi of H using a Parr shaker. After 18 h, the mixture was filtered and washed several times with MeOH. The filtrate was concentrated to afford the title compound (1.3 g, 92%) as an off-white foam which was used without further purification; LC/MS (ES) m/e 293 (M+H) .

(c) (±)-1,1-dimethylethyl [(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- methyl-3-pyrrolidinyl)methyl]carbamate

(±)-1 ,1-Dimethylethyl [(3-methyl-3-pyrrolidinyl)methyl]carbamate (500 mg, 2.34 mmol) and 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (500 mg, 2.34 mmol) were mixed in EtOH (1 mL) and heated at 90 ⁰C over 24 h. The solution was then concentrated and the residue was purified via column chromatography (silica, 0-10% MeOH in DCM) yielding the title compound (520 mg, 53%) as an off-white foam; LC/MS (ES) m/e 419 (M+H) .

(d) (+)-[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-methyl-3- pyrrolidinyl)methyl]amine

To a solution of (±)-1,1-dimethylethyl [(1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]carbamate (520 mg, 1.25 mmol) in DCM (15 mL) at 25 ⁰C was added dropwise an HCI solution (1.2 mL, 4.8 mmol, 4M HCI in dioxane). After 24 h, the solution was concentrated to afford the HCI salt of the title compound (485 mg, quantit.) as a yellow foam which was used without further purification: LC/MS (ES) m/e 319 (M+H) .

(e) (+)-6-({[(1 -{2-[3-Fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-methyl-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one

To a solution of the HCI salt of (±)-[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]amine (100 mg, 0.257 mmol) in MeOH (3 mL) were added NaHCO (215 mg, 2.57 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2- ό][1 ,4]thiazine-6-carbaldehyde (51 mg, 0.317 mmol). After 24 h at 25 ⁰C, NaBH (15 mg, 0.398 mmol) was added. After 1h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO , concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1 % NH OH)) yielding the title compound (30 mg, 24%) as a brown oil: LC/MS (ES) m/e 497 (M + H)⁺; ¹H NMR (CDCI₃, 400 MHz) δ 8.8 (bs, 1H), 8.65 (s, 1 H) ,8.22 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (s, 2H), 3.46-3.50 (m, 2H), 2.9(m, 4H), 2.5 (m, 3H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1 H), 1.1 (S, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 73

Preparation of (+)-6-(flT1-f2-r3-fluoro-6-(methyloxy)-1.S-naphthyridin^-yllethyll-S-methyl- 3-pyrrolidinvDmethvπamino)methyl)-2f/-pyridof3,2-ά1f1 ,41oxazin-3(4M-one Prepared essentially according to the procedure for Example 73, except substituting 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-jb][1 ,4]oxazine-6-carbaldehyde (47 mg, 0.26 mmol) for 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-ιfc>][1 ,4]thiazine-6-carboxaldehyde. The title compound (20 mg, 16%) was obtained as an off-white solid: LC/MS (ES) m/e 481 (M + H)⁺; ¹ H NMR (CDCI₃, 400 MHz) 8.65 (s, 1 H) ,8.22 (d, J = 9.0 Hz, 1 H), 7.2 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 4.6 (s, 2H), 4.05 (s, 3H), 3.8 (s, 2H), 3.50 (s, 2H), 3.3(m, 2H), 2.8 (m, 4H)₁ 2.5 (m, 3H), 2.3 (m,1H), 1.85 (m, 1H), 1.55 (m, 1 H), 1.1 (s, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 74

Preparation of (+H(1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vπethylV-3-methyl-3- pyrrolidinyl)methyl1(H ,31oxathiolof5,4-c1pyridin-6-ylmethyl)amine

Prepared essentially according to the procedure for Example 73, except substituting [1 ,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (44 mg, 0.26 mmol) for 3-oxo- 3,4-dihydro-2H-pyrido[3,2-/)][1 ,4]thiazine-6-carboxaldehyde. The title compound (39 mg, 32%) was obtained: LC/MS (ES) m/e 470 (M + H)⁺; ¹ H NMR (CDCl₃, 400 MHz) 8.65 (s, 1H) ,8.22 (d, J = 9.0 Hz, 1H), 7.9(s, 1H), 7.15 (s, 1H), 7.10 (d, J = 9.0 Hz, 1H) , 5.7 (s, 2H), 4.05 (s, 3H), 3.8 (s, 2H), 3.50 (m, 2H), 2.8 (m, 4H), 2.5 (m, 3H), 2.3 (m,1H), 1.85 (m, 1H), 1.55 (m, 1 H), 1.1 (s, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 75

Preparation of (±)-(2,3-d vdroH ,4ldioxinof2,3-ci ^»Pyridin-7-ylmethvπr(1-(2-f3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl1ethyl)-3-rnethyl-3-pyrrolidinyl)rnethyllarnine

Prepared essentially according to the procedure for Example 72, except 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (42 mg, 0.26 mmol) for 3-oxo-3,4- dihydro-2H-pyrido[3,2-ό][1 ,4]thiazine-6-carboxaldehyde. The title compound (27 mg, 22%) was obtained: LC/MS (ES) m/e 468 (M + H)⁺; ¹ H NMR (CDCI₃, 400 MHz) δ 8.65 (s, 1H) ,8.22 (d, J = 9.0 Hz, 1H), 8.05(s, 1 H), 7.10 (d, J = 9.0 Hz, 1 H) , 6.8 (s, 1H), 5.7 (s, 2H), 4.32 (m, 2H), 4.30 (m, 2H), 4.05 (s, 3H), 3.8 (d, 2H), 3.50 (m, 2H), 2.8 (m, 4H), 2.5 (m, 3H), 2.3 (m,1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H). This material, as a solution in MeOH₁ was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 76

Preparation of (±)-4-(2-r3-methyl-3-«r(3-oxo-3,4-dihvdro-2f/-pyridor3,2-£iri ,41thiazin-6- yl)methyllamino)methyl)-1-pyrrolidinvnethyll-6-(methyloxy)-3-quinolinecarbonitrile

(a) (±)-1 ,1-dimethylethyl [(1-{2-[3-cyano-6-(methyloxy)-4-quinolinyl]ethyl}-3-methyl-3- pyrrolidinyl)methyl]carbamate

(+)-1 , 1 -Dimethylethyl [(3-methyl-3-pyrrolidinyl)methyl]carbamate (407 mg, 1.9 mmol) and 4-ethenyl-6-(methyloxy)-3-quinolinecarbonitrile (400 mg, 1.9 mmol) were mixed in DMF (1 mL) and heated at 90 °C over 1O h. The solution was then concentrated and the residue was purified via column chromatography (silica, 0-5% MeOH in DCM) yielding the title compound (247 mg, 30%) as an off-white solid; LC/MS (ES) m/e 425 (M+H) .

(b) (±)-4-{2-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3- quinolinecarbonitrile

To a solution of (±)-1,1 -dimethylethyl [(1-{2-[3-cyano-6-(methyloxy)-4- quinolinyl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]carbamate (247 mg, 0.58 mmol) in DCM (5 mL) at 25 ⁰C was added dropwise an HCl solution (0.6 mL, 2.4 mmol, 4M HCI in dioxane). After 24 h, the solution was concentrated to afford the HCI salt of the title compound (50 mg) which was used without further purification: LC/MS (ES) m/e 325 (M+H) .

(c) (±)-4-{2-[3-methyl-3-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-ib][1 ,4]thiazin-6- yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-6-(methyloxy)-3-quinolinecarbonitrile

To a solution of the HCI salt of 4-{2-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]ethyl}- 6-(methyloxy)-3-quinolinecarbonitrile (50 mg) in MeOH (2 mL) and DCM (2 mL) were added NaHCO (130 mg, 1.6 mmol) followed by 3-oxo-3,4-dihydro-2W-pyrido[3,2~ Jb][1,4]thiazine-6-carbaldehyde (30 mg, 0.18 mmol). After 24 h at 25 ⁰C, NaBH (10 mg, 0.27 mmol) was added. After 1h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO , concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1 % NH OH)) yielding the title compound (20 mg) as a brown oil: LC/MS (ES) m/e 503 (M+H) ; ¹ H NMR (CDCI3, 400 MHz) δ 8.85 (s, 1H)₁ 8.22 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.35 (S₁ 1H), 6.95 (d, J = 7.8 Hz₁ 1H)₁ 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (m, 3H), 2.9- 2.5 (m, 6H), 2.3 (m, 1H)₁ 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 77

Preparation of (+)-4-r2-(3-methyl-3-(f(H ,31oxathiolor5,4-cipyridin-6- ylmethyl)amino1methylV1-pyrrolidinyl)ethvπ-6-(methyloxy)-3-quinolinecarbonitrile

According to the procedure for Example 76, except substituting [1,3]oxathiolo[5,4- c]pyridine-6-carbaldehyde (26 mg, 0.15 mmol) for 3-oxo-3,4-dihydro-2H-pyrido[3,2- /b][1,4]thiazine-6-carboxaldehyde. The title compound (24 mg, 34%) was obtained as an oil: LC/MS (ES) m/e 476 (M+H) ; ¹ H NMR (CDCI₃, 400 MHz) δ 8.8 (s, 1H) ,8.22 (d, J = 9.0 Hz, 1H), 8.5(s, 1 H), 7.5 (d, J = 9.0 Hz, 1H) , 7.35 (s, 1H), 7.20 (s, 1H), 5.7 (s, 2H), 4.05 (s, 3H)₁ 3.8 (s, 2H)₁ 3.50 (m, 2H)₁ 2.8 (m, 4H)₁ 2.5 (m, 3H)₁ 2.3 (m,1 H), 1.85 (m, 1 H), 1.55 (m, 1H)₁ 1.1 (s, 3H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 78

Preparation of 6-flT1-(f3f?)-1-f2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethvU-3- pyrrolidinyl)-1-methylethvπamino}methvO-2^/-pyridof3,2-ά1f1 ,41thiazin-3(4f/)-one (a) (3R)-1-(phenylmethyl)-3-pyrrolidiny| methanesulfonate

To a solution of (3R)-1-(phenylmethyl_3-pyrrolidinol (11 g, 60 mmol) in DCM (100 mL) with triethylamine (13.05 ml.) at 0 ⁰C was added methenesulfonyl chloride (5.8 ml_) slowly. After stirring at 0 ⁰C for 3 h, the mixture was concentrated. The resulting residue was diluted partitioned between diethyl ether and water. The aqueous solution was extracted several times with diethyl ether. The organic fractions were combined, washed with brine, drived over Mg SO and concetrated to afford the title compound as an oil (15.72 g, 99%) which was used without further purification: LC/MS (ES) m/e 256 (M + H)⁺

(b) (3S)-1 -(phenylmethyl)-3-pyrrolidinecarbonitrile

(3R)-1-(phenylmethyl)-3-pyrrolidinyl methanesulfonate (12.9 g, 50.6 mmol) and tertrabytulamonium cyanide (25 g, 93.3 mmol) was mixed in DCM (20 mL) and refluxed at 60 °C for 6 h. The resulting soluton was cooled down to room temperature and diluted with saturated sodium bicarbonate solution in water. The aqueous phase was extracted several times with toluene. The organic fractions was combined, washed with brine and concentrated to provide the title compound as an oil( 10.3 g, quantit.) which was used without further purification: LC/MS (ES) m/e 187 (M + H)⁺.

(c) 2-[(3S)-1 -(phenylmethyl)-3-pyrrolidinyl]-2-propanamine

A solution of anhydrous trichlorocerium (41.6 g, 0.17 mol) in THF (520 mL), which was sounicated with stirring for 2.5 h, was cooled down to -70 °C and treated with a solution of Methyl Lithium (167 mL, 167 mmol, 1M in THF) followed with a solution of (3S)-1-(phenylmethyl)-3-pyrrolidinecarbonitrile (10.3 g, 55.4 mmol) in THF (20 mL). After stirring at -70 ⁰C for 2.5 h, the resulting mixture was diluted with the aqueous solution of NH OH(26 ml_). DCM (300 ml_) was added to generate a suspension which was subsequently filtered. The filterate was concetrated and purified with column chromatography (silica, 10-20% MeOH in DCM) affording the title compound as an oil (6.75 g, 56%): LC/MS (ES) m/e 219 (M + H)⁺.

(d) 1 ,1-dimethylethyl {1-methyl-1-[(3S)-1-(phenylmethyl)-3-pyrrolidinyl]ethyl}carbamate

To a solution of 2-[(3S)-1-(phenylmethyl)-3-pyrrolidinyl]-2-propanamine (6.75 g, 31 mmol) in DCM (100 mL) was added bis(1 ,1-dimethylethyl) dicarbonate (6.78 g, 31 mmol) followed with triethylamine (4.8 g, 47.5 mmol). After stirring at room temperature for 24 h, the solution was partitioned between DCM and water. The aquesous solution was extracted several times with DCM. The organic fractions were pooled, concentrated and purified with column chromatography (silica, 30-50% ethyl acetate in hexane) providing the title compound as an oil (5.85 g, 59%): LC/MS (ES) m/e 319 (M + H)⁺.

(e) 1 ,1-dimethylethyl {1-methyl-1-[(3S)-3-pyrrolidinyl]ethyl}carbamate

To a solution of 1 ,1-dimethylethyl {1-methyl-1-[(3S)-1-(phenylmethyl)-3- pyrrolidinyl]ethyl}carbamate (5.85 g, 18.4 mmol) in MeOH (100 mL) was added Pd/C (5 g, 10%). The suspension was hydrogenated at 50 psi of H using a Parr shaker. After 24 h, the mixture was filtered and washed several times with MeOH. The filtrate was concentrated to afford the title compound (4.8 g, quantit.) as an oil, which was used without further purification: LC/MS (ES) m/e 229 (M + H)⁺.

(T) 1 ,1-dimethylethyl [1-((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)-1-methylethyl]carbamate

A solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (600 mg, 2.95 mmol) in ethyl acetate (1mL) and 1,1-dimethylethyl {1-methyl-1-[(3S)-3- pyrrolidinyl]ethyl}carbamate (670 mg, 2.94 mmol) were mixed in EtOH (3 mL) and heated at 90 ⁰C for 24 h. DMF (2 mL) was added and the mixture was hearted at 90 ⁰C for another 10 h. The solution was then concentrated and the residue was purified via column chromatography (silica, 1-10% MeOH in DCM) yielding the title compound (0.46 g, 36%) as an oil: LC/MS (ES) m/e 433 (M + H)⁺.

(g) 2-((3R)- 1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-2- propanamine

To a solution of 1 ,1-dimethylethyl [1-((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-1-methylethyl]carbamate (0.46 g, 1.06 mmol) in DCM (10 mL) at 25 ⁰C was added dropwise an HCI solution (4.22 mL, 4.24 mmol, 1 M HCI in dioxane). After 24 h, the solution was concentrated to afford the hydrochloride salt of the title compound as an off-white residue (0.43 g, quantit), which was used without further purification: LC/MS (ES) m/e 333 (M + H)⁺.

(h) 6-({[1-((3f?)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-1- methylethyl]amino}methyl)-2H-pyrido[3_I2-ό][1 ,4]thiazin-3(4H)-one

To a solution of the hydrochloride salt of 2-((3ft)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-2-propanamine (100 mg, 0.25 mmol) in DCM:EtOH (6 ml_, 1:1) were added NaHCO (210 mg, 2.5 mmol) followed by 3-oxo-3,4-dihydro-2f/- pyrido[3,2-6][1 ,4]thiazine-6-carbaldehyde (47 mg, 0.25 mmol). After 12 h at 25 ⁰C, NaBH (10 mg, 0.28 mmol) was added. After 1h, the reaction was concentrated and the residue was partitioned between DCM and water. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO , concentrated and purified via column chromatography (silica, 0-1 % MeOH in DCM (1% NH OH)) yielding the title compound (47 mg, 37%) as an off-white solid: LC/MS (ES) m/e 512 (M + H)⁺; H NMR (CDCI , 400 Hz) δ 8.59 (s, 1 H), 8.17 (d, J = 9.1 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.05 (d, J - 9.0 Hz, 1 H), 6.98 (d, J = 7.8 Hz, 1 H), 4.07 (s, 3H), 3.76 (s, 2H), 3.39-3.43 (m, 4H), 2.76-2.96 (m, 4H), 2.55-2.64 (m, 2H), 2.39-2.44 (m, 1 H), 1.85-1.88 (m, 1 H), 1.72- 1.78 (m, 1 H), 1.09 (s, 3H), 1.08 (s, 3H). This material, as a solution in MeOH, was treated with 2 equivalents of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 79

Preparation of Λ/-(2,3-dihvdrori ,4ldioxinor2,3-clpyridin-7-ylmethyl)-2-((3ffl-1-(2-f3-fluoro-6- (methyloχy)-1 ,5-naphthyridin-4-yl1ethyl)-3-pyrrolidinyl)-2-propanamine

According to the procedure for Example 78, except 2,3-dihydro[1 ,4]dioxino[2,3- c]pyridine-7-carbaldehyde (40 mg, 0.25 mmol) for 3-oxo-3,4-dihydro-2f/-pyrido[3,2- b){\ ,4]thiazine-6-carbaldehyde. The title compound (30 mg, 26%) was obtained as an off- white solid: LC/MS (ES) m/e 483 (M+H) ; ¹H NMR (CDCI , 400 MHz) δ 8.60 (s, 1H), 8.16 (d, J = 9.1 Hz, 1H), 8.07 (s, 1H), 7.06 (d, J = 9.0 Hz, 1 H), 6.86 (s, 1 H), 4.31-4.33 (m, 2H)₁ 4.25-4.27 (m, 2H), 4.08 (s, 3H), 3.74 (s, 2H), 3.41-3.45 (m, 2H), 2.85-2.91 (m, 3H), 2.75- 2.80 (m, 1H), 2.52-2.57 (m, 2H), 2.42-2.46 (m, 1H), 1.84-1.89 (m, 1H), 1.72-1.76 (m, 1H), 1.09 (s, 6H). This material, as a solution in MeOH, was treated with 2 equivalents of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 80

Preparation of AZ-F(QSVI -te-rS-fluoro-β-dnethyloxyΗ ,5-naphthyridin-4-yllethyl)-3- pyrrolidinyl)methvn-3-oxo-3,4-dihvdro-2/-/-pyridof3,2-άlf1 ,41thiazine-6-carboxamide

To a stirred solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (105 mg, 0.34 mmole) in dry in DMF (25 mL) at RT was added diisopropylethylamine (0.18 mL, 1.02 mmole), 3-oxo-3,4-dihydro-2/-/- pyrido[3,2-ύ][1 ,4]thiazine-6-carboxylic acid (0.93 mg, 0.44 mmole), hydroxybenzotriazole hydrate (51 mg, 0.38 mmole) and EDC (73 mg, 0.38 mmole). After 18h, the reaction contents were concentrated under high vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (30 mg, 17%) as a light yellow solid:

¹H NMR (400 MHz, CD₃OD) δ 8.62 (m, 1H)₁ 8.56 (s, 1H), 8.16 (d, J=9.04Hz, 1H), 7.99 (m, 1H), 7.83 (d, J=7.91Hz, 1H)₁ 7.76 (d, J=7.92Hz, 1 H), 7.05 (d, J=9.04Hz, 1 H), 4.07 (s, 3H)₁ 3.53 (d, 2H), 2.43-3.51 ( br m, 11 H), 2.06 (m, 1H)₁ 1.58 (m, 1H). LC-MS (ES) m/e 497 (M + H)⁺. This material, as a solution in MeOH₁ was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 81

Preparation of Λ/-r((3S)-1-f2-r6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3- pyrrolidinvπmethvn-3-oxo-3,4-dihydro-2/-/-pyridor3,2-ibiri.41thiazine-6-carboxamide

To a stirred solution of [((3S)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amine (0.14 g, 0.49 mmole) in dry in DMF (25 ml_) at RT was added diisopropylethylamine (0.10 mL, 0.54 mmole), 3-oxo-3,4-dihydro-2H-pyrido[3,2- jb][1 ,4]thiazine-6-carboxylic acid (0.10 g, 0.49 mmole), hydroxybenzotriazole hydrate (0.73 g, 0.54 mmole) and EDC (0.10 g, 0.54 mmole). After 18h, the reaction contents were concentrated under high vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5%

NH4OH) afforded the title compound (0.17 g, 75%) as a light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 9.05 (m, 1H), 8.47 (d, J = 9.2 Hz, 1H), 8.25 (m, 2H), 7.92 (m, 1H), 7.72 (m, 1H), 7.62 (d, J = 9.2 Hz₁ 1H), 4.22 (s, 3H)₁ 3.91 (m, 2H), 3.82 (m, 2H), 3.67 (s, 2H), 3.65 (m, 2H), 3.44 (m, 2H), 3.18 (m, 2H), 2.98 (m, 1 H), 2.37 (m, 1 H), 2.05 (m, 1H). LC-MS (ES) m/e 479 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 82

Preparation of A/-r((3S,4S)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-4- hydroxy-3-pyrrolidinyl)methvn-3-oxo-3₁4-dihydro-2/-/-pyridof3,2-άiri ,41thiazine-6- carboxamide To a stirred solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.27 g, 0.84 mmole) in dry in DMF (25 mL) at RT was added diisopropylethylamine (0.44 mL, 2.52 mmole), 3-oxo-3,4-dihydro-2/-/- pyrido[3,2jb][1 ,4]thiazine-6-carboxylic acid (0.18 g, 0.84 mmole), hydroxybenzotriazole hydrate (0.12 g, 0.92 mmole) and EDC (0.18 g, 0.92 mmole). After 18h, the reaction contents were concentrated under high vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.49 g, 58%) as a light yellow solid:

¹ H NMR (400 MHz, CDCI₃) δ 8.56 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.72 (d, J= 7.8 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.34 (m, 1H), 4.07 (s, 3H), 3.69 (m, 2H), 3.54 (m, 2H), 3.39 (s, 2H), 3.14 (m, 1 H), 2.98 (m, 2H), 2.77 (m, 2H), 2.45 (m, 2H). LC-MS (ES) m/e 479 (M + H)⁺. LC-MS (ES) m/e 513 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 83

Preparation of (±)-/V-f(c/^'s-1-{2-r3-f[uoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl)-4- hvdroxy-3-pyrrolidinyl)methyl1-Λ/-methyl-3-oxo-3₁4-dihvdro-2/-/-pyridof3₁2-άiπ_i41thiazine-6- carboxamide

To a stirred solution of (±)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 4-[(methylamino)methyl]-3-pyrrolidinol (1.5 g, 4.49 mmole) [from procedure 24] in dry in DMF (25 mL) at RT was added diisopropylethylamine (2.35 mL, 13.5 mmole), 3-oxo-3,4- dihydro-2W-pyrido[3,2ό][1 ,4]thiazine-6-carboxylic acid (0.94 g, 4.49 mmole), hydroxybenzotriazole hydrate (0.67 g, 4.94 mmole) and EDC (0.95 g, 4.94 mmole). After 18h, the reaction contents were concentrated under high vacuum. Purification on silica (CHCIβ/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (1.62 g, 69%) as

a light yellow solid: ¹H NMR (400 MHz, CDCI₃) δ 8.61 (s, 1H), 8.19 (d, J = 9.0 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 4.32 (m, 2H), 4.09 (S, 3H), 3.51 (s, 3H), 3.42 (m, 4H), 3.14 (m, 2H), 2.98 (m, 4H), 2.80 (m, 1H), 2.63 (m, 1H). LC-MS (ES) m/e 527 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 84

Preparation of (±)-ΛH(H2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl>-3- pyrrolidinvnmethvn-Λ/-methyl-3-oxo-3,4-dihvdro-2f/-pyridof3,2-£)iπ ,41thiazine-6- carboxamide (a) (±)-1 , 1 -Dimethylethyl 3-[(methylamino)methyl]-1 -pyrrolidinecarboxylate

To a solution of 1 ,1 -dimethylethyl 3-formyl-1-pyrrolidinecarboxylate (500 mg, 2.51 mmol) in MeOH/DCM (6 ml_, 1 :1) were added NaHCO (1.05 g, 12.6 mmol) followed by methylamine (2.51 mL, 5.02 mmol, 2.0 M in MeOH). After 12 h at 25 ⁰C, NaBH (1.05 g, 12.6 mmol) was added. After 1h, the reaction was concentrated and the residue was partitioned between DCM and H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO^ concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (512 mg, 95%) as a brown oil: LC/MS (ES) m/e 215 (M+H) .

(b) (±)-1 , 1 -Dimethylethyl S-tfmethylKS-oxo-S^-dihydro^W-pyridotS^-ύHI ,4]thiazin-6- yl)carbonyl]amino}methyl)-1 -pyrrolidinecarboxylate

To a solution of 1 ,1-dimethylethyl 3-[(methylamino)methyl]-1- pyrrolidinecarboxylate (153 mg, 0714 mmol) in DMF (2 ml_) were added triethylamine (0.1 ml_, 0.714 mmol) followed by DPPA (0.154 ml_, 0.714 mmol) and 3-oxo-3,4-dihydro-2/-/- pyrido[3,2-ό][1 ,4]thiazine-6-carboxylic acid (150 mg, 0.714 mmol). After stirring at room temperature for 24 h, the solution was partitioned between ethyl acetate and K CO solution (5% in H O). The aqueous layer was extracted several times with ethyl acetate. The organic fractions were combined, dried over MgSO , concentrated and purified with column chromatography (silica, 0-5% MeOH in DCM) to provide the title compound as an off-white solid (240 mg, 83%): LC/MS (ES) m/e 407 (M+H) .

(c) (+)-Λ/-Methyl-3-oxo-Λ/-(3-pyrrolidinylmethyl)-3,4-dihydro-2W-pyrido[3,2-ib][1,4]thia2ine- 6-carboxamide

To a solution of 1 ,1-dimethylethyl 3-({methyl[(3-oxo-3,4-dihydro-2H-pyrido[3,2- o][1 ,4]thiazin-6-yl)carbonyl]amino}methyl)-1-pyrrolidinecarboxylate (240 mg, 0.59 mmol) in DCM (5 mL) at 25 ⁰C was added dropwise an HCI solution (0.75 ml_, 3.0 mmol, 4M HCI in dioxane). After 24 h, the solution was concentrated to afford the HCI salt of the title compound (238 mg, quantit.) as a yellow foam, which was used without further purification: LC/MS (ES) m/e 307 (M+H) .

(d) (+)-Λ/-[(1-{2-[3-Fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]- N-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-6][1,4]thiazine-6-carboxamide

Λ/-Methyl-3-oxo-Λ/-(3-pyrrolidinylmethyl)-3,4-dihydro-2H-pyrido[3,2-ib][1 ,4]thiazine- 6-carboxamide (225 mg, 0.734 mmol), diisopropylethylamine (0.26 mL, 1.47 mmol) and 1- ethenyl-2-fluoro-7-(methyloxy)naphthalene (150 mg, 0.734 mmol) were mixed in DMF (1 mL) with catalytic amount of DMAP. The resulting mixture was heated at 94 ⁰C over 24 h. The solution was then concentrated and the residue was purified via column chromatography (silica, 0-10% MeOH in DCM) yielding the title compound (82 mg, 22%) as an off-white foam; LC/MS (ES) m/e 511 (M+H) ; H NMR This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 85

Preparation of (3S,4S)-4-(f(2,3-dihvdroπ ,41dioxinof2,3-c1pyridin-7-ylmethyl)amino1methyl>- 1-{2-r6-(methyloxy)-1 ,5-naphthyridin-4-yl1ethyl)-3-pyrrolidinol

a) phenylmethyl [((3S,4S)-4-hydroxy-1-{2-[6~(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]carbamate

To a stirred solution of 8-ethenyl-2-(methyloxy)-1,5-naphthyridine (4.2 mmole) in EtOH (5 mL) was added phenylmethyl {[(3R,4S)-4-hydroxy-3- pyrrolidinyl]methyl}carbamate (1.05 g, 4.2 mmole). After 24 h at 80 ⁰C the reaction contents were purified on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) affording the

title compound (1.46 g, 80%) as a light yellow foam: LC-MS (ES) m/e 437 (M+H)⁺.

b) (3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol

To a solution of phenylmethyl [((3S,4S)-4-hydroxy-1 -{2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyljcarbamate (1.46 g, 3.34 mmole) in MeOH (100 ml_) in a round bottom flask was added Pd(OH)2 (~ 100 mg). The reaction contents were stirred under a balloon of H2 overnight at RT. The reaction contents were filtered

through Celite® (MeOH) and concentrated to give the title compound (x g, quant.) as a light yellow foam: LC-MS (ES) m/e 303 (M+H)⁺.

c) (3S,4S)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-1 -{2-[6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol To a stirred solution of (3S,4S)-4-(aminomethyl)~1-{2-[6-(methyloxy)-1,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.30 g, 1.0 mmole) in dry CH2CI2 (25 ml_) and dry EtOH (10 mL) at RT was added 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.165 g, 1.0 mmole). After 24h, at RT was added NaBH(OAc)3 (0.32 g, 1.5 mmole). After 2h, the reaction solution was concentrated under vacuum and purified on silica (CHCI₃/MeOH, 9:1 containing 5% NH₄OH) to afford the title compound (0.12 g, 27%) as

light yellow solid: ¹ H NMR (400 MHz, CD₃OD) δ 8.67 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 4.5 Hz, 1 H), 7.25 (d, J = 9.0 Hz, 1H), 7.02 (s, 1H), 4.61 (m, 1H), 4.38 (m, 4H), 4.20 (s, 2H), 4.15 (s, 3H), 3.60 (m, 8H), 3.42 (m, 1H), 3.25 (m, 1H), 2.82 (m, 1H). LC-MS (ES) m/e 452 (M + H)⁺. This material, as a solution in MeOH, was treated with an excess of 4M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 86

Preparation of 6-((f((3S,4S)-1-(2-r8-fluoro-6-(methyloxy)-4-αuinolinvnethylV4-hvdroxy-3- pyrrolidinyl)methyllamino)methvπ-2H-pyridor3₁2-άiri ,41thiazin-3(4H)-one Prepared essentially according to the procedure of Example 85 except substituting (3S,4S)-4-(aminomethyl)-1-{2-[8-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol (98 mg, 0.307 mmol) for (3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinol, and substituting 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-jb][1 ,4]thiazine-6- carbaldehyde (54 mg, 0.278 mmol) for 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde, the title compound (84 mg, 55%) was prepared as an orange solid: LCMS (+ve ion electrospray) m/z 498 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.67 (d, J=4.38Hz, 1H), 7.55 (d, J=7.79Hz, 1H), 7.27 (d, J=4.47Hz, 1 H), 7.10-7.06 (m, 2H), 6.89 (d, J=7.82Hz, 1 H), 4.58-4.45 (m, 1 H), 3.93 (s, 3H), 3.87-3.77 (m, 2H), 3.45 (s, 2H), 3.28-3.17 (m, 2H), 3.08-2.99 (m, 1H), 2.98-2.74 (m, 6H), 2.67-2.54 (m, 1H), 2.52-2.40 (m, 1 H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 87

Preparation of 6-({f ((3S,4S)-1 -{2-r8-fluoro-6-(methyloxy)-4-quinolinyl1ethyll-4-hydroxy-3- pyrrolidinyl)methvnamino)methyl)-2H-pyridor3,2-άiri ,41oxa2in-3(4Ay)-one

The title compound (61 mg, 41%) was prepared as a yellow solid prepared essentially according to Example 86, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[8- fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol (98 mg, 0.307 mmol) for (3S,4S)-4- (aminomethyl)-i -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde (56 mg, 0.312 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 482 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.65 (d, J=4.32Hz, 1H)₁ 7.26 (d, J=4.36Hz, 1 H), 7.17 (d, J=8.04Hz, 1H), 7.11-7.01 (m, 2H)₁ 6.84 (d, J=8.05Hz, 1H), 4.59 (s, 2H), 4.56-4.42 (m, 1H), 3.92 (s, 3H), 3.89-3.71 (m, 2H), 3.48 (s, 2H), 3.29-3.12 (m, 2H), 3.09-2.98 (m, 1H), 2.97-2.71 (m, 5H), 2.66-2.53 (m, 1H), 2.53-2.41 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 88

Preparation of 6-((r((3S,4S)-1-(2-r6-fluoro-5-(methyloxy)-4-quinolinvnethyl)-4-hvdroxy-3- pyrrolidinyl)methvnamino>methvπ-2H-pyridor3,2-ibiπ ,41oxazin-3(4H)-one

The title compound (83 mg, 42%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[6-fluoro-5- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol (130 mg, 0.407 mmol) for (3S,4S)-4- (aminomethyl)-1-{2-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol and 3-oxo- 3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde (78 mg, 0.438 mmol) for 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 482 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.70 (d, J=4.42Hz, 1 H), 7.91-7.84 (m, 1H), 7.58-7.46 (m, 1 H), 7.24 (d, J=4.34Hz, 1 H), 7.19 (d, J=8.03Hz, 1 H), 6.85 (d, J=8.05Hz, 1H), 4.63 (s, 2H), 4.57-4.48 (m, 1 H), 4.07 (s, 3H), 3.90-3.72 (m, 2H), 3.57-3.34 (m, 2H), 3.04-2.92 (m, 1H), 2.91-2.70 (m, 5H), 2.61-2.50 (m, 1 H), 2.49-2.39 (m, 1 H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 89

Preparation of 6-(W(3S,4S)-142-f6-fluoro-5-(methyloxy)-4-αuinolinvπethyl)-4-hvdroxy-3- pyrrolidinvπmethvnamino>methyl)-2f/-pyridof3^*,2-ά1f1 ,4lthiazin-3(4fy)-one

The title compound (45 mg, 22%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[6-fluoro-5- (methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol (130 mg, 0.407 mmo!) for (3S,4S)-4- (aminomethyl)-i -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (94 mg, 0.484 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 498 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.69 (d, J=4.42Hz, 1H), 7.93- 7.82 (m, 1H), 7.56 (m, J=7.79Hz, 1 H), 7.52-7.44 (m, 1 H), 7.22 (d, J=4.12Hz, 1H), 6.89 (d, J=7.82Hz, 1 H), 4.56-4.45 (m, 1 H), 4.06 (s, 3H), 3.90-3.74 (m, 2H), 3.57-3.31 (m, 5H), 3.09-2.94 (m, 1H), 2.93-2.73 (m, 5H), 2.62-2.52 (m, 1H), 2.51-2.39 (m, 1 H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 90

Preparation of 6-({r((3S,4S)-1-(2-r3,8-difluoro-6-(methyloxy)-4-quinolinyllethyl)-4-hvdroxy- 3-pyrrolidinvπmethvnamino)methyl)-2H-pyridor3,2-d1f1 ,41oxazin-3(4H)-one The title compound (182 mg, 65%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3,8-difluoro- 6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol (190 mg, 0.563 mmol) for (3S,4S)-4- (aminomethyl)-1-{2-[6-(rnethyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol and 3-oxo- 3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde (114 mg, 0.640 mmol) for 2,3- dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 500 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.54 (s, 1 H), 7.15 (m, J=8.02Hz, 1 H), 7.08-6.94 (m, 2H), 6.83 (d, J=8.05Hz, 1H), 4.55 (s, 2H), 4.52-4.41 (m, 1H), 3.91 (s, 3H), 3.85-3.73 (m, 2H), 3.30-3.13 (m, 2H), 3.09-2.96 (m, 1 H), 2.94-2.70 (m, 6H), 2.69-2.52 (m, 1H), 2.51- 2.39 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 91

6-(ff((3S,4S)-142-f3.8-difluoro-6-(methyloxy)-4-quinolinvnethyl>-4-hvdroxy-3- pyrrolidinyl)methvnamino)methyl)-2/^-pyridor3,2-61f1 ,41thiazin-3(4f/)-one

The title compound (162 mg, 63%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4-(aminomethyl)-1-{2-[3,8-difluoro- 6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol (190 mg, 0.563 mmol) for (3S,4S)-4- (aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazine-6-carbaldehyde (99 mg, 0.510 mmol) for 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 516 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.58 (s, 1 H), 7.56 (m, J=8.02Hz, 1H), 7.10-6.98 (m, 2H), 6.89 (d, J=7.82Hz, 1H), 4.56-4.46 (m, 1 H), 3.95 (s, 3H), 3.91-3.74 (m, 2H), 4.43 (s, 2H), 3.31-3.18 (m, 2H), 3.09-2.96 (m, 1H), 2.94-2.74 (m, 6H), 2.69-2.59 (m, 1 H), 2.56-2.40 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 92

6-(fffl3S,4S)-1-f2-(9-chloro-2,3-dihvdrof1 ,41dioxinof2,3-/lαuinolin-10-yl)ethyll-4-hvdroxy-3- PVrrolidinyl|methyl)amino1nnethyl)-2H-pyrido[3,2-όlf1₁4lthiazin-3(4/-/)-one

The title compound (25 mg, 26%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4-(aminomethyl)-1-[2-(9-chloro-2,3- dihydro[1 ,4]dioxino[2,3-/]quinolin-10-yl)ethyl]-3-pyrrolidinol (190 mg, 0.563 mmol) for (3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazine-6-carbaldehyde (99 mg, 0.510 mmol) for 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 542 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.60 (s, 1 H), 7.69-7.51 (m, 2H), 7.36-7.22(m, 1H), 6.91 (d, J=7.82Hz, 1H), 4.58-4.49 (m, 1H), 4.47-4.31 (m, 4H), 3.94-3.76 (m, 2H), 3.74-3.58 (m, 2H), 3.47 (s, 2H), 3.19-3.04 (m, 1H), 2.99-2.68 (m, 6H)₁ 2.61-2.51 (m, 1 H), 2.51-2.39 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 93

Preparation of 6-{[({(3S,4S)-1-[2-(9-chloro-2,3-dihydro[1 ,4]dioxino[2,3-/]quinolin-10- yl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)amino]methyl}-2/-/-pyrido[3,2-b][1,4]oxazin-3(4/-0- one The title compound (35 mg, 38%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4-(aminomethyl)-1-[2-(9-chloro-2,3- dihydro[1,4]dioxino[2,3-/]quinolin-10-yl)ethyl]-3-pyrrolidinol (190 mg, 0.563 mmol) for(3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol, and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde (34 mg, 0.191 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 526 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.59 (s, 1 H), 7.60 (d, J=9.10Hz, 1H), 7.28 (d, J=9.11Hz, 1H), 7.18 (d, J=8.01 Hz, 1 H), 6.86 (d, J=8.04Hz, 1 H), 4.60 (s, 2H), 4.58-4.49 (m, 1 H), 4.46-4.32 (m, 4H), 3.91-3.74 (m, 2H), 3.72-3.60 (m, 2H), 3.49 (s, 2H), 3.18-3.06 (m, 1 H), 2.99-2.71 (m, 5H), 2.62-2.53 (m, 1H), 2.52-2.40 (m, 1 H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 94

Preparation of 6-ffffl3S,4S)-1-r2-(2,3-dihvdrof1.41dioxinor2.3-/1αuinolin-10-yDethylM- hvdroxy-3-pyrrolidinyl>methyl)amino1methyl)-2H-pyridof3,2-ά1f1.41oxazin-3(4/-/)-one

Prepared essentially according to the procedure of Example 85 except substituting (3S,4S)-4-(aminomethyl)-1-[2-(2,3-dihydro[1 ,4]dioxino[2,3-/]quinolin-10-yl)ethyl]-3- pyrrolidinol for (3S,4S)-4-(aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol and substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazine-6- carbaldehyde for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde, the title compound was prepared as a yellow solid: LCMS (+ve ion electrospray) m/z 492 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.54 (d, J=4.42Hz, 1H), 7.64 (d, J=9.11 Hz, 1H), 7.27 (d, J=9.13Hz, 1H), 7.14 (d, J=8.00Hz, 1H), 7.09 (d, J=4.46Hz, 1H), 6.82 (d, J=8.04Hz, 1H), 4.56 (s, 2H), 4.52-4.44 (m, 1 H), 4.42-4.29 (m, 4H), 3.90-3.70 (m, 2H), 3.51-3.32 (m, 2H), 3.09-2.99 (m, 1 H), 2.92-2.68 (m, 6H), 2.59-2.37 (m, 2H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 95

Preparation of 6-((f((3S,4S)-4-hvdroxy-1-{2-r6-(methyloχy)-1 ,5-naphthyridin-4-vnethyl)-3- Pyrrolidinv0methyl1amino)methv0-2H-pyrido[3,2-άiri ,41oxazin-3(4f/)-one

The title compound (56 mg, 45%) was prepared as a brown solid essentially according to Example 85, except substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine-6-carbaldehyde (49 mg, 0.272 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3- c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 465 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.61 (d, J=4.48Hz, 1H), 8.16 (d, J=9.01 Hz, 1 H), 7.39 (d, J=4.50Hz, 1 H), 7.13 (d, J=8.01 Hz, 1 H), 7.06 (d, J=9.03Hz, 1 H), 6.80 (d, J=8.05Hz, 1H), 4.56 (s, 2H), 4.52-4.42 (m, 1H), 4.04 (s, 3H), 3.83-3.66 (m, 2H), 3.46 (s, 1H), 3.42-3.30 (m, 2H), 3.09- 2.68 (m, 7H), 2.65-2.52 (m, 1 H), 2.51-2.37 (m, 1 H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 96

Preparation of (3S₁4S)-1-l2-f6-(methyloxy^')-1.5-naphthyridin-4-vilethyl|-4- (f(ri ,31oxathiolof5,4-c1pyridin-6-ylmethyl)amino1methyl)-3-pyrrolidinol

The title compound (61 mg, 41%) was prepared as a yellow solid essentially according to Example 85, except substituting [1 ,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (37 mg, 0.22 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 454 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.66 (d, J=4.47Hz, 1 H), 8.19 (d, J=9.04Hz, 1H), 8.02 (s, 1H), 7.43 (d, J=4.47Hz, 1 H), 7.19-7.03 (m, 2H), 5.76 (s, 2H), 4.58-4.46 (m, 1 H), 4.09 (s, 3H), 3.87-3.72 (m, 2H), 3.49-3.31 (m, 2H), 3.12-3.01 (m, 1H), 2.97-2.69 (m, 6H), 2.60-2.51 (m, 1H), 2.50-2.37 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 97

Preparation of 7-chloro-6-({r((3S,4S)-4-hvdroxy-1-f2-f6-(methyloxy)-1 ,5-naphthyridin-4- vnethyl|-3-pyrrolidinvπmethyllamino}methyl)-2H-pyridof3,2-biπ ,41oxazin-3(4H)-one

The title compound (21 mg, 11%) was prepared as a yellow solid essentially according to Example 85, except substituting 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine-6-carbaldehyde (79 mg, 0.372 mmol) for 2,3-dihydro[1,4]dioxino[2,3- c]pyridine-7-carbaldehyde: LCMS (+ve ion electrospray) m/z 499 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.66 (d, J=4.46Hz, 1 H), 8.19 (d, J=9.03Hz, 1H), 7.43 (d, J=4.48Hz, 1 H), 7.20 (s, 1 H), 7.10 (d, J=9.03Hz, 1 H), 4.59 (s, 2H), 4.57-4.48 (m, 1H), 4.07 (s, 3H), 4.01-3.81 (m, 2H), 3.49-3.38 (m, 2H), 3.24-2.81 (m, 8H), 2.80-2.69 (m, 1 H), 2.63-2.50 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 98

(3S,4S)-4-αr(7-fluoro-2.3-dihvdro-1,4-benzodioxin-6-yl)methyllamino>methyl)-1-{2-f6- (methyloxy)-i ,5-naphthyridin-4-vnethyl)-3-pyrrolidinol (GSK713092A) The title compound (77 mg, 47%) was prepared as a tan solid essentially according to Example 85, except substituting 7-fluoro-2,3-dihydro-1 ,4-benzodioxin-6- carbaldehyde (67 mg, 0.368 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7- carbaldehyde: LCMS (+ve ion electrospray) m/z 498 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.62 (d, J=4.47Hz, 1H), 8.16 (d, J=9.01 Hz, 1 H), 7.40 (d, J=4.48Hz, 1 H), 7.09 (d, J=9.05Hz, 1 H)₁ 6.98 (d, J=9.26Hz, 1 H), 6.84 (d, J=6.42Hz, 1H), 4.54-4.41 (m, 1 H), 4.06 (s, 3H), 3.73 (s, 2H), 3.49-3.29 (m, 4H), 3.04-2.73 (m, 7H), 2.71-2.61 (m, 1H), 2.53-2.39 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 99

Preparation of (3S,4S)-4-(flY7-fluoro-2,3-dihvdro-1 ,4-benzodioxin-6- yl)methyl1amino)methyl)-1-{2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl)-3- pyrrolidinol

The title compound (75 mg, 41%) was prepared as a yellow solid essentially according to Example 85, except substituting (3S,4S)-4~(aminomethyl)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (120 mg, 0.375 mmol) for (3S,4S)-4- (aminomethyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol and 7-fluoro- 2,3-dihydro-1 ,4-benzodioxin-6-carbaldehyde for 2,3-dihydro-1 ,4-benzodioxin-6- carbaldehyde (69 mg, 0.378 mmol) for: LCMS (+ve ion electrospray) m/z 487 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.57 (s, 1H), 8.13 (d, J=9.04Hz, 1H), 7. 04 (d, J=9.04Hz, 1H), 6.71 (d, J=7.19Hz, 1 H), 6.57 (d, J=10.41Hz, 1H), 4.99-4.39 (m, 1H), 4.28-4.16 (m, 4H), 4.06 (s, 3H), 3.67 (s, 2H), 3.42-3.30 (m, 2H), 3.02-2.92 (m, 1 H), 2.88-2.63 (m, 6H), 2.58- 2.46 (m, 1H), 2.43-2.32 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 100

Preparation of 7-fluoro-6-((r((3S,4S)-4-hvdroxy-1-{2-f6-(methyloxy)-1 ,5-naphthyridin-4- vπethyl)-3-pyrrolidinyl)methvnamino>metriyl)-2H-1 ,4-benzothiazin-3(4H)-one

The title compound (67 mg, 36%) was prepared as a yellow solid essentially according to Example 85, except substituting 7-fluoro-3-oxo-3,4-dihydro-2H-1 ,4- benzothiazine-6-carbaldehyde (78 mg, 0.371 mmol) for 7-chloro-3-oxo-3,4-dihydro-2H- pyrido[3,2-b][1 ,4]oxazine-6-carbaldehyde: LCMS (+ve ion electrospray) m/z 498 (M+H)⁺; H NMR (CHCI , 400MHz) δ 8.62 (d, J=4.47Hz, 1H)₁ 8.16 (d, J=9.01 Hz, 1 H), 7.40 (d, J=4.48Hz, 1 H), 7.09 (d, J=9.05Hz, 1H), 6.98 (d, J=9.26Hz, 1 H), 6.84 (d, J=6.42Hz, 1 H), 4.54-4.41 (m, 1 H), 4.06 (s, 3H), 3.73 (s, 2H), 3.47-3.29 (m, 4H), 3.01-2.72 (m, 7H), 2.71- 2.60 (m, 1H), 2.51-2.39 (m, 1H). This material, as a solution in MeOH, was treated with excess of 2M HCI in diethyl ether and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 101

Preparation of 6-((f ((3S,4S)-4-hvdroxy-1 -(2-f6-(methyloxy)-4-quinolinvnethvn-3- PVrrolidinyl)methynamino)methyl)-2A-/-pyridof3,2-b1f1 ,41thiazin-3(4H)-one

The title compound (120 mg, 58%) was prepared as a yellow foam essentially according to Example 85, except substituting 4~ethenyl-6-(methyloxy)quino!ine (740 mg, 4 mmol) for 8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine and substituting 3-oxo-3,4-dihydro- 2H-pyrido[3,2-ύ][1 ,4]thiazine-6-carbaldehyde for 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7- carbaldehyde: LC/MS (ES) m/e 480 (M+H) ; H NMR (CD OD, 400 Hz) δ 8.54 (s, 1 H), 7.89 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1 H), 7.36-7.40 (m, 3H), 7.0 (d, J = 8.8 Hz, 1H), 4.35-4.38 (m, 1H), 3.95 (s, 3H), 3.8 (d, J = 3.2 Hz, 2H), 3.48 (s, 2H), 3.22-3.26 (m, 2H)₁ 3.13-3.17 (m, 1 H), 2.98-3.02 (m, 1 H), 2.87-2.95 (m, 3H), 2.7-2.72 (m, 1H), 2.6-2.65 (m, 1 H)₁ 2.5-2.52 (m, 1H)₁ 2.42-2.45 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound as a yellow solid.

Example 102

Preparation of 6-((f ((3S,4S)-4-hvdroxy-1 -{2-r6-(methyloxy)-4-αuinolinvnethylV3- PVrrolidinyl)methvnamino)methyl)-2H-pyrido|^'3,2-biπ ,41oxazin-3(4/-/)-one

The title compound (120 mg, 60%) was prepared as a white foam according to Example 85, except substituting 4-ethenyl-6-(methyloxy)quinoline (740 mg, 4 mmol) for 8- ethenyl-2-(methyloxy)-1 ,5-naphthyridine and 3-oxo-3,4-dihydro-2H-pyrido[3,2- £][1 ,4]oxazine-6-carbaldehyde (77 mg, 0.42 mmol) for 2,3-dihydro[1 ,4]dioxino[2,3- c]pyridine-7-carbaldehyde:^' LC/MS (ES) m/e 465 (M+H) ; H NMR (CD OD, 400 Hz) δ 8.53 (s, 1 H), 7.89 (d, J = 8.3 Hz₁ 1 H), 7.36-7.44 (m, 3H)₁ 7.24 (d, J = 8.0 Hz₁ 1 H)₁ 6.94 (d, J = 8.0 Hz₁ 1 H), 4.62 (s, 2H), 4.37-4.39 (m, 1 H), 3.95 (s, 3H), 3.77 (s, 2H), 3.22-3.24 (m, 2H)₁ 3.15-3.17 (m, 1H)₁ 2.97-3.02 (m, 1H), 2.86-2.93 (m, 3H)₁ 2.66-2.7 (m, 1 H)₁ 2.58- 2.6 (m, 1H), 2.5-2.54 (m, 1H), 2.4-2.44 (m, 1H). This material, as a solution in MeOH, was treated with an excess of 4M HCl in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 103

Preparation of (3S,4S)-4-(r(2,3-dihvdrof 1 ,41dioxinor2,3-clpyridin-7-ylmethyl)aminolmethyl)- 1-{2-r6-(methyloxy)-4-quinolinvnethyl)-3-pyrrolidinol

The title compound (96 mg, 49%) was prepared as a clear oil essentially according to Example 85, except substituting 4-ethenyl-6-(methyloxy)quinoline (740 mg, 4 mmol) for 8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine: LC/MS (ES) m/e 451 (M+H) ; H NMR (CD OD, 400 Hz) δ 8.55 (s, 1H), 8.0 (s, 1H), 7.91 (d, J = 10.0 Hz, 1H), 7.36-7.40 (m, 3H), 6.95 (s, 1H), 4.29-4.41 (m, 5H), 3.97 (s, 3H), 3.76 (d, J = 4.6 Hz, 2H), 3.16-3.28 (m, 3H), 2.98-3.01 (m, 1 H), 2.85-2.89 (m, 3H), 2.67-2.7 (m, 1H), 2.6-2.63 (m, 1H), 2.5-2.54 (m, 1H), 2.42-2.47 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 104

Preparation of /V-r((3R4S)-1-f2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vπethyl)-4- hvdroxy-S-pyrrolidinvDmethvn-S-oxo-SΛ-dihvdro-ΣH-I Λ-benzothiazine-e-sulfonamide

To a solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (225 mg, 0.703 mmol) in DIPEA (188 μl_, 1.05 mmol) and DCM (7 ml_) at 0⁰C was added 3-oxo-3,4-dihydro-2A7-1 ,4-benzothiazine-6-sulfonyl chloride (210 mg, 0.845 mmol) in one portion. The solution stirred for 0.5h and was concentrated. The resulting residue was purified by column chromatography (silica, 2-4% MeOH in DCM (1% NH OH)) yielding the title compound (290 mg, 75%) as a white foam: LC/MS (ES) m/e 548 (M+H) ; H NMR (CD OD, 400 Hz) δ 8.65 (s, 1 H), 8.22 (d, J = 9.1 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1 H), 7.45-7.48 (m, 2H), 7.20 (d, J = 9.1 Hz, 1 H), 4.28-4.31 (m, 1H), 4.14 (S₁ 3H), 3.55 (s, 2H), 3.42-3.46 (m, 2H), 3.21-3.23 (m, 1H), 3.05-3.15 (m, 1 H), 2.91-3.05 (m, 2H), 2.86-2.90 (m, 2H), 2.51-2.62 (m, 2H), 2.33-2.4 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound.

Example 105

Preparation of Λ/-r((3S,4S)-1-(2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vπethylV-4- hydroxy-3-pyrrolidinyl)methvπ-3-oxo-3₁4-dihvdro-2rt-pyridor3,2-άiri,4^'loxazine-6- carboxamide

To a solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinol (230 mg, 0.719 mmol) in DCM-DMF (6:1 , 7 ml_) at 25⁰C were added 3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][1 ,4]oxazine-6-carboxylic acid (140 mg, 0.719 mmol), EDC (134 mg, 0.836 mmol) and HOBT (117 mg, 0.863 mmol). After 12h, the solution was concentrated and purified by column chromatography (silica, 2-3% MeOH in DCM (1% NH OH)) yielding the title compound (130 mg, 36%) as a yellow foam: LC/MS (ES) m/e 497 (M+H) ; H NMR (CD OD, 400 Hz) δ 8.4 (s, 1H), 7.95 (d, J = 9.1 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1 H), 4.63 (AB quart., 2H), 4.20-4.24 (m, 1 H), 3.9 (s, 3H), 3.55-3.59 (m, 1H), 3.40-3.43 (m, 1 H), 3.23-3.28 (m, 2H), 3.16-3.19 (m, 1 H), 2.91-2.94 (m, 1 H), 2.7-2.82 (m, 2H), 2.49-2.52 (m, 2H), 2.37-2.42 (m, 1 H). This material, as a solution in MeOH, was treated with an excess of 4M HCI in dioxane and evaporated to dryness to provide the dihydrochloride salt of the title compound. Example 106

Preparation of (±)-6-f(ff(3R,4RV(3S.4SV1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- vnethyl)-4-(rivdroxynπethvπ-3-pyrrolidinvnmethyl>amino)methvn-2H-pyridor3,2- 6in .4Tthiazin-3(4H)-one (8)

a) N-Benzyl-N-cyanomethyl-N-trimethylsilylmethylamine

To trimethylsilylbenzyl amine (Aldrich;10g, 52 mmol) at room temperature was added HCI (1 N, 51.6 mL) which caused formation of white precipitate. To the mixture were added THF (28 mL), KCN (4.2g, 64mmol) and formaldehyde (4.96 mL, 55 mmol, 37% solution in water). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with ether, washed with H O, NaCI, dried over Na SO4 and concentrated under reduce pressure to give desired product as liquid (12.7g, 100%). LC/MS 233 (M+H) .

b) (±)-Ethyl (3S,4R)/(3R,4S)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylate

To a solution of N-benzyl-N-cyanomethyl-N-trimethylsilylmethylamine (11.7g, 50 mmol) in CH CN (160 mL) was added ethyl-cis-beta-cyanoacrylate (Aldrich, 6.62g, 53 mmol) followed by AgF (6.7g, 53 mmol). The resulting mixture was stirred overnight at room temperature in the dark. The resulting mixture was diluted with CH Cl and filtered through the pad of celite. Chromatography on silica gel eluting with 80:20 CHCI -EtOAc gave desired product as oil (6.9g, 54%). LC/MS 259 (M+H) .

c) (+)-[(3S,4S)/(3R,4R)-4-(aminomethyl)-1-(phenylmethyl)-3-pyrrolidinyl]methanol

To a cooled solution of ethyl (3RS,4f?S)-4-cyano-1-(phenylmethyl)-3- pyrrolidinecarboxylate (4g, 15 mmol) in THF (80 mL) was added LiAIH (31 mL, 31 mmol, 1N solution in THF). The resulting mixture was stirred at O⁰C for 2hour. The reaction mixture was quenched with 2mL H O, 2.4mL of NaOH (40%) followed by 5.4mL of H 0. The resulting gel cake was filtered through the pad of celite. Organic layer concentrated under reduce pressure to give desired product as oil (3.26g, 95%). LC/MS 221 (M+H) .

d) (±)-1 , 1 -dimethylethyl [(3S,4S)/(3R/4R)-4-[({[(1 , 1 - dimethylethyl)oxy]carbonyl}amino)methyl]-1-(phenylmethyl)-3-pyrrolidinyl]methyl carbonate

To a solution of [(3RS,4RS)-4-(aminomethyl)-1-(phenylmethyl)-3- pyrrolidinyl]methanol (3.26g, 14.8 mmol) in CH Cl (50 mL) was added Boc-anydride (7.1g, 32 mmol) followed by Triethylamine (10.3mL, 75 mmol). The resulting mixture was stirred at room temperature for 24 hours. The resulting mixture was diluted with CH Cl , washed with H O, brine, dried over MgSO . Chromatography on silica gel eluting with 5:20 EtOAc-hexane gave desired product as oil (2.8g, 45%). LC/MS 421 (M+H) . e) (±)-1 ,1 -dimethylθthyl [(3S,4R)/(3R,4S)-4-[({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)methyl]-3-pyrrolidinyl}methyl carbonate

To a solution of 1 ,1-dimethylethyl [(3RS.4RS)- 4-[({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)methyl]-1-(phenylmethyl)-3-pyrrolidinyl]methyl carbonate (1.85g, 4.4 mmol) in MeOH (50 ml_) was added 10% Pd over carbon (1.5g). The resulting mixture was shaken in the Parr Shaker at 50psi of H at room temperature for 24 hours. The resulting mixture was diluted with MeOH and filtered through the pad of celite. The organic layer was concentrated under reduce pressure to give desired product as an oil (1.2 g, 82%). LC/MS 330 (M+H) .

f) (+)-1 ,1-dimethylethyl ((3f?,4R)/(3S,4S)-4-[({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)methyl]-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl carbonate

To a solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (0.74g, 3.6 mmol) in DMF (2 ml_) was added 1 ,1-dimethylethyl [(3f?S,4RS)-4-[({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)methyl]-3-pyrrolidinyl}methyl carbonate (1.2g, 3.6mmol). After 24h at 100 ⁰C, the reaction contents were concentrated under vacuum and purified on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) to give the title

compound (1.43 g, 73%) as yellow oil: LC-MS (ES) m/e 535 (M + H)⁺.

g) (±)-((3f?,4R)/(3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methanol

To a stirred solution of 1 ,1-dimethylβthyl ((3/?S,4/?S)-4-[({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)methyl]-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl carbonate (1.32 g, 2.4 mmol) in DCM (10 mL) was added 4M HCI (2.5mL, 4M in dioxane). After 3 h at RT, the suspension was concentrated under vacuum and afforded the title compound (0.8g, 100 %) as light yellow solid: LC-MS (ES) m/e 335 (M + H)⁺.

h) (±)-6-[({[(3R4R)/(3S,4S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- (hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4/-/)- one

To a solution of ((3/?S,4f?S)-4-(aminomethyl)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methanol (0.12 g, 0.27 mmole) in dry CH2CI2 (3 mL) and dry MeOH (3 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-/)][1 ,4]thiazine-6~ carbaldehyde (60 mg, 0.27 mmole) followed by NaHCO3 (02 g, 2.7 mmol). After 24h, at RT was added NaBH4 (79 mg, 2.08 mmole). After 2h, silica gel (5g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHC^/MeOH, 9:1 containing 5% NH4OH) afforded the title

compound (0.04 g, 28%) as light yellow solid: LC-MS (ES) m/e 513 (M + H)⁺. ¹H NMR (400 MHz, CDCI ) δ ppm 2.10 - 2.20 (2 H, m) 2.49 - 2.60 (1 H, m) 2.61 - 2.71 (1 H, m) 2.71 - 2.91 (3 H, m) 3.02 - 3.13 (2 H, m) 3.37 (2 H, t, J=7.33 Hz) 3.42 - 3.53 (4 H, m) 3.69 (1 H, dd, J=11.75, 9.47 Hz) 3.74 - 3.86 (2 H₁ m) 3.97 (1 H, s) 4.07 (3 H, s) 6.90 (1 H, d, J=7.83 Hz) 7.06 (1 H, d, J=9.09 Hz) 7.57 (1 H, d, J=7.83 Hz) 8.17 (1 H, d, J=9.09 Hz) 8.60 (1 H, s). Example 107

Preparation of (±V6-r({r(3R.4RV(3S,4SV142-f3-fluoro-6-(methyloxyV1 ,5-naphthyridin-4- vnethyl)-4-(hvdroxymethyl)-3-pyrrolidinvnmetriyl>amino)methvn-2H-pyridof3,2- tflM ,41thiazin-3(4H)-one

Prepared essentially according to the procedure for Example 106, except substituting 3-oxo-3,4-dihydro-2H-pyrido[3,2-ύ][1 ,4]oxazine-6-carbaldehyde for 3-oxo-3,4- dihydro-2W-pyrido[3,2-£][1 ,4]thia2ine-6-carbaldehyde, the title compound (300 mg, 23%) was prepared as a light yellow solid: LC-MS (ES) m/e 497 (M + H)⁺. 1 H NMR (400 MHz, CDCI ) δ ppm 2.10 - 2.20 (2 H, m) 2.49 - 2.60 (1 H, m) 2.61 - 2.71 (1 H, m) 2.71 - 2.91 (3 H, m) 3.02 - 3.13 (2 H, m) 3.37 (2 H, t, J=7.33 Hz) 3.42 - 3.53 (4 H, m) 3.69 (1 H, dd, J=11.75, 9.47 Hz) 4.9 (2 H, m) 3.97 (1 H, s) 4.07 (3 H, s) 6.90 (1 H, d, J=7.83 Hz) 7.06 (1 H, d, J=9.09 Hz) 7.57 (1 H, d, J=7.83 Hz) 8.17 (1 H, d, J=9.09 Hz) 8.60 (1 H, s). Enantiomers were separated on chiral prep HPLC ( chiralpak AS-H) of 210 mg racemate to give E1 (85 mg ; E1 retention time 3.78 min > 98 % ee), E2 (85 mg ; E2 retention time 4.39 min > 98.4 % ee),

Example 108

Preparation of (+)-((3R.4R)/f3S.4S)-4-fr(2,3-dihvdrof1 ,41dioxinor2.3-c1pyridin-7- ylmethyl)amino1methyl>-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl)-3- pyrrolidinvDmethanol

Prepared essentially according to the procedure of Example 106, except substituting 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (126 mg, 0.76 mmole) for 3-0X0-3, 4-dihydro-2/-/-pyrido[3,2-6][1 ,4]thiazine-6-carbaldehyde, the title compound (100 mg, 27%) was prepared as a light yellow solid: LC-MS (ES) m/e 484 (M + H)⁺. H NMR (400 MHz, CDCI ) δ ppm 2.00 - 2.14 (1 H, m) 2.55 (1 H, d, J=6.82 Hz) 2.61 - 2.88 (4 H, m) 3.01 - 3.18 (1 H, m) 3.37 (1 H, t, J=7.83 Hz) 3.47 (1 H, dd, J=11.75, 3.16 Hz) 3.62 - 3.84 (3 H, m) 4.07 (3 H, s) 4.21 - 4.42 (6 H, m) 6.75 (1 H, s) 7.06 (1 H, d, J=9.09 Hz) 7.25 - 7.33 (1 H₁ m) 8.13 - 8.23 (1 H, m) 8.60 (1 H, s).

Example 109

Preparation of 6-f((f(3R4Z)-1-(2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl}-4- (hvdroxyimino)-3-pyrrolidinyl1rnethyl>arnino)rnethyll-2/-/-pyridor3,2-άiri ,41thiazin-3(4/-/)-one

a) 1 ,1-dimethylethyl (4f?)-3-oxo-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1- pyrrolidinecarboxylate

Dissolve 1 , 1 -dimethylethyl (3R,4R)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl} amino)methyl]-1-pyrrolidinecarboxylate (1.0g, 2.85 mmol) in methylene chloride (20 mL). Add PCC (1.23g, 5.7 mmol) and Florisil (2.5g) and stir at ambient temperature for 16 hours. Add 3 more equivalents of PCC (1.84g, 8.55 mmol) and stir for 48 hours. Dilute solution with ether and filter through a pad of celite. The solvent was removed under reduced pressure yielding a crude oil. The crude mixture was purified on silica gel. (0.598 g, 60%). LCMS: m/z 349.4 (MH+).

b) 1 ,1-dimethylethyl (3Z,4/?)-3-(hydroxyimino)-4- [({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate

f Dissolve 1 ,1-dimethylethyl (4R)-3-oxo-4-[({[(phenylmethyl)oxy]carbonyl}amino )methyl]-1-pyrrolidinecarboxylate (0.87g, 2.49 mmol) in 5:1 MeOH/H O (10 ml_). Add in hydroxylamine HCI (0.177g, 2.54 mmol) and sodium acetate (2.04g, 24.9 mmol). The mixture was heated to reflux and allowed to stir 3 hours. After the reaction was complete the solution was concentrated under reduced pressure and extracted with CHCI3 (3X). The organic layer was washed with 0.5 M HCI and brine. The solution was dried over Na₂SO₄₁ and evaporated to yield an oil. (0.9Og, quant). LCMS: m/z 364.6 (MH+).

c) Phenylmethyl {[(3S,42)-4-(hydroxyimino)-3-pyrrolidinyl] methyl}carbamate HCI salt

Dissolve 1 , 1 -dimethylethyl (3Z,4f?)-3-(hydroxyimino)-4-[({[(phenylmethyl)oxy] carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.9Og, 2.53 mmol) in methylene chloride (10 mL). Add HCI/dioxane (excess) and stir at ambient temperature for 3 hours. Concentrate solution under reduced pressure. (0.66g, quant). LCMS: m/z 254.4 (MH+).

d) Phenylmethyl {[(3f?,4Z)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- (hydroxyimino)-3-pyrrolidinyl]methyl}carbamate

To 3-Fluoro-6-methoxy-4-vinyl-quinoline (0.554g, 2.72 mmol) was added DMF (2.0 mL). Phenylmethyl {[(3S,42)-4-(hydroxyimino)-3-pyrrolidinyl] methyljcarbamate (0.66 g, 2.21 mmol) and TEA (0.76 mL, 5.44 mmol) were added to the mixture and the reaction was heated and stirred at 90 degrees C for 18 hours. The solution was concentrated under reduced pressure and was chromatographed on silica gel to yield an oil (0.180 g, 18%). LCMS: m/z 468.4 (MH+). e) (az^/^^CaminomethyO-i^-p-fluoro-^β-CmethyloxyJ-i .δ-naphthyridin-Φ-yllethylJ-S- pyrrolidinone oxime

Phenylmethyl {[(3R,4Z)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- (hydroxyimino)-3-pyrrolidinyl]methyl}carbamate (0.18Og, 0.39 mmol) was dissolved in 1 :1 (MeOH/THF) (10 mL). Catalytic 10% Palladium on carbon was added and the solution subjected to H at 55 PSI on a Parr shaker for 6 hours. The. solution was filtered through a pad of celite and concentrated under reduced pressure. (0.174g, quant.) LCMS: m/z 334.4 (MH+).

f) 6-[({[(3/?,42)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-(hydroxyimino)- 3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4/-/)-one

(3Z,4R)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 3-pyrrolidinone oxime (0.087 g, 0.261 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/Me0H (10 mL). 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazine-6-carbaldehyde (0.048 g, 0.261 mmol) was added followed by NaHCO₃ (0.109 g, 1.30 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.010 g, 0.261 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO₄ and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.047 g, 35%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.042 g). LCMS: m/z 512.4 (MH+). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.52 (1 H, s) 2.82 (1 H, s) 2.85 (2 H, d, J=6.82 Hz) 3.00 (2 H, s) 3.07 - 3.19 (2 H, m) 3.34 - 3.46 (6 H, m) 3.72 - 3.83 (2 H, m) 3.83 - 3.93 (1 H, m) 4.03 - 4.10 (3 H, m) 6.86 (1 H, d, J=7.83 Hz) 6.99 - 7.08 (1 H, m) 7.49 (1 H, d, J=7.83 Hz) 8.11 - 8.20 (1 H, m) 8.54 - 8.63 (1 H, m).

Example 110

Preparation of 6-IYir(3R4Z)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin -4-yllethyl}-4- (hvdroxyimino)-3-pyrrolidinvπmethyl>arnino)methvπ-2f/-pyridof3,2-/3iri₁41oxazin-3(4H)-one

(3Z,4/?)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 3-pyrrolidinone oxime (0.098 g, 0.294 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/MeOH (10 mL). 3-oxo-3,4-dihydro-2H-pyrido[3,2-jfc>][1 ,4]oxazine-6-carbaldehyde (0.052 g, 0.294 mmol) was added followed by NaHCO₃ (0.123 g, 1.47 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.011 g, 0.294 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO_4i and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.110 g, 75%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.12 g). LCMS: m/z 496.4 (MH+). H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (1 H, t, J=8.21 Hz) 2.79 - 2.91 (3 H, m) 2.94 - 3.05 (1 H, m) 3.05 - 3.13 (1 H, m) 3.19 (1 H, t, J=7.96 Hz) 3.33 - 3.44 (3 H, m) 3.71 (1 H, d, J=13.89 Hz) 3.86 (2 H, d, J=13.39 Hz) 4.02 - 4.13 (3 H, s) 4.52 - 4.63 (2 H, s) 6.80 (1 H, d, J=8.08 Hz) 7.00 (1 H, d) 7.10 (1 H, d, J=7.83 Hz) 8.12 (1 H, d, J=9.09 Hz) 8.56 - 8.64 (1 H, s). Example 111

Preparation of (3Z,4K)-4-fr(2,3-dihydro[1₁41dioxinor2,3-c1pyridin-7-ylmethyl)amino1methyl)- H2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl1ethyl}-3-pyrrolidinone oxime

(3Z,4R)-4-(aminornethyl)-1-{2-[3-fluoro-6-(rnethyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 3-pyrrolidinone oxime (0.087 g, 0.261 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/MeOH (10 ml_). 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.043 g, 0.261 mmol) was added followed by NaHCC>3 (0.109 g, 1.30 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.011 g, 0.294 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO_4i and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.083 g, 66%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.085g). LCMS: m/z 483.4 (MH+). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.50 - 2.58 (1 H, m) 2.76 - 2.81 (1 H, m) 2.82 - 2.94 (3 H, m) 3.01 - 3.09 (1 H, m) 3.12 (1 H, m) 3.34 - 3.45 (3 H, m) 3.73 (1 H, m) 3.77 - 3.86 (2 H, m) 4.05 - 4.15 (3 H, m) 4.20 - 4.30 (2 H, m) 4.32 (2 H, dd, J=5.68, 2.40 Hz) 6.81 - 6.90 (1 H, m) 7.07 (1 H, d, J=9.09 Hz) 8.04 - 8.12 (1 H, m) 8.18 (1 H, d, J=8.84 Hz) 8.61 (1 H, s).

Example 112

Preparation of (±)-(3S,4SV(3R,4R)-1-f2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- vnethv[)-4-({f(3-oxo-3,4-dihvdro-2H-pyridor3,2-/)iri .41thiazin-6-vnmethvnamino^'ymethvn-3- pyrrolidinecarboxamide

a) ^l-(3S,4R)/(3R,4S)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid

Dissolve ethyl (3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylate (2.Og, 7.72 mmol) in 4:1 methanol/water (50 ml_). The solution was cooled to 0 degrees C and potassium hydroxide (0.867g, 15.4 m,mol) was added. The reaction was allowed to stir at 0 degrees C for 1 hour. 1 N HCI was added with cooling and the solution brought to pH = 7. The solvent was removed under reduced pressure yielding a crude solid (3.244g) which was taken on to the next step. LCMS: m/z 231.4 (MH+).

b) i±l-(3S,4R)/(3R,4S)-4-cyano-1 -(phenylmethyl)-3-pyrrolidinecarboxamide

Crude (3S,4/?)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid (3.24g) was dissolved in THF (50 mL). N-methyl morpholine (0.93mL, 8.49mmol) was added and the solution allowed to stir overnight. A bit of solid remains undissolved. The solution was cooled to -15 degrees C in an ethylene glycol/dry ice bath, lsobutyl chloroformate (1.1 mL, 8.49 mL) was added and the reaction sirred at -15 degrees C for 1 hour. Ammonia was then bubbled through the solution for 20 minutes. The solution was allowed to warm to ambient temperature and the solvent removed under reduced pressure. The crude material was chromatographed on silica gel to yield a solid (1.56 g, 88% over 2 steps). LCMS: m/z 230.4 (MH+).

c) (+)-(3S,4S)/(3R,4R)-4-(aminomethyl)-1-(phenylmethyl)-3- pyrrolidinecarboxamide

Dissolve (3S,4R)-4-cyano-1-(phenylmethyl)-3-pyrrolidinecarboxamide (1.50g, 6.55 mmol) in methanol (10 mL). Add NiCI 6H O (3.11 g, 13.1 mmol) followed by NaBH (0.99g, 26.2 mmol) portionwise. The reaction was stirred for 2 hours, but it was not complete. Additional NaBH (0.5g) was added and the reaction stirred another 1 hour. The solution was filtered through a plug of celite and washed with methanol. The solvent was evaporated under reduced pressure yielding a crude oil (1.51g). LCMS: m/z 234.4 (MH+).

d) (+)-1 , 1 -dimethylethyl {[(3S,4S)/(3R,4R)-4-(aminocarbonyl)-1 -(phenylmethyl)-3- pyrrolidinyl]methyl}carbamate

Crude (3S,4S)-4-(aminomethyl)-1 -(phenylmethyl)-3- pyrrolidinecarboxamide (1.51g, 6.55 mmol) was dissolved in CH Cl (20 mL). Triethylamine (1.OmL, 7.21 mmol) was added followed by di-t-butyl dicarbonate(1.57g, 7.21 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was diluted with water and extracted 2 times with methylene chloride, washed with brine, dried over Na₂SO₄ and evaporated. This was chromatographed on silica gel to yield an off-white solid (0.49 g, 22%). LCMS: m/z 334.4 (MH+).

e) (±)-1 ,1 -dimethylethyl {[(3fi,4S)/(3S,4R)-4-(aminocarbonyl)-3- pyrrolidinyl]methyl}carbamate

1 ,1 -dimethylethyl {[(3S,4S)-4-(aminocarbonyl)-1-(phenylmethyl)-3- pyrrolidinyl]methyl}carbamate (0.49g, 1.47 mmol) was dissolved in methanol (5.0 mL). Catalytic 20% palladium hydroxide was added and the solution subjected to H using a balloon. The reaction was allowed to stir 4 hours and then filtered through a plug of celite. The solution was concentrated under reduced pressure yielding an oil (0.34 g, 100%). LCMS: m/z 244.4 (MH+). f) (±)-1 ,1-dimethylethyl [((3S,4S)/(3R,4R)-4-(aminocarbonyl)-1-{2-[3-fluoro-6-(methyloxy)- 1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate

To 1 ,1-dimethylethyl {[(S^SM-føminocarbonylJ-S-pyrrolidinylJmethylJcarbarnate (0.34g, 1.47 mmol) was added DMF (2.0 mL). 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5- naphthyridine (0.31 g, 1.52 mmol) was added to the mixture and the reaction was heated and stirred at 90 degrees C for 18 hours. The solution was concentrated under reduced pressure and was chromatographed on silica gel to yield an oil (0.512 g, 78%). LCMS: m/z 448.4 (MH+).

g) (+)-(3S,4S)/(3R,4R)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinecarboxamide

1 ,1-dimethylethyl [((3S,4S)-4-(aminocarbonyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.51g, 1.14 mmol) was dissolved in methylene chloride (5 mL). HCI in dioxane (2.87 mL, 11.14 mmol) was added and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. (0.534g, quant.) LCMS: m/z 348.4 (MH+).

h) (+)- (3S,4S)/(3R,4R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-({[(3- oxo-3,4-dihydro-2/-/-pyrido[3,2-ϋ][1 ,4]thiazin-6-yl)methyl]amino}methyl)-3- pyrrolidinecarboxamide

(±)-(3S₎4S)/(3R,4R)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinecarboxamide (0.085 g, 0.246 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/MeOH (10 mL). 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine- 6-carbaldehyde (0.045 g, 0.246 mmol) was added followed by NaHCO₃ (0.103 g, 1.23 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.009 g, 0.246 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO_4] and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.106 g, 82%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.113 g). LCMS: m/z 526.6 (MH+). 1 H NMR (400 MHz, CDCI3) δ ppm 2.34 (1 H, dd, J=8.97, 6.19 Hz) 2.51 (1 H₁ d, J=4.04 Hz) 2.64 - 2.85 (5 H, m) 2.85 - 2.95 (2 H, m) 2.99 (1 H, t, J=8.59 Hz) 3.07 - 3.17 (1 H, m) 3.39 (2 H, t, J=7.45 Hz) 3.47 (3 H, d, ./=1.01 Hz) 3.81 (2 H, q, J=14.15 Hz) 4.07 (3 H, s) 6.19 (1 H, d, J=2.02 Hz) 6.91 (1 H, d, J=7.83 Hz) 7.06 (1 H, d, J=9.09 Hz) 7.55 (1 H, d, J=7.83 Hz) 7.63 (1 H, d, J=2.53 Hz) 8.17 (1 H, d, J=8.84 Hz) 8.60 (1 H, s).

Example 113

Preparation of (+H3S.4Sy(3R.4R)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- vnethyl)-4-((f(3-oxo-3,4-dihvdro-2H-pyridor3,2-ibiri .41oxazin-6-yl)methvnamino)methyl)-3- pyrrolidinecarboxamide

(±)-(3S,4S)/(3R,4R)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinecarboxamide (0.085 g, 0.246 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/Me0H (10 mL). 3-oxo-3,4-dihydro-2H-pyrido[3,2-t>][1 ,4]oxazine- 6-carbaldehyde (0.044 g, 0.246 mmol) was added followed by NaHCO₃ (0.103 g, 1.23 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.009 g, 0.246 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reation mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO_4i and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.115 g, 92%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.12 g). LCMS: m/z 510.6 (MH+). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.34 (1 H, dd, J=9.09, 6.06 Hz) 2.45 - 2.59 (1 H, m) 2.63 - 2.73 (1 H, m) 2.73 - 2.83 (4 H, m) 2.89 - 2.94 (1 H, m) 2.99 (1 H, t, J=8.59 Hz) 3.08 - 3.23 (1 H, m) 3.39 (2 H, t, J=7.45 Hz) 3.78 (2 H, dd) 4.06 (13 H, s) 4.60 (2 H, s) 6.45 (1 H, d, J=1.77 Hz) 6.85 (1 H, d, J=8.08 Hz) 7.05 (1 H, d, J=8.84 Hz) 7.15 (1 H, d, J=8.08 Hz) 7.78 (1 H, d, J=2.27 Hz) 8.16 (1 H, d, J=9.09 Hz) 8.59 (1 H, s)

Example 114

Preparation of (±)-(3S.4SV(3R.4R)-4-(r(2,3-dihvdrof1 ■41dioxinor2,3-clpyridin-7- ylmethyl)amino1methyl>-1-(2-f3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-vnethyl>-3- pyrrolidinecarboxamide

(±)-(3S,4S)/(3R,4R)-4-(aminomethyl)~1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinecarboxamide (0.146 g, 0.380 mmol) was dissolved in a 1:1 mixture of CH₂CI₂/Me0H (10 mL). 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7- carbaldehyde (0.380 g, 0.380 mmol) was added followed by NaHCO₃ (0.160 g, 1.90 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.029 g, 0.760 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO_4] and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.130 g, 69%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.141g). LCMS: m/z 497.6 (MH+). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (1 H, dd, J=8.97, 5.94 Hz) 2.44 (1 H, dd, J=7.96, 4.42 Hz) 2.57 - 2.67 (3 H, m) 2.71 - 2.82 (3 H, m) 2.84 (2 H₁ d) 2.92 - 2.97 (1 H, m) 3.11 (1 H, dd, J=8.72, 4.93 Hz) 3.40 (2 H, t, J=7.33 Hz) 3.71 - 3.82 (2 H, m) 4.08 (3 H, s) 4.26 - 4.35 (14 H, m) 5.35 (1 H, d, J=2.78 Hz) 6.75 (1 H, s) 7.06 (1 H, d, J=9.09 Hz) 7.70 (1 H, d, J=2.78 Hz) 8.09 (1 H, s) 8.16 (1 H, d, J=9.09 Hz) 8.60 (1 H, s).

Example 115

Preparation of 4-(2-r(3S,4S)-3-hvdroxy-4-((r(3-oxo-3,4-dihvdro-2/-/-pyridof3,2- ib1f1 ,41thiazin-6-yl)methyllamino>methyl)-1-pyrrolidinvnethyl|-6-(methyloxy)-1 ,5- naphthyridine-3-carbonitrile

a) 1 , 1 -dimethylethyl (3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinecarboxylate

Dissolve 1 , 1 -dimethylethyl (3S,4S)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl} amino)methyl]-1-pyrrolidinecarboxylate (0.75g, 2.14 mmol) in methanol (10 mL). Add 20% PdOH (catalytic) and subject to H at 55 PSI on a Parr hydrogenation apparatus. The solution was filtered through a plug of celite and concentrated under reduced pressure to yield an oil. (0.712g, quantitative) LCMS: m/z 133.2 (MH+).

b) (1 ,1 -dimethylethyl (3S,4S)-3-hydroxy-4~{[(trifluoroacetyl)amino]methyl}-1- pyrrolidinecarboxylate

1 , 1 -dimethylethyl (3S,4S)-3-(aminomethyl)-4-hydroxy-1 -pyrrolidinecarboxylate (0.238g, 1.10 mmol) was dissolved in methylene chloride (10 ml_). Triethylamine (0.322mL, 2.31 mmol), trifluoroacetic anhydride (0.163mL, 1.16 mmol), and DMAP (0.013g, 0.11 mmol) were added and the reaction stirred at ambient temperature for 5 hours. The reaction was quenched with water and extracted 3X with methylene chloride. The solution was dried over Na₂SO₄ and evaporated. This was chromatographed on silica gel to yield a white solid (0.193 g, 56%). LCMS: m/z 313.4 (MH+).

c) 2,2,2-trifluoro-Λ/-{[(3/?,4S)-4-hydroxy-3-pyrrolidinyl]methyl}acetamide

(1 ,1 -dimethylethyl (3S,4S)-3-hydroxy-4-{[(trifluoroacetyl)amino]methyl}-1- pyrrolidinecarboxylate (0.192g, 0.615 mmol) was dissolved in methylene chloride (5 ml_). HCI in dioxane (1.0 ml_, 4.0 mmol) was added and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. (0.137g, quant.) LCMS: m/z 213.2 (MH+).

d) tø-[((3S,4S)-1-{2-[3-cyano-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]-2,2,2-trifluoroacetamide

To 2,2,2-trifluoro-Λ/-{[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}acetamide HCI (0.137g, 0.552 mmol) was added EtOH (2.0 mL). 4-ethenyl-6-(methyloxy)-1 ,5~ naphthyridine-3-carbonitrile (0.117 g, 0.552 mmol) was added to the mixture along with TEA (0.231 mL, 1.66 mmol) and the reaction was heated and stirred at 95 degrees C for 18 hours, allowing the ethanol to evaporate. The solution was concentrated under reduced pressure and was chromatographed on silica gel to yield an oil (0.110 g, 47%). LCMS: m/z 424.4 (MH+).

e) 4-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1 -pyrrolidinyl]ethyl}-6-(methyloxy)-1 ,5- naphthyridine-3-carbonitrile

Λ/-[((3S,4S)-1-{2-[3-cyano-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-4-hydroxy-3- pyrrolidinyl)methyl]-2,2,2-trifluoroacetamide (0.110g, 0.26 mmol) was dissolved in methanol (5 mL). 10% aqueous K CO was added to the original solution and it was stirred at ambient temperature for 2 hours. The solution was extracted 3X with chloroform and washed with brine. The solvent was removed under reduced pressure. (0.076g, 89%) LCMS: m/z 328.6 (MH+).

f) 4-{2-[(3S,4S)-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-jb][1 ,4]thiazin-6- yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-6-(methyloxy)-1 ,5-naphthyridine-3- carbonitrile

4-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-6-(methyloxy)-1,5- naphthyridine-3-carbonitrile (0.070 g, 0.214 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/MeOH (10 mL). 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]thiazine-6-carbaldehyde (0.039 g, 0.214 mmol) was added followed by NaHCO₃ (0.090 g, 1.07 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.024 g, 0.642 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO₄₎ and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.015 g, 14%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.019 g). LCMS: m/z 506.4 (MH+). 1H NMR (400 MHz, CDCI3) δ ppm 2.42 (1 H, d, J=5.05 Hz) 2.64 (1 H, dd, J=9.22, 6.44 Hz) 2.76 - 2.88 (4 H, m) 2.90 - 2.99 (3 H, m) 3.40 - 3.51 (3 H, m) 3.54 - 3.65 (2 H, m) 3.74 - 3.84 (2 H, m) 3.87 - 3.91 (1 H, m) 4.04 - 4.14 (4 H, m) 4.45 (1 H, td, J=6.44, 3.28 Hz) 6.88 (1 H, d, J=7.83 Hz) 7.22 (1 H, d, J=9.09 Hz) 7.52 - 7.61 (1 H, m) 8.22 (1 H, d, J=9.09 Hz) 8.79 - 8.86 (1 H, m).

Example 116

Preparation of 4-(2-r(3S,4S)-3-hvdroxy-4-({r(3-oxo-3,4-dihvdro-2/-/-pyridor3, 2- /?iriΛ1oxazin-6-vπmethvπamino)methyl)-1-pyrrolidinvπetriyl)-6-(methyloxy)-1.5- naphthyridine-3-carbonitrile

4-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-6-(methyloxy)-1 ,5- naphthyridine-3-carbonitrile (0.070 g, 0.214 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/Me0H (10 ml_). 3-oxo-3,4-dihydro-2W-pyrido[3,2-jb][1 ,4]oxazine-6-carbaldehyde (0.038 g, 0.214 mmol) was added followed by NaHCO₃ (0.090 g, 1.07 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.024 g, 0.642 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reation mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO₄₁ and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.037 g, 35%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.041 g). LCMS: m/z 490.4 (MH+). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38 (1 H, t, J=7.33 Hz) 2.59 - 2.69 (1 H, m) 2.77 (1 H, s) 2.80 - 2.88 (1 H, m) 2.95 (3 H, t, J=7.58 Hz) 3.00 - 3.14 (2 H, m) 3.48 (2 H, s) 3.53 - 3.62 (2 H, m) 3.85 - 3.95 (1 H, m) 4.09 (3 H, s) 4.51 - 4.59 (3 H, m) 6.89 (1 H, d, J=8.08 Hz) 7.18 (1 H₁ d, J=7.83 Hz) 7.21 (1 H, d, J=9.09 Hz) 7.27 (1 H, s) 8.19 (1 H, d, J=9.09 Hz) 8.78 (1 H, s).

Example 117

Preparation of 4-f2-((3S.4SV3-f IY2,3-dihvdroπ ,41dioxinor2,3-clpyridin-7- ylmethyl)aminolmethyl)-4-rivdroxy-1-pyrrolidinyl)ethyl1-6-(rnethyloxy)-1,5-naphthyridine-3- carbonitrile

4-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-6-(methyloxy)-1,5- naphthyridine-3-carbonitrile (0.070 g, 0.214 mmol) was dissolved in a 1 :1 mixture of CH₂CI₂/MeOH (10 ml_). 2,3-dihydro[1 ,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.035 g, 0.214 mmol) was added followed by NaHCO₃ (0.090 g, 1.04 mmol). The solution was allowed to stir at ambient temperature for 17 hours. It was then cooled to 0 degrees C, excess sodium borohydride was added (0.024 g, 0.642 mmol) and it was allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into a saturated solution of NaHCO₃ and extracted with CHCI₃. (3X). The organic layer was washed with water (2X) and brine, dried over Na₂SO₄ and evaporated to yield a yellow oil. This was chromatographed on silica gel (90:10:1 CHCI₃/MeOH/NH₄OH) to yield an off-white solid (0.033 g, 32%). The di-HCI salt was then prepared by dissolving the product in chloroform and adding 2 equivalents of HCI/ether. The solution was stirred for 15 minutes and the solvent removed under reduced pressure yielding an off white solid (0.035g). LCMS: m/z 497.6 (MH+). ¹H NMR (400 MHz, CHLOROFORM-c/) δ ppm 2.33 - 2.46 (1 H, m) 2.55 (1 H, dd, J=9.09, 7.07 Hz) 2.71 (1 H, dd, J=9.85, 3.54 Hz) 2.80 - 2.87 (3 H, m) 2.90 (2 H₁ td, J=7.64, 4.42 Hz) 3.04 (1 H, dd, J=9.98, 5.94 Hz) 3.60 (2 H₁ 1, J=7.71 Hz) 3.76 (2 H, d, J=6.06 Hz) 4.08 - 4.16 (3 H, m) 4.25 - 4.35 (5 H, m) 4.47 (1 H₁ td, J=6.44, 3.79 Hz) 6.73 (1 H, s) 7.22 (1 H, d, J=9.09 Hz) 8.10 (1 H, s) 8.20 (1 H, d, J=9.09 Hz) 8.82 (1 H₁ s). Example 118

Preparation of (+)-6-fr((3S.4R)/(3R.4S)-4-hvdroxy-1-f2-r6-(methyloxy)-1 ,5-naphthyridin-4- vnethyl)-3-pyrrolidinyl')aminolmethyl>-2/-/-pyridor3,2-ib1f1.41thiazin-3(4/-/)-one

a) phenylmethyl 2,5-dihydro-1H-pyrrole-1-carboxylate

²O To a solution of 2,5-dihydro-1H-pyrrole (3.3 ml_, 43.4 mmol) and Et N (9 mL, 65.1 mmol) in DCM (200 mL) at 0⁰C was added dropwise benzyl chloroformate (7.3 mL, 52 mmol). After 1h, the solution was partitioned between H O-DCM. The organic phase was back extracted several times with DCM and the combined organic fractions were dried (Na SO ), concentrated and purified via column chromatography (silica, DCM) yielding the title compound (6g, 68%) as a yellow oil: LCMS ES (m/e) 204 (M+H) .

b) phenylmethyl (+)-(3S,4ft)/(3R,4S)-3-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-4- hydroxy-1 -pyrrolidinecarboxylate .OH ZN Ov NHBoc To a solution of Boc-carbamate (3.57 g, 30.54 mmol) in nPrOH (93 mL) at 25°C was added an NaOH solution (44 mL, prepared from 1.2 g of NaOH in 49 mL H O) followed by tBuOCI (3.45 mL, 30.05 mmol). After 15 min, phenylmethyl 2,5-dihydro-1H- pyrrole-1-carboxylate (2 g, 9.85 mmol) in nPrOH (5 mL) was added followed by K OsO (OH) (145 mg, 0.394 mmol) dissolved in the remaining NaOH solution prepared above (5 mL). After 1 h, the solution was extracted with EtOAc, concentrated and purified via column chromatography (2% MeOH in DCM (1% NH OH)) yielding the title compound (1g, contaminated with residual Boc-carbamate) as a clear oil: LCMS (ES) m/e 281 (M+H) . c) (±)-1 , 1 -dimethylethyl [(3S,4R)/(3R,4S)-4-hydroxy-3-pyrrolidinyl]carbamate

...OH HN. NHBoc To a solution of phenylmethyl (3S,4R)-3-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)- 4-hydroxy-1-pyrrolidinecarboxylate (~1 g, 2.98 mmol) in EtOH (30 mL) was added Pd(OH) (600 mg, 60 wt.%). The reaction stirred under 1 atm of H for 12h, was filtered through Celite, concentrated and purified via column chromatography (silica, 3-10% MeOH in DCM (1% NH OH)) yielding the title compound (400 mg, 20%-2 steps) as a white solid: LCMS (ES) m/e 147 (M-tBu) .

d) (+)-1 ,1-dimethylethyl ((3S,4R)/(3R,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1,5-naphthyridin- 4-yl]ethyl}-3-pyrrolidinyl)carbamate

A solution of 1 ,1 -dimethylethyl [(3S,4R)-4-hydroxy-3-pyrrolidinyl]carbarnate (200 mg, 0.990 mmol) and 8-ethenyl-2-(methyloxy)-1 ,5-naphthyridine (184 mg, 0.990 mmol) in EtOH (1 mL) was stirred at 85°C over 12h. The slurry was concentrated and the residue purified via column chromatography (silica, 2.5% MeOH in DCM (1 % NH OH)) yielding the title compound (327 mg, 85%) as a yellow foam: LCMS (ES) m/e 389 (M+H) .

e) (±)-(3R,4S)/(3S,4R)-4-amino-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol

To a solution of 1,1 -dimethylethyl ((3S,4R)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)carbamate (327 mg, 0.843 mmol) in MeOH (4 mL) at 25°C was added dropwise a 4M HCI in dioxane solution (1.5 mL, 5.9 mmol). After 12h, the solution was concentrated and the residue neutralized with excess MP carbonate resin in DCM to afford the title compound (242 mg, quant.) as a yellow oil: LCMS (ES) m/e 289 (M+H) .

f) (+)-6-{[((3S,4R)/(3R,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)amino]methyl}-2/-/-pyrido[3,2-£)][1 ,4]thiazin-3(4/-/)-one (GSK675294)

A solution of (3R,4S)-4-amino-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol (120 mg, 0.417 mmol), 3-oxo-3,4-dihydro-2/-/-pyrido[3,2-£>][1 ,4]thiazine-6- carbaldehyde (81 mg, 0.417 mmol) and Na SO (89 mg, 0.625 mmol) in DCM-MeOH (2 ml_, 5:1) was stirred at 25°C over 12h. NaBH(OAc) (132 mg, 0.626 mmol) was then added in one portion. After an additional 2h, the solution was partitioned between NaHCO (sat)-DCM. The aqueous phase was back extracted several times with DCM and the combined organic fractions were dried (Na SO ), concentrated and purified via column chromatography (silica, 2% MeOH in DCM (1 % NH OH)) yielding the title compound (89 mg, 46%) as a yellow solid: LCMS (ES) m/e 467 (M+H) ; H NMR (CD OD, 400 MHz) δ 8.63 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 4.5 Hz, 1H), 7.23 (d, J = 9.0 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1H), 4.25- 4.27 (m, 1 H), 4.12 (s, 3H), 3.85 (AB quart., 2H), 3.52 (s, 2H), 3.35-3.45 (m, 2H), 3.22-3.30 (m, 2H), 3.11-3.16 (m, 1H), 2.98-3.02 (m, 2H), 2.72-2.75 (m, 1H), 2.57-2.61 (m, 1 H).

Example 119

Preparation of (+)-6-(f((3S,4/?)/(3R,4S)-1-(2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- vnethyl>-4-hvdroxy-3-pyrrolidinyl)aminolmethyl)-2/-/-pyridof3,2-ib1l^'1 ,41thiazin-3(4/-/)-one

The title compound (65 mg, 31%) was prepared as a yellow solid essentially according to Example 118, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1 ,5- naphthyridine (202 mg, 0.990 mmol) for 8-ethenyl-2-(methyloxy)-1 ,5-naphthyιϊdine: LCMS (ES) m/e 485 (M+H) ; H NMR (CD OD, 400 MHz) δ 8.65 (s, 1H), 8.21 (d, J = 9.0 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 9.0 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 4.23- 4.26 (m, 1 H), 4.13 (s, 3H), 3.85 (AB quart., 2H), 3.52 (s, 2H), 3.42-3.48 (m, 2H), 3.23-3.29 (m, 2H), 3.12-3.16 (m, 1H), 2.93-2.97 (m, 2H), 2.70-2.74 (m, 1 H), 2.56-2.60 (m, 1 H).

Example 120

Antimicrobial Activity Assay:

Whole-cell antimicrobial activity was determined by broth microdilution using the National Committee for Clinical Laboratory Standards (NCCLS) recommended procedure, Document M7-A6, "Methods for Dilution Susceptibility Tests for Bacteria that Grow Aerobically". The compounds were tested in serial two-fold dilutions ranging from 0.016 to 16 mcg/mL. Compounds were evaluated against a panel of Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis and Enterococcus faecium. In addition, compounds were evaluated against a panel of Gram-negative strains including Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae and Stenotrophomonas maltophilia. The minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to assist in determining the MIC endpoint. One skilled in the art would consider any compound with a MIC of less than 20 mg/mL to be a potential lead compound. For instance, each of the listed Examples (1 to 119), as identified in the present application, had a MIC <20 mg/ml against at least one of the organisms listed above. Example 121

Rat Infection Model

Certain compounds of this invention were tested in the rat infection model. Specific pathogen-free male Sprague-Dawley CD rats were used for all bacterial strains. Each therapy group consists of 5 animals. Infection was carried out by intrabronchial instillation of 100 ml bacterial suspension for H. influenzae H128, and 50 ml of bacterial suspension for S.pneumoniae 1629 via non-surgical intubation. All compounds were administered at 1 , 7, 24 and 31 hour post infection via oral gavage. In each experiment, an additional group of animals was included and served as untreated infected controls. Approximately 17 hour after the end of therapy, the animals were killed and their lungs excised and enumeration of the viable bacteria was conducted by standard methods. The lower limit of detection was 1.7 Iog10 CFU/lungs. In vivo, activity was observed in infection models in rats versus S. pneumoniae 1629 at doses ranging from 25-100 mg/Kg with oral dosing and for some compounds versus H. influenzae H128 at doses from 25-100 mg/Kg with oral dosing. Certain formula (I) compounds showed a greater than 2 log drop in viable counts in the lungs compared to non-treated controls versus S. pneumoniae 1629. Certain compounds of formula (I) showed greater than a 4 log drop in viable counts in the lungs compared to non-treated controls versus H. influenzae H 128. At least some of the compounds of this invention are particularly interesting due to their low toxicity with no toxicity being observed in rats with dosing twice daily for 2 days at 50mg/Kg. It is to be understood that the invention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims. Table of Examples

Claims

What is claimed is:

1. 1. A compound of formula (I)

(I) wherein:

1a Z₁, Z₃, and Z₄ are each independently N or CR ;

Z₂, Z₅ and Z₆ are each CR^1a;

Ri and R^1a are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (C-i_β)alkoxy unsubstituted or substituted by (C«i_Q)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any of which is unsubstitued or N-substituted by one or two (C^ _ e)alkyl, acyl, (C-]_g)alkylsulphonyl, CONH2, hydroxy, (C-j_Q)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C-]_6)alkylsulphonyloxy; (C-_|. g)alkyl; (C^_g)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C^_g)alkylsulphonyl; (C-_|_g)alkylsulphoxide; arylsulphonyl; arylsulphoxide; or an amino, piperidyl, guanidino or amidino group unsubstituted or N-substituted by one or two (C<|_6)alkyl, acyl or (C-j_g)alkylsulphonyl groups; or R₁ and R^1a of Z₂, or R₁ and R^1a of Z₁ together form ethylenedioxy;

A is CR₂R₃;

W₁ is CR₄R₅; R₄ is hydrogen; halogen; hydroxy; (C_1-6)alkyl; (C_1-6)hydroxyalkyl; C(=O)-NR^1dR^1d'; (C_1- ₆)alkoxy; NR^1bR^1b'or acyloxy; and R₅ is hydrogen or (C_1-6)alkyl; or R₄ and R₅ together are =N-OH;

R^1b and R^1b' are each independently hydrogen; (C_1-6)alkyl; aryl; heteroaryl; or together with the nitrogen they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring is optionally substituted with 1 to 3 substitutents selected from halogen, (C_1-6)alkyl, hydroxy or aryl);

W₂ is CR₆;

R₆ is hydrogen; halogen; hydroxy; (C_1-6)alkyl; NR^1cR^1c'; acyloxy; or (C₁^aIkOXy;

R^1c and R^1c' are each independently hydrogen; (Ci_-6)alkyl; aryl; heteroaryl; or together with the nitrogen they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring is optionally substituted with 1 to 3 substitutents selected from halogen, (Ci-₆)alkyl, hydroxy or aryl);

R^1d and R1^d> are each independently hydrogen or (Ci.₆)alkyl;

B is CR₇R₈ or a bond;

R₇ and R₈ are each independently hydrogen or (Ci_-6)alkyl;

Ra is hydrogen; aryl; heteroaryl; (C-|_β)alkyl unsubstituted or substituted by one or two (C<|_g)alkoxy, acyloxy, carboxy, hydroxy, amino, piperidyl, piperazinyl, morpholino, guanidino, or amidino, any of which is unsubstituted or N-substituted by one or two aryl, heteroaryl, halogen, unsubstituted (C-i_β)alkyl, acyl, (C-i_6)alkylsulphonyl, arylsulphonyl, hydroxy, (C-|_g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy, or (C-|.Q)alkylsulphonyloxy, so long as the substitution does not lead to an unstable compound; (Ci_6)alkylcarbonyl; or (C2_6)alkenylcarbonyl; R₁₀ is a group -U-R₁₁ where R₁₁ is a substituted or unsubstituted bicyclic carbocyclic or heterocyclic ring system (A):

containing up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic; X is C or N when part of an aromatic ring or CR₁₂ when part of a non aromatic ring; 2 X is N, NR₁₃, O, S(O)_x, CO or CR₁₂ when part of an aromatic or non- aromatic ring or may in addition be CR₁₄R₁₅ when part of a non aromatic ring; X and X are independently N or C; Y is a 0 to 4 atom linker group each atom of which is independently selected from N, NR₁₃, O, S(O)_x, CO and CRi₂ when part of an aromatic or non- aromatic ring or may additionally be CR₁₄R₁₅ when part of a non aromatic ring, Y is a 2 to 6 atom linker group, each atom of Y being independently selected from N, NR₁₃, O, S(O)_x, CO and CR₁₂ when part of an aromatic or non- aromatic ring or may additionally be CR₁₄R₁₅ when part of a non aromatic ring; R₁₂, R₁₄ and R₁₅ are at each occurrence independently selected from: H; (C-) _ 4)alkylthio; halo; (C-|_4)alkyl; (C2_4)alkenyl; hydroxy; hydroxy(C-|_4)alkyl; mercapto(C-)_4)alkyl; (Ci_4)alkoxy; trifluoromethoxy; nitro; cyano; carboxy; amino or aminocarbonyl unsubstituted or substituted by (C-j_4)alkyl;

R₁₃ is at each occurrence independently hydrogen; trifluoromethyl; (C-μ 4>alkyl unsubstituted or substituted by hydroxy, carboxy, (C-|_4)alkoxy, (C-μ ρ)alkylthio, halo or trifluoromethyl; (C2-4)alkenyl; or aminocarbonyl wherein the amino group is optionally substituted with (C-j_4)alkyl;

each x is independently 0, 1 or 2;

U is C(=O); SO₂; or CR₁₆R₁₇; and R₁₆ and R₁₇ are independently selected from H; aryl; heteroaryl; (C-] _ g)alkyl; (C-|_g)alkyl substituted by (Ci_6)alkoxy, hydroxy, amino, piperidyl, piperazinyl, morpholino, guanidino, or amidino, any of which is substituted or N- substituted by one or two H, aryl, heteroaryl, halogen, cyano, CF3, (C-j__β)alkyl, acyl, (C-f _6)alkylsulphonyl, arylsulphonyl, hydroxy, (C-j_g)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy, or (C-|_6)alkylsulphonyloxy, so long as the substitution does not lead to an unstable compound; (Ci_6)alkoxy- substituted(C-]_Q)alkyl; hydroxy-substituted(C-i_6)alkyl; amino-substituted(C-_|_ ø)alkyl, which is N-substituted by one or two (C<_|_6)alkyl, acyl, (C-i_ g)alkylsulphonyl, or arylsulphonyl; (C-_|_g)alkylcarbonyl; (C2-6)alkenylcarbonyl; (Ci_g)alkoxycarbonyl; CO2H; or CF3; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, wherein: Z₁ and Z₄ are N; and Z₃ is CR^1a.

3. A compound according to claim 1 , wherein: Z₁ and Z₃ are N; and Z₄ is CR^1a.

4. A compound according to claim 1, wherein: Z₁ and Z₃ are CR^1a; and Z₄ is N.

5. A compound according to claim 1, wherein: R₁ is OCH 3^"

13 6. A compound according to claim 1 , wherein R is at each occurrence independently hydrogen; halogen; or cyano.

7. A compound according to claim 2, wherein: R^1a of Z₂, Z₃ and Z₅ are each hydrogen; R^1a of Z₆ is hydrogen, halogen or cyano; and R₁ is OCH₃.

8. A compound according to claim 1 , wherein: Ri and R^1a of Z₁ together form ethylenedioxy.

9. A compound according to claim 1, wherein: R₂ is hydrogen or hydroxy.

10. A compound according to claim 1, wherein: B is CH₂.

11. A compound according to claim 1 , wherein: R₄ is hydroxy; and R₅ is hydrogen.

12. A compound according to claim 1 , wherein: R₉ is hydrogen.

13. A compound according to claim 1, wherein: U is CH₂.

14. A compound according to claim 1, wherein Ri₁ is: 4H-Pyrido[3,2-b][1 ,4]thiazin-3-oxo-6-yl; 2,3-Dihydro-benzo[1,4]dioxin-6-yl; 4f/-Pyrido[3,2-jb][1,4]oxazin-3-oxo-6-yl; 4H-benzo[1,4]thiazin-3-oxo-6-yl; 2,3-Dihydro-furo[2,3-c]pyridin-5-yl; 7-Chloro-4H-pyrido[3,2-ib]oxazin-3-oxo-6-yl; 2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl; 2,3-Dihydro-benzofuran-7-carbonitrile-5-yl; 7-Methyl-4H-pyrido[3,2-6][1 ,4]thiazin-3-oxo-6-yl; 3-Oxa-1-thia-5-aza-indan-5-yl; 5-Methyl-2,3-dihydro-benzo[1 ,4]dioxin-6-yl; 6-Fluoro-2,3-dihydro[1,4]dioxin-7-yl; 2 , 3-Dihydro-benzof uran-5-yl ; 7-Fluoro-4W-benzo[1 ,4]thiazin-3-oxo-6-yl; 4H-Benzo[1 ,4]thiazin-3-oxo-6-yl; or 8-Methyl-2,3-dihydro-benzo[1 ,4]dioxin-6-yl.

15. A compound according to claim 1, wherein the compound is: a) 6-({[((3S)-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-/b][1 ,4]thiazin-3(4/^/)-one; b) 6-({[((3R)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4/-/)-one; c) (2,3-dihydro-1-benzofuran-5-ylmethyl)[((3S)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; d) [(7-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)methyl][((3S)-1 -{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyf)methyl]amine; e) (2,3-dihydro-1 ,4-benzodioxin-6-ylmethyl)[((3S)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; f) θ-^KCS^-i^-lS.δ-difluoro-δ-CmethyloxyJ^-quinolinyllethylJ-S- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4/-/)-one; 9) 6-({[((3S)-1 -{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ό][1 ,4]thiazin-3(4/-0-one; h) 6-({[((3S)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]oxazin-3(4H)-one; i) 5-({[((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2,3-dihydro-1-benzofuran-7-carbonitrile; j) 7-chloro-6-({[((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methy!]amino}methyl)-2/-/-pyrido[3,2-ib][1 ,4]oxazin-3(4H)-one; k) 7-fluoro-6-({[((3R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-1 ,4-benzothiazin-3(4H)-one; I) (2,3-dihydrofuro[2,3-c]pyridin-5-ylmethyl)[((3S)-1-{2-[3-fluoro-6- (methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; m) 6-(methyloxy)-4-{2-[(3S)-3-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- b]t1,4]thiazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-3-quinolinecarbonitrile; n) 6-(methyloxy)-4-[2-((3S)-3-{[([1 ,3]oxathiolo[5,4-c]pyridin-6- ylmethyl)amino]methyl}-1-pyrrolidinyl)ethyl]-3-quinolinecarbonitrile; o) 6-(methyloxy)-4-{2-[(3S)-3-({[(3-oxo-3,4-dihydro-2W-pyrido[3,2- /)][1,4]oxazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-3-quinolinecarbonitrile; p) 6-(methyloxy)-4-{2-[(3S)-3-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1 ,4]thia2in-6-yl)methyl]amino}methyl)-1 -pyrrolidinyl]ethyl}-1 ,5-naphthyridine-3- carbonitrile; q) 1-[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyOmethylJfCδ-methyl^.S-dihydro-i^-benzodioxin-θ-yOmethyllamine; r) 1 -((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)-W-[(8-methyl-2,3-dihydro-1 ,4-benzodioxin-6-yl)methyl]methanamine; s) 6-({[((3S)-1-{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethy)}- 3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one; t) 6-({[((3S)-1 -{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 3-pyrrolidinyl)methyl]amino}methyl)-2/V-pyrido[3,2-ό][1,4]oxazin-3(4H)-one; u) [((3S)-1 -{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrro!idinyl)methyl]([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amine; v) 6-({[((3S)-1-{2-[3,8-difIuoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; w) 6-({[((3S)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-/)][1 ,4]thiazin-3(4/-/)-one; x) [((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amine; y) 7-chloro-6-({[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jt)][1 ,4]oxazin-3(4/-/)-one; z) 6-({[((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; aa) 6-({[((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-6][1 ,4]thiazin-3(4/-/)-one; ab) (2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)[((3S)-1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; ac) 6-({[((3S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-7-methyl-2W-pyrido[3,2-/>][1,4]thiazin-3(4H)-one; ad) 6-({[((3S)-1-{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-b][1 ,4]thiazin-3(4H)-one; ae) 6-({[((3S)-1 -{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]oxazin-3(4H)-one; af) 6-({[((3R)-1 -{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-ό][1 ,4]oxazin-3(4H)-one; ag) 6-({[((3R)-1-{(2S)-2-hydroxy-2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; ah) 6-({[((3S)-1-{(2R)-2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]-2- hydroxyethyl}-3-pyrrolidinyl)methyl]amino}nnethyl)-2/-/-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; ai) Λ/-[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2H-1 ,4-benzothiazine-6-sulfonamide; aj) Λ/-[((3R)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2Λ/-1 ,4-benzothiazine-6-sulfonamide; ak) W-KCS^-i^-tS-fluoro-θ-CmethyloxyJ-i .δ-naphthyridin^-yllethylJ-S- pyrrolidinyl)methyl]-2,3-dihydro-1,4-benzodioxin-6-sulfonamide; al) Λ/-[((3R)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2/-/-1 _l4-benzothiazine-6-sulfonamide; am) Λ/-[((3/?)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2/-/-1 ,4-benzothiazine-6-sulfonamide; an) Λ/-[((3R)-1 -{2-[3-cyano-6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2W-1 ,4-benzothiazine-6-sulfonamide; ao) (±)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; ap) (±)-6-({[(fraπs-3,4)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4H)- one; aq) 6-({[(frans-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][1 ,4]thiazin-3(4/-0- one; ar) 6-({[(frans-3,4)-1-{2~[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4H)- one; as) (±)-6-({[(fra/7S-3,4)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methy!)-2W-pyrido[3,2-ib][1,4]oxazin-3(4H)- one; at) 6-({[(fra/7S-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 _l5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-/t)][1 ,4]oxazin-3(4H)- one; au) 6-({[(trans-3,4)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ό][1 ,4]oxazin-3(4W)- one; av) (±)-6-({[((cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ib][1 ,4]thiazin-3(4H)- one; aw) 6-({[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4/-0- one; ax) 6-({[((3R,4R)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-£>][1,4]thiazin-3(4H)- one; ay) 6-({[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-/?][1 ,4]oxazin-3(4/-/)- one; az) 6-({[((3R,4R)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ύ][1 ,4]oxazin-3(4fO- one; ba) (±)-7-chloro-6-({[((cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2- b][~\ ,4]oxazin-3(4/-/)-one; bb) T-chloro-e-^^CSS^SJ-i^-tS-fluoro-θ-CmethyloxyJ-i .δ-naphthyridin- 4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]oxazin- 3(4H)-one; be) 7-chloro-6-({[((3R,4f?)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]oxazin- 3(4H)-one; bd) (±)~ (cis-3,4)-4-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol; be) (3S,4S)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol; bf) (3R,4R)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylrnethyOarninolmethylJ-i^-tS-fluoro-θ-CmethyloxyJ-i .δ-naphthyridin^-yOethylJ-S- pyrrolidinol; bg) 8-fluoro-6-({[((3S,4S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin- 4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-1,4-benzoxazin-3(4W)-one; bh) 6-({[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4/-0-one; bi) 6-({[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-£)][1 ,4]oxazin-3(4H)-one; bj) (±)-6-({[((cis-3,4)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-/)][1_l4]thiazin-3(4H)-one; bk) 6-({[((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2Ay-pyrido[3,2-ifc⁾][1_I4]thiazin-3(4/V)-one; bl) (±)-6-({[((cis-3,4)-4-hydroxy-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; bm) 6-({[((3S,4S)-1-{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-6][1 ,4]oxazin-3(4H)- one; bn) 6-({[((3S,4S)-1-{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyriclin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4/-0- one; bo) (3S,4S)-1 -{2-[3-chloro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- {[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)annino]methyl}-3-pyrrolidinol; bp) (+)-6-[({[(cis-3,4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-(methyloxy)-3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2-b][1 ,4]thiazin- 3(4H)-one; bq) (±)-6-[({[(cis-3,4)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-(methyloxy)-3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2-b][1 ,4]oxazin- 3(4H)-one; br) (+)-6-({[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4/-0-one; bs) (±)-(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)[(3-fluoro-1-{2- [3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amine; bt) (±)-6-({[((3S,4f?)-4-f!uoro-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin- 3(4H)-one; bu) (+)-6-({[((3S,4S)-4-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-jb][1,4]thiazin- 3(4H)-one; bv) (±)-6-({[(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-methyl-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4H)- one; bw) (±)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-3-methyl-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-ό][1 ,4]thiazin-3(4H)- one; bx) (±)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-4-methyl-3-pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-jb][1 ,4]thiazin-3(4H)- one; by) (+)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- hydroxy-4-methyl-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ib][1 ,4]thiazin-3(4H)- one; bz) (±)-6-({[(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- methyl-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-6][1 ,4]thiazin-3(4f/)-one; ca) (+)-6-({[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- methyl-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-ώ][1 ,4]oxazin-3(4AV)-one; cb) (+)- [(1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- methyl-S-pyrrolidinyOmethylKCI.Sloxathiolotδ^-clpyridin-δ-ylmethyOamine; cc) (±)-(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)[(1-{2-[3-fluoro- 6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]amine; cd) (+)-4-{2-[3-methyl-3-({[(3-oxo-3,4-dihydro-2W-pyrido[3,2- /)][1 ,4]thiazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-6-(nnethyloxy)-3- quinolinecarbonitrile; ce) (±)-4-[2-(3-methyl-3-{[([1 ,3]oxathiolo[5,4-c]pyridin-6- ylmethyl)amino]methyl}-1-pyrrolidinyl)ethyl]-6-(methyloxy)-3-quinolinecarbonitrile; cf) e-^i-CCS^-i^-tS-fluoro-e-CmethyloxyJ-i .δ-naphthyridin^-ylJethyl}- 3-pyrrolidinyl)-1-methylethyl]amino}methyl)-2H-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; eg) /V-(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)-2-((3R)-1-{2-[3- fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)-2-propanamine; ch) Λ/-[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyOmethyll-S-oxo-S^-dihydro^H-pyridotS^-όlCi ^lthiazine-δ-carboxamide; ci) Λ/-[((3S)-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyI)methyl]-3-oxo-3,4-dihydro-2H-pyrido[3,2-/)][1,4]thiazine-6-carboxamide; S cj) /V-[((3S,4S)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 4-hydroxy-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2/-/-pyrido[3,2-/)][1 ,4]thiazine-6- carboxamide; ck) (±)-W-[((cis-3₎4)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-Λ/-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2- ύ][1 ,4]thiazine-6-carboxamide; cl) (±)-Λ/-[(1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methyl]-Λ/-methyl-3-oxo-3,4-dihydro-2W-pyrido[3,2-/b][1,4]thiazine-6- carboxamide; cm) (3S,4S)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyOaminoJrnethylJ-i^-Cδ-CrriethyloxyJ-I .S-naphthyridiri^-ylJethylJ-S-pyrrolidinol; en) 6-({[((3S,4S)-1-{2-[8-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-jt)][1,4]thia2in-3(4H)-one; co) 6-({[((3S,4S)-1-{2-[8-fluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; cp) 6-({[((3S,4S)-1-{2-[6-fluoro-5-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-b][1 ,4]oxazin-3(4H)-one; cq) 6-({[((3S,4S)-1-{2-[6-fluoro-5-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-ό][1,4]thiazin-3(4/V)-one; cr) 6-({[((3S,4S)-1-{2-[3,8-difluoro-6-(methyloxy)-4-quinolinyl]ethyl}-4- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2W-pyrido[3,2-/?][1 ,4]oxazin-3(4H)-one; cs) e-αtCCSS^SJ-i^-IS.δ-difluoro-θ-CmethyloxyJ^-quinolinylJethylH- hydroxy-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3₎2-jb][1 ,4]thiazin-3(4/-/)-one; ct) 6-{[({(3S,4S)-1-[2-(9-chloro-2,3-dihydro[1 ,4]dioxino[2,3-/|quino!in- 10-yl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)amino]methyl}-2H-pyrido[3,2-jb][1 ,4]thiazin- 3(4H)-one; cu) 6-{[({(3S,4S)-1-[2-(9-chloro-2,3-dihydro[1 ,4]dioxino[2,3-/|quinolin- 10-yl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)amino]nnethyl}-2/-/-pyrido[3,2-jb][1_l4]oxazin- 3(4H)-one; cv) 6-{[({(3S,4S)-1-[2-(2,3-dihydro[1 ,4]dioxino[2,3-/]quinolin-10-yl)ethyl]- 4-hydroxy-3-pyrrolidinyl}methyl)amino]methyl}-2H-pyrido[3,2-6][1,4]oxazin-3(4H)-one; cw) 6-({[((3S,4S)-4-hydroxy-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; ex) (3S,4S)-1 -{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-4- {[([1 ,3]oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]methyl}-3-pyrrolidinol; cy) 7-chloro-6-({[((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl3ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][1,4]oxazin- 3(4H)-one; cz) (3S,4S)-4-({[(7-fluoro-2,3-dihydro-1 ,4-benzodioxin-6- yl)methyl]amino}methyl)-1-{2-[6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol; da) (3S,4S)-4-({[(7-fIuoro-2,3-dihydro-1 ,4-benzodioxin-6- yl)methyl]amino}methyl)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinol; db) 7-fluoro-6-({[((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]amino}methyl)-2H-1 ,4-benzothiazin-3(4H)- one; dc) 6-({[((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2f/-pyrido[3,2-jb][1 ,4]thiazin-3(4H)-one; dd) 6-({[((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-4-quinolinyl]ethyl}-3- pyrrolidinyl)methyl]amino}methyl)-2/-/-pyrido[3,2-jb][1 ,4]oxazin-3(4H)-one; de) (3S,4S)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1-{2-[6-(methyloxy)-4-quinolinyl]ethyl}-3-pyrrolidinol; df) Λ/-[((3f?,4S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-hydroxy-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2/-/-1 ,4-benzothiazine-6- sulfonamide; dg) Λ/-[((3S,4S)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}- 4-hydroxy-3-pyrrolidinyl)methyl]-3-oxo-3,4-dihydro-2W-pyrido[3,2-ύ][1 ,4]oxazine-6- carboxamide; dh) (±)-6-[({[(3R, 4S)/(3S, 4R)-I -{2-[3-fluoro-6-(methyloxy)-1 , 5- naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2f/- pyrido[3,2-6][1 _l4]thiazin-3(4H)-one; di) (±)-6-[({[(3R,4SJ/f3S,4R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2/-/- pyrido[3 , 2-b][ 1 ,4]thiazin-3(4H)-one; dj) 6-[({[(3R,4SJ^»1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-(hydroxymethyl)-3-pyrrolidinyl]methyl}amino)methyl]-2H-pyrido[3,2- b][1,4]thiazin-3(4H)-one; dk) (±)-6-[({[(3S,4RJ/f3S,4R)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin^-yllethylH-ChydroxymethyO-S-pyrrolidinylJmethylJaminoJmethyO^H- pyrido[3,2-ό][1 ,4]thiazin-3(4H)-one; dl) (±M(3R4Sj/|f3S,4R)--4-{[(2>dihydro[1 ,4]dioxino[2,3-φyridin-7- ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinyl)methanol; dm) 6-[({[(3R,4Z)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-(hydroxyimino)-3-pyrrolidinyl]methyl}amino)methyl]-2/-/-pyrido[3,2-jb][1 ,4]thiazin- 3(4H)-one; dn) 6-[({[(3R_J4Z)-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-(hydroxyimino)-3-pyrrolidinyl]methyl}amino)methyl]-2fy-pyrido[3,2-jb][1 ,4]oxazin- 3(4H)-one; do) (3Z,4f?)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1-{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinone oxime; dp) (±)-(3S,4S)/(3R,4R)-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4- yllethylH-^tCS-oxo-S^-dihydro^H-pyrido^^-όJCI^lthiazin-θ-yOmethylJaminoJmethyO-S- pyrrolidinecarboxamide; dq) (+)-(3S,4S)/(3R,4R)-1-{2-[3-fluoro-6-(methyIoxy)-1 ,5-naphthyridin-4- yl]ethyl}-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1 ,4]oxazin-6-yl)methyl]amino}methyl)-3- pyrrolidinecarboxamide; dr) (±)-(3S,4S)/(3R,4R)-4-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-1 -{2-[3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yl]ethyl}-3- pyrrolidinecarboxamide; ds) 4-{2-[(3S,4S)-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2W-pyrido[3,2- ^[I^Jthiazin-δ-yOmethylJaminoJmethyO-i-pyrrolidinyllethylJ-θ-Cmethyloxy)-! ^- naphthyridine-3-carbonitrile; dt) 4-{2-[(3S,4S)-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- jb][1,4]oxazin-6-yl)methyl]amino}methyl)-1-pyrrolidinyl]ethyl}-6-(methyloxy)-1 ,5- naphthyridine-3-carbonitrile; du) 4-[2-((3S,4S)-3-{[(2,3-dihydro[1 ,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-4-hydroxy-1-pyrrolidinyl)ethyl]-6-(methyloxy)-1,5-naphthyridine-3- carbonitrile; dv) (±)-6-{[((3S,4f?)/(3R,4S)-4-hydroxy-1-{2-[6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)amino]methyl}-2H-pyrido[3,2-ib][1 ,4]thiazin-3(4H)- one; dw) (±)-6-{[((3S,4R)/(3R, 4S)-I -{2-[3-fluoro-6-(methyloxy)-1 ,5- naphthyridin-4-yl]ethyl}-4-hydroxy-3-pyrrolidinyl)amino]methyl}-2W-pyrido[3,2- ό][1,4]thiazin-3(4H)-one; or a pharmaceutically acceptable salt, solvate or N-oxide thereof.

16. A process for preparing an intermediate useful in the synthesis of a compound of formula (I), a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide of a compound of formula (I), which process comprises: (1) reacting a compound of formula (a) with a compound of formula (b) to form a compound of formula (c):

wherein: Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, R₁, W₁, VV₂, A, B and R₉ are as defined in formula (I); X is oxirane, CH=CH₂, or CH₂CH₂-L; L is a leaving group; P is hydrogen, a suitable protecting group or Ri₀; and when P is R₁₀; (2) optionally forming a pharmaceutically acceptable salt, solvate or derivative thereof. In some embodiments of the processes of this invention, R₄ Of W₁ is OH and R₅ is H. In some aspects, this invention describes a process for preparing intermediates useful in the preparation of compounds of formula (1), and compounds of formula (I) wherein R₄ Of W₁ is OH and R₅ is H comprising the: (1) reaction of a compound of formula (d) with a compound of formula (e) to form a compound of formula (f); and (2) cleavage of the N-O bond with: (a) retention of P; or (b) cleavage of P and subsequent reintroduction of P; and (3) removal of P-i to form the compound of formula (a)

^(d) (^e) (f) (g)

wherein P is at each occurrence an independently selected protecting group. In other aspects of this invention, a process is described for preparing a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, which process comprises: (1 ) reacting a compound of formula (c), wherein P is hydrogen, with a compound of formula (h): L₁-U-R₁₁ (h) wherein: U and R₁₁ are as previously defined; Li is a leaving group; or reacting a compound of formula (c), wherein P is hydrogen, with a compound of formula (h_a): CHO-R₁₁

and reducing the resulting imine; and (2) optionally forming a pharmaceutically acceptable salt, solvate or derivative thereof.

17. A process for preparing a compound of formula (I) or a useful intermediate in the preparation of a compound of formula (I), said process comprising: (1) reacting a compound of formula (i) with CN or CH₃NO₂ to yield a compound of formula (j):

(i) G) wherein: P₂ is a protecting group; Z is CN or CH₂NO₂; and (2) reducing Z to CH₂NH₂ to form a compound of formula (k); and (3) converting CH₂NH₂ to CH₂NHP₃ or CH₂NHR₁₀, to form a compound of formula (I); and (4) removing protecting group P₂ to generate a compound of formula (m); and (5) reacting said compound of formula (m) with a compound of formula (a) to generate a compound of formula (n)

(n)

18. A process according to claim 50, wherein the compound of formula (j), (k), (I), (m) or (n) is reacted with a trialkyl- or triarylphosphine and a dialkyldiazodicarboxylate in the presence of an organic acid optionally followed by cleavage of the resultant ester to form the corresponding 3,4-(cis)-substituted compounds of formula (o), (p), (q), (r) or (s):

(W)

wherein M is a metal; P₄ is hydrogen, (Ci.₆)alkyl, benzyl (wherein the phenyl group of said benzyl is optionally substituted with from 1-3 substitutents independently selected from halogen, (C_1-6)alkyl, NO₂, CN and CF₃); and (3) optionally treated under conditions suitable for removal of P₄; and (4) optionally forming a pharmaceutically acceptable salt, solvate or N-oxide thereof.

19. A compound according to claim 1 and at least one pharmaceutically acceptable excipient.

20. A method of treating bacterial infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound according to formula (I).