Compounds for the treatment of multi-drug resistant bacterial infections   

Abstract: The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

BACKGROUND OF THE INVENTION

The international health community continues to express serious concern that the evolution of antibacterial resistance will result in strains against which currently available antibacterial agents will be ineffective. For example, resistant strains of Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium are both difficult to treat and difficult to eradicate. Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.

SUMMARY

These and other needs are met by the invention disclosed herein which is directed to a compound of formula I:

L-U1-M-U2-R  I

or a pharmaceutically acceptable salt thereof, or N-oxides thereof, wherein:

L is a group of formula L1-L15:

” indicates the point of attachment;

Z3, Z6, and Z7 are C or N provided that when Z3, Z6, or Z7 is N, then R2a, R2c, or R2d are absent;

R2a, R2b, R2c, R2d, R2e, and R2f, are each independently H, halo, cyano, carboxy, nitro, carbamoyl, —CO—(C1-C6)alkyl, CO2—(C1-C6)alkyl, (C1-C6)alkyl, hydroxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO—(C1-C6)alkyl, SO2(C1-C6)alkyl, SO2NH(C1-C6)alkyl, or SO2N((C1-C6)alkyl)2;

R2g, R2g′, and R2g″ are each independently H, (C1-C6)alkyl, or halo(C1-C6)alkyl;

U1 is CRaRb-CRcRd or CRaRb-CRcRd-CReRf, wherein Ra, Rb, Rc, Rd, Re, and Rf are each independently hydrogen or (C1-C6)alkyl;

M is a group of formula M1-M5:

” indicate points of attachment;

Ry and Ry′ are each independently H, halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, CO2R″, wherein R″ is H, (C1-C6)alkyl, or halo(C1-C6)alkyl, or Ry and Ry′ together with the carbon to which they are attached form C═O; or Ry and Ry′ together form a bridge;

X and Y are each independently CH2, O, or NR′; “- - - -” is a bond or is absent;

n is 1, or 2, or 3;

when M is a group of formula M1 or M4, U2 is NR′—W, wherein W is CH2, CO, SO2,

CH2CH2, CH2CH═CH, or CH2C≡C, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl;

when M is a group of formula M2, M3, or M5, U2 is W wherein W is as defined herein above;

R′ at each occurrence is independently H, (C1-C6)alkyl, —(C1-C6)alkylcarboxy, —CO—(C1-C6)alkyl, —CO2 (C1-C6)alkyl, —CO—NH(C1-C6)alkyl, —CO—N((C1-C6)alkyl)2, or SO2(C1-C6)alkyl, any of which may be optionally substituted on carbon with halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, SO2(C1-C6)alkyl, NH2, NH(C1-C6)alkyl, or N((C1-C6)alkyl)2;

when W is CH2, CO or SO2, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic heteroaryl, or when W is

CH2CH2, CH2CH═CH, or CH2C≡C, R is aryl, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (C1-C6)alkyl; and

any of L, U1, M, U2, or R may be optionally substituted on carbon by one, two or three substituents selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, heteroaryl, heterocyclyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or acetylamino;

with the proviso that when L is a group of formula L8 or L15, W is not CO.

What is also provided is a compound of formula I which is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein

R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy;

“- - - -” is a bond or is absent;

Z is CH or N when “- - - -” is a bond, or Z is O or NH when “- - - -” is absent;

U1 is CRaRb-CRcRd or CRaRb-CRcRd-CReRf, wherein Ra, Rb, Rc, Rd, Re and Rf are each independently hydrogen or (C1-C6)alkyl;

M is a group of formula M1a or M2-M5:

in the trans configuration relative to “*”, wherein R2 is H or carboxy;

Ry and Ry′ are each independently H, hydroxy, fluoro, chloro, methoxy, carboxy, CO2(C1-C6)alkyl, or (C1-C6)alkyl, or together with the carbon to which they are attached form C═O; or Ry and Ry′ together form a bridge;

X is CH2, NH, N[CO—(C1-C6)alkyl], N[SO2(C1-C6)alkyl], N(C1-C6)alkyl, or O;

Y is CH2, NH, N[CO—(C1-C6)alkyl], N[SO2(C1-C6)alkyl], N(C1-C6)alkyl, or O;

“- - - -” is a bond or is absent;

n is 1, 2, or 3;

when M is a group of formula M1a or M4, U2 is NR′—W, wherein R′ is H, (C1-C6)alkyl, —(C1-C6)alkylcarboxy, —CO—(C1-C6)alkyl, —CO2(C1-C6)alkyl, —CO—NH(C1-C6)alkyl, —CO—N((C1-C6)alkyl)2, any of which may be optionally substituted on carbon with halo, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, SO2 (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, or N((C1-C6)alkyl)2;

W is CH2, CO, SO2, CH2CH2, CH2CH═CH, or CH2C≡C, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl;

when M is a group of formula M2, M3, or M5, U2 is W; and

when W is CH2, CO or SO2, R is aryl, heteroaryl, heterocyclyl or ortho-fused bicyclic heteroaryl, or when W is CH2CH2, CH2CH═CH, or CH2C≡C, R is aryl, heteroaryl, heteroaryl(C1-C6)alkyloxy, heteroaryl(C1-C6)alkylthio, heteroaryl(C1-C6)alkylsulflnyl, heteroaryl(C1-C6)alkylsulfonyl, heteroaryl(C1-C6)alkylamino; wherein any R may be optionally substituted on carbon; and wherein any ring nitrogen in R may be optionally substituted by (C1-C6)alkyl.

What is also provided is a compound of formula I which is a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein

R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy;

Z is CH or N when “- - - -” is a bond, or, when “- - - -” is absent, Z is O or NH;

Y′ is N or CR2, wherein R2 is H, hydroxy, or carboxy;

U2 is NR\'-W, wherein W is CH2, CO, SO2, CH2CH2, CH2CH═CH, or CH2C≡C, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; and

R is

What is also provided is a compound of formula I which is a compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein

R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, nitro, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO—(C1-C6)alkyl, SO2(C1-C6)alkyl, SO2NH(C1-C6)alkyl, or SO2N((C1-C6)alkyl)2;

Z is CH or N when “- - - -” is a bond, or, when “- - - -” is absent, Z is O or NH;

R′ is H or (C1-C6)alkyl;

W is CO, SO2, or CH2, wherein each hydrogen may be optionally replaced by halo or (C1-C6)alkyl; and

R is

What is also provided is a compound of formula I which is a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein

R2a, R2b, R2c, and R2d are each independently H, fluoro, chloro, cyano, nitro, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy, NHCO—(C1-C6)alkyl, SO2(C1-C6)alkyl, SO2NH(C1-C6)alkyl, or SO2N((C1-C6)alkyl)2;

Z is CH or N when “- - - -” is a bond, or, when “- - - -” is absent, Z is O or NH; and

R is

What is also provided by the invention is a compound which is: 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinolin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinolin-4(1H)-one; Methyl 1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-1H-indole-2-carboxylate; 6-[({1-[2-(7-Methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; 2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile; 6-[({1-[2-(7,8-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(7-Fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinolin-2(1H)-one; 6-[({1-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; (3S,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid; (3S,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylic acid; Methyl (3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate; Methyl (3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate; (3R,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic acid; (3R,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylic acid; Methyl (3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate; Methyl (3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate; Cis(±)6-[({1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one; 6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzothiazin-3(4H)-one; 6-[({1-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-fluoro-2H-1,4-benzoxazin-3(4H)-one; 6-[({1-[2-(6-Chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-{[(1-{2-[3-Oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-[({1-[2-(6-Bromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-1-yl]ethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-[({1-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-[2-(4-{[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-[({trans-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 3-Oxo-4-[2-(trans-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6-Nitro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbonitrile; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide; Methyl 3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate; 6-[({1-[2-(6-Acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-Acetyl-4-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2H-1,4-benzoxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methyl-2H-1,4-benzoxazin-3(4H)-one; 3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2H-1,4-benzoxazin-3(4H)-one; 6-{[(1-{2-[6-(1-Hydroxyethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; Ethyl N-{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}-N-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]glycinate; 6-{[(1-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-{[(1-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(7-Methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 7-Methoxy-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dione; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopiperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one; 6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-({4-[3-(7-Methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)propyl]piperazin-1-yl}methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-{3-[4-(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-1-yl]propyl}-6-methoxy-2H-1,4-benzoxazin-3(4H)-one; 4-[2-({1-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperidin-4-yl}amino)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one; 4-(3-{4-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperazin-1-yl}propyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one; 6-[({1-[2-(6-Methoxy-2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; Methyl 1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate; 4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]piperidine-3-carboxylic acid; 7-Fluoro-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dione; 7-Chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxin[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,8-naphthyridin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one; 6-[({1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-fluoroquinoxalin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one; 6-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6,7-difluoroquinoxalin-2(1H)-one; 6-[({1-[2-(6,7-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7,8-difluoroquinoxalin-2(1H)-one; 6-[({1-[2-(7,8-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6,7-Dimethoxy-2-oxo quinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(7-M ethoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-4(1H)-one; Cis(±)6-[({1-[2-(5,7-difluoro-2-oxo quinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 7-Fluoro-2-oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-5-carbonitrile; 5-Fluoro-2-oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile; 7-Fluoro-1-[2-(4-{[(2-oxo-1,2-dihydro quinolin-3-yl)methyl]amino}piperidin-1-yl)ethyl]quinoxalin-2(1H)-one; 1-[2-(4-{[(2,2-Dimethyl-3,4-dihydro-2H-chromen-6-yl)methyl]amino}piperidin-1-yl)ethyl]-5,7-difluoro quinolin-2(1H)-one; 1-[2-(4-{[(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]amino}piperidin-1-yl)ethyl]-57-difluoroquinolin-2(1H)-one; 5,7-Difluoro-1-(2-{4-[(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one; 5,7-Difluoro-1-[2-(4-{[(6-fluoro-4H-1,3-b enzo dioxin-8-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one; 5,7-Difluoro-1-(2-{4-[(1H-indol-6-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro-1H-inden-5-ylmethyl)amino]piperidin-1-yl}ethyl)-5,7-difluoroquinolin-2(1H)-one; 5,7-Difluoro-1-[2-(4-{[(1-methyl-1H-1,2,3-benzotriazol-5-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one; 5,7-Difluoro-1-(2-{4-[(1H-indol-5-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one; 5,7-Difluoro-1-[2-(4-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one; 1-(2-{4-[(2,1,3-Benzoxadiazol-5-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one; N-{1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-6-sulfonamide; N-{1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide; 5-Fluoro-N-{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-1H-indole-2-carboxamide; N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-6-morpholin-4-ylnicotinamide; N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide; N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-1-methyl-1H-1,2,3-benzotriazole-5-carboxamide; N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-3-(2-methyl-1,3-thiazol-4-yl)benzamide; N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide; 3-Oxo-4-[2-((2R,5S)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 3-Oxo-4-[2-((2S,5R)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-[({1-[2-(5,7-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-[({1-[2-(6,8-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoxaline-6-carbonitrile; 3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile; 6-[({1-[2-(6-Methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one; 6-[({1-[2-(6-Chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 6-Chloro-4-(2-{4-[(2,3-dihydro[1,4]dioxin[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,2,4-benzotriazin-3(4H)-one 1-oxide; 6-[({1-[2-(6-Chloro-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 4-(2-{(2S,5R)-5-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile; 6-[({1-[2-(7-Bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one; 2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile; 2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-methylpiperidin-1-yl}ethyl)-5,7-difluoroquinolin-2(1H)-one; 1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; Cis±4(1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylic acid; Methyl (Cis±4)-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate; Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; Cis±1-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile; 5,7-Difluoro-1-(2-{4-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one; Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-methoxypiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; Cis±1-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile;

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