CZ20002322A3 - 4-Hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents - Google Patents

Abstract

The solution provides 4-hydroxyquinoline-3-carboxamide and hydrazine compounds of formula I. These compounds are useful for the treatment and prevention of herpesvirus infections, particularly human cytomegalovirus infection.

Description

4-F^hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents

Technical field

The invention includes derivatives of 4-hydroxyquinoline-3-carboxamide and more particularly includes N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide of formula I. These compounds are useful antiviral agents, particularly agents against herpes viruses.

State of the art

Herpesviruses comprise a large family of viruses with double-stranded DNA. They are the source of the most common human viral diseases. Eight herpesviruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpesviruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.

HSV-1 and HSV-2 cause cold sores on the lips and genitals. They also cause eye infections and encephalitis. HCMV causes birth defects in children and various diseases in immunocompromised patients, such as retinitis, pneumonia, and gastrointestinal diseases. VZV causes chickenpox and cold sores. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease. HHV-6 causes roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. The association of HHV-7 is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Kaposi's sarcoma, body cavity lymphomas, and multiple myeloma.

The compounds of the invention differ from all other pharmaceutical hydroxyquinoline agents in that the unique position of the chloro substituent on the N-phenylmethyl of formula I is critical for useful antiviral activities. These compounds are useful for the treatment or prevention of the above-mentioned herpesvirus infections, particularly human cytomegalovirus infection.

US Patent 4,959,363 describes quinolines of structure 3 useful as agents against herpes viruses

• · · · • · · · • * · · • · · · · 99

where R is hydrogen, hydroxy, amino or lower alkyl, R ¹ is lower alkyl, lower alkenyl, cycloalkyl, pyridinyl, phenyl or substituted phenyl, R ² is hydrogen, amino or hydroxy, R ⁶ is H or F, and R ⁷ is phenyl, pyridyl or other selected heterocycles. It does not describe compounds where R is alkylaryl (substituted) and R 1 is hydrogen.

Related compounds in which the NHR group of structure 3 is replaced by groups such as N(CH3)2, NHOCH3 or N(CH3)OH are described in the Journal of Medicinal Chemistry, 36, 1580-1596 (1993) and Book of Abstracts, 21 l ^th National ACS Meeting, New Orleans, LA (1996).

German patent application 1,908,548 describes antiviral agents of structure 4

where R1 is H, -OH, halogen, -SH or lower alkyl sulfide, ^R2 is H, -COOH, -CN, -CHO, lower alkyl carboxyl, ^-CONHR4 or -CON( ^R4 )2, R1 is a wide variety of substituent groups and ^R4 is lower alkyl, aryl, arylalkyl or lower alkylamine. However, the application does not describe the preparation or testing of any carboxamide-quinoline compounds.

U.S. Patent 5,175,151 describes compounds of structures 5 and 6 having antiviral and antihypotensive properties. A large number of quinoline compounds are also described generically, including structures 5 and 6. Preferred compounds of this patent are described as carboxylic esters of :r ² >,

H ³

About %r ⁴ r ⁵

OR ¹

O

N^N \=J • » • · • 4

I * l· » · · « » · · « ♦ ♦ ··

Among the groups described are the following: RJ is alkyl, alkenyl, acyl or other group, R ² is alkyl, alkoxy, aryloxy, aralkoxy, halogen and a wide variety of polar and/or acidic functional groups, R ³ is H, alkyl, aryl, aralkyl and other groups, R ⁴ and R ⁵ are H, alkyl, aryl, aralkyl, alkenyl, heteroalkyl, heteroaryl and other groups. They are the same or different. All of these compounds have an oxygen substituent or an imidazolyl group at the 2-position on the quinoline ring.

Japanese patent JP 08151268 describes compounds of structure 7 having activity against herpes viruses:

• · • · ·· ··

N' where R1 is alkenyl, cycloalkyl, aryl or heterocycle, ^R2 is optionally substituted aryl or heterocycle, X is H or halogen and A is N or -CN.

Japanese patent JP 02264724 describes antiviral agents having the structure 8:

R ² o

where R1 is alkyl, alkenyl, cycloalkyl, aryl or heterocycle, ^R2 is H, halogen, alkoxy, OH, protected OH or mono or dialkyl amine, ^R3 is optionally substituted cycloalkyl or vinyl, A is N or C( ^R4 ) and ^R4 is H or halo.

Japanese patent JP 02152966 describes compounds of structure 9 useful as anti-asthma and anti-allergy agents:

·· ·* « · · · · · · ι« · · · 9

9 · 9

99

HO Ο eyes.'‘ ‘Ν'

R ¹ ·9

9 · » • · · 9

9 9 · • · · ·

C< ·* where R.1 is H, lower alkyl, phenyl or phenyl-lower alkyl, R.2 is hydrogen or lower alkyl and R.3 is alkyl (optionally substituted on the phenyl ring with lower alkyl, halogen, lower alkoxy or sulfamoyl) or naphthyl-lower alkyl. The combination of R- and on a heterocycle comprising an amide nitrogen is also described.

Phenethyl compounds, such as structures 10 to 14, have been reported as synthetic intermediates in the synthesis of antimalarial compounds (Indian J. of Chemistry, 1010 (1969), Indian J. of Chemistry Vol. 24B, 737 (1985)).

Compound No. r! r! r! 10 H H H 11 H Cl H 12 Ome H H 13 H Ome H 14 H H Ome

U.S. Patent 4,450,167 describes compounds of structure 15 useful as anxiolytics:

R

R ⁴

R ¹ = H, alkyl, phenyl, PhCH ₂ R ⁴ = alkyl, aryl, heteroaryl R ³ = H, OH

R = 6- or 7-H, halide, alkyl, cycloalkyl, etc.

These compounds are derivatives of arylamines and alkylamines, unlike the compounds of the invention, which are derivatives of benzylamine (arylalkylamine).

U.S. Patent 4,786,644 describes quinoline carboxamides of structure 16 useful as analgesics:

R ¹ , R ² = halide, lower alkyl, lower alkoxy group, identical or different

R ³ = phenyl or heteroaryl, optionally substituted, m, n = 0 or 1

US Patent 4,397,856 describes structural variations of 4-hydroxyquinolines, such as structure 17, which have analgesic activity.

X = H, halide, lower alkyl, lower alkoxy group, OCF ₃ , SCF ₃ or CF ₃ R ¹ = H, lower alkyl

R ² = H or a ring which is optionally unsaturated or optionally heterocyclic, optionally substituted.

{ ·· ·* « · · * « · · · • · · 9

9 9 t «« · 9

99

9 9 · • · * I • · « *

R ³ = H, lower alkyl, halide R ⁴ = H or halide R ⁵ = halide

DE 3808118 describes synthetic intermediates of general structure 18.

R = lower alkyl, phenyl or substituted phenyl

R ⁵ , R ⁶ = Η, NO2 or halide, identical or different

R ⁷ = H, lower alkyl, halide, amino group or substituted amino group

R ⁸ = H, lower alkyl, alkoxy group (1-3 carbons), alkylmercapto group (1-3 carbons), halide, nitro group, alkoxycarbonyl or cyano group

These compounds are derivatives of arylamines and alkylamines, unlike the compounds of the invention, which are derivatives of benzylamine (arylalkylamine).

The use of quinolines, such as general structure 19, as synthetic intermediates in the synthesis of antibiotics, such as general structure 20, is described in many sources, for example, in U.S. Patent 3,864,329. U.S. Patent 3,951,955, EP 736531 (which describes alpha-substituted pyrazino quinoline compounds) and DD 279887. In some of these references, the structures below, which are derivatives of phenylglycine, are drawn as tautomers of the quinolone.

► · · • » t • ·· • · 7 • · * k · · • * • · Φ • · «· ·»·

X = OH, OCH2CH3

X - A beta lactam fragment of the antibiotic ^β2 °ϊχΧ ^κ ' ^οη2_χ

X = a beta lactam antibiotic R ¹ , R ² = H or acyl

Hydroxyquinoline-beta lactam conjugates, such as structure 21, are also described, for example, in US Patent 5,019,570 (and its equivalent EP 304158) and US Patent 5,091,139.

US Patent 3,496,184 (and its equivalents, GB 1270412 and DE 1929165) describe carboxylic esters of the general structure 22 as growth promoters for farm animals. The corresponding carboxylic acids, amides, nitriles and hydrazides are claimed generically. The amides and hydrazides are described as optionally substituted on the nitrogen with one or more alkyl or aralkyl groups. One amide, 23, and one hydrazide, 24, are described in the examples.

At least one of R ¹ , R ² , R ³ or R ⁴ is (cycloalkyl-AX-), where X = S or O and A = -(CH ₂ ) _n - or a single bond between the alkyl or cycloalkyl group and A.

* 9 «9 99

US Patent 3,960,868 describes acids, esters and amides of structure 25 having anti-inflammatory, analgesic, antimicrobial and histamine release inhibiting activities.

• 9 99

9 9 » • 9 99 • 9 9 9 9

9 9 9

9 9 9

R _x = OH, lower alkoxy group, -NH ₂ , lower alkylamino group, lower dialkylamino cyclic amines, phenylamines (anilines) and arylalkylamines such as benzyl, optionally substituted.

Ro = H, alkyl, OH or lower alkoxy group.

R 1 = alkyl or cycloalkyl, optionally substituted.

R ₂ = cycloalkyl, cycloalkenyl or 1-adamentyl.

R3 = alkyl, halide or hydrogen.

US Patent 5,563,141 describes compounds of structure 26 containing an acidic and a basic functional group separated by a suitable linker as antagonists of adhesion molecules.

( _CH2 ) _n -X

R = H, alkyl or phenyl-(CH ₂ ) _n X = amino-substituted aromatic heterocycle

Y = acidic functional group

These compounds contain an amine-substituted heterocycle attached by a suitable linker to the carboxamide nitrogen.

Published PCT application WO 96/16046 describes pyrimidine derivatives, including structures 27 and 28, as antibacterial agents.

R ¹ = OH, alkoxy group, amino group or (hydroxyalkyl)amino group

R ² and R ³ = H, F, OH or OMe, the same or different

R ⁴ = Br or higher alkoxy group

R ⁵ = lower alkoxy group

All compounds described by structures 27 and 28 contain a diaminopyrimidine group attached to a quinoline ring via a piperazine or phenyl ring insert.

Published PCT application WO 95/11592 describes substituted quinolines 29 as marine antifouling agents. WO 96/32015 claims the same broad group of quinolines as antifungal agents.

X 1 , X ₂ , X 3 , X 5 , X ₆ and X 7 are independently any of a broad group of substituents including OH, (C = O)NHR, where R is C 1 -C 12 alkyl.

Published PCT application WO 97/15557 describes a method for preparing combinatorial libraries of substituted quinolines of structure 29. According to the broad definitions of X^-X^, any of the quinoline ring substituents can be independently OH or (C=O)NHR7, where R7 is an aralkyl group. "Nuc" is defined as a chemical group having a reactive pair of electrons, including, but not limited to, amines, enolates, Grignard reagents, alkoxides, and cyanide.

fc· fcfc fc · * fc » v

A number of sources describe the synthesis of hydrazides by their conversion to acylhydrazones 30 as follows: J. Ind. Chem. Soc. vol. 14b, 138-141 (1991), J. Sci. Ind. Res. vol. 14c, 228-230 (1955), and J. Sci. Ind. Res. vol. 14b, 261-263 (1955).

Compounds of structure 30 are substituted on the external hydrazide nitrogen through a carbon-nitrogen double bond.

The chemical synthesis of acylthiosemicarbazides 31 was reported in Indian J. Chem. Vol. 16B, 231-234 (1978). Structures 32 are listed in the CAS registry, but do not appear to have corresponding literature references.

R = aryl, alkyl, cycloalkyl

R = CH ₂ Ph, tert.butyl

The compounds described by the two structures above have a carbonyl (C=O) or thiocarbonyl (C=S) group attached to the outer hydrazine nitrogen atom.

U.S. Patent 5,318,96, U.S. Patent 4,777,252 and Canadian Patent Application 2,024,282 describe compounds of structures 33 and 34.

♦· « 9 9 *

9 9 9 • 9 9 9 9 • · · «

9· <9

99 · · · • · 99 • · · 9

9 9 9 • 9 9· “ΧίυΛ*

Η .0 -SO,-NH-C-NHCT

The Ιχ

NCO-CH. H ^M O

-O

HjN )r ^s .

"y"

HIM

HIM

ALL-ALL-ALL·

O SO ₃ H

US Patent 5,610,192 describes compounds of structure 35 useful as metazoan protease inhibitors, where X is a planar linking group including amide, urea, fumarate bisamides and Nacylhydrazones.

R = aryl or heteroaryl

The quinoline ring is optionally substituted with OH or various other groups on one or both rings.

Compounds of structure 35 have a substituent on the external hydrazide nitrogen across the carbon-nitrogen double bond.

Japanese patent application JP 8301849-A describes a heterocyclic compound of structure 36 as a tachykinin receptor antagonist:

B

CONR—(CH ₂ ) _n

wherein ring A is an optionally substituted homocyclic or heterocyclic ring, B is an optionally substituted amino group or an optionally substituted hydroxyl group, ring C is an optionally substituted homocyclic or heterocyclic ring, -X-Y- is a group in which (1) one element is -NRp (Rj is H or an optionally substituted hydrocarbon group) or -O and the other element is -CO- or -CS- or (2) one element is -N= and the other element is -CR2- (R2 is H, halogen, an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxyl group), R is H or an optionally substituted hydrocarbon group and n is 1-3.

Published PCT application WO 98/12180 describes compounds of structure 37 for controlling undesirable plants:

Where Rj, R2 are hydrogen, nitro, halogen, nitrile, SCN, hydroxyl, thiol, optionally substituted alkyl(1-6), alkoxy(1-6), alkylthio(C1-6), alkylsulfinyl(C1-6), alkylsulfonyl(C1-6), alkoxysulfonyl(C1-6) or optionally substituted phenyl, phenylthio, phenyloxy, phenylsulfinyl or phenylsulfonyl, Z is an optionally substituted 4-membered unsaturated, partially or fully saturated chain of three carbon atoms and one nitrogen atom, Q is an optionally substituted cyclohexane-1,3-dione attached at the 2-position.

WO 97/48694 describes compounds of structure 38 useful for regulating bone growth:

R ⁵ where R 4 is a series of substituents including alkyl optionally substituted with halogen and alkenyl, R 6 is an optionally substituted carbocyclic or heterocyclic ring.

DE 19642290 describes compounds of structure 39 useful for the treatment of Alzheimer's disease:

where R ¹ is hydrogen, halogen, alkyl(1-4) or alkoxy(1-4), R ² is hydrogen, halogen, alkyl(1-4) optionally substituted with fluorine, alkylthio(1-4) optionally substituted with fluorine, alkoxy(1-4) optionally substituted with fluorine, O(CH2)0-3(aryl)amino. R ³ and R ⁴ are hydrogen, alkyl(1-4) or alkoxy(1-4), (CH2)0_N(alkyl)j_2, amides linked to alkyl amino, -C5HN(CH2)0-9Ph(OS).

U.S. Patent 4,870,182 describes compounds of structure 40 useful as antiallergic agents:

where Y is CONR'R", R' and R" are hydrogen or alkyl(1-4), R" can also be phenyl, R ² can be nitro, amino, cyano, alkyl(1-3), alkoxy(1-3), alkylmercapto(1-3), alkylsulfonyl(1-3) or phenylsulfonyl, X ³ , X ⁴ and X ³ are hydrogen, halogen, nitro, cyano, alkyl(1-3), alkoxy(1-3), alkylmercapto(1-3), alkylsulfonyl(1-3) or phenylsulfonyl group which is optionally substituted on the aryl.

U.S. Patent 4,965,266 describes compounds of structure 41 useful as antiallergic agents:

where A is an alkylene group, X is NCHPh2 or C=CPh2, R1 is hydrogen, halogen, hydroxy, alkyl(1-6), alkoxy(1-6), nitro or cyano.

♦ ♦ ·· • · · • · · • · · • · · • 9 9 9 • « l* · · · · * * · • · *· * · • · · 9 · * ♦ • · · · · · ·· ·« * · * · · ·

Published PCT application WO 97/04779 describes compounds of structure 42 useful as inhibitors of phosphodiesterase IV esterase and/or tumor necrosis factor activity.

Structure 42, where R ¹ is optionally substituted alkyl(1-6), alkylcycloalkyl(1-6), alkylaryl(1-6), alkylheterocyclo(1-6) or alkylheteroaryl(1-6), is not similar to compounds of this invention where R 1 is hydrogen.

The essence of the invention

The invention provides a compound of general formula I

(I) or a pharmaceutically acceptable salt thereof, wherein A is:

a) -Cffy-or

b) -NH-,

R', R ² , R^ and R ⁴ are independently

a) -H,

b) halogen,

c) -CN,

d) -no ₂ ,

Φ φ

φ φ

φφ φφ

»· • Φ ♦ · · φ Φ • · • · ♦ • ΦΦ φ · Φ • · * • ♦ · φ Φ « φ Φ « Φ · Φ ·

e) aryl,

f) het,

g) -OR ⁵ ,

h) C1- _C12 alkyl,

O ^c 1 - ^c 12 ^alkyl substituted with one to three -CN, halo, -NO2, -OR ⁵ , -C(=O)R ⁵ ,

COOR ⁵ , het, aryl, -SR ⁵ , -OR ⁶ , -NR ⁷ R ⁸ , -OP(=O)(R ⁹ )2, -OPH(=O)R ⁹ , -OC(=O)R ¹⁰ , -O glycyl, -O-valyl or -O-lysyl,

j) -OCR ¹¹ ,

k) -CH=CH-R ¹² ,

-(CH ₂ ) _m C(=O)R ¹³ ,

m) -SR ¹⁴ ,

n) -C(=S)R ¹⁵ ,

o) -(CH ₂ ) _m -SO _i R ¹ 3,

p) -NR ⁷ R8,

q) -NHSOjR ¹³ ,

r) R ¹ and R ² taken together are het or C 1-8 cycloalkyl or

s) R ² and R ³ taken together are het or C 4-6 cycloalkyl,

^R5 is

a) -H,

b) C4.C3 alkyl optionally substituted with one to three -OH, -CN, C1.C4 alkoxy, halo, _-NO2 , het or aryl,

c) aryl or

d) het,

^R6 is

a) -SO2C1.6 alkyl,

b) -SO2-(CH2) _m -aryl or

c) -SO ₂ -(CH ₂ ) _m -het,

R ⁷ and R ¹¹ are independently

a) -H, • fc fc fc · • · • · · • fcfc • fc • fc fc • fc •

• « fc « fcfc ·* • fcfc · fc fcfc » • · · · · • fcfc fc

b) C1-C8 alkyl optionally substituted with one to three -NO2, halo, het, C1-C8 cycloalkyl, C1-C8 alkynyl, C1-C8 alkenyl, ^-SR14 or ^{-NR16R17 ,}

c) aryl,

d) het,

e) -(CH ₂ ) _m -C(=O)OR ⁵ ,

f) -(CH ₂ ) _m -C(=O)R ⁵ or

g) R ⁷ and R ⁸ taken together form het,

^R9 is

a) -OH or

b) _-OC1-8 alkyl,

^R10 is

a) -H,

b) C1-C8 alkyl,

c) -NR ⁷ R ⁸ ,

d) C1-C8 alkyl substituted with one to two halogens, het, ^-NR7R8 , ^-COOH , O( _CH2 ) _m -COOH or -C(=O)N(C1-4 alkyl)( _CH2 ) _nS (=O) _2O -M+,

^R11 is

a) C1-C8 alkyl,

b) C1-C8 alkyl substituted with one to three -CN, halogens, _-NO2 , ^-COOR5 , C(=O) ^R5 , ^-SR5 , aryl, ^-OR5 , ^-NR7R8 , -OP(=O)( ^R9 ) ² _, -OPH(=O) ^R9 , -OC(=O) ^R10 , -Oglycyl, -O-valyl or -O-seluptamatyl or

c) -(CH ₂ ) _m -het,

^R12 is

a) -H,

b) -CN,

c) C1-C8 alkyl,

d) C1-C8alkyl substituted with one to three -CN, halo, _-NO2 , -C(=O) ^{R5 , -COOR5} , aryl, het, ^-SR5 , ^-OR5 , ^-NR7R8 , -OP(=O)( ^R9 ) ₂ or -OPH(=O) ^R9 ,

e) -C(=O)R ⁵ or ·· 99 ♦ * « « · ·· • · # • · « • · · » * · ·· ·« ·· ·« · · · · • · 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9

999 999 99 99

f) -COOR ⁵ ,

^R13 is

a) C1- _C8 alkyl,

b) C1-C8 alkyl substituted with one to three -CN, halo, -NO2, -C(=O) ^R5 , het, aryl,

-COOR ⁵ , -SR ⁵ , -OR ⁵ or -NR ⁷ R ⁸ ,

c) het,

d) aryl,

e) -NR ⁷ R ⁸ ,

f) -OR ⁵ ,

g) hello,

^R14 is

a) C μC ₈ alkyl or

b) C1- _C8 alkyl substituted with one to three -CN, halo, -NO2, -C(=O) ^R5 , ^COOR5 , het, aryl, ^-OR5 or ^{-NR7R8 ,}

^R15 is

a) -NH2 or

b) -NHNH ₂ ,

R16 and ^R17 are independently

a) -H,

b) C1X4 alkyl,

c) -C(O=) C1.C4 alkyl or

d) -C(O=)-(CH ₂ ) _m -aryl, aryl is phenyl or naphthyl optionally substituted with R^ ⁸ , het is a 5-, 6- or 7- membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the heterocyclic ring is optionally linked to a benzene ring, wherein aryl, het and the benzene ring are optionally substituted with R^ ⁸ ,

R ¹⁸ is a) halo,

9 · ·

9 99

9 9 9 • 9 9 9

9 9

9 9 9

9 9 9

9 9 9 9

9 9 9

b) -N0 ₂ ,

c) phenyl optionally substituted with one to five -OH, -CN, halo, _-NO2 , C1-C8 alkyl, het, or -OC1-C4 alkyl,

d) C1-C8 alkyl optionally substituted with one to three halo, -CN, _-NO2 , aryl, ^-SR5 , ^-OR5 or ^-NR7R8 ,

e) -OR ⁵ or

f) -SO ₂ NH ₂ ,

M is a sodium, potassium or lithium atom, i is 1 or 2, m is 0, 1, 2 or 4, n is 0, 1,2,3 or 4, with the following proviso:

(a) when R ² , R ⁵ and R ⁴ are all hydrogen, then Rl is other than methoxy, (b) when R ⁴ is Cl and R ² and R ⁵ are all hydrogen, then Rl is other than methyl, (c) when Rl is hydrogen, and R ² and R ⁴ are all fluoro, R ⁵ is het, then het is other than substituted piperazinyl, (d) when Rl and R ⁵ are all hydrogen, R ² is fluoro, then R ⁴ is other than fluoro, (e) when R ² and R ⁴ are all hydrogen, Rl is fluoro, then R ⁵ is other than fluoro, (f) when Rl and R ⁵ are all hydrogen, R ² is chloro, then R ⁴ is other than chloro, (g) when Rl, R ² and R ⁵ are all hydrogen, then R ⁴ is not bromo, (h) when Rl, R ⁵ and R ⁴ are all hydrogen, then R ² is not trifluoromethoxy, (i) when Rl, R ² and R ⁴ are all hydrogen, then R ⁵ is not trifluoromethoxy and (j) when R 1 , R ² and R ⁵ are all hydrogen, then R ⁴ is not morpholinyl.

Another aspect of the invention also includes an antiviral pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, and a method for treating and preventing herpesvirus infections in mammals including humans, and further the use of a compound of formula I for the preparation of a medicament for treating and preventing herpesvirus infections in mammals including humans.

For the purposes of this invention, the carbon atom content of various hydrocarbon-containing groups is indicated by a suffix indicating the minimum and maximum number of carbon atoms in the group, for example, the suffix Cj_Cj group from the integer "i" to the integer, j" carbon atoms *

«· ·· 9 • · ♦ · · · • ·

99 999

9

9 9 99 9

9 9 9 9

9 9 9 9 · • » · · ·

999 99 99 inclusive. Thus, for example, (C1-C4)alkyl refers to alkyl of one to three carbon atoms inclusive or methyl, ethyl, propyl and isopropyl, their linear and branched forms.

The compounds of the invention are named according to the IUPAC nomenclature system or

TIME.

The term "C1-C8", "C1-C8" and "C1-C4" alkyl refers to an alkyl group having one to eight, one to six and one to four carbon atoms, respectively, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric forms thereof.

The term "C 1 -C 6 alkynyl" refers to an alkynyl group with at least one triple bond having two to six carbon atoms.

The term "C 1 -C 6 alkenyl" refers to an alkenyl group with at least one double bond having two to six carbon atoms.

The term "C3-C6 cycloalkyl" refers to a saturated or unsaturated ring having three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and isomeric forms thereof.

The term "C1-C4 alkoxy" refers to an alkyl group having one to four carbon atoms attached to the oxygen atom of the hydroxyl group, such as, for example, methoxy, ethoxy, propoxy, butoxy, and isomeric forms thereof.

The term "aryl" refers to phenyl or naphthyl, which are optionally substituted with one to five suitable substituents.

The term “het” refers to a 5- or 6-membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be in a protected form. “Het” is optionally substituted with one to three suitable substituents. Examples of “het” are thiadiazolyl, thiazolyl, benzothiazolyl, pyridinyl, morpholinyl, imidazolyl, indolyl, pyrrolyl, morpholinyl, thiophenyl and 2-oxo-oxazolyl.

The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

Abbreviations in the description of the invention are well known to the skilled person and may be used such as "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours, "tm" for room temperature.

The compounds of the invention may be in the form of pharmaceutically acceptable salts.

• · « » • · · • · ·· « · 4 • · ( » · · I ·· ·· • · "Pharmaceutically acceptable salts" refers to those salts which have the biological activity and properties of the parent compound and which are not biologically or otherwise undesirable.

"N-oxide" refers to the oxidized form of the nitrogen in the ring of the 4-hydroxyquinoline compounds of the invention. The preparation of such compounds is well known to those skilled in organic chemistry, including methods such as oxidation with metachloroperoxybenzoic acid.

"Electron-withdrawing group" means any substituent on a ring that tends to withdraw electron density from the ring. Examples of such groups include halogen, nitro, cyano, carboxylic acids, carboxylic esters, sulfoxides, sulfones, sulfonamides, ketones, and aldehydes.

Compounds of the invention may alternatively be designed according to the tautomeric structure of general formula II, in which the variables are the same as defined in general formula I.

The following Schemes A through V describe the preparation of compounds of the invention. All starting compounds are prepared by the procedures set forth in these Schemes or by procedures analogous thereto, which are well known to one skilled in the art of organic chemistry. All final compounds of the invention are prepared by the procedures set forth in these Schemes or by procedures analogous thereto, which are well known to one skilled in the art of organic chemistry. All variables used in the Schemes are defined below or in the claims.

In Scheme A, the compounds of the invention can be prepared by one of several methods starting from suitable 4-hydroxyquinoline-3-carboxylic esters a-1. In the first method A-1, the ester a-1 is suspended in 5 to 10 parts of the amine and the mixture is heated to 190 to 200 °C for 30 minutes to 4 hours. The product a-2 is isolated by diluting the cooled reaction mixture with hexanes or toluene and collecting the solid precipitate by filtration. In some cases, it is necessary to further purify the starting product by chromatography or recrystallization from a suitable solvent mixture, typically acetic acid/water.

·· ·· · 9 · • · ·· • · · ·

9 9 9 ·

9

9

9·9 999

9 9

9 9

9 9

9 9 9

99

In the second method A-2, the ester a-1 is reacted with one or more equivalents of the dimethylaluminum salt of the appropriate amine to form the desired amide. The product a-2 is separated from the aluminum salt present in the reaction mixture by treatment with hydrochloric acid and further purified by recrystallization or chromatography. This method has the advantage of requiring less heating of the reactants than the first method and is therefore successful in some cases where the first method is not applicable.

In the third procedure A-3, the ester a-1 is hydrolyzed to the corresponding carboxylic acid a-3 by treatment with sodium or lithium hydroxide followed by neutralization. The carboxylic acid a-3 is converted to the imidazolide a-4 by treatment with 1,1°-carbonyldiimidazole. The imidazolide, which can either be isolated or used in situ, is converted to the desired amide a-2 by reaction with an appropriate amine. The product is typically isolated from the reaction mixture by evaporation of the solvent followed by chromatography or recrystallization, or by precipitation of the product from the reaction mixture by dilution with multiple volumes of water.

In the fourth method A-4, the carboxylic acid a-3 is converted to the acid chloride by treatment with thionyl chloride and then converted to the desired amide a-2 in a manner similar to that described for the imidazolide a-4. The starting materials a-1 used in this scheme are prepared by a well-known procedure, by reaction of an appropriately substituted aniline with diethyl ethoxymethylene malonate, followed by pyrolysis of the resulting adduct (J. Amer. Chem. Soc., 68, 1264 (1946) and other references cited below).

Compounds of the invention can also be prepared according to the procedures shown in Scheme B. This procedure is further elaborated in Examples 38 to 47.

Compounds of the invention can also be prepared according to the procedures shown in Scheme C. This procedure is further elaborated in Examples 48-49.

Compounds of the invention can also be prepared according to the procedures shown in Scheme D. This procedure is further elaborated in Examples 54-55.

Compounds of the invention can also be prepared according to the procedures shown in Scheme E. Condensation of aniline of structure e-1 with diethylethoxymethylenemalonate (neat, 140°C, 1.5 hours) gives the enamine intermediate. Addition of diphenyl ether to the reaction mixture containing this intermediate followed by heating to 250°C for 2 hours gives quinoline intermediate e-2. This ester is converted to the desired amide of formula e-3 by simply heating to 190°C for 1.5 hours.

Compounds of the invention can also be prepared according to the procedures shown in Scheme F. Commercially available 2-fluoroaniline (f-1) is converted to ethyl 8-fluoro-4-hydroxy-3-quinolinecarboxylate (f-2) by reaction with diethyl ethoxymethylenemalonate and heating to 135 °C for 1 • 4

I I ·· • 4 44

4 4 4

4 4 4

4 4 4

4 4 4

44 hours followed by dilution with diphenyl ether and heating to 260 °C for an additional 3 hours. The resulting ester is saponified with aqueous lithium hydroxide to give the acid f-3, which is then activated with 1,1°carbonyldiimidazole to give the imidazolide f-4. Reaction with various amines gives the desired amides of formula f-5. The amides are prepared either as discrete analogues or as part of a parallel synthetic effort.

Compounds of the invention can also be prepared according to the procedures shown in Scheme G.

In Scheme G, a solution of compound g-1 and a primary amine are heated at 90 °C overnight to give compound g-2.

Compounds of the invention can also be prepared according to the procedures shown in Scheme H.

In Scheme H, acetylenes h-2 are coupled to iodoquinolines h-1 under spallation. The resulting quinolines l-acetylenes h-3 are partially reduced with hydrogen over a poisoned palladium catalyst to give cis-alkenes h-4. Alternatively, quinolines l-acetylenes h-3 are completely reduced with hydrogen over an active palladium catalyst to give the corresponding alkanes h-5.

Compounds of the invention can also be prepared according to the procedures shown in Scheme I.

In Scheme I, quinolines substituted with heterocycles h-2 are prepared by the palladium-catalyzed coupling of the corresponding tributyltin heterocycle to iodoquinoline h-1.

Compounds of the invention can also be prepared according to the procedures shown in Scheme J.

In Scheme J, cyano-substituted quinolines j-2 are prepared from iodoquinolines j-1 by palladium-catalyzed potassium cyanide coupling. Cyanoquinolines j-2 are then reacted with hydrogen sulfide to give the corresponding thioamides j-3. Thioamides j-3 are versatile intermediates for the synthesis of various heterocycles. For example, reaction of thioamide j-3 with bromoacetaldehyde diethyl acetal leads to thiazole j-4. Alternatively, thioamide j-3 is reacted with methyl triflate and then with hydrogen sulfide and hydrazine to give thiocarbonylhydrazide j-5. This is also a versatile intermediate for the synthesis of heterocycles. For example, reaction with acetyl chloride gives methylthiadiazole j-6.

Compounds of the invention can also be prepared according to the procedures shown in Scheme K.

In Scheme K, the thiocyanates k-1 are prepared by electrophilic aromatic substitution reactions of anilines using ammonium thiocyanate and bromine. Conversion of the thiocyanate to benzyl sulfide is achieved by alkaline hydrolysis followed by alkylation of the thiol intermediate with benzyl chloride to give compounds k-2. Attachment of the aniline to the 4-hydroxyquinoline ring system represented by k-3 is achieved by heating with diethyl ethoxymethylenemalonate, first at 135 to 150 °C, then in refluxing diphenyl ether. Reaction of the esters k-3 with 4-chlorobenzylamine at elevated temperature causes aminolysis leading to compounds of formula k-4. Oxidation of the sulfide to

4» «4 • 4 4

4 4 4

4 4 «4 4 «4 4

4 4

44

444 4 sulfonyl chloride is obtained by reaction with chlorine in acetic acid. The resulting sulfonyl chlorides of formula k-5 are transformed into sulfonamides k-6 by reaction with amines in pyridine solution.

Compounds of the invention can also be prepared according to the procedures shown in Scheme L.

In Scheme L, compounds 1-1 are phosphitylated with di-tert-butyldiethylphosphoramidite to give an intermediate phosphite, which is oxidized in situ with m-chloroperbenzoic acid to give di-tert-butyl phosphates 1-2. Reaction of the phosphates with trifluoroacetic acid cleaves the tert-butyl groups to give phosphoric acids 1-3. If the oxidation step with m-chloroperbenzoic acid is omitted from the phosphitylation reaction, mono-tert-butyl phosphites 1-4 can be isolated. Their reaction with trifluoroacetic acid gives phosphites 1-5.

Compounds of the invention can also be prepared according to the procedures shown in Scheme M.

In Scheme M, alcohols m-1 are coupled with the triethylammonium salt of suleptanoic acid (triethylammonium salt of 2-[(7-carboxyheptanoyl)(methylamino]-1-ethanesulfonate) using diisopropylcarbodiimide and 4-diaminopyrimidine to give the corresponding esters. Exchange of the triethylammonium salt with sodium ion gives the sodium salts m-2.

Compounds of the invention can also be prepared according to the procedures shown in Scheme N.

In the N scheme, alkylation of 3-mercaptoaniline with benzyl chloride gives benzyl sulfide n-1. The attachment of the aniline to the ring system of 4-hydroxyquinoline n-2 is achieved by heating with diethylethoxymethylene malonate, first at 135 °C, then in refluxing diphenyl ether. Reaction of the ester n-2 with 4-chlorobenzylamine at elevated temperature causes aminolysis leading to compounds of formula n-3. Oxidation of the sulfide to the sulfonyl chloride is achieved by reaction with chlorine in acetic acid. The resulting sulfonyl chlorides of formula n-4 are transformed into sulfonamides n-5 by reaction with amines in pyridine solution.

Compounds of the invention can also be prepared according to the procedures shown in Scheme O.

In Scheme O, intermediate o-2 is prepared by reacting phenol o-1 with chloroethanol and sodium hydroxide. Hydrogenation of o-2 in the presence of a palladium catalyst gives o-3, which itself, when mixed with ethoxymethylenemalonate, gives intermediate o-4. Selective acetylation of the hydroxyl group in o-4 with a mixture of acetic acid and acetic anhydride gives intermediate o-5, which is cyclized in refluxing diphenyl ether. This gives hydroxyquinoline o-6. Reaction of this compound with a benzylamine derivative at 190 °C gives the desired product o-7.

Compounds of the invention can also be prepared according to the procedures shown in Scheme P.

In Scheme P, the reaction of 4-cyanobenzyl bromide p-1 with sodium azide in dimethylformamide gives benzyl azide p-2. This intermediate is reduced with triphenylphosphine in moist tetrahydrofuran, which ·· *· » · · >

· 9 · • 9 · 9 « • 9 9 ·

will give the desired amine p-3. The amine p-3 is used as the amine component in the amide bond forming reactions as shown in Schemes A, B, C, D and F.

Compounds of the invention can also be prepared according to the procedures shown in Scheme Q.

In Scheme Q, aniline q-1 is reacted with diethyl ethoxymethylene malonate at 135 °C and the resulting adduct is heated in refluxing diphenyl ether. Reaction of q-2 with dithiothreitol gives thiol q-3, which is alkylated with a suitable alkyl halide to give q-4. Reaction of q-4 with 4-chlorobenzylamine at 190 °C gives amide q-5. Reaction of this amide with a single equivalent of meta-chloroperbenzoic acid gives sulfoxide q-7, while the use of two or more equivalents gives sulfone q-6.

Compounds of the invention can also be prepared according to the procedures shown in Scheme R.

In Scheme R, N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide r-1 is converted to 6-carboxamide r-2 by reaction with palladium(II) acetate, 1,3-bis(diphenylphosphino)propane, and various amines under a carbon monoxide atmosphere with heating.

Compounds of the invention can also be prepared according to the procedures shown in Scheme S.

In Scheme S, N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide s-1 is converted to the 6-carboxylic acid s-2 by reaction with palladium(II) acetate, 1,3bis(diphenylphosphino)propane, and water under a carbon monoxide atmosphere with heating. The acid s2 is reacted with thionyl chloride to give the acid chloride. This is then converted to the 6-carboxamide s-3 by reaction with p-chlorobenzylamine in pyridine.

Compounds of the invention can also be prepared according to the procedures shown in Scheme T.

In Scheme T, 3-([(4-chlorobenzyl)amino]carbonyl)-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid from Example 1 t-1 is converted to the 6-tert-butyl carbamate t-2 by reaction with diphenylphosphoryl azide in tert-butanol with heating. The carbamate is removed with trifluoroacetic acid to give 6-aminoquinoline t-3. The amine is sulfonated with 4-methoxyphenylsulfonyl chloride to give 6-sulfonamide t-4.

Compounds of the invention can also be prepared according to the procedures shown in Scheme U.

In Scheme U, 1-fluoro-4-nitrobenzene u-1 is converted to 2-(4-nitroanilino)-1-ethanol u-2 (R=H) by heating with ethanolamine in ethanol. 2-(4-nitroanilino)-1-ethanol u-2 is converted to 2-(4-nitroanilino)ethyl acetate u-3 by reaction with acetyl chloride. The nitro group is reduced to the free amine with palladium on carbon and hydrogen gas to give v-2. The resulting aniline is reacted with diethylethoxymethylenemalonate to give u-4. The enamine is then cyclized by heating in diphenyl ether to give quinoline u-5. Reaction with excess p-chlorobenzylamine gives 3-carboxamide u-6.

• ·

Compounds of the invention can also be prepared according to the procedures shown in Scheme V. In Scheme V, 2-(4-nitroanilino)-1-ethanol v-1 (R=H) is reduced with palladium on carbon and hydrogen gas. The resulting aniline is reacted with diethylethoxymethylenemalonate to give v-2. Reaction with 1,1°carbonyldiimidazole cyclizes v-2 to give v-3. The enamine is then cyclized by heating in diphenyl ether to give quinoline v-4. Reaction with excess p-chlorobenzylamine gives carboxamide v-5.

It will be apparent to one skilled in the art that the synthetic procedures described are only representative in nature and that alternative synthetic procedures are known to those skilled in organic chemistry.

Examples according to the invention are:

(1) N-[(4-chlorophenyl)methyl]-4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxamide, (2) 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide, (3) N-[(4-chlorophenyl)methyl]-8-fluoro-4,6-dihydroxy-3-quinolinecarboxamide, (4) 6-Bromo-[(4-chlorophenyl)methyl]-8-fluoro-3-quinolinecarboxamide, (5) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide, (6) N- [(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide, (7) N- [(4-chlorophenyl)methyl]-4-hydroxy-7-methoxy-3 -quinolinecarboxamide, (8) N-[(4-chlorophenyl)methyl]-4-hydroxy-5,7-bis(trifluoromethyl)-3quinolinecarboxamide, (9) N-[(4-chlorophenyl)methyl]-7-fluoro-4-hydroxy-3-quinolinecarboxamide, (10) N-[(4-chlorophenyl)methyl]-6-fluoro-4-hydroxy-3-quinolinecarboxamide, (11) N-[(4-chlorophenyl)methyl]-4-hydroxy-7-methyl-3-quinolinecarboxamide, (12) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (13) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-nitro-3-quinolinecarboxamide, (14) N-[(4-chlorophenyl)methyl]-5,6,7,8-tetrafluoro-4-hydroxy-3-quino linecarboxamide, (15) N-[(4-chlorophenyl)methyl]-6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxamide, (16) 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide, (17) N-[(4-chlorophenyl)methyl]-5,8-difluoro-4-hydroxy-3-quinolinecarboxamide, (18) N-[(4-chlorophenyl)methyl]-7,8-difluoro-4-hydroxy-3-quinolinecarboxamide, (19) 6-benzoyl-N-[(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide, (20) N-[(4-chlorophenyl)methyl]-4-hydroxy-8-methoxy-3-quinolinecarboxamide, (21) 6-chloro-N-[(4-chlorophenyl)methyl]- 4-Hydroxy-3-quinolinecarboxamide, (22) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-methyl-3-quinolinecarboxamide, (23) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-methoxy-3-quinolinecarboxamide, (24) N-[(4-chlorophenyl)methyl]-6-cyano-4-hydroxy-3-quinolinecarboxamide, (25) 7-(Acetylamino)-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide, (26) N-[(4-chlorophenyl)methyl]-4-hydroxy-7-((methylsulfonyl)amino)-3-quinolinecarboxamide, (27) N-[(4-chlorophenyl)methyl]-7-(dimethylamino)-4-hydroxy-3-quinolinecarboxamide, (28) 6-Amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide, (29) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-((methylsulfonyl)amino)-3-quinolinecarboxamide, (30) N-[(4-chlorophenyl)methyl]-6-(dimethylamino)-4-hydroxy-3-quinolinecarboxamide, (31) 6-(acetylamino)-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide, (32) N-[(4-chlorophenyl)methyl]-4-hydroxy-7-( 1 -pyrrolyl)-3-quinolinecarboxamide, (33) N-[(4-chlorophenyl)methyl]-4-hydroxy-7-((phenylsulfonyl)amino)-3-quinolinecarboxamide, (34) N-[(4-chlorophenyl)methyl]-4-hydroxy-7- (((phenylmethyl)sulfonyl)amino)-3-quinolinecarboxamide, (35) [(4-chlorophenyl)methyl] -7- [(4-chlorophenyl) sulfonyl)amino)-4-hydroxy-3-quinolinecarboxamide, (36) 8-fluoro-4-hydroxy-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide, (37) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxamide, (38) (278) N-[(4-chlorobenzyl)-8-hydroxy-[l ,3]-dioxolo[4,5-g]quinoline-7-carboxamide, (39) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-iodo-3-quinolinecarboxamide, (40) N-[(4-chlorophenyl)methyl]-6-(cyanomethyl)-4-hydroxy-3-quinolinecarboxamide, (41) N-[(4-chlorophenyl)methyl]-4,5-dihydroxy-3-quinolinecarboxamide, (42) 7,8-dichloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide, (43) N-[(4-chlorophenyl)methyl]-4,6-dihydroxy-3-quinolinecarboxamide, (44) N-[(4-chlorophenyl)methyl]-4,8-dihydroxy-3-quinolinecarboxamide, (45) 8-chloro-N-[(4-chlorophenyl)methyl] 1)methyl]-4-hydroxy-3-quinolinecarboxamide, (46) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-[[(1-phenyl-1H-pyrazol-5-yl)amino]sulfonyl]-3-quinolinecarboxamide, (47) N-[(4-chlorophenyl)methyl]-8-cyano-4-hydroxy-3-quinolinecarboxamide, (48) N-[(4-chlorophenyl)methyl]-4-hydroxy-8-nitro-3-quinolinecarboxamide, (49) 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-8-methyl-3-quinolinecarboxamide, (50) N-[(4-chlorophenyl)methyl]-6-cyano-8-fluoro-4-hydroxy-3-quinolinecarboxamide, • · ti titi ti e « ř»· * • ti ti ti ti ti ti (51) 6-(Aminothioxomethyl)-N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-3quino linecar boxamide, (52) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(3-hydroxy-1 -propynyl)-3quino linecar boxamide, (53) 8-Fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide, (54) 8-Fluoro-4-hydroxy-6-methyl-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide, (55) N-[(4-chlorobenzyl)-7-chloro-4-hydroxy-3-quinolinecarboxamide, (56) N-[(4-chlorophenyl)methyl]-6-bromo-4-hydroxy-3-quinolinecarboxamide, (57) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-phenyl-3-chmolinecarboxamide, (58) N-[(4-chlorophenyl)methyl]-8-chloro-4-hydroxy-5-trifluoromethyl-3-quinolinecarboxamide, (59) N-[(4-chlorophenyl)methyl]-6,8-dimethoxy-4-hydroxy-3-quinolinecarboxamide, (60) N-[(4-chlorophenyl)methyl]-6,7-dimethoxy-4-hydroxy-3-quinolinecarboxamide, (61) N-[(4-chlorophenyl)methyl]-4-hydroxy-5-methyl-3-quinolinecarboxamide, (62) N-[(4-chlorophenyl)methyl]-6-(1,1-dimethylethyl)-4-hydroxy-3-quino linecarboxamide, (63) N-[(4-chlorophenyl)methyl]-7,8-dihydro-4-hydroxy-6H-cyclopenta[g]quinoline-3carboxamide, (64) N-[(4-chlorophenyl)methyl]-1,4-dihydro-8-(methylthio)-4-oxo-3-quinolinecarboxamide, (65) N-[(4-Chlorophenyl)methyl]-9-hydroxythiazolo[5,4-f]-quinoline-8-carboxamide, (66) Sodium 2-[(8-{[3-(3-{[4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-8oxooctanoyl)(methyl)amino]-1-ethanesulfonate, (67) 2-[(8-{[3-(3- Sodium {[4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2propynyl)oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanesulfonate, (68) Sodium 2-[(8-{[3-(3-{[4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propoxy]8-oxooctanoyl)(methyl)amino]-1-ethanesulfonate, (69) N-[(4-chlorobenzyl)-4-hydroxy-7-{[( 1 -naphthylmethyl)amino]sulfonyl}-3quinolinecarboxamide, (70) 2-(4-chlorobenzyl)-4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxamide, (71) N-[(4-chlorophenyl)methyl]-4-hydroxy-6-(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxamide, (72) 3-(3-{[4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl hydrogen phosphate, (73) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(2-thiazolyl)-3-quinolinecarboxamide, i

• · i

β * w (74) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(2-thiophenyl)-3-quinolinecarboxamide, (75) N-[(4-chlorophenyl)methyl]-4-hydroxy-5-trifluoromethyl-3-quinolinecarboxamide, (76) N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(2-methylphenyl)-3-quinolinecarboxamide, (77) N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-(tetrahydro-2H-pyran-4-oxy)-3quinolinecarboxamide, (78) N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-methoxy-3-quinolinecarboxamide, (79) N-[(4-chlorophenyl)methyl]-7,8-methoxy-6-fluoro-4-hydroxy-3-quinolinecarboxamide, (80) N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(4-hydroxymethyl)phenoxy)-3quinolinecarboxamide, (81) N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-methoxy-3-quinolinecarboxamide, (82) N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(2-(methoxy)ethoxy)-3quinolinecarboxamide, (83) N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-(2-(methoxy)ethoxy)-3quinolinecarboxamide, (84) N-[(4-chlorophenyl)methyl]-7,8- di(2-(methoxy)ethoxy)-6-fluoro-4-hydroxy-3quinolinecarboxamide, (85) N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(1-methylethoxy)-3quinolinecarboxamide, (86) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(1,3-thiazol-2-yl)-3-quinolinecarboxamide, (87) N-[(4-chlorobenzyl)-6,8-difluoro-4-hydroxy-7-[(2-methoxy)ethyl)-3-quinolinecarboxamide, (88) N-[(4-chlorobenzyl)-6-(5-cyano-1-pentynyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (89) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinyl)-3-quinolinecarboxamide, (90) N'-[(4-chlorophenyl)-4-hydroxy-6-iodo-3-quinoline carbohydrazide, (91) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[2-(2-pyridinyl)ethynyl]-3-quinolinecarboxamide, (92) N-[(4-chlorobenzyl)-6,8-difluoro-4-hydroxy-7-[(2-hydroxyethyl)amino]-3-quinolinecarboxamide, (93) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-hydroxy-1-butynyl)-3-quinolinecarboxamide, (94) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-methoxy-1-propynyl)-3-quinolinecarboxamide, (95) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide. -butynyl)-3-quinolinecarboxamide,, (96) 6-(4-bromo-2-thienyl-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (97) N-[(4-chlorobenzyl)-8-fluoro-6-(hydrazinocarbothioyl)-4-hydroxy-3-quinolinecarboxamide, (98) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-hydroxy-1 -butyl)-3-quinolinecarboxamide, (99) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-3-quinolinecarboxamide, (100) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-3-quinolinecarboxamide, (100) -propynyl)-3-quinolmcarboxamide, (101) 7-(aminocarbothioyl)-N-[(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide, (102) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-methoxypropyl)-3-quinolinecarboxamide, (103) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-4-hydroxy-1-butenyl)-3-quinolinecarboxamide, (104) N-[(4-chlorobenzyl)-6-(5-cyanopentyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (105) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-3-methylbutyl)-3-quinolinecarboxamide, (106) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxy-1-pentynyl)-3-chmolinecarboxamide, (107) 6-{3-[benzyl(methyl)amino]propyl}N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (108) methyl-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6quinolinecarboxylate), (109) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide, (110) N-[(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxypropyl)-3-quinolinecarboxamide, (111) ethyl-((E)-3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6quinolinyl)-2-propenoate), (112) Sodium 2-[ {8-[3-(3-{ [(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate, (113) 2-[{ 8-[3-(3- {[(4-chlorobenzyl)amino]carbonyl)-8-fluoro-4-hydroxy-6-quinolinyl)• ·' • · • · «,

-2-propanoic acid, (114) 5-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-pentynoic acid, (115) N-[(4-chlorophenyl)methyl]-9]hydroxy-3H-pyrazolo[4,3-f]quinoline-8-carboxamide, (116) N-[(4-chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide, (117) N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide, (118) N-[(4-chlorobenzyl)-4-hydroxy-8-methoxy-6-(3-methoxy-1-propynyl)-3-quinolinecarboxamide, (119) N-[(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy propyl)-8-methoxy-3-quinolinecarboxamide, (120) N-[(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethyl)-3quinolinecarboxamide, (121) N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-methoxy-3-quinolinecarboxamide. -propynyl)-8-(trifluoromethyl)-3quinolinecarboxamide, (122) N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-(trifluoromethyl)-3quinolinecarboxamide, (123) N-(4-chlorobenzyl)-4-hydroxy-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-3-quinolinecarboxamide, (124) N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1,1 -dimethylpropyl)-3-quinolinecarboxamide, (125) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-methylsulfanyl)-1-propynyl)-3-quinolinecarboxamide, (126) N-((4-chlorobenzyl)-6-(3-ethylsulfanyl)-1-propynyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (127) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-3-(methylsulfanyl)-l-propenyl]-3-quinolinecarboxamide, (128) N-[(4-chlorobenzyl)-6-[(Z)-3-(ethylsulfanyl)-l-propenyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (129) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-(methylsulfanyl)-propyl]-3-quinolinecarboxamide, (130) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2propynyl formate, (131) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinyl] linecarboxamide, « φ φ · « φ φ *« φφ

I Φ > φ ·· • φ

I Φ Φ Φ • Φ Φ·

♦ · (132) N-[(4-chlorobenzyl)-6-[(E)-2-cyanoethenyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (133) N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1 - propynyl)-3-quinolinecarboxamide, (134) N-[(4-chlorobenzyl)-6-[(Z)-3-hydroxy-1-quinolinecarboxamide -propenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide, (135) N-[(4-chlorobenzyl)-6- [(E)-3-hydroxy-1-propenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide, (136) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-3-hydroxy-1-propenyl] -propenyl]-3-quinolinecarboxamide, (137) N-[(4-chlorobenzyl)-6-(2-cyanoethyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (138) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-oxopropyl)-3-quinolinecarboxamide, (139) N-[(4-chlorobenzyl)-4-hydroxy-7-(4-hydroxybutyl)-3-quinolinecarboxamide, (140) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide, (141) 3-(3- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl methanesulfonate, (142) N-[(4-chlorobenzyl)-8-fluoro-6-(3-fluoro-1-propynyl)-4-hydroxy-3-quinolinyl] Lincarboxamide, (143) N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide, (144) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-bromoacetate, (145) 3-(3- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2- [(tert.butoxycarbonyl)amino]-3-methylbutanoate, (146) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2(4-morpholinyl)acetate, (147) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-(Dimethylamino)acetate, (148) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-amino-3-methylbutanoate, (149) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynylphenylcarbamate, (150) N-(4-chlorobenzyl)-4-hydroxy-6-propyl-3-quinolinecarboxamide, (151) N-(4-chlorobenzyl)-4-hydroxy-6-(3 -hydroxy-1 -butynyl)-3-quinolinecarboxamide, (152) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(E)-3-oxo-l-butenyl]-3-quinolinecarboxamide, v* ·· • · * · • · ·♦ • · · · • · · · • · « · • · · · * 9 4 • · · * • · » ·

9 9 9 « · ·. · (153) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxypentyl)-3-quinolinecarboxamide, (154) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinoline l)propyl

2.6- bis[(tert.butoxycarbonyl)amino]hexanoate, (155) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl

2.6- Aminohexanoate, trifluoroacetic acid salt, (156) N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinecarboxamide, (157) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(morpholinyl)methyl-3-quinolinecarboxamide, (158) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl phenylcarbamate, (159) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-oxobutyl)-3-quinolinecarboxamide, (160) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1}- 4-hydroxy-6-quinolinyl)-2-propynyl

2.6- bis[(tert.butoxycarbonyl)amino]hexanoate, (161) 3-(3- {[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl 2,6aminohexanoate, trifluoroacetic acid salt, (162) N-[(4-chlorobenzyl)-4-hydroxy-6-(2-hydroxyethoxy)methyl)-3-quinolinecarboxamide, (163) N-[(4-chlorobenzyl)-4-hydroxy-6- {[2-hydroxy-1 -(hydroxymethyl)ethoxy]methyl} 3-quinolinecarboxamide, (164) methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinecarboxylate, (165) N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide, (166) 6-chloro-N-[(4-chlorobenzyl)-4-hydroxy-8-methyl-3-quinolinecarboxamide, (167) N-(4-chlorobenzyl)-5,6,8-trifluoro-4-hydroxy-3-quinolinecarboxamide, (168) N-(4-chlorobenzyl)-6,7-difluoro-4-hydroxy-3-quinolinecarboxamide, (169) N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide, (170) N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-[(hydroxyethyl)sulfanyl]-3-quinolinecarboxamide, (171) 6-[(2-aminoethyl)sulfanyl]-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methyl)hydrobromide 1)-3-quino linecarboxamide lsulfanes, (172) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(2-methoxyethoxy)methyl] sulfanyl}-3quino linecarboxamide, (173) N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-2-(4-morpho liny l)ethy 1] sulfanyl}-3quino linecarboxamide, » 9 • 9 ··.

I» 9 9 ·

9 99

9 ·

9 9 »

9 9 ·

9 9 » •99 99» »9 ·· ♦· · · · ·

9 9 • 9 · « · · ♦ (174) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfinyl)-3-quinolinecarboxamide, (175) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfonyl)-3-quinolinecarboxamide, (176) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-hydroxyethyl)sulfmyl]-3-quinolinecarboxamide, (177) N-(4-chlorobenzyl)-4-hydroxy-6-(2-thienyl)-3-quinolinecarboxamide, (178) N-(4-chlorobenzyl)-4-hydroxy-6-(2-hydroxyethoxy)-3-quinolinecarboxamide, (179) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylcarbonyl)-3-quinolinecarboxamide, (180) N ⁵ -(4-chlorobenzyl)-8-fluoro-4-hydroxy-N6-(2-hydroxyethyl)-3,6-quinolinecarboxamide, (181) N ³ -(4-chlorobenzyl)-8-fluoro-4-hydroxy-N ⁶ ,N-6-dimethyl-3,6-quinolinecarboxamide, (182) N ³ -(4-chlorobenzyl)-8-fluoro-4-hydroxy-N6-(6-hydroxyphenethyl)-3,6quinolinecarboxamide, (183) N ³ -(4-chlorobenzyl)-8-fluoro-4-hydroxy-3,6-quinolinecarboxamide, (184) N ³ , N6-bis(4-chlorobenzyl)-8-fluoro-4-3,6-quinolinecarboxamide, (185) 6-amino-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (186) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[4-methoxyphenyl)sulfonyl]amino}-3-quinolinecarboxamide, (187) N-(4-chlorobenzyl)-4-hydroxy-6-(2-hydroxyethyl)amino]-3-quinolinecarboxamide, (188) N-(4-chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]-4-hydroxy-3-quinolinecarboxamide, (189) N-(4-chlorobenzyl)-4-hydroxy-6-(2-oxo-1,3-oxazolin-3-yl)-3-quinolinecarboxamide, (190) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholmyl)methyl-3-quinolinecarboxamide, (191) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(1-naphthylmethyl)amino])sulfonyl} -3-quinolinecarboxamide, (192) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-(1-H-indol-3-yl)ethyl]amino}sulfonyl)-3-quinolinecarboxamide, (193) N-[(4-chlorobenzyl)-8-fluoro-6-{[(2-ylmethyl]amino]sulfonyl}-4-hydroxy-3-quinolinecarboxamide, (194) 6-{[bis(2-hydroxyethyl)amino]sulfonyl}-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (195) ethyl-(2- {[(3- {[(4-chlorobenzyl)amino]carbonyl} - 8-fluoro-4-hydroxy-6quinolines 1)sulfonyl]amino}acetate), ♦·♦·

(196) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(2-hydroxyethyl)-amino]sulfonyl}-3-quinolinecarboxamide, (197) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinyl)sulfonyl}-3-quinolinecarboxamide, (198) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinylmethyl)amino]sulfonyl}-3-quinolinecarboxamide, (199) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinyl)amino]sulfonyl}-3-quinoline-carboxamide, (200) N-[(4-chlorobenzyl)-6-{[cyclohexylmethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide linecarboxamide, (201) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-( 1 -methyl-2-pyrrolidinyl)-ethylamino } sulfonyl)-3-quino linecarboxamide, (202) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({ [2-(1 -2-pyrrolidinyl)ethyl]amino}-sulfone 1)-3-quinolinecarboxamide, (203) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(2-furylmethyl)amino]sulfonyl}-4-hydroxy-3-quinolinecarboxamide, (204) N-[(4-chlorobenzyl)-6-({[3-(cyclohexylamino)propyl]amino}sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (205) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(1-naphthylmethyl)amino]sulfonyl} -3-quinolinecarboxamide, (206) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-( 1 -H-imidazol-4-yl)ethyl]amino}-sulfonyl)-3-quinolinecarboxamide, (207) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-tetrahydro-2-furanylmethyl)amino]-sulfonyl}-3-quinolinecarboxamide, (208) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(thienylmethyl)amino]sulfonyl}-3-quinolinecarboxamide, (209) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(2-(1-H-indol-3-yl)ethyl]amino}sulfonyl)-3-quinolinecarboxamide, (209) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(2-(5-methoxy-1-H-indol-3-yl)ethyl]amino} sulfones 1)-3-quino linecarboxamide, (210) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-(5-methoxy-1 -H-indol-3-yl)ethyl]amino}sulfonyl)-3-quino linecarboxamide, (211) 6- {[(1,3-benzodioxol-5-ylmethyl)amino}sulfonyl} -N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (212) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-(4-morpholinyl)ethyl]amino}-sulfonyl)-3-quinolinecarboxamide, (213) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[3-(4-morpholinyl)propyl]amino}-sulfone) 1)-3-quino linecarboxamide, (214) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[({2-[5-nitro-2-pyridinyl)amino]-sulfonyl}-3-quinolinecarboxamide, (215) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinylmethyl)amino]sulfonyl}-3-quinolinecarboxamide, (216) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({ [2-(2-pyridinyl)ethyl]amino}-sulfonyl)-3-quino linecarboxamide, (217) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-pyridinylmethyl)amino]sulfonyl}-3-quino linecarboxamide, (218) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-pyridylmethyl)amino]sulfonyl}-3-quino linecarboxamide, (219) N-[(4-chlorobenzyl)-6- {[(4-chlorobenzyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quino linecarboxamide, (220) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(4-methoxybenzyl)amino]sulfonyl}-3-quino linecarboxamide, (221) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(neopentylamino)sulfonyl]-3-quino linecarboxamide, (222) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-hydroxypropyl)amino]sulfonyl}-3quino linecarboxamide, (223) N-[(4-chlorobenzyl)-6-{[(2,3-dihydroxypropyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (224) N-[(4-chlorobenzyl)-6-{[(2,2-diphenylethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (225) 1 l-{[3-{[4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)sulfonyl]amino}undecanoic acid, (226) 6-({[2-acetylamino)ethyl]amino}sulfonyl)-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (227) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[2-hydroxyethoxy]ethyl]amino}sulfonyl)-3-quinolinecarboxamide, (228) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-hydroxyethyl)amino]sulfonyl}-3-quinolinecarboxamide, • · i:

(229) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(phenethylamino)sulfnyl]-3-quinolinecarboxamide, (230) N-[(4-chlorobenzyl)-6- {[(4-chlorophenethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (231) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[2-propynylamino)sulfonyl]-3-quinolinecarboxamide, (232) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(isopenylamino)sulfonyl]-3-quinolinecarboxamide, (233) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[3-phenylpropyl)amino]sulfonyl}-3-quinolinecarboxamide, (234) N-[(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-[(pentylamino)sulfonyl]-3-quinolinecarboxamide, (235) 6-({[bis(trifluoromethyl)benzyl]amino}sulfonyl)-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (236) N-[(4-Chlorobenzyl)-6-({[2-(1-cyclohexene)-1 -yl)ethyl]amino}sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (237) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-( 1 -naphthylamino)ethyl] amino } -sulfonyl)-3-quinolinecarboxamide, (238) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(methylamino)sulfonyl]-3-quinolinecarboxamide, (239) N-[(4-chlorobenzyl)-6-{[(cyanomethyl)amino]sulfonyl}-3-quinolinecarboxamide, (240) N-[(4-chlorobenzyl)-6- {[(2,4-dimethoxybenzyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (241) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[3-iodobenzyl]amino]sulfonyl} sulfonyl}-3-quinolinecarboxamide, (242) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[2,2,2-trifluoroethyl)amino]sulfonyl}-3-quinolinecarboxamide, (243) 6-{[(2-bromoethyl)amino]sulfonyl}-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (244) N-[(4-chlorobenzyl)-6-{[(2-chloroethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (245) N-[(4-chlorobenzyl)-6-{[(3,4-dihydroxyphenethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, » · (246) N-[(4-chlorobenzyl)-6-({[2-ethylsulfanyl)ethyl] amino}sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (247) 6-{[(3-bromopropyl)amino]sulfonyl}-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (248) 6-( {[4-(aminosulfonyl)benzyl]amino}sulfonyl)-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide Lincarboxamide, (249) 6-[({2-[bis(2-chloroethyl)amino}sulfonyl)-8-fluoro-4-hydroxy-3-quinoline-carboxamide, (250) N-[(4-chlorobenzyl)-6-( {[2-ethylsulfanyl)ethyl] amino}sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (251) N-[(4-chlorobenzyl)-6- {[3,4-dimethylbenzyl)amino]sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (252) N-[(4-chlorobenzyl)-6-{[(cyclopropylmethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (253) 6-{[(bromo)benzyl)amino]sulfonyl}-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (254) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[2-(2-thienyl)ethyl]amino}sulfonyl)-3-quinolinecarboxamide, (255) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-(phenoxyethyl)amino]sulfonyl}-3-quinolinecarboxamide, (256) tert.butyl 2-{[(3- {[4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)sulfonyl]amino}acetate, (257) tert-butyl 3-{[(3-{[4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)sulfonyl]amino}propanoate, (258) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[3-trifluoromethoxy)benzyl]-amino}sulfonyl)-3-quino linecarboxamide, (259) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[} 2- {[2-hydroxymethyl)phenyl]-sulfanyl}-benzyl)amino]sulfonyl}-3-quinolinecarboxamide, (260) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(4-(1,2,3-thiadiazol-4-yl)benzyl)amino]-amino] sulfonyl)-3-quinolinecarboxamide, (261) N-[(4-chlorobenzyl)-6-{[(4-chloro-2-fluorobenzyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (262) N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[( {2-(2-hydroxyethyl)sulfanyl]ethyl}-amino)sulfonyl]-3-quinolinecarboxamide, (263) 6- {[(2-amino-2-methylpropyl)amino]sulfonyl} -N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (264) 6-{[(2-amino-2-oxoethyl)amino]sulfonyl}- N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (265) 6-{[(4-aminobenzyl)amino]sulfonyl}-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, linecar boxamide, (266) di(tert.butyl) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinoliny l)propyl phosphate, (267) 3-(3-{[(4-chlorobenzyl)amino] carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate, (268) 3-(3-{[(4-chlorobenzyl)amino]amino] carbonyl}-4-hydroxy-6-quinolines l)propyl dihydrogen phosphate, (269) tert-butyl 3-(3-{[(4-chlorobenzyl)amino] carbonyl}-4-hydroxy-6-quinolinyl)-propylphosphonate, (270) tert-butyl 3-(3-{[(4-chlorobenzyl)amino] carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propylphosphonate, (269) tert-butyl 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-propylphosphonate, (270) tert-butyl 3-(3- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propylphosphonate, (271) (E)-3-(3- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propenoic acid or (272) N-[(4-chlorophenyl)methyl]-4-hydroxy-7-iodo-3-quinolinecarboxamide.

Preferred compounds according to the invention are:

(1) 7-amino-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide, (2) N-(4-chlorobenzyl)-4-hydroxy-7-methoxy-3-quinolinecarboxamide, (3) N-(4-chlorobenzyl)-7-fluoro-4-hydroxy-3-quinolinecarboxamide, (4) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (5) 6-chloro-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide, (6) N-(4-chlorobenzyl)-4-hydroxy-6-methyl-3-quinolinecarboxamide (7) N-[(4-chlorobenzyl)-4-hydroxy-6-methoxy-3-quinolinecarboxamide, (8) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxamide, (9) N-(4-chlorobenzyl)-4-hydroxy6-iodo-3-quinolinecarboxamide, (10) N-(4-chlorobenzyl)-4-hydroxy-6-phenyl-3-quinolinecarboxamide, (11) N-(4-chlorobenzyl)-4-hydroxy-6,8-dimethoxy-3-quinolinecarboxamide, (12) 6-(tert-butyl)-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide, (13) N-[(4-chlorobenzyl)-6-(cyanomethyl)-4-hydroxy-3-quinolinecarboxamide, (14) N-(4-chlorobenzyl)-9-hydroxy-[ 1,3-thiazolo[5,4-f]quinoline-8-carboxamide, (15) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide, (16) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(1,3-thiazol-2-yl)-3-quinolinecarboxamide, (17) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-thienyl)-3-quinolinecarboxamide, (18) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-methoxy-1-propynyl)-3-quinolinecarboxamide, (19) 6-(4-Bromo-2-thienyl)-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (20) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-hydroxybutyl)-3-quinolinecarboxamide, (21) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-4-hydroxy-1-butenyl]-3-quinolinecarboxamide, (22) N-(4-chlorobenzyl)-6,8-difluoro-4-hydroxy-7-[4-(hydroxymethyl)phenoxy]-3-quinolinecarboxamide, (23) N-(4-chlorobenzyl)-6,8-difluoro-4-hydroxy-7-methoxy-3-quinolinecarboxamide, (24) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxy-1-pentynyl)-3quinolinecarboxamide, (25) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynylformate;

(26) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide;

(27) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxypropyl)-3-quinolinecarboxamide;

(28) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinecarboxamide;

(29) N-(4-chlorobenzyl)-6-[(E)-2-cyanoethene 1]-8-fluoro-4-hydroxy-quinolinecarboxamide;

(30) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quino linecarboxamide;

(31) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide;

0· 0 0 »0 * • 0 0 • < · ·0 · • ·· ··

0· *· • 0 0

0·« »0 • ·0 · • 0 0· ·

(32) N-(4-Chlorobenzyl)-4-hydroxy-8-methoxy-6-(3-methoxy-1-propynyl)-3-quino linecarboxamide;

(33) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-3-hydroxy-1-propenyl]-3-quino linecarboxamide;

(34) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-oxopropyl)-3-quinolinecarboxamide;

(35) N-(4-chlorobenzyl)-4-hydroxy-7-(4-hydroxybutyl)-3-quinolinecarboxamide;

(36) N-(4-chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide;

(37) N-(4-chlorobenzyl)-8-fluoro-6-(3-fluoro-1-propynyl)-4-hydroxy-3-quinolinecarboxamide;

(38) N (4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide;

(39) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-bromoacetate;

(40) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-[( tert -butoxycarbonyl)amino)-3-methylbutanoate;

(41) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-amino-3-methylbutanoate;

(42) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynyl phenylcarbamate;

(43) N-((4-chlorobenzyl)-4-hydroxy-6-propyl-3-quinolinecarboxamide (44) N-((4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-methoxy-3-quinolinecarboxamide;

(45) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide;

(46) N-(4-Chlorobenzyl)-4-hydroxy-7-{[(1-naphthylmethyl)amino)sulfonyl}-3-quinolinecarboxamide;

(47) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(E)-3-oxo-1-butenyl]-3-quino linecarboxamide;

(48) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethoxy)-3-quinolinecarboxamide;

(49) Sodium 2-[{8-[3-(3-{[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate;

(50) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate;

(51) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2,6-bis[(tert.butoxycarbonyl)amino)hexanoate, (52) tert.butyl 13-(3 - {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6• * · <

• · · « • · « *

9* • ·« » · 4

-quinolinyl propylphosphonate;

(53) Sodium 2- [(8- {[3-(3- {[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy6-quinolinyl)-2-propynyl)oxy}-8-oxooctanoyl)(methyl)amino)-1-ethanesulfonate, (54) N-(4-Chlorobenzyl)-4-hydroxy-6-(2-hydroxyethoxy)-3-quinolinecarboxamide;

(55) 3-(3-([(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl salt

Trifluoroacetic acid 2,6-diaminohexanoate (56) N-(4-chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethyl)amino]-3-quinolinecarboxamide;

(57) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinecarboxamide;

(58) 2-[(8-{[3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl]-oxy}-8-oxooctanoyl)(methyl)amino)-1-ethanesulfonate, (59) Sodium 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl 1)amino]-1-ethanesulfonate, (60) tert-butyl 3-(3-([(4-chlorobenzyl)amino)carbonyl)-4-hydroxy-6-quinolinyl)propyl phosphonate;

(61) 3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate;

(62) N-(4-chlorobenzyl)-4-hydroxy-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-3-quinolinecarboxamide;

(63) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide;

(64) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-oxobutyl)-3-quinolinecarboxamide;

(65) N-(4-chlorobenzyl)-4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl)-3-quinolinecarboxamide;

(66) 3-(3-([(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propmyl 2,6bis[( tert -butoxycarbonyl)amino]hexanoate;

(67) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-1-propenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;

(68) N-(4-Chlorobenzyl)-6-[(E)-3-hydroxy-1-propenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;

(69) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl

2,6-diaminohexanoate salt of trifluoroacetic acid;

(70) 3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)propyl hydrogenphosphonate;

• 9 • 9 * · • · • 9 (71) N-(4-chlorobenzyl)-4-hydroxy-6-(2-thienyl)-3-quinolinecarboxamide;

(72) N-(4-chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethoxy)methyl)-3-quinolinecarboxamide;

(73) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1,1-dimethylpropyl)-3-quinolinecarboxamide;

(74) N-(4-chlorobenzyl)-4-hydroxy-6-{[2-hydroxy-1-(hydroxymethyl)ethoxy)methyl}-3-quino linecarboxamide;

(75) N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide;

(76) methyl-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinecarboxylic acid; or (77) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide. More preferred compounds of the invention are:

(1) N-(4-chlorobenzyl)-4-hydroxy-7-methoxy-3-quino linecarboxamide;

(2) N-(4-chlorobenzyl)-7-fluoro-4-hydroxy-3-quinolinecarboxamide;

(3) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quino linecarboxamide;

(4) N-(4-chlorobenzyl)-4-hydroxy-6-methoxy-3-quinolinecarboxamide;

(5) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-thienyl)-3-quinonecarboxamide;

(6) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-hydroxybutyl)-3-quinolinecarboxamide;

(7) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-4-hydroxy-1-butenyl)-3-quino linecarboxamide;

(8) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide;

(9) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxypropyl)-3-quinolinecarboxamide, (10) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide;

(11) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide;

(12) N-(4-chlorobenzyl)-4-hydroxy-8-methoxy-6-(3-methoxy-1-propynyl)-3-quinoline-carboxamide;

□ (13) N-(4-chlorobenzyl)-4-hydroxy-7-(4-hydroxybutyl)-3-quinolinecarboxamide;

(14) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide;

(15) 3-(3-{[(4-Chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-bromoacetate;

(16) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-(2-amino-3-methylbutanoate);

(17) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-methoxy-3-quinolinecarboxamide;

(18) Sodium 2-[ {8-[3 -(3- {[(4-chlorobenzyl)amino)carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate, (19) 3-(3-( [(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate);

(20) 3-(3- (((4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2,6-bis[( tert -butoxycarbonyl)amino]hexanoate;

(21) tert-butyl-(3-(3-([(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propylphosphonate);

(22) 3-(3-([(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2,6-diaminohexanoate trifluoroacetic acid salt;

(23) N-(4-chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethyl)amino)-3-quinolinecarboxamide;

(24) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinecarboxamide, (25) Sodium 2-[(8-([3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl)oxy}-8-oxooctanoyl)(methyl)amino)-1-ethanesulfonate;

(26) 2-[(8-[3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)propoxy)-8-oxooctanoyl}(methyl)amino)-1-ethanesulfonate;

(27) tert-butyl-(3-(3-(((4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6quinoline 1)propyl phosphonate);

(28) 3-(3-([(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate;

(29) N-(4-chlorobenzyl)-4-hydroxy-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-3-quino linecarboxamide;

(30) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide;

(31) 3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl

2,6-bis[(tert.butoxycarbonyl)amino]hexanoate;

(32) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-1-propenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;

(33) N-(4-chlorobenzyl)-6-((E)-3-hydroxy-1-propenyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;

(34) 3-(3-([(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl

2.6- diaminohexanoate salt of trifluoroacetic acid;

(35) 3-(3-([(4-Chlorobenzyl 1)amino]carbonyl}-4-hydroxy-6-quinoline 1)propyl hydrogenphosphonate;

(36) N-(4-chlorobenzyl)-4-hydroxy-6-(2-thienyl)-3-quinolinecarboxamide (37) N-(4-chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethoxy)methyl]-3-quinolinecarboxamide;

(38) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1,1-dimethylpropyl)-3-quinolinecarboxamide;

(39) methyl-(3-{[(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinecarboxylate); or (40) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide. The most preferred compounds of the invention are:

(1) N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide;

(2) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide;

(3) N-(4-chlorobenzyl)-4-hydroxy-8-methoxy-6-(3-methoxy-1-propynyl)-3-quinolinecarboxamide;

(4) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide, (5) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-methoxy-3-quinolinecarboxamide;

(6) Sodium 2-[(8-{[3-(3-{[(4-Chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl)-oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanesulfonate, (7) 2-[{8-[3-(3- {[(4-Chlorobenzyl)amino)carbonyl}] -4-hydroxy-6-quinolinyl)propoxy)-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate, (8) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate;

(9) N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-1-propenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;

(10) N-(4-Chlorobenzyl)-6-[(E)-3-hydroxy-1-propenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;

(11) 3-(3-{[(4-chlorobenzyl)amino)carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl

2,6-diaminohexanoate salt of trifluoroacetic acid;

(12) 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl hydrogenphosphonate;

(13) N-(4-chlorobenzyl)-4-hydroxy-6-(2-thienyl)-3-quinolinecarboxamide;

(14) N-((4-chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethoxy)methyl)-3-quinolinecarboxamide;

or (15) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide.

«·

9 9

9 9

9 9

9 9 9 • 9 9 9 «9 •99 999

Examples of embodiments of the invention

The compounds of the invention and their pharmaceutically acceptable salts are useful antiviral agents. Thus, these compounds are useful for combating viral infections in animals including humans. Specifically, these compounds have antiviral activity against the herpes virus, cytomegalovirus (CMV). These compounds are also active against other herpes viruses, such as varicella zoster virus (VZV), Epstein-Barr virus (EBV), herpes simplex virus and human herpes virus type 8 (HHV-8).

Since many of the compounds of the invention have also shown activity against CMV polymerase, these compounds may be active against cytomegalovirus by this or another mechanism of action. Accordingly, the description below of the activity of these compounds is not intended to limit the invention to a specific mechanism of action.

The compounds of the invention also showed activity in one or more of the assays described below. All of these assays are indicative of the activity of the compounds and thus their use as antiviral agents.

HCMV polymerase assays are performed using the scintillation proximity assay (SPA) described in a number of references, such as N.D. Cook et al., Pharmaceutical Manufacturing International, pages 49-53 (1992), K. Takeuchi, Laboratory Practice, September edition (1992), U.S. Patent No. 4,568,649 (1986), which are incorporated herein by reference. Reactions are performed in 96-well plates. Assays are performed in a 100 μΐ volume with 5.4 mM HEPES (pH 7.5), 11.5 mM KCl, 4.5 mM MgCl, 0.36 mg/ml BSA, and 90 nM 3H-dTTP. Assays are performed with and without CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) at a final concentration of 2 mM. HCMV polymerase is diluted in enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 0.100 mg/ml BSA and 0.01 sodium azide. HCMV polymerase, which was expressed in baculovirus-infected SF-9 cells and purified according to literature procedures, is added at 10% (or 10 μΐ) of the final reaction volume, e.g. 100 μΐ. Compounds are diluted in 50% dimethyl sulfoxide and 10 μΐ is added to each well. Control wells contain the same concentration of dimethyl sulfoxide. Unless otherwise noted, the reaction was initiated by adding 6 nM biotinylated poly(dA)-oligo(dT) template/primer to the reaction mixture containing enzyme, substrate and compound. Plates are incubated in a 25°C or 37°C bath and terminated by adding 40 μΐ per reaction of 0.5 M EDTA (pH 8) to the well. Reactions are terminated within a time frame in which substrate incorporation is linear and which varies depending on the enzyme and conditions used, e.g. 30 minutes for HCMV polymerase. After the reaction is complete, 10 μΐ of streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added. Plates are incubated at 37°C for 10 minutes, then equilibrated at room temperature and read on a Packard Popcount. Linear regression is performed and IC5Q is calculated using computer programs.

A modified version of the HCMV polymerase assay above is performed as described above, but with the following changes: Compounds are diluted in 100% dimethyl sulfoxide, 4.5 mM dithiotherotol (DTT) is added to the stock polymerase solution. A different batch of CMV polymerase is also used, which appears to be more active, resulting in a faster polymerase reaction. The results of testing the compounds of the present invention are shown in Table 1 below. Other viral polymerase assays are performed using procedures similar to those described above.

The compounds of the invention are administered in pharmaceutical compositions containing the compound in combination with a suitable excipient to make the composition useful in combating viral infections. Pharmaceutical compositions containing a compound suitable for antiviral use are prepared by methods and contain excipients known to those skilled in the art. A generally recognized compendium of such methods and components is Remington's Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co. 15th ed., 1975), which is incorporated herein by reference.

The compounds of the invention are administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, rectally, depending on whether the preparation is used to treat internal or external viral infections.

For internal infections, the compositions are administered orally or parenterally at dosage levels calculated as the free base of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of body weight of the mammal, and in humans are used in unit dosage forms administered one to four times daily in an amount of 1 to 1000 mg per unit dose.

For parenteral administration or administration in drops, such as for eye infections, the compounds are presented as an aqueous solution at a concentration of from about 0.1 to 10%, more preferably about 0.1 to 7%. It may contain other ingredients such as emulsifiers, antioxidants and buffers.

The precise regimen of administration of the compounds and compositions described herein will necessarily depend on the needs of the individual subjects being treated, the type of treatment, and of course the judgment of the attending physician.

9

9

9 • » * · o • 9 9 ·

9 99 • · · · ·

9 9 9

99

TABLE 1

Example No. IC50 values of antiviral selective polymerase polymerase IC50(pM) 1 CMV HSV VZV 38.2 35.5 13.3 2 CMV HSV VZV 5.2 3.5 0.6 3 CMV 24.0 4 CMV 3.4 5 CMV 5.8 6 CMV HSV VZV 7.6 2.3 0.7 7 CMV HSV VZV 4.9 5.5 0.7 8 CMV 55.3 9 CMV HSV VZV <2.3 <2.3 2.5 10 CMV HSV VZV 9.7 14.0 3.9 11 CMV 21.2 12 CMV HSV VZV 1.4 3.4 <3.1 13 CMV HSV VZV <2.3 3.0 <2.3 14 CMV HSV VZV 11.5 7.9 3.6 15 CMV HSV VZV 20.8 22.0 13.1 16 CMV HSV VZV 2.7 2.8 1.3 17 CMV 3.3 18 CMV <3.1 20 CMV 6.5 21 CMV 4.4 22 CMV 4.0 23 CMV 3.4 24 CMV 4.9 25 CMV HSV VZV 13.5 18.5 8.4 26 CMV HSV VZV 17.0 25.0 14.0 27 CMV 16.0

φ« *· • ♦ · φ φ · • · · • · · · • Φ *· ·· *· • « • ·* ··· • · · · ♦ » · · • »»

Example No. IC50 values of antiviral selective polymerase polymerase IC50(pM) 28 CMV HSV VZV 18.0 19.7 8.3 29 CMV HSV VZV 34.1 70.6 25.2 30 CMV HSV VZV 10.6 14.3 7.5 31 CMV HSV VZV 26.2 81.5 26.0 32 CMV HSV VZV 22.0 <100.0 53.8 33 CMV 24.3 34 CMV 17.9 35 CMV 9.2 36 CMV 7.8 38 CMV 3.2 39 CMV <3.1 40 CMV 3.5 41 CMV 12.1 42 CMV 19.2 43 CMV 1.3 44 CMV 28.7 45 CMV 4.6 46 CMV 2.8 47 CMV 39.7 48 CMV 6.5 49 CMV 3.7 50 CMV 6.9 51 CMV 12.2 52 CMV no,o 53 CMV HSV VZV <0.78 0.64 0.39 54 CMV 8.6 55 CMV 5.0 56 CMV 3.1 57 CMV 5.2 58 CMV 1 59 CMV 33.1 60 CMV 4.0 61 CMV 3.1 62 CMV 4.6 63 CMV 7.0 64 CMV 8.5 65 CMV 3.3 66 CMV 0.29 72 CMV 9.4 75 CMV HSV VZV 0.17 0.43 0.16 76 CMV 5.2

»9 • o • « ·9 »

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9 • 99 *99

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9 9

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Example No. IC50 values of antiviral selective polymerase polymerase IC50(pM) 77 CMV 4.0 78 CMV 0.71 79 CMV 0.96 80 CMV 2.4 81 CMV 7.8 82 CMV 2.5 83 CMV 4.3 84 CMV 0.79 85 CMV 18.1 86 CMV 10.7 87 CMV 7.9 88 CMV 30.3 89 CMV 7.2 90 CMV 2.9 91 CMV 3.8 92 CMV 20.6 94 CMV 5.3 95 CMV 1.9 96 CMV 4.5 97 CMV 18.6 98 CMV 1.3 99 CMV HSV VZV 0.14 0.20 0.09 100 CMV 6.7 101 CMV 25.8 102 CMV 4.6 103 CMV 2.5 104 CMV <0.78 105 CMV 10.4 106 CMV HSV VZV 10.3 16.4 9.6 107 CMV 5.4 108 CMV 6.5 109 CMV 11 110 CMV 0.28 11 CMV 2.6 112 CMV 14.0 113 CMV 10.4 114 CMV 2.2 115 CMV 6.1 116 CMV 16.5 117 CMV 8.7 118 CMV HSV VZV 0.67 0.2 0.66 119 CMV HSV VZV 1.5 0.57 0.73 120 CMV HSV VZV 0.27 0.08 0.25 121 CMV 15.0 122 CMV 1.8

• · · ·

Example No. IC50 values of antiviral selective polymerase polymerase IC50(pM) 123 CMV 2.2 124 CMV HSV VZV 0.25 0.6 0.39 ¹²⁵ CMV HSV VZV 0.87 2.5 1.7 126 CMV 19.7 127 CMV 23.5 128 CMV 0.46 129 CMV 1.0 130 CMV 1.1 131 CMV 1.8 132 CMV 0.64 133 CMV HSV VZV 4.0 2.2 3.2 134 CMV HSV VZV 0.9 0.19 0.72 135 CMV 0.78 136 CMV HSV VZV 0.68 0.7 0.39 137 CMV 0.60 138 CMV HSV VZV 4.7 2.0 3.5 139 CMV 1.9 140 CMV HSV VZV 1.4 1.0 1.7 141 CMV 10.1 142 CMV HSV VZV 3.8 2.1 2.9 143 CMV 3.0 144 CMV HSV VZV 0.28 0.07 0.28 145 CMV HSV VZV 2.9 2.5 3.5 146 CMV 38.7 147 CMV 7.0 148 CMV HSV VZV 2.4 1.0 1.4 149 CMV 6.3 150 CMV 4.8 151 CMV 0.91 152 CMV 5.4 153 CMV 8.3 154 CMV 3.4 155 CMV >50 156 CMV 15.9

4« «4 « • 4 4 4 44 4 • 4 44 · • 4 « 4 4 4

4 4 4 4

44 4444

Example No. IC50 values of antiviral selective polymerase polymerase LC50(µM) 157 CMV HSV vzv 0.92 1.8 0.89 158 CMV <0.78 159 CMV 5.0 160 CMV 1.2 163 CMV 0.59 164 CMV 2.3 165 CMV 6.7 166 CMV 7 167 CMV 5 168 CMV HSV VZV 10 8.4 4.1 169 CMV 3.7 170 CMV 4.4 171 CMV 1.9 172 CMV 35.1 173 CMV 12.8 174 CMV 28.9 175 CMV 7.2 176 CMV 11.4 177 CMV 7.2 178 CMV HSV VZV 0.15 0.8 0.64 179 CMV HSV VZV 1.8 0.66 1.4 180 CMV 28.2 181 CMV 39.2 182 CMV 5.0 183 CMV 32.0 184 CMV 30.4 185 CMV 32.8 186 CMV 13.8 187 CMV 17.7 188 CMV 2.1 189 CMV 19.4 190 CMV 2.7 191 CMV HSV VZV 0.5 0.63 0.64 192 CMV 1.6 193 CMV 2.7 194 CMV 15.3 195 CMV 18.3 196 CMV 19.4 197 CMV 19.6 198 CMV 21.0 199 CMV 26.4 200 CMV 38.8 201 CMV 6.0 202 CMV >50 203 CMV 38.8

• · β • · · ·

Example No. IC50 values of antiviral selective polymerase polymerase IC50(pM) 204 CMV 13.8 205 CMV >50 206 CMV 2.4 207 CMV 14.4 208 CMV 41.6 209 CMV 8.6 210 CMV 4.8 211 CMV 5.1 212 CMV 14.5 213 CMV 18.9 214 CMV 29.7 215 CMV 8.6 216 CMV 18.7 217 CMV 15.2 218 CMV 17.6 219 CMV 11.0 220 CMV 10.7 221 CMV 12.5 222 CMV 11.5 223 CMV 14.5 224 CMV 21.6 225 CMV 8.5 226 CMV 18.5 227 CMV 26.7 228 CMV 44.3 229 CMV 10.7 230 CMV 9.6 231 CMV 8.3 232 CMV 23.4 233 CMV 11.2 234 CMV 8.9 235 CMV 11.8 236 CMV 6.6 237 CMV 6.9 238 CMV 1.6 239 CMV 13.1 240 CMV 11.4 241 CMV 16.0 242 CMV 8.4 243 CMV 15.5 244 CMV 19.0 245 CMV 13.3 246 CMV 8.6 247 CMV 10.2 248 CMV 11.6 249 CMV 7.6 250 CMV 45.2 251 CMV 18.7 252 CMV 18.9 253 CMV 20.6 254 CMV 14.7 255 CMV 12.1 256 CMV 9.3 257 CMV 16.3

• · 9 ·· 99

Example No. IC50 values of antiviral selective polymerase polymerase IC50(pM) 258 CMV 15.2 259 CMV 6.1 260 CMV 5.7 261 CMV 15.1 262 CMV 9.9 263 CMV 23.1 264 CMV 90.2 265 CMV 11.4 266 CMV 10.1 267 CMV 52.2 268 CMV 9.5 269 CMV 9.8 270 CMV 2.8 271 CMV 20.4 272 CMV 8.6 273 CMV 11.5 274 CMV 16.5 275 CMV 28.4 277 CMV 0.77 278 CMV 2.1 279 CMV 4.9 280 CMV 57.8

Example 1

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxamide

OH O

Cl

To a solution of 0.892 g of Ι,Γ-carbonyldiimidazole in 30 ml of tetrahydrofuran was added 1.29 g of 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid. The reaction mixture was stirred at room temperature for 1 hour. A solution of 0.91 ml of 4-chlorobenzylamine in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 100 ml of dichloroethane and filtered. The filtrate was chromatographed twice, eluting with 5% methanol/dichloroethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. This gave a pale yellow solid. The solid was recrystallized from ethyl acetate to give 0.298 g of the title compound as a white crystalline solid.

The physical characteristics are as follows;

NMR (DMSO) delta 12.96, 10.28, 8.92, 8.46, 8.08, 7.79, 7.43-7.36, 4.58.

¹³ C NMR (DMSO) delta 175.4, 164.0, 145.0, 138.7, 138.5, 131.3, 129.1, 128.3, 127.3 120.5, 116.7, 11.7, 41.4.

IR (Nujol) 3185, 3077, 3028, 1647, 1614, 1600, 1570, 1534, 1478, 1319, 1170, 1143 cm -1 . MS (E1) m/z 380 (M ⁺ ) 362,240,213,184,140, 125.

Analysis found: C 56.74, H 3.44, N 9.04, Cl 9.04.

Example 2

7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

A suspension of 0.91 mL of 4-chlorobenzylamine and 0.200 g of ethyl 4-hydroxy-3-quinolinecarboxylate was heated at 180°C for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate was added. The resulting solid was collected and washed with ethyl acetate to give 0.071 g of the title compound as a tan solid.

The physical characteristics are as follows:

Melting point 224-245 °C (decomposition).

NMR (DMSO) delta 12.10, 10.63, 8.44, 7.85, 7.37, 7.31, 6.67, 6.53, 6.13, 4.49.

13 C NMR (DMSO) delta 175.9, 165.6, 153.4, 142.8, 141.9, 139.3, 131.8, 129.6, 128.8, 127.1, 116.9, 114.8, 109.8, 97.9, 41.7.

IR (mull) 3480, 3357, 2748, 1650, 1586, 1553, 1528, 1506, 1494, 1480, 1281, 789, 737, 621 cm'l.

MS (E1) m/z 327 (M ⁺ ) 329, 327, 188, 187, 186, 160, 140, 132, 125, 104.

HRMS (EI) found: 327.0778.

·· ·· • · • · • · ·

Example 3

N-[(4-chlorophenyl)methyl]-8-fluoro-4,6-dihydroxy-3-quinolinecarboxamide

To a mixture of 10% Pd/C and 2.0 g of 3-fluoro-4-nitrophenol in 10 ml of tetrahydrofuran was added 4.817 g of ammonium formate. After the reaction mixture was stirred at room temperature for 1 hour, it was filtered. To the residue was then added 2.57 ml of diethylethoxymethylenemalonate and 10 ml of xylene. The mixture was heated to 135 °C for 1 hour with a Dean-Stark trap to collect the ethanol. The reaction mixture was cooled. The solid was dissolved in 50 ml of diphenyl ether and heated to 250 °C for 3 hours with a Dean-Stark trap to collect the ethanol. The solution was cooled and diluted with hexanes. The resulting solid was collected, washed with hexanes, and dried to give 0.527 g. A solution of 0.415 g of this solid in 4 mL of 4-chlorobenzylamine was heated at 180°C for 1 hour. The solution was cooled and diluted with diethyl ether. The resulting solid was collected and recrystallized from acetone/hexanes to give 0.226 g of the title compound as a tan solid.

The physical characteristics are as follows:

Melting point 310 to 313 °C.

1 H NMR (DMSO) delta 12.73, 10.34, 8.51, 7.35, 7.18, 4.52.

IR(mull) 3195, 3127, 3097, 3068, 1651, 1639, 1612, 1538, 1493, 1399, 1352, 1283, 1193, 1142, 793 cm ^-1 .

MS (E1) m/z 346 (M ⁺ ) 348, 346, 207, 206, 179, 151, 150, 142, 140, 125.

Example 4

6-Bromo-[(4-chlorophenyl)methyl]-8-fluoro-3-quinolinecarboxamide

A mixture of 9.50 g of 4-bromo-2-fluoroaniline and 10.81 g of diethyl ethoxymethylenemalonate was heated at 130 °C for 1 hour in a flask equipped with a Dean-Stark trap to collect the ethanol formed. The mixture was then cooled to 75 °C and diluted with hexanes. The resulting solid was collected and dried. The solid was dissolved in 50 mL of diphenyl ether and heated at 250 °C for 2 hours in a flask equipped with a Dean-Stark trap to collect the ethanol. The solution was allowed to cool to room temperature and the resulting solid was collected and washed with hexanes and dried to give 8.69 g. This material (0.49 g) and 5 mL of 4-chlorobenzylamine were heated at 180 °C for 1 hour. The reaction mixture was cooled and poured into 80 mL of diethyl ether. The resulting solid was filtered and recrystallized from ethyl acetate/hexanes to give the title compound (0.35 g) as an off-white solid.

The physical characteristics are as follows:

Melting point 254 to 255 °C.

iHNMR(DMSO) delta 10.16, 8.61, 8.11, 8.03, 7.38, 7.33, 4.52.

IR(mull) 3168, 3075, 1650, 1611, 1590, 1572, 1524, 1489, 1347, 1297, 1283, 1238, 1182, 804 cm'l.

MS (ES-) 408.9 (MH ⁺ ).

Analysis found: C 49.84, H 3.05, N 6.70, Cl 8.87.

Example 5

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide

OH O

F

A mixture of 11.85 g of 2-fluoro-4-iodoaniline and 10.81 g of diethylethoxymethylenemalonate was heated to 130°C for 1 hour in a flask equipped with a Dean-Stark trap to collect the ethanol formed.

• · • 9 9 • 9 9

9 9 9 • 9 9

The mixture was then cooled to 75 °C and diluted with hexanes. The resulting solid was collected and dried. The solid was dissolved in 60 mL of diphenyl ether and heated at 250 °C for 3 h in a flask equipped with a Dean-Stark trap to trap the ethanol. The solution was allowed to cool to room temperature and the resulting solid was collected and washed with hexanes and dried to give 11.73 g. This material (0.55 g) and 3 mL of 4-chlorobenzylamine were heated at 180 °C for 1 h. The reaction mixture was cooled and poured into 75 mL of diethyl ether. The resulting solid was filtered and recrystallized from ethyl acetate/hexanes to give the title compound (0.45 g) as an off-white solid.

The physical characteristics are as follows:

Melting point 268 to 270 °C.

ΪΗ NMR (DMSO) delta 10.17, 8.59, 8.29, 8.05, 7.37, 7.33, 4.51.

IR(mull) 3180, 3078, 3004, 1647, 1607, 1551, 1524, 1489, 1344, 1297, 1285, 1240, 1183,

805 cm" ¹ .

MS (ES-) 454.9 (M-H+).

HRMS (FAB) found: 456.9628.

Example 6

N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

A mixture of 0.50 g of ethyl 4-hydroxy-3-quinolinecarboxylate (J. Amer. Chem. Soc, 68, 1264 (1946)) and 5.0 ml of 4-chlorobenzylamine was stirred at 200°C for 18 hours. The mixture was cooled to 25°C and diluted with 25 ml of hexanes. After stirring for an additional 1 hour, the solid precipitate was collected by filtration and washed with 25 ml of hexanes. It was dried at 2.026 MPa for 18 hours. The yield was 0.28 g.

The physical characteristics are as follows:

Melting point 245 to 248 °C.

1 H NMR (DMSO) delta 10.58, 8.76, 8.23, 7.74-7.66, 7.45-7.20, 4.53.

MS (El) m/z 312 (M ⁺ ) 173,172,145,142,140,125,117,116, 89.

Analysis found: C 64.42, H 4.34, N 8.79.

Preparation 1

Ethyl-(4-hydroxy-6-(trifluoromethoxy)-3-quinolinecarboxylate)

F ₃ C-0

o-ch ₂ ch ₃

A mixture of 4.14 g of 4-trifluoromethylaniline and 5.2 ml of diethylethoxymethylenemalonate was stirred at 130 °C for 2 hours. The resulting solid was collected and dried in a stream of air. It was further dried at 2.026 MPa and 34 °C for 18 hours. This gave the condensation product as 5.09 g of solid. This solid was suspended in 20 ml of diphenyl ether and the mixture was refluxed for 1 hour. The mixture was cooled to 25 °C and diluted with 100 ml of hexanes. After stirring for 20 minutes, the solid was collected by filtration and dried at 2.026 MPa and 45 °C for 18 hours. The ester was obtained as 1.8 g of solid.

The physical characteristics are as follows:

MS (E1) m/z 301 (M ⁺ ) 302,256,255, 254,228,227,186, 69.

Analysis found: C 51.83, H 3.38, N 4.66.

Example 7

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-methoxy-3-quinolinecarboxamide

OH O

HA

A mixture of 0.50 g of ethyl-(4-hydroxy-7-methoxy-3-quinolinecarboxylate) (J. Amer. Chem. Soc, 68, 1268 (1946)) and 3.0 ml of 4-chlorobenzylamine was stirred for 1 hour at 200°C. The mixture was cooled to 25°C and diluted with 25 ml of hexanes. After stirring for an additional 1 hour, the solid precipitate was collected by filtration and washed with 25 ml of hexanes. It was dried in a stream of air and then suspended in 20 ml of glacial acetic acid. The mixture was heated until the solid was completely dissolved and the resulting solution was diluted with 200 ml of distilled water. The mixture was allowed to cool to 25°C and the solid was collected by filtration. Wash with a small volume of 10% aqueous acetic acid and then dry at 2.026 MPa and 45 °C for 18 hours. Yield 0.39 g.

The physical characteristics are as follows:

Melting point 230 to 235 °C.

^! H NMR (DMSO) delta 12.5, 10.48, 8.67, 8.12, 7.42-7.31, 7.06-7.03, 4.51, 3.86.

MS (E1) m/z 342 (M+) 344, 203, 202, 201, 176, 175, 140, 132, 125.

Analysis found: C 62.45, H 4.55, N 8.00.

Example 8

N-[(4-chlorophenyl)methyl]-4-hydroxy-5,7-bis(trifluoromethyl)-3-quinolinecarboxamide

Cl

A mixture of 0.35 g of ethyl 4-hydroxy-5,7-bis(trifluoromethyl)-3-quinolinecarboxylate (FR 2537140) and 3.0 ml of 4-chlorobenzylamine was stirred at 200 °C for 1 hour. The mixture was cooled to 25 °C and diluted with 25 ml of hexanes. After stirring for another 1 hour, the solid precipitate was collected by filtration and washed with 10 ml of hexanes. It was dried in a stream of air and then suspended in 20 ml of glacial acetic acid. The mixture was heated until the solid completely dissolved and the resulting solution was diluted with 200 ml of distilled water. The mixture was allowed to cool to 25 °C and the solid was collected by filtration. It was washed with a small volume of 10% aqueous acetic acid and then dried at 2.026 MPa and 45 °C for 18 hours. The yield is 0.23 g.

The physical characteristics are as follows:

Melting point 115 to 118 °C.

1 H NMR (DMSO) delta 13.09, 10.10, 8.93, 8.38, 7.40-7.32, 4.53.

• · • · • · · • · · · • · · · · · · · · ·

MS (EI) m/z 448 (M ⁺ ) 450, 449, 288, 281, 142, 141, 140, 127, 125. Analysis found: C 50.08, H 5.94, N 7.43.

Example 9

N-[(4-chlorophenyl)methyl]-7-fluoro-4-hydroxy-3-quinolinecarboxamide

To a 0 °C solution of 4-chlorobenzylamine (0.52 ml) in 5 ml of toluene was added a 2.0 M solution of trimethylaluminium in toluene. The solution was stirred at 0 °C for 5 min and then a suspension of 0.50 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate in 5 ml of toluene was added. The solution was stirred at 0 °C for a further 10 min and then stirred at 90 °C for 18 h. The mixture was cooled to 25 °C and poured into a mixture of a large excess of 3 M hydrochloric acid and ice. After 30 min of vigorous stirring, it was filtered. The solid was dissolved in 50 ml of warm glacial acetic acid and distilled water was added to the resulting solution until cloudy. The mixture was then allowed to stand for several hours at 5 °C. Filtration of this mixture gave the desired amide as 150 mg of solid.

The physical characteristics are as follows:

Melting point 248 to 259 °C.

1 h NMR (DMSO) delta 12.79, 10.30, 8.78, 8.29, 7.47, 7.41-7.32, 4.54.

MS (E1) m/z 330 (M+) 332, 190, 163, 142, 135, 127, 125, 107.

Analysis found: C 61.69, H 3.79, N 8.38.

Example 10

N-[(4-chlorophenyl)methyl]-6-fluoro-4-hydroxy-3-quino linecarboxamide

To a 0 °C solution of 4-chlorobenzylamine (0.52 ml) in 5 ml of toluene was added 2.13 ml of a 2.0 M solution of trimethylaluminium in toluene. The solution was stirred at 0 °C for 5 minutes and then a suspension of 0.50 g of ethyl 6-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Amer. Chem. Soc, 69, 371 (1947)) in 5 ml of toluene was added. The solution was stirred at 0 °C for a further 10 minutes and then stirred at 90 °C for 18 hours. The mixture was cooled to 25 °C and poured into a mixture of a large excess of 3 M hydrochloric acid and ice. After 30 minutes of vigorous stirring, it was filtered. The solid was dissolved in 50 ml of warm glacial acetic acid and distilled water was added to the resulting solution until it became cloudy. The mixture was then allowed to stand for several hours at 5° C. Filtration of this mixture gave the desired amide as 390 mg of a solid.

The physical characteristics are as follows:

Melting point 264 °C.

1 h NMR (DMSO) delta 12.95, 10.35, 8.76, 7.86, 7.81-7.76, 7.70-7.63, 7.39-7.32, 4.53.

MS (E1) m/z 330 (M ⁺ ) 332,190,163, 142,140,134,127,125,107.

Analysis found: C 61.77, H 3.75, N 8.39, Cl 10.70.

Example 11

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-methyl-3-quinolinecarboxamide

A mixture of 0.50 g of ethyl 4-hydroxy-7-methyl-3-quinolinecarboxylate (J. Indian Chem. Soc, 31 (1954)) and 5.0 ml of 4-chlorobenzylamine was stirred for 1 hour at 200°C. The mixture was cooled to 25°C and diluted with 25 ml of hexanes. After stirring for another 1 hour, the solid precipitate was collected by filtration and washed with 10 ml of hexanes. It was dried in a stream of air and then suspended in 20 ml of glacial acetic acid. The mixture was heated until the solid was completely dissolved and the resulting solution was diluted with 200 ml of distilled water. The mixture was allowed to cool to 25 °C and the solid was collected by filtration. It was washed with a small volume of 10% aqueous acetic acid and then dried at 2.026 MPa and 45 °C for 18 hours. The yield was 0.23 g.

The physical characteristics are as follows:

Melting point over 255 °C.

1 H NMR (DMSO) δ 12.55, 10.45, 8.70, 8.12, 7.44, 7.42-7.32, 7.29, 4.53, 2.46.

MS (E1) m/z 326 (M ⁺ ) 328, 186, 160, 159, 140, 130, 125, ΊΊ.

Analysis found: C 65.96, H 4.66, N 8.55.

Example 12

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide

A mixture of 0.50 g of ethyl-(8-fluoro-4-hydroxy-7-methoxy-3-quinolinecarboxylate) (J. Med. Chem., 22, 816 (1979)) and 3.0 ml of 4-chlorobenzylamine was stirred for 1 hour at 200°C. The mixture was cooled to 25°C and diluted with 25 ml of hexanes. After stirring for an additional 1 hour, the solid precipitate was collected by filtration and washed with 10 ml of hexanes. It was dried in a stream of air and then suspended in 20 ml of glacial acetic acid. The mixture was heated until the solid was completely dissolved and the resulting solution was diluted with 200 ml of distilled water. The mixture was allowed to cool to 25°C and the solid was collected by filtration. Wash with a small volume of 10% aqueous acetic acid and then dry at 2.026 MPa and 45 °C for 18 hours. Yield 0.52 g.

The physical characteristics are as follows:

Melting point 226 to 228 °C.

!h NMR (DMSO) δ 12.90, 10.28, 8.63, 8.05, 7.73-7.68, 7.49-7.45, 7.40-7.34, 4.54 MS (El) m/z 330 (M+) 332, 331,190,163,142,141,140,135,134.

• · · · * · • · ·· · • · · · · · • · · · · ·» ··· ·· 4» • 9 · • · 9 • 9 · • · · · «Φ *·

Analysis found: C 61.75, H 3.63, N 8.45.

Example 13

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-nitro-3-quinolinecarboxamide

A mixture of 0.65 g of ethyl 4-hydroxy-6-nitro-3-quinolinecarboxylate (J. Amer. Chem. Soc, 68, 1264 (1946)) and 5.0 ml of 4-chlorobenzylamine was stirred for 1 hour at 200°C. The mixture was cooled to 25°C and diluted with 25 ml of hexanes. After stirring for another 1 hour, the solid precipitate was collected by filtration and washed with 10 ml of hexanes. It was dried in a stream of air and then suspended in 20 ml of glacial acetic acid. The mixture was heated until the solid was completely dissolved and the resulting solution was diluted with 200 ml of distilled water. The mixture was allowed to cool to 25°C and the solid was collected by filtration. Wash with a small volume of 10% aqueous acetic acid and then dry at 2.026 MPa and 45 °C for 18 hours. Yield 0.41 g.

The physical characteristics are as follows;

Melting point over 250 °C.

1 h NMR (DMSO) delta 13.10, 10.11, 8.87, 8.51, 7.89, 7.41-7.35, 4.56.

MS (E1) m/z 357 (M+) 359,190,171,144,142,140,127,125, 89.

Analysis found: C 57.14, H 3.50, N 11.64.

• · • · • · « ♦ · « • · · · » • ·

Example 14

N-[(4-chlorophenyl)methyl]-5,6,7,8-tetrafluoro-4-hydroxy-3-quinolinecarboxamide

To a 0 °C solution of 4-chlorobenzylamine (0.080 ml) in 5 ml of toluene is added 0.70 ml of a 2.0 M solution of trimethylaluminum in toluene. The solution was stirred at 0°C for 5 minutes and then a suspension of 0.20 g of ethyl 5,6,7,8-tetrafluoro-4-hydroxy-3-quinolinecarboxylate (U.S. Patent No. 4,940,710) in 5 mL of toluene was added. The solution was stirred at 0°C for a further 10 minutes and then stirred at 90°C for 3 hours. The mixture was cooled to 25°C and poured into 10 mL of 3 M hydrochloric acid and 10 mL of crushed ice. After 20 minutes of vigorous stirring, it was filtered. The solid was dissolved in 50 mL of warm glacial acetic acid and distilled water was added to the resulting solution until cloudy. The mixture was then allowed to stand for several hours at 5°C. Filtration of this mixture gave the desired amide as 0.12 mg of solid.

The physical characteristics are as follows:

Melting point 241 to 243 °C.

!hNMR(DMSO) delta 13.13, 8.58, 7.42-7.31, 4.52.

MS (E1) m/z 384 (M+) 386, 244,189,188, 142,140,127,125, 77.

Analysis found: C 52.70, H 2.51, N 7.10.

Example 15

N-[(4-Chlorophenyl)methyl]-6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxamide

To a 0°C solution of 4-chlorobenzylamine (0.45 mL) in 5 mL of toluene was added 1.84 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution was stirred at 0°C for 5 min and then 0.20 g of ethyl [6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate] (Tetrahedron 48, 29 (1992)) was added. The solution was stirred at 0°C for a further 30 min and then stirred at 25°C for 18 h. The mixture was poured into a mixture of 50 mL of 3 M hydrochloric acid and 50 mL of crushed ice. The mixture was extracted with three successive portions of 75 mL of ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in a small volume of ethyl acetate and hexanes were added until the solution became cloudy. The mixture was then allowed to stand for 1 hour. Filtration of this mixture gave the desired amide as 0.25 g of a solid.

The physical characteristics are as follows:

Melting point 244 to 250°C.

ΪΗ NMR (DMSO) δ 13.20; 10.10; 8.64; 8.03-7.90; 7.44-7.31; 4.54.

MS (El): m/z 366 (M+) 368, 226, 199, 171, 170, 143, 142, 141, 140, 125.

Analysis found: C 55.47; H 2.91; N 7.53.

Preparation 2

6,7,8-Trifluoro-4-hydroxy-3-quinolinecarboxylic acid

F

A mixture of 5.0 g of ethyl [6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylate] (Tetrahedron 48, 6135-6150 (1992)), 146 ml of tetrahydrofuran, 146 ml of methanol and 74 ml of 1.0 M aqueous lithium hydroxide solution was stirred for 4 days at 25°C. The solution was neutralized with 16 ml of 3 M hydrochloric acid and the volume of the resulting mixture was reduced to 30 ml by evaporation under reduced pressure. The solid precipitate that formed was collected by filtration and partitioned between ethyl acetate and water. The aqueous phase was washed several times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate. The solution was filtered and the solvent was removed from the filtrate by evaporation under reduced pressure. The title compound was obtained as 3.22 g of a solid.

The physical characteristics are as follows:

NMR (400 MHz, DMSO) δ 8.72; 7.75.

MS (ES-): m/z 242 (M-H+).

Example 16

6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide

To a solution of 1.0 g of 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc, 68, 1264 (1946)) (the sample used in this procedure was shown by Karl Fischer titration to be a hydrate containing 0.4 equivalents of water) in 15 ml of a 99:1 (v/v) mixture of dimethylformamide and triethylamine was added 1.01 g of carbonyldiimidazole. The mixture was stirred for 3 days and then transferred to a volumetric flask and diluted to a total volume of 25 ml with dimethylformamide. To 1.22 ml of this solution was added 39 mg of 4-chlorophenylhydrazine hydrochloride. The mixture was stirred for 18 hours at 25 °C, then 15 ml of distilled water was added. The precipitate was collected by filtration and dried in a stream of air. This procedure gave the title compound as 45 mg of a solid.

The physical characteristics are as follows:

Melting point 210-216°C (decomposition).

·· 9 9 99

9999 · · «9 «··

9999 9 9 999

99 9« 9 9 99 >9

9999 9 9 999

9 999 999 99 ^{1 H} NMR (DMSO) δ 13.36; 11.03; 8.63; 8.19; 8.04; 7.17; 6.75.

MS (EI): m/z 366.1 (M-H+)

Analysis found: C 50.62; H 2.87; N 11.24.

Preparation 3

4-(Phenylmethyl)thio-3-trifluoromethylaniline

A solution of 338 g of stannous chloride dihydrate in 340 ml of concentrated hydrochloric acid was added to a stirred suspension of 104 g of 4-(phenylmethyl)thio-3-trifluoromethylnitrobenzene (J. Med. Chem., 845 (1978)) in 100 ml of concentrated hydrochloric acid. The mixture was heated on a steam bath during the addition and for one hour after the addition was complete. The mixture was cooled in ice and the solid was filtered and dried in a stream of air. The solid was dissolved in 500 ml of 0°C 6 M aqueous sodium hydroxide solution and extracted with diethyl ether. The ether extract was washed with distilled water and then brine. It was dried over sodium sulfate and filtered. The solvent was removed to give 91 g of solid. This solid was recrystallized from methanol to give 39.7 g of the title compound.

The physical characteristics are as follows:

Melting point 75-76.5°C.

Analysis found: C 59.59; H 4.16; N 4.79; S 11.68.

Preparation 4

4-hydroxy-6-[(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxylic acid • · ·· · · · · 9 · • · · · ·· ·· · « «

A mixture of 54 g of diethylethoxymethylenemalonate and 71.0 g of 4-(phenylmethyl)-3-trifluoromethylaniline was stirred at 100-160°C until no further evolution of ethanol was observed. The mixture was diluted with 750 ml of diphenyl ether and the mixture was refluxed for 1 hour. The solution was cooled to 25°C and diluted with an equal volume of petroleum ether. The mixture was filtered and the solid was washed with petroleum ether. This gave 95 g of a light brown solid. A mixture of 81.5 g of this solid and 1.012 N aqueous sodium hydroxide solution was refluxed for 4 hours. The cooled mixture was neutralized with concentrated hydrochloric acid. The solid was collected by filtration and dried under reduced pressure. This gave 65.7 g of the title compound as a solid.

The physical characteristics are as follows:

Melting point 225-235°C.

Analysis found: C 57.20; H 3.43; N 3.58; S 8.33.

Preparation 5

5,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid

To a suspension of 6.0 g of ethyl [5,8-difluoro-4-hydroxy-3-quinolinecarboxylate] (Magn. Reson. Chem., 34, 972-978 (1996)) in 400 ml of a 1:1 (v/v) mixture of methanol and tetrahydrofuran is added 100 ml of 1.0 M aqueous lithium hydroxide solution. After three days, another 20 ml of 1.0 M aqueous lithium hydroxide solution is added and the mixture is heated to 50°C. After another three days, the solution is cooled to 25°C and diluted with 15 ml of glacial acetic acid. The volume of the solution is reduced to two-thirds by evaporation under reduced pressure. The precipitate is collected by filtration and washed with four

with subsequent 150 mL portions of distilled water. The solid is dried at 2.026 MPa and 80°C for 24 hours. This procedure gives the title compound as 4.96 g of an off-white solid.

The physical characteristics are as follows.

Melting point > 240°C.

1 h NMR (DMSO) δ 8.61; 7.87-7.79; 7.37-7.26.

MS (ES-) m/z 224 (M-H+).

Example 17

N-[(4-chlorophenyl)methyl]-5,8-difluoro-4-hydroxy-3-quinolinecarboxamide

To a mixture of 0.25 g of 5,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid and 10 ml of dimethylformamide was added 0.20 g of carbonyldiimidazole. The mixture was stirred for 18 hours at 50°C, then cooled to 25°C. The mixture was reacted with 0.10 ml of distilled water and stirred for 5 minutes. To the resulting solution was added 0.15 ml of 4-chlorobenzylamine. After stirring for 18 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of refluxing glacial acetic acid. Hot water (100°C) was added dropwise until the solution became cloudy, and the temperature of the mixture was allowed to drop to 25°C. The precipitate was collected by filtration and washed with two subsequent 5 ml portions of 50% aqueous acetic acid. Dry at 2.026 MPa and 90°C for 18 hours. This procedure gives the title compound as 173 mg of a white powder.

The physical characteristics are as follows:

Melting point 259-260°C.

1 H NMR (400 MHz, DMSO) δ 8.56; 7.70; 7.39; 7.35; 7.17; 4.52.

HRMS (FAB) found: 349.0564.

Analysis found: C 57.89; H 3.23; N 7.85.

• · φ« · · · · · · ····· · ·?···· ···· · · ···· ·· ·· ··· ··· ·· ··

Preparation 6

7,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid

To a suspension of 2.0 g of ethyl [7,8-difluoro-4-hydroxy-3-quinolinecarboxylate] (Magn. Reson. Chem., 34, 972-978 (1996)) in 160 ml of a 1:1 (v/v) mixture of methanol and tetrahydrofuran was added 40 ml of 1.0 M aqueous lithium hydroxide solution. After three days, the volume of the solution was reduced to two-thirds by evaporation under reduced pressure. 20% aqueous acetic acid was added until further addition caused no further precipitate to form. The precipitate was collected by filtration and washed with three successive 50 ml portions of distilled water. The solid was dried at 2.026 MPa and 75 °C for 18 hours. This procedure gave the title compound as 1.54 g of a white solid.

The physical characteristics are as follows:

Melting point > 240°C.

1d NMR (DMSO) δ 8.69; 8.38-8.20; 8.62-8.73.

MS (ES-) w/z 224 (MH ¹ )

Example 18

N-[(4-chlorophenyl)methyl]-7,8-difluoro-4-hydroxy-3-quinolinecarboxamide

HIM

F

F

O

II

Cl • Φ φφ • φ φ φ φ φ φφ φ φ φ φ φ φ φ φ φ

To a mixture of 0.25 g of 7,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid and 10 ml of dimethylformamide was added 0.20 g of carbonyldiimidazole. The mixture was stirred at 50°C for 18 hours and then cooled to 25°C. The mixture was reacted with 0.10 ml of distilled water and stirred for 5 minutes. To the resulting solution was added 0.15 ml of 4-chlorobenzylamine. After stirring for 18 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of refluxing glacial acetic acid. Hot water (100°C) was added dropwise until the solution became cloudy and the mixture was allowed to cool to 25°C. The precipitate was collected by filtration and washed with two subsequent 5 ml portions of 50% aqueous acetic acid. Dry at 2.026 MPa and 90°C for 18 hours. This procedure gives the title compound as 280 mg of a white powder.

The physical characteristics are as follows:

Melting point 247-248°C.

1 H NMR (DMSO) δ 8.62; 8.12-8.03; 7.53; 7.38; 7.34; 4.53.

HRMS (FAB) found: 349.0561.

Analysis found: C 56.35; H 3.45; N 7.31.

Preparation 7

5,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid

To a suspension of 8.0 g of ethyl [5,7-difluoro-4-hydroxy-3-quinolinecarboxylate] (Magn. Reson. Chem., 34, 972-978 (1996)) in 600 ml of a 1:1 (v/v) mixture of methanol and tetrahydrofuran was added 150 ml of 1.0 M aqueous lithium hydroxide solution. After three days, another 35 ml of 1.0 M aqueous lithium hydroxide solution was added and the mixture was heated to 50°C. After another three days, the solution was cooled to 25°C and diluted with 20 ml of glacial acetic acid. The volume of the solution was reduced to two-thirds by evaporation under reduced pressure. The precipitate was collected by filtration and washed with four subsequent 150 ml portions of distilled water. NMR analysis of this material revealed the presence of a small amount of the methyl ester of the desired acid, so it was redissolved in the mixture » « ·· • ♦ • ·

260 ml of tetrahydrofuran, 260 ml of methanol and 130 ml of 1.0 N aqueous lithium hydroxide solution. The mixture is stirred for 48 hours at 50°C and then cooled to 25°C. It is reacted with 25 ml of glacial acetic acid. The volume of the solution is reduced to two thirds by evaporation under reduced pressure. The precipitate is collected by filtration and washed with four successive 150 ml portions of distilled water. It is dried at 2.026 MPa and 80°C for three days. This procedure gives the title compound as 4.82 g of an off-white solid.

The physical characteristics are as follows:

*H NMR (DMSO) δ 8.89; 7.50-7.37.

MS (ES-) w/v 224 (MH ⁺ ).

Preparation 8

6,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid

To a suspension of 5.0 g of ethyl 6,8-difluoro-4-hydroxy-3-quinolinecarboxylate (Magn. Reson. Chem., 34, 972-978 (1996)) in 400 ml of a 1:1 (v/v) mixture of methanol and tetrahydrofuran is added 100 ml of 1.0 M aqueous lithium hydroxide solution. After three days, another 25 ml of 1.0 M aqueous lithium hydroxide solution is added and the mixture is heated to 50°C. After another three days, the solution is cooled to 25°C and stirred for another day. Dilute with 25 ml of glacial acetic acid. The volume of the solution is reduced to two-thirds by evaporation under reduced pressure. The precipitate is collected by filtration and washed with four subsequent 150 ml portions of distilled water. The solid was dried at 2.026 MPa and 80°C for three days. This procedure gave the title compound as 4.0 g of a white solid. The physical characteristics are as follows:

1 h NMR (DMSO) δ 8.64; 8.00; 7.80.

MS (ES-) m/z 224 (M-H+).

44

4 4 4

4 4 «

4 4 4

4 4 4

4 4 4 • 4

44

4*44 4

4 44 · 4 4 4

4 4 4

44 4

Example 20

N-[(4-chlorophenyl)methyl]-4-hydroxy-8-methoxy-3-quinolinecarboxamide

To a mixture of 0.50 g of 4-hydroxy-8-methoxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc, 68, 1268 (1946)) and 10 ml of dimethylformamide was added 0.41 g of carbonyldiimidazole. The mixture was stirred for 20 hours at 37°C, then cooled to 25°C. The mixture was reacted with 0.25 ml of distilled water and stirred for 5 minutes. To the resulting solution was added 0.31 ml of 4-chlorobenzylamine. After stirring for 18 hours, the mixture was heated to 40°C and stirred for a further 24 hours. The solution was then cooled to 25°C and diluted with 10 ml of distilled water. After 30 minutes, the precipitate was collected by filtration and washed with two subsequent 5 ml portions of 10% aqueous acetic acid. Dry for 18 hours at 25°C in a stream of air. This procedure gives the title compound as 485 mg of a light brown solid. The physical characteristics are as follows:

Melting point > 240°C.

1 H NMR (DMSO) δ 8.59; 7.86; 7.54-7.32; 4.53; 4.02.

MS (ES-) m/z 341 (M-H + , 70%), 343 (M + 2 - H ⁺ , 25%).

HRMS (EI) found: 342.0766.

Analysis found: C 62.45; H 4.53; N 8.09.

Example 21

6-chloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide • 9 ·· • · · · 9 • · ·· • · · · 9 • 9 9 · ·· 99 ·

9

99 • 9 9 9 • 9 · · • 9 9 9

9 9 9

99

Cl.

OH

N'

O

To a mixture of 0.365 g of 6-chloro-4-hydroxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc, 68, 1264 (1946)) and 5 ml of dimethylformamide was added 0.29 g of carbonyldiimidazole. The mixture was stirred for 18 hours at 60°C, then cooled to 25°C. To the resulting solution was added 0.22 ml of 4-chlorobenzylamine. After stirring for 18 hours, the mixture was diluted with 10 ml of distilled water. After 30 minutes, the precipitate was collected by filtration and washed with two subsequent 10 ml portions of water. It was then washed with 5 ml of diethyl ether. It was dried for 48 hours at 85°C at 2.026 MPa. This procedure gave the title compound as 251 mg of an off-white solid.

The physical characteristics are as follows:

Melting point > 245°C.

¹ H NMR (DMSO) δ 8.78; 8.16; 7.80; 7.74; 7.42-7.32; 4.54.

MS (ES-) w/z 345 (M-H+).

HRMS (EI) found: 346.0265.

Analysis found: C 58.02; H 3.54; N 7.94; Cl 20.33.

Example 22

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-methyl-3-quinolinecarboxamide

H,C

A mixture of 230 mg of ethyl [4-hydroxy-6-methyl-3-quinolinecarboxylate] (J. Chem. Soc, 68, 893 (1948)) and 0.7 ml of 4-chlorobenzylamine was stirred for 1 hour at 210°C. The mixture was cooled to 25°C and diluted with 1.5 ml of toluene. The mixture was filtered and the filtrate was dissolved in a minimum amount of refluxing glacial acetic acid. The hot solution was treated dropwise with distilled water until it became cloudy and then allowed to cool to 25°C. The precipitate was collected by filtration and washed with ...

-T< · · ·· · 9 9 9 9 9 /J 9 9 9 9 9 9 9 9 9 9 9 9 ···· 9 9 9 9 9 9

99 999 999 99 ·· with a small amount of dilute aqueous acetic acid. The solid is dried at 2.026 MPa and 85°C for 48 hours. This procedure gives the title compound as 47 mg of a light yellow-brown solid. The physical characteristics are as follows:

Melting point > 245°C.

1 H NMR (DMSO) δ 8.71; 8.02; 7.59; 7.39; 7.35; 4.54; 2.43.

HRMS (EI) found: 326.0829.

Analysis found. C 65.50; H 4.71; N 8.55.

Example 23

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-methoxy-3-quinolinecarboxamide

A mixture of 320 mg of ethyl [4-hydroxy-6-methoxy-3-quinolinecarboxylate] (J. Amer. Chem. Soc, 68, 1204 (1946)) and 1.0 ml of 4-chlorobenzylamine was stirred for 1 hour at 210°C. The mixture was cooled to 25°C and diluted with 2.0 ml of toluene. The mixture was filtered and the filtrate was dissolved in a minimum amount of refluxing glacial acetic acid. The hot solution was treated dropwise with distilled water until it became cloudy and then allowed to cool to 25°C. The precipitate was collected by filtration and washed with a small amount of dilute aqueous acetic acid. It was dried in a stream of air and then dissolved in refluxing acetonitrile. The solution was allowed to cool to 25°C and after a further 2 hours the solid was collected by filtration. The solid was dried at 2.026 MPa and 85°C for 48 hours. This procedure gave the title compound as 64 mg of a light tan solid.

The physical characteristics are as follows:

Melting point 221-222°C.

1 H NMR (DMSO) δ 8.64; 7.69-7.61; 7.43-7.30; 4.54; 3.85.

MS (ES-)/n. z341 (MH ⁺ ).

HRMS (EI) found: 342.0772.

9 44 44

4 4 4 4 4 9 4

4 9 4 9 4

4 4 9 4 9 4

4 4 4 9 4

444 444 49 94 ·· *· • * · ·

4 44

4 4 4

4 4 9

94

Analysis found: C 62.60; H 4.44; N 8.10.

Preparation 9

6-Cyano-4-hydroxy-3-quinolinecarboxylic acid

To a suspension of 5.15 g of ethyl [6-cyano-4-hydroxy-3-quinolinecarboxylate] (FR 2002888) in 212 ml of a 1:1 (v/v) mixture of methanol and tetrahydrofuran is added 53 ml of 1.0 M aqueous lithium hydroxide solution. After 24 hours, another 50 ml of 1.0 M aqueous lithium hydroxide solution is added and the mixture is stirred for a further 24 hours. It is neutralized by the dropwise addition of 3.0 N hydrochloric acid. The volume of the solution is reduced to two thirds by evaporation under reduced pressure. The precipitate is collected by filtration and washed with several portions of distilled water. This procedure gives the title compound as 3.39 g of a white solid.

The physical characteristics are as follows:

1 H NMR (DMSO) δ 8.85; 8.55; 7.87; 7.79.

MS (ES-) m/z 213 (M-H+, 100%).

Example 24

N-[(4-chlorophenyl)methyl]-6-cyano-4-hydroxy-3-quinolinecarboxamide

A suspension of 0.25 g of 6-cyano-4-hydroxy-3-quinolinecarboxylic acid in 5 ml of thionyl chloride is treated with one drop of dimethylformamide. The mixture is stirred for 24 hours at 25°C, then the excess thionyl chloride is evaporated in a stream of nitrogen. The final traces of thionyl chloride are • ·

·.,··..* .:. ... ·· ·· is removed under high vacuum (6.66 Pa) and the solid is suspended in 5 ml of dichloromethane. The suspension is reacted with 0.46 ml of 4-chlorobenzylamine. The resulting mixture is stirred for two weeks at 25 °C. The mixture is partitioned between 50 ml of ethyl acetate and 50 ml of a solution prepared by diluting a saturated aqueous solution of sodium dihydrogen phosphate with an equal volume of water. The organic phase is washed with a further 50 ml of this buffer and then with brine. The solution is dried (MgSO4) ^and the solvent is evaporated under reduced pressure. The remaining oil is treated with 10 ml of diethyl ether, which causes the oil to crystallize. The solid is collected by filtration and washed with a minimum volume of ethyl acetate. The solid is dissolved in 1.5 ml of refluxing glacial acetic acid and the resulting solution is diluted with 3 ml of distilled water. The mixture was allowed to cool to 25°C. The pale yellow solid that precipitated was collected by filtration. The solid was washed with 1.0 mL of 50% aqueous acetic acid and dried in a stream of air. The title compound was thus obtained as 50 mg of a pale yellow solid.

The physical characteristics are as follows:

Melting point > 265°C.

1 h NMR (DMSO) δ 8.84; 8.59; 8.11; 7.84; 7.39; 7.35; 4.55.

MS (ES-) m/z 337 (M-H+).

HRMS (EI) found: 337.0621.

Analysis found: C 60.76; H 3.83; N 11.84.

Example 25

7-(Acetylamino)-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

A solution of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide in 1 ml of anhydrous pyridine was reacted with 0.032 ml of acetic anhydride. After 24 hours, another 0.005 ml of acetic anhydride was added and the mixture was stirred for another 48 hours. The mixture was diluted with 2 ml of distilled water and the precipitate was collected by filtration. It was washed with two 1 ml portions of distilled water and dried in a stream of air. It was dried at 2.026 MPa and 75°C for 16 hours. The product was obtained as 78 mg of a light yellow-brown solid.

The physical characteristics are as follows:

Melting point > 250°C.

^! H NMR (DMSO) δ 12.65; 10.42; 10.45; 8.61; 8.27; 8.12; 7.42-7.28; 4.52; 2.10.

MS (El) m/z 369 (M+), 371, 230,229,203,202,186,160,140, 125.

HRMS (EI) found: 369.0878.

Example 26

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-[(methylsulfonyl)amino]-3-quinolinecarboxamide

Methanesulfonyl chloride was added to a solution of 200 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide in 1.0 ml of anhydrous pyridine. The mixture was stirred for 20 hours, then diluted with two 2 ml portions of distilled water. It was dried in a stream of air and then further dried at 2.026 MPa and 70°C for 2 hours. The product was obtained as 225 mg of a dark orange powder. The physical characteristics are as follows.

Melting point > 220°C.

^! H NMR (400 MHz, DMSO) δ 12.63; 10.50; 10.41; 8.64; 8.15; 7.51; 7.40-7.29; 7.22; 4.52; 3.13.

MS (E1) m/z 405 (M+), 266, 265, 238, 187, 186, 159, 142, 140, 125.

Analysis found: C 57.02; H 4.19; N 11.24. (The presence of 1.0 equivalent of pyridine was confirmed by 1HNMR).

Example 27

N-[(4-chlorophenyl)methyl]-7-(dimethylamino)-4-hydroxy-3-quinolinecarboxamide » · • *

9· 9 · **

Sodium cyanoborohydride (96 mg) was added to a mixture of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide and 91 mg of paraformaldehyde in 5 mL of acetic acid. After 2 days, the mixture was diluted with 5 mL portions of distilled water (using more water caused the product to precipitate as an oil). The mixture was stirred for a further 10 minutes and then the product was collected by filtration. Washed with three 1 mL portions of 50% aqueous acetic acid. Air dried and then further dried at 2.026 MPa and 75°C for 24 hours. The product was obtained as 25 mg of an off-white powder.

The physical characteristics are as follows:

Melting point > 240°C.

MS (EI) m/z 355 (M+), 357, 216, 215, 214, 189, 188, 187, 159, 132. Analysis found: C 63.56; H 5.13; N 11.57.

Example 28

6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-nitro-3-quinolinecarboxamide (500 mg) was suspended in 50 ml of freshly degassed dimethylformamide and treated with 0.5 ml of 50% Raney nickel in water (Aldrich). The mixture was stirred under 310 kPa of hydrogen pressure for 24 hours and then filtered through celite. The solvent was removed by evaporation under reduced pressure. The residue was suspended in 5 ml of absolute ethanol and collected by filtration. After drying at 133 Pa and 100°C for 1.5 hours, the product was obtained as 387 mg of a pale yellow powder.

The physical characteristics are as follows:

Melting point > 225°C.

*H NMR (DMSO) δ 8.51; 7.43-7.27; 7.30; 7.07; 5.52; 4.53.

MS (E1) m/z 327 (M+), 329, 188, 187, 186, 161, 160, 140, 131, 104.

HRMS (EI) found: 327.0787.

Analysis found: C 61.55; H 4.53; N 12.71.

Example 29

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-[(methylsulfonyl)amino]-3-quinolinecarboxamide

O

II ^C 'N

H

Cl

This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare N-[(4-chlorophenyl)methyl]-4-hydroxy-7-[(methylsulfonyl)amino]-3-quinolinecarboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide. The product is obtained as a light yellow-brown powder.

The physical characteristics are as follows;

Melting point > 200°C.

1 h NMR (DMSO) δ 10.42; 8.71; 8.07; 7.70; 7.62; 7.39; 7.35; 4.54; 3.00.

MS (E1) m/z 405 (M+), 265, 264, 238, 186, 185, 159, 142, 140, 125.

HRMS (EI) found: 405.0541.

Analysis found: C 52.31; H 4.24; N 9.97.

Example 30

N-[(4-chlorophenyl)methyl]-6-(dimethylamino)-4-hydroxy-3-quinolinecarboxamide

This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare N-[(4-chlorophenyl)methyl]-7-(dimethylamino)-4-hydroxy-3-quinolinecarboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide (29805JT 118). The product is obtained as a light yellow-brown powder.

The physical characteristics are as follows:

Melting point > 225°C.

1 h NMR (DMSO) δ 8.58; 7.57; 7.43-7.28; 4.53; 2.98.

MS (E1) m/z 355 (M+), 357, 216, 215, 214, 188, 187, 173, 159, 145.

HRMS (EI) found: 355.1093.

Analysis found: C 61.03; H 5.03; N 10.85.

Example 31

6-(Acetylamino)-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

This compound is prepared from 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide using a procedure similar to that used to prepare 7-(acetylamino)-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide from 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide. The product is obtained as a light yellow-brown powder.

The physical characteristics are as follows:

Melting point > 220°C.

• ·

9 9 * ♦ • · ·

9 9

9 · 99 *H NMR (DMSO) δ 8.67; 8.48; 7.96; 7.64; 7.41-7.32; 4.54; 2.07.

MS (EI) m/z 369 (M+), 230, 229, 228, 203, 202, 186, 160, 140, 125. Analysis found: C 61.38; H 4.47; N 11.06.

Example 32

N-[(4-Chlorophenyl)methyl]-4-hydroxy-7-(1-pyrrolyl)-3-quinolinecarboxamide

ZTN

O

If

C.

Cl

A mixture of 100 mg of 7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide and 0.043 ml of 2,5-dimethoxytetrahydrofuran in 1 ml of acetic acid is refluxed for 4 hours. (The mixture darkens very quickly). Cool to 25°C. The precipitate is collected by filtration. Wash with three 1 ml portions of acetic acid and dry in a stream of air. After drying at 75°C, the product is obtained as 20 mg of a brown powder.

The physical characteristics are as follows:

Melting point > 200°C.

ΪΗ NMR (400 MHz, DMSO) δ 8.77; 8.27; 7.74; 7.73; 7.48; 7.42-7.32; 6.37; 4.54.

MS (E1) m/z 377 (M+), 238, 237, 236, 211, 210, 154, 142, 140, 125.

HRMS (EI) found: 377.0918.

Analysis found: C 65.15; H 4.42; N 10.51.

Example 33

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-[(phenylsulfonyl)amino]-3-quinolinecarboxamide

A solution of 40 mg of 6-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide in 1.0 ml of anhydrous pyridine was reacted with 16.9 μΐ of benzenesulfonyl chloride. The mixture was stirred for 3 hours at 25°C, then for 24 hours at 50°C. The reaction mixture was diluted with 2 ml of distilled water. The solid that precipitated was collected by filtration. It was washed with two 1 ml portions of distilled water and dried at 2.026 MPa and 75°C for 16 hours. The yield was 36 mg.

The physical characteristics are as follows:

Melting point > 200°C.

*H NMR (DMSO) δ 8.62; 8.06; 8.87; 7.67-7.52; 7.46; 7.40-7.30; 7.15; 4.52.

MS (El) m/z 467 (M+), 327, 301, 300, 187, 186, 159, 142, 140, 125, 77.

Analysis found: C 59.91; H 4.24; N 9.79. (The presence of 0.4 equivalents of pyridine was confirmed by 1HNMR).

Example 34

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-[[(phenylmethyl)sulfonyl]amino]-3-quinolinecarboxamide

This compound was prepared by the procedure used to prepare the title compound in Example 33 above, except that 25 mg of α-toluenesulfonyl chloride was used instead of benzenesulfonyl chloride. The yield was 48 mg.

The physical characteristics are as follows:

Melting point > 225°C.

··

1 · · « t · · 4 » · · 1 ·· ·* 1H NMR (DMSO) δ 8.65; 8.13; 7.52; 7.42-7.22; 7.19; 4.61; 4.54.

MS (EI)zw/z481 (M+), 314, 187, 186, 160, 159, 140, 125, 106, 91, 77.

Analysis found: C 61.11; H 4.50; N 9.73. (The presence of 0.5 equivalent of pyridine was confirmed by 1HNMR).

Example 35

N-[(4-chlorophenyl)methyl]-7-[[(4-chlorophenyl)sulfonyl]amino]-4-hydroxy-3-quinolinecarboxamide

This compound was prepared by the procedure used to prepare the title compound in Example 33 above, except that 28 mg of 4-chlorobenzenesulfonyl chloride was used instead of benzenesulfonyl chloride. The yield was 52 mg.

The physical characteristics are as follows.

Melting point > 200°C.

*Η NMR (DMSO) δ 8.57; 8.08; 7.85; 7.66; 7.46; 7.42-7.27, 7.16, 4.51.

MS (ΕΓ) m/z 501 (M+), 336, 334, 187, 186, 159, 142, 140, 131, 125, 111.

Preparation 10

8-fluoro-4-hydroxy-3-quinolinecarboxylic acid

To a suspension of 3.53 g of ethyl [8-fluoro-4-hydroxy-3-quinolinecarboxylate] (J. Med. Chem., 22, 816 (1979)) in 150 ml of tetrahydrofuran and 150 ml of methanol was added 3.14 g of lithium hydroxide hydrate as a solution in 75 ml of water. The mixture was heated to 55°C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove volatiles.

·..··..· ..........

of the substance. The aqueous phase is cooled to 0°C and treated dropwise with 6N hydrochloric acid to pH 4. The precipitate formed is collected by filtration and washed with dilute phosphate buffer pH 4 and air dried. The residue is recrystallized from dimethylformamide-water and dried in vacuo. This gives 2.75 g of the title compound.

The physical characteristics are as follows:

1 h NMR (DMSO) 614.9; 13.6; 8.6; 8.1; 7.8; 7.6.

MS (ES-)/t2O6(MH ⁺ ).

Preparation 11 (8-fluoro-4-hydroxy-3-quinolinoyl)-1H-imidazole

To a flame-dried flask under argon was added 1.04 g of 8-fluoro-4-hydroxy-3-quinolinecarboxylic acid, 0.9 g of Ι,Γ-carbonyldiimidazole, and 50 mL of dry tetrahydrofuran. The mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, treated with an additional 0.15 g of 1,1-carbonyldiimidazole, and heated again. After refluxing overnight, the suspension was cooled to room temperature, and the resulting precipitate was collected by filtration. The solid was washed with tetrahydrofuran, diethyl ether, and hexanes, and dried in vacuo. This gave 1.34 g of the crude title compound, which was used without further purification.

The physical characteristics are as follows:

1 H NMR (DMSO): δ 8.4; 8.2; 8.0; 7.7; 7.6; 7.4; 7.0.

MS (ES-) m/z 256 (M-OH).

Example 36

8-Fluoro-4-hydroxy-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide ♦ · ·· ··

The physical characteristics are as follows:

*H NMR (DMSO) δ 13.0; 11.2; 8.6; 8.2; 8.1; 7.7; 7.5; 7.2; 6,7. MS (ES-) zzz/z 330 (MH ⁺ ).

Example 38

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxamide

F

A mixture of 5.0 g of 2-fluoro-6-methylaniline and 8.64 g of diethylethoxymethylenemalonate was heated at 130°C for 2 hours with removal of ethanol via a Dean-Stark trap. The mixture was then cooled to 75°C and 50 mL of diphenyl ether was added. The solution was heated at 250°C for 2 hours with removal of ethanol via a Dean-Stark trap, then cooled to room temperature. The resulting solid was collected, washed with hexanes and dried to give 5.564 g of ethyl [8-fluoro-4-hydroxy-6-methylquinoline-3-carboxylate]. A mixture of this ester (0.50 g) and 3.0 mL of 4-chlorobenzylamine was heated at 180°C for 1 hour. The reaction mixture was cooled and poured into 50 mL of diethyl ether. The resulting solid was filtered, dried and purified by trituration in acetone to give the desired product (0.54 g).

The physical characteristics are as follows:

Melting point 278-279°C (decomposition).

1 H NMR (300 MHz, DMSO-d _ft ) δ 12.37; 10.30; 8.57; 7.82; 7.55; 7.37; 7.33; 4.53; 2.43.

IR (mull) 3086, 3008, 1665, 1614, 1580, 1543, 1512, 1493, 1484, 1432, 1268, 991, 796, 661,

-and

651 cm.

• φ • · · • ·· • · · • · ·

MS (electrospray) 345.1 (M+H), 367.1 (M+Na), 343.1 (M-H). Analysis found: C 62.38; H 4.05; N 8.04; Cl 10.35.

Example 39

N-[(4-chlorophenyl)methyl]-4-hydroxy-7-iodo-3-quinolinecarboxamide

OH O

3-Iodoaniline (8.50 mL) and diethylethoxymethylenemalonate (14.30 mL) were heated at 130°C for 1 hour. The reaction mixture was cooled to room temperature and 70 mL of diphenyl ether was added. The solution was heated at 250°C for 1.5 hours with ethanol removed via a Dean-Stark trap. The reaction mixture was cooled to room temperature and the resulting solid was filtered, washed with hexanes and dried. The solid was triturated in ethyl acetate to give ethyl [4-hydroxy-7-iodoquinoline-3-carboxylate]. A mixture of this ester (0.35 g) and 3.0 mL of 4-chlorobenzylamine was heated at 180°C for 1 hour. The reaction mixture was cooled to 70°C and poured into 50 mL of diethyl ether. A tan solid was obtained which crystallized slowly from diethyl ether. The solid was recrystallized from ethyl acetate/hexanes to give the desired product (0.22 g).

The physical characteristics are as follows:

Melting point 248-250°C.

1 H NMR (300 MHz, DMSO-dg) δ 12.60; 10.29; 8.74; 8.07; 7.95; 7.76; 7.38; 7.33; 4.52.

IR (mull) 3343, 3245, 3200, 3149, 3064, 1640, 1623, 1603, 1552, 1530, 1513, 1492, 1352, 1191.791 cm' ¹ .

MS (electrospray) 438.9 (M+H).

HRMS (EI) found: 437.9637.

Example 40

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-iodo-3-quinolinecarboxamide

4-Iodoaniline (8.60 g) and diethylethoxymethylenemalonate (7.90 mL) were heated at 130°C for 1 hour. The reaction mixture was cooled to room temperature and 60 mL of diphenyl ether was added. The solution was heated at 250°C for 1.5 hours with ethanol removed via a Dean-Stark trap. The reaction mixture was cooled to room temperature and the resulting solid was filtered, washed with hexanes and dried to give 11.20 g of ethyl [4-hydroxy-7-iodoquinoline-3-carboxylate]. A mixture of this ester (0.58 g) and 4.0 mL of 4-chlorobenzylamine was heated at 180°C for 1.5 hours. The reaction mixture was cooled and poured into 50 mL of diethyl ether. The resulting solid was filtered, triturated in ethyl acetate, and filtered again to give the desired product (0.50 g).

The physical characteristics are as follows.

Melting point 297-299°C.

1 H NMR (300 MHz, DMSO-dg) δ 12.71; 10.27; 8.76; 8.50; 8.02; 7.50; 7.38; 7.33; 4.52.

IR (mull) 3151, 3078, 3039, 1631, 1610, 1572, 1563, 1545, 1527, 1512, 1491, 1433, 1351, 1303, 799 cm' ¹ .

MS (electrospray) 438.9 (M+H), 460.9 (M+Na), 436.9 (M-H).

Analysis found: C 46.61; H 2.81; N 6.34; Cl 8.19.

Example 41

N-[(4-chlorophenyl)methyl]-6-(cyanomethyl)-4-hydroxy-3-quinolinecarboxamide

OH O

N=C

Cl • 9

9

99

9 9 9

9 99

9 9 9

9 9 9

99

9· 99

A suspension of 4-aminobenzyl cyanide (6.61 g) and diethyl ethoxymethylene malonate (10.1 mL) was heated at 95°C for 1 h. The reaction mixture was cooled to room temperature and poured into 50 mL of hexanes to wash out impurities. The desired enamine intermediate, which formed upon cooling, was filtered and collected. In a 3-neck round bottom flask connected to a Dean-Stark trap, 75 mL of diphenyl ether was added to the enamine and the solution was heated at 250°C for 2 h. The crude product was washed with hot MeOH and dried to give 3.40 g of ethyl [6-cyanomethyl-4-hydroxyquinoline-3-carboxylate] as an orange solid. A mixture of this ester (0.50 g) and 3.5 mL of p-chlorobenzylamine was heated at 180°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with CH ₂ Cl ₂ and ether. The solvents were evaporated. The residue was chromatographed on silica eluting with 3% methanol in CH ₂ Cl ₂ . Fractions homogeneous by TLC were combined, condensed, and recrystallized from ethyl acetate/hexanes to give 0.162 g of the desired product as a pale yellow solid.

The physical characteristics are as follows:

Melting point 244-246°C.

1 H NMR (300 MHz, DMSO) δ 10.39; 8.75; 8.22; 7.73; 7.39; 7.34; 4.54; 4.21.

IR (mull) 3084, 3060, 3039, 3018, 1644, 1626, 1616, 1578, 1548, 1530, 1490, 1294, 804, 800, 723 cm \

MS (EI) w/z 351 (M ⁺ ), 353, 351, 211, 184, 156, 155, 142, 140, 127, 125.

HRMS (FAB) found: 352.0863.

Example 42

N-[(4-chlorophenyl)methyl]-4,5-dihydroxy-3-quinolinecarboxamide

OH OH OH

A mixture of 5.457 g of 3-aminophenol and 10.81 g of diethylethoxymethylenemalonate is heated at 130°C for 2 hours with the removal of ethanol via a Dean-Stark trap. The reaction mixture is cooled to 80°C and 50 ml of diphenyl ether is added. The solution is heated at 250°C for 30 minutes with the removal of ··

9« ·· • * ♦ • 9 ·· • 9

9 9 9 • 9 9 9 ethanol through a Dean-Stark trap. The solution was cooled to 80°C and the resulting solid was collected and washed with hexanes. A portion of this solid was adsorbed onto silica and chromatographed, eluting with 5% methanol in dichloroethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. This gave ethyl [4,5-dihydroxyquinoline-3-carboxylate] as a gold solid. A mixture of this ester (0.125 g) and 4-chlorobenzylamine (0.379 g) was heated at 180°C for 1 hour. The solution was cooled to room temperature. The crude reaction mixture was chromatographed on silica, eluting with 2% methanol in dichloroethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. The residue was sonicated with dichloromethane/hexanes. The resulting solid was collected and dried to give 0.050 g of the desired product as a light yellow solid.

The physical characteristics are as follows:

Melting point 235-238°C.

*H NMR (300 MHz, DMSO) δ 13.71; 13.04; 9.72; 8.87; 7.59; 7.38; 7.34; 7.08; 6.71; 4.52.

¹³ C NMR (75 MHz, DMSO) δ 181.0; 164.1; 161.4; 145.3; 140.6; 139.1; 135.3; 131.8; 129.7; 128.8; 113.5; 110.4; 110.2; 108.5; 42.0.

IR(mull) 3184, 3118, 3042, 1654, 1630, 1561, 1531, 1493, 1328, 1286, 1248, 1210, 819, 740,

-and

604 cm.

MS (E1) m/z 328 (M ⁺ ), 330, 328, 188, 161, 142, 140, 133, 125, 104, 77.

Analysis found: C 61.75; H 4.07; N 8.21; Cl 11.04.

Example 43

7,8-Dichloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

OH O

Cl

2,3-Dichloroaniline (7.83 g) and diethylethoxymethylenemalonate (9.76 g) were heated at 130°C for 1.5 hours. The reaction mixture was cooled to 60°C and the solution was poured into hexanes. The enamine intermediate was collected and dried. The solid was taken up in 70 mL of diphenyl ether and heated to

250°C for 1.5 hours with removal of ethanol via a Dean-Stark trap. The reaction mixture was cooled to room temperature. The product was collected by filtration, washed thoroughly with hexanes and dried to give 11.32 g of ethyl [7,8-dichloro-4-hydroxyquinoline-3-carboxylate]. A mixture of this ester (0.48 g) and 1.0 ml of 4-chlorobenzylamine was heated at 180°C for 1 hour. The reaction mixture was cooled to room temperature and diethyl ether was added. The resulting solid was filtered, washed twice with diethyl ether and dried. The solid was adsorbed onto silica and purified by Biotage Flash 40S chromatography (eluent 2% methanol in dichloroethane). The fractions containing the product were evaporated. This gave a white solid (0.12 g).

The physical characteristics are as follows:

Melting point 295-297°C.

*H NMR (300 MHz, DMSO-dg) δ 12.43; 10,12; 8.65; 8.18; 7.68; 7.37; 7.34; 4.52.

IR (mull) 3204, 3094, 3077, 3026, 1663, 1603, 1586, 1553, 1526, 1492, 1443, 1330, 1272, 1095, 786 cm \

MS (El) m/z 380 (M ⁺ ), 382, 380, 242, 240, 215, 213, 142, 141, 140, 125.

HRMS (EI) found: 379.9857.

Example 44

N-[(4-chlorophenyl)methyl]-4,6-dihydroxy-3-quinolinecarboxamide

A mixture of 5.457 g of 4-aminophenol and 10.81 g of diethylethoxymethylenemalonate was heated at 130°C for 2 hours with the ethanol removed via a Dean-Stark trap. The reaction mixture was cooled to room temperature. 50 mL of diphenyl ether was added. The solution was heated at 250°C for 45 minutes with the ethanol removed via a Dean-Stark trap. The solution was cooled to 80°C and the resulting solid was collected and washed with hexanes. The solid was suspended in 250 mL of MeOH and brought to a boil. The insoluble material was filtered. The filtrate was adsorbed onto silica and chromatographed eluting with 5% methanol in dichloroethane, then 10% methanol.

9 99

9 9 9 ::

» 9 9

99 in dichloroethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. This gave 0.644 g of ethyl [4,6-dihydroxyquinoline-3-carboxylate]. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) was heated at 180°C for 1 hour. The solution was cooled to room temperature and diluted with dichloromethane. The resulting solid was collected and chromatographed on silica eluting with 3% methanol in dichloromethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. The residue was sonicated with dichloromethane/hexanes. The resulting solid was collected and dried to give 0.372 g of the desired product as an off-white solid.

The physical characteristics are as follows:

Melting point 319-320°C.

1 H NMR (300 MHz, DMSO) δ 12.58; 10.52; 9.97; 8.63; 7.54; 7.38; 7.33; 7.23; 4.53.

¹³ C NMR (75 MHz, DMSO) δ 175.9; 165.4; 155.4; 142.4; 139.3; 133.0; 131.8; 129.7; 128.8; 128.1; 123.2; 121.1; 109.7; 108.3; 41.8.

IR (mull) 3214, 3118, 3084, 3062, 3042, 1634, 1618, 1540, 1493, 1444, 1356, 1296, 1233, 1223, 800 cm' ¹ .

MS (El) m/z 328 (M ⁺ ), 330, 328, 189, 188, 187, 161, 142, 140, 133, 125.

Analysis found: C 61.92; H 3.82; N 8.44; Cl 10.78.

Example 45

N-[(4-chlorophenyl)methyl]-4,8-dihydroxy-3-quinolinecarboxamide

A mixture of 5.457 g of 4-aminophenol and 10.81 g of diethylethoxymethylenemalonate was heated at 130°C for 2 hours with removal of ethanol via a Dean-Stark trap. The reaction mixture was cooled to room temperature. 50 ml of diphenyl ether was added. The solution was heated at 240°C for 90 minutes with removal of ethanol via a Dean-Stark trap. The solution was cooled to room temperature and the resulting solid was collected and washed with hexanes. The crude solid was recrystallized from acetone. This gave 0.650 g of ethyl [4,8-dihydroxyquinoline-3-carboxylate]. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) was heated at 180°C for 1 hour. The solution was cooled to room temperature and diluted with dichloromethane. The resulting solid was collected and chromatographed on silica eluting with 3% methanol in dichloroethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. The residue was sonicated with dichloromethane/hexanes. The resulting solid was collected and dried to give 0.349 g of the desired product as an off-white solid. The physical characteristics are as follows:

Melting point 319-320°C.

'hNMR (300 MHz, DMSO) δ 10.46; 8.57; 7.65; 7.38; 7.33; 7.26; 7.15; 4.52.

¹³ C NMR (75 MHz, DMSO) δ 176.6; 165.2; 147.7; 143.1; 139.2; 131.8; 129.8; 129.7; 128.8; 127.9; 125.5; 115.9; 115.5; 111.0; 41.8.

ER (mull) 3144, 3080, 3041, 1651, 1624, 1606, 1538, 1490, 1479, 1359, 1280, 1211, 1194, 1016, 772 cm' ¹ .

MS (El) m/z 328 (M ⁺ ), 330, 328, 188, 161, 140, 127, 125, 104, 89.

HRMS (EI) found: 328.0627.

Example 46

8-Chloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

Ethyl 8-chloro-4-hydroxyquinoline-3-carboxylate (1.21 g) and 4-chlorobenzylamine (1.8 ml) were heated at 180°C for 2 hours. The reaction mixture was cooled to room temperature. The resulting solid was filtered, washed thoroughly with diethyl ether and dichloromethane and dried. This gave

1.44 g of the desired product.

The physical characteristics are as follows:

Melting point 279-281°C.

• · · · • 4» · · • 9 9 · * <i · · » »9 · · • 9 99 • · 9 9 • · · ·

9 9 9 · « 9 9 · ^! H NMR (300 MHz, DMSO-d ₆ ) δ 12.25; 10.20; 8.65; 8.20; 7.94; 7.45; 7.37; 7.34; 4.52.

ER(mull) 3217, 3190, 1660, 1600, 1558, 1551, 1527, 1492, 1442, 1433, 1331, 1281, 803, 749, 726 cm \

MS (E1) m/z 346 (M ⁺ ), 348, 346, 206, 181, 179, 151, 142, 140, 125, 89.

Analysis found: C 58.86; H 3.61; N 8.05; Cl 18.81.

Example 47

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-[[(1-phenyl-1H-pyrazol-5-yl)amino]sulfonyl]-3-quinolinecarboxamide

A solution of 6.23 g of sulfapyridine and 5.406 g of diethylethoxymethylenemalonate was heated at 135°C for 1 hour. The mixture was cooled to room temperature. 50 mL of diphenyl ether was added and the mixture was heated to 250°C for 30 minutes. The mixture was cooled to room temperature and poured into 250 mL of hexanes. An oily residue formed and the solvents were decanted. The residue was taken up in dichloroethane. Hexanes was added and the solid formed was collected and dried. The solid was chromatographed on silica eluting with 5% methanol in dichloroethane. Fractions homogeneous by TLC were combined and concentrated in vacuo. This gave 0.254 g of the desired ester as a light yellow solid. A mixture of this ester (0.200 g) and 4-chlorobenzylamine (0.28 mL) was heated at 180°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The resulting solid was collected, dried, and chromatographed on silica eluting with 5% methanol in dichloroethane. Fractions that were homogeneous by TLC were combined and concentrated in vacuo. The resulting solid was recrystallized from acetone/hexanes to give 0.031 g of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 185-187°C.

··

IR(mull) 3251, 3089, 3066, 1652, 1624, 1612, 1598, 1553, 1521, 1502, 1338, 1166, 760, 692, 683 cm \

MS (FAB) m/z 534 (MH), 536, 535, 534, 160, 142, 139, 125, 123, 105, 103.

HRMS (FAB) found: 534.1023.

Example 48

N-[(4-chlorophenyl)methyl]-8-cyano-4-hydroxy-3-quinolinecarboxamide

Anthranilonitrile (8.23 g) and diethylethoxymethylenemalonate (14 mL) were heated at 130°C for 1 hour. The reaction mixture was cooled to 60°C, poured into 50 mL of hexanes, and the resulting enamine intermediate was filtered and dried. The enamine was added to 60 mL of diphenyl ether and heated to 250°C for 1 hour with ethanol removed via a Dean-Stark trap. The reaction mixture was cooled to room temperature and the orange-brown solid was filtered, washed thoroughly with hexanes, and dried to give 5.69 g of ethyl [8-cyano-4-hydroxyquinoline-3-carboxylate]. A mixture of this ester (1.00 g) was added to 60 mL of 1:1 THF.MeOH. Lithium hydroxide (1.0 M solution, 16 ml) was added dropwise and the reaction mixture was heated to 40°C overnight. The reaction mixture was poured into 20 ml of acetic acid. The volume was reduced by half by rotary evaporation, whereupon a solid precipitated. The solid was filtered, washed with water and dried. Another crop of the desired acid was obtained by further reducing the volume of the filtrate. The yields were combined to give 0.72 g of 8-cyano-4-hydroxyquinoline-3-carboxylic acid. The acid (0.24 g) and carbonyldiimidazole (0.20 g) were added to 10 ml of freshly distilled tetrahydrofuran and the mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and 4-chlorobenzylamine (0.13 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 hours, then at reflux for 6 hours. The reaction mixture was cooled and the white solid was filtered and dried to give 0.17 g of the desired product.

The physical characteristics are as follows:

Melting point 287-289°C.

« · » « • »

¹ H NMR (300 MHz, DMSO-d _fr ) δ 10.76; 10.13; 8.64; 8.51; 7.58; 7.37; 7.34; 4.52.

IR (mull) 3193, 1666, 1615, 1606, 1594, 1573, 1556, 1521, 1487, 1435, 1327, 1287, 805, 755, 737 cm \

MS (electrospray) 338.1 (M+H), 336.1 (M-H).

HRMS (EI) found: 337.0639.

Analysis found: C 61.52; H 3.56; N 12.13; Cl 10.08.

Example 49

N-[(4-chlorophenyl)methyl]-4-hydroxy-8-nitro-3-quinolinecarboxamide

A mixture of 6.907 g of 2-nitroaniline and 10.812 g of diethylethoxymethylenemalonate was heated at 130°C for 2 hours with removal of ethanol via a Dean-Stark trap. The reaction mixture was cooled to 80°C and 60 mL of diphenyl ether was added. The mixture was heated to 250°C for 2 hours. The solution was cooled to room temperature. The resulting solid was collected, washed with hexanes and dried to give 3.447 g of ethyl[4-hydroxy-8-nitroquinolone-3-carboxylate] as a gold solid. To a mixture of this ester (1.2 g) in 66 mL of 1:1 THF:MeOH was added 18 mL of 1.0 M LiOH. The reaction mixture was maintained at 40°C overnight. The reaction mixture was cooled to room temperature, then diluted with 35 ml of glacial acetic acid. The resulting precipitate was collected, washed with water and hot isopropanol and dried to give 0.639 g of 4-hydroxy-8-nitroquinoline-3-carboxylic acid as a yellow solid. A mixture of this acid (0.20 g) and p-chlorobenzylamine (0.10 ml) was dissolved in 25 ml of xylenes and heated to reflux. PCl ₃ (0.037 ml) was added dropwise and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and water was added to destroy excess PCl ₃ . An orange solid precipitated, which was collected, washed with ether and dried. The crude product was recrystallized from hot methanol. This gives 0.0367 g of the desired product as a yellow solid.

The physical characteristics are as follows:

Melting point 275-278°C (decomposition).

*H NMR (300 MHz, DMSO-dg) δ 10.08; 8.82; 8.70; 7.65; 7.39; 7.35; 4.54.

IR (mull) 3261, 3231, 1667, 1592, 1567, 1550, 1502, 1434, 1321, 1267, 1260, 1182, 782, 745, 725 cm ^l .

MS (E1) m/z 357 (M ⁺ ), 357, 217, 200, 190, 171, 144, 142, 140, 89, 53.

HRMS (FAB) found: 358.0600.

Example 50

7-amino-N-[(4-chlorophenyl)methyl]-4-hydroxy-8-methyl-3-quinolinecarboxamide

2-Methyl-3-nitroaniline (10.17 g) and diethylethoxymethylenemalonate (13.65 mL) were reacted at 130°C for 2 h. The reaction mixture was cooled to room temperature and 80 mL of diphenyl ether was added. The solution was heated to 250°C for 1 h with ethanol removed via a Dean-Stark trap. The reaction mixture was cooled to room temperature and the resulting ethyl[4-hydroxy-8-methyl-7-nitroquinoline-3-carboxylate] was filtered, washed thoroughly with hexanes and dried (7.82 g). Ethyl[4-hydroxy-8-methyl-7-nitroquinoline-3-carboxylate] (0.40 g) and 4-chlorobenzylamine (2.0 mL) were heated at 180°C for 1 h. The reaction mixture was cooled to room temperature and poured into 50 mL of diethyl ether. The resulting solid was filtered and dried. The solid was then triturated in ethyl acetate, filtered and dried. This gave 0.12 g of the desired product.

The physical characteristics are as follows:

Melting point 256-258°C.

1 H NMR (300 MHz, DMSO-dg) δ 11.44; 10.62; 8.42; 7.82; 7.37; 7.32; 6.77; 5.89; 4.49; 2.15.

IR (mull) 3349, 3234, 3029, 1653, 1623, 1619, 1571, 1553, 1517, 1493, 1422, 1409, 1299,

1273, 800 cm ^-1 .

MS (El) m/z 341 (M ), 341, 216, 202, 201, 200, 175, 174, 146, 145, 144.

• · · · • * · · • · ·· • · · · · • · · · · 0 ·

HRMS (FAB) found: 342.1020.

Analysis found: C 60.47; H 4.66; N 11.48; Cl 9.24.

Example 51

N-[(4-chlorophenyl)methyl]-6-cyano-8-fluoro-4-hydroxy-3-quinolinecarboxamide

F

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 5 (0.19 g), Pd(PPh ₃ ) ₄ (0.10 g) and KCN (0.06 g) were heated at 60°C in 60 ml of freshly distilled tetrahydrofuran. The reaction mixture was cooled to room temperature. The solid from the reaction mixture was filtered. Thin layer chromatography showed the desired product in both the filtrate and the solid. Both were dissolved in a mixture of methanol and dichloroethane and adsorbed onto silica. The residue was chromatographed eluting with 3% methanol in dichloroethane (11), then 4% methanol in dichloroethane (11) and 5% methanol in dichloroethane (11). The fractions containing the product were evaporated to give 0.08 g of an off-white solid.

The physical characteristics are as follows:

Melting point > 300°C.

^! H NMR (300 MHz, DMSO-dQ δ 13.23; 10.03; 8.63; 8.41; 8.26; 7.37; 7.33; 4.53.

IR (mull) 3079, 3063, 3019, 1653, 1634, 1608, 1597, 1574, 1565, 1520, 1493, 1301, 1287, 1272, 806 cm' ¹ .

MS (EI)zw/r355 (M ⁺ ), 355, 215, 188, 160, 159, 142, 141, 140, 132, 125.

HRMS (EI) found: 355.0548.

Example 52

6-(aminothioxomethyl)-N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide

N-[(4-Chlorophenyl)methyl]-6-cyano-8-fluoro-4-hydroxy-3-quinolinecarboxamide (0.32 g) was dissolved in 15 ml of dimethylformamide. To the reaction mixture heated to 95°C was added 0.25 ml of triethylamine. H ₂ S was bubbled into the reaction mixture for 2.5 hours. After this time, the reaction mixture was cooled to 35°C and stirred overnight. The reaction mixture was diluted with 50 ml of water and the resulting yellow solid was filtered and dried. The solid was dissolved in a mixture of ethyl acetate and methanol and adsorbed onto silica. Purification by chromatography on a Biotage Flash 40S (eluent 3% methanol in dichloroethane (11), then 5% methanol in dichloroethane (11)) gave 0.17 g of the desired product as a yellow solid.

The physical characteristics are as follows:

Melting point 247-248°C.

1 h NMR (300 MHz, DMSO-dg) δ 13.0; 10.19; 10.10; 9.78; 8.61; 8.16; 7.37; 7.34; 4.54.

IR (mull) 3303, 3194, 3084, 3062, 3023, 1653, 1630, 1612, 1555, 1524, 1486, 1435, 1283, 1187, 806 cm' ¹ .

MS (E1) m/z 389 (M ⁺ ), 389, 355, 222, 215, 188, 160, 142, 141, 140, 125.

Analysis found: C 54.91; H 3.76; N 10.17.

Example 53

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide

HIM

• ·

100 ···

To a mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 5 (0.466 g) in 15 mL of diethylamine was added CuI (0.010 g) and ( _Ph3P )2PdCl2 (0.035 g). Propargyl alcohol (0.058 mL) was then added and the reaction mixture was stirred overnight at room temperature. The diethylamine was removed in vacuo. The residue was partitioned between ethyl acetate and water. The insoluble material was filtered off and saved. The organic layer was washed with brine, dried and condensed. The residue was combined with the insoluble material, adsorbed onto silica and chromatographed eluting with 3% methanol in dichloroethane. Fractions homogeneous by TLC were combined and condensed to give 0.192 g of the desired product as a tan solid. The physical characteristics are as follows:

Melting point 277-279°C.

1 H NMR (300 MHz, DMSO-dg) δ 13.02; 10.15; 8.59; 8.00; 7.76; 7.40; 7.33; 5.41; 4.52; 4.32.

IR (mull) 3137, 3070, 3008, 1661, 1632, 1608, 1577, 1550, 1520, 1495, 1307, 1289, 1198, 1017, 802 cm' ¹ .

MS (El) m/z 384 (M ⁺ ), 386, 384, 271, 244, 217, 142, 141, 140, 125, 60.

HRMS (FAB) found. 385.0773.

Example 54

8-Fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide

To a solution of ethyl [8-fluoro-4-hydroxy-6-iodoquinolone-3-carboxylate] (1.5 g) in 60 mL of 1:1 THF:MeOH was added 16 mL of 1.0 M LiOH. The reaction mixture was kept at 40°C overnight. The reaction mixture was cooled to room temperature, then diluted with 40 mL of glacial acetic acid. The resulting precipitate was collected, washed with water, and dried to give 0.890 g of 8-fluoro-6-iodoquinoline-3-carboxylic acid as a white solid. This acid (0.25 g) and 1,1-carbonyldiimidazole (0.146 g) were dissolved in 25 mL of anhydrous tetrahydrofuran and heated at 65°C for 3 days. When the reaction mixture was cooled to room temperature, 4« ·

101 ·· · · ·*· ·»· « 9 4 9 ·♦ *·

-chlorophenylhydrazine (0.161 g) and diisopropylethylamine (0.16 mL). The reaction mixture was heated at 65°C overnight to dissolve the reactants. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layers were washed with brine (once), dried over _Na2SO4 and condensed. The crude product was recrystallized from ethyl acetate/hexanes to give 0.13 g of the desired product as an off-white solid.

The physical characteristics are as follows:

Melting point 179-182°C.

1 h NMR (300 MHz, DMSO-dg) δ 13.12; 11.05; 8.58; 8.37; 8.20; 8.12; 7.16; 6.72.

IR (mull) 3211, 3170, 3075, 1660, 1611, 1598, 1560, 1524, 1491, 1345, 1291, 1243, 868, 823, 802 cm \

MS (El) m/z 457 (M+), 459, 457, 316, 189, 162, 161, 144, 142, 133, 107.

HRMS (FAB) found: 457.9566.

Example 55

8-Fluoro-4-hydroxy-6-methyl-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide

To a solution of ethyl [8-fluoro-4-hydroxy-6-methylquinolone-3-carboxylate] (0.50 g) in 30 mL of 1:1 THF:MeOH was added 8 mL of 1M LiOH. The reaction mixture was kept at 40°C overnight. The reaction mixture was cooled to room temperature, then diluted with 20 mL of glacial acetic acid. The resulting precipitate was collected, washed with water, and dried to give 0.382 g of 8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxylic acid as a white solid. To a solution of this acid (0.23 g) and 4-chlorophenylhydrazine (0.21 g) in 10 mL of DMF were added triethylamine (0.16 mL), EDC (0.24 g), and HOBt (0.16 g). The mixture was stirred at room temperature for 3 days. After diluting the reaction mixture with 100 ml of H ₂ °C, an orange solid precipitates. The crude product is adsorbed onto silica and • 44

102 ·· 44 ♦ 4 4

4 4» • 4

4 4

4 ·

4· Chromatograph, eluting with 4% methanol in dichloromethane. Fractions homogeneous by TLC are condensed and recrystallized from ethyl acetate/hexanes to give 0.0181 g of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 256-258°C.

1 H NMR (300 MHz, DMSO-d ₆ ) δ 12.94; 11.20; 8.55; 8.19; 7.90; 7.61; 7.17; 6.73; 2.46. HRMS (FAB) found: 346.0747.

Example 56

7-Chloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

Cl

7-Chloro-4-hydroxy-3-quinolinecarboxylic acid (500 mg) (Org. Syn. Coll. 3:272-275 (1955)) was dissolved in N,N-dimethylformamide (20 ml) and 1,1 carbonyldiimidazole (399 mg) was added. The mixture was heated at 50°C for 20 hours, then allowed to cool to room temperature. The mixture was treated with 200 ml of water and then 300 ml of 4-chlorobenzylamine was added after 5 minutes. The mixture was allowed to stir at room temperature for 2 days, then poured into 50 ml of water. The resulting white precipitate was filtered. The crude product was recrystallized (acetic acid, water) to give the title compound (418 mg) as a white solid.

The physical characteristics are as follows:

Melting point 237-239°C.

H NMR (300 MHz, DMSO) δ 12.70; 10.29; 8.79; 8.22; 7.74; 7.49; 7.37; 4.52.

¹³ C NMR (100 MHz, DMSO) δ 176.04; 164.73; 144.95; 140.34; 139.09; 137.72; 131.85; 129.65; 128.12; 125.72; 125.25; 118.67; 111.74; 41.90.

IR (mull) 3065, 2954, 2854, 1657, 1625, 1613, 1570, 1536, 1492, 1461, 1356, 1200, 1096, 1079, 1016, 908, 799 cm' ¹ .

Analysis found: C 58.50; H 3.78; N 7.87.

• 9 *

103

99 ♦ · 9

9 *

9 9 • ·9 *

99

MS (ESI-) for _{Ci7Hi2Cl2N2O2 m} / _{z 345} (MH)'.

Example 57

6-Bromo-N-[(4-chlorophenyl)methyl]-4-hydroxy-3-quinolinecarboxamide

A mixture of 4-bromoaniline (3.44 g) and diethylethoxymethylenemalonate (4.0 mL) was heated at 135°C for 2 hours. The resulting mixture was diluted with diphenyl ether (40 mL) and heated at reflux for 1 hour with a Dean-Stark trap. The mixture was allowed to cool to room temperature and then poured into hexane (50 mL). The solvent was decanted and the solid was triturated with hexane (25 mL) and diethyl ether/hexane (1/1, 2x25 mL) and filtered to give 5.52 g of quinoline carboxylate ethyl ester. The ester (592 mg) and 4-chlorobenzylamine (2.43 mL) were heated at 190°C for 1 hour. The resulting mixture was diluted in toluene (5 mL) and allowed to cool to room temperature. The crude product was filtered, washed with toluene (2 mL) and then hexane (2 x 5 mL) and then recrystallized (acetic acid, water) to give the title compound (640 mg) as a white solid.

The physical characteristics are as follows:

Melting point 282-283°C.

Ή NMR (300 MHz, DMSO) δ 12.84; 10.26; 8.78; 8.30; 7.90; 7.66; 7.37; 4.33.

¹³ C NMR (100 MHz, DMSO) δ 175.27; 164.70; 144.67; 139.10; 128.53; 135.55; 131.83; 129.67; 128.80; 128.02; 127.95; 122.08; 118.17; 111.54; 41.89.

IR (mull) 3049, 2924, 2855, 1665, 1632, 1572, 1546, 1515, 1492, 1471, 1352, 1291, 1195, 1090, 1017, 846, 827, 816, 799, 647 cm ¹ .

Analysis found: C 51.85; H 3.24; N 7.09; Br 20.40; Cl 9.01.

MS (ESI-) for Ci ₇ Hi ₂ BrClN ₂ O ₂ m/z 389 (MH)-.

104 ·· • » · • 9 ·

9 9

9 9

Example 58

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-phenyl-3-quinolinecarboxamide

A mixture of 4-aminobiphenyl (0.846 g) and diethylethoxymethylenemalonate (1.0 mL) was heated at 135°C for 2 h. The resulting mixture was diluted with diphenyl ether (25 mL) and heated at reflux for 0.5 h with a Dean-Stark trap. The mixture was allowed to cool to room temperature and then poured into hexane (50 mL). The solid was filtered, washed with hexane (15 mL) and hexane/diethyl ether (1/1, 2x15 mL) and recrystallized (DMF) to give 1.35 g of quinolinecarboxylate ethyl ester. The resulting ester (500 mg) and 4-chlorobenzylamine (2.07 mL) were heated at 190°C for 1 h. The mixture was diluted with toluene (5 mL) and allowed to cool to room temperature. The crude product was filtered, washed with toluene (2 mL) and then hexane (2 x 5 mL) and then recrystallized (acetic acid, water) to give the title compound (359 mg) as a pale yellow solid.

The physical characteristics are as follows:

Melting point 255-257°C.

1 h NMR (300 MHz, DMSO) δ 12.79; 10.43; 8.77; 8.45; 8.08; 7.78; 7.73; 7.50; 7.38; 4.55.

^B C NMR (100 MHz, DMSO) δ 176.59; 165.05; 144.13; 139.91; 139.51; 137.21; 131.85; 129.65; 128.81; 128.28; 127.26; 126.88; 123.12; 120.31; 111.29; 41.91.

IR (mull) 3336, 3166, 3062, 2924, 1656, 1639, 1625, 1576, 1515, 1479, 1422, 1364, 1305, 1206, 1095, 1017, 822, 789, 763, 701 cm' ¹ .

Analysis found: C 70.72; H 4.54; N 7.18; Cl 9.04.

MS (ESI-) for C ₂₃ Hi ₇ ClN ₂ O ₂ m/z 387 (MH)'.

105

999 9 ·· ··>

9 9

9 99

9 9

9 9 ·

9 9

9 9

9 9

9 9

9 9

99

Example 59

8-chloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-5-trifluoromethyl-3-quinolinecarboxamide

A mixture of 2-chloro-5-trifluoromethylaniline (3.91 g) and diethylethoxymethylenemalonate (4.0 mL) was heated at 190°C for 2 hours and then diluted with diphenyl ether (30 mL). The mixture was allowed to cool to room temperature, filtered, and the white solid was washed with hexane (2 x 10 mL) to give 1.632 g of diethylaminomethylenemalonate. The resulting intermediate (2.63 g) was suspended in diphenyl ether (30 mL) and heated at reflux with a Dean-Stark trap for 3 hours. The mixture was allowed to cool to room temperature and then poured into hexane (50 mL). The solid was filtered and then washed with hexane (20 mL) and hexane/diethyl ether (1/1, 20 mL) to give 1.273 g of quinolinecarboxylate ethyl ester. The ester (400 mg) and 4-chlorobenzylamine (1.52 mL) were heated at 190°C for 1 hour. The resulting mixture was diluted with toluene (4 mL) and allowed to cool to room temperature before pouring into hexane (50 mL). The solvent was decanted and the residual oil was crystallized (acetic acid, water) to give the title compound (285 mg) as a brown solid. The physical characteristics are as follows:

Melting point 270-271°C.

1 h NMR (300 MHz, DMSO) δ 12.33; 10.06; 8.68; 8,10; 7.86; 7.36; 4.52.

^B C NMR (100 MHz, DMSO) δ 175.05; 164.07; 144.36; 139.12; 138.20; 132.42; 131.85; 129.84; 128.77; 128.44; 126.70 (q); 125.84; 125.20; 122.22; 113.75; 42.00.

IR (mull) 3187, 3091, 2925, 2855, 1657, 1604, 1567, 1531, 1462, 1417, 1377, 1366, 1348, 1307, 1272, 1210, 1158, 1139, 1128, 1106, 854, 841, 802, 726 cm' ¹ .

Analysis found: C 52.12; H 2.78; N 6.70; Cl 16.85.

MS (ESI-) for C 1 gHnChFsNjOi m/z 412 (M-H)'.

• · ·

9 · 9 • 9 9

106

9·

999 • 9 9

9 9 ♦ ♦ ·9 •

Example 60

N-[(4-chlorophenyl)methyl-4-hydroxy]-6,8-dimethoxy-3-quinolinecarboxamide

OH O

_CH3O

A mixture of 2,4-dimethoxyaniline (3.06 g) and diethylethoxymethylenemalonate (4.0 mL) was heated at 135°C for 2 hours. The resulting mixture was diluted with diphenyl ether (40 mL) and heated at reflux for 1 hour with a Dean-Stark trap. The mixture was allowed to cool to room temperature and then poured into hexane (50 mL). The solid was filtered, washed with hexane (25 mL) and hexane/diethyl ether (1/1, 30 mL) to give 4.68 g of quinoline carboxylate ethyl ester. A mixture of ethyl ester (500 mg) and 4-chlorobenzylamine (2.19 mL) was heated at 190°C for 1 hour. The resulting mixture was diluted with toluene (5 mL) and allowed to cool to room temperature. The crude product was filtered, washed with toluene (2 mL) and then hexane (2 x 5 mL) and then recrystallized (acetic acid, water) to give the title compound (270 mg) as a white solid.

The physical characteristics are as follows:

Melting point 270-271°C.

H NMR (300 MHz, DMSO) δ 12.30; 10.50; 8.49; 7.35; 7.18; 6.98; 4.52; 4.00; 3.84.

°C NMR (100 MHz, DMSO) δ 175.61; 165.17; 157.58; 150.50; 141.86; 139.09; 131.85; 129.62; 128.82; 128.18; 125.31; 110.66; 103.91; 96.35; 57.05; 55.97; 41.88.

IR (mull) 3171, 3129, 3092, 2925, 2855, 1712, 1623, 1551, 1455, 1421, 1396, 1375, 1307, 1287, 1199, 1157, 1146, 1070, 1053, 1032, 801 cm' ¹ .

Analysis found: C 60.89; H 4.72; N 7.40; Cl 9.49.

MS (ESI+) for Ci ₉ Hi ₇ C 1 N ₂ O 4 m/z 373 (MH) ⁺ .

107

99 • 9 9 9

9 >9

9 9 9

9 9 9

9 9 9

9 9 9

9 9 · ·9 9

99

Example 61

N-[(4-chlorophenyl)methyl]-4-hydroxy-6,7-dimethoxy-3-quinolinecarboxamide

A mixture of ethyl 6,7-dimethoxy-4-hydroxy-3-quinolinecarboxylate (J. Am. Chem. Soc., 68, 1264 (1946)) (139 mg) and 4-chlorobenzylamine (0.61 ml) was heated at 190°C for 1 hour. The resulting mixture was diluted with toluene (1.5 ml) and allowed to cool to room temperature. The crude product was purified by column chromatography (dichloromethane/methanol, 100/1, 100/5) and recrystallization (acetic acid, water) to give the title compound (26 mg) as a white solid.

The physical characteristics are as follows:

Melting point 184°C.

^] H NMR (300 MHz, DMSO) δ 12.50; 10.62; 8.63; 7.56; 7.37; 7.10; 4.52; 3.88; 3.84.

IR (mull) 3392, 3223, 3069, 2924, 1648, 1613, 1544, 1503 1459, 1408, 1377, 1274, 1220, 1114, 1030.799 cm' ¹ .

HRMS (FAB) found: 373.0952.

MS (ESI-) for _{C19Hi7ClN2O4 m} /z 371 (MH)' _.

Example 62

N-[(4-chlorophenyl)methyl]-4-hydroxy-5-methyl-3-quinolinecarboxamide

108 • · · • titi ·· ·· ti· ·· • ti ♦ • · · • ti · • ti ·

A mixture of 2-chloro-5-methylaniline (2.83 g) and diethylethoxymethylenemalonate (4.04 ml) was heated at 135°C for 2 hours. The resulting mixture was diluted with diphenyl ether (40 ml) and heated at reflux for 1 hour with a Dean-Stark trap. The mixture was allowed to cool to room temperature and then poured into hexane (50 ml). The solid was filtered, washed with hexane (20 ml) and hexane/diethyl ether (1/1, 2x30 ml) to give 4.89 g of ethyl 8-chloro-6-methyl-quinolinecarboxylate. The ethyl ester (2.0 g) was dissolved in acetic acid (150 ml) together with NaOAc.3H2O (1.12 g) and 5% palladium on carbon (750 mg). The mixture was placed under hydrogen pressure (193 kPa) in a Parr hydrogenator for 3 hours. The mixture was filtered through a pad of celite, concentrated in vacuo and suspended in water (10 mL). The crude product was filtered, washed with water and recrystallized (DMF) to give 964 mg of 5-methylquinolinecarboxylate ethyl ester. The resulting ester (463 mg) and 4-chlorobenzylamine (2.43 mL) were heated at 190°C for 1 hour. The resulting mixture was diluted with toluene (5 mL) and allowed to cool to room temperature to give a white solid. The crude product was filtered, washed with toluene (2 mL) and then hexane (4 mL) and then recrystallized sequentially from acetic acid/water then ethyl acetate to give the title compound (426 mg) as a white solid.

The physical characteristics are as follows.

Melting point 205-206°C.

H NMR (300 MHz, DMSO) δ 12.50; 10.46; 8.64; 7.55; 7.47; 7.37; 7.15; 4.51; 2.83.

¹³ C NMR (100 MHz, DMSO) δ 179.47; 165.26; 143.30; 141.17; 140.60; 139.33; 132.26; 131.80; 129.75; 128.77; 127.97; 125.04; 117.56; 112.18; 41.84; 24,21.

IR (mull) 3404, 2924, 2855, 1645, 1628, 1604, 1574, 1545, 1498, 1467, 1459, 1342, 1224, 1170, 1097, 1016, 816, 783, 75 cm' ¹ .

HRMS (FAB) found: 326.0803.

MS (ESI-) for _{Ci8H15ClN2O2 m} /z 325 (MH ₎ .

Preparation 12

6-(1,1-Dimethylethyl)-4-hydroxy-3-quinolinecarboxylic acid ethyl ester • 9

99

9 9

9 99

9 9

9 9 *

99

9 9

9 9 9

99

O''

A 100 mL round bottom flask equipped with a Dean-Stark trap and reflux condenser was charged with 4-tert-butylaniline (5.3 mL) and diethylethoxymethylenemalonate (6.8 mL). The reaction mixture was heated at 140°C for 1.5 hours. The mixture was allowed to cool to room temperature and 50 mL of diphenyl ether was added. The resulting mixture was heated at 250°C for 1.5 hours. The solution was allowed to cool to room temperature and 50 mL of diphenyl ether was added. The resulting mixture was heated at 250°C for 1.5 hours. The solution was allowed to cool to room temperature and then poured into toluene and hexane. A solid slowly precipitated and was collected by filtration to give 0.678 g of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 262-264°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 8.49; 8.11; 7.78; 7.54; 4.19; 1.32; 1.26 ppm.

¹³ C NMR (75 MHz, DMSO-d _{2 O} ) δ 173.6; 165.0; 147.4; 144.6; 137.1; 130.6; 126.9; 120.9; 118.8; 109.6; 59.6; 34.7; 31.1; 14.5 ppm.

IR (mull) 3182, 3095, 3054, 3019, 1700, 1633, 1584, 1572, 1531, 1493, 1291, 1255, 1189, 1119, 606 cm \

MS (E1) m/z 273 (M+), 274, 273, 258, 228, 227, 213, 212, 184, 144, 115.

Analysis found: C 70.46; H 7.11; N 5.03.

Example 63

N-[(4-chlorophenyl)methyl]-6-(1,1-dimethylethyl)-4-hydroxy-3-quinolinecarboxamide * ·

110 • · fcfc * fc fcfc · ·· • · fcfc · fcfc fcfc fc * • · · · · fcfc fcfc ··

H,C

H,C

H,C

• fc • fcfc • · · • fc fc • fcfc · • fc fcfc

A solution of the title compound from Preparation 12 (0.350 g) in p-chlorobenzylamine (1.6 mL) was heated at 190°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature and poured into toluene and hexane. A precipitate formed which was collected by filtration to give 0.255 g of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 266°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 10.50; 8.71; 8.19; 7.85; 7.63; 7.40-7.33; 4.53; 1.33 ppm.

^B C NMR (75 MHz, DMSO-d ₆ ) δ 176.0; 164.7; 147.4; 143.3; 138.6; 137.2; 131.3; 130.8;

129.1 (2); 128.3 (2); 125.5; 120.3; 118.9; 110.3; 41.3; 34.5; 30.7 (3) ppm.

IR(mull) 3163, 3054, 3009, 1634, 1616, 1563, 1548, 1523, 1490, 1359, 1351, 1300, 839, 831, 804 cm \

MS (El) m/z 368 (M+), 370, 368, 229, 228, 212, 202, 201, 186, 140, 125.

Analysis found: C 68.22; H 5.60; N 7.45.

Example 64

N-[(4-chlorophenyl)methyl]-7,8-dihydro-4-hydroxy-6H-cyclopenta[g]quinoline-3-carboxamide

The title compound was prepared according to the procedure described in Preparation 12 and Example 63, substituting 5-aminoindane for 4-tert-butylaniline. Crystallization from CH ₂ Cl 2 /EtOAc/hexane/Et ₂ O gave 0.03 g of the title compound as a brown solid.

»

111 ·* »· I» · · • · ·· • * · « · · ► · · i ř · · ·

I · · · • · <··

The physical characteristics are as follows:

Melting point 260-261°C (decomposition).

^! H NMR (300 MHz, DMSO-d ₆ ) δ 12.6; 10.51; 8.66; 8.03; 7.49; 7.30-7.32; 4.52; 3.01-2.93; 2.10-2.03 ppm.

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 176.5; 165.3; 150.7; 143.3; 142.3; 139.3; 138.7; 131.8; 129.7; 128.8; 125.6; 120.3; 114.3; 110.6; 41.8; 32.9; 32.2; 25.9 ppm.

IR (mull) 3243, 3216, 3170, 3089, 3025, 1645, 1620, 1578, 1551, 1531, 1518, 1492, 1436, 1230, 797 cm ^-1 .

MS (El) m/z 352 (M+), 354, 352, 213, 212, 211, 186, 185, 184, 140, 125.

Analysis found: C 67.77; H 4.94; N 7.96.

Example 65

N-[(4-chlorophenyl)methyl]-1,4-dihydro-8-(methylthio)-4-oxo-3-quinolinecarboxamide

The title compound was prepared according to the procedure described in Preparation 12 and Example 63, substituting 4-tert-butylaniline for 2-(methylmercapto)aniline. This procedure gave 0.355 g of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 225-228°C.

H NMR (300 MHz, CDCl ₃ ) δ 10.33; 8.94; 8.38; 7.90; 7.43; 7.33-7.28; 4.64; 2.48 ppm.

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 175.7; 164.7; 145.1; 138.7; 132.1; 131.2; 130.5; 129.1; 128.4; 128.2; 126.6; 124.4; 123.4; 110.6; 41.3; 16.6 ppm.

• ·

112 ·····* · · · 4 ^ίΙΖι ···· · · · « • · * · © · · ··· ··

IR (mull) 3236, 3210, 3184, 1657, 1609, 1577, 1558, 1491, 1440, 1329, 1286, 800, 774, 747 cm \

MS (El) m/z 358 (M+), 360, 358, 219, 218, 203, 192, 191, 176, 142, 140.

Analysis found: C 60.28; H 4.32; N 7.85; Cl 9.98; S 8.81.

Example 66

N-[(4-chlorophenyl)methyl]-9-hydroxythiazolo[5,4-f]quinoline-8-carboxamide

Cl

The title compound was prepared according to the procedure described in Preparation 12 and Example 63, substituting 4-tert-butylaniline for 6-aminobenzothiazole. This procedure gave 0.342 g of the title compound monohydrate as a pale yellow solid.

The physical characteristics are as follows:

Melting point 193°C (decomposition).

H NMR (300 MHz, DMSO-d ₆ ) δ 10.44; 9.47; 8.88; 8.42; 7.90; 7.38; 4.57 ppm.

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 173.8; 164.5; 158.0; 150.3; 143.9; 138.8; 131.2; 130.3; 129.2; 128.8; 128.4; 128.2; 127.2; 120.8; 118.9; 111.0; 41.3.

IR (mull) 3236, 3189, 3156, 3062, 1647, 1618, 1571, 1547, 1492, 1359, 1313, 1292, 1093, 819, 802 cm ¹ .

MS (El) m/z 369 (M+), 371, 369, 229, 202, 174, 173, 146, 142, 140, 125.

Analysis found: C 55.81; H 3.67; N 10.64.

Example 72

N-[(4-chlorophenyl)methyl]-4-hydroxy-6-[(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxamide

113

A mixture of 0.15 g of 4-hydroxy-6-[(phenylmethyl)thio]-7-(trifluoromethyl)-3-quinolinecarboxylic acid and 1.2 ml of dimethylformamide was reacted with 0.075 g of carbonyldiimidazole. The mixture was stirred at 35-40°C for 20 hours. The solution was cooled to 25°C and treated with 0.075 ml of distilled water and then stirred for 10 minutes. The solution was treated with 0.053 ml of 4-chlorobenzylamine and stirred for 18 hours. The reaction mixture was diluted with 1.0 ml of distilled water and then decanted from the dark oily precipitate. The precipitate was treated with 1 ml of glacial acetic acid and the mixture was shaken for 5 minutes. The solid that formed was collected by filtration and washed with several ml of 50% aqueous acetic acid. The solid was dried in a stream of air. This gives 48 mg of the title compound.

The physical characteristics are as follows:

Melting point 185-188°C.

H NMR (DMSO) δ 8.86; 8.33; 7.53-7.18; 4.55; 4.39.

Analysis found: C 58.63; H 3.62; N 5.43.

Example 75

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(2-thiophenyl)-3-quinolinecarboxamide

To a solution of the title compound of Example 5 in 12.5 mL of dioxane and 0.5 mL of HMPA were added 2-(tributylstannyl)thiophene (0.64 mL) and PdCl ₂ (PPh ₃ ) 2 (84.2 mg). The mixture was stirred at 100°C for 2 days. The reaction mixture was cooled to room temperature and then filtered to remove excess

114

9« palladium. After diluting the filtrate with CH2Cl2 and _H2O , a white solid precipitated. The solid was filtered and dried to give 0.262 g of the desired product.

The physical characteristics are as follows:

Melting point 298-301°C.

H NMR (300 MHz, DMSO) δ 10.26; 8.59; 8.16; 8,10; 7.69; 7.63; 7.37; 7.16; 4.54.

IR (mull) 3158, 3073, 3020, 1657, 1612, 1574, 1554, 1531, 1516,1490, 1303, 1287, 846, 804, -1

696 cm.

Analysis found: C 60.92; H 3.63; N 6.86.

Example 76

N-[(4-chlorophenyl)methylj- 4-hydroxy-5-trifluoromethyl-3-quinolinecarboxamide

_F3COH

Cl

N-[(4-Chlorophenyl)methyl]-8-chloro-4-hydroxy-5-trifluoromethyl-3-quinolinecarboxamide (2.00 g) from Example 59 was dissolved in 100 ml of glacial acetic acid together with NaOAc.3H ₂ O (937 mg) and 5% palladium on carbon (666 mg). The mixture was placed under hydrogen pressure (172 kPa) in a Parr hydrogenator for 3 hours. The reaction mixture was filtered through a pad of celite, concentrated, suspended in water (30 ml) and filtered. The resulting solid (500 mg) and 4-chlorobenzylamine (2.13 ml) were then heated at 190°C for 1 hour. The crude product was purified by column chromatography (dichloromethane/methane, 50/1) to give the title compound (62 mg) as a white solid.

The physical characteristics are as follows:

Melting point 224-226°C.

HNMR (DMSO-d ₆ ) δ 12.92; 10.26; 8.79; 8.00; 7.88; 7.36; 4.52.

115

9 · * « · ·· ·· • 9 · · * · · · 9 · · ·

99 9 9 9999 • 99 99 9 999 99 9 • ••9 · 9 99··

99 99· ··· 99 99 ¹³ C NMR (DMSO-d ₆ ) δ 175.3; 164.7; 143.9; 141.7; 139.3; 132.4; 131.8; 129.8; 128.8; 127.5; 125.3; 123.5; 122.6; 113.1; 41.9.

IR (mull) 3072, 1651, 1627, 1611, 1563, 1544, 1492, 1438, 1309, 1288, 1224, 1153, 1131, 1120, 826 cm' ¹ .

MS (ESI-) for Ci ₈ Hi ₂ C1F ₃ N ₂ O ₂ .H ₂ O m/z 379 (MH)'

Analysis found (C _I8 Hi ₂ C1F ₃ N ₂ O ₂ .H ₂ O): C 53.82; H 3.60; N 6.91; Cl 8.82; F 14.57.

Example 77

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-(2-methylphenyl)-3-quinolinecarboxamide

F

Cl

6-Iodo-8-fluoro-4-hydroxy-3-quinolinecarboxamic acid ethyl ester from Example 5 (903 mg) and o-tolueneboronic acid (374 mg) were dissolved in 50 mL of DMF and a solution of barium hydroxide octahydrate (1.18 g) in 5 mL of water was added at 50°C followed by palladium tetrakistriphenylphosphine (58 mg). The mixture was heated at 80°C for 20 h, allowed to cool to room temperature, poured into 200 mL of water and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine (25 mL), dried (MgSO4) and concentrated. The solid was then triturated with MTBE and filtered to give 382 mg of 6-(2-methylphenyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester. The crude ester was mixed with 4-chlorobenzylamine (380 mg) and heated at 190°C for 1 hour. The mixture was diluted with toluene (4 mL), allowed to cool to room temperature, poured into a mixture of 50% acetic acid (10 mL) and 1N hydrochloric acid (25 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was dried (MgSO4) and allowed to crystallize. Recrystallization from acetic acid/water gave 166 mg of the title compound.

The physical characteristics are as follows:

Melting point 259-265°C.

116 ·· 00 0 9 · 9 • 0 9 9 *0 0 ·· 0

0 · · • 9 9 · • 0 0 ·

0 0 ·

0· 0

0·

Η NMR (DMSO- d ) δ 12.99; 10.26; 8.64; 7.93; 7.79; 7.40-7.26; 4.53; 2.25.

C NMR (DMSO-d ₆ ) δ 175.8; 164.6; 152; 144.1; 139.1; 138.3; 135.4; 131.9; 131.1; 130.1; 129.7; 128.8; 128.6; 128.2; 127.8; 126.7; 121.4; 118.9; 112.0; 41.9; 20.5.

IR (tnuli) 3143, 3060, 3020, 1656, 1612, 1551, 1521, 1490, 1309, 1284, 1206, 1187, 805, 799, 751 cm \

MS (ESI-) for _{C24H18C1FN2O2 m} /z 419 (MH ₎ . Analysis found: C 68.36; H 4.47; N 6.67 _; Cl 8.46.

Example 78

N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-(tetrahydro-2H-pyran-4-oxy)-3-quinolinecarboxamide

N-[(4-chlorophenyl)methyl]-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example 15 and sodium hydride (60% dispersion, 40 mg) were dissolved in 10 mL DMF and tetrahydro-2H-pyran-4-ol (114 μΐ) was added to the mixture. Additional sodium hydride (60 mg) was added and the mixture was heated to 140°C for 1 hour. The reaction mixture was allowed to cool to room temperature, poured into 30 mL water, acidified with 1 N hydrochloric acid (10 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with brine (10 mL), dried (MgSO ₄ ) and concentrated. The resulting solid was triturated with heptane (10 mL) and filtered. This gives the title compound (153 mg) as a white solid.

The physical characteristics are as follows:

Melting point 287°C (decomposition).

^J HNMR (DMSO-d ₆ ) δ 12.20; 10.21; 8.62; 7.82; 7.39-7.31; 4.62; 4.52; 3.90, 3.35; 2.00-1.70.

117 «· 9 9 * · · · 9 9

9 9 9 9 9 9 9 9 9 9 9

9 99 9 · 9 9 9 9

9 9 9 9 · 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 ·· ··· ··· ·· 99 ¹³ C NMR (DMSO-d ₆ ) δ 175.2; 164.5; 148.8; 146.09; 144.5; 139.0; 135.3; 132.0; 131.9; 129.6; 128.8; 122.7; 111.2; 106.4; 80.49; 65.34; 41.92; 32.7.

IR (mull) 3192, 3084, 1649, 1611, 1583, 1576, 1535, 1485, 1306, 1279, 1171, 1108, 1089, 1007, 802 cm' ¹ .

MS (ESI-) _{for C22H19C1F2N2O4 m / z 447} (MH)-. Analysis found: C 58.57; H 4.50; N 6.16; Cl 7.67.

Example 79

N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-methoxy-3-quinolinecarboxamide

N-[(4-chlorophenyl)methyl]-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example 15 and sodium hydride (60% dispersion, 40 mg) were dissolved in 10 ml DMF and methanol (0.200 μΐ) was added to the mixture. Additional sodium hydride (40 mg) was added and the mixture was heated to 140°C for 1 hour. The reaction mixture was allowed to cool to room temperature, poured into 50 ml water, acidified with acetic acid (10 ml) and filtered. The crude product was purified by column chromatography (hexane/2-propanol, 95/5) to give the title compound (68 mg) as a white solid.

The physical characteristics are as follows:

Melting point 248-251°C.

1 H NMR (DMSO-d 2 ) δ 12.60; 10.21; 8.59; 7.78; 7.39-7.31; 4.51; 4.14.

¹³ C NMR (DMSO- dg ) δ 175.1; 164.5; 150.0; 145.4; 144.2; 139.0; 138.1; 131.9; 131.0; 129.7; 128.8; 122.6; 111.2; 105.7; 62.8; 41.9.

IR (mull) 1658, 1635, 1617, 1585, 1579, 1560, 1546, 1486, 1439, 1309, 1287, 1117, 1105, 1085, 799 cm' ¹ .

• 4» • · · · • φ · · ♦ · * · Φ«·»

ПО · * ·· * * ♦ · · ·

IlO · · · · φ · ·»····

4 4 9 4 · · · · · «· ·· ··· »·· ·· *·

MS (ESI-) for CieHnCHWb m/z 377 (M-H)'·

Analysis found: C 56.75; H 3.67; N 7.30; Cl 9.33.

Example 80

N-[(4-chlorophenyl)methyl]-7,8-dimethoxy-6-fluoro-4-hydroxy-3-quinolinecarboxamide

N-[(4-chlorophenyl)methyl]-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example 15 and sodium hydride (60% dispersion, 160 mg) were dissolved in 10 mL DMF and methanol (0.200 μΐ) was added to the mixture. The mixture was heated to 140°C for 1 hour. The reaction mixture was allowed to cool to room temperature, poured into 40 mL water, acidified with acetic acid (10 mL) and filtered. The crude product was recrystallized from acetic acid/water and then from toluene to give 174 mg of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 228-229°C.

*H NMR (DMSO-d ₆ ) δ 12.38; 10.28; 8.56; 7.67; 7.36; 4.51; 4.02.

^B C NMR (DMSO- d g ) δ 175.3; 164.7; 153.7; 143.9; 143.8; 142.4; 139.1; 131.9; 131.3; 129.7; 128.8; 122.1; 110.8; 105.9; 62.3; 62.2; 41.9.

IR (mull) 1656, 1628, 1610, 1597, 1568, 1544, 1438, 1428, 1307, 1282, 1105, 1081, 1016, 799, 726 cm' ¹ .

MS (ESI+) for Ci ₉ H ₁₆ C1FN ₂ O4 m/z 389 (M+H)+

Analysis found: C 58.19; H 4.13; N 7.14; Cl 9.06.

Preparation 13

N-[(4-chlorophenyl)methyl]-1,4-dihydro-4-oxo-6,7,8-trifluoro-1-[2(trimethylsilyl)ethoxy]methyl-3-quinolinecarboxamide

119 ·»·· 9 9 9 9 · · 9 ♦

9 99 9 * »«·»

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999

9 · · 999 999 9 · ··

N-[(4-Chlorophenyl)methyl]-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (6.00 g) from Example 15 was suspended in 100 mL of DMF and sodium hydride (60% dispersion, 720 mg) was added. The mixture was allowed to stir at room temperature for 15 min and then 2-(trimethylsilyl)ethoxymethyl chloride (2.90 mL) was added. After 3.5 h, the reaction mixture was poured into a mixture of 200 mL of water and 100 mL of saturated aqueous ammonium chloride and extracted with ethyl acetate (2 x 100 mL, 200 mL). The organic layer was washed with brine, (50 mL), dried (MgSO ₄ ) and concentrated. The crude solid was recrystallized from ethanol to give the title compound (5.943 g) as a white solid.

The physical characteristics are as follows:

Melting point 141-143°C.

H NMR (DMSO-d ₆ ) δ 9.96; 9.02; 8,10; 7.40-7.32; 5.83; 4.53; 3.57; 0.82, -0.13.

^B C NMR (DMSO-d^ δ 174.1; 163.7; 151.0; 148.2; 143.2; 142.2; 138.9; 131.9; 129.7; 128.8; 126.5; 124.4; 110.7; 108.7; 85.8; 66.2; 42.1; 17.5, -1.0.

IR (mull) 1660, 1607, 1591, 1581, 1569, 1542, 1492, 1485, 1418, 1248, 1125, 1104, 1056, 849, 805 cm' ¹ .

MS (ESI+) for Czjl^ClFjN1CbSi m/z 497 (M+H) ⁺ .

Analysis found: C 55.51; H 4.84; N 5.59; Cl 7.14.

Example 81

N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(4-hydroxymethyl)phenoxy)-3-quinolinecarboxamide • 9 9»

120 • 9 9 9 • 9 9 · • · ·· • · 9 9 • · 9 ·

9 · ·

9 9 9

9 9 ·

9 9 9

99

N-[(4-chlorophenyl)methyl]-4-oxo-6,7,8-trifluoro-1-(2-(trimethylsilyl)ethoxy)methyl-3-quinolinecarboxamide (1.0 g) from Preparation 13 and 4-hydroxymethylphenol (500 mg) were dissolved in 20 mL of DMF. Sodium hydride (60% dispersion, 80 mg) was added and the mixture was heated at 140°C for 1 h. The reaction mixture was allowed to cool to room temperature, poured into 100 mL of saturated aqueous ammonium chloride and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (heptane/ethyl acetate, 1/1, 1/5), then recrystallization to give the title compound (145 mg) as a white solid.

The physical characteristics are as follows:

Melting point 235-240°C.

HNMR (DMSO-d ₆ ) δ 13.10; 10.20; 8.65; 7.92; 7.41-7.28; 7.05; 5.19; 4.55; 4.46.

^B C NMR (DMSO- d g ) δ 174.8; 164.4; 156.2; 152.6; 146.1; 144.5; 139.0; 138.5; 134.4; 131.9; 129.7; 128.8; 128.6; 127.6; 115.5; 111.5; 107.4; 62.7; 42.0.

IR (shift) 3056, 1651, 1612, 1579, 1574, 1563, 1557, 1543, 1505, 1483, 1310, 1236, 1200, 1038, 791 cm' ¹ .

MS (ESI-) for C ₂ 4 H ₇ C 1 F ₂ N ₂ O ₄ m/z 469 (MH)'.

Analysis found: C 60.82; H 3.76; N 5.78; Cl 7.38.

Example 82

N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-methoxy-3-quinolinecarboxamide

121

4· · 4 » • 4 4 » • 4 4 4

4 4 4

4 4 4

N-[(4-chlorophenyl)methyl]-4-oxo-6,7,8-trifluoro-1-(2-(trimethylsilyl)ethoxy)methyl-3-quinolinecarboxamide (1.00 g) from Preparation 13 and methanol (0.163 mL) were dissolved in 20 mL DMF. Sodium hydride (60% dispersion, 80 mg) was added and the mixture was heated to 140°C for 1 h. The mixture was allowed to cool to room temperature, poured into 100 mL saturated aqueous ammonium chloride and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (heptane/ethyl acetate, 4/1.3/1) to give N-[(4-chlorophenyl)methyl]-6,8-difluoro-7-methoxy-4-oxo-1-(2-(trimethylsilyl)ethoxy)methyl-3-quinolinecarboxamide. The resulting crude amide was suspended in 15 mL of ethanol, heated to 85°C, and 50% aqueous hydrochloric acid (5 mL) was added. The mixture was heated for a further 1.5 h and allowed to cool to room temperature. The reaction mixture was neutralized with solid sodium bicarbonate and filtered. The solids were washed with ethanol (10 mL), then ethyl acetate (20 mL), and the combined filtrates were concentrated to give a tan solid. The crude product was purified by recrystallization from acetic acid/water followed by column chromatography (heptane/2-propanol, 95/5) to give the title compound (27 mg). The physical characteristics are as follows:

Melting point 217-219°C.

HNMR (DMSO-d ₆ ) δ 12.94; 10.23; 8.61; 7.79; 7.41-7.33; 4.54; 4.14.

IR (shift) 3060, 2987, 2956, 1653, 1609, 1568, 1561, 1488, 1435, 1311, 1290, 1237, 1038, 799 cm \

Analysis found: C 56.87; H 3.59; N 7.56.

HRMS (FAB) found: 379.0655.

Examples 83-85

N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(2-(methoxy)ethoxy)-3-quinolinecarboxamide,

122 • ··

9 · · * » 9

9 9 ·

9 9 ·

9 9 9 ·

9 9 9

99

N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-(2-(methoxy)ethoxy)-3-quinolinecarboxamide and

N-[(4-chlorophenyl)methyl]-7,8-di(2-(methoxy)ethoxy)-6-fluoro-4-hydroxy-3-quinolinecarboxamide

N-[(4-chlorophenyl)methyl]-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (500 mg) from Example 15 and sodium hydride (60% dispersion, 163 mg) were dissolved in 10 mL of DMF and 2-methoxyethanol (0.536 mL) was added to the mixture. The mixture was heated to 140°C for 1 hour. The reaction mixture was allowed to cool to room temperature, poured into 25 mL of 20% aqueous acetic acid and filtered. The crude products were purified by column chromatography to give 28 mg of 6,8-difluoro-7-(2-(methoxy)ethoxy)-derivative (Example 83), 124 mg of 6,7-difluoro-8-(2-(methoxy)ethoxy)-derivative (Example 84) and 194 mg of 6-fluoro-7,8-di(2-(methoxy)ethoxy)-derivative (Example 85).

83) N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(2-(methoxy)ethoxy)-3-quinolinecarboxamide

The physical characteristics are as follows:

Melting point 193-198°C.

*Η NMR (DMSO-d ₆ ) δ 12.90; 10.20; 8.58; 7.77; 7.35; 4.52; 4.43; 3.66; 3.27.

IR (mull) 3196, 3056, 1650, 1608, 1569, 1542, 1485, 1310, 1282, 1237, 1109, 1096, 1034, 1016, 794 cm' ¹ .

HRMS (FAB) found: 423.0915.

·· ··

123 • · ·« « · · · · • 9 9 ·

99

9 ·

9 9

9 9

9 9 9

99

84) N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-8-(2-(methoxy)ethoxy)-3-quinolinecarboxamide

Melting point 167-168°C.

H NMR (DMSO- d g ) δ 12.30; 10.22; 8.63; 7.79; 7.36; 4.52; 4.46; 3.72; 3.23.

C NMR (DMSO-d ₆ ) d 175.2; 164.5; 148.9; 145.6; 144.4; 139.0; 137.4; 131.9; 131.3; 129.7; 128.8; 122.6; 111.2; 106.0; 74.3; 71.2; 58.5; 41.9.

IR (mull) 3217, 3067, 2814, 1648, 1617, 1573, 1546, 1488, 1310, 1288, 1130, 1106, 1091, 1070, 807 cm' ¹ .

HRMS (FAB) found: 423.0919.

85) N-[(4-chlorophenyl)methyl]-6-fluoro-7,8-di(2-(methoxy)ethoxy)-4-hydroxy-3-quinolinecarboxamide

The physical characteristics are as follows:

• 9

124 • · 9 · • 9 · · • · 99

9 9 · • 9 9 · ··

9«

9 9

9 9 • 9 9 • 9 9 9

99

Melting point 160-161.5°C.

1 h NMR (DMSO-d ₆ ) δ 12.00; 10.29; 8.61; 7.67; 7.36; 4.51; 4.38; 4.32; 3.70; 3.65; 3.28; 3.24.

³ C NMR (DMSO-d 2 ) δ 175.4; 164.8; 153.8; 143.9; 142.9; 141.6; 139.1; 131.9; 131.6; 129.7; 128.8; 122.1; 110.7; 105.8; 73.6; 73.4; 71.5; 71.3; 58.6; 58.5; 41.9.

IR (mull) 1660, 1631, 1611, 1574, 1564, 1538, 1495, 1307, 1293, 1195, 1111, 1100, 1062, 1044, 794 cm' ¹ .

MS (ESI-) for _{C23H24C1FN2O6 m} /z 477 (MH ₎ -. Analysis found: C 57.69; H 5.02; N 5.85 _; Cl 7.47.

Example 86

N-[(4-chlorophenyl)methyl]-6,8-difluoro-4-hydroxy-7-(1-methylethoxy)-3-quinolinecarboxamide

N-[(4-chlorophenyl)methyl]-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (500 mg) from Example 15 and sodium hydride (60% dispersion, 109 mg) were dissolved in 10 mL DMF and 2-propanol (0.115 mL) was added to the mixture. After heating for 1 hour, additional sodium hydride (50 mg) was added and the mixture was heated for an additional 1 hour. The reaction mixture was allowed to cool to room temperature, poured into 25 mL saturated aqueous ammonium chloride and filtered. The crude product was purified by column chromatography (dichloromethane/methanol, 100/1) to give the title compound (62 mg) as a white solid.

The physical characteristics are as follows:

Melting point 207-209°C.

1 H NMR (DMSO-d 2 ) 812.90; 10.20; 8.58; 7.78; 7.40-7.31; 4.63; 4.52; 1.32.

IR (tnuli) 3240, 3173, 3091, 3037, 1641, 1610, 1573, 1549, 1538, 1311, 1280, 1105, 1024, 797, 723 cm''.

MS (ESI-) for C20H17CIF2N2O3 sap 405 (MH) ^- .

Analysis found: C 59.02; H 4.13; N 6.89; Cl 8.76.

Example 87

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(1,3-thiazol-2-yl)-3-quinolinecarboxamide

To a suspension of the title compound of Example 52 (0.14 g) and p-toluenesulfonic acid (8.4 mg) in 2 mL of acetic acid was added bromoacetaldehyde diethyl acetal (0.08 mL). The reaction mixture was heated to 100°C for about 45 minutes. The reaction mixture was cooled to room temperature and diluted with 30 mL of ethyl acetate. The solid was filtered and dried to give the desired product (0.11 g).

The physical characteristics are as follows.

Melting point 296-298°C.

1 h NMR (300 MHz, DMSO-d ₆ ) δ 13.08; 10.18; 8.60; 8.49; 8.19; 7.98; 7.87; 7.38; 7.35; 4.54.

IR (mull) 3069, 1659, 1634, 1611, 1577, 1558, 1529, 1494, 1411, 1352, 1302, 1194, 1016, 800, 651 cm \

MS (E1) m/z 413 (M+), 415,413, 274,273, 247,246, 218, 142, 140, 58.

HRMS (FAB) found: 414.0495.

Example 88

N-[(4-chlorobenzyl)-6,8-difluoro-4-hydroxy-7-[(2-methoxyethyl)amino]-3-quinolinecarboxamide

A solution of the title compound of Example 15 (0.32 g) and 2-methoxyethylamine (2.0 mL) was heated at 90°C overnight. The reaction mixture was then cooled to room temperature and dichloromethane was added and the residue was adsorbed onto silica. A Biotage Flash 40S silica gel column (eluent 2.5% methanol in dichloromethane) gave the desired product as an oil which crystallized from dichloromethane:hexanes (0.21 g).

The physical characteristics are as follows:

Melting point 208-209°C.

1 h NMR (300 MHz, DMSO-d _g ) δ 12.47; 10.34; 8.46; 7.57; 7.37; 7.32; 6.24; 4.50; 3.54; 3.49; 3.23.

IR (mull) 3387, 3347, 1653, 1608, 1630, 1584, 1553, 1527, 1510, 1494, 1441, 1314, 1131, 1090, 1016, 794 cm' ¹ .

MS (E1) m/z 421 (M+), 423, 421, 282, 281, 255, 254, 235, 209, 180, 140.

HRMS (EI) found: 421.0993.

Example 89

N-[(4-chlorobenzyl)-6-(5-cyano-1-pentynyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

127 ·· ·· • · · 9

4 49

9 9 4

4 4 4

4 9 4

To a solution of _{the title compound of Example 5 (0.35 g), CuI (0.042 g), and Pd(PPh3)2Cl2 ( 0.012} g) in 10 mL of diethylamine was added 5-hexynitrile (0.085 mL). The reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over _MgSO4 , filtered, and adsorbed onto silica. Biotage Flash 40S (eluent 3% methanol in dichloromethane) gave the desired product. The product was crystallized from dichloromethane:methanol:hexanes. A second crop of crystals was obtained by concentrating the filtrate. Total yield of the title compound was 0.21 g).

The physical characteristics are as follows:

Melting point 208-210°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 12.99; 10.17; 8.59; 8.01; 7.77; 7.37; 7.33; 4.52; 2.65; 2.57;

1.85.

IR (mull) 3192, 3076, 3057, 1651, 1636, 1607, 1576, 1543, 1516, 1492, 1350, 1304, 1283, 1198, 804 cm ¹ .

MS (El) m/z 421 (M+), 423, 421, 281, 255, 254, 200, 171, 142, 140, 125.

HRMS (EI) found: 421.0982.

Example 90

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinyl)-3-quinolinecarboxamide

To a solution of the title compound of Example 5 (0.844 g) in 12.5 ml of dioxane and 0.5 ml of HMPA were added 2-(tributylstannyl)pyridine (0.74 ml) and PdCl ₂ (PPh ₃ ) ₂ (84.2 mg). The mixture was stirred at 100°C for 2 days. The reaction mixture was cooled to room temperature and then filtered to remove excess palladium. After diluting the filtrate with water, a yellow solid precipitated. The crude product was dissolved in methanol, adsorbed onto silica and chromatographed with 2% methanol.

128 titi titi ti ti ti • titi • titi · • titi · • ti titi • ti • ti titi • ti ti titi • ti ti • ti ti • titi ti • ti ·· in dichloroethane. Fractions homogeneous by TLC were combined, condensed, and recrystallized from ethyl acetate/hexanes to give 0.207 g of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 304-305°C.

H NMR (300 MHz, DMSO-d ₃ ) δ 13.01; 10.29; 8.77; 8.70; 8.65; 8.40; 8.11; 7.93; 7.38; 4.55.

ER(mull) 3074, 1662, 1639, 1590, 1576, 1543, 1508, 1492, 1317, 1288, 1223, 808, 802, 786, 684 cm \

MS (ESI) for C22H15ClFN3O2 m/z 406.0 (M-H). Analysis found: C 64.48; H 3.80; N 10.26.

Example 91

4-Hydroxy-6-iodo-3-quinolinecarboxylic acid 2-(4-chlorophenyl)hydrazide

Ethyl [4-hydroxy-6-iodo-3-quinolonecarboxylate] (1.4 g) was dissolved in 60 mL of 1:1 THF:MeOH and 16 mL of 1M LiOH. The reaction mixture was heated to 40°C overnight. After diluting the reaction mixture with 25 mL of acetic acid, a white precipitate formed. The solid was filtered, washed with water, and dried to give 1.09 g of the desired acid as a white solid.

The acid from above (250 mg) and Ι,Γ-carbonyldiimidazole (154.4 mg) were dissolved in 25 mL of anhydrous tetrahydrofuran and heated at 65°C for 2 days. When the reaction mixture had cooled to room temperature, 4-chlorobenzylamine (170.5 mg) and diisopropylethylamine (0.17 mL) were added. The reaction mixture was heated at 65°C overnight to dissolve the reactants and an additional 20 mL of tetrahydrofuran was also added. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layers were washed with brine (once), dried over Na ₂ SO 4 and condensed. The crude product was recrystallized from ethyl acetate/hexanes and filtered to give the product in very low yield. After

129

99 • · · · ·· • > · · · • 9 ·· »

999 • 9 ·

9 * • · « • » 9 • 9 99 storing the filtrate in the refrigerator for 1 month a pure solid precipitates and is filtered. This gives 25.5 mg of the desired product as a pink solid.

The physical characteristics are as follows:

Melting point 250-252°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 12.94; 11.19; 8.77; 8.55; 8.18; 8.06; 7.54; 7.16; 6.72.

HRMS (FAB) found: 439.9673.

Example 92

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[2-(2-pyridinyl)ethynyl]-3-quinolinecarboxamide

A solution of the title compound of Example 5 (540.3 mg), 2-ethynylpyridine (172 mg), PdCl2( _PPh3 ) ₂ (21.1 mg) and triethylamine (0.75 mL) in 3 mL DMF was heated at 90°C for 1 h. The reaction mixture was cooled to room temperature and diluted with water. A tan solid precipitated which was collected, dissolved in methanol/dichloromethane and adsorbed onto silica. The crude product was chromatographed eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed and recrystallized from hot methanol/dichloromethane and hexanes to give 0.302 g of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 275-277°C.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.09; 10.17; 8.62; 8.18; 7.98; 7.87; 7.70; 7.41; 4.56.

IR (mull) 3064, 3027, 1684, 1613, 1591, 1561, 1532, 1519, 1494, 1484, 1435, 1295, 1248, 801, 772 cm' ¹ .

HRMS (EI) found: 431.0823.

Example 94

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-hydroxy-1-butynyl)-3-quinolinecarboxamide

To a mixture of the title compound of Example 5 (0.457 g), copper (II) iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 ml of diethylamine was added 3-butyn-1-ol (0.076 ml). The reaction mixture was allowed to stir overnight. The solvents were evaporated and the residue was chromatographed on silica eluting with 3% methanol in dichloromethane. This gave 0.279 g of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 253-255°C.

IR (mull) 3197, 3068, 1654, 1630, 1609, 1575, 1556, 1521, 1493, 1305, 1292, 1195, 1030, 1016, 804 cm' ¹ .

H NMR (300 MHz, DMSO-d ₆ ) δ 12.99; 10.18; 8.61; 7.99; 7.75; 7.37; 4.54; 3.61; 2.60.

MS (E1) m/z 398 (M+), 400,398,258,232,231,200, 171, 142, 140, 125.

HRMS (EI) found: 398.0831.

Example 95

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-methoxy-1-propynyl)-3-quinolinecarboxamide

A solution of the title compound of Example 5 (540.3 mg) methyl propargyl ether (0.14 mL) PdCl2( _PPh3 )2 (21.1 mg) and triethylamine (0.75 mL) in 3 mL DMF was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer

131 was washed _{with ethyl acetate (4x). The combined organic layers were dried over Na2SO4 and} condensed. This gave a dark residue. The residue was diluted with MeOH, adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed and recrystallized from ethyl acetate/hexanes to give 0.218 g of the desired product as a white solid.

The physical characteristics are as follows.

Melting point 222-224°C.

H NMR (300 MHz, DMSO-d _g ) δ 13.03; 10.16; 8.62; 8.05; 7.84; 7.38; 4.55; 4.37; 3.33.

IR (mull) 1655, 1635, 1610, 1585, 1572, 1564, 1543, 1536, 1517, 1490, 1305, 1287, 1185, 1095, 805 cm' ¹ .

MS (E1) m/z 398 (M+), 400, 398, 258, 231, 200, 171, 142, 141, 140, 125.

Analysis found: C 63.01; H 4.23; N 6.99.

Example 96

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide

A solution of the title compound of Example 5 (540.3 mg) 3-butyn-2-ol (0.13 mL), _PdCl2 ( _PPh3 ) ₂ (21.1 mg) and triethylamine (0.75 mL) in 3 mL DMF was heated at 90°C for 1 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl _{acetate (3 x). The combined organic layers were dried over Na2SO4 and} concentrated. This gave a brown residue. The residue was diluted with MeOH, adsorbed onto silica and chromatographed eluting with 2.5% methanol in dichloromethane. Fractions homogeneous by TLC were combined, concentrated and recrystallized from ethyl acetate/hexanes to give 0.207 g of the desired product as a cream solid.

132

The physical characteristics are as follows: Melting point 232-234°C.

H NMR (300 MHz, DMSO) δ 13.01; 10.17; 8.60; 7.98; 7.73; 7.38; 5.55; 4.60; 4.55; 1.38.

IR (mull) 3153, 3113, 3061, 1652, 1637, 1610, 1579, 1562, 1546, 1514, 1491, 1305, 1285, 1001, 804 cm' ¹ .

MS (EI) m/z 398 (M+), 400, 398, 258, 231, 216, 188, 187, 142, 140, 125. Analysis found: C 62.92; H 4.22; N 6.96.

Example 97

6-(4-Bromo-2-thienyl)-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

To a solution of the title compound of Example 5 (684 mg) and PdCl2PPlbh (68.8 mg) in 10.1 mL of dioxane and 0.41 mL of HMPA was added 2-(tributylstannyl)-4-bromothiophene (732 mg). The reaction mixture was maintained at 100°C overnight. The reaction mixture was cooled to room temperature and then filtered to remove excess palladium. The filtrate was diluted with water and extracted with dichloromethane (3x). The combined organic layers were washed with brine (1x), dried over _Na2SO4 and condensed. This gave a yellow solid. The crude product was dissolved in dichloromethane/methanol, adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane. The product was recrystallized from ethyl acetate/hexanes to give 0.358 g of the desired product as a yellow solid.

The physical characteristics are as follows:

Melting point 281-283°C.

’h NMR (300 MHz, DMSO) δ 13.00; 10.22; 8.61; 8.17; 7.75; 7.36; 4.53.

133

·· ft · · · · · • fc · · · • · · · · 9 • · fc Λ · • ··· fcfc fcfc

IR (mull) 3140, 3114, 3089, 3059, 3019, 1652, 1638, 1611, 1577, 1550, 1530, 1515, 1490 1305, 804 cm'\

MS (El) m/z 490 (M+), 492, 490, 352, 350, 325, 323, 142, 141, 140, 125.

Analysis found: C 51.42; H 2.85; N 5.68.

Example 98

N-[(4-chlorobenzyl)-8-fluoro-6-(hydrazinecarbthioyl)-4-hydroxy-3-quinolinecarboxamide

To a suspension of the title compound of Example 52 (0.60 g) in 20 ml of a 1:1 mixture of tetrahydrofuran and dichloromethane at room temperature was added methyl triflate (0.2 ml). The reaction mixture was stirred for 45 min. After this time everything went into solution. Pyridine (0.38 ml) was added and then H2S was bubbled in for 1 h. The reaction mixture was then purged with nitrogen for 30 min. Hydrazine monohydrate (0.28 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h. After this time the solution turned from orange to pale yellow and a precipitate was observed. The solid in the reaction mixture was filtered and dried to give 0.26 g of the desired product.

The physical characteristics are as follows:

Melting point 317-319°C.

HNMR (300 MHz, DMSO-dQ 5 10.27; 8.62; 8.49; 8.05; 7.38; 7.34; 4.54; 4.07; 3.30.

IR (mull) 3238, 3199, 3164, 3044, 3019, 1656, 1615, 1578, 1558, 1524, 1491, 1314, 1280, 898, 810 cm' ¹ .

MS (FAB) m/z 405 (MH + ), 407, 406, 405, 404, 388, 125, 87, 73, 71, 55.

HRMS (FAB) found: 405.0590.

99

9 9 9 9

9 99

9 9 9 9

9 9 9

99 9

134

Example 99

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-hydroxybutyl)-3-quinolinecarboxamide

A solution of the title compound of Example 94 (180 mg), Pd/BaSCh (10%, 75.3 mg) and pyridine (5 mL) in ethyl acetate (25 mL) was kept under an atmosphere of H ₂ (bottle) for 3 h. The crude product was recrystallized from ethyl acetate/hexanes to give 81.6 g of the desired product as an off-white solid.

The physical characteristics are as follows.

Melting point 210-212°C.

Η NMR (300 MHz, DMSO) δ 12.83; 10.33; 8.61; 7.86; 7.61; 7.38; 4.55; 4.38; 3.38; 2.71; 1.63; 1.41.

IR (mull) 3264, 3196, 3161, 3082, 1662, 1641, 1615, 1577, 1544, 1507, 1491, 1306, 1266, 804, 685 cm \

MS (El) m/z 402 (M+), 404, 402, 263, 262, 236, 235, 176, 147, 142, 140.

Analysis found: C 62.48; H 4.95; N 6.88.

Example 100

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-3-quinolinecarboxamide

A solution of the title compound of Example 98 (0.24 g) and acetyl chloride (0.05 mL) in 10 mL of freshly distilled THF was heated at 65°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated. This gave a yellow solid. The solid was triturated with diethyl ether, filtered, and dried to give 0.20 g of the desired thiadiazole.

The physical characteristics are as follows:

Melting point 292-294°C.

H NMR (300 MHz, DMSO-d _fi ) δ 13.13; 10.14; 8.63; 8.43; 8.25; 7.38; 7.35; 4.54; 2.79.

IR (shift) 3077, 3058, 3040, 3024, 2945, 1673, 1616, 1585, 1550, 1527, 1489, 1444, 1277, 1199, 798 cm' ¹ .

MS (E1) m/z 428 (M+), 428, 289, 288, 262, 261, 233, 142, 141, 140, 125.

HRMS (FAB) found: 429.0583.

Example 101

N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide

To a mixture of the title compound of Example 39 (0.439 g), copper (II) iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (II) (0.035 g) in 15 ml of diethylamine was added propargyl alcohol (0.058 ml). The reaction mixture was allowed to stir overnight. The solvents were evaporated and the residue

136 • · · » « •999 99 9

9 99 9

9 * 9 9 «

9 9 9 9 chromatograph on silica eluting with 3% methanol in dichloromethane. This gives 0.271 g of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 218-220°C.

H NMR (300 MHz, DMSO) δ 12.72; 19.36; 1.80; 8.21; 7.72; 7.46; 7.38; 4.55; 4.37;

3.17.

IR (mull) 3066, 3055, 3006, 1651, 1634, 1595, 1575, 1531, 1496, 1320, 1242, 1031, 869, 833, 797 cm' ¹ .

MS (El) m/z 366 (M+), 368, 366, 227, 226, 200, 199, 142, 140, 125, 115.

HRMS (FAB) found: 367.0840.

Example 102

7-(aminocarbthioyl)-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide

WITH

N

AND

H

Cl

To a solution of the title compound of Example 39 (1.0 g) in 30 ml of freshly distilled THF were added KCN (0.30 g) and Pd(PPh ₃ ) ₄ (0.49 g). The reaction mixture was heated at 60°C overnight. The reaction mixture was cooled to room temperature and the solvents were removed. The residue was dissolved in methanol/dichloromethane/ethyl acetate and adsorbed onto silica. Purification on a Biotage Flash 40S silica gel column (eluent 2% methanol in dichloromethane) gave the desired product as a yellow solid (0.52 g).

A solution of the above solid (0.52 g) and triethylamine (0.44 ml) in 10 ml DMF was heated to 95°C. H ₂ S was bubbled into the reaction mixture for about 4 hours. The bubbler was removed and the reaction mixture was allowed to stir at 30°C for 3 days. Water was added to the reaction mixture and the resulting solid was filtered and dried. This solid was confirmed to be the starting material, so the solid • · · φ φ φ φ φ φ φ φ φ φ φ φ φ · · · φφ φφ φ

137 • φ « φ · φ • · φ φ • φ φ « φ φ φ φ φ φ · φ φφ φφ is redissolved in DMF and subjected to the same reaction conditions. The solid obtained after adding water to the reaction mixture contains the desired product. The solid is dissolved in methanol/dichloromethane and adsorbed onto silica. A Biotage Flash 40S silica gel column (eluent 2.5% methanol in dichloromethane (1 L), then 4% methanol in dichloromethane (1 L)) gives the desired product (0.38 g).

The physical characteristics are as follows:

Melting point 255-256°C.

*H NMR (300 MHz, DMSO-d ₆ ) δ 12.87; 10.34; 10.15; 9.78; 8.77; 8.22; 8.12; 7.78; 7.38; 7.35; 4.53.

IR (mull) 3291, 3210, 1666, 1660, 1639, 1617, 1609, 1558, 1531, 1514, 1492, 1354, 1309, 1297, 621 cm' ¹ .

MS (ESI) 372.1 (M+H) ⁺ ; 394.0 (M+Na) ⁺ ; 370.0 (MH)'.

HRMS (FAB) found: 372.0573.

Analysis found: C 56.83; H 3.87; N 10.90.

Example 103

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-methoxypropyl)-3-quinolinecarboxamide

A mixture of the title compound from Example 95 (113 mg) and Pd/C (10%, 22.6 mg) was dissolved in 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at 172 kPa hydrogen pressure and monitored with OAMS for complete reduction of acetylene. The reaction was complete in 1 hour and filtered through a pad of celite. The filtrate was condensed. This gave a white solid. The product was recrystallized from ethyl acetate/hexanes to give 32.0 mg of the desired product.

The physical characteristics are as follows:

• 4

138

44 • 4 · · • 4 44 • 4 4 · • 4 4 · • 4 44

Melting point 189-192°C.

’h NMR (300 MHz, DMSO) δ 12.82; 10.30; 8.58; 7.83; 7.61; 7.38; 7.33; 4.53; 3.30; 3.21; 2.75; 1.82.

IR (shift) 3079, 3014, 2963, 2935, 2892, 2854, 2826, 1660, 1613, 1575, 1541, 1507, 1306, 1266, 804 cm' ¹ .

MS (ESI)' for C ₂ iH ₂ oClFN ₂ 0 ₃ m/z 401.0 (MH).

Analysis found: C 63.09; H 5.16; N 6.89.

Example 104

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-4-hydroxy-1-butenyl]-3-quinolinecarboxamide

F

A solution of the title compound of Example 94 (393 mg), pyridine (3 mL) and Pd/C (10%, 80.0 mg) in 3:1 dichloromethane:methanol was kept under an atmosphere of H ₂ (bottle) for 3 h. More Pd/C (10%, 40 mg) was added and the reaction mixture was placed in a Parr hydrogenator at 172 kPa hydrogen pressure for an additional 3 h. The reaction mixture was filtered through a pad of celite. The filtrate was condensed and then placed under high vacuum to remove residual pyridine. The crude product was recrystallized from ethyl acetate/hexanes to give 218 mg of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 195-197°C.

H NMR (300 MHz, DMSO) δ 12.92; 10.28; 8.61; 7.97; 7.68; 7.36; 6.56; 5.83; 4.68; 4.52; 3.52; 2.50.

IR (shift) 3181, 3076, 3059, 3014, 2932, 1651, 1610, 1548, 1519, 1490, 1347, 1307, 1283, 808, 798 cm' ¹ .

φ φ φ φ ♦ φ · φ φ · φ φ ·

4 4

4 44

139

HRMS (FAB) found: 401.1082.

Analysis found: C 62.56; H 4.64; N 6.91.

Example 105

N-(4-chlorobenzyl)-6-(5-cyanopentyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

To a suspension of the title compound of Example 89 (0.11 g) in 25 mL of ethyl acetate was added triethylamine (0.08 mL) and pyridine (5 mL) to aid dissolution. When 10% Pd/C (50 mg) was added, the reaction mixture was placed under a hydrogen balloon. After 2 hours the reaction was complete and then filtered through a pad of celite. The filter cake was washed with ethyl acetate. The filtrate was concentrated. This gave a tan solid. This was further dried under vacuum to give 88 mg of the desired product.

The physical characteristics are as follows:

Melting point 213-215°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 12.98; 10.33; 8.60; 7.87; 7.64; 7.40; 7.36; 4.55; 2.74; 2.48; 1.58; 1.37.

IR (shift) 3194, 3158, 3060, 2935, 1651, 1613, 1568, 1558, 1544, 1524, 1489, 1304, 1288, 804, 724 cm' ¹ .

MS (ESI) 426.0 (M+H) ⁺ , 424.0 (MH) ^- .

HRMS (FAB) found: 426.1371.

Analysis found: C 64.95; H 5.17; N 9.69.

99

9

9

9 ·

99 » 9 «

I 9 ·· » · · 4 » 9 9 « ·· ··

140

9··

Example 106

N-(4-chlorobenzene 1)-8-fluoro-4-hydroxy-6-(3-hydroxy-3-methylbutyl)-3-quinolinecarboxamide

To a mixture of the title compound of Example 5 (0.457 g), copper (II) iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (Π) (0.035 g) in 15 ml of diethylamine was added 2-methyl-3-butyn-2-ol (0.097 ml). The reaction mixture was allowed to stir overnight. The solvents were evaporated and the residue was chromatographed on silica eluting with 3% methanol in dichloromethane. This gave 0.248 g of the desired product as a white solid.

Acetylene from above (190 mg) was dissolved in 3:1 dichloromethane:methanol. 10% Pd/C and Pd/C (38.0 mg) were added. The reaction mixture was placed in a Parr hydrogenator at 172 kPa hydrogen pressure and monitored with OAMS for complete reduction of acetylene. The reaction was complete in 1 hour and filtered through a pad of celite to remove residual palladium. The filtrate was condensed. This gave a white solid. The product was recrystallized from ethyl acetate/hexanes to give 32.0 mg of the desired product.

The physical characteristics are as follows:

Melting point 219-222°C.

H NMR (300 MHz, DMSO) δ 12.85; 10.33; 8.60; 7.86; 7.61; 7.41; 7.36; 4.55; 4.32; 2.77; 1.68; 1.51.

IR (shift) 2977, 2962, 2942, 1647, 1614, 1561, 1525, 1490, 1303, 1287, 1207, 1199, 808, 798, 724 cm' ¹ .

HRMS (FAB) found: 417.1382.

Analysis found: C 63.65; H 5.53; N 6.69.

• 4 44

4 4 «

4 44

4 4 ·

4 4 «

44

141 • 4 44

Example 107

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxy-1-pentynyl)-3-quinolinecarboxamide

A solution of the title compound of Example 5 (540.3 mg), 4-pentyn-1-ol (0.16 mL), _PdCl2 ( _PPh3 ) ₂ (21.1 mg) and triethylamine (0.75 mL) in 3 mL DMF was heated at 90°C for 1 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl _{acetate (3 x). The combined organic layers were dried over Na2SO4 and} concentrated. This gave a reddish-brown residue. The residue was diluted with dichloromethane and chromatographed eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined, concentrated and recrystallized from ethyl acetate/hexanes to give 0.296 g of the desired product as a white solid.

The physical characteristics are as follows.

Melting point 208-209°C.

H NMR (300 MHz, DMSO) δ 13.00; 10.19; 8.61; 7.98; 7.73; 7.41; 7.36; 4.54; 3.52; 2.51; 1.71 (m, 2H).

IR (shift) 3290, 2966, 2934, 1659, 1610, 1574, 1563, 1558, 1543, 1538, 1523, 1303, 1031, 869, 804 cm' ¹ .

MS (ESI) ^- for C _{2 2} H ₁₈ C 1FN ₂ O 3 m/z 411.1 (MH)~.

Analysis found: C 63.65; H 4.41; N 6.62.

Example 108

6-{3-[benzyl(methyl)amino]propyl}N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

142

_{To a solution of the title compound of Example 5 (0.37 g), Cu1 (58 mg) and Pd(PPh3)2Cl2 ( 11} mg) in 10 ml of diethylamine was added N-methyl-N-propargylbenzylamine (0.15 ml). The reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over _MgSO4 , filtered and adsorbed onto silica. A Biotage Flash 40S column (eluent 2.5% methanol in dichloromethane (1 L), then 3% methanol in dichloromethane (1 L)) gave an intermediate, acetylene, which was further recrystallized from dichloromethane/hexanes (0.25 g).

The product from above (0.16 g) was suspended in 25 mL of ethyl acetate. 0.1 mL of triethylamine was added followed by 2 mL of pyridine to achieve dissolution. When 10% Pd/C (60 mg) was added, the reaction mixture was placed under a hydrogen balloon and stirred at room temperature. After 1.5 hours the reaction was complete and then filtered through a pad of celite. The filtrate was concentrated. This gave a liquid which crystallized from ethyl acetate/hexanes to give 56 mg of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 161-162°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 10.35; 8.59; 7.84; 7.56; 7.37; 7.33; 7.26; 4.52; 3.46; 2.72; 2.35; 2.11; 1.81.

IR (offset) 3160, 3060, 2935, 1651, 1634, 1573, 1567, 1548, 1525, 1489, 1285, 805, 724, 699 cm \

MS (ESI) 492.0 (M+H) ⁺ , 490.0 (MH)~.

HRMS (FAB) found: 492.1839.

Example 109

Methyl 3- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylate

<*« 99 • · · 0 • · · *

9 9 9

9 9 9 • 9 99

A solution of the title compound of Example 5 (1.0 g), triethylamine (0.61 mL), methanol (3.55 mL), Pd(OAc) ₂ (13.7 mg), 1,3-bis(diphenylphosphine)propane (25.2 mg) in 12 mL DMSO was stirred at room temperature until all dissolved. CO gas was slowly bubbled into the reaction mixture for 3 h and the reaction mixture was maintained at 70°C overnight. The following day, CO gas was bubbled into the reaction mixture for an additional 4 h. The reaction mixture was cooled to room temperature and diluted with water. The white solid that precipitated was collected while the filtrate was partitioned against dichloromethane. The aqueous layer was washed with dichloromethane (3 x). The combined organic layers were dried over Na ₂ SO ₄ and condensed to give an orange residue. The residue was placed under high vacuum to remove residual DMSO. The solid collected was combined with the residue, dissolved in methanol and adsorbed onto silica. The crude product was chromatographed with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed and recrystallized from ethyl acetate/hexanes to give 418 mg of the desired product as a white solid.

Melting point 288-290°C.

H NMR (300 MHz, DMSO) δ 13.17; 10.09; 8.63; 8.58; 8.04; 7.39; 7.34; 4.54; 3.30.

IR (shift) 3071, 1727, 1660, 1634, 1611, 1576, 1557, 1527, 1496, 1311, 1288, 1234, 1191, 803, 765 cm' ¹ .

HRMS (FAB) found: 389.0706.

Analysis found: C 58.64, H 3.84, N 7.24.

Example 110

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide

A suspension of the title compound of Example 53 (300 mg) and 10% Pd/C (0.03 g) in 25 mL of 3:1 dichloromethane:methanol was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered through a pad of celite. The filtrate was condensed. The crude product was recrystallized from ethyl acetate/hexanes to give 200 mg of the desired product as a pale yellow solid.

The physical characteristics are as follows:

Melting point 224-226°C.

H NMR (300 MHz, DMSO) δ 12.8; 10.33; 8.60; 7.86; 7.61; 7.38; 4.53; 3.42; 3.32; 2.77; 1.76.

IR (shift) 3045, 2950, 2931, 1651, 1611, 1582, 1563, 1557, 1537, 1532, 1492, 1301, 1015, 808 cm' ¹ .

MS (FAB) m/z 389 (MH + ), 391, 390, 389, 248, 139, 125, 123, 105, 91, 86.

HRMS (FAB) found: 389.1060.

Example 111

N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxypropyl)-3-quinolinecarboxamide

HIM.

you you

145

• · those • • e • • those those those • • • • • you you w • • those • • • • · • you • • you you • you you you • ♦ · •

A mixture of the title compound from Example 101 (190 mg) and Pd/C (10%, 37.9 mg) was dissolved in 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at 172 kPa hydrogen pressure and monitored with OAMS for complete reduction of acetylene. The reaction mixture was filtered and fresh catalyst was added each time the reaction mixture was removed from the Parr hydrogenator. The reaction was complete in 3.5 hours and filtered through a pad of celite to remove palladium. The filtrate was condensed to give a residue. The residue was dissolved in methanol, adsorbed onto silica, and chromatographed eluting with 4% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed, and recrystallized from ethyl acetate/hexanes to give 91.4 mg of the desired product as a white solid.

The physical characteristics are as follows.

Melting point 166-168°C.

H NMR (300 MHz, DMSO) δ 12.60; 10.46; 8.71; 8.15; 7.45; 7.36; 4.53; 3.41; 2.75;

1.75.

IR (shift) 3284, 2946, 1652, 1635, 1612, 1582, 1562, 1539, 1492, 1474, 1053, 860, 849, 795, 753 cm' ¹ .

HRMS (FAB) found: 371.1155.

Analysis found: C 64.47; H 5.14; N 7.46.

Example 112

Ethyl-(E)-3-(3-{[(4-chlorobenzyl)amino jcarbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propenoate

A mixture of the title compound from Example 5 (1.05 g), triethylamine (6 ml), ethyl acrylate (0.3 ml), palladium acetate (5.1 mg) and tris(o-tolyl)phosphine (42 mg) in 5 ml DMF was heated to

146 • 9 t · 9 99 ·9 « 9» · · · · · · « · · • 9 9* 9 9 · 9 9 9 · · 9 9 9 999 9*9 «··· 9 9 9999 ·« *· 999 * 9 » 9 · ··

100°C for 24 hours in a pressure tube. The reaction mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (3 x). The combined organic layers were filtered, dried over Na ₂ SO ₄ , filtered and condensed. The crude product was purified by trituration with hot ethyl acetate to give 0.461 g of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 278-280°C.

H NMR (300 MHz, DMSO) δ 13.01; 10.23; 8.61; 8.21; 7.78; 7.40; 6.78; 4.55; 4.21;

1.27.

MS (ESI-) for C ₂₂ H ₁₈ C 1FN ₂ O ₄ m/z 427.1 (MH)-.

Example 113 (E)-3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propenoic acid

A mixture of the title compound of Example 5 (913 mg), acrylic acid (0.17 mL), palladium acetate (4 mg) and triethylamine (0.70 mL) in 5 mL DMF was heated at 100°C for 24 hours in a pressure box. The reaction mixture was cooled and diluted with 50 mL of 10% aqueous HCl. The resulting solid was collected, dried and recrystallized from ethanol to give 564 mg of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 296-298°C.

’h NMR (300 MHz, DMSO) δ 13.05; 10.23; 8.60; 8.21; 7.71; 7.39; 6.67; 4.56.

MS (ESI-) for C ₂₀ Hi ₄ C 1FN ₂ O 4 m/z 399.1 (MH)-.

147

Example 114

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propanoic acid

To a mixture of the title compound of Example 113 (250 mg) and triethylamine (0.09 mL) in 100 mL of 3:1 dichloromethane:methanol was added Pd/C (10%, 50 mg). The mixture was hydrogenated at 206.8 kPa of hydrogen for 6 h. The reaction mixture was filtered through a pad of celite and the filtrate was condensed. The crude product was dissolved in DMF (~25 mL) and acidified with 1 N HCl (25 mL). The resulting solid was collected, dried, and recrystallized from ethanol to give 152 mg of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 284-286°C.

’h NMR (300 MHz, DMSO) δ 12.85; 12.19; 10.32; 8.60; 7.89; 7.69; 7.40; 7.36; 4.55; 2.96; 2.62.

MS (ESI-) for C ₂₀ Hi ₆ C 1FN ₂ O 4 m/z 401.0 (MH)-.

Example 115

5-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-pentinoic acid

148 • · · ·

A * * * • β · « • · · 9 9 • · · · • · » * • · <

I · · 4 ·· ··

To a mixture of the title compound of Example 5 (0.457 g), copper (II) iodide (0.010 g) and dichlorobis(triphenylphosphine)palladium (Π) (0.035 g) in 15 ml of diethylamine was added 4-pentynoic acid (0.098 ml). The reaction mixture was allowed to stir overnight. The solvents were evaporated and the residue was chromatographed on silica eluting with 10% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed. The residue was recrystallized from ethyl acetate/hexanes to give 0.057 g of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 148-155°C.

H NMR (300 MHz, DMSO) δ 12.9; 12.3; 10.19; 8.61; 7.97; 7.71; 7.38; 4.55; 2.68;

2.56.

IR (shift) 1660, 1656, 1650, 1645, 1633, 1607, 1579, 1574, 1567, 1563, 1557, 1552, 1538, 1524, 1519 cm' ¹ .

MS (FAB) w/z 427 (MH+), 581, 429, 428, 427, 371, 286, 127, 125, 71, 57.

HRMS (FAB) found: 427.0856.

Example 116

N-[(4-chlorophenyl)methyl]-9-hydroxy-3H-pyrazolo[4,3-f]quinoline-8-carboxamide (formula E-3, where R3=R4=H, R1 and _R2 are together diazole. See Scheme E)

149 • ·

HN

A.a ·

Cl

The title compound was prepared according to the procedure described in Preparation 12 and Example 63, substituting 4-tert-butylaniline for 5-aminoindazole. This procedure gave 0.137 g of the title compound as a brown solid.

The physical characteristics are as follows:

Melting point 268-271°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 13.66; 10.80; 8.87; 8.78; 8.01; 7.69; 7.41; 4.60 ppm.

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 175.7; 164.7; 141.0; 138.8; 135.7; 131.2; 129.2; 128.9; 128.7; 128.2; 128.0; 119.1; 118.3; 117.0; 112.2; 41.3 ppm.

IR (mull) 3202, 3045, 1647, 1626, 1580, 1542, 1491, 1409, 1260, 1093, 946, 817, 801, 761, 710 cm' ¹ .

MS (EI)z»/z352 (M+), 352, 213, 212, 211, 185, 156, 140, 129, 127, 125.

HRMS (EI) found: 352.0726.

% Water (KF): 3.80.

Analysis found: C 59.00; H 4.07; N 14.90.

Example 117

N-(4-chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide

150 ft· *· * ·· · · • 9 9 9 9 9 9 * · 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9

9 99 9 9 9 9 9

N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.95 g) from Example 5 and sodium hydride (60% dispersion, 520 mg) were suspended in 60 mL DMF and methanol (0.288 mL) was added to the mixture. After heating at 135°C for 1 hour, additional sodium hydride (200 mg) was added and the mixture was heated for an additional 1 hour. The reaction mixture was allowed to cool to room temperature and then poured into 200 mL saturated aqueous ammonium chloride. The resulting precipitate was filtered and washed with 20 mL water, 20 mL tert-butyl methyl ether and 20 mL heptane. The crude product was purified by column chromatography (heptane/2-propanol, 9/1, 4/1) to give the title compound (1.68 g, 56%) as a white solid. Recrystallization (acetic acid, water) gave the hydrate (1H ₂ O).

The physical characteristics are as follows:

Melting point 241-243°C.

H NMR (300 MHz, DMSO-dg) δ 12.43; 10.28; 8.57; 8.09; 7.61; 7.41-7.34; 4.53; 4.04.

¹³ C NMR (CF 3 CO 2 D) δ 173.3; 167.3; 149.0; 141.4; 134.8; 133.2; 129.8; 129.2; 129.0; 124.9; 124.5; 122.5; 106.7; 94.4; 56.4; 44.0.

IR (shift) 3072, 1646, 1612, 1594, 1558 (s), 1530 (s), 1492, 1306, 1298, 1255, 1202, 1082, 851, 846, 804 (s) cm' ¹ .

MS (ESI-) for m/z 467 (M-H).

Analysis found for C 12 H 2 ClINiO 2 .H 2 O: C 44.39; H 3.46; N 5.76; Cl 7.34.

Water (KF): 3.67.

Example 118

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide • · ♦

Φ · · · • · · · ·

151 ·· ·· • 9 4 Φ • · · t • Φ Φ Φ Φ • · · ·

N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg) from Example 117, copper (I) iodide (57 mg) and bis(triphenylphosphine)palladium (II) chloride (35 mg) were suspended in 15 mL of diethylamine. Propargyl alcohol (0.070 mL) was added and the mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (2x50 mL). The organic layer was washed with saturated aqueous ammonium chloride (3x10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The crude product was purified by column chromatography (dichloroethane/methanol, 50/1, 33/1, 25/1, 20/1) to give the title compound (289 mg, 73%) as a white solid.

The physical characteristics are as follows: Melting point 207-208°C.

HNMR (DMSO- d ) δ 12.45; 10.3; 8.58; 7.79; 7.42-7.34; 5.38; 4.53; 4.34; 4.05.

13.

C NMR (DMSO-d ₆ ) δ 178.0; 167.1; 151.8; 145.9; 141.5; 134.2; 132.6; 132.1; 131.2; 129.6; 122.5; 121.7; 117.0; 114.4; 93.3; 86.1; 59.5; 52.3; 44.3.

IR (shift) 3196 (b), 3157 (b), 3074, 2234 (w), 1649, 1603, 1568, 1562, 1523 (s), 1491, 1314, 1200, 1089, 1021, 805 cm'\

Analysis found for C ₂ iHi7ClN ₂ O ₄ : C 63.26; H 4.35; N 7.07; Cl 8.94.

Example 119

N-(4-chlorobenzyl)-4-hydroxy-8-methoxy-6-(3-methoxy-1-propynyl)-3-quinolinecarboxamide

152 • · * · • · * » • · 4» • · * · » • · · · ♦ · ·* • ·· Μ •» * · · Φ

9 9 9 9

9 9 9 9 9

9 9 9 9 • »«· *4 ··

N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg) from Example 117, copper (I) iodide (57 mg) and bis(triphenylphosphine)palladium (H) chloride (35 mg) were suspended in 15 mL of diethylamine. Methyl propargyl ether (0.101 mL) was added and the mixture was allowed to stir at room temperature for 64 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (2x50 mL). The organic layer was washed with saturated aqueous ammonium chloride (3x10 mL) and brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated. The crude product was purified by column chromatography (heptane/2-propanol, 12/1, 10/1, 5/1) to give the title compound (188 mg, 46%) as a white solid.

The physical characteristics are as follows:

Melting point 211-213°C.

HNMR (DMSO-d ₆ ) δ 12.47; 10.30; 8.58; 7.82; 7.42-7.32; 4.54; 4.37; 4.05; 3.36.

13.

C NMR (CF ₃ CO ₂ D) δ 174.1; 167.3; 149.2; 141.5; 134.8; 133.2; 130.2; 129.0; 128.9; 125.1; 121.6; 118.9; 117.1; 106.5; 86.2; 84.9; 59.7; 56.8; 56.2; 43.9.

IR (shift) 2231 (w), 1988 (w), 1931 (w), 1652 (s), 1608, 1571, 1551 (s), 1524 (s), 1354, 1307, 1289, 1192, 1095, 1083, 804cm'\

MS (ESI-) m/z 409 (M-H).

Analysis found for C ₂₂ Hi ₉ ClN ₂ O ₄ : C 64.25; H 4.81; N 6.84; Cl 8.60.

Example 120

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-methoxy-3-quinolinecarboxamide » ·

153

9 9 9 · · · · '9 9

9 9 9

9 9 »

9 9 9

9 9 ·

9 99

9 9

N-[(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide from Example 118 (397 mg) was dissolved in 80 mL of 1:1 dichloromethane:methanol and palladium on carbon (5%, 80 mg) was added. The mixture was placed under a hydrogen atmosphere (158.6 kPa) for 1 hour, filtered through celite and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol, 50/1 to 20/1) to give the title compound (251 mg, 63%) as a white solid.

The physical characteristics are as follows:

Melting point 201-204°C.

1 h NMR (DMSO-d ₆ ) δ 12.28; 10.47; 8.56; 7.60; 7.41-7.39; 7.24; 4.54; 4.50; 4.43; 4.03; 2.75; 1.78.

¹³ C NMR (CF ₃ CO ₂ D) δ 176.3; 165.2; 149.2; 142.8; 140.0; 139.2; 131.9; 129.6; 128.8; 128.5; 127.3; 115.6; 113.6; 111.2; 60.5; 56.8; 41.9; 34.6; 32.4.

IR (shift) 3315, 3170 (b), 3047 (b), 2938, 1651, 1608, 1569, 1554, 1531 (s), 1490, 1292, 1266, 1090, 1059, 802 cm ¹ .

MS (ESI-) for m/z 399 (MH) ^- .

Analysis found for C21H21CIN2O4: C 62.87; H 5.59; N 7.02.

Example 121

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethyl)-3-quinolinecarboxamide • 9

A mixture of 4-bromo-2-trifluoromethylaniline (10.0 g) and diethylethoxymethylenemalonate (8.42 ml) was heated at 135°C for 2 hours. The reaction mixture was diluted with 50 ml of diphenyl ether and heated at reflux for 30 minutes with ethanol removal via a Dean-Stark trap. The resulting precipitate was poured into heptane, filtered and recrystallized (DMF) to give 6.66 g (44%) of 6-bromo-8-trifluoromethylquinoline ethyl ester. A mixture of quinoline ethyl ester (5.0 g) and 4-chlorobenzylamine (8.4 ml) was heated at 190°C for 1 hour. The mixture was diluted with toluene (25 ml), allowed to cool to room temperature and filtered. The crude product was recrystallized (acetic acid) to give 5.35 g (85%) of the amide. The resulting amide (2.30 g), bis(triphenylphosphine)palladium(II) chloride (0.175 g) and 5 mL of triethylamine were dissolved in 50 mL of DMF. Propargyl alcohol (2.5 mL) was added over 20 h at 90°C. The reaction mixture was allowed to cool to room temperature, poured into 200 mL of saturated aqueous ammonium chloride and extracted with ethyl acetate (4 x 50 mL). The organic layer was washed with saturated aqueous brine (10 mL). The aqueous layer was back-extracted with ethyl acetate (20 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol, 100:1, 50/1, 100/3, 25/1) and recrystallization (ethyl acetate) to give 0.928 g (43%) of the title compound as a tan solid.

The physical characteristics are as follows:

Melting point 256°C (decomposition).

Η NMR (DMSO-d ₆ ) δ 12.18; 10.05; 8.67; 8.49; 8.15; 7.42-7.34; 5.45; 4.55; 4.36.

13.

C NMR (CF ₃ CO ₂ D) δ 175.1; 163.9; 145.5; 138.9; 134.9; 133.5; 133.3; 131.9; 129.7; 128.8; 127.9; 123.3; 118.8; 118.7; 112.7; 92.7; 81.8; 49.9; 42.0.

IR (shift) 1661 (s), 1609, 1587, 1559, 1519, 1463, 1293, 1212, 1193, 1168, 1132 (s), 1114, 1017,914, 802 cm' ¹ .

MS (FAB) m/z 435 (MH) ⁺ .

• φ • ΦΦΦ φ φ · φ φ φ · φ φ φ φ φ φ φ φ φ φ φ φ φ ♦ φ φ φ φ * φ φ

155 · · · · φφφφφφ φφ ·φ φφφ φφφ φφ φφ

Analysis found for C21H14CIF3N2O3.2H2O: C 53.63; H 3.69; N 6.04; Cl 7.54.

Example 122

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethyl)-3-quinolinecarboxamide

A mixture of 4-bromo-2-trifluoromethoxyaniline (10.0 g) and diethylethoxymethylenemalonate (7.9 ml) was heated at 135°C for 2 hours. The reaction mixture was diluted with 90 ml of diphenyl ether and heated at reflux for 30 minutes with removal of ethanol via a Dean-Stark trap. The resulting precipitate was poured into heptane and filtered to give 10.83 g (73%) of 6-bromo-8-trifluoromethoxyquinoline ethyl ester. A mixture of quinoline ethyl ester (5.0 g) and 4-chlorobenzylamine (12.0 ml) was heated at 190°C for 1 hour. The mixture was diluted with toluene (25 ml), allowed to cool to room temperature and filtered. The crude product was recrystallized (acetic acid, water) to give 5.03 g (80%) of the amide. The resulting amide (469 mg), bis(triphenylphosphine)palladium(II) chloride (0.175 g) and 5 ml triethylamine were dissolved in 50 ml DMF. Propargyl alcohol (2.5 ml) was added over 20 h at 90°C. The reaction mixture was allowed to cool to room temperature, poured into 200 ml saturated aqueous ammonium chloride and extracted with ethyl acetate (4 x 50 ml). The organic layer was washed with saturated aqueous brine (10 ml). The aqueous layer was back-extracted with ethyl acetate (20 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol, 100:1, 50/1, 100/3) to give 580 mg (26%) of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 262°C (decomposition).

1 h NMR (DMSO-d ₆ ) δ 12.89; 10,12; 8.64; 8.20; 7.86; 7.42-7.34; 5.42; 4.55; 4.35.

0

0

156

0

0 0 0 0 0 0 0

127.3; 126.3; 123.6; 123.2; 120.6; 107.3; 84.8; 84.1; 55.5; 44.1.

IR (shift) 1936 (w), 1657 (s), 1602, 1574, 1544, 1517 (s), 1279 (s), 1268, 1223 (s),

1212 (s), 1183, 1161 (s), 1048, 1020, 802 cm' ¹ .

MS (ESI-) m/z 449 (MH) ^- .

Analysis found for C21H14ClF3N2O4: C 55.86; H 3.16; N 6.09; Cl 7.96.

Example 123

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-8-(trifluoromethyl)-3-quinolinecarboxamide

OH

Cl

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-(trifluoromethyl)-3-quinolinecarboxamide from Example 121 (397 mg) was dissolved in 87 mL of 1:1 methanol/dichloromethane and palladium on carbon (5%, 80 mg) was added. The mixture was placed under a hydrogen atmosphere (193 kPa) for 1 hour, filtered through celite and concentrated. The crude product was purified by column chromatography (dichloromethane/methanol, 100/1 to 100/3) to give the title compound (43 mg, 10%) as a white solid.

The physical characteristics are as follows:

Melting point 249-250°C.

1 H NMR (DMSO- _d ) δ 12.03; 10.20; 8.67; 8.38; 8.06; 7.42-7.34; 4.57-4.50; 3.42; 2.85;

1.79.

157

9 • 9 99

9 * 9 • · 99

9 9 9

9 9 9

99

99

9 9

9 9

9 9

9 9

99

IR (shift) 1656 (s), 1613, 1579, 1553 (s), 1526 (s), 1461, 1427, 1371, 1345, 1295, 1209, 1187, 1155, 1121 (s) cm' ¹ .

MS (ESI-) for m/z 399 (M-H).

Analysis calculated for C21H18ClF3N2O3: C 57.48; H 4.13; N 6.38; Cl 8.08. Found: C 57.18; H 4.14; N 6.18; Cl 7.93.

Example 124

N-(4-chlorobenzyl)-4-hydroxy-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-3-quinolinecarboxamide

To a suspension of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxainide (2.28 g) from Example 5 in 75 mL of DMF was added sodium hydride (60% dispersion in oil, 600 mg) followed by 2-benzyloxyethanol (1.42 mL). The reaction mixture was heated to 135°C and stirred for 1 hour. The reaction mixture was cooled to room temperature and poured into 200 mL of saturated aqueous ammonium chloride. The aqueous layer was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (dichloromethane/methanol, 98/2). Fractions homogeneous by TLC were combined and concentrated in vacuo to give a yellow solid which was recrystallized from ethanol to give 1.568 g (53%) of the amide intermediate as an off-white solid. To a suspension of this material (1.149 g) in 24 mL of diethylamine was added copper (I) iodide (111 mg) and bis(triphenylphosphine)palladium(II) chloride (69 mg) followed by propargyl alcohol (0.16 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated aqueous

4

4

158

44 «4 »4 · ·

4 44

4 4

4 4 4

4 4

4 4

4 4 4

44 ammonium chloride (50 mL), dried with MgSO ₄ , filtered, and concentrated in vacuo. The resulting brown solid was purified by column chromatography (dichloromethane/methanol, 98/2). Fractions homogeneous by TLC were combined and concentrated in vacuo to give a tan solid, which was recrystallized from ethanol to give 181 mg (18%) of the propargyl compound as a tan crystalline solid. This material (400 mg) was dissolved in 50 mL of 1:1 dichloromethane:methanol and hydrogenated over 10% Pd/C (80 mg) at 241 kPa for 3.5 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by column chromatography (dichloromethane/methanol, 98/2). Fractions homogeneous by TLC were combined and concentrated in vacuo to give a white solid which was recrystallized from ethyl acetate/methanol. This gave 90 mg (27%) of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 250-252°C.

H NMR (300 MHz, DMSO-d _fi ) δ 12.10; 10.49; 8.61; 7.60; 7.42-7.34; 7.24; 4.56; 4.49; 4.24; 3.44; 2.74; 1.77.

C NMR (75 MHz, DMSO- d _g ) δ 176.3; 165.1; 148.5; 142.8; 140.0; 139.2; 131.8; 129.7; 128.8; 128.7; 127.4; 115.6; 114.4; 111.3; 71.3; 60.4; 59.9; 41.9; 34.6; 32.4.

IR (shift) 3234, 1661, 1649, 1613, 1572, 1550, 1532 (s), 1491, 1311, 1301, 1267, 1096, 1076, 1059, 806 cm' ¹ .

MS (ESI-) for m/z 429 (MH) ^- .

Analysis found: C 61.41; H 5.47; N 6.51; Cl 7.53.

Example 125

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1,1-dimethylpropyl)-3-quinolinecarboxamide

159 ·· ·· • 9 9 · 9

9 99

9 9 9 9

9 9 ·

99 9

99 99

9 9 9 9

9 9 9 9

9 9 9 9 9

9 9 9 9

999 99 99

To a suspension of 3-methyl-3-(4-nitrophenyl)butanoic acid (16.2 g) (J. Amer. Chem. Soc., 103, 7768-7773 (1981) and (J. Amer. Chem. Soc., 370-371 (1948)) in 70 ml of THF was added 103 ml of a 1.0 M borane/THF solution. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into water (500 ml). The aqueous layer was saturated with potassium carbonate and extracted with dichloromethane (3 x 500 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. This gave 16.16 g of the alcohol as a yellow solid. The alcohol (9.41 g) was dissolved in 100 ml of THF. Sodium hydride (60% dispersion in oil, 5.40 g) and then benzyl bromide (16 mL) was added. The reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was partitioned between water (400 mL) and dichloromethane (400 mL). The aqueous layer was extracted with dichloromethane (2 x 400 mL). The combined organic layers were washed with brine (400 mL), dried with MgSO4, filtered and concentrated in vacuo. The resulting yellow oil was purified by column chromatography to give the benzyl-protected compound as a yellow oil. This material (8.51 g) was suspended in 200 mL of 1/1 concentrated HCVethanol and _SnCl2.2H2O was added _. The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and water (400 mL) was added. The pH of the aqueous layer was adjusted to pH 12 with ammonium hydroxide and extracted dichloromethane (2 x 400 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting brown oil was purified by column chromatography (dichloromethane, dichloromethane/methanol, 98/2). This gave the amine as a yellow oil (1.306 g; 17%). This material (1.306 g) was combined with diethylethoxymethylenemalonate (0.98 mL) and heated at 120°C for 2 h. The reaction mixture was purified by column chromatography (dichloromethane, dichloromethane/methanol, 98/2). This gave 2.044 g (96%) of the malonate intermediate as a yellow oil. This material (2.007 g) was dissolved in 10 mL of diphenyl ether and heated at reflux for 30 min with the ethanol removed via a Dean-Stark trap. The reaction mixture was cooled to room temperature and heptane and ethyl acetate were added. The reaction mixture was allowed to stand at room temperature overnight. The precipitate formed was filtered off and triturated with ethyl acetate to give 0.572 g (32%) of the ester as an off-white

160 ·· a · * · · » 9 99 99 • · ·9 · ·

9 · · 9 9 9 · 9 9 · ·

99 ·99 999 • 9 9»

9 9 9

9 9 9

9 9 9

9 9 9

99 solid. The ester (0.517 g) and 4-chlorobenzylamine (1.60 mL) were combined and heated at 190°C for 1 hour. The reaction mixture was cooled to room temperature and heptane and ethyl acetate were added. The mixture was allowed to stand in the freezer for 3 days. The resulting precipitate was filtered off and recrystallized from ethyl acetate/heptane to give 0.479 g (75%) of the amide as an off-white solid. This material (402 mg) was dissolved in 60 mL of 25% dichloromethane/methanol and hydrogenated over 10% Pd/C (80 mg) at 241.3 kPa for 45 minutes. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by column chromatography (dichloromethane, dichloromethane/methanol, 99/1; dichloromethane/methanol 98/2). Fractions homogeneous by TLC were combined and concentrated in vacuo to give a white solid which was recrystallized from ethyl acetate/methanol. This gave 163 mg (50%) of the title compound as a white crystalline solid.

The physical characteristics are as follows:

Melting point 184-192°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 12.69; 10.51; 8.75; 8.17; 7.85; 7.67; 7.44-7.25; 4.57; 4.27; 3.19; 1.86; 1.34.

C NMR (75 MHz, DMSO-d ₆ ) δ 176.6; 165.2; 165.1; 146.5; 143.7; 139.9; 139.1;

137.6; 131.9; 131.6; 129.6; 128.9; 128.8; 127.8; 127.3; 126.1; 121.6; 119.4; 111.1; III;0 58.2; 46.7; 42.6; 37.1; 29.5.

IR (shift) 3059, 2966, 2947, 2919, 2885, 2424 (w), 2315 (w), 1985 (w), 1933 (w), 1647 (s), 1616, 1579, 1552 (s), 1527 (s), 1493 cm' ¹ .

HRMS (FAB) found. 399.1480.

Analysis found: C 66.88; H 6.18; N 7.05; Cl 6.63.

Example 126

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide

A mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 5 (1.57 g), propargyl methyl sulfide (0.355 g, 4.12 mmol), copper (II) iodide (0.125 g) and dichlorobis(triphenylphosphine)palladium (Π) (0.462 g) in 38 mL of diethylamine was stirred at room temperature overnight. An additional 92 mg of propargyl methyl sulfide was added and the mixture was stirred for an additional 5 h. The reaction mixture was then concentrated in vacuo and the residue was suspended in 100 mL of water and extracted with three portions of ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. Column chromatography (eluting with 5-10% methanol/dichloromethane) gave the title compound as a solid.

The physical characteristics are as follows:

Melting point 259-261°C.

H NMR (300 MHz, DMSO-dJ δ 13.00; 10.20-10.17; 8.60; 8.00; 7.77; 7.40-7.32; 4.52; 3.63; 2.22 ppm.

ER (displacement) 3195, 3175, 3165, 3154, 3076, 3062, 1645, 1604, 1582, 1549, 1524, 1492, 1306, 1285, 801 cm'\

MS (E1) m/z 414 (M+), 414, 274, 247, 200, 171, 142, 140, 125, 106, ΊΊ.

HRMS (EI) calcd for _{C21H16C1FN2O2S} : _414.0605 . _Found . _414.0608 .

Example 127

N-[(4-chlorophenyl)methyl]-6-(3-ethylthio)-1-propynyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

162 fcfc fcfc • fcfc · • · fcfc • fcfc · • fcfc · fcfc fcfc

• fcfc fcfc fcfc • · · · • fcfc · • fcfc · • fcfc · • fc ··

A mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 5 (1.5 g), propargyl ethyl sulfide (1.04 g, 10.4 mmol), copper (II) iodide (0.125 g) and dichlorobis(triphenylphosphine)palladium (Π) (0.462 g) in diethylamine was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue was suspended in 100 mL of water and extracted with four 50 mL portions of ethyl acetate. The combined organic layers were then dried over MgSO ₄ , filtered and concentrated in vacuo. Column chromatography (elution with 5-10% methanol/dichloromethane) gave the title compound as a solid.

The physical characteristics are as follows:

Melting point 232-233°C.

'h NMR (400 MHz, DMSO-dQ δ 13.10; 10.21-10.18; 8.61; 8.00; 7.78; 7.42-7.35; 4.55; 3.69; 2.73; 1.27 ppm.

ER (shift) 3159, 3081, 3059, 2936, 1653, 1609, 1568, 1546, 1520, 1489, 1304, 1285, 1185, 808, 724 cm' ¹ .

MS (E1) m/z 430 (M + ), 370, 263, 229, 228, 201, 172, 142, 140, 127, 125.

Analysis found: C 61.17; H 4.62; N 6.44.

Example 128

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[(1Z)-3-(methylthio)-1-propenyl]-3-quinolinecarboxamide

163 ·*

HO 9 sec.

F

A mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide from Example 126 (226 mg) and Pd/C (10%, 32 mg) in 20 mL of 3:1 dichloromethane:methanol was placed in a Parr hydrogenator under 262 kPa hydrogen pressure and shaken for 2 hours. An additional 60 mg of Pd/C was added and the resulting mixture was shaken under 344.7 kPa. The reaction mixture was then filtered through a pad of celite and concentrated in vacuo. Crystallization from ethyl acetate gave 48 mg of the title compound as a solid.

The physical characteristics are as follows:

Melting point 201-202°C.

H NMR (300 MHz, DMSO-d ₆ ) δ 12.92; 10.25-10.22; 8.60; 7.99; 7.67; 7.40-7.33; 6.65; 5.92-5.83; 4.53; 3.39; 2.02.

IR (shift) 3196, 3157, 3081, 3059, 2937, 1650, 1610, 1569, 1544, 1521, 1490, 1298, 1287, 807, 799 cm' ¹ .

MS (E1) m/z 416 (M ⁺ ), 418, 416, 372, 371, 370, 278, 276, 251, 249, 228.

Analysis found: C 60.27; H 4.40; N 6.72.

Example 129

N-[(4-chlorophenyl)methyl]-6-[(1Z)-3-(ethylthio)-1-propenyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide

F • you you you

1/1 ······ · · · · you

104 * · · · · · * · · • ti «9 tititi tititi titi

A mixture of N-[(4-chlorophenyl)methyl]-6-[3-(ethylthio)-1-propynyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide from Example 127 (0.15 g) and Pd/C (10%, 0.06 g) in 20 mL of 3:1 dichloromethane:methanol was placed in a Parr hydrogenator under 275.8 kPa hydrogen pressure and shaken for 3 hours. The reaction mixture was then filtered through a pad of celite and concentrated in vacuo. Crystallization from MeOH gave the title compound as a solid.

The physical characteristics are as follows:

Melting point 203-205°C.

H NMR (40 MHz, DMSO-d ₆ ) δ 12.98; 10.29-10.26; 8.62; 8.02; 7.72; 7.42-7.36; 6.66; 5.93-5.87; 4.55; 3.46; 2.54-2.49; 1.06 ppm.

IR (shift) 3159, 3081, 3059, 2936, 1653, 1609, 1568, 1546, 1520, 1489, 1304, 1285, 1185, 808, 724 cm' ¹ .

MS (El) m/z 430 (M+), 370, 263, 229, 228, 201, 172, 142, 140, 127, 125.

Analysis found: C 61.17; H 4.62; N 6.44.

Example 130

N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-propyl]-3-

A mixture of N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide from Example 126 (0.07 g) and Pd/C (10%, 120 mg) in 20 mL of 3:1 dichloromethane:methanol was placed in a Parr hydrogenator under a hydrogen pressure of 310.3 kPa and shaken for 4 hours. An additional 0.08 g of Pd/C was added and the resulting mixture was shaken for 2 hours. The reaction mixture was then filtered through a pad of celite, 120 mg of fresh catalyst was added and the resulting mixture was shaken under

165 • «/ hydrogen for 6 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. Crystallization from ethyl acetate gave 15 mg of the title compound as a solid.

The physical characteristics are as follows:

Melting point 178-180°C.

H NMR (400 MHz, DMSO-d ₆ ) δ 12.90; 10.35-10.32; 8.61; 7.88; 7.66; 7.42-7.35; 4.55; 2.84-2.81; 2.49-2.45; 2.05; 1.91-1.87 ppm.

MS (El) m/z 418 (M+), 278, 251, 203, 147, 142, 140, 125, 91, 77, 61.

Analysis found: C 60.22; H 4.87; N 6.59.

Example 131

-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynyl formate

A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example 53 (0.15 g) in 6 mL of formic acid was heated at 100°C for 6 hours. Once the reaction mixture had cooled to room temperature, it was partitioned between dichloromethane and water. The organic layer was washed with water, saturated NaHCO ₃ and again with water. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. This gave a residue which was crystallized from dichloromethane/hexanes to give the product (70 mg, 44%).

The physical characteristics are as follows:

Melting point 231-233°C.

NMR (300 MHz, DMSO-d _fi ) 13.05; 10.14; 8.62; 8.34; 8.06; 7.84; 7.40; 7.36; 5.08;

4.54.

IR (shift) 1732, 1656, 1651, 1608, 1579, 1574, 1567, 1563, 1557, 1548, 1538, 1519,

1186, 1160, 805 cm* ¹ .

166 » ·· • ··

MS (ESI) for m/z 411.1 (M-H)-. HRMS (FAB) found: 413.0726.

Example 132

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinecarboxamide

Cl

F

A mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide from Example 96 (173.7 mg) and 10% Pd/C (34.7 mg) was dissolved in 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator and monitored with OAMS for complete reduction of acetylene. The reaction was complete in 1 hour and filtered through a pad of celite to remove palladium. The filtrate was condensed. This gave a yellow solid. The crude product was recrystallized from ethyl acetate/hexanes to give 123.8 mg (71%) of the desired product as an off-white solid.

The physical characteristics are as follows:

Melting point 216-218°C.

1 H NMR (300 MHz, DMSO) 12.83; 10.33; 8.60; 7.87; 7.61; 7.38; 4.51; 3.57; 2.77; 1.66; 1.09.

IR (shift) 3197, 3157, 3092, 3062, 2966, 2934, 1649, 1614, 1550, 1525, 1489, 1303, 1288, 806, 724 cm' ¹ .

MS (ESI) 403.0 (M+H) ⁺ , 401.1 (MH)'.

Analysis found: C 62.27; H 5.22; N 6.86.

167 • · 0 0 • » · · • 0 00 0 ·· 0

0 0 0

0 0 0

00 * · 0 0 • ·0 0

0 0 0

0 0 0

0 0 0

Example 133

N-(4-chlorobenzyl)-6-[(E)-2-cyanoethenyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide

A sealed tube was charged with N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (0.76 g) from Example 5, Pd(OAc) ₂ (7.0 mg), P(o-tolyl) 3 (33 mg), acrylonitrile (0.14 mL), NEt ₃ (0.59 mL), and DMF (4 mL). The tube was tightly sealed and heated to 100°C overnight under a heat shield. The reaction mixture was cooled to room temperature and poured into 20 mL of 1N HCl. The resulting solid was filtered, dissolved in hot ethanol, and adsorbed onto silica. Chromatography on a Biotage Flash 40S column (eluent 1.5% methanol in dichloromethane (21), then 2.5% methanol in dichloromethane (11) and 3% methanol in dichloromethane (11)) gave the desired product as a tan solid (0.47 g, 74%).

The physical characteristics are as follows:

Melting point 285-287°C.

’h NMR (300 MHz, DMSO-dQ 13.07; 10.20; 8.62; 8.25; 8.13; 7.85; 7.40; 7.36; 6.63;

4.56.

IR (shift) 3080, 3059, 3016, 1654, 1611, 1577, 1544, 1517, 1492, 1305, 1289, 1196, 1184, 804, 725 cm' ¹ .

MS (ESI) for m/z 382.0 (M+H) ⁺ ; 404.0 (M+Na) ⁺ ; 380.0 (MH)'.

Analysis found: C 60.82; H 3.77; N 10.58.

Example 134

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide

168 · ·· « · · « • · · · ·

• · · · • 9 ··

To a mixture of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 40 (0.494 g) in 12.9 mL of diethylamine was added CuI (10.8 mg) and dichlorobis(triphenylphosphine)palladium(II) (39.7 mg). DMF (2 mL) was added to solubilize the reactants. To this solution was added propargyl alcohol (0.066 mL). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to remove diethylamine. The resulting residue was partitioned between dichloromethane (3 x) and water. The brown solid that precipitated from the dichloromethane layer was filtered and collected to give the pure product as shown by NMR. The organic layers were combined, dried _{over Na2SO4} , and concentrated to a brown residue. The residue was placed under high vacuum to remove residual DMF. The residue was adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane and 3% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed and recrystallized from ethyl acetate/hexanes to give a beige solid. Two crops gave 325.4 mg (79%) of the desired product as a tan solid.

The physical characteristics are as follows:

Melting point 248-250°C.

*H NMR (300 MHz, DMSO) 12.85; 10.31; 8.78; 8.22; 7.78; 7.70; 7.38; 5.39; 4.55;

4.33.

IR (shift) 3161, 3073, 3003, 2960, 2914, 1656, 1614, 1557, 1517, 1487, 1299, 1014, 1006, 826, 805 cm ¹ .

MS (ESI) 367.0 (M+H) + ; 365.1 (MH) ^- .

Analysis found: C 65.23; H 4.24; N 7.60.

• · · ·

99

169 » · ·· » · · · · * · · 9

9 99

9 9 1

9 · 9 <

• · 9 I • · 9 9

Examples 135 and 136

Example 135

N-[(4-Chlorophenyl)methyl]-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide

Example 136

N-[(4-Chlorophenyl)methyl]-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide

A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example 134 (5.48 g) and Pd/C (10%, 0.55 g) in 3:1 dichloromethane:methanol (150 mL) was placed in a Parr hydrogenator under 344.7 kPa hydrogen pressure and shaken for 4 hours. An additional 0.30 g of Pd/C was added and the resulting mixture was shaken for 2 hours. The reaction mixture was then filtered through celite, 0.55 g of fresh catalyst was added and the resulting mixture was shaken under hydrogen for 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. Trituration from trichloromethane/methanol gave a solid which was purified by HPLC chromatography on a 0.46 x 25 cm Chiracel OD-H column eluting with ethanol at 0.3 mL/min to give 383 mg of N-[(4-chlorophenyl)methyl]-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide (cis title compound) and 492 mg of N-[(4-chlorophenyl)methyl]-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide (trans title compound). Crystallization of the cis isomer from ethyl acetate gave 0.29 g of the title • · *ΪΛ · · · · · · · * i / V « » « « · · 99999' «99· · · 9 9 9' «· «· 999 «9« ·» ·· cis compound as a solid. Crystallization of the trans isomer from dichloromethane/methanol gave 0.289 g of the title trans compound as a solid.

The physical characteristics of N-[(4-chlorophenyl)methyl]-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide (Example 135) are as follows:

Melting point 188-191°C.

1 h NMR (400 MHz, DMSO-d ₆ ) δ 12.77; 10.47-10.41; 8.75; 8.05; 7.71-7.65; 7.42-7.36; 6.58; 5.91; 4.98; 4.56; 4.30 ppm.

IR (shift) 3257, 3249, 3210, 3166, 3083, 3063, 3018, 2971, 2941, 1646, 1616, 1552, 1525, 1489, 798 cm' ¹ .

MS (E1) m/z 368 (M+), 228, 201, 154, 142, 140, 127, 125, 115, 89, 77.

HRMS (FAB) _calcd for _C20H17ClN2O3 + _H : 369.1006. Found: 369.0996.

The physical characteristics of N-[(4-chlorophenyl)methyl]-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide (Example 136) are as follows.

Melting point 212-215°C.

HNMR (400 MHz, DMSO-d ₆ ) δ 12.74; 10.45; 8.73; 8.16; 7.92; 7.66; 7.42-7.33; 6.72; 6.54-6.47; 4.92; 4.56; 4.17 ppm.

IR (shift) 3078, 3059, 3053, 3026, 3010, 2971, 2928, 1651, 1615, 1576, 1552, 1525, 1490, 1297, 802 cm' ¹ .

MS (E1) m/z 368 (M+), 228, 201, 198, 142, 140, 127, 125, 89, 77, 73.

HRMS ( _FAB ) calcd for _C20H17C1N2O3 +H: _{369.1006 .} Found: 369.0993.

Example 137

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(Z)-3-hydroxy-1-propenyl]-3-quinolinecarboxamide

171 «· ·· « 9 9 *

9 ·· · · 4

4 4 4

4 4 · 4· 99

9 · 9 9 9 9 4

4 4 ··* • «^ 4 4 4 «

4 4 4 4 4

444 444 4 4 44

To a solution of N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example 53 (0.24 g) in 60 mL of 3:1 dichloromethane:methanol was added 5% Pd/CaCO ₃ using a spatula tip. The reaction mixture was placed under a hydrogen atmosphere from the bottle. After 2 hours, the Pd catalyst was filtered off through celite, fresh catalyst was added to the filtrate, and the reaction mixture was placed under a hydrogen atmosphere from the bottle again. This catalyst regeneration was repeated 8 times and the reaction was monitored by MS until complete. The reaction mixture was then filtered through celite and the filter cake was washed thoroughly with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to give a tan solid which was a 2:1 mixture of the desired product and overreduced material as shown by NMR. This mixture was further purified by HPLC (Cyclobond 2000) to give 72 mg (30%) of the desired product.

The physical characteristics are as follows.

Melting point 234-235°C.

H NMR (300 MHz, DMSO-d ₆ ) 12.94; 10.27; 8.61; 7.86; 7.65; 7.40; 7.36; 6.56; 5.94; 5.0; 4.55; 4.28.

IR (shift) 3078, 3059, 3016, 1654, 1610, 1554, 1521, 1293, 1282, 1190, 1031, 1021,

889, 805, 798 cm ^-1 .

MS (ESI) for m/z 387.0 (M+H) ⁺ ; 409.0 (M+Na) ⁺ ; 385.1 (MH) ^- . HRMS (FAB) found: 387.0917.

Analysis found: C 61.31; H 4.36; N 7.05.

• ·

• · « · ♦ ·

172

Example 138

N-(4-chlorobenzyl)-6-(2-cyanoethyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

To a solution of N-(4-chlorobenzyl)-6-[(E)-2-cyanoethenyl]-8-fluoro-4-hydroxy-3-quinolinecarboxamide) from Example 133 (0.13 g) and Et ₃ N in 50 mL of 3:1 dichloromethane:methanol was added 10% Pd/CO (40 mg). The reaction mixture was placed under a hydrogen atmosphere from a bottle for 4 h. The reaction mixture was filtered through Celite for Pd, the filter cake was washed thoroughly with methanol, and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was recrystallized from ethyl acetate/hexanes to give the desired product as an off-white solid (84 mg, 63%).

The physical characteristics are as follows:

Melting point 273-274°C.

H NMR (300 MHz, DMSO-d ₆ ) 12.89; 10.31; 8.62; 7.99; 7.73; 7.40; 7.36; 4.56; 3.05;

2.90.

IR (shift) 3201, 3062, 2948, 1650, 1613, 1569, 1524, 1490, 1431, 1300, 1285, 1267, 1199, 804, 724 cm' ¹ .

MS (ESI) for m/z 382.1 (M-H)'.

HRMS (FAB) found: 384.0889.

Analysis found: C 60.46; H 4.19; N 10.40.

173 * · · · • · ·· • · · · · · · «·

Μ ·· • · · ♦ • · « · • · · · • · · · • ♦ · «

Example 139

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-oxopropyl)-3-quinolinecarboxamide

To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (0.39 g) from Example 5, CuI (0.043 g) and dichlorobis(triphenylphosphine)palladium (II) (0.013 g) in 10 ml of diethylamine was added propiolaldehyde diethyl acetal (0.13 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, then dried over _MgSO4 , filtered and adsorbed onto silica. Biotage Flash 40S column chromatography (eluent 3% methanol in dichloromethane (1 L)) gave the intermediate, acetylene, as a solid which was further purified by recrystallization from dichloromethane/hexanes (0.17 g, 42%). The product from above (0.099 g) was dissolved in 30 mL of ethyl acetate (0.5 mL of pyridine was added to aid dissolution). 0.030 mL of triethylamine was added followed by 10% Pd/C (30 mg) and the reaction mixture was placed under a hydrogen atmosphere from a bottle. After 3.5 h, the reaction mixture was filtered through celite. The filter cake was rinsed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure to give a residue which was recrystallized from dichloromethane/hexanes. The intermediate, a straight chain acetal, was obtained as a white solid (63 mg, 62%). The product from above (0.11 g) was stirred in 20 mL of a 1:1 solution of 3N HCl:THF. The reaction mixture was allowed to stir overnight. The reaction mixture was partitioned between ethyl acetate and water. The solid which did not dissolve in either layer was filtered off (A). The aqueous layer was then extracted twice with ethyl acetate and once with dichloromethane. The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. This gave a white solid (B). Both solids (A) and (B) were the desired product as shown by NMR. The total yield of product was 56 mg (58%).

The physical characteristics are as follows:

Melting point 242 to 244°C.

^! H NMR (300 MHz, DMSO-d ₆ ) 12.83; 10.31; 9.72; 8.60; 7.89; 7.65; 7.40; 7.36; 4.55;

3.01; 2.87.

174 «« ·· · » «♦ ·· < · · « ·· ♦· · · « * ··· · · 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9· 99 999 999 ·· ·*

IR (shift) 3196, 3158, 3090, 3061, 2940, 1722, 1646, 1614, 1569, 1525, 1489, 1302, 1288, 805, 724 cm' ¹ .

HRMS (FAB) found: 387.0891.

Analysis found: C 61.11; H 4.38; N 6.94.

Example 140

N-(4-chlorobenzyl)-4-hydroxy-7-(4-hydroxybutyl)-3-quinolinecarboxamide

Example 39, 3-butyn-1-ol (0.16 mL), bis(triphenylphosphine)palladium(II) chloride (26.0 mg) and 0.93 mL DMF were heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The orange solid precipitated from the organic layer was filtered and collected to give the pure product as shown by NMR. The aqueous layer was washed with ethyl acetate (3 x). The combined organic layers were dried over Na ₂ SO 4 and condensed. This gave an orange-brown residue. The residue was adsorbed onto silica and chromatographed eluting with 4% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed and recrystallized from ethyl acetate/hexanes to give a white solid. Two crops gave 412 mg (74%) of the desired product as an orange and white solid. A mixture of acetylene from above (300 mg) and 10% Pd/C (60.0 mg) was dissolved in 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator and monitored with OAMS for complete reduction of acetylene. After 1 hour, OAMS indicated that complete reduction of acetylene had not been achieved. The palladium catalyst was replaced with fresh palladium catalyst (60.0 mg) and placed in the Parr hydrogenator for an additional 1 hour. The reaction was complete in a total of 2 hours and filtered through celite to remove palladium. The filtrate was condensed. This gave a yellow solid. The crude product was adsorbed onto silica and chromatographed, eluting with 4% methanol in dichloromethane. Fractions homogeneous by TLC were condensed and recrystallized from ethyl acetate/hexanes to give 186.2 mg (61%) of the desired product as a white solid.

175 • · 99

9 9 9

9 99

9 9 9 9

9 9 · ·· 99 ·· · ·

99

9 9 9

9 9 9 • 9 9 9

9 9 9

99

The physical characteristics are as follows:

Melting point 189 to 191°C.

*H NMR (300 MHz, DMSO) 12.60; 10.47; 8.71; 8.15; 7.46; 7.37; 4.55; 4.36; 3.42; 2.74; 1.67; 1.46.

IR (shift) 3271, 3265, 3246, 3216, 3088, 3067, 3026, 1652, 1609, 1559, 1536, 1491, 1475, 797, 751 cm *.

MS (ESI) 385.1 (M+H) ⁺ ; 383.1 (MH)-.

Analysis found: C 65.27; H 5.68; N 7.23.

Example 141

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide

Methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylate from Example 109 (150 mg) was dissolved in 45 mL of distilled THF. The solution was heated to 35°C to bring the starting material into solution, then cooled to 18°C to add L1AIH4 (27.0 mg). After 2 hours, additional L1AIH4 (27.0 mg) was added as no significant progress was observed towards complete conversion to product. Complete conversion to product was achieved after 6.5 hours. The reaction was quenched by adding 0.1 mL of _H2O and 0.1 mL of 15% NaOH to the reaction mixture. The reaction mixture was filtered to remove the aluminum salt that had precipitated. The filtrate was condensed to give a green residue. The green residue was adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane and 3% methanol in dichloromethane. Fractions homogeneous by TLC were condensed to give 76.8 mg (55%) of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 263 to 265°C.

• Φ ··

176 φφ • * · · • φφφ • φ φ φ • φ φ φ «· ·· φφφ φφφ φ φ φ φ φ · φ φ φ φ φ φ · φ φφ φφ

Η NMR (300 MHz, DMSO) 12.85; 10.32; 8.62; 8.03; 7.63; 7.41; 7.36; 5.49; 4.62;

4.55.

IR (shift) 3082, 2939, 1658, 1614, 1575, 1543, 1514, 1495, 1346, 1301, 1292, 1265, 891,800, 679^ ¹ .

MS (ESI) 361.1 (M+H) ⁺ ; 359.1 (MH) ^- .

Analysis found: C 59.76; H 4.00; N 7.85.

Example 142

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl methanesulfonate

To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.13 g) in 10 mL DMF was added NEt ₃ (0.05 mL) and DMAP on a spatula tip. Methanesulfonyl chloride (0.030 mL) was added dropwise and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3 x). The organic layers were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give a yellow liquid. The residue was dissolved in dichloromethane, adsorbed onto silica and chromatographed on a Biotage Flash 40S column (eluent 1% methanol in dichloromethane (1 L), then 3% methanol in dichloromethane (2 L)) to give the desired product as a white solid which was further purified by recrystallization from dichloromethane/hexanes (0.045 g, 0.097 mmol, 29%).

The physical characteristics are as follows:

Melting point 200 to 201°C.

*H NMR (300 MHz, DMSO-d ₆ ) 12.86; 10.33; 8.61; 7.90; 7.66; 7.40; 7.36; 4.55; 4.21;

3.18; 2.84; 2.03.

• · • ·

9

177 ··

9 9

9 99

9 9

9 9 ·

9 9 · • · 9 9 9

9 9 9

IR (shift) 1651, 1612, 1569, 1550, 1523, 1360, 1350, 1301, 1284, 1170, 980, 936, 838, 807, 725 cm ⁴ .

MS (ESI) for m/z 467.0 (M+H) + ; 488.9 (M+Na) ⁺ ; 465.0 (MH)'.

HRMS (EI) found: 466.0764.

Example 143

N-(4-chlorobenzyl)-8-fluoro-6-(3-fluoro-1-propynyl)-4-hydroxy-3-quinolinecarboxamide

In a three-necked round-bottomed flask connected to a condenser and flask to flask by a distillation apparatus were placed N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (1.2 g) from Example 5, dichlorobis(triphenylphosphine)palladium (Π) (92.6 mg) and CuI (25.1 mg) in 30 mL of diethylamine. The solution was cooled with a dry ice/acetone bath and propargyl fluoride was distilled into the reaction mixture. After the propargyl fluoride was distilled into the reaction mixture, the dry ice/acetone bath was replaced with an ice-water bath to allow the reaction mixture to warm to 0°C and then to room temperature overnight. The reaction mixture was stripped to remove diethylamine. The resulting residue was partitioned between dichloromethane (3 x) and water. The combined organic layers were dried over Na ₂ SO ₄ and condensed to give a residue. The residue was chromatographed eluting with 1% methanol in dichloromethane. Fractions homogeneous by TLC were combined, condensed and recrystallized from ethyl acetate/hexanes to give a sample consisting of starting material and product. The solid was re-exposed to the reaction conditions and purification process twice. Almost complete conversion to product was achieved. The final solid was purified by HPLC to give 151.2 mg (15%) of the desired product as an off-white solid.

The physical characteristics are as follows:

Melting point 278 to 280°C.

1 H NMR (300 MHz, DMSO) 13.07; 10.14; 8.63; 8,10; 7.89; 7.40; 7.36; 5.47; 5.31;

4.55.

178 * ·

IR (shift) 3067, 2923, 1656, 1629, 1607, 1576, 1551, 1520, 1493, 1306, 1294, 1198, 988, 885, 801 cm' ¹ .

MS (ESI) for m/z 387.1 (M+H) + ; 385.1 (M-H).

Analysis found: C 61.54; H 3.26; N 7.18.

Example 144

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide

Example 134 (231.0 mg) and Pd/C (10%, 46.2 mg) were dissolved in 40 mL of 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at 179.3 kPa and monitored with OAMS for complete reduction of acetylene. The reaction was complete in 25 minutes and filtered through celite to remove palladium. The filtrate was condensed. This gave a solid. The solid was suspended in ether, filtered, and collected to give 31.8 mg (14%) of the desired product as a white solid.

The physical characteristics are as follows:

Melting point 192 to 194°C.

NMR (300 MHz, DMSO) 12.68; 10.49; 8.72; 8.05; 7.63; 7.38; 4.55; 4.53; 3.42; 2.76; 1.76.

ER (shift) 3238, 3164, 2934, 2888, 2861, 1660, 1621, 1575, 1539, 1488, 1365, 845, 823, 806, 677 cm' ¹ .

MS (ESI) 371.1 (M+H) ⁺ ; 369.1 (MH).

Analysis found: C 64.69; H 5.16; N 7.55.

• 999 · · ·

99 999 999 9

Example 145

3-(3-( [(4-Chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-bromoacetate

A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.23 g), triethylamine (0.090 mL) and a catalytic amount of DMAP (5-10 mol%) in 20 mL of DMF was cooled to 0°C. Bromoacetyl bromide (0.050 mL) was added in one portion. The reaction mixture was stirred at 0°C for 20 min, then at room temperature for 1.5 h. Once the reaction was complete, it was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (3 x). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a liquid which then crystallized to an off-white solid when dried on a vacuum pump overnight. The solid was triturated in dichloromethane/hexanes, filtered, and dried to give the desired product (0.27 g, 0.53 mmol, 91%).

The physical characteristics are as follows:

Melting point 197 to 199°C (decomposition).

H NMR (300 MHz, DMSO-d _δ ) 12.85; 10.31; 8.60; 7.89; 7.65; 7.40; 7.36; 4.55; 4.16; 4.13; 2.82; 1.97.

IR (displacement) 3060, 2946, 1722, 1650, 1613, 1569, 1544, 1523, 1489, 1300, 1283, 1268,

-and

1198, 805, 724 cm

MS (ESI) for m/z 509.0 (M+H)+; 531.0 (M+Na)+; 507.1 (M-H)-. Analysis found: C 51.77; H 3.77; N 5.49.

Example 146

-(3 - {[(4-chlorobenzyl)amino]carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl)propyl180 ·« ·· » · · · » · ·· » 9 9 « » · · I ··

99 • · · <

• · · I

9 9 9 « • 9 9 I ·· ··

-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate,

N-Boc-valine (0.13 g) was added to a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.15 g), EDC hydrochloride (0.11 g) and DMAP (0.016 g) in 4 ml of pyridine. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was washed once with water and once with brine. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This gave a yellow liquid. The residue was adsorbed onto silica and chromatographed on a Biotage Flash 40S column (eluent 1% methanol in dichloromethane (1 L), then 2% methanol in dichloromethane (2 L)). The product was obtained as a white solid which was further purified by recrystallization from dichloromethane/hexanes (0.17 g, 74%).

The physical characteristics are as follows:

Melting point 164 to 165°C.

H NMR (300 MHz, DMSO-d ₆ ) 12.85; 10.32; 8.61; 7.89; 7.63; 7.39; 7.36; 7.17; 4.55; 4.06; 3.83; 2.8; 1.93; 1.38; 0.88; 0.86.

IR (shift) 2967, 1734, 1714, 1652, 1613, 1569, 1550, 1524, 1492, 1366, 1302, 1286, 1183, 1159, 804 cm' ¹ .

MS (ESI) for m/z 587.9 (M+H) ⁺ , 610.0 (M+Na) ⁺ , 586.0 (MH)-.

Example 147

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2-morpholine acetate

181 • · ti titi • » • titi • ti • ti • ti ti • ti titi • ti ti • ti ti • ti ti • titi ti • ti titi

F

Morpholine (0.03 mL) was added to a solution of 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2-bromoacetate from Example 145 (0.10 g) and triethylamine (0.040 mL) in 5 mL DMF. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was partitioned between dichloromethane (50 mL) and water (25 mL). The organic layer was washed twice with water and once with brine. The aqueous layers were combined and back-extracted with dichloromethane. The organic layers were combined, dried over Na ₂ SO 4 , filtered, and concentrated in vacuo to give a yellow liquid. The liquid was redissolved in dichloromethane and adsorbed onto silica. Chromatography on a Biotage Flash 40S column (eluent 1% methanol in dichloromethane (1 L), then 2% methanol in dichloromethane (2 L) and 5% methanol in dichloromethane (1 L)) gave the desired product as a white solid (0.070 g, 68%).

The physical characteristics are as follows:

Melting point 165 to 167°C.

H NMR (300 MHz, DMSO-d ₆ ) 12.85; 10.44; 8.63; 7.87; 7.60; 7.40; 7.35; 4.55; 4.06; 3.56; 3.20; 2.80; 2.47; 1.95.

MS (ESI) for m/z 516.1 (M+H) ⁺ ; 538.0 (M+Na) ⁺ ; 514.1 (MH)'.

Example 148

-(3 - {[(4-chlorohenzy l)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2-(dimethylamino)acetate φ · »

β* *

»» • ·

Φ « • · • · • Φ ·· ·

9 • *

Φ ·

9·

N,N-Dimethylglycine (0.12 g) was added to a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.23 g), EDC hydrochloride (0.22 g) and DMAP (0.022 g) in 7 ml of pyridine. The reaction mixture was allowed to stir overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic layer was washed once with water and once with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was adsorbed onto silica and chromatographed on a Biotage Flash 40S column (eluent 1.5% methanol in dichloromethane (1 L), then 2.5% methanol in dichloromethane (1 L) and 4% methanol in dichloromethane (1 L)). The product-containing fractions were concentrated in vacuo to give a white solid which was further triturated in EtOH, filtered, washed with hexanes and dried (0.14 g, 51%).

The physical characteristics are as follows:

Melting point 173 to 175°C.

1 h NMR (300 MHz, DMSO-d ₆ ) 12.80; 10.32; 8.61; 7.87; 7.64; 7.40; 7.36; 4.55; 4.06; 3.16; 2.80; 2.24; 1.95.

IR (shift) 3200, 2940, 1727, 1652, 1613, 1572, 1546, 1524, 1489, 1300, 1286, 1268, 1198, 1185, 80.5 cm' ¹ .

MS (ESI) for m/z 474.1 (M+H) ⁺ ; 496.0 (M+Na) + ; 472.1 (MH) ^- .

Analysis found: C 59.93; H 5.32; N 8.57.

Example 149

-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2-amino-3-methylbutanoate

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate from Example 146 (0.13 g) was stirred in a mixture of 4 mL of trifluoroacetic acid and 7 mL of dichloromethane at 0°C for about 1.5 h. Once the reaction was complete, the mixture was partitioned between dichloromethane and saturated NaHCO ₃ . After neutralization with TFA, all undissolved material was filtered off. The organic layer was washed once with water. The combined aqueous layers were back-extracted with dichloromethane and ethyl acetate. The organic layers were combined, dried over Na ₂ SO 4 , filtered and concentrated in vacuo. This gave a white solid. The solid was crystallized from a minimum amount of EtOH (40 mg, 0.082 mmol, 35%).

The physical characteristics are as follows:

Melting point 198 to 199°C.

H NMR (300 MHz, DMSO-d ₆ ) 10.46; 8.63; 7.87; 7.59; 7.40; 7.36; 4.55; 4.07; 3.22; 2.81; 1.92; 0.88; 0.84.

IR (displacement) 3197, 2958, 1729, 1651, 1613, 1569, 1549, 1525, 1489, 1300, 1285, 1198,

1182, 806, 724 cm.

MS (ESI) for m/z 488.0 (M+H) ⁺ ; 486.1 (MH). Analysis found: C 60.40; H 5.54; N 8.33.

Example 150

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynylphenylcarbamate

• · · · • · · · • · · · · • · · · » · · · · *

A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (400 mg) from Example 5, propynyl-N-phenylcarbamate (217.2 mg), dichlorobis(triphenylphosphine)palladium (Π) (15.4 mg), and 0.56 mL of triethylamine in 2.22 mL of anhydrous DMF was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (3 x). The combined organic layers were dried over Na ₂ SO ₄ and condensed. This gave a reddish-brown residue. The residue was chromatographed, eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 121.6 mg (28%) of the title compound as a yellow solid.

The physical characteristics are as follows:

Melting point 227 to 229°C.

1 H NMR (300 MHz, DMSO) 13.07; 10.15; 9.90; 8.63; 8.06; 7.83; 7.48; 7.33; 7.02; 5.07; 4.55.

IR (shift) 3274, 3197, 1713, 1661, 1611, 1577, 1552, 1521, 1498, 1445, 1316, 1234, 1060, 765, 751 cm' ¹ .

MS (ESI) 503.9 (M+H) + ; 502.0 (MH) ^- .

Analysis found: C 64.10; H 3.78; N 8.27.

Example 151

N-[(4-Chlorobenzyl)-4-hydroxy-6-propyl-3-quinolinecarboxamide

N

H

Cl

9 9

99

185

9 99 • 9 9

9 · • · · • · ·

9 9 9

A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example 134 (500 mg) and Pd/C (10%, 100 mg) was dissolved in 80 mL of 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at 206.8 kPa and monitored by mass spectroscopy for complete reduction of acetylene. The old palladium catalyst was replaced with fresh catalyst whenever the reaction mixture was removed from the Parr apparatus. The reaction mixture was filtered through celite to remove palladium. The filtrate was condensed. The crude solid was adsorbed onto silica and chromatographed, eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 16.3 mg (3%) of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 225 to 227°C.

1 H NMR (300 MHz, DMSO) 12.68; 10.49; 8.73; 8.04; 7.63; 7.38; 4.55; 2.71; 1.64;

0.90.

MS (ESI) 355.1 (M+H) ⁺ ; 353.1 (MH)-.

Analysis found: C 67.38; H 5.25; N 7.98.

Example 152

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide

A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 40 (800 mg), 3-butyn-2-ol (0.20 mL), dichlorobis(triphenylphosphine)palladium (II) (32.3 mg), and 1.16 mL of triethylamine in 4.64 mL of anhydrous DMF was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (3 x). The combined organic layers were dried over Na2SO4 and condensed. This gave a reddish-brown residue. The residue was chromatographed eluting with 3% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 139.2 mg (20%) of the title compound as a brown solid.

• · Φ ·

186 • Φ φ φ • · · · φ • · ·· • · Φ · · • · · · • Φ Φ · 9

φ * · ·

Φ · Φ Φ

The physical characteristics are as follows:

Melting point 180 to 182°C.

*H NMR (300 MHz, DMSO) 12.84; 10.31; 8.77; 8.20; 7.72; 7.38; 5.52; 4.62; 4.55;

1.40.

IR (shift) 3243, 3053, 2992, 2977, 2961, 1656, 1614, 1555, 1518, 1486, 1300, 1091, 917, 825, 805 cm'\

MS (ESI) 381.1 (M+H) ⁺ ; 379.1 (MH)-.

Example 153

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(E)-3-oxo-1-butenyl)-3-quinolinecarboxamide

A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxaniide (1.0 g) from Example 5, Pd(OAc) ₂ (9 mg), P(o-tolyl) 3 (45.7 mg), methyl vinyl ketone (0.23 mL), and triethylamine (0.78 mL) in 5.28 mL of anhydrous DMF was heated in a sealed tube at 100°C overnight. The reaction mixture was cooled to room temperature and then cooled in an ice bath. The cooled reaction mixture was poured into 20 mL of ice-cold 1N HCl. A brown solid precipitated and was collected. The crude product was adsorbed onto silica and chromatographed, eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 453.4 mg (52%) of the title compound as a yellow solid.

The physical characteristics are as follows:

Melting point 286 to 289°C.

1 h NMR (300 MHz, DMSO) 13.02; 10.22; 8.62; 8.30; 8.19; 7.79; 7.39; 6.93; 4.57;

2.37.

4 « · ·

4 ·

4 4

187 ·· ·«

IR (shift) 1692, 1651, 1609, 1577, 1514, 1352, 1314, 1306, 1262, 1241, 1195, 1182, 1132, 984, 804 cm ¹ .

MS (ESI) 399.1 (M+H) ⁺ ; 397.1 (MH) ^- .

Analysis found: C 62.84; H 4.12; N 6.93.

Example 154

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxypentyl)-3-quinolinecarboxamide

A mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(5-hydroxy-1-pentynyl)-3-quinolinecarboxamide from Example 107 (230 mg) and Pd/C (10%, 46.0 mg) was dissolved in 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at 262 kPa hydrogen pressure and monitored by mass spectroscopy for complete reduction of acetylene. The reaction was complete in 1.5 hours and filtered through celite to remove palladium. The filtrate was condensed. This gave 129.3 mg (56%) of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 193 to 195°C.

1 h NMR (300 MHz, DMSO) 12.83; 10.32; 8.60; 7.85; 7.62; 7.38; 4.55; 4.32; 3.37; 2.73; 1.62; 1.43; 1.33.

MS (ESI) 417.1 (M+H) ⁺ ; 415.2 (MH)-.

Analysis found: C 63.10; H 5.31; N 6.65.

Example 155

-(3-{[(4-Chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2,6-bis[(tert-butoxycarbonyl)amino]hexanoate

99

188 • * · · • · ·· • · · · · • · · ·

99

· · • · · « · · • ·

To a solution of N-[(4-chlorophenylyl)-methyl]-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (0.21 g), EDC hydrochloride (0.22 g) and dimethylaminopyridine (0.030 g) in 5 ml of pyridine was added di-Boc-lysine (0.38 g) in 4 ml of pyridine. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (3 x). The organic layers were combined, dried over _Na2SO4 and filtered. The filtrate was concentrated in vacuo. This gave a clear residue. The residue was redissolved in dichloromethane/methanol and adsorbed onto silica. Purification by a Biotage Flash 40S silica gel column (eluent 1% methanol in dichloromethane (2 L), 2% methanol in dichloromethane (1 L), 2.5% methanol in dichloromethane (1 L), 3% methanol in dichloromethane (1 L)) gave the desired product as an oil. Dichloromethane and hexanes were added and the solvents were removed to give the product as a white solid (0.26 g, 67%).

The physical characteristics are as follows:

Melting point 125 to 126°C.

¹ H NMR (300 MHz, DMSO-d ₆ ) 12.85; 10.32; 8.60; 7.88; 7.62; 7.39; 7.35; 7.21; 6.75; 4.55; 4.05; 3.90; 2.88; 2.80; 1.93; 1.59; 1.37; 1.35.

IR (shift) 2976, 2933, 1710, 1654, 1613, 1569, 1549, 1524, 1366, 1349, 1300, 1284, 1268, 1250, 1173 cm' ¹ .

HRMS (FAB) found. 717.3081.

Analysis found: C 59.23; H 6.43; N 7.65.

Example 156

-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2,6-diaminohexanoate, trifluoroacetic acid salt

189 ·· ·· * ♦ · ♦ • · · · • · · ·

Trifluoroacetic acid (5 mL) was added to a solution of 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl-2,6-bis[(tert-butoxycarbonyl)amino]hexanoate from Example 155 (0.12 g) in 7 mL of dichloromethane cooled to 0°C. The reaction mixture was stirred for 80 min while allowing to warm to room temperature. The solvents were removed in vacuo. This gave an oil which crystallized from dichloromethane/methanol/hexanes. Once the solvents were removed, the product was obtained as a white solid (0.12 g, 93%).

The physical characteristics are as follows:

Melting point 151 to 154°C.

1 h NMR (300 MHz, DMSO-dQ 10.28; 8.64; 7.91; 7.66; 7.40; 7.36; 4.56; 4.19; 4.03; 2.84; 2.77; 2.00; 1.78; 1.40.

IR (shift) 3052, 3036, 3028, 2998, 1744, 1675, 1646, 1614, 1568, 1551, 1522, 1203, 1135, 799, 723 cm' ¹ .

MS (ES) m/z 517.1 (M+H) ⁺ ; 515.1 (MH)'.

HRMS (FAB) found: 517.2018.

Analysis found: C 47.01; H 4.43; N 7.10.

Example 157

N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxybutyl)-3-quinolinecarboxamide

A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide from Example 152 (106.3 mg) and Pd/C (10%, 21.3 mg) was dissolved in 40 mL of 3:1 dichloromethane:

methanol. The reaction mixture was placed in a Parr hydrogenator at a hydrogen pressure of 234.4 kPa and monitored by mass spectroscopy for complete reduction of acetylene. The old palladium catalyst was replaced with fresh palladium catalyst whenever the reaction mixture was removed from the Parr apparatus. In this case, the reaction mixture was removed from the Parr apparatus twice. The reaction was complete in 130 minutes. The reaction mixture was filtered through celite to remove the palladium. The filtrate was condensed to give a solid. The crude product was adsorbed onto silica and chromatographed, eluting with 4% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 30.0 mg (28%) of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 199-201°C.

1 H NMR (300 MHz, DMSO) 12.68; 10.49; 8.72; 8.05; 7.63; 7.38; 4.56; 4.50; 3.60; 2.77; 1.65; 1.09.

IR (shift) 3236, 3078, 3052, 3015, 2966, 2931, 2858, 1660, 1620, 1574, 1540, 1488, 1365, 822, 806 cm' ¹ .

MS (ESI) 385.2 (M+H) ⁺ ; 383.2 (MH) ^- .

Analysis found: C 65.27; H 5.48; N 7.16.

Example 158

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide

A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example 141 (500 mg), collidine (0.21 mL) and DMAP (28.3 mg) in 25 mL DMF was cooled to 0°C. Methanesulfonyl chloride (0.12 mL) was added dropwise. The reaction mixture was stirred at room temperature and monitored by mass spectroscopy for complete conversion of N-(4chlorobenzyl)-6-(chloromethyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide (approximately 2-3 hours and the reaction mixture turned yellow). Morpholine (0.24 mL) was added. The reaction was monitored by mass spectrometry.

9 9

9 9

191

99 9

9 9 · ·· ·

9 «9 9

9 9 9 9 9

9 9 9 9

99 999 9

99 spectroscopy for complete conversion. The product was precipitated by addition of 25 mL of water. The white solid was filtered and collected to give 459.3 mg (78%) of the title compound.

The physical characteristics are as follows.

Melting point 230 to 232°C (decomposition).

NMR (300 MHz, DMSO) 12.87; 10.30; 8.62; 7.99; 7.65; 7.38; 4.56; 3.59; 2.39. HRMS (FAB) found: 430.1329.

Example 159

-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propylphenylcarbamate

A mixture of 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynylphenylcarbamate from Example 150 (100 mg) and Pd/C (10%, 20 mg) was dissolved in 80 mL of 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at a hydrogen pressure of 172.4 kPa and monitored by mass spectroscopy for complete reduction of acetylene. The old palladium catalyst was replaced with fresh palladium catalyst whenever the reaction mixture was removed from the Parr apparatus. The reaction was complete in 40 minutes. The reaction mixture was filtered through celite to remove the palladium. The filtrate was condensed. The mixture was adsorbed onto silica and chromatographed, eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 11.3 mg (11%) of the title compound as a white solid.

The physical characteristics are as follows.

Melting point 182 to 183°C.

*H NMR (300 MHz, DMSO) 12.86; 10.31; 9.60; 8.61; 7.91; 7.67; 7.39; 7.26; 6.97;

4.55; 4.09; 2.86; 2.00.

HRMS (FAB) found: 508.1450.

192 * · ·· ·· • · · · · · · * • · · · · · · • ····· • · · · · « · ··· ··· ·9 ··

Example 160

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-oxobutyl)-3-quinolinecarboxamide

To a mixture of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(E)-3-oxo-1-butenyl)-3-quinolinecarboxamide from Example 153 (100 mg) and triethylamine (0.35 mL) in 80 mL of 3:1 dichloromethane:methanol was added Pd/C (10%, 20 mg). The reaction mixture was placed in a Parr hydrogenator at a hydrogen pressure of 200 kPa and monitored by mass spectroscopy for complete reduction of the alkene. The old palladium catalyst was replaced with fresh palladium catalyst whenever the reaction mixture was removed from the Parr apparatus. In this case, the reaction mixture was removed from the Parr apparatus once. The reaction was complete in 45 minutes. The reaction mixture was filtered through celite to remove the palladium. The filtrate was condensed. The crude mixture was separated by HPLC. This gives 38.7 mg (8%) of the title compound as a yellow solid.

The physical characteristics are as follows:

Melting point 218 to 222°C.

*H NMR (300 MHz, DMSO) 12.67; 10.48; 8.62; 7.86; 7.56; 7.38; 4.55; 2.88; 2.10.

IR (shift) 2945, 1711, 1638, 1613, 1571, 1524, 1488, 1431, 1350, 1305, 1287, 1183, 805, 799, 724 cm' ¹ .

HRMS (FAB) found: 401.1067.

Example 161

-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl-2,6-bis[(tert-butoxycarbonyl)amino]hexanoate

193

To a solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example 134 (0.22 g), EDC hydrochloride (0.24 g) and dimethylaminopyridine (0.040 g) in 5 ml of pyridine was added di-Boc-lysine (0.44 g) in 5 ml of pyridine. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (3 x). The organic layers were combined, dried over Na ₂ SO 4 , filtered and then adsorbed onto silica. Purification by a Biotage Flash 40S silica gel column (eluent dichloromethane (1 L), 2% methanol in dichloromethane (1 L), 4% methanol in dichloromethane (1 L)) gave the desired product as a clear oil. The oil was dissolved in dichloromethane, hexanes were added and the solvents were removed to give the product as a white solid (0.28 g, 66%).

The physical characteristics are as follows:

Melting point 148 to 150°C.

H NMR (300 MHz, DMSO-dJ 12.86; 10.29; 8.78; 8.24; 7.78; 7.71; 7.40; 7.36; 7.29; 6.75; 5.02; 4.55; 3.97; 2.87; 1.64; 1.38; 1.36; 1.25; 0.86.

MS (ES) m/z 695.1 (M+H) ⁺ ; 717.1 (M+Na) + ; 693.1 (MH). HRMS (FAB) found: 695.2826.

Analysis found: C 61.17; H 6.63; N 7.40.

Example 162

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl-2,6-aminohexanoate, trifluoroacetic acid salt

194

Trifluoroacetic acid (10 mL) was added to a solution of 3-(3-([(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl-2,6-bis[(tert-butoxycarbonyl)amino]hexanoate from Example 161 (0.60 g) in 20 mL of dichloromethane cooled to 0°C. The reaction mixture was stirred for 2 hours. The solvents were removed in vacuo. This gave a pale yellow/orange oil. The oil crystallized by adding methanol and removing the solvent in vacuo. The product was dried on a vacuum pump (0.41 g, 0.57 mmol, 66%).

The physical characteristics are as follows:

Melting point 128 to 130°C (sublimates).

H NMR (300 MHz, DMSO-d ₆ ) 13.06; 10.26; 8.80; 8.57; 8.26; 7.84; 7.79; 7.75; 7.40; 7.36; 5.18; 4.55; 4.16; 2.76; 1.84; 1.57; 1.44.

IR (shift) 3047, 2994, 2984, 2954, 1676, 1649, 1614, 1551, 1516, 1487, 1203, 1135, 837, 799, 722 cm' ¹ .

MS (ES) for m/z 495.1 (M+H)+; 493.1 (M-H). HRMS (FAB) found: 495.1797.

% water (KF): 2.07.

Analysis found: C 46.97; H 4.07; N 7.23.

Example 163

N-[(4-chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethoxy)methyl]-3-quinolinecarboxamide

HIM.

O

Cl

To a suspension of Ag ₂ O (4.50 g) in 37 mL of distilled dichloromethane was added 2-benzyloxyethanol (2.62 mL). The mixture was stirred at room temperature for 15-30 min. 4-nitrobenzyl bromide (3.98 g) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through a pad of celite to remove Ag ₂ O. The filtrate was condensed. This gave a yellow residue. The residue was chromatographed, eluting with 7% ethyl acetate in hexanes. The TLC plates were stained in polymolybdic acid to visualize the product. Fractions homogeneous by TLC were combined and condensed to give 4.46 g (84%) of 1-{[2-(benzyloxy)ethoxy]methyl}-4-nitrobenzene as a yellow residue. To a suspension of 1-{[2-(benzyloxy)ethoxy]methyl}-4-nitrobenzene (~240 mg) in 11 mL of ethyl acetate was added PtO ₂ (48 mg). The reaction mixture was placed in a Parr hydrogenator at 144.8 kPa of hydrogen pressure and monitored by TLC for complete reduction of the nitro group. The reaction was complete in 25 minutes. The reaction mixture was filtered through celite to remove the catalyst. The filtrate was condensed. This gave 4-{[2-(benzyloxy)ethoxy]methyl}aniline as an orange residue contaminated with residual ethyl acetate. In a 3-necked round-bottomed flask fitted with a Dean-Stark trap, a suspension of 4-{[2-(benzyloxy)ethoxy]methyl}aniline (~384 mg) and diethyl ethoxymethylene malonate (0.32 mL) was refluxed for 2 hours. The reaction mixture was cooled to room temperature. 2.5 mL of diphenyl ether was added and the reaction mixture was heated at 230°C for 2 h. The reaction mixture was cooled to room temperature and diluted with a minimum amount of dichloromethane (~1 mL). The slurry was directly applied to a silica column and chromatographed eluting with 100% dichloromethane, then 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed. This gave 123.9 mg (21%) of ethyl 6-{[2-(benzyloxy)ethoxy]methyl}-4-hydroxy-3-quinolinecarboxylate as a cream solid. A mixture of ethyl 6-{[2-(benzyloxy)ethoxy]methyl}-4-hydroxy-3-quinolinecarboxylate (250 mg) and Pd/C (10%, 50 mg) was dissolved in 20 mL of 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at 137.9 kPa hydrogen pressure and monitored by mass spectroscopy for complete conversion to the desired product. The old palladium catalyst was replaced with fresh palladium catalyst whenever the reaction mixture was removed from the Parr apparatus. In this case, the reaction mixture was removed from the Parr apparatus once. The reaction was complete in 18.5 hours. The reaction mixture was filtered through celite to remove palladium. The filtrate was condensed to give a solid. The crude product was adsorbed onto silica and chromatographed, eluting with 5% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 116.2 mg (61%) of ethyl 4-hydroxy-6-[(2hydroxyethoxy)methyl]-3-quinolinecarboxylate as a white solid. Ethyl 4-hydroxy-6[(2-hydroxyethoxy)methyl]-3-quinolinecarboxylate (134.2 mg) and p-chlorobenzylamine (0.84 mL) were heated neat at 180°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2 x). The organic

99 9 9 99 99

9 9 9 9 9 9 9 9 9 9 9

1AZ* 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 999999

9999 9 9 9999

99 999 «99 99 99 The layers were combined, dried over _Na2SO4 and condensed. This gave a yellow residue. The residue was chromatographed eluting with 4% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 133.6 mg (75%) of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 180 to 182°C.

NMR (300 MHz, DMSO) 12.68; 10.47; 8.76; 8.20; 7.71; 7.39; 4.66; 4.63; 4.56;

3.53.

IR (shift) 3248, 3176, 3086, 3053, 2933, 1646, 1610, 1568, 1531, 1490, 1360, 1108, 1090, 816, 797 cm' ¹ .

MS (ES) 387.1 (M+H) ⁺ ; 385.2 (MH)-.

Analysis found: C 61.89; H 4.94; N 7.27.

Example 164

N-(4-chlorobenzyl)-4-hydroxy-6-{[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl}-3-quinolinecarboxamide

To a suspension of Ag2O (5.12 g) in 37 mL of distilled dichloromethane was added 1,3-dibenzyloxy-2-propanol (4.55 mL). The reaction mixture was stirred at room temperature for 15-30 min. 4-Nitrobenzyl bromide (3.98 g) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through a pad of celite to remove Ag2O. The filtrate was condensed. This gave a yellow residue. The residue was diluted with a minimum amount of ethyl acetate (~ 1 mL) and chromatographed, eluting with 7% ethyl acetate in hexanes. Fractions homogeneous by TLC were combined and condensed to give 4.69 g (63%) of 1-({[2-benzyloxy]-1-[(benzyloxy)methyl]ethoxy)methyl)-4-nitrobenzene as a yellow residue. To a suspension of 1-({[2-benzyloxy]-1-[(benzyloxy)methyl]ethoxy}methyl)-4-nitrobenzene (4.69 g) in 15 mL of ethyl acetate was added PtCl (938.3 mg). The reaction mixture was placed in a Parr hydrogenator at 137.9 kPa hydrogen pressure and monitored by TLC for complete reduction of the nitro

197 e« 9« »9 <· • 9 » « * · 9 « 9 9 « 9 • · 9« · 9 9 9 9 9 ····« · 9····« • 999 9 9 9999

99 999 »99 99 99 groups. The reaction is complete in about 1 hour. The reaction mixture is filtered through celite to remove the catalyst. The filtrate is condensed. This gives 4-({[2-benzyloxy]-1-[(benzyloxy) methyl] ethoxy} methyl)aniline as an orange residue contaminated with residual ethyl acetate. In a three-necked round-bottomed flask fitted with a Dean-Stark trap, a suspension of 4-({[2-benzyloxy]-1-[(benzyloxy) methyl] ethoxy} methyl)aniline (2.539 g) and diethyl ethoxymethylene malonate (1.36 ml) is refluxed for 2 hours. The reaction mixture is cooled to room temperature. 10 ml of diphenyl ether is added and the reaction mixture is heated at 250°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with a minimum amount of dichloromethane (~1-2 mL). The slurry was directly applied to a silica column and chromatographed eluting with 100% dichloromethane, then 1% methanol in dichloromethane and 3% methanol in dichloromethane. The product was eluted with 3% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed. This gave 913.6 mg (27%) of ethyl 6-({2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy}methyl)-4hydroxy-3-quinolinecarboxylate as a tan solid. A mixture of ethyl 6-((2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy}methyl)-4-hydroxy-3-quinolinecarboxylate (261.3 mg) and Pd/C (10%, 52.3 mg) was dissolved in 20 mL of 3:1 dichloromethane:methanol. The reaction mixture was placed in a Parr hydrogenator at a hydrogen pressure of 172.4 kPa and monitored by mass spectroscopy for complete conversion to the desired product. The old palladium catalyst was replaced with fresh palladium catalyst whenever the reaction mixture was removed from the Parr apparatus. The reaction was complete in 40 hours. The reaction mixture was filtered through celite to remove the palladium. The filtrate was condensed to give a solid. The crude product was adsorbed onto silica and chromatographed eluting with 10% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 55.3 mg (33%) of ethyl 4-hydroxy-6-{[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl}-3-quinolinecarboxylate as a white solid. Ethyl 4-hydroxy-6-{[2hydroxy-1-(hydroxymethyl)ethoxy]methyl}-3-quinolinecarboxylate (53.1 mg) and 4-chlorobenzylamine (0.30 mL) were heated neat at 180°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water (2 x). The organic layers were combined, dried over Na ₂ SO ₄ and condensed. This gave a yellow residue. The residue was chromatographed eluting with 5% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 18.8 mg (27%) of the title compound as a cream solid.

The physical characteristics are as follows:

Melting point 182 to 184°C.

1 H NMR (300 MHz, DMSO) 12.72; 10.47; 8.75; 8.21; 7.78; 7.67; 7.38; 4.75; 4.58;

3.48.

198

MS (ES) 417.2 (M+H) ⁺ ; 415.2 (MH)'.

Example 165

Methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinecarboxylate

A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 40 (30.0 g), triethylamine (19.1 mL), methanol (110.6 mL), Pd(OAc) ₂ (431 mg), α1,3-bis(diphenylphosphine)propane (791.9 mg) in 375 mL of anhydrous DMF was stirred at room temperature until all dissolved. CO gas was slowly bubbled into the reaction mixture over 2 days and the reaction mixture was maintained at 70°C. The reaction mixture was cooled to room temperature. The product was precipitated by adding 160 mL of 1N HCl to the reaction mixture. An orange solid precipitated and was collected. The solid was triturated with ethyl acetate, filtered and washed with dichloromethane to give 23.8 mg (93%) of the title compound as an off-white solid.

The physical characteristics are as follows:

Melting point 290 to 292°C.

HNMR (300 MHz, DMSO) 12.96; 10.26; 8.83; 8.25; 7.80; 7.39; 4.57; 3.9.

IR (shift) 3222, 1724, 1646, 1619, 1574, 1544, 1512, 1489, 1404, 1359, 1288, 1277, 1242, 1210, 738 cm' ¹ .

HRMS (FAB) found: 371.0794.

Analysis found: C 61.54; H 3.88; N 7.51.

199 • · · • ·· • » » • · * · · · • · · · ♦ ♦ · · • · # * € » • ·<#··· • · · · · ·

Example 166

N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide

In a 1 L, flame-dried, three-necked round-bottom flask, methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinecarboxylate from Example 165 (3.0 g) was dissolved in 700 mL of distilled THF. The suspension was heated to 67°C to solubilize the starting material. The reaction mixture was allowed to cool to room temperature and then cooled to 10°C in an ice bath. Lithium aluminum hydride (552.2 mg) was added in one portion. The reaction mixture was stirred at 25°C and monitored by mass spectroscopy for complete conversion to the desired product. The reaction was quenched by adding 2 mL of water, 2 mL of 15% NaOH, and 2 mL of water to the reaction mixture. The reaction mixture was filtered to remove the aluminum salt that had precipitated. The filtrate was condensed. This gives a yellow-green residue. The residue is adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane (11), 3% methanol in dichloromethane (2 L), 4% methanol in dichloromethane (2 L), 5% methanol in dichloromethane (1 L), 6% methanol in dichloromethane (1 L) and 7% methanol in dichloromethane (2 L). The desired product elutes with 4-7% methanol in dichloromethane. Fractions homogeneous by TLC are condensed to give 1.85 g (67%) of the title compound as yellow crystals.

The physical characteristics are as follows:

Melting point 288 to 289°C.

1 H NMR (300 MHz, DMSO) 12.71; 10.48; 8.74; 8.21; 7.71; 7.66; 7.39; 5.38; 4.63;

4.56.

MS (ES) 343.3 (M+H) + ; 341.3 (MH) ^- .

Example 167

6-chloro-N-[(4-chlorophenyl)methyl]-4-hydroxy-8-methyl-3-quinolinecarboxamide

200

A mixture of 3.0 g of ethyl-(6-chloro-4-hydroxy-8-methyl-3-quinolincarboxylate) (Maybridge Chemical Co.) and 7.0 ml of 4-chlorobenzylamine was stirred at 190°C for 3 hours. The mixture was cooled to 25°C and diluted with 35 ml of hexanes. The precipitate was collected by filtration and washed with 10 ml of hexanes. It was dried in a stream of air and then recrystallized from 30 ml of glacial acetic acid. It was dried at 2.67 kPa and 100°C for 20 hours. The yield was 1.6 g (40%).

The physical characteristics are as follows:

Melting point > 230°C.

*H NMR (400 MHz, DMSO-d ₆ ) 12.0; 10.3; 8.61; 8.01; 7.68; 7.41-7.32; 4.52; 2.53.

MS (ES-) w/z 359 (M-H)-.

HRMS (FAB) calcd for C18H14Cl2N2O2+H1: 361.0510. Found: 361.0502. Analysis found: C 59.98, H 3.96, N 7.69.

Preparation 14

5,6,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid

OH

A mixture of 1.5 g of ethyl [5,6,8-trifluoro-4-hydroxy-3-quinolinecarboxylate] and 1.3 g of sodium hydroxide in 70 ml of a 2:1 (v/v) mixture of distilled water and ethanol is refluxed for 4.5 hours. The condenser is then removed and the volume of the solution is reduced to one third by distillation. To the resulting mixture is slowly and carefully added 5 ml of glacial acetic acid. The mixture is allowed to cool ti ti » « ti ti

201 • ti ·· ·· ti· titi · ·· ti • ti ti · ti * • · ti · ti ti ti • ti titititi • titi «· ti · · titi at 25°C and stored at this temperature for 18 hours. The solid precipitate was collected by filtration and washed with distilled water. It was dried in a stream of air and then dried at 2.67 kPa and 120°C for 3 days. This procedure gave the title compound as 1.1 g (88%) of a white solid.

The physical characteristics are as follows:

Melting point > 230°C.

H NMR (400 MHz, DMSO-d ₆ ) 8.56; 8.32-8.21.

MS (ES-) m/z 242 (M-H).

HRMS (FAB) calcd for C10H4F3N1O3 + Hf 244.0222. Found: 244.0228. Analysis found: C 49.23; H 1.75; N 5.67.

Example 168

N-[(4-chlorophenyl)methyl]-5,6,8-trifluoro-4-hydroxy-3-quinolinecarboxamide

A mixture of 0.50 g of 5,6,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid from Preparation 14 and 0.366 g of carbonyldiimidazole in 8 ml of anhydrous dimethylacetamide was stirred at 65°C for 2.5 hours. The mixture was cooled to 25°C and 1 drop of distilled water was added to destroy excess CDI. After 5 minutes of stirring, 0.30 ml of 4-chlorobenzylamine was added. After 3 hours of stirring at 25°C, the mixture was diluted with 10 ml of distilled water. The precipitate was collected by filtration and washed with three successive 10 ml portions of distilled water. The solid was dried in a stream of air and then at 2.67 kPa and 120°C for 3 days. The yield was 0.49 g (65%) of a white solid.

The physical characteristics are as follows:

Melting point > 230°C.

H NMR (400 MHz, DMSO-d ₆ ) 12.9; 10.96; 8.55; 8.13; 7.40-7.30; 4.51.

202 ·

* · « « • 9 9 · • · · · • 9 · · • · ·

MS (ES-) m/z 365 (M-H)-.

HRMS (FAB) calcd for C17H10CIF3N2O2 + H1: 367.0461. Found: 367.0461.

Preparation 15

6,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid

OH

This compound is prepared according to a procedure similar to that described in Preparation 14. The physical characteristics are as follows:

Melting point > 230°C.

H NMR (400 MHz, DMSO-d ₆ ) 8.90; 8.15-8.06; 7.80-7.72.

MS (ES) m z 224 (mM-H+).

HRMS (FAB) calcd for _C10H5F2N03 + _H : _226.0316 . Found: 226.0320. Analysis found: C 52.16; H 2.26; N 5.93.

203 « » fc ♦ · · · · fc · fc • · fcfc · « · · · · fc···· fc ······ • fcfcfc · · fcfcfcfc »· 9· fcfcfc ··· ·· fcfc

Example 169

N-[(4-chlorophenyl)methyl]-6,7-difluoro-4-hydroxy-3-quinolinecarboxamide

A mixture of 0.5 g of 6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid from Preparation 15 and 0.435 g of carbonyldiimidazole in 8 ml of anhydrous dimethylacetamide was stirred at 65 °C for 4 hours. The reaction mixture was cooled to 25 °C and 2 drops of distilled water were added. After another 10 minutes, 0.34 ml of 4-chlorobenzylamine was added. The mixture was stirred at 25 °C for 26 hours and then diluted with 10 ml of distilled water. After another 30 minutes of standing, the precipitate was collected by filtration and washed with three 10 ml portions of distilled water. The solid was dried in a stream of air and then at 2.67 kPa and 120 °C for 3 days. The yield was 0.51 g (70%) of a white solid.

The physical characteristics are as follows:

Melting point over 220°C.

HRMS (EI) calcd for C17HHCIF2N2O2 + H: 349.0555; found 349.0551.

Analysis _found for _{C17H11ClF2N2O2.0.3H2O} : C _64.13 ; H 4.51; _N 8.29.

Preparation 16

Ethyl-(6-(cyanosulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate)

A mixture of 48 g of 4-(cyanosulfanyl)-2-fluoroaniline and 57.7 g of diethylethoxymethylenemalonate was stirred at 130°C. After 1.5 hours, the mixture was diluted with a 1:1 mixture of cyclohexane and toluene. The mixture was cooled to 0°C and the precipitate was collected by filtration. It was washed with two 75 ml portions of a 1:1 mixture of cyclohexane and

204 • 9

9··

9 9 9 • 9 9 ·

99 • 9 *

9 ·

9 9

9 9 • 9 99 toluene, dried in a stream of air and then dissolved in 400 ml of diphenyl ether. The mixture was refluxed for 1 hour and then cooled to 25°C. It was diluted with 1 l of 1:1 toluene/cyclohexane and the precipitate was collected by filtration. The solid was dried in a stream of air to give 20 g of the title compound.

The physical characteristics are as follows:

MS (ESI+) for Ci ₃ Hi ₀ FN ₂ O ₃ S m/z 293 (M + H) ⁺

Analysis found: C 53.08; H 3.19; N 9.48.

Preparation 17

Ethyl-(8-fluoro-4-hydroxy-6-sulfanyl-3-quinolinecarboxylate)

CH ₃

A mixture of 20 g of ethyl (6-(cyanosulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate from Preparation 16, 125 ml of DMF and 12.6 g of dithiothreitol was stirred at 25°C for 5 hours. It was poured into 1 L of oxygen-free water and the precipitate was collected by filtration, washed with two 200 ml portions of distilled water and then dried under a stream of nitrogen. The title compound was obtained as 10.5 g of a white solid.

The physical characteristics are as follows.

MS (ESI+) for C ₁₂ Hi ₀ FNO ₃ S m/z 268 (M + H) ⁺ .

Analysis found for _{C12H10FN03SO.3H2O :} C _52.62 ; H 3.55; N 5.23.

Preparation 18

Ethyl-(8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxylate)

F

205 • · · · • · ·♦ • * · » • · « · ·· ··

9 9

9 « • · ·

9 9

A suspension of 2.0 g of ethyl (8-fluoro-4-hydroxy-6-sulfanyl-3-quinolinecarboxylate) from Preparation 17 in 15 ml of DMF was deoxygenated under a stream of nitrogen. The mixture was treated with 0.56 ml of methyl iodide and then with 1.24 ml of triethylamine. After 20 minutes, the mixture was poured into 15 ml of distilled water. The precipitate was collected by filtration, washed three times with water and then with methanol. It was dried in a stream of air. This gave 1.38 g of the title compound as a white powder.

The physical characteristics are as follows:

MS (ESI+) for Ci ₃ H ₁₃ FNO ₃ S m/z 282 (M + H) ⁺ .

Analysis found for Ci ₃ Hi ₃ FNO ₃ S.0.1 H2O: C 55.08, H 4.27, N 5.04.

Preparation 19

Ethyl-(8-fluoro-4-hydroxy-6-((2-hydroxyethylsulfanyl-3-quinolinecarboxylate)

This compound was prepared using a procedure similar to that described in Preparation 17, except that a small excess of 2-chloroethanol was used instead of methyl iodide and the reaction was allowed to proceed for 14 hours before the mixture was poured into water.

The physical characteristics are as follows:

MS (ESI+) for C44H15FNO4S m/z 312 (M + H) ⁺ .

Analysis found for C14H14FNO4S.0.3H2O. C 53.38, H 4.51, N 4.62.

Preparation 20

Ethyl-(8-fluoro-4-hydroxy-6-{[(2-methoxyethoxy)methyl]sulfanyl}-3-quinolinecarboxylate) (31565-JT-146.)

This compound was prepared using a procedure similar to that described in Preparation 18, except that a small excess of methoxyethoxymethyl chloride was used instead of methyl iodide and the reaction was allowed to proceed for 0.5 hour before the mixture was poured into water.

The physical characteristics are as follows:

206 ·· · * ♦ ♦ · 9 • 9 9 9 9 9 • · ·«···· • · · · · 9

999 99 9 9 9 99

MS (ESI+) for C ₁₆ H ₁₉ FNO ₅ S m/z 356 (M + H) ⁺

Preparation 21

Ethyl-(8-fluoro-4-hydroxy-6-{[(2-(4-morpholinyl)ethyl]sulfanyl}-3-quinolinecarboxylate (31565-JT-143.)

This compound was prepared using a procedure similar to that described in Preparation 18, except that a small excess of N-(2-chloroethyl)morpholine was used instead of methyl iodide and the reaction was allowed to proceed for 18 hours before the mixture was poured into water. The product was dissolved in ethyl acetate to remove insoluble impurities. Evaporation of the filtrate gave the title compound.

The physical characteristics are as follows:

MS (ESI+) for C ₁₈ H ₂₂ FN ₂ O ₄ S m/z 381 (M + H) ⁺ .

Preparation 22

Ethyl-(8-fluoro-4-hydroxy-6-((2-aminoethyl)sulfanyl)-3-quinolinecarboxylate) hydrobromide (31565-JT-140.)

A suspension of 1.0 g of ethyl (8-fluoro-4-hydroxy-6-sulfanyl-3-quinolinecarboxylate) from Preparation 17 in 10 ml of DMF was deoxygenated under a stream of nitrogen. The mixture was reacted with 0.85 g of 2-bromoethylamine hydrobromide and then with 0.57 ml of triethylamine. After 15 minutes, the reaction mixture was diluted with 20 ml of ethyl acetate. The solid was washed with two 30 ml portions of distilled water and finally with two 30 ml portions of ethyl acetate. The solid was dried in a stream of air. This gave 0.42 g of the title compound as a white powder.

The physical characteristics are as follows:

MS (ESI+) for C ₁₄ H ₁₆ FN ₂ O 3 S m/z 311 (M + H) ⁺

Analysis found for C14H15FN2O3S.HBr.H2O: C 42.30, H 4.37, N 6.80.

Example 170

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide

207

9 9 9 9

9 99

9 9 9 9

9 9 9

99 9

9 9

9 · • « ·

9 9 9

99

This compound was prepared from ethyl (8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxylate) (Preparation 18) using a procedure similar to that described in Example 167.

The physical characteristics are as follows.

MS (ESI+) for C ₁₈ H ₁₅ C 1FN ₂ O 2 S m/z 377 (M + H) ⁺ .

Analysis found for C13H15ClFN2O2S.H2O. C 54.49, H 3.91, N 7.04.

Example 171

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(2-hydroxyethyl)sulfanyl]-3-quinolinecarboxamide

This compound was prepared from ethyl (8-fluoro-4-hydroxy-6-((2-hydroxyethylsulfanyl-3-quinolinecarboxylate) (Preparation 19) using a procedure similar to that described in Example 167.

The physical characteristics are as follows:

MS (ESI+) for C ₁₉ H ₁₇ C 1FN 2 _{O 3} S m/z 407 (M + H) ⁺ .

Analysis _found for _{C19H16ClFN2O3S.0.3H2O} : C 55.08, H _3.92 , N 6.78.

Example 172

6-[(2-Aminoethyl)sulfanyl]-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide hydrobromide

208

0 0 • 0 · 0 • · · · • 0 00 • · · 0 0 « «0 0 »♦ 00

0· 00

0 0 ·

0 0 ·

0 0 0 0

0 0 0

00

This compound was prepared from ethyl (8-fluoro-4-hydroxy-6-((2-aminoethyl)sulfanyl)-3-quinolinecarboxylate) hydrobromide (Preparation 22) using a procedure similar to that described in Example 167. The product was isolated by distilling off excess 4-chlorobenzylamine at 133.3 Pa and trituration of the crude product with methanol.

The physical characteristics are as follows:

MS (ESI+) for C ₁₉ H ₁₈ C 1FN 3 O ₂ S m/z 406 (M + H) ⁺ .

Analysis found for C19H17ClFN3O2S.1.5 HBr: C 42.95, H 3.36, N 7.84.

Example 173

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-methoxyethoxy)methyl]sulfanyl}-3-quinolinecarboxamide

This compound was prepared from ethyl (8-fluoro-4-hydroxy-6-{[(2-methoxyethoxy)methyl] sulfanyl}-3-quinolinecarboxylate) (Preparation 20) using a procedure similar to that described in Example 167. The product was isolated by adding 2 mL of toluene, 4 mL of hexanes, and 10 mL of 20% aqueous acetic acid to the cooled reaction mixture. The product was collected by filtration and purified by recrystallization from ethyl acetate/diethyl ether followed by a second crystallization from 2% acetic acid and methanol. The physical characteristics are as follows:

209 • · · · · · · • 9

MS (ESI+) for C21H21ClFN2O4S m/z 451 (M + H) ⁺ .

Example 174

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-2-(4-morpholinyl)ethyl]sulfanyl}-3-quinoline-carboxamide

This compound was prepared from ethyl (8-fluoro-4-hydroxy-6-{[(2-(4-morpholinyl)ethyl]sulfanyl}-3-quinolinecarboxylate) (Preparation 21) using a procedure similar to that described in Example 167. The product was precipitated from the cooled reaction mixture by addition of ethyl acetate and diethyl ether, collected by filtration, and washed with a small amount of ether. The physical characteristics are as follows:

Analysis found: C 57.52, H 4.89, N 8.69.

Example 175

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfinyl)-3-quinolinecarboxamide

A suspension of 150 mg of N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide from Example 170 and 0.75 ml of DMF in 15 ml of chloroform was treated with 79 mg of m-chloroperbenzoic acid. After stirring for 10 minutes, the mixture was treated with 10 ml of concentrated aqueous sodium bisulfite solution. After stirring for a further 5 minutes, the phases were separated and the organic layer was washed with 15 ml of saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO 4 ) and the solvent was evaporated under reduced pressure. The remaining solid was washed with a small volume of diethyl ether and dried. This gave 95 mg of a white solid.

The physical characteristics are as follows:

210

MS (ESI+) for C18H32ClF32O3S m/z 393 (M + H) ⁺ .

Analysis found for C18H14ClFN2O3S*0.6H2O: C 53.34, H 3.61, N 6.96.

Example 176

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfonyl)-3-quinolinecarboxamide

A mixture of 200 mg of N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide from Example 170, 20 ml of chloroform, 0.75 ml of DMF and 200 mg of m-chloroperbenzoic acid was stirred at 25°C. After 18 hours, a further 140 mg of m-chloroperbenzoic acid was added and the mixture was refluxed for 7 hours. The cooled mixture was filtered and the solid was washed with two 5 ml portions of diethyl ether. It was recrystallized from 3 ml of acetic acid. This gave the title compound as 62 mg of a white powder.

The physical characteristics are as follows:

MS (ESI+) for Ci ₈ H ₁₅ C 1FN ₂ O 4 S m/z 409 (M + H) ⁺ .

Analysis found for C18H14ClFN2O4S.0.4H2O: C 51.97, H 3.59, N 6.73.

Example 177

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-hydroxyethyl)sulfmyl]-3-quinolinecarboxamide

211 • 9 99 ·· 99 99 • 9*9 99 99 9999

99 9 9 «999

99999 9 999999

9999 9 9 9999

99 999 999 99 99

This compound was prepared from N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(hydroxyethyl)sulfanyl]-3-quinolinecarboxamide (Example 171) and an equimolar amount of m-chloroperbenzoic acid according to a procedure similar to that described in Example 175. The physical characteristics are as follows:

MS (ESI+) for C19H17CIFN2O4S m/z 423 (M + H) ⁺ .

Example 178

N-[(4-chlorobenzyl)-4-hydroxy-6-(2-thienyl)-3-quinolinecarboxamide

A deoxygenated mixture of 0.75 g of N-[(4-chlorophenyl)methyl]-4-hydroxy-6-iodo-3-quinolinecarboxamide from Example 40, 0.75 g of 2-(tributylstannyl)thiophene, 60 mg of dichlorobis(triphenylphosphine)palladium (II), 7.5 mL of dioxane, and 2.5 mL of DMPU was stirred at 100°C for 2 hours. The cooled mixture was diluted with 20 mL of hexanes and 60 mL of distilled water. The mixture was stirred for 5 minutes and then filtered. The solid was washed with two 50 mL portions of 1 distilled water and then two 25 mL portions of methyl t-butyl ether. It was then dissolved in 20 mL of refluxing acetic acid, treated with 2 g of activated carbon, and filtered through celite. The volume of the filtrate is reduced to 10 ml and the hot solution is diluted with 10 ml of distilled water. After cooling, 0.3 g of the title compound precipitates and is collected by filtration.

The physical characteristics are as follows:

MS (ESI+) for C2iH ₁₅ ClN ₂ O ₂ SNa m/z 417 (M + Na)+

Analysis found for C ₂ iHi5ClN ₂ O ₂ S.0.2 H ₂ O: C 63.25, H 3.66, N 7.02.

Example 179

N-[(4-chlorobenzyl)-4-hydroxy-6-(2-hydroxyethoxy)-3-quinolinecarboxamide ·· ··

212 • · ·· ·· • · 9 9 · 9 · 9

9 9 9 9 9

9 9 9 9 9 9

99 9

Sodium hydroxide (6.22 g) was added to a solution of 4-nitrophenol (21.45 g) in 300 ml of DMF and stirred until the reagents were completely dissolved. After adding 10.66 ml of 2-chloroethanol dropwise, the reaction mixture was heated at 100°C for 72 hours. After filtration and evaporation of the solvent under reduced pressure, the resulting oil was recrystallized from methanol/water and filtered. This gave 21.62 g (92%) of 2-(4-nitrophenoxy)-1-ethanol. A mixture of 2-(4-nitrophenoxy)-1-ethanol (6.17 g) and palladium on carbon (0.08 g) in 120 ml of ethanol was hydrogenated in a 500 ml Parr hydrogenator at 227.5 kPa for 18 hours. Vacuum filtration through celite and evaporation under reduced pressure gave 5.00 (96%) of 2-(4-aminophenoxy)-1-ethanol. This material was combined with diethyl-(ethoxymethylenemalonate) (7 mL) and heated at 130°C for 1 hour in a round-bottomed flask under a gentle stream of nitrogen. The mixture was cooled, diluted with 20 mL of a 1:1 mixture of cyclohexane and toluene, and filtered. This gave 9.1 g (86%) of diethyl 2-{(4-(2-hydroxyethoxy)]anilino]methylenemalonate. A solution of the resulting malonate (8.59 g) in 15 ml of acetic acid and 4 ml of acetic anhydride was heated at 60°C for 36 hours. The reaction mixture was diluted with water, extracted with ethyl acetate and washed with saturated sodium bicarbonate. Evaporation under reduced pressure left a brown oil which was recrystallized from 1:1 methanol/water to give 7.09 g (73%) of diethyl 1-(2-((4-(2-(acetyloxy)ethoxy)anilino]methylene)malonate. Diethyl (2-((4-(2-(acetyloxy)ethoxy)]anilino]methylene)malonate) (6.55 g) was dissolved in 75 ml of diphenyl ether and refluxed at 190°C 1 hour. When the mixture was cooled and diluted with toluene, the resulting precipitate was collected by filtration, washed with toluene, and recrystallized from aqueous acetic acid. This gave 0.50 g (9%) of ethyl (6-[2-(acetyloxy)ethoxy)-4-hydroxy-3-quinolinecarboxylate. The resulting carboxylate ester (0.49 g) and 4-chlorobenzylamine (0.90 mL) were heated at 175°C for 2 hours. When the mixture was cooled and diluted with xylenes, the dark solid was filtered off. Recrystallization from acetic acid and water gave 150 mg (26%) of the title compound as a beige solid.

The physical characteristics are as follows:

Melting point 246 to 248°C.

¹ H NMR (DMSO-d ₆ ) 12.7, 10.65, 8.7, 7.6, 7.4, 4.89, 4.5, 4.1, 3.8.

213 ·· η» • · · « • · ·· • · · · · • · · · ♦ » ·· ·· ·· • · · « · · • · · • · · · ··

HRMS (FAB) for (M+H) ⁺ calcd 373.0955. Found: 373.0946.

Preparation 23

4-(aminomethyl)benzonitrile

A mixture of 4-(bromomethyl)benzonitrile (7.1 g) and sodium azide (2.6 g) in 40 mL DMF was stirred for 19 h. The reaction mixture was diluted with water and extracted with ether (2 x 50 mL). The organic layers were combined, washed with water (50 mL) and brine (50 mL) and dried over MgSO4. Filtration and evaporation of the solvent left 5.5 g of 4-(azidomethyl)benzonitrile as a clear oil.

Triphenylphosphine (7.67 g) was added to a solution of 4-(azidomethyl)benzonitrile (4.19 g) in 30 ml of THF. Water (10 ml) was added and the solution was stirred for 16 h. The reaction mixture was diluted with ether (50 ml) and extracted with HCl (3N, 3 x 25 ml) and water (1 x 25 ml). The aqueous phases were combined and washed with ether (50 ml). Sodium hydroxide was added until the pH was about 12. After extraction with ether (2 x 50 ml), the solution was dried with MgSO 4 . The solvent was evaporated under reduced pressure. The resulting crude mixture was then purified by flask-to-flask distillation at 150°C and 133.3 Pa. This gave 1.74 g (50%) of the title compound as a clear colorless oil.

The physical characteristics are as follows:

Melting point 148 to 150°C.

1 h NMR (DMSO-d 2 ) 7.7, 7.5, 3.8 1.9.

Example 180

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylcarbonyl)-3-quinolinecarboxamide

To a pressure tube containing N-[(4-chlorophenyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (0.23 g) from Example 5, Pd(OAc) ₂ (12 mg) and 1,3bis(diphenylphosphino)propane (20 mg) was added DMF (5 mL), triethylamine (0.14 mL) and morpholine (0.13 mL). The reaction mixture was placed under an atmosphere of carbon monoxide gas, tightly sealed and heated to 60°C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous phosphate

214 • » ·· • · · * • · «« • · · · · · • · · » »· ·· «· · «»· A buffer (Ο.ΙΜ, pH = 4). The organic layer was washed with aqueous phosphate buffer (0.1M, pH = 10), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica eluting with 2% methanol in dichloromethane to 8% methanol in dichloromethane. The fractions containing the product were evaporated to give 0.13 g of the title compound as a tan solid.

The physical characteristics are as follows:

*H NMR (300 MHz, CDCl ₃ ) 10.3, 8.7, 8.2, 7.6, 7.3, 4.6, 3.7.

MS (ESI) m/z 444 (M+H+).

Example 181

N -(4-Chlorobenzyl)-8-fluoro-4-hydroxy-N6-(2-hydroxyethyl)-3,6-quinolinecarboxamide

To a pressure tube containing N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (0.46 g) from Example 5 was added DMF (4 ml) under a carbon monoxide atmosphere. The suspension was treated with triethylamine (0.28 ml), Pd(OAc)2 (23 mg) and 1,3-bis(diphenylphosphine)propane (41 mg). The mixture was treated with ethanolamine (0.24 ml), then tightly sealed and heated to 90°C overnight with vigorous stirring. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adsorbed onto silica and chromatographed eluting with 3% methanol in dichloromethane to 9% methanol in dichloromethane. The product-containing fractions were evaporated to give 0.23 g of the title compound as a tan solid.

The physical characteristics are as follows:

*H NMR (300 MHz, DMSO-d ₆ ) 10.2, 8.8, 8.6, 8.1, 7.4, 4.5, 3.5, 3.3.

MS (ES) m/z 418 (M+H+).

215

Example 182

N ⁵ -(4-chlorobenzyl)-8-fluoro-4-hydroxy-N ,N ⁶ -dimethyl-3,6-quinolinecarboxamide

Using the procedure of Example 181, the following compound was also isolated.

The physical characteristics are as follows:

1 h NMR (300 MHz, DMSO-d ₆ ) 13.0, 10.2, 8.7, 8.0, 7.8, 7.4, 4.5, 3.0.

MS (ES) m/z 402 (M+H+).

Example 183

N ⁵ -[(4-chlorobenzyl)-8-fluoro-4-hydroxy-N 5 -(4-hydroxyphenethyl)-3,6-quinolinecarboxamide

F

Using the procedure of Example 181, the following compound was also isolated from the reaction with tyramine.

The physical characteristics are as follows:

1 H NMR (300 MHz, DMSO-d ₆ ) 13.0, 10.2, 9.1, 8.7, 8.6, 8.0, 7.4, 7.0, 6.6, 4.5, 3.4, 2.7.

MS (ES) m/z 494 (M+H+).

216

4 ·* »· '·· · · · 9 9 ·

9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9

9 99 9 9 9 »9

Example 184

TSÚ-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3,6-quinolinecarboxamide

also isolates the following compound from the reaction

Using the procedure of Example 181, with hydroxylamine in DMF.

The physical characteristics are as follows:

NMR (300 MHz, DMSO-d ₆ ) 13.0, 10.2, 8.6, 8.3, 8.1, 7.6, 7.4, 4.5.

MS (ES) m/z 374 (M+H+).

Preparation 24

- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid

To a flask containing N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (0.23 g) from Example 5 and potassium carbonate (2.24 g) was added N-methylpiperidine (9 ml) under an atmosphere of carbon monoxide gas. The reaction mixture was treated with Pd(OAc) ₂ (0.5 g) and then water (1 ml) and heated at 90°C overnight. The reaction mixture was cooled to room temperature and added to stirred diethyl ether (150 ml). The precipitate formed was collected by filtration. The precipitate was dissolved in a small amount of methanol:acetonitrile, decanted and reprecipitated from diethyl ether. The solid formed was collected by filtration and dried in vacuo to give 0.40 g of the title compound as a light green solid.

217 tititi· · · · · « · • ti ti « ·· · · · · · ♦ • ti titi · · ···· • •••ti · ·····<

···· ti · «tititi • ti C « «titi « ti · titi »·

The physical characteristics are as follows:

1 H NMR (300 MHz, DMSO-d ₆ ) 10.1, 8.6, 8.0, 7.4, 4.5.

MS (ES) m/z 375 (M+H+).

Example 185

N ³ , N 3 -bis(4-chlorobenzyl)-8-fluoro-4-hydroxy-3,6-quinolinecarboxamide

To a flask containing 3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid from Preparation 24 (0.11 g) and THF (3 mL) was added thionyl chloride (0.075 mL). The reaction mixture was stirred overnight, then treated with one drop of DMF. After 4 h, the reaction mixture was concentrated under reduced pressure. The residue was triturated with toluene (2 x) and dried in vacuo to give a light yellow solid. The solid was dissolved in pyridine (3 mL), treated with p-chlorobenzylamine (0.04 mL), and a small amount of 4-dimethylaminopyridine was added. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The residue was triturated with toluene (3 x) and dried in vacuo. The residue was adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane to 6% methanol in dichloromethane. The fraction containing the product was evaporated to give a solid which was recrystallized from methanol/toluene to give 0.04 g of the title compound. The physical characteristics are as follows:

^] 1 H NMR (300 MHz, DMSO-d ₆ ) 13.0, 10.2, 9.4, 8.6, 8.1, 7.4, 4.6, 4.5.

HRMS (EI) found: 497.0708.

Preparation of 25 tert.butyl 3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarbamate • « · · » 9 9

218 «· 99

To a flask containing 3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxylic acid from Preparation 24 (1.33 g) and tert-butanol (20 mL) under argon gas was added triethylamine (2.0 mL) and diphenylphosphoryl azide (1.0 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was adsorbed onto silica and chromatographed, eluting with 2% methanol in dichloromethane to 6% methanol in dichloromethane. The product-containing fractions were evaporated to give 0.93 g of the title compound as a tan solid.

The physical characteristics are as follows:

^! H NMR (300 MHz, DMSO-d ₆ ) 12.8, 10.3, 9.9, 8.5, 8.1, 7.8, 7.4, 4.5, 1.48.

MS (ESI) m/z 446 (M+H+).

Example 186

6-amino-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

To a flask containing tert-butyl-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarbamate) from Preparation 25 (0.06 g) and dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was triturated with toluene (3 x) and dried in vacuo. The residue was adsorbed onto silica and chromatographed on silica, eluting with 2% methanol in dichloromethane to 6% methanol in dichloromethane. The product-containing fractions were evaporated to give 0.04 g of the title compound as a tan solid.

219 · · 0 · · 0 » · ·

0 0 0 0 · ······

9·· · ⁴ 9 9 9 9

9 9 9 99 9 99 9 9 9 9 99

The physical characteristics are as follows:

1 h NMR (300 MHz, DMSO-d ₆ ) 12.5, 10.5, 8.4, 7.4, 7.1, 7.0, 4.5.

MS (FAB) m/z 346 (M+H+).

HRMS (FAB) found: 346.0761 (M+H+)

Example 187

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(4-methoxyphenyl)sulfonyl]amino}-3-quinolinecarboxamide

To a flask containing 6-amino-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide from Example 186 (0.06 g) and pyridine (1.5 mL) was added 4-methoxyphenylsulfonyl chloride (0.04 g). The reaction mixture was stirred for 2 hours, then concentrated under reduced pressure. The residue was triturated with toluene (2 x) and dried in vacuo. The residue was adsorbed onto silica and chromatographed eluting with 2% methanol in dichloromethane to 6% methanol in dichloromethane. The product-containing fractions were evaporated to give 0.04 g of the title compound as a white solid.

The physical characteristics are as follows:

*H NMR (300 MHz, DMSO-d ₆ ) 12.9, 10.7, 10.2, 8.5, 7.7, 7.4, 7.0, 4.5, 3.8.

MS (ESI) m/z 516 (M+H+).

Analysis found: C 55.99, H 3.81, N 7.85.

Example 188

N-[(4-chlorobenzyl)-4-hydroxy-6-(2-hydroxyethyl)amino]-3-quinolinecarboxamide • · • 4

220 • · 4 · • · · • 4 4 4

4 »4

To a pressure tube containing 1-fluoro-4-nitrobenzene (10.6 mL) and absolute ethanol (20 mL) was added ethanolamine (7.2 mL) under argon gas. The reaction was sealed and heated to 90°C. After 1 hour, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dried in vacuo. The solid was crystallized from 95% ethanol to give 4.1 g of 2-(4-nitroanilino)-1-ethanol as yellow crystals.

To a flask containing 2-(4-nitroanilino)-1-ethanol (0.91 g) in dichloromethane (20 ml) was added triethylamine (1.8 ml), acetyl chloride (0.85 ml) and 4-dimethylaminopyridine (0.06 g) at 0°C. The reaction mixture was allowed to warm to room temperature over 3 hours. The reaction mixture was diluted with ether, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica eluting with 50% ethyl acetate in heptane. The product-containing fractions were evaporated to give 0.61 g of 2-(4-nitroanilino)ethyl acetate as a yellow solid.

To a Parr hydrogenator containing 2-(4-nitroanilino)ethyl acetate (0.61 g) and ethyl acetate (10 mL) was added 10% palladium on carbon (0.05 g). The reaction mixture was shaken for 2 hours under 344.7 kPa of hydrogen gas. The reaction mixture was filtered through celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was treated with diethyl ethoxymethylenemalonate (0.60 mL) and heated to 135°C under a stream of argon gas. After 1 hour, the reaction mixture was cooled to room temperature, adsorbed onto silica, and chromatographed with 60% to 80% ethyl acetate in heptane. The product-containing fraction was evaporated to give 0.45 g of diethyl 2-{(4-(2-(acetyloxy)ethyl)anilino]amino)methylene)malonate as a yellow solid.

To a flask containing 2-{(4-(2-(acetyloxy)ethyl)anilino]amino)methylene) malonate (0.18 g) was added diphenyl ether (2 ml). The reaction mixture was heated from room temperature to 250°C over 30 minutes under a stream of argon gas. The reaction mixture was cooled to room temperature and filtered. The collected precipitate was washed repeatedly with methanol:dichloromethane and the filtrate was adsorbed onto silica and chromatographed on silica eluting with 5% to 50% methanol in dichloromethane. The product-containing fractions were evaporated to give 0.04 g of ethyl (6-(2-(acetyloxy)ethyl)amino]-4-hydroxy-3-quinolinecarboxylate).

221 • · · * *

I · ·· • · · · · • · · · «» *· ·

To a flask containing 6-{(2-(acetyloxy)ethyl)amino]-4-hydroxy-3-quinolinecarboxylate (0.04 g) was added p-chlorobenzylamine (0.5 mL). The reaction was sealed and heated to 160°C overnight. The reaction mixture was cooled to room temperature, adsorbed onto silica, and chromatographed eluting with 3% to 10% methanol in dichloromethane. The fractions containing the product were evaporated to give 0.02 g of the title compound as a yellow solid.

The physical characteristics are as follows:

Melting point 189 to 192°C.

1 h NMR (300 MHz, DMSO-d ₆ ) 10.7, 8.5, 7.4, 7.3, 7.2, 6.1, 4.7, 4.5, 3.6, 3.2.

HRMS (FAB) found: 372.1122 (M+H+)

Example 189

N-[(4-chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]-4-hydroxy-3-quinolinecarboxamide

Following a procedure similar to that described in Example 188, the title compound was prepared from 2-(ethylamino)-1-ethanol.

The physical characteristics are as follows:

Melting point 189 to 192°C.

1 h NMR (300 MHz, DMSO-d ₆ ) 12.5, 10.6, 8.5, 7.5, 7.4, 7.3, 4.7 4.5, 3.5, 3.4, 1.1.

HRMS (FAB) found: 400.1429 (M+H ⁺ ).

Example 190

N-[(4-chlorobenzyl)-4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl)-3-quinolinecarboxamide • · · 9

222 • · · · »· • · · · · • · · · « · • » · · » • · ·» · ··· • · · · t*

To a Parr hydrogenator containing 2-(4-nitroanilino)-1-ethanol (1.1 g) and ethanol (25 mL) was added 10% palladium on carbon (0.06 g). The reaction mixture was shaken for 1 hour under 344.7 kPa of hydrogen gas. The reaction mixture was filtered through celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was treated with diethyl ethoxymethylenemalonate (1.4 mL) and heated to 140°C under a stream of argon gas. After 1 hour, the reaction mixture was cooled to room temperature, adsorbed onto silica, and chromatographed, eluting with 60% to 100% ethyl acetate in heptane. The product-containing fraction was evaporated to give 1.08 g of diethyl 1-(2-((4-((2-hydroxyethyl)amino)anilino]methylene)malonate) as a yellow solid.

To a flask containing 2-{(4-(2-hydroxyethyl)amino)anilino]methylene)malonate (0.48 g) and 1,1'-carbonyldiimidazole (0.32 g) was added toluene (15 ml). The reaction mixture was heated to reflux overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and phosphate buffer (0.1 M, pH = 7). The phases were separated and the aqueous layer was extracted with two additional portions of ethyl acetate. The combined organic layers were washed with buffer, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate. The product-containing fractions were evaporated to give 0.46 g of diethyl 2-((4-(2oxo-1,3-oxazolidin-3-yl)anilino)ethylenemalonate as a cream solid.

To a flask containing diethyl (2-[(4-(2-oxo-1,3-oxazolidin-3-yl)anilino)ethylenemalonate) (0.46 g) was added diphenyl ether (6 mL). The reaction mixture was heated from room temperature to 235°C over 2 hours under a stream of argon gas. After 1 hour at 235°C, the reaction mixture was cooled to room temperature, diluted with diethyl ether, and filtered. The collected precipitate was washed repeatedly with diethyl ether and dried in vacuo to give 0.17 g of ethyl (4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl-3-quinolinecarboxylate) as a tan solid.

To a flask containing ethyl (4-hydroxy-6-(2-oxo-1,3-oxazolidin-3-yl)-3-quinolinecarboxylate) (0.17 g) was added p-chlorobenzylamine (1.0 mL). The reaction was tightly sealed and heated to 185°C for 1 hour. The reaction mixture was cooled to room temperature and triturated with diethyl ether. The residue was adsorbed onto silica and chromatographed on silica eluting with 3% to 12% methanol.

223

• · • * and • • and and · • 9 • • • · • • and • • and • • • · · • • • 9 • • • w • 49 « · -· 9 • and · · • a * a and • and • 4 • and •

in dichloromethane. The fractions containing the product were evaporated to give 0.12 g of the title compound as an off-white solid.

The physical characteristics are as follows:

¹ H NMR (300 MHz, DMSO-d ₆ ) 12.8, 10.4, 8.7, 8.2, 7.7, 7.4, 4.5, 4.4, 4.1.

HRMS (FAB) found: 398.0915 (M+H+)

Example 191

N-[(4-chlorobenzyl)-4-hydroxy-6-(4-morpholine 1methyl)-3-quinolinecarboxamide

A solution of N-[(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example 166 (1.0 mg), collidine (0.45 mL) and DMAP (60.0 mg) in 50 mL of anhydrous DMF was cooled to 0°C. Methanesulfonyl chloride (0.25 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 2 to 3 hours. Morpholine (0.34 mL) was added. The product was precipitated by addition of water. The crude product was adsorbed onto silica and chromatographed, eluting with 2% methanol in dichloromethane. Fractions homogeneous by TLC were combined and condensed to give 352 mg of the title compound as a white solid.

The physical characteristics are as follows:

Melting point 219 to 220°C.

1 H NMR (300 MHz, DMSO) 12.73, 10.46, 8.75, 8.16, 7.70, 7.38, 4.56, 3.58, 2.37.

IR (shift) 2977, 2929, 2901, 1660, 1620, 1536, 1490, 1362, 1295, 1113, 865, 844, 828, 799, 675 cm ^- l.

HRMS (FAB) calcd for C22H22CIN3O3+H: 412.1428. Found: 412.1440.

Analysis found: C 61.01, H 5.34, N 10.03.

Preparation 26

3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinesulfonyl chloride

224 ·· · · ·· fcfc • fcfc · · · fcfc · · · fc • · ·· fc · fcfcfc· • · · · * · fcfcfcfcfcfc • fcfcfc · fc ···· fcfc fcfc fcfcfc fcfcfc fcfc fcfc

To a solution of 22.2 g of 2-fluoroaniline in 100 ml of acetic acid was added 32 g of ammonium thiocyanate. The flask was immersed in an ice bath and the mixture was stirred while 32 g of bromine in 40 ml of acetic acid was added dropwise. After the addition, which took about 40 minutes, the mixture was stirred for 1 hour at 0°C and then poured into 700 ml of rapidly stirring ice water. Concentrated aqueous ammonia was added to neutralize the HBr and the pH of the mixture was adjusted to 4.0. The resulting yellow solid was filtered, washed well with water and dried in vacuo to give 27.72 g of 4-amino-3-fluorobenzenesulfenyl cyanide as a pale yellow solid.

A stirred biphasic mixture of 3.36 g of 4-amino-3-fluorobenzenesulfonyl cyanide and 4.8 g of 50% aqueous NaOH in 40 mL of THF and 20 mL of water was refluxed under argon for 1 h. Benzyl chloride (2.8 mL) was added and refluxing was continued for 16 h. The mixture was then partitioned between water and ether and the organic phase was washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to give 5.8 g of a yellow oil. Flash chromatography on silica eluting with 20% ethyl acetate in heptane gave 3.59 g of 4-(benzylsulfanyl)-2-fluoroaniline as a yellow oil.

A pure mixture of 3.58 g of the compound 4-(benzylsulfanyl)-2-fluoroaniline and 3.48 g of diethylethoxymethylenemalonate was heated to 135°C under a slow stream of argon for 1 hour, then diluted with diphenyl ether (25 mL), heated to 260°C while maintaining a stream of argon and held at this temperature for 90 minutes. The mixture was then cooled to about 100°C and added to 300 mL of stirred heptane. The precipitate was filtered, washed with heptane and dried in vacuo to give 4.01 g of ethyl-(6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate) as a yellow solid.

A solution of 3.93 g of ethyl (6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate) in 8.8 g of 4-chlorobenzylamine was heated at 165°C under argon for 16 h, then cooled and diluted with chloroform and methanol. The solution was washed with dilute HCl, dried (Na ₂ SO 4 ), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica eluting with 3% to 6% methanol in dichloromethane gave 4.73 g (95%) of 4-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide as a yellow solid.

♦ Φ • ·

225 • Φ · • ·· φ Φ · φ Φ ♦ φ φ φ Φ φφ φφ » ♦ « * φ · φ · φ φ · · · • φ φ · φ» φφ

Chlorine gas is bubbled into 12.0 mL of glacial acetic acid placed in a weighed scintillation tube cooled in an ice bath. After about 3 to 5 minutes, 1.32 g of Cl2 is absorbed, giving an approximate concentration of 1.8 M. A solution of 330 mg of 4-(benzylsulfanyl)-8-fluoro-4hydroxy-3-quinolinecarboxamide in 10 mL of acetic acid and 1.0 mL of water is prepared by heating and this solution is cooled to 0°C for addition of the freshly prepared chlorine solution. The solution is stirred for 15 minutes at 0°C, then added to 50 mL of ether. The volatiles are removed under reduced pressure to give 337 mg of sulfonyl chloride as a yellow solid of sufficient purity for amine sulfonylation. The physical characteristics are as follows:

MS EC 426.8.

Example 192

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(1-naphthylmethyl)amino])sulfonyl}-3-quinolinecarboxamide

To a stirred solution of 0.073 mL of 1-naphthylmethylamine in 0.5 mL of pyridine was added 100 mg of the sulfonyl chloride of formula K-5 (where X=F). The solution was stirred for 1-18 hours, then 3.5 mL of rapidly stirred 2 M aqueous HCl was added dropwise. The solid was filtered, washed well with water, and dried in vacuo. Flash chromatography on silica eluting with 2-5% methanol in dichloromethane gave 57 mg of the title compound as a white solid.

The physical characteristics are as follows:

1 h NMR (CDCl 3 +CF 3 CO 2 D) δ 4.70, 4.74, 7.2-7.6, 7.82, 8.29, 9.35.

TLC Rf 0.29 (4% methanol in dichloromethane).

HRMS (EI) 549.0922.

226

Example 193

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-(1-H-indol-3-yl)ethyl]amino}sulfonyl)-3quinolinecarboxamide

The title compound was prepared analogously to the method described in Example 192.

The physical characteristics are as follows:

1 h NMR (CDCl ₃ +CD ₃ OD) δ 2.86, 3.31, 4.64, 6.82, 6.91, 7.11, 7.24, 7.31, 7.56, 8.37, 8.71, 10.36.

TLC Rf 0.28 (4% methanol in dichloromethane).

HRMS (EI) 552.1033.

Example 194

N-(4-Chlorobenzyl 1)-8-fluoro-6-{[(2-furylmethylamino]sulfonyl}-4-hydroxy-3-quinolinecarboxamide

The title compound was prepared analogously to the method described in Example 192. The physical characteristics are as follows:

1 H NMR (CDCl ₃ +CD ₃ OD) δ 4.20, 4.64, 6.11, 7.13, 7.31, 7.79, 8.57, 8.75.

TLC Rf 0.36 (6% methanol in dichloromethane).

HRMS (EI) 489.0556.

Analysis found: C 53.76, H 3.43, N 8.54.

227

Φ· ·· • · φ • φ φφ • 9 9

4 4

99 •4 94 44 · 4 4 4 9 9 » ♦ * · « Φ · • Φ Φ · · Φ Φ

Φ Φ · Φ φ Φ

ΦΦ ΦΦΦΦ 94 44

Example 195

6-{[bis(2-hydroxyethyl)amino]sulfonyl}-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide

The title compound was prepared analogously to the method described in Example 192.

The physical characteristics are as follows:

1 h NMR (CDCl ₃ +CD ₃ OD) δ 5.05, 3.8, 4.64, 7.32, 7.88, 8.61, 8.78.

TLC Rf 0.29 (8% methanol in dichloromethane).

HRMS (FAB) 498.0914.

Example 196

Ethyl-(2- {[(3- {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)sulfonyl]amino}acetate)

The title compound was prepared analogously to the method described in Example 192. The physical characteristics are as follows:

1 H NMR (CDCl ₃ +CD ₃ OD) δ 1.18, 3.84, 4.06, 4.64, 7.31, 7.91, 8.65, 8.76.

TLC Rf 0.47 (8% methanol in dichloromethane).

228

99 * •999 99 9 • 9 99 9

9 9 9 9 9

9 9 9 9

99 999 9 • · 4

4 9

9 9

9 9

99

HRMS (FAB) 496.0763.

Example 197

N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-hydroxyethyl)-amino]sulfonyl}-3-quinolinecarboxa

The title compound was prepared analogously to the method described in Example 192. The physical characteristics are as follows:

1 h NMR (CDCl 3 +CD 3 OD) δ 3.07, 3.61, 4.64, 7.32, 7.91, 8.64, 8.78.

TLC Rf 0.24 (8% methanol in dichloromethane).

HRMS (EI) 453.0558.

Analysis found: C 50.20, H 3.90, N 9.00.

Example 198

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(4-morpholinylsulfonyl}-3-quinolinecarboxamide

The title compound was prepared analogously to the method described in Example 192. The physical characteristics are as follows:

1H NMR (CDCl 3 +CD 3 OD) δ 3.06, 3.76, 4.64, 7.31, 7.77, 8.56, 8.78.

TLC Rf 0.50 (6% methanol in dichloromethane).

9· 99 • 9 9 · 99

9 9

9 · • 9 99

229 • *

9 9 • 9 9

9 9 • 9 9

HRMS (EI) 479.0713.

Example 199

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinylmethyl)amino]sulfonyl}-3-quinolinecarboxamide

The title compound was prepared analogously to the method described in Example 192.

The physical characteristics are as follows:

1 H NMR (CDCl ₃ +CD ₃ OD) δ 4.27, 4.64, 7.18, 7.3, 7.36, 7.67, 7.87, 8.39, 8.62, 9.62, 9.74. TLC Rf 0.39 (8% methanol in dichloromethane).

HRMS (EI) 500.0709.

Analysis found: C 54.38, H 3.64, N 10.89.

Example 200

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(2-pyridinyl)amino]sulfonyl}-3-quinolinecarboxamide

The title compound was prepared analogously to the method described in Example 192. The physical characteristics are as follows:

1 HNMR (CDCl ₃ +CD ₃ OD) δ 4.62, 6.81, 7.3-7.4, 7.72, 7.97, 8.75.

·· ·· » · 9 • · · • · · ·* ·♦ »· • ·

230 • · ··

TLC Rf 0.41 (8% methanol in dichloromethane).

HRMS (EI) 486.0563.

Preparation 27

Parallel synthesis of sulfonamides

The amines (0.2 mmol each) were dissolved or suspended in 0.25 mL aliquots of pyridine in screw-capped tubes. Liquid amines were dispensed by volume, solids by weight. In cases where amine salts were used, 0.034 mL of diisopropylethylamine per equivalent of acid was added. 22±1 mg (0.050 mmol) of sulfonyl chloride of formula K-5 was introduced into each tube and the tubes were placed on a shaker for 4 to 20 hours. At the end of the reaction time, each solution was added dropwise to 1.6 mL of rapidly stirred 2M HCl. The mixtures were rapidly stirred for 5 minutes, then filtered through Burdick and Jackson fritted plastic wells. The solids were washed well with water and dried under vacuum to give the paired products. The following examples were prepared according to this procedure.

Example

201

202

203

204

205

206

207

208

Compound name (formula K-6)

N-(4-chlorobenzyl)-6- {[(cyclohexylmethyl)-amino]sulfone 1}-8-fluoro-4-hydroxy-3-quinolinecarboxamide N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-( 1 -methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-3-quinolinecarboxamide N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[2-( 1-pyrrolidinyl)ethyl]amino}sulfonyl)-3-quinolinecarboxamide N-(4-chlorobenzyl)-8-fluoro-6-{[(2-phorylmethyl)amino]sulfonyl}-4-hydroxy-3-quinolinecarboxamide

N-(4-chlorobenzyl)-6-( {[3-(cyclohexylamino)propyl]amino}sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(1-naphthylmethyl)amino]sulfonyl}-3-quinolinecarboxamide

N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-( 1 -H-imidazol-4-yl)ethylamino}sulfonyl)-3-quinolinecarboxamide N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(thienylmethyl)aminoisosulfone 1}-3-quinolinecarboxamide

MS(ES-)

504

519

505

488

547

548

502

492

504

209

231 • ·

210 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-(1-H-indol-3-yl)ethyl]amino}sulfone 1)-3-quinolinecarboxamide 551 211 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-(5-methoxy-1-H-indole- -3-yl)ethyl]amino}sulfones 1)-3-quinolinecarboxamide 581 212 6- {[(1,3-benzodioxol-5-ylmethyl)amino} sulfones 1}-N- [(4- -chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 542 213 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[2-morpholineethyl]amino}sulfonyl)-3-quinolinecarboxamide 521 214 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[3-morpholinepropyl]- amino}sulfones 1)-3-quinolinecarboxamide 535 215 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[({2-[(5-nitro- 2-pyridines 1)amino]ethyl}amino)sulfones 1]-3-quinolinecarboxamide 181 216 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-pyridinylmethyl)- aminoisosulfonyl}-3-quinolinecarboxamide 499 217 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-(2-pyridinyl) ethyl]amino}sulfonyl)-3-quinolinecarboxamide 513 218 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(3-pyridinylmethyl)amino]sulfonyl}-3-quinolinecarboxamide 499 219 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(4-pyridinylmethyl)- amino]sulfonyl}-3-quinolinecarboxamide 499 220 N-(4-chlorobenzyl)-6-{[(4-chlorobenzyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide 532 221 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(4-methoxybenzyl)amino]sulfonyl}-3-quinolinecarboxamide 528 222 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(neopentylamino)sulfone 1]-3-quinolinecarboxamide 478 223 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6- {[(2-hydroxypropyl)aminoisosulfonyl}-3-quinolinecarboxamide 466 224 N-(4-chlorobenzyl)-6-{[(2,3-dihydroxypropyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide 482 225 N-(4-chlorobenzyl)-6-{[(2,2-diphenylethyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide 588 226 1 l-{[(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)sulfonyl]amino}undecanoic acid 409

• · · · • · ·· • 9 · · • · · ·

232

227 6-({[2-acetylamino)ethyl]amino)sulfonyl)-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 493 228 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[2-(2-hydroxyethoxy)- ethyl]amino}sulfonyl)-3-quinolinecarboxamide 496 229 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2-hydroxyethyl)- amino]sulfonyl}-3-quinolinecarboxamide 452 230 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(phenethylamino)- sulfonyl]-3-quinolinecarboxamide 512 231 N-(4-chlorobenzyl)-6-{[(4-chlorophenethyl)amino]sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 546 232 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(2-propynylamino)- sulfonyl]-3-quinolinecarboxamide 446 233 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(isopentylamino)sulfonyl]-3-quinolinecarboxamide 478 234 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(3-phenylpropyl)amino]sulfonyl}-3-quinolinecarboxamide 526 235 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(pentylamino)sulfonyl]-3-quinolinecarboxamide 478 236 6-({[3,5-bis(trifluoromethyl)benzyl]amino}sulfonyl)-N-[(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 466 237 N-(4-Chlorobenzyl)-6-({[2-(1-cyclohexen-1-yl)ethyl]amino)sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 516 238 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[2-(1-naphthylamino)- ethyl]amino}sulfonyl)-3-quinolinecarboxamide 577 239 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[(methylamino)- sulfonyl]-3-quinolinecarboxamide 422 240 N-(4-chlorobenzyl)-6-{[(cyanomethyl)amino]sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 447 241 N-(4-chlorobenzyl)-6-{[(2,4-dimethoxybenzyl)amino]sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 558 242 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(3-iodobenzyl)amino]sulfonyl}-3-quinolinecarboxamide 624 243 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2,2,2-trifluoroethyl)amino]sulfonyl}-3-quinolinecarboxamide 490

233 • ti • ti titi • titi ti • · ti ti • titi ti • titi ti

244 6- {[(2-bromomethyl)amino]sulfonyl}-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 516 245 N-(4-chlorobenzyl)-6- {[(2-chloroethyl)amino]sulfonyl}-8- -Fluoro-4-hydroxy-3-quinolinecarboxamide 470 246 N-(4-chlorobenzyl)-6-{[(3,4-dihydroxyphenethyl)- amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide 544 247 N-(4-chlorobenzene 1)-6-({[2-ethylsulfanyl)ethyl]amino}sulfonyl)- -8-fluoro-4-hydroxy-3-quinolinecarboxamide 496 248 6- {[(3-bromopropyl)amino]sulfonyl}-N-(4-chlorobenzyl)-8- -Fluoro-4-hydroxy-3-quinolinecarboxamide 530 249 6-( {[4-(amino sulfonyl)benzyl] amino} sulfonyl)-N-(4- -chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 409 250 6-[({2-[bis(2-hydroxyethyl)amino]ethyl}amino)sulfonyl]- N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 539 251 N-(4-chlorobenzyl)-6-({[2-(ethylsulfanyl)ethyl]amino}- sulfonyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 496 252 N-(4-chlorobenzyl)-6-{[(3,4-dimethylbenzyl)amino]sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide 526 253 N-(4-chlorobenzyl)-6-{[(cyclopropylmethyl)amino]sulfonyl}- -8-fluoro-4-hydroxy-3-quinolinecarboxamide 462 254 6- {[(4-bromobenzyl)amino]sulfonyl}-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 578 255 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[2-(2-thienyl)- ethyl]amino)sulfonyl)-3-quinolinecarboxamide 518 256 N-(4-chlorobenzene 1)-8-fluoro-4-hydroxy-6-{[(2-phenoxyethyl 1)amino]sulfonyl}-3-quinolinecarboxamide 528 257 tert-butyl-2- {[(3 - {[(4-chlorobenzyl)amino]carbonyl}-8-fluoro- -4-hydroxy-6-quinolinyl)sulfonyl]amino}acetate 522 258 tert-Butyl 3-{[(3-{[(4-chlorobenzyl)amino]carbonyl)-8-fluoro-4-hydroxy-6-quinoline 1)sulfone 1]amino}propanoate 536 259 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-( {[3-(trifluoromethoxy)benzyl]amino}sulfonyl)-3-quinolinecarboxamide 378 260 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-{[(2- {[2-(hydroxymethyl)phenyl]sulfanyl}benzyl)amino]sulfonyl}-3-quinolinecarboxamide 636

771 · 4 ♦ < · · · · · · · · • · · · 4 44 44 44 4 4 4 4 4 4 • 4 4 4 4 4 4 4 4 4 4 »4 44 261 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-({[4-(1,2,3-thiadiazol-4-yl)benzyl]amino}sulfonyl)-3-quinolinecarboxamide 582 262 N-(4-chlorobenzyl)-6-{[(4-chloro-2-fluorobenzyl)amino]- sulfonyl}-8-fluoro-4-hydroxy-3-quinolinecarboxamide 550 263 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-[({2-[(2-hydroxyethyl)- sulfanyl]ethyl}amino)sulfonyl]-3-quinolinecarboxamide 512 264 6- {[(2-amino-2-methylpropyl)amino]sulfonyl)-N-(4- -chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide 479 265 6-{[(2-amino-2-oxoethyl)amino]sulfonyl}-N-(4-chlorobenzyl)- -8-fluoro-4-hydroxy-3-quinolinecarboxamide 465 266 6-{[(4-aminobenzyl)amino]sulfonyl}-N-(4-chlorobenzyl)- -8-fluoro-4-hydroxy-3-quinolinecarboxamide 513

Example 267 di(tert-butyl)-3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl phosphate

To a stirred solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110 (78 mg) and 17 mg of ΙΗ-tetrazole in 1 mL of 1:1 chloroform:methanol was added under argon 0.077 mL of di-tert-butyldiethylphosphoramidite. After 4 h, the solution was cooled to 0°C and a small excess (ca. 80 mg) of m-CPBA was added. The solution was stirred for 20 min, then quenched with aqueous NaHSO ₃ . The organic layer was washed with dilute aqueous HCl and NaHCO ₃ , dried (Na 2 SO 4 ), and concentrated under reduced pressure. Flash chromatography of the residue on silica eluting with 2-4% methanol in dichloromethane gave 118 mg of the title compound as a white solid.

The physical characteristics are as follows:

1 H NMR (CDCl ₃ ) δ 1.50; 2.0; 2.9; 4.0; 4.6; 7.2-7.3; 7.9-8.1; 8.9; 10.6 ppm.

HRMS 580.1478.

235 ·« «· · · ·· ·· < * φ » ·· · · · · · · ···· · » · * « φ ····· · ·»*··«· • e · 0 · · β »· · «· »* ««« »·♦ «· ··

Example 268

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate

A solution of 95 mg of the compound from Example 267 (F-2, where X=CH2 and Y=F) in 1 mL of 1:1 TFA:dichloromethane was stirred for 30 min, then added dropwise to 50 mL of rapidly stirring 2:1 ether-hexane. The solid was filtered, washed with hexane, and dried in vacuo to give 65 mg of the title compound as a white solid.

The physical characteristics are as follows:

^! H NMR (CDCl 3 ) δ 2.1; 2.9; 4.0; 4.65; 7.3; 7.4; 8.0; 8.9 ppm.

HRMS 469.0742.

Example 269

3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl dihydrogen phosphate

Prepared from N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide (Example 144) according to the method described in Examples 267 and 268. The physical characteristics are as follows:

1 h NMR (CDCl ₃ ) δ 2.1; 3.0; 3.4; 4.0; 4.66; 7.3; 7.8; 8.2 ppm.

HRMS 451.0831.

Example 270 tert-butyl-3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propylphosphonate

To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 144 (75 mg) and 30 mg of ΙΗ-tetrazole in 2 mL of 1:1 chloroform:THF stirred under argon was added 0.130 mL of di-tert-butyldiethylphosphoramidite. After 18 h, the solution was washed with dilute aqueous HCl, the aqueous phase was extracted with two portions of chloroform. The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was flash chromatographed on silica eluting with 2-4% methanol in dichloromethane to give 90 mg of the title compound as a white solid.

The physical characteristics are as follows:

iHNMR (CDCl ₃ ) δ 1.53; 2.1; 2.9; 4.0; 4.6; 5.75; 7.2; 7.4; 8.06; 8.2; 8.8 ppm.

IR 2979, 1662, 1527, 1490, 1260, 973 cm''.

HRMS 491.1494.

Example 271 tert-butyl 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propylphosphonate

Prepared from N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide (Example 110) according to the method described in Example 270.

·· »* 9 • · · 3* C · * ^2*7 · · · · ·

FROM? / «··»>· • · · · ·

0· * · · · · ·

The physical characteristics are as follows:

1 h NMR (CDCl 3 ) δ 1.53; 2.1; 2.9; 4.1; 4.6; 5.75; 7.2; 8.0; 8.07; 8.9; 10.6 ppm.

HRMS 509.1424.

Example 272

3-(3-([(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propyl hydrogenphosphonate

of propylphosphonate from Example 270 in 0.5 mL of 1:1 TFA:dichloromethane was stirred for 2 hours, then added slowly to 20 mL of rapidly stirring hexane. The resulting solution was concentrated under reduced pressure to give 45.6 mg of the title compound as a white crystalline solid.

The physical characteristics are as follows.

^] Η NMR (CDCl 3 ) δ 2.0; 2.9; 4.0; 4.6; 5.8; 7.3; 7.7; 7.9; 8.0; 8.1 ppm.

HRMS 435.0871.

Example 273

Sodium 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propoxy]-8-oxooctanoyl} (methyl)amino]-1-ethanesulfonate

Cl

To a stirred mixture of 78 mg of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example 110, 27 mg of DMAP and 0.46 ml of a 0.65 M solution of triethylammonium salt

238

9 9 9

9« · · suleptanoic acid in 1 ml 1:1 chloroform:THF was added 0.038 ml diisopropylcarbodiimide. The solution was stirred for 18 hours, then concentrated under reduced pressure. Flash chromatography of the residue on silica using 5-15% methanol in dichloromethane gave a solid. This was dissolved in chloroform-butanol-methanol and the solution was mixed with saturated aqueous sodium sulfate. The organic phase was filtered through anhydrous sodium sulfate and concentrated under reduced pressure to give 121 mg of the title compound as a white solid.

The physical characteristics are as follows:

1HNMR (CDCl ₃ ) δ 1.1-1.6; 2.0-2.4; 2.8-3.3; 3.7-4.1; 4.7; 6.8; 7.3; 8.0; 8.1; 8.8 ppm.

HRMS 688.1858.

Example 274

Sodium 2-[(8-{[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)-2-propynyl]oxy}-8oxooctanoyl)(methyl)amino]-1-ethanesulfonate

Cl

Prepared from N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide (Example 134) according to the method described in Example 273.

The physical characteristics are as follows:

² H NMR (CDCl ₃ ) δ 1.2-1.7; 2.2-2.5; 2.9-3.2; 3.4; 3.8; 4.6; 4.9; 6.7; 7.3; 7.5-7.7; 8.1; 8.4;

8.8 ppm.

HRMS 643.1749.

Example 275

Sodium 2-[(8-{[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)-2-propynyloxy}-8-oxooctanoyl)(methyl)amino]-1-ethanesulfonate

Prepared from N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide according to the method described in Example 273.

The physical characteristics are as follows:

1 h NMR (CDCl 1 ) δ 1.2-1.7; 2.2-2.4; 3.0-3.2; 3.7; 4.6; 4.9; 7.3; 7.4; 8.2; 8.8 ppm.

HRMS 684.1561.

Example 276

Sodium 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinyl)propoxy]-8-oxooctanoyl} (methyl)amino]-1-ethanesulfonate

Prepared from N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide (Example 144) according to the method described in Example 273.

The physical characteristics are as follows:

1 H NMR (CDCl 3 ) δ 1.3; 1.5-1.7; 2.0; 2.2-2.5; 2.8-3.3; 3.8; 4.1; 4.6; 6.8; 7.1-7.4; 7.5; 8.1; 8.2;

8.8 ppm.

HRMS 647.2073.

240 ♦ · ·· ·· ♦ · « • Φ 4

Preparation 28

-(benzylsulfanyl)aniline

To a cold (0°C) stirred suspension of 1.7 g sodium hydride (60% dispersion in oil) in 100 ml dry THF was added via cannula under argon, 4.95 g 3-aminothiophenol. After 5 min, 4.6 ml benzyl chloride was added. The mixture was allowed to warm to room temperature and stirred for 18 h, then cooled to 0°C and then partitioned between water and diethyl ether. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography on silica using 30% ethyl acetate in heptane gave 7.57 g of the title compound, which could be recrystallized from ether-hexane.

The physical characteristics are as follows:

^! H NMR (CDCl 3 ) δ 3.7; 4.10; 6.5; 6.6; 6.7; 7.0; 7.2-7.3 ppm.

HRMS 216.0837.

Analysis found: C 72.54; H 6.13; N 6.55; S 14.84.

Preparation 29

Ethyl [7-(benzylsulfanyl)-4-hydroxy-3-quinolinecarboxylate]

A mixture of 7.40 g of 3-(benzylsulfanyl)aniline from Preparation 28 and 7.70 g of diethylethoxymethylenemalonate was stirred at 135°C under a gentle stream of argon for 2 hours, then diluted with 30 mL of diphenyl ether and then heated to 260-270°C. After 45 minutes, the solution was added to 500 mL of stirred heptane. The resulting solid was filtered and washed well with hexane and dried in vacuo to give 8.32 g of the title compound.

The physical characteristics are as follows:

ΪΗ NMR (CDCl 3 ) δ 1.5; 4.4; 4.6; 7.2-7.5; 7.7; 7.8; 8.3; 9.2 ppm.

MS ES+ 340.

Preparation 30

7-(Benzylsulfanyl)-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide

A mixture of 4.07 g of ethyl [7-(benzylsulfanyl)-4-hydroxy-3-quinolinecarboxylate] from Preparation 29 and 8.5 g of 4-chlorobenzylamine was heated at 165°C for 18 hours, then cooled and partitioned between 1 N HCl and fcfc fcfc

I fcfc « > · fcfc » fcfc 4 * · · 4 fcfc fc *

241 fc fcfc ·· «· · fcfc « • fcfcfc· • fcfc · · fc • · · · · · • ··· ·· fcfc chloroform-methanol. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was flash chromatographed on silica using 2-5% methanol in dichloromethane to give 4.82 g of the title compound.

The physical characteristics are as follows:

1 H NMR (CDCl ₃ ) δ 4.13; 4.6; 7.1-7.4; 8.2; 8.6 ppm.

MS ES+ 435.

Preparation 31

- {[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-7-quinolinesulfonyl chloride

Chlorine gas is bubbled into 10.0 ml of glacial acetic acid placed in a weighed scintillation tube cooled in an ice bath. After about 3-5 minutes, 1.29 g of Cl2 is absorbed, giving an approximate concentration of 1.8 M. A solution of 306 mg of 7-(benzylsulfanyl)-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide from Preparation 30 in 10 ml of acetic acid and 1.0 ml of water is prepared by heating and this solution is cooled to 0°C for the addition of 1.8 ml of freshly prepared chlorine solution. The solution is stirred for 15 minutes at 0°C, then added to 50 ml of ether. The volatiles are removed under reduced pressure and 50 ml of toluene is added to the residue. Concentration of this solution under reduced pressure afforded 344 mg of sulfonyl chloride as a yellow solid of sufficient purity for sulfonylation of amines.

The physical characteristics are as follows:

MS (ES+) 409.411.

Example 277

N-(4-chlorobenzyl)-4-hydroxy-7-{[(1-naphthylmethyl)amino]sulfonyl}-3-quinolinecarboxamide

To a stirred solution of 0.044 ml of 1-naphthylmethylamine and 0.051 ml of diisopropylethylamine in 0.5 ml of pyridine is added 100 mg of 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-7-quinolinesulfonyl242 • · · · 9 9 99 ·· • · · 9 · · · « · 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 · 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9· · · · · · · · · 99 9 9 chloride from Preparation 31. After 18 hours, the solution was added to 3.5 mL of rapidly stirred 2 N aqueous HCl. The resulting solid was filtered and washed well with water and dried in vacuo. Flash chromatography on silica using 2-5% methanol in dichloromethane gave 48 mg of the title compound as a white solid.

The physical characteristics are as follows.

^} H NMR (CDCl ₃ ) δ 4.70; 4.79; 7.2-7.5; 7.6; 7.8; 8.2; 9.5 ppm.

HRMS 531.1010.

Example 278

N-(4-chlorobenzyl)-4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxamide

A neat mixture of 2.8 g of the 3-methylthioaniline compound and 4.0 g of diethylethoxymethylenemalonate was heated to 135°C under a slow stream of argon for 1 hour, then diluted with diphenyl ether (25 mL), heated to 260°C while maintaining a stream of argon and held at this temperature for 90 minutes. The mixture was then cooled to about 100°C and added to 300 mL of stirred 1:1 ether-hexane. The precipitate was filtered, washed with hexane and dried in vacuo to give 1.35 g of crude material as a tan solid which was recrystallized from acetic acid-water to give 1.06 g of ethyl [4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxylate].

A solution of 50 mg of ethyl [4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxylate] in 0.200 mL of 4-chlorobenzylamine was heated at 190°C under argon for 16 hours, then cooled and diluted with chloroform and methanol. The solution was washed with dilute HCl, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica using 2-4% methanol in dichloromethane gave 62.4 mg (92%) of N-(4-chlorobenzyl)-4-hydroxy-7-(methylsulfanyl)-3-quinolinecarboxamide.

The physical characteristics are as follows:

1 H NMR (CDCl ₃ ) δ 2.54; 2.6; 4.63; 7.3; 8.2; 8.6 ppm.

« and • ·

243 aa a a aa a a a a aa aa a a a a a a a aa a · «a#· a a a a a a a a a a a a · « a a a a a a a a a a aa aaa aaa aa ··

HRMS 358.0561.

Analysis found: C 60.11; H 4.28; N 7.82.

Example 279

N-(4-Chlorobenzyl)-8-hydroxy-[1,3]dioxolo[4,5-g]quinoline-7-carboxamide

Prepared from ethyl (8-hydroxy-[1,3]dioxolo[4,5-g]quinoline-7-carboxylate) using the aminolysis conditions described in Example 278.

The physical characteristics are as follows:

1 h NMR (CDCl 3 +CD 3 OD) δ 4.63; 6.12; 6.90; 7.3; 7.67; 8.60 ppm.

HRMS (FAB) 357.0638.

Example 280

6-Benzoyl-N-(4-chlorobenzyl)-4-hydroxy-3-quinolinecarboxamide

Prepared from 4-aminobenzophenone using the conditions described in Example 278.

The physical characteristics are as follows:

1 H NMR (CDCl 3 +CD 3 OD) δ 4.62; 7.3; 7.5; 7.6; 7.8; 8.2; 8.7 ppm.

HRMS (FAB) 417.1001.

Analysis found: C 68.84; H 4.25; N 6.71.

244

SCHEME A ·· ·· • 9 ♦ · • · ·· • · · · · · · » · · · »· ·· • · · · • * ·

9 9

9 · ·♦ 99

A-1

yes

A-4 a-3

a-5 a-2

245 • 9 • 9

SCHEME B • 9 ·· • 9 9 ·

9 99

9 9 9

9 9 9

99

9 *

9 9

9 9

9 9

99

• 9 ··

246

SCHEME D

SCHEME E

247 • 0 • 0 ··

0 0 0 ·

0 0· • 0 0 0 ·

0· ·

00 ·

00 • 0 · • 0 ·

0 0

0 0 « 00 00

SCHEME F

F

248 • ·

SCHEME G

F g-1

SCHEME H • * 99 • *9 · • · ♦♦ • · 9 · · • · · · ·· ··

SCHEME I

i-1 i-2

9* 99

9 9

9 9

9 9

9 9 9 **

9

999 9

249

SCHEME J • 9 99 • 9 9

9 99

9 9

9 9

99

j-6

99

9 9 9

9 9 9 · ·· 9

9 9 9

99

250 • 9

999

SCHEME K • 9 · 9 9

9 99

9 9 9 9

9 9 9

99 9

9

9

9

9

251 « 99 99

999« • »999

9 9 9 9 9 » · 9 9 9 « *99 99 99

SCHEME L

SCHEME M

HO X

Cl

252

SCHEME N

Π-3 η-4

Φ · φφ • · · · φ φ ·· • φ φ φ · • · · · ·· ·· φφ

IZ

N

CI η-5 • · ··

253 • · · · φ · φφ < · v « · « φ · φ φ* ·· φ

φ #Μ • · * · Φ Φ • 9 9 9 4 • Φ Φ · · · • · · · ·

SCHEME Ο “Ό. ^So ₂ 0-1 -► ^ΝΟ ₂ ο-2 Η0'^ ^χ - ^χ0 'Ύί5 ^Γ \ ^nh ₂ 0-3 ^•Α 0 0 ^NH 0 S^OCHjCH, cAoCHjCHj 0-4 ^yOCHjCH; O^OCH ₂ CH ₃ 0-5 ο __ A OH 0 OH O o-7 υζΓ ^{c 3} o*6

SCHEME P "X" o-1 n ₃ - _xť p-2 NH2 - p-3

• · » »

254

SCHEME Q

>

OH O

'0 CH ₃ q-3

OH O

• 0 • ·

255

SCHEME R

SCHEME S • 0 0 « • 0 · · • · · c · * 0 0 0

0 0 0

s-3 • 00 ·· 0 0 0 ·

0 0 0 0

0 0 0 0 · 0 0 0 0 0

000 00 00

99 9 9

9 9 ·

9 9 9 9

9 9 9

9 99

256

SCHEME ch ₃ i

• · 9 9 • e · ·

9·9

9 9 «

9 9 9

99

257

SCHEME U

258

• * 44 » 4 44 4 4 • • • 4 • 4 4 4 4 4 4 • 4 4 4 *4 4 4 • 4 4 4 4 • • 4 · 4 4 4 4 4 4 • · 4 · • 4 4 4 4 4 4 4 4 4

SCHEME V

v-5

259 ·· 9«

Claims (15)

PATENTOVÉ 1. A compound of formula (I) (2) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8-methoxy-3-quinolinecarboxamide; ·· ·· ·· ·· 289 • · • in ♦ · ·· ·· A compound according to claim 1, wherein A is -CH 2 -. (3) N- (4-chlorobenzyl) -4-hydroxy-8-methoxy-6- (3-methoxy-1-propynyl) -3-quinolinecarboxamide; (3 9) methyl 1- (3 - {[(4-chlorobenzyl) amino (carbonyl) -4-hydroxy-6-quinolinecarboxylate) or (40) N- (4-chlorobenzyl) -4-hydroxy-6- ( 4-morpholinylmethyl) -3-quinolinecarboxamide. The compound of claim 1 which is (1) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide; (3 6) N- (4-chlorobenzyl) -4-hydroxy-6- (2-thienyl) -3-quinolinecarboxamide (37) N- (4-chlorobenzyl) -4-hydroxy-6 - [(2) -hydroxyethoxy) methyl] -3-quinolinecarboxamide; (38) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1,1-dimethylpropyl) -3-quinolinecarboxamide; (3,5) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl) -4-hydroxy-6-quinolinyl) propyl hydrogenphosphonate; (3 0) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide; (31) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl-2,6-bis [(tert-butoxycarbonyl) amino] hexanoate; (32) N- (4-chlorobenzyl) -6 - [(Z) -3-hydroxy-1-propenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide; (33) N- (4-chlorobenzyl) -6 - [(E) -3-hydroxy-1-propenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide; (34) trifluoroacetic acid salt of 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl-2,6-diaminohexanoate; (3) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide; A compound according to claim 1, wherein R ¹ , R ² , R ³ and R ⁴ are independently (a) halo, b) -CN, c) -NO ₂ , d) phenyl, e) het f) -OR ⁵ g) C 1 -C 8 alkyl, h) C 1 -C 8 alkyl substituted with one to three -CN, halo, -OR ⁵ , -C (= O) R ⁵ , het, -COOR ⁵ , phenyl, -OP (= O) (R ⁹ ) ₂ , -OPH (= O) R ⁹ or -OC (= O) R ¹⁰ , i) -C = CR ⁿ j) -CH = CH-R ^12, k) -C (= O) R ¹³ , l) -SR ¹⁴ , m) -SO2R ¹³ , (n) -NR ⁷ R ⁸ , o) -NHSO ³ R ¹³ or p) R ¹ and R ² taken together are 264 fc fc fc fcfc R ⁵ is a) -H, b) C 1-4 alkyl optionally substituted with one to three -OH, halo, -CN, C 1-4 alkoxy or phenyl; or (c) phenyl; R ⁷ and R ⁸ are independently a) -H, b) C 1 -C 4 alkyl, optionally substituted with one to three -NO ₂ , halo, -CN, OR ⁵ or phenyl, c) aryl, d) - (CH ₂ ) _m -C (= O) OR ⁵ or e) - (CH ₂ ) _m -C (= O) R ⁵ , R ⁹ is (a) -OH; or b) -OC ₁ -C ₈ alkyl, R ¹⁰ is a) -H, b) -NR ⁷ R ⁸ , or c) C ₁ -C ⁸ alkyl substituted with one to two halo, het, -NR ⁷ R ⁸ or -C (= O) N (C ₁ -C ₄ alkyl) (CH ₂ ) _n S (= O) ₂ O-M +, R ¹¹ is a) C 1 -C 8 alkyl substituted with one to three -CN, -C (= O) R ⁵ , phenyl, -OR ⁵ , -NR ⁷ R ⁸ or -OC (= O) R ¹⁰ , R ¹² is a) -CN b) -C (= O) R ⁵ or c) C 1 -C 4 alkyl substituted with one to three -CN, halo or -OR ⁵ ; R ¹³ is a) C1-4 alkyl, • 0 0 » 265 0 0 0 0 00 00 0 0 0 0 0 0 0 00 b) C 1-4 alkyl substituted with one to three -phenyl, -OR ⁴⁵ or -NR ⁷ R ⁸ ; (c) phenyl; (d) -NR ⁷ R ⁸ ; e) -OR ⁵ R14 is a) C 1 -C 4 alkyl, optionally substituted with phenyl, aryl is phenyl or naphthyl, at each occurrence phenyl is optionally substituted with R ⁸ , het is pyrrolyl, morpholinyl, thiophenyl, thiazolyl, pyridinyl, thiadiazolyl or 2-oxo-oxazolyl, wherein het is optionally substituted with R ⁸ , R ⁸ is (a) halo, b) phenyl c) C 1 -C 4 alkyl, optionally substituted with one to three halo or -OR ⁵ , or d) -OR ⁵ M is sodium, potassium or lithium, i is 2, m is 0, 1, 2 or 4, n is 1, 2, 3 or 4. (4) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide, (4) N- (4-chlorobenzyl) -4-hydroxy-6-methoxy-3-quinolinecarboxamide; 99 99 a) C 1 -C 8 alkyl, b) C 1 -C 8 alkyl substituted with one to three -CN, halo, -NO 2, -COOR ⁵ , -C (= O) R ⁵ , -SR ⁵ , aryl, -OR ⁵ , -NR ⁷ R ⁸ , -OP ( = O) (R ⁹ ) ₂ , -OPH (= O) R ⁹ or -OC (= O) R ¹⁰ or c) - (CH _{2) m} Het, R ¹² is a) -H, b) -CN, c) C ₁ -C ₈ alkyl, d) C 1 -C 8 alkyl substituted with one to three -CN, halo, -NO 2, -C (= O) R ⁵ , -COOR ⁵ , aryl, het, -SR ⁵ , -OR ⁵ , -NR ⁷ R ⁸ , - OP (= O) (R ⁹ ) ₂ or -OPH (= O) R ⁹ , e) -C (= O) R ⁵ or f) -COOR ⁵ , R ¹³ is a) C 1 -C 8 alkyl, b) - (CH 2) _m -alkyl substituted with one to three -CN, halo, -NO 2, -C (= O) R ⁵ , het, aryl, -COOR ⁵ , -SR ⁵ , -OR ⁵ or -NR ⁷ R ⁸ , c) het, d) aryl, e) -NR ⁷ R ⁸ or O-OR ⁵ , R ¹⁵ is (a) -NH 2; or b) -NHNH ₂ , aryl is phenyl or naphthyl, optionally substituted with R 6, het is a 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the heterocyclic the ring is optionally linked to a benzene ring and optionally substituted with R ⁸ , R ⁸ is (a) halo, 270 b) -NO ₂ , c) phenyl, optionally substituted with one to five -OH, -CN, halo, -NO 2, C 1 -C 8 alkyl or -OC ₁ -C ₄ alkyl, d) C 1 -C 8 alkyl, optionally substituted with one to three halo, -CN, -NO ₂ , aryl, -SR 6 -OR 8 or -NR 7r 8 or e) -OR ⁵ M is sodium, potassium or lithium, i is 1 or 2, m is 0, 1, 2 or 4, n is 1, 2, 3 or 4, with the following reservations: (a) when R 7 is hydrogen, R ² and R ⁴ are all fluoro, R ² is het, then het is other than substituted piperazinyl, (b) when R, R ² and R are all hydrogen, then R ⁴ is not morpholinyl (c) when R 1, R ² , R ⁴ and R ⁴ are independently -NR 6 R ⁶ then R ² and R 6 are not hydrogen or alkyl, (d) het is other than a cyclic amine. 4 4 · 4 4 · 4 4 4 4 4 4 4 4 4 44 44 4 4 4 4 44 44 269 • t 4 4 4 The compound of claim 1, wherein R ^{1 is} H, R ² , R ³ and R 6 are independently (a) fluorine; b) het c) -OR ⁵ d) C 1 -C ⁵ alkyl substituted with halo, -OR ⁵ , -C (= O) R ⁵ , -OP (= O) (R 6) 2, het, -OPH (= O) R 6, or -OC (= O) ) R ¹⁰ , e) -OCR ¹¹ f) R ¹² -CIKH g) -C (= O) R ¹³ or 266 ·· ·· h) -NR ⁷ R ⁸ R ⁵ is a) -Or b) C 1 -C 4 alkyl, optionally substituted with -OH, halo or C 1 -C 4 alkoxy, R ⁷ and R ⁸ are independently a) -H, b) C 1 -C 4 alkyl optionally substituted with one to two halo, -OR ³ or phenyl; c) -C (= O) R ⁵ , R ⁹ is (a) -OH; or b) -OC 1 -C 4 alkyl, R 1 is C 1 -C 8 alkyl substituted with one to two of the following a) -C (= O) N (C _M alkyl) (CH _{2) n} S (= O) ₂ OM ⁺ (b) halo; or (c) -NR ⁷ R ⁸ ; R 11 is C 4 -C 4 alkyl substituted with -OR ³ , -NR ⁷ R ⁸ or -OC (= O) R 6, R ¹² is ( ⁴ X ⁴ alkyl substituted with -OR ³ , R ¹³ is C 4 X 4 alkyl substituted with -OR ³ , het is morpholinyl or thiophenyl, M is sodium, potassium or lithium and n is 1 or 2. (5) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -8-methoxy-3-quinolinecarboxamide; (5) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (2-thienyl) -3-quinolinecarboxamide; The compound of claim 1, wherein R 1 and R ³ are independently H, R ⁴ is a) H, (b) fluorine; or c) -OR ³ , (a) thiophenyl, 267 ························ (6) 2 - [(8 - {[3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl) oxy} -8-oxooctanoyl) ( sodium methyl] amino] -1-ethanesulfonate, (6) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (4-hydroxybutyl) -3-quinolinecarboxamide; A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ⁴ are independently a) het, b) C ₁ -C ₁₂ alkyl substituted with one to three -C (= O) R ⁵ , het, aryl, -NR ² R 8, -OP (= O) (R ⁹ ) ₂ , -OPH (= O) R ⁹ , -OC (= O) R ¹⁰ c) -OCR ¹¹ d) -CH = CH-R ^12, e) -C (= S) R ^5, 268 ············································ (f) -NR ⁷ R ⁸ ; g) -NHSO ³ R ¹³ , h) R ¹ and R ⁷ taken together are het or C 4 -C 6 cycloalkyl; i) R 2 _and r 3 taken together are het or C 4 -C 8 cycloalkyl, R ⁵ is a) -H, b) C 1 -C 8 alkyl, optionally substituted with one to three -OH, -CN, C 1 -C 8 alkoxy, halo, -NO ₂ , het or aryl, (c) aryl; or d) het, R ⁷ and R ⁸ are independently a) -H, b) C 1 -C 8 alkyl, optionally substituted with one to three -NO 2, halo, -CN, -OR ⁵ , aryl or het, c) aryl, d) het, e) - (CH ₂ ) _m -C (= O) OR ⁵ , f) - (CH ₂ ) _m -C (= O) R ⁵ or g) R ⁷ and R ⁸ taken together form het, R ⁹ is (a) -OH; or b) -OC 1 -C 8 alkyl, R ¹⁰ is a) -H, b) C 1 -C 8 alkyl, (c) -NR ⁷ R ⁸ ; d) C 1 -C 8 alkyl substituted with one to two halo, het, -NR ⁷ R ^8, or -O (= Ο) Ν (0ι. ₄ ^ _Υ 1) (0Η2) _η δ (= Ο) 2θ-Μ +, RUje (7) 2 - [{8- [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propoxy) -8-oxooctanoyl} (methyl) amino] -1- ethanesulfonate, (7) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(Z) -4-hydroxy-1-butenyl) -3-quinolinecarboxamide; A method of treating herpes virus infections comprising administering to a patient in need thereof an effective amount of a compound of Formula I. (8) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propyl dihydrogen phosphate; (8) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide; The method of claim 7, wherein the herpes virus is herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes virus 6, human herpes virus 7 or human herpes viruses. (9) N- (4-chlorobenzyl) -6 - [(Z) -3-hydroxy-1-propenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide; 9 · · · 288 (25) 2 - [(8 - {[3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl) oxy} -8-oxooctanoyl) sodium (methyl) amino] -1-ethanesulfonate; (26) 2 - [{8- [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propoxy] -8-oxooctanoyl} (methyl) amino] -1- ethanesulfonate; (27) tert-butyl (3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propyl phosphonate); (28) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propyl dihydrogen phosphate; (29) N- (4-chlorobenzyl) -4-hydroxy-8- (2-hydroxyethoxy) -6- (3-hydroxypropyl) -3-quinolinecarboxamide; 9 · · < (9) N- (4-chlorobenzyl) -4-hydroxy-7- (3-hydroxypropyl) -3-quinolinecarboxamide; (10) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1); -propinyl) -8-methoxy-3-quinolinecarboxamide; 9 · · Φ · · Φ Φ 282 ΦΦ • · · Φ · · Φ Φ · Φ Φ Φ ΦΦ · * (247) 6 - {[(3-bromopropyl) amino] sulfonyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (248) 6 - ({[4- (aminosulfonyl) benzyl] amino} sulfonyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (249) 6 - [({2- [bis (2-hydroxyethyl) amino] ethyl] (amino) sulfonyl] -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (250) N- (4-chlorobenzyl) -6 - ({[2- (ethylsulfanyl) ethyl] amino) (sulfonyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (251) N- (4-chlorobenzyl) -6 - {[(3,4-dimethylbenzyl) amino] sulfonyl) -8-fluoro-4-hydroxy -3-quinolinecarboxamide, (252) N- (4-chlorobenzyl) -6 - {[(cyclopropylmethyl) amino] sulfonyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (253) 6 - {[(4- bromobenzyl) amino] sulfonyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (254) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ({ [2- (2-thienyl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (255) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2-phenoxyethyl) amino] sulfonyl} -3-quinolinecarboxamide, (256) tert-butyl [2 - {[(3 - {[(4-chlorobenzyl) amino] carbonyl) -8-fluoro-4-hydroxy-6-quinolinyl) sulfonyl] amino} acetate], (257) tert-butyl [3 - {[(3 - {[(4-chlorobenzyl) (amino) carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) sulfonyl] amino} propanoate], (258) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ({[3 - (trifluoromethoxy) benzyl] amino} sulfonyl) -3-quinolinecarboxamide, (259) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2 - {[2- (hydroxymethyl) phenyl]] sulfanyl} benzyl) amino] sulfonyl) -3-quinolinecarboxamide, (260) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(4- (1,2,3-thiadiazole-4) -yl) benzyl] amino} sulfonyl) -3-quinolinecarboxamide, (261) N- (4-chlorobenzyl) -6 - {[(4-chloro-2-fluorobenzyl) amino] sulfonyl) -8-fluoro-4- hydroxy-3-quinolinecarboxamide, (262) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [({2 - [(2-hydroxyethyl) sulfanyl] ethyl} amino) sulfonyl] -3-quinolinecarboxamide , 283:. :: ::. .......... (263) 6 - {[(2-amino-2-methylpropyl) amino] sulfonyl} -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (264) 6 - {[(2) -amino-2-oxoethyl) amino] sulfonyl} -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (265) 6 - ([(4-aminobenzyl) amino] sulfonyl} -N - (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (266) di (tert-butyl) [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro- 4-hydroxy-6-quinolinyl) propyl phosphate], (267) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyldihydrogen phosphate, (268) 3 - (3 - {[(4-chlorobenzyl) amino] carbonyl] -4-hydroxy-6-quinolinyl) propyl dihydrogen phosphate, (269) tert-butyl [3- (3 - {[(4-chlorobenzyl) amino] carbonyl] - 4-hydroxy-6-quinolinyl) propylphosphonate], (270) tert-butyl [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propylphosphonate], (269) tert-butyl [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propylphosphonate], (270) tert-butyl [3- (3 - {[( 4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinol inyl) propyl phosphonate], (271) [E] -3- (3 - {[(4-chlorobenzyl) amino] carbonyl] -8-fluoro-4-hydroxy-6-quinolinyl) -2-propenoic acid or (272) N - [(4-chlorophenyl) methyl] -4-hydroxy-7-iodo-3-quinolinecarboxamide. The compound of claim 1 which is (1) 7-amino-N- (4-chlorobenzyl) -4-hydroxy-3-quinolinecarboxamide, (2) N- (4-chlorobenzyl) -4-hydroxy-7-methoxy -3-quinolinecarboxamide, (3) N- (4-chlorobenzyl) -7-fluoro-4-hydroxy-3-quinolinecarboxamide, (4) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide (5) 6-chloro-N- (4-chlorobenzyl) -4-hydroxy-3-quinolinecarboxamide, (6) N- (4-chlorobenzyl) -4-hydroxy-6-methyl-3-quinolinecarboxamide, (7) N- (4-chlorobenzyl) -4-hydroxy-6-methoxy-3-quinolinecarboxamide, (8) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxamide, · • · (9) N- (4-chlorobenzyl) -4-hydroxy-6-iodo-3-quinolinecarboxamide, (10) N- (4-chlorobenzyl) -4-hydroxy-6-phenyl-3-quinolinecarboxamide, (11) N- (4-chlorobenzyl) -4-hydroxy-6,8-dimethoxy-3-quinolinecarboxamide; (12) 6- (tert-butyl) -N- (4-chlorobenzyl) -4-hydroxy-3- quinolinecarboxamide, (13) N- (4-chlorobenzyl) -6- (cyanomethyl) -4-hydroxy-3-quinolinecarboxamide, (14) N- (4-chlorobenzyl) -9-hydroxy [1,3] thiazolo [ 5,4-f] quinoline-8-carboxamide, (15) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide, (16) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (1,3-thiazol-2-yl) -3-quinolinecarboxamide, (17) N- (4-chlorobenzyl) -8-fluoro-4 -hydroxy-6- (2-thienyl) -3-quinolinecarboxamide, (18) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-methoxy-1-propynyl) -3-quinolinecarboxamide, (19) 6- (4-bromo-2-thienyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (20) N- (4-chlorobenzyl) -8-fluoro- 4-hydroxy-6- (4-hydroxybutyl) -3-quinolinecarboxamide, (21) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(Z) -4-hydroxy-1-but enyl] -3-quinolinecarboxamide, (22) N- (4-chlorobenzyl) -6,8-difluoro-4-hydroxy-7- [4- (hydroxymethyl) phenoxy] -3-quinolinecarboxamide, (23) N- (4 (24) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (5-hydroxy-1-chlorobenzyl) -6,8-difluoro-4-hydroxy-7-methoxy-3-quinolinecarboxamide; (25) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) -2-propynyl formate, (26) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide, (27) N- (4-chlorobenzyl) -4-hydroxy-7- (3-hydroxypropyl) -3 -quinolinecarboxamide, (28) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxybutyl) -3-quinolinecarboxamide, (29) N- (4-chlorobenzyl) -6 - [(E (2-cyanoethenyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (3 0) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8-methoxy -3-quinolinecarboxamide, (31) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide, (3 2) N- (4-chlorobenzyl) - 4-hydroxy-8-methoxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide, (33) N- (4-ch (34) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(Z) -3-hydroxy-1-propenyl] -3-quinolinecarboxamide; 6- (3-oxopropyl) -3-quinolinecarboxamide, (35) N- (4-chlorobenzyl) -4-hydroxy-7- (4-hydroxybutyl) -3-quinolinecarboxamide, (3 6) N- (4-chlorobenzyl) -4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide, (37) N- (4-chlorobenzyl) -8-fluoro-6- (3-fluoro-1-propynyl) -4-hydroxy-3- quinolinecarboxamide, (38) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide, (3 9) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} - 8-fluoro-4-hydroxy-6-quinolinyl) propyl bromoacetate, (40) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl-2 - [(tert-butoxycarbonyl) amino] -3-methylbutanoate, (41) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl-2- amino-3-methylbutanoate, (42) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) -2-propynylphenylcarbamate, (43) N- (4) (44) N- (4-chlorobenzyl) -4-hydroxy-6-propyl-3-quinolinecarboxamide; yl) -4-hydroxy-6- (3-hydroxypropyl) -8-methoxy-3-quinolinecarboxamide, (45) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (methylsulfanyl) -3- quinolinecarboxamide, (46) N- (4-chlorobenzyl) -4-hydroxy-7- ([(1-naphthylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (47) N- (4-chlorobenzyl) -8-fluoro- 4-hydroxy-6 - [(E) -3-oxo-1-butenyl] -3-quinolinecarboxamide, (48) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8- (trifluoromethoxy) -3-quinolinecarboxamide, (49) 2 - [(8- (3- (3 - ([(4-chlorobenzyl) amino) carbonyl) -8-fluoro-4-hydroxy-6-quinolinyl) 1] (propoxy) -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate, (50) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl) -8-fluoro-4-hydroxy- 6-quinolinyl) propyl dihydrogen phosphate, (51) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl-2,6-bis [(tert-butyl) -butoxycarbonyl) amino] hexanoate, (52) tert-butyl [3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propylphosphonate], (53) 2 - [(8 - ((3- (3 - (((4-chlorobenzyl) amino) carbonyl) -8-fluoro-4-hydr) (54) N- (4-chlorobenzyl) -4-hydroxy-6- (2-hydroxyethoxy) -1-ethanesulfonate (54) oxo-6-quinolinyl 1) 2-propynyl] oxy} -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate ) -3-quinolinecarboxamide, (55) trifluoroacetic acid 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2,6-diaminohexanoate salt, ( 56) N- (4-chlorobenzyl) -4-hydroxy-6 - [(2-hydroxyethyl) amino] -3-quinolinecarboxamide; (57) N- (4-chlorobenzyl) -4-hydroxy-6- (3- hydroxybutyl) -3-quinolinecarboxamide; 286 (58) 2 - [(8 - ([3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl) oxy} -8-oxooctanoyl) ( (59) 2 - [{8- [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propoxy] -8- (methyl) amino] -1-ethanesulfonate sodium oxooctanoyl} (methyl) amino] -1-ethanesulfonate, (60) tert-butyl [3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propylphosphonate], (61) ) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propyl dihydrogen phosphate, (62) N- (4-chlorobenzyl) -4-hydroxy-8- (2-hydroxyethoxy) -6- (3-hydroxypropyl) -3-quinolinecarboxamide, (63) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide, (64) N- ( 4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-oxobutyl) -3-quinolinecarboxamide, (65) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (2-oxo) -1,3-oxazolidin-3-yl) -3-quinolinecarboxamide, (66) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl-2 , 6-bis [(tert-butoxycarbonyl) amino] hexanoate, (67) N- (4-chlorobenzyl) -6 - [(Z) -3-hydroxy-1-propene yl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide, (68) N- (4-chlorobenzyl) -6 - [(E) -3-hydroxy-1-propenyl] -4-oxo-1, 4-dihydro-3-quinolinecarboxamide, (69) trifluoroacetic acid 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl-2,6-diaminohexanoate salt, (70) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl) -4-hydroxy-6-quinolinyl) propyl hydrogenphosphonate, (71) N- (4-chlorobenzyl) -4-hydroxy-6- (2-) thienyl) -3-quinolinecarboxamide, (72) N- (4-chlorobenzyl) -4-hydroxy-6 - [(2-hydroxyethoxy) methyl] -3-quinolinecarboxamide, (73) N- (4-chlorobenzyl) -4- hydroxy-6- (3-hydroxy-1,1-dimethylpropyl) -3-quinolinecarboxamide, (74) N- (4-chlorobenzyl) -4-hydroxy-6- ([2-hydroxy-1- (hydroxymethyl) ethoxy) methyl} -3-quinolinecarboxamide, (75) N- (4-chlorobenzyl) -4-hydroxy-6- (hydroxymethyl) -3-quinolinecarboxamide, (76) methyl [3 - ([(4-chlorobenzyl) amino] carbonyl] } -4-hydroxy-6-quinolinecarboxylate or (77) N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide. The compound of claim 1 which is (1) N- (4-chlorobenzyl) -4-hydroxy-7-methoxy-3-quinolinecarboxamide; 287 (2) N- (4-chlorobenzyl) -7-fluoro-4-hydroxy-3-quinolinecarboxamide; 9 9 9 99 99 281 (229) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- [281] (phenethylamino) sulfonyl] -3-quinolinecarboxamide, (230) N- (4-chlorobenzyl) -6 - {[(4-chlorophenethyl) amino] sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (231) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(2-propylamino) sulfonyl] -3-quinolinecarboxamide, (232) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy -6 - [(isopenylamino) sulfonyl] -3-quinolinecarboxamide, (233) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(3-phenylpropyl) amino] sulfonyl} -3- quinolinecarboxamide, (234) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(pentylamino) sulfonyl] -3-quinolinecarboxamide, (23 S) 6- ({[3,5-bis (trifluoromethyl) (benzyl] amino} sulfonyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (236) N- (4-chlorobenzyl) -6 - ({[2- (1-cyclohexene) (1-yl) ethyl] amino} sulfonyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (237) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- ({[2- (1-naphthylamino) ethyl] amino} sulfonyl) -3-quinolinecarb oxamide, (238) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(methylamino) sulfonyl] -3-quinolinecarboxamide, (239) N- (4-chlorobenzyl) -6 - {[( cyanomethyl) amino] sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (240) N- (4-chlorobenzyl) -6 - {[(2,4-dimethoxybenzyl) amino] sulfonyl} -8-fluoro- 4-hydroxy-3-quinolinecarboxamide, (241) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(3-iodobenzyl) amino] sulfonyl} -3-quinolinecarboxamide, (242) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2,2,2-trifluoroethyl) amino] sulfonyl} -3-quinolinecarboxamide, (243) 6 - {[(2-bromoethyl) amino] sulfonyl} -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (244) N- (4-chlorobenzyl) -6 - {[(2-chloroethyl) amino] sulfonyl} -8- fluoro-4-hydroxy-3-quinolinecarboxamide, (245) N- (4-chlorobenzyl) -6 - {[(3,4-dihydroxyphenethyl) amino] sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, ( 246) N- (4-chlorobenzyl) -6 - ({[2- (ethylsulfanyl) ethyl] amino} sulfonyl) -8-fluoro-4-hydroxy-3 ·· · 9 9 · 9 · · 8 · * • Φ « Φ Φ · Φ Φ Φ · Φ · ·· 280 (212) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ({[2- (4-morpholinyl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (213) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ({[3- (4-morpholinyl) propyl] amino) (214) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [({2 - [(5-nitro-2-pyridinyl) amino] sulfonyl} -3-sulfonyl) -3-quinolinecarboxamide -quinolinecarboxamide, (215) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ([(2-pyridinylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (216) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ({[2- (2-pyridinyl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (217) N- (4-chlorobenzyl) -8-fluoro-4 -hydroxy-6 - {[(3-pyridinylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (218) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(4-pyridines) (219) N- (4-chlorobenzyl) -6 - {[(4-chlorobenzyl) amino] sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (1-methyl) amino] sulfonyl} -3-quinolinecarboxamide, (219) 220) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(4-methoxybenzyl) amine] ino] sulfonyl} -3-quinolinecarboxamide, (221) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(neopentylamino) sulfonyl] -3-quinolinecarboxamide, (222) N- (4- chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2-hydroxypropyl) amino] sulfonyl} -3-quinolinecarboxamide, (223) N- (4-chlorobenzyl) -6 - {[(2,3-dihydroxypropyl) (amino) sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (224) N- (4-chlorobenzyl) -6 - {[(2,2-diphenylethyl) amino] sulfonyl} -8-fluoro-4 -hydroxy-3-quinolinecarboxamide, (225) 11 - {[(3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) sulfonyl] amino} undecanoic acid, ( 226) 6 - ({[2- (acetylamino) ethyl] amino} sulfonyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (227) N- (4-chlorobenzyl) - 8-fluoro-4-hydroxy-6 - ({[2- (2-hydroxyethoxy) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (228) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy -6 - {[(2-hydroxyethyl) amino] sulfonyl} -3-quinolinecarboxamide; The method of claim 7, wherein the herpes virus is a human cytomegalovirus. 9 9 »· w r 4 9 9 9 9 9 9 9 9 9 99 99 999 b) C 1 -C 8 alkyl substituted with -OR ⁵ , -OP (= O) (OH) ₂ , -OPH (= O) (OH) or -OC (= O) R ¹⁰ , c) -OCR ¹¹ d) -CH = CH-R ^12, R ⁵ is a) -H or b) C1-4 alkyl, optionally substituted with -OH or C1-4 alkoxy, R 10 is C 1 -C 8 alkyl substituted with one to two of the following a) -C (= O) N (C _1-4 alkyl) (CH ₂ ) _n S (= O) ₂ OM ⁺ , b) -NH ₂ , rH is C 1 -C 4 alkyl substituted with -OR ⁵ or -OC (= O) R 6, R ¹² is C 1 -C 4 alkyl substituted with -OR ^5a M is sodium. 9 9 9 9 9 9 9 9 9 9 9 9 · 99 9 9 · · · · 9 9 9 9 ·· 99 9 9 9 '' -J / T '· »99 99 9 9 999' ΖΟΖ «99 9« 99 999 99 ' 999 «9 9 999 ' 99 99 999 R.15 is (a) -NH 2; or b) -NHNH ₂ R @ ¹ and R ¹ 7 _S j ou independently a) -H, b) C ₁ -C ₄ alkyl, c) -C (O =) C 1-4 alkyl; d) -C (O =) - (CH ₂ ) _m -aryl, aryl is phenyl or naphthyl, optionally substituted with R ¹⁸ , het is a 5-, 6- or 7-membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the heterocyclic ring is optionally linked to a benzene ring, wherein the aryl, het and benzene ring are optionally substituted with R ¹⁸ , R ¹⁸ is (a) halo, b) -NO ₂ , c) phenyl, optionally substituted with one to five -OH, -CN, halo, -NO ₂ , C 1 -C 8 alkyl, het, or -OC 1 -C 4 alkyl, d) C 1 -C 8 alkyl, optionally substituted with one to three halo, -CN, -NO ₂ , aryl, -SR 4, -OR 4, or -NR ⁷ R ⁸ , e) -OR 2 or (i) -SO ₂ NH ₂ , M is sodium, potassium or lithium, i is 1 or 2, m is 0, 1, 2 or 4, n is 0, 1, 2, 3 or 4, with the following reservations: (a) when R ⁷ , r 3 and R 6 are all hydrogen, then R ¹ is other than methoxy, (b) when R 6 is Cl and R ⁷ and R 6 are all hydrogen, then R ¹ is other than methyl, 263 (c) when R ¹ is hydrogen and R ² and R ⁴ are all fluoro, R ³ is het, then het is other than substituted piperazinyl, (d) when R and R ³ are all hydrogen, R ² is fluorine, then R ⁴ is other than fluorine, (e) when R ² and R ⁴ are all hydrogen, R ¹ is fluorine, then R ³ is other than fluorine, (f) when R ¹ and R ³ are all hydrogen, R ² is chlorine, then R ⁴ is other than chlorine, (g) when R ¹ , R ² and R ³ are all hydrogen, then R ⁴ is not bromine, (h) when R ¹ , R ³ and R ⁴ are all hydrogen, then R ² is not trifluoromethoxy, (i) when R ^1, R ² and R ⁴ are all hydrogen, then R ³ is not trifluoromethoxy, and (j) when R ^1, R ² and R ³ are all hydrogen, then R ⁴ is not morpholinyl; or a pharmaceutically acceptable salt thereof. 9 9 9 9 9 9 9 9 9 99 99 Claims ZOQ Q - € £ where A is: a) -CH ₂ - or b) -NH- R a R ² , R 3 and R ⁴ are independently a) -H, (b) halo, c) -CN, d) -NO ₂ , (e) aryl; f) het g) -OR ⁵ h) C ₁ -C ₁₂ alkyl, i) C ₁ -C ₁₂ alkyl substituted with one to three -CN, halo, -NO ₂ , -OR ⁵ , -C (= O) R ⁵ , -COOR ⁵ , het, aryl, -SR ⁵ , -OR ⁶ , - NR ⁷ R ⁸ , -OP (= O) (R ⁹ ) ₂ , -OPH (= O) R ⁹ , -OC (= O) R ¹⁰ , -O-glycyl, -O-valyl or -O-lysyl, j) -C1 CR11, k) -CH = CH-R ¹² ; l) - (CH ₂ ) _m C (= O) R 13, m) -SR ¹⁴ n) -C (= S) R ¹⁵ , o) - (CH ₂ ) _m -SO 1 R 13, (p) -NR ⁷ R ⁸ , 9ΑΠ ···· · · · έ · ν «<<<<<<<<<<<<<<<<< q) -NHSO ³ R ¹³ , r) R 1 and R ² taken together are het or C ₄ -C ₆ cycloalkyl; s) R ² and R ³ taken together are het or C ₄ -C 8 cycloalkyl, R ⁵ is a) -H, b) C 1-8 alkyl optionally substituted with one to three -OH, -CN, C ₁ -C ₄ alkoxy, halo, -NO ₂ , het or aryl, (c) aryl; or d) het, R ⁶ is a) -SO2C1-6 alkyl, (b) -SO ₂ - (CH ₂ ) _m -aryl or (c) -SO ₂ - (CH ₂ ) _m -het, R ⁷ and R ⁸ are independently a) -H, b) C 1 -C 8 alkyl optionally substituted with one to three -NO ₂ , halo, -CN, OR ⁵ , aryl, het, C 3. -C 1-3 cycloalkyl, C 1 -C 8 alkynyl, C 1 -C 8 alkenyl, -SR ⁴ R ⁴ or -NR ⁴ R ⁷ , c) aryl, d) het, e) - (CH ₂ ) _m -C (= O) OR 5, O - (CH ₂ ) _m -C (= O) R ⁵ or g) R ⁷ and R ⁸ taken together form het, R ⁹ is (a) -OH; or b) -OC ₁ -C ₈ alkyl, R ¹⁰ is a) -H, b) C ₁ -C ₈ alkyl, (c) -NR ⁷ R ⁸ ; 261 d) C ₁ -C ₈ alkyl substituted with one to two halo, het, -NR ⁷ R ⁸ , -COOH, -O (CH 2) _m COOH or -C (= O) N (C _1-4 alkyl) (CH ₂ ) n S ( = O) ₂ OM ⁺ RH is a) C 1 -C 8 alkyl, b) C 1 -C 8 alkyl substituted with one to three -CN, halo, -NO 2, -COOR ⁵ , -C (= O) R ⁵ , -SR ⁵ , aryl, -OR ⁵ , -NR ⁷ R ⁸ , -OP ( = O) (R ⁹ ) ₂ , -OPH (= O) R ⁹ , -OC (= O) r 10, -O-glycyl, -O-valyl or c) - (CH _{2) m} Het, R12 is a) -H, b) -CN, c) C ₁ -C ₈ alkyl, d) C ₁ -C ₈ alkyl substituted with one to three -CN, halo, -NO 2, -C (= O) R ⁵ , -COOR ⁵ , aryl, het, -SR ⁵ , -OR ⁵ , -NR ⁷ R ⁸ , -OP (= O) (R ⁹ ) ₂ or -OPH (= O) R ⁹ , e) -C (= O) R ⁵ or f) -COOR ⁵ , R ¹³ is a) C ₁ -C ₈ alkyl, b) C ₁ -C ₈ alkyl substituted with one to three -CN, halo, -NO 2, -C (= O) R ⁵ , het, aryl, COOR ⁵ , -SR ⁵ , -OR ⁵ or -NR ⁷ R ⁸ , c) het, d) aryl, (e) -NR ⁷ R ⁸ ; f) -OR ^5; or (g) halo; R ¹⁴ is a) C ₁ -C ₈ alkyl; or b) C ₁ -C ₈ alkyl substituted with one to three -CN, halo, -NO 2, -C (= O) R ⁵ , -COOR ⁵ , het, aryl, -OR ⁵ or -NR ⁷ R ⁸ ; · · · ♦ ·· 9 ··. 9 999 99 9 (10) N- (4-chlorobenzyl) -6 - [(E) -3-hydroxy-1-propenyl] -4-oxo-1,4-dihydro-3-quinolinecarboxamide; The method of claim 7, wherein the effective amount of the compound of claim 1 is administered orally, parenterally or topically. (11) trifluoroacetic acid salt of 3- (3 - {[(4-chlorobenzyl) amino) carbonyl) -4-hydroxy-6-quinolinyl) -2-propynyl-2,6-diaminohexanoate; (11) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide; The method of claim 7, wherein the effective amount of the compound of claim 1 is an amount of from 0.1 to 300 mg / kg body weight. • · (12) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propyl hydrogenphosphonate; (12) N- (4-chlorobenzyl) -4-hydroxy-8-methoxy-6- (3-methoxy-1-propynyl) -3-quinoline carboxamide; The method of claim 7, wherein the effective amount of the compound of claim 1 is an amount of from 1 to 30 mg / kg body weight. (13) N- (4-chlorobenzyl) -4-hydroxy-6- (2-thienyl) -3-quinolinecarboxamide; (13) N- (4-chlorobenzyl) -4-hydroxy-7- (4-hydroxybutyl) -3-quinolinecarboxamide; (14) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide; (15) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2-bromoacetate; (16) 3- (3 - {[(4-chlorobenzyl) amino) carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl (2-amino-3-methylbutanoate); (17) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -8-methoxy-3-quinolinecarboxamide; (18) 2 - [{8- [3- (3 - {[(4-chlorobenzyl) amino) carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propoxy] -8-oxooctanoyl) (methyl) amino sodium-1-ethanesulfonate, (19) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyldihydrogenphosphate); (20) 3- (3 - (((4-chlorobenzyl) amino) carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2,6-bis [(tert-butoxycarbonyl) amino] hexanoate; (21) tert-butyl (3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propylphosphonate); (22) trifluoroacetic acid salt of 3- (3 - [(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2,6-diaminohexanoate; (23) N- (4-chlorobenzyl) -4-hydroxy-6 - [(2-hydroxyethyl) amino) -3-quinolinecarboxamide; (24) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxybutyl) -3-quinolinecarboxamide; I · ·· A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. The compound of claim 1 which is (1) N - [(4-chlorophenyl) methyl] -4-hydroxy-7-trifluoromethyl-3-quinolinecarboxamide, (2) 7-amino-N - [(4-chlorophenyl) (methyl) -4-hydroxy-3-quinolinecarboxamide, (3) N - [(4-chlorophenyl) methyl] -8-fluoro-4,6-dihydroxy-3-quinolinecarboxamide, (4) 6-bromo-N- [ (4-chlorophenyl) methyl] -8-fluoro-3-quinolinecarboxamide, (5) N - [(4-chlorophenyl) methyl] -8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide, (6) N - [(4-chlorophenyl) methyl] -4-hydroxy-3-quinolinecarboxamide, (7) N - [(4-chlorophenyl) methyl] -4-hydroxy-7-methoxy-3-quinolinecarboxamide, (8) N- [ (4-chlorophenyl) methyl] -4-hydroxy-5,7-bis (trifluoromethyl) -3-quinolinecarboxamide, (9) N - [(4-chlorophenyl) methyl] -7-fluoro-4-hydroxy-3-quinolinecarboxamide (10) N - [(4-chlorophenyl) methyl] -6-fluoro-4-hydroxy-3-quinolinecarboxamide, (n) N - [(4-chlorophenyl) methyl] -4-hydroxy-7-methyl-3 (12) N - [(4-chlorophenyl) methyl] -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (13) N - [(4-chlorophenyl) methyl] -4-hydroxy-6-nitro -3-quinolinecarboxamide, (14) N - [(4-chlorophenyl) methyl l] -5,6,7,8-tetrafluoro-4-hydroxy-3-quinolinecarboxamide, (15) N - [(4-chlorophenyl) methyl] -6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxamide (16) 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid 2- (4-chlorophenyl) hydrazide, (17) N - [(4-chlorophenyl) methyl] -5,8-difluoro-4 -hydroxy-3-quinolinecarboxamide, (18) N - [(4-chlorophenyl) methyl] -7,8-difluoro-4-hydroxy-3-quinolinecarboxamide, (19) 6-benzoyl-N- (4-chlorobenzyl) -4-hydroxy-3-quinolinecarboxamide, (20) N - [(4-chlorophenyl) methyl] -4-hydroxy-8-methoxy-3-quinolinecarboxamide, (21) 6-chloro-N - [(4-chlorophenyl) methyl] -4-hydroxy-3-quinolinecarboxamide, (22) N - [(4-chlorophenyl) methyl] -4-hydroxy-6-methyl-3-quinolinecarboxamide, (23) N - [(4-chlorophenyl) methyl] -4-hydroxy-6-methoxy-3-quinolinecarboxamide, (24) N - [(4-chlorophenyl) methyl] -6-cyano-4-hydroxy-3-quinolinecarboxamide, (25) 7- (acetylamino) -N- [(4-chlorophenyl) methyl] -4-hydroxy-3-quinolinecarboxamide, (26) N - [(4-chlorophenyl) methyl] -4-hydroxy-7 - [(methylsulfonyl) amino] -3-quinolinecarboxamide, (27) N - [(4-chlorophenyl) methyl] -7- (dimethyla (mino) -4-hydroxy-3-quinolinecarboxamide 272 (28) 6-Amino-N - [(4-chlorophenyl) methyl] -4-hydroxy-3- quinolinecarboxamide, (29) N - [(4-chlorophenyl) methyl] -4-hydroxy-6 - [(methylsulfonyl) amino] -3-quinolinecarboxamide. (30) N - [(4-chlorophenyl) methyl] -6- (dimethylamino) -4-hydroxy-3-quinolinecarboxamide; (31) 6- (acetylamino) -N - [(4-chlorophenyl) methyl] -4- hydroxy-3-quinolinecarboxamide, (32) N - [(4-chlorophenyl) methyl] -4-hydroxy-7- (1-pyrrolyl) -3-quinolinecarboxamide, (33) N - [(4-chlorophenyl) methyl] - 4-hydroxy-7 - [(phenylsulfonyl) amino] -3-quinolinecarboxamide, (34) N- [(4-chlorophenyl) methyl] -4-hydroxy-7 - [[(phenylmethyl) sulfonyl] amino] - 3-quinolinecarboxamide, (35) N - [(4-chlorophenyl) methyl] -7 - [[(4-chlorophenyl) sulfonyl] amino] -4-hydroxy-3-quinolinecarboxamide, (36) 2- (4-chlorophenyl) 8-fluoro-4-hydroxy-3-quinolinecarboxylic acid hydrazide, (37) N - [(4-chlorophenyl) methyl] -8-fluoro-4-hydroxy-6-methyl-3-quinolinecarboxamide, (38) N- (4-chlorobenzyl) -8-hydroxy- [1,3] -dioxolo [4,5-g] quinoline-7-carboxamide, (3 9) N - [(4-chlorophenyl) methyl] -4-hydroxy-6 - iodo-3-quinolinecarboxamide, (40) N - [(4-chlorophenyl) methyl] -6- (cyanomethyl) -4-hydroxy-3-quinolinecarboxamide, (41) N - [(4-chlorophenyl) methyl] -4 , 5-dihydroxy-3-quinolinecarboxamide, (42) 7,8-dichloro-N - [(4-chloro) orphenyl) methyl] -4-hydroxy-3-quinolinecarboxamide, (43) N - [(4-chlorophenyl) methyl] -4,6-dihydroxy-3-quinolinecarboxamide, (44) N - [(4-chlorophenyl) methyl] -4,8-dihydroxy-3-quinolinecarboxamide, (45) 8-chloro-N - [(4-chlorophenyl) methyl] -4-hydroxy-3-quinolinecarboxamide, (46) N - [(4-chlorophenyl) methyl] -4-hydroxy-6 - [[(1-phenyl-1H-pyrazol-5-yl) amino] sulfonyl] -3-quinolinecarboxamide, (47) N - [(4-chlorophenyl) methyl] -8-cyano-4 -hydroxy-3-quinolinecarboxamide, (48) N - [(4-chlorophenyl) methyl] -4-hydroxy-8-nitro-3-quinolinecarboxamide, (49) 7-amino-N - [(4-chlorophenyl) methyl] -4-hydroxy-8-methyl-3-quinolinecarboxamide, (50) N - [(4-chlorophenyl) methyl] -6-cyano-8-fluoro-4-hydroxy-3-quinolinecarboxamide, (51) 6- (aminothioxomethyl) ) -N - [(4-chlorophenyl) methyl] -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (52) N - [(4-chlorophenyl) methyl] -8-fluoro-4-hydroxy-6- (3- (53) 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylic acid 2- (4-chlorophenyl) hydrazide, (54) 2- (4-chlorophenyl) hydroxy-1-propynyl-3-quinolinecarboxamide 8-fluoro-4-hydroxy-6-methyl-3-quinolinecarbone hydrazide xylic acids, (55) N - [(4-chlorophenyl) methyl] -7-chloro-4-hydroxy-3-quinolinecarboxamide, (56) N - [(4-chlorophenyl) methyl] -6-bromo-4-hydroxy -3-quinolinecarboxamide, 273 (57) N - [(4-chlorophenyl) methyl] -4-hydroxy-6-phenyl-3-quinolinecarboxamide, (58) N - [(4-chlorophenyl) methyl] -8-chloro-4-hydroxy-5 -trifluoromethyl-3-quinolinecarboxamide, (59) N - [(4-chlorophenyl) methyl] -6,8-dimethoxy-4-hydroxy-3-quinolinecarboxamide, (60) N - [(4-chlorophenyl) methyl] -6 , 7-dimethoxy-4-hydroxy-3-quinolinecarboxamide, (61) N - [(4-chlorophenyl) methyl] -4-hydroxy-5-methyl-3-quinolinecarboxamide, (62) N - [(4-chlorophenyl) methyl] -6- (1,1-dimethylethyl) -4-hydroxy-3-quinolinecarboxamide, (63) N - [(4-chlorophenyl) methyl] -7,8-dihydro-4-hydroxy-6H-cyclopenta [g] quinoline-3-carboxamide, (64) N - [(4-chlorophenyl) methyl] -1,4-dihydro-8- (methylthio) -4-oxo-3-quinolinecarboxamide, (65) N - [(4-chlorophenyl)] methyl] -9-hydroxythiazolo [5,4-f] quinoline-8-carboxamide, (66) 2 - [(8 - {[3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy) (67) 2 - [(8 - {[3- (3 - {[(4-chloro-2-propyl) oxy] -8-oxooctanoyl) (methyl) amino] -1-ethanesulfonate; chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) -2-propynyl] oxy} -8-oxooctanoyl) (methyl (amino) -1-ethanesulfonate, (68) 2 - [{8- [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propoxy] -8-oxooctanoyl sodium (methyl) amino] -1-ethanesulfonate, (69) N- (4-chlorobenzyl) -4-hydroxy-7 - {[(1-naphthylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (70) N- (4-chlorobenzyl) -4-hydroxy-7- (methylsulfanyl) -3-quinolinecarboxamide, (71) N - [(4-chlorophenyl) methyl] -4-hydroxy-6 - [(phenylmethyl) thio] -7- ( trifluoromethyl) -3-quinolinecarboxamide, (72) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) propylhydrogenphosphonate, (73) N - [(4-chlorophenyl) (methyl) -8-fluoro-4-hydroxy-6- (2-thiazolyl) -3-quinolinecarboxamide, (74) N - [(4-chlorophenyl) methyl] -8-fluoro-4-hydroxy-6- (2) -thiophenyl) -3-quinolinecarboxamide, (75) N - [(4-chlorophenyl) methyl] -4-hydroxy-5-trifluoromethyl-3-quinolinecarboxamide, (76) N - [(4-chlorophenyl) methyl] -8- Fluoro-4-hydroxy-6- (2-methylphenyl) -3-quinolinecarboxamide, (77) N - [(4-chlorophenyl) methyl] -6,7-difluoro-4-hydroxy-8- (tetrahydro-2H-pyran) -4-oxy) -3-quinolinecarboxamide, (78) N - [(4-chloroph enyl) methyl] -6,7-difluoro-4-hydroxy-8-methoxy-3-quinolinecarboxamide, (79) N - [(4-chlorophenyl) methyl] -7,8-methoxy-6-fluoro-4-hydroxy -3-quinolinecarboxamide, (80) N - [(4-chlorophenyl) methyl] -6,8-difluoro-4-hydroxy-7- (4- (hydroxymethyl) phenoxy) -3-quinolinecarboxamide, (81) N- [ (4-chlorophenyl) methyl] -6,8-difluoro-4-hydroxy-7-methoxy-3-quinolinecarboxamide, 274 * · (82) N - [(4-chlorophenyl) methyl] -6,8-difluoro-4-hydroxy-7- (2- (methoxy) ethoxy) -3-quinol inkcarboxamide d, (83) N- [ (4-chlorophenyl) methyl] -6,7-difluoro-4-hydroxy-8- (2- (methoxy) ethoxy) -3-quinolinecarboxamide, (84) N - [(4-chlorophenyl) methyl] -7,8 -di (2- (methoxy) ethoxy) -6-fluoro-4-hydroxy-3-quinolinecarboxamide, (85) N - [(4-chlorophenyl) methyl] -6,8-difluoro-4-hydroxy-7- ( 1-methylethoxy) -3-quinolinecarboxamide, (86) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (1,3-thiazol-2-yl) -3-quinolinecarboxamide, (87) N (88) N- (4-chlorobenzyl) -6,8-difluoro-4-hydroxy-7 - [(2-methoxyethyl) amino] -3-quinolinecarboxamide; 1-pentynyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (89) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (2-pyridinyl) -3-quinolinecarboxamide, (90) (N) - (4-chlorophenyl) -4-hydroxy-6-iodo-3-quinolinecarbohydrazide, (91) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- [2- (2-pyridinyl)] (ethynyl) -3-quinolinecarboxamide, (92) N- (4-chlorobenzyl) -6,8-difluoro-4-hydroxy-7 - [(2-hydroxyethyl) amino] -3-quinolinecarboxamide, (93) N- ( 4-chlorob enzyl) -8-fluoro-4-hydroxy-6- (4-hydroxy-1-butynyl) -3-quinolinecarboxamide, (94) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3) -methoxy-1-propynyl) -3-quinolinecarboxamide, (95) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxy-1-butynyl) -3-quinolinecarboxamide, (96) 6- (4-bromo-2-thienyl) -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (97) N- (4-chlorobenzyl) -8-fluoro-6- ( hydrazinocarbothioyl) -4-hydroxy-3-quinolinecarboxamide, (98) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (4-hydroxybutyl) -3-quinolinecarboxamide, (99) N- (4- chlorobenzyl) -8-fluoro-4-hydroxy-6- (5-methyl-1,3,4-thiadiazol-2-yl) -3-quinolinecarboxamide, (100) N- (4-chlorobenzyl) -4-hydroxy- 7- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide, (101) 7- (aminocarbothioyl) -N- (4-chlorobenzyl) -4-hydroxy-3-quinolinecarboxamide, (102) N- (4-chlorobenzyl) ) -8-fluoro-4-hydroxy-6- (3-methoxypropyl) -3-quinolinecarboxamide, (103) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(Z) -4- hydroxy-1-butenyl) -3-quinolinecarboxamide, (104) N- (4-chlorobenzyl) -6- (5-cyanopentyl) -8-fluoro-4-hydroxy- 3-quinolinecarboxamide, (105) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxy-3-methylbutyl) -3-quinolinecarboxamide, (106) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (5-hydroxy-1-pentynyl) -3-quinolinecarboxamide, (107) 6- {3- [benzyl (methyl) amino] propyl} -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (108) methyl [3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinecarboxylate], (109) N - (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxypropyl) -3-quinolinecarboxamide, (110) N- (4-chlorobenzyl) -4-hydroxy-7- (3-hydroxypropyl) - 3-quinolinecarboxamide, (111) ethyl [(E) -3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) -2-propenoate], (112) 2 - [{8- [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propoxy] -8-oxooctanoyl} (methyl) amino] Sodium -1-ethanesulfonate, (113) 2 - [{8 - [3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propanoic acid, (114) ) 5- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinoline yl) -4-pentinoic acid, (115) N - [(4-chlorophenyl) methyl] -9-hydroxy-3H-pyrazolo [4,3-f] quinoline-8-carboxamide, (116) N - [(4) (117) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8-methoxybenzyl) -4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide -3-quinolinecarboxamide, (118) N- (4-chlorobenzyl) -4-hydroxy-8-methoxy-6- (3-methoxy-1-propynyl) -3-quinolinecarboxamide, (119) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -8-methoxy-3-quinolinecarboxamide, (120) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8- (trifluoromethyl) -3-quinolinecarboxamide, (121) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-propynyl) -8- (trifluoromethoxy) -3-quinolinecarboxamide, (122) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxypropyl) -8- (trifluoromethyl) -3-quinolinecarboxamide, (123) N- (4-chlorobenzyl) -4-hydroxy-8- (2- hydroxyethoxy) -6- (3-hydroxypropyl) -3-quinolinecarboxamide, (124) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1,1-dimethylpropyl) -3-quinolinecarboxamide, (125) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- [3- (m (126) N- (4-chlorobenzyl) -6- [3- (ethylsulfanyl) -1-propynyl] -8-fluoro-4-hydroxy-3-quinolinecarboxamide, 276 (127) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(Z) -3- (methylsulfanyl) - 1-Propenyl] -3-quinoline carboxamide, (128) N- (4-chlorobenzyl) -6 - [(Z) -3- (ethylsulfanyl) -1-propenyl] -8-fluoro-4-hydroxy-3-quinolinecarboxamide , (129) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- [3- (methylsulfanyl) propyl] -3-quinolinecarboxamide, (130) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) -2-propynyl formate, (131) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-hydroxybutyl) -3 quinolinecarboxamide, (132) N- (4-chlorobenzyl) -6 - [(E) -2-cyanoethenyl] -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (133) N- (4-chlorobenzyl) -4 -hydroxy-6- (3-hydroxy-1-propynyl) -3-quinolinecarboxamide, (134) N- (4-chlorobenzyl) -6 - [(Z) -3-hydroxy-1-propenyl] -4-oxo -1,4-dihydro-3-quinolinecarboxamide, (135) N- (4-chlorobenzyl) -6 - [(E) -3-hydroxy-1-propenyl] -4-oxo-1,4-dihydro-3- quinolinecarboxamide, (136) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(Z) -3-hydroxy-1-propenyl] -3-quinolinecarboxamide, (137) N- (4-) chlorobenzyl) -6- (2-cyanoethyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (138) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-oxopropyl) - 3-quinolinecarboxamide, (139) N- (4-chlorobenzyl) -4-hydroxy-7- (4-hydroxybutyl) -3-quinolinecarboxamide, (140) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy- 6- (hydroxymethyl) -3-quinolinecarboxamide, (141) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl methanesulfonate, (142) N- ( 4-chlorobenzyl) -8-fluoro-6- (3-fluoro-1-propynyl) -4-hydroxy-3-quinolinecarboxamide, (143) N- (4-chlorobenzyl) -4-hydroxy-6- (3- hydroxypropyl) -3-quinolinecarboxamide, (144) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2-bromoacetate, (145) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2 - [(tert-butoxycarbonyl) amino] -3-methylbutanoate, (146) 3 - (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2- (4-morpholinyl) acetate, (147) 3- (3 - {[ (4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) p Ropyl 2- (dimethylamino) acetate 277 (148) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl-2-amino-3-methylbutanoate, (149) 3- ( 3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) -2-propynylphenylcarbamate, (150) N- (4-chlorobenzyl) -4-hydroxy-6-propyl- 3-quinolinecarboxamide, (151) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxy-1-butynyl) -3-quinolinecarboxamide, (152) N- (4-chlorobenzyl) -8-fluoro- 4-hydroxy-6 - [(E) -3-oxo-1-butenyl] -3-quinolinecarboxamide, (153) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (5-hydroxypentyl) -3-quinolinecarboxamide, (154) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl-2,6-bis [(tert-butoxycarbonyl) (amino) hexanoate, (155) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propyl 2,6-diaminohexanoate, trifluoroacetic acid salt, ( 156) N- (4-chlorobenzyl) -4-hydroxy-6- (3-hydroxybutyl) -3-quinolinecarboxamide, (157) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (4). -morpholinylmethyl) -3-quinolinecarboxamide, (158) 3- (3 - {[(4-chlorobenzyl) amino] k arbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) propylphenylcarbamate, (159) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (3-oxobutyl) -3-quinolinecarboxamide; ) 3- (3 - {[(4-chlorobenzyl) amino] carbonyl] -4-hydroxy-6-quinolinyl) -2-propynyl-2,6-bis [(tert-butoxycarbonyl) amino] hexanoate, (161) 3- (3 - ([(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinyl) -2-propynyl-2,6-diaminohexanoate, trifluoroacetic acid salt, (162) N- (4-chlorobenzyl) -4-hydroxy-6 - [(2-hydroxyethoxy) methyl] -3-quinolinecarboxamide, (163) N- (4-chlorobenzyl) -4-hydroxy-6 - {[2-hydroxy-1- (hydroxymethyl) ethoxy] methyl} -3-quinolinecarboxamide, (164) methyl [3 - {[(4-chlorobenzyl) amino] carbonyl} -4-hydroxy-6-quinolinecarboxylate], (165) N- (4-chlorobenzyl) -4-hydroxy -6- (hydroxymethyl) -3-quinolinecarboxamide, (166) 6-chloro-N- (4-chlorobenzyl) -4-hydroxy-8-methyl-3-quinolinecarboxamide, (167) N- (4-chlorobenzyl) -5 , 6,8-trifluoro-4-hydroxy-3-quinolinecarboxamide, (168) N- (4-chlorobenzyl) -6,7-difluoro-4-hydroxy-3-quinolinecarboxamide, (169) N- (4-chlorobenzyl) -8-fluo r-4-hydroxy-6- (methylsulfanyl) -3-quinolinecarboxamide, (170) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(hydroxyethyl) sulfanyl] -3-quinolinecarboxamide, (171) 6 - [(2-aminoethyl) sulfanyl] -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide hydrobromide, (172) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2-methoxyethoxy) methyl] sulfanyl} -3-quinolinecarboxamide, (173) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[2- (4-morpholinyl) ethyl] sulfanyl} -3-quinolinecarboxamide, (174) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (methylsulfinyl) -3-quinolinecarboxamide, (175) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (methylsulfonyl) -3-quinolinecarboxamide, (176) N- (4-chlorobenzyl) -8- fluoro-4-hydroxy-6 - [(2-hydroxyethyl) sulfinyl] -3-quinolinecarboxamide, (177) N- (4-chlorobenzyl) -4-hydroxy-6- (2-thienyl) -3-quinolinecarboxamide, (178) ) N- (4-chlorobenzyl) -4-hydroxy-6- (2-hydroxyethoxy) -3-quinolinecarboxamide, (179) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- (4-morpholinylcarbonyl) ) -3-quinolinecarboxamide, (180) N ^3- (4-chlorobenzyl) -8-fluoro-4-hydroxy-N - (2-hydroxyethyl) -3,6-quinolinedicarboxamide, (181) N ^3- (4-) chlorobenzyl) -8-fluoro-4-hydroxy-N ^I 'N ~ 6-dimethyl-3,6-chinolindikarboxamid, (182) N ³ - (4-chlorobenzyl) -8-fluoro-4-hydroxy-N? - (6-hydroxyphenethyl) -3,6-quinolinedicarboxamide, (183) N ³ - (4-chlorobenzyl) -8-fluoro-4-hydroxy-3,6-quinolinedicarboxamide, (184) N ³ , N -bis (4-chlorobenzyl) -8-fluoro-4-hydroxy-3,6-quinolinedicarboxamide (185) 6-amino-N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (186) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- { [4-methoxyphenyl) sulfonyl] amino} -3-quinolinecarboxamide, (187) N- (4-chlorobenzyl) -4-hydroxy-6 - [(2-hydroxyethyl) amino] -3-quinolinecarboxamide, (188) N- ( 4-chlorobenzyl) -6- [ethyl (2-hydroxyethyl) amino] -4-hydroxy-3-quinolinecarboxamide, (189) N- (4-chlorobenzyl) -4-hydroxy-6- (2-oxo-1,3) -oxazolidin-3-yl) -3-quinolinecarboxamide, (190) N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide, (191) N- (4-chlorobenzyl) - 8-fluoro-4-hydroxy-6 - {[(1-naphthylmethyl) amino]) sulfonyl} -3-quinolinecarboxamide, (192) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- { [(2- (1-H-indol-3-yl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (193) N- (4-chlorobenzyl) -8-fluoro-6 - {[(2-furylmethyl) amino] sulfonyl} -4-hydroxy-3-quinolinecarboxamide, (194) 6 - {[bis (2-hydroxyethyl) amino] sulfonyl} -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide • 0 0> 0 · 0 0 0 279 • 00 (195) ethyl [2 - {[(3 - {[(4-chlorobenzyl) amino] carbonyl} -8-fluoro-4-hydroxy-6-quinolinyl) sulfonyl] amino} acetate], (196) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2-hydroxyethyl) amino] sulfonyl} -3-quinolinecarboxamide, (197) N- (4-chlorobenzyl) -8-fluoro- 4-hydroxy-6- (4-morpholinylsulfonyl) -3-quinolinecarboxamide, (198) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2-pyridinylmethyl) amino] sulfonyl} -3 -quinolinecarboxamide, (199) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - [(2-pyridinylamino) sulfonyl] -3-quinolinecarboxamide, (200) N- (4-chlorobenzyl) -6- {[cyclohexylmethyl) amino] sulfonyl} -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (201) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - ({[2- (1- methyl-2-pyrrolidinyl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (202) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- ({[2- (1-pyrrolidinyl) ethyl] ethyl) amino) sulfonyl) -3-quinolinecarboxamide, (203) N- (4-chlorobenzyl) -8-fluoro-6 - {[(2-furylmethyl) amino] sulfonyl} -4-hydroxy-3-quinolinecarboxamide, (204) N- (4-chlorobenzyl) -6 - ({[3- (cyclohexylamino)] - (propyl) amino} sulfonyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, (205) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(1-naphthylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (206) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {{2- (1-H-imidazol-4-yl) ethyl] amino} sulfone 1) -3-quinolinecarboxamide, (207) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(tetrahydro-2-furanylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (208) N - (4-chlorobenzyl) -8-fluoro-4-hydroxy-6 - {[(2-thienylmethyl) amino] sulfonyl} -3-quinolinecarboxamide, (209) N- (4-chlorobenzyl) -8-fluoro-4- hydroxy-6 - {[(2- (1H-indol-3-yl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (210) N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-6- ({[2- (5-methoxy-1H-indol-3-yl) ethyl] amino} sulfonyl) -3-quinolinecarboxamide, (211) 6 - {[(1,3-benzodioxol-5-ylmethyl) amino} sulfonyl} -N- (4-chlorobenzyl) -8-fluoro-4-hydroxy-3-quinolinecarboxamide, φφ ·· (14) N - ((4-chlorobenzyl) -4-hydroxy-6 - [(2-hydroxyethoxy) methyl] -3-quinolinecarboxamide; or (15) N- (4-chlorobenzyl) -4-hydroxy-6- (4-morpholinylmethyl) -3-quinolinecarboxamide.