Discovery of 7-aryl-substituted (1,5-naphthyridin-4-yl)ureas as Aurora kinase inhibitors

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DOI: 10.1002/cmdc.201300384

Discovery of 7-Aryl-Substituted (1,5-Naphthyridin-4-yl)

ureas as Aurora Kinase Inhibitors

Julien Defaux,^[a]Maud Antoine,^{[a, c]}Marc Le Borgne,^{[a, d]}Tilmann Schuster,^[b]Irene Seipelt,^[b]

Babette Aicher,^[b]Michael Teifel,^[b]Eckhard Gꢀnther,^[b]Matthias Gerlach,^[b]and

Pascal Marchand*^[a]

As part of our research projects to identify new chemical enti-

ties of biological interest, we developed a synthetic approach

and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)-

ureas as a novel class of Aurora kinase inhibitors for the treat-

ment of malignant diseases based on pathological cell prolifer-

ation. 1,5-Naphthyridine derivatives showed excellent inhibito-

ry activities toward Aurora kinases A and B, and the most

active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-

yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC₅₀values of 13

and 107 nm against Aurora kinases A and B, respectively. In ad-

dition, the selectivity toward a panel of seven cancer-related

protein kinases was highlighted. In vitro ADME properties were

also determined in order to rationalize the difficulties in corre-

lating antiproliferative activity with Aurora kinase inhibition. Fi-

nally, the good safety profile of these compounds imparts

promising potential for their further development as anticanc-

er agents.

Introduction

Aurora kinases are a family of three highly homologous serine/

threonine protein kinases that play a critical role in regulating

many of the processes pivotal to mitosis.^[1]Three Aurora kinas-

es, designated Aurora A, B, and C, have so far been identified

in mammalian cells. They are involved in multiple mitotic

events such as regulation of the spindle assembly checkpoint

pathway and in the function of centrosomes, cytoskeleton,

and cytokinesis.^[2]

meres from prophase to the metaphase/anaphase transition,

and is required for correct chromosome segregation and cyto-

kinesis. Aurora C plays a role in the regulation of cilia and flag-

ella, localizes to centrosomes from anaphase to cytokinesis,

and is predominantly expressed in testis. Overexpression of

Aurora A and B has been reported in a number of human ma-

lignancies, including colon, breast, pancreatic, and ovarian

tumors. The role of Aurora C within tumorigenesis is less well

understood.

Aurora A localizes to centrosomes during early S phase, and

is involved in centrosome maturation and separation, bipolar

spindle assembly, mitotic entry, and mitotic exit. Aurora B,

a chromosomal passenger protein, is localized to the centro-

Both Aurora A and B have been validated as targets for

cancer therapy.^[3]A number of Aurora kinase inhibitors have

been described in recent years,^[4]and there are currently about

30 Aurora kinase inhibitors in various stages of preclinical and

clinical development.^[5]For this reason, continued efforts are

being made by numerous research groups to discover new

small molecules that target Aurora A or B selectively, or that

display dual inhibitory activity. A broad diversity of chemical

scaffolds has been reported, including pyrazolopyrimidine

[a] Dr. J. Defaux, Dr. M. Antoine, Prof. M. Le Borgne, Prof. P. Marchand

Universitꢀ de Nantes, Nantes Atlantique Universitꢀs

Laboratoire de Chimie Thꢀrapeutique, Cibles et Mꢀdicaments des

Infections et du Cancer IICiMed EA 1155

UFR des Sciences Pharmaceutiques et Biologiques

1 rue Gaston Veil, 44035 Nantes (France)

E-mail: pascal.marchand@univ-nantes.fr

1

(VX-680)^[6]and 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

2

(PHA739358)^[7]as pan-Aurora inhibitors, 5H-pyrimido[5,4-d]-

[2]benzazepine derivative 3 (MLN8237)^[8]as a selective Auro-

ra A inhibitor, and pyrazoloquinazoline 4 (AZD1152)^[9]as a selec-

tive Aurora B inhibitor (Figure 1).

[b] Dr. T. Schuster, Dr. I. Seipelt, Dr. B. Aicher, Dr. M. Teifel, Dr. E. Gꢁnther,

Dr. M. Gerlach

Æterna Zentaris GmbH

Weismuellerstrasse 50, 60314 Frankfurt/Main (Germany)

[c] Dr. M. Antoine

More recently, imidazo[4,5-b]pyridine-based derivatives were

reported as potent pan-Aurora kinase inhibitors.^[10]Compound

5 (Figure 2), an orally bioavailable dual FLT3/Aurora kinase in-

hibitor, has been selected as a preclinical development candi-

date for the treatment of acute myeloid leukemia. Bisanilino-

pyrimidine 6 was identified as a highly potent and selective

cell-permeable inhibitor of Aurora A and B.^[11]Pyrrolotriazine 7

was shown to display the same pharmacological and pharma-

cokinetic properties.^[12]In addition, it exhibits durable antitu-

Current address: AtlanChim Pharma

3 rue Aronnax, 44821 Saint Herblain Cedex (France)

[d] Prof. M. Le Borgne

Current address: Universitꢀ de Lyon

Universitꢀ Lyon 1, Facultꢀ de Pharmacie-ISPB

EA 4446 Biomolꢀcules Cancer et Chimiorꢀsistances

SFR Santꢀ Lyon-Est CNRS UMS3453-INSERM US7

8 avenue Rockefeller, 69373 Lyon Cedex 8 (France)

Supporting information for this article is available on the WWW under

http://dx.doi.org/10.1002/cmdc.201300384.

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of kinase inhibitors, we previous-

ly described

a synthetic ap-

proach and the biological evalu-

ation of promising pyridopyra-

zines for the treatment of malig-

nant diseases based on patho-

logical cell proliferation.^[19]We

were especially interested in

obtaining 1,5-naphthyridine de-

rivatives, considered bioisosteres

of pyrido[2,3-b]pyrazines (Fig-

ure 3).^[20]Many 1,5-naphthyridine

derivatives have been found to

exert biological activities in

a broad range of therapeutic

areas.^[21,22]Nevertheless, only

a few reports discuss 1,5-naph-

thyrine-based kinase inhibitors

as antitumor agents.^[23]Herein

we report the development of

Figure 1. Structures of Aurora kinase inhibitors in clinical development.

mor activity in a nude rat HCT116 tumor xenograft model and

good in vivo tolerability. Imidazo[1,2-a]pyrazine 8 was de-

scribed as a dual Aurora A/B kinase inhibitor, and off-target

kinase selectivity was achieved by introducing a 3-fluoro-4-py-

ridylacetamide moiety on the pyrazole ring.^[13]

new

(1,5-naphthyridin-4-yl)ureas

substituted

at

the

7-position of the ring by an aryl group (Figure 3). Biological

evaluations were performed in order to identify new potent

Aurora kinase inhibitors.

The 5,6-diphenylfuro[2,3-d]pyrimidin-4-amine derivative

9

exhibited antiproliferative activity in tests against the HCT116

colon cancer cell line (IC₅₀=400 nm) and showed pan-Aurora

kinase inhibition (Figure 2).^[14]Structure-based lead optimiza-

tion of 9 resulted in the identification of 10 as a potent Aurora

kinase inhibitor with improved physicochemical properties as

well as good in vivo efficacy in a HCT116 tumor xenograft

mouse model.^[14]The rational redesign of furopyrimidine 9 led

to the identification of quinazoline-based Aurora kinase inhibi-

tor 11 with improved antitumor activity (HCT116 IC₅₀=

23 nm).^[15]

Results and Discussion

Chemistry

The synthetic route of target heterocyclic ureas 38–60 is out-

lined in Schemes 1 and 2. The strategy required initial access

to the key precursor, 3-bromo-8-chloro-1,5-naphthyridine 18a.

The 1,5-naphthyridine ring was built via Skraup synthesis, from

3-amino-5-bromopyridine 15 in the presence of glycerol under

oxidative conditions to afford compound 16 in moderate yield

(Scheme 1).^[24,21c,e]Starting material 15 was commercially avail-

able or was readily prepared via Hofmann rearrangement of

5-bromopyridine-3-carboxamide obtained by subsequent

chlorination and amination of the corresponding pyridine-3-

carboxylic acid.^[25]As previously reported,^[24b]cyclization took

A literature survey revealed that fused polycyclic derivatives

were very recently described as pan-Aurora kinase inhibitors.

5H-Benzo[c][1,8]naphthyridin-6-ones 12 exhibited selective

sub-nanomolar Aurora kinase inhibition coupled with antiproli-

ferative effects in a pancreatic

cell line, MIAPaCa-2.^[16]Benzo[e]-

pyridoindolones 13 provided

water-soluble

inhibitors

of

Aurora kinases, exhibiting anti-

proliferative activity in the nano-

molar range (for maleate salts,

HeLa cells IC₅₀=114 nm (13a)

and HeLa cells IC₅₀=63 nm

(13b)).^[17]Finally, phthalazinone

pyrazoles 14 showed high Auro-

ra A inhibitory activity, with

>1000-fold selectivity over Au-

rora B and good oral bioavaila-

bility.^[18]

Scheme 1. Reagents and conditions: a) glycerol, FeSO₄·7H₂O, H₃BO₃, H₂SO₄, m-NO₂PhSO₃Na, 1358C, 18 h;

b) mCPBA, CH₂Cl₂, RT, 18 h; c) POCl₃, CH₂Cl₂, reflux, 2.5 h; d) Meldrum’s acid, CH(OEt)₃, EtOH, 908C, 2 h;

As part of our ongoing efforts

to identify new chemical classes e) Dowtherm A, 2408C, 10 min; f) POCl₃, reflux, 2 h.

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of byproducts such as 1,2,3,4-tetrahydro-1,5-naph-

thyridine derivatives and 3-methyl- or 3-ethyl-1,5-

naphthyridine analogues has also been described.^[24b]

Meisenheimer reaction of 1,5-naphthyridine-N-oxide

has been reported to afford the 2- and 4-chloro-1,5-

naphthyridine isomers.^[26]Thus, 3-bromo-1,5-naph-

thyridine 16 underwent N-oxidation with 3-chloro-

perbenzoic acid to give 7-bromo-1,5-naphthyridine-1-

oxide 17a in 60% yield, but in mixture with its regio-

isomer 17b in 20% yield.^[21e]The compounds were

easily separated by silica gel chromatography. Com-

pound 17a then reacted with phosphorus(III) oxy-

chloride in dichloromethane at reflux to furnish

target 3-bromo-8-chloro-1,5-naphthyridine 18a in

54% yield. As expected,^[26]7-bromo-2-chloro-1,5-

naphthyridine isomer 18b was formed and isolated

in 18% yield. This could be an interesting approach

to obtain both isomers for further SAR study, but the

goal of this medicinal chemistry work was to provide

new 4,7-disubstituted 1,5-naphthyridines of biological

interest. For this reason, we decided to find an alter-

native synthetic pathway to circumvent the forma-

tion of isomers and to enhance the overall yield of

17% for three steps.

The synthesis of 3-bromo-8-chloro-1,5-naphthyri-

dine was previously described^[27]from 3-amino-5-bro-

mopyridine 15 via ethyl 7-bromo-4-hydroxy-1,5-naph-

thyridine-3-carboxylate. Hydrolysis of the ester in

aqueous sodium hydroxide to the corresponding

acid, followed by decarboxylation in quinoline at

reflux afforded 7-bromo-1,5-naphthyridin-4-ol. Chlori-

nation of this hydroxy compound by treatment with

phosphoryl chloride at reflux gave the desired

1,5-naphthyridine in 28% overall yield. This method-

ology required a five-step reaction from 15 and also

gave poor yield.

In the same manner, to introduce a chlorine atom

at position 4 of the 1,5-naphthyridine scaffold, we de-

cided to prepare the corresponding hydroxy precur-

sor (Scheme 1). Nevertheless, this intermediate was

prepared by thermolysis (220–2408C) of the 3-pyri-

dylaminomethylene derivative of Meldrum’s acid as

described for quinolone synthesis.^[28,21f]The use of

such an enamine allowed us to carry out thermal cyc-

lization and subsequent decarboxylation in a one-pot

procedure.^[29]In this context, treatment of 3-amino-5-

bromopyridine 15 with Meldrum’s acid and triethyl

orthoformate furnished the corresponding enamine

19 in 86% yield (Scheme 1). Ring formation was ac-

complished in Dowtherm A at 2408C to readily afford

the 1,5-naphthyridin-4-ol derivative 20 in 70% yield,

without a trace of its 1,7-regioisomer.^[28c]Finally, compound 20

reacted with phosphorus(III) oxychloride at reflux to give key

precursor 18a in very good yield.^[21e]The choice of this second

synthetic pathway appeared to be justified, as compound 18a

was obtained in 56% yield for three steps from 15, in contrast

to the 17% yield for three steps in the first route.

Figure 2. Structures of recently described Aurora kinase inhibitors.

place exclusively at the 2-position of aminopyridine 15, and

none of the 1,7-isomer was detected. In addition, the starting

aromatic amine was not recovered, and the poor yield (50%)

can be explained by the electron-withdrawing effect of the

pyridine nitrogen and bromine atoms, rendering the pyridine

ring a poor electron donor in the cyclization step. Formation

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served for the corresponding cycloalkylureas 49–52, but these

exhibited better activities, and cyclopropylurea 49 was the

most active compound of the series (IC₅₀=13 and 107 nm

against Aurora B and A, respectively). Introduction of a phenyl

ring on the urea function (compound 55) was deleterious for

activity (IC₅₀=1.26 mm against Aurora B), and kinase inhibition

was recovered by inserting an alkyl chain between the phenyl

group and the nitrogen atom of the urea function (compounds

56–58, IC₅₀66–147 nm against Aurora B). Finally, fluorine ana-

logues 59 and 60 of compounds 45 and 49, respectively, dem-

onstrated a great loss of potency; 2,2-difluorocyclopropylurea

60 was 60-fold less active against Aurora B than the most

active compound 49. All the compounds tested on both

Aurora kinases A and B were only slightly selective toward Au-

rora B and can be considered as pan-Aurora kinase inhibitors.

Compounds 38–60 were also tested for their selective inhib-

ition toward a panel of seven cancer-related protein kinases,

which include mitogen-activated protein kinase (Erk2),^[34]

serine/threonine kinases (HIPK1, Pim1),^[35,36]receptor tyrosine

kinases (KDR, TrkA),^[37,38]and non-receptor tyrosine kinases

(c-Abl, Yes).^[39,40]Data showed that besides inhibiting two

Aurora kinases, no additional inhibition was detected for this

set of seven protein kinases (see Supporting Information).

Regarding cellular data, cell line assays (HCT116 colon, MDA-

MB468 breast, PC3 prostate, A549 NSCLC, and U87MG CNS)

were carried out to correlate antiproliferative activity and

Aurora kinase inhibition. Unfortunately, only phenylurea 55

from the pyrazolyl series translated into moderate cell activity

(IC₅₀A549: 1.16 mm and IC₅₀HCT116: 3.64 mm), as all the com-

pounds remained inactive toward the tested tumor cell lines.

Moreover, 55 was observed to be among the less active com-

pounds against Aurora kinase B (IC₅₀=1.26 mm).

Figure 3. General structure of synthesized compounds.

Selective amination of compound 18a, by substitution of

the chlorine atom, was performed in the presence of ammoni-

um hydroxide in a sealed tube at 1608C to give key heterocy-

clic amine 21, a suitable compound for a broad pharmacomo-

dulation at positions 4 and 7 of the 1,5-naphthyridine scaffold

(Scheme 2).^[30](7-Bromo-1,5-naphthyridin-4-yl)ureas 22–37

were prepared from azaheterocyclic amine 21 using various

isocyanates in pyridine at reflux,^[31]or in two steps in the pres-

ence of triphosgene,^[32]triethylamine, and then adding the de-

sired amine. Finally, aromatic moieties were introduced at posi-

tion 7 of the ring under a palladium-catalyzed Suzuki–Miyaura-

type reaction, using boronic acids or esters and leading to

target compounds 38–60 in low to good yields (Scheme 2).^[33]

Biological activity

(7-Aryl-1,5-naphthyridin-4-yl)ureas 38–60 were first examined

for their ability to inhibit Aurora kinases A and B (Table 1). In

a general trend, all compounds were found to be active

against Aurora A and B, except tert-butylureas 41–43, which

displayed only weak inhibition of Aurora A (IC₅₀ꢀ2.76 mm). In-

terestingly, their ethylurea analogues 38–40 and cyclopropylur-

ea counterpart 44 proved to be more active. Introduction of

a 1-methylpyrazol-4-yl moiety at position 7 of the 1,5-naph-

thyridine ring was very promising, as compounds 45, 54, and

49, respectively bearing ethyl, tert-butyl, and cyclopropyl sub-

stituents, displayed very good activities relative to 38–44 (IC₅₀

(Aurora A) from 0.107 to 0.613 mm versus 0.197 to 5.77 mm, and

IC₅₀(Aurora B) from 0.013 to 0.112 mm versus 0.048 to 1.58 mm).

Consequently, the pyrazolyl substituent was kept for additional

SAR study by designing compounds 45–60.

In vitro ADME properties and safety data

The reason behind the lack of translation of Aurora kinase in-

hibition into antiproliferative activity is unknown, and must be

investigated. Some explanations for the lack of activity include:

1) physicochemical parameters of the compounds are unsuita-

ble for cell membrane permeability, and 2) compounds are ex-

cluded from the cells by an efflux mechanism.

Linear alkylureas 45–48 showed decreased activity correlat-

ed with increasing in chain length. The same features were ob-

Scheme 2. Reagents and conditions: a) NH₄OH, dioxane, sealed tube, 1408C, 24 h; b) RNCO, pyridine, sealed tube, 1408C, 24 h; c) 1. triphosgene, Et₃N, CH₂Cl₂,

reflux, 1 h, 2. RNH₂, reflux, 2 h; d) arylboronic acid or ester, Pd(PPh₃)₄, Na₂CO₃, DMF/H₂O (10:1), 808C, 5–16 h.

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Table 1. (7-Aryl-1,5-naphthyridin-4-yl)urea Aurora kinase inhibitors 38–60 used in this study and their antiproliferative activity.

Compd

R

Ar

Enzyme assays

Cell proliferation

IC₅₀[mm]^[a]

PC3

IC₅₀[mm]^[a]

Aurora A

Aurora B

HCT116

MDA-MB468

13.18

A549

U87MG

9.72

38

39

Et

0.881

1.60

0.136

>50

13.80

>50

0.370

0.227

>50

40

Et

0.197

>50

41

42

tBu

2.76

5.77

0.714

1.58

>50

43

tBu

cPr

3.62

0.500

>50

44

0.623

0.048

12.26

4.59

13.48

14.63

>50

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

Et

nPr

nBu

nHex

cPr

cBu

cPent

cHex

iPr

tBu

Ph

pyrazolyl

0.506

0.163

ND

0.038

0.026

0.164

0.885

0.013

0.048

0.108

0.354

0.137

0.112

1.26

0.066

0.086

0.141

0.129

0.784

12.28

13.92

8.64

15.80

15.38

6.72

5.98

5.03

3.45

16.69

3.64

>50

6.93

>50

15.01

>50

8.73

10.24

20.15

20.50

7.42

7.35

5.78

5.84

10.49

>50

4.26

13.81

13.55

13.77

15.80

>50

15.47

9.57

14.57

9.07

>50

13.45

ND

15.80

>50

ND

>50

ND

>50

ND

18.65

26.85

>50

15.14

13.01

8.74

>50

1.16

>50

15.80

>50

15.80

ND

0.107

0.284

ND

0.613

ND

>50

7.97

>50

16.25

>50

16.39

>50

Bn

CH₂CH₂Ph

(CH₂)₄Ph

CH₂CF₃

2,2-diF-cPr

3.83

ND

>50

13.51

15.80

>50

0.332

ND

[a] Values, within ꢁ15% SD, are the mean of at least two independent determinations; ND: not determined; pyrazolyl:

To determine the lipophilicity profile of the naphthyridine

ureas, their partition coefficients at pH 7.4, expressed as logD,

was derived directly from measurements of their chromato-

graphic hydrophobicity index (CHI; Table 2).^[41]CHI values

could be estimated rapidly by using a gradient method on

a UPLC system. LogD_7.4values ranged from 1.6 to 2.8 and

were found acceptable for cell permeability. Compounds 45,

49, 54, 58, and 59 were profiled for aqueous solubility in phos-

phate-buffered saline (PBS), mouse liver microsomal and

plasma stability, and cell permeability in Caco-2^[42]cells

(Table 2). The aqueous solubility (93–185 mm) in PBS was con-

sistent with the observed lipophilicity and was not a deleterious

parameter for cellular assays. Stability tests revealed three ana-

logues—45, 49, and 54—that showed excellent metabolic sta-

bility in mouse plasma. Furthermore, compounds 46 (4.9%),

58 (15.0%), 50 (15.1%), 45 (22.2%), and 49 (51.8%) exhibited

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Table 2. In vitro ADME properties and safety data for compounds 45, 46, 48–51, 53, 54, and 56–59.

[b]

Compd

R

CHI^[a]

LogD_7.4

Solubility

[mm]^[c]

MLM [%]^[d]

MP [%]^[e]

Caco-2

[10^ꢂ6cms^ꢂ1

CYP3A4

inhibition [mm]

hERG

binding [mm]

[f]

]

45

46

48

49

50

51

53

54

56

57

58

59

Et

nPr

nHex

cPr

cBu

cPent

iPr

tBu

52.5

61.2

88.4

58.7

64.9

71.8

60.8

71.8

72.3

76.9

90.2

63.5

1.6

1.9

2.7

1.8

2.0

2.2

1.9

2.2

2.4

2.8

2.0

185

ND

181

ND

93

22.2

4.9

ND

51.8

15.1

ND

83.9

ND

15.0

88.2

96.6

ND

92.4

ND

90.3

ND

59/33

ND

>100

ND

>200

>100

ND

>60

ND

Bn

ND

94

CH₂CH₂Ph

(CH₂)₄Ph

CH₂CF₃

42/20

ND

>200

ND

[a] Chromatographic hydrophobicity index, determined by RP-UPLC. [b] Calculated from CHI. [c] Measured at pH 7.4, PBS medium +1% BSA. [d] Mouse

liver microsomes, percent remaining after 1h. [e] Mouse plasma, percent remaining after 6h. [f] Caco-2 permeability b!a/a!b, determined in the pres-

ence of 1% BSA. ND: not determined.

low to moderate metabolic stability in liver microsomes, but

analogues 54 (83.9%) and 59 (88.2%) were found to be very

stable. Moreover, the data listed in Table 2 indicate that hit

compound 49, toward Aurora kinase inhibition, had very good

cell permeability, with decreased efflux (0.56; ratio=0.56, [b!

a/a!b]). Phenylbutylurea 58 showed lower but acceptable

permeability, with a decreased efflux ratio of 0.48. We observed

no inhibition of cytochrome P450, CYP3A4,^[43]for compounds

46, 49, 50, and 59, and no undesired activities at the human

hERG^[44]channel for compounds 49 and 50.

efficacy on isolated enzyme is higher than that on cells. This is

likely a consequence of the combination of several factors in-

cluding interaction with other targets within the cell (multi-

target effects), nonspecific binding to cellular proteins (ionic or

hydrophobic interactions), intracellular metabolism and possi-

ble inactivation, limitations in passage across biological mem-

branes (plasma membrane, nuclear envelope), and high intra-

cellular ATP concentrations. The described derivatives possess

good cell-penetration parameters, but their efficiency on the

signaling pathway was insufficient to induce significant cell

death. In conclusion, this series constitutes a very promising

starting point for the design of anticancer agents. Based on

the interesting 1,5-naphthyridine scaffold, further pharmaco-

modulations are in progress with the aim of reaching in vitro

and in vivo antiproliferative activities associated with kinase in-

hibition.

Conclusions

The identification of novel (7-aryl-1,5-naphthyridin-4-yl)ureas,

inhibitors of Aurora kinases A/B, is reported herein. Com-

pounds showed excellent Aurora A and B inhibitory activities

in the nanomolar range and also displayed selectivity in an

enzyme-based inhibition assay against a panel of seven kinas-

es. Unfortunately, all the compounds suffered from a lack of

antiproliferative activity in tests against five tumor cell lines.

For the most active compound 49 against Aurora kinases A

and B (IC₅₀values of 13 and 107 nm, respectively), we observed

permeability values higher than 10 (P_appvalue a!b direction:

59) and we saw no hints for efflux for this compound (b!a/

a!b ratio <1). Therefore, it seems we have a very highly per-

meable structure class in hand. In addition, analogue 49 dem-

onstrated very good aqueous solubility, excellent plasma stabil-

ity, and acceptable microsomal stability in mouse, associated

with a good safety profile. The fact that there is no direct cor-

relation between measured kinase inhibitory potencies and an-

tiproliferative activities with these compounds is difficult to ex-

plain. As is almost always observed with kinase inhibitors, the

Experimental Section

Chemistry

General methods: Melting points were determined with an Elec-

trothermal IA9300 digital melting point apparatus and are uncor-

1

rected. H and ¹³C NMR spectra were recorded on a Bruker Avance

400 spectrometer (400 MHz). Chemical shifts (d) are expressed in

ppm relative to tetramethylsilane as internal standard. NMR signals

are described as follows: s=singlet, d=doublet, t=triplet, q=

quadruplet, sext=sextuplet, m=multiplet and br=broad. Cou-

pling constants (J) are given in hertz. IR spectra were obtained in

KBr pellets using a PerkinElmer Paragon FTIR 1000 PC spectrome-

ter. Only the most significant absorption bands are reported. Elec-

trospray mass spectrometric analysis was performed on a Waters

Acquity UPLC System ZQ 2000 single quadrupole. All tested com-

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pounds displayed purity of >97%. All reactions were monitored

by thin-layer chromatography (TLC) using 0.2-mm-thick silica gel

plates 60 F₂₅₄(5735 Merck). Column chromatography was carried

out with silica gel 60 (70–230 mesh, ASTM, Merck). Chemicals and

solvents used were commercially available. Elemental analyses

were performed on a Thermo Scientific Elemental Analyzer Flash

EA 1112 and were found to be within ꢁ0.4% of theoretical values.

J=8.8, 2.4 Hz, 1H), 7.80 ppm (dd, J=8.8, 8.4 Hz, 1H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=152.7, 152.1, 143.6, 141.8, 138.5, 137.1,

125.5, 120.1 ppm; IR (KBr): n˜ =3009, 1553, 1451, 1189, 1062 cm^ꢂ1

;

MS (ESI) m/z (%): 209.0 (100) [M+H]⁺, 211.1 (100) [M+H+2]⁺;

Anal. calcd for C₈H₅BrN₂: C 45.96, H 2.41, N 13.40, found: C 45.91, H

2.40, N 13.46.

7-Bromo-1,5-naphthyridine-1-oxide (17a) and 3-bromo-1,5-

naphthyridine-1-oxide (17b): To a solution of 7-bromo-1,5-naph-

thyridine 16 (4.43 g, 21.2 mmol) in CH₂Cl₂(165 mL) was added por-

tionwise at 08C meta-chloroperbenzoic acid (mCPBA; 5.23 g,

21.2 mmol). The reaction mixture was stirred at RT for 18 h. The or-

ganic layer was washed with an aqueous solution of NaOH (1m,

200 mL), the aqueous layer was extracted with CH₂Cl₂(400 mL),

dried over anhyd Na₂SO₄, filtered, and the solvent was removed

under reduced pressure. The crude mixture was separated by

column chromatography on silica gel, eluting with CH₂Cl₂/EtOH

98:2!96:4 to afford compounds 17a as a pale-yellow solid

(3.05 g, 64%) and 17b as a yellow solid (1.00 g, 21%).

3-Amino-5-bromopyridine (15): In SOCl₂(300 mL) under argon

was added 5-bromonicotinic acid (30.0 g, 150 mmol). The reaction

mixture was held at reflux for 8 h. After cooling to RT, excess SOCl₂

was removed under reduced pressure. Dichloroethane was added

(300 mL), and the solution was cooled to ꢂ308C. NH₃gas was bub-

bled through the reaction mixture for 20 min, and the mixture was

then allowed to cool to RT. H₂O (300 mL) was added, and the aque-

ous layer was extracted with EtOAc (2ꢂ400 mL). The organic ex-

tracts were combined and washed with an aqueous solution of

NaHCO₃(300 mL). The combined extracts were dried over anhyd

Na₂SO₄, and the solvents were removed under reduced pressure to

give 5-bromopyridine-3-carboxamide as a white powder (26.5 g,

88%): R_f=0.39 (CH₂Cl₂/EtOH, 96:4); mp: 218–2198C (lit.^[25]219–

7-Bromo-1,5-naphthyridine-1-oxide (17a): R_f=0.18 (CH₂Cl₂/EtOH,

96:4); mp: 148–1498C; ¹H NMR (400 MHz, [D₆]DMSO): d=9.21 (d,

J=2.1 Hz, 1H), 9.10 (d, J=2.1 Hz, 1H), 8.75 (d, J=6.1 Hz, 1H), 8.06

(d, J=8.8 Hz, 1H), 7.80 ppm (dd, J=8.8, 6.1 Hz, 1H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=154.0, 143.6, 137.8, 136.6, 129.5, 126.4,

125.8, 120.7 ppm; IR (KBr): n˜ =3009, 1646, 1487, 1398, 1254,

1086 cm^ꢂ1; MS (ESI) m/z (%): 225.0 (100) [M+H]⁺, 227.1 (100) [M+

H+2]⁺; Anal. calcd for C₈H₅BrN₂O: C 42.70, H 2.24, N 12.45, found:

C 42.63, H 2.26, N 12.47.

1

219.58C); H NMR (400 MHz, [D₆]DMSO): d=9.02 (d, J=2.1 Hz, 1H),

8.89 (d, J=2.1 Hz, 1H), 8.47 (t, J=2.1 Hz, 1H), 8.27 (brs, 1H),

7.79 ppm (brs, 1H); ¹³C NMR (100 MHz, [D₆]DMSO): d=164.9,

152.5, 147.2, 137.5, 131.3, 120.0 ppm; IR (KBr): n˜ =3388, 3192, 3033,

1657, 1621, 1420, 1396 cm^ꢂ1; MS (ESI) m/z (%): 201.0 (100)

[M+H]⁺, 203.1 (100) [M+H+2]⁺.

To a solution of NaOH (29.8 g, 746 mmol) in H₂O (250 mL) was

added Br₂(7.6 mL, 149 mmol) at 08C and then 5-bromopyridine-3-

carboxamide (25 g, 124 mmol). The reaction mixture was allowed

to cool to RT for 20 min and then was heated at 808C for 35 min.

The resulting solution was cooled at 08C and HCl was added until

the mixture reached pH 2. The reaction mixture was washed with

CH₂Cl₂(300 mL). The aqueous layer was adjusted to pH 10 by the

addition of NaOH pellets. The aqueous layer was extracted with

CH₂Cl₂(500 mL), the combined organic phases were dried over

anhyd Na₂SO₄, filtered, and then the solvent was removed under

reduced pressure. The crude product was purified by column chro-

matography on silica gel, eluting with CH₂Cl₂/EtOH 98:2 to afford

compound 15 as a red solid (15.3 g, 71%); R_f=0.28 (CH₂Cl₂/EtOH,

96:4); mp: 64–658C (lit.^[25]69–69.58C); ¹H NMR (400 MHz,

[D₆]DMSO): d=7.92 (d, J=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.14

(t, J=2.4 Hz, 1H), 5.67 ppm (brs, 2H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=146.6, 136.7, 135.1, 121.5, 120.3 ppm; IR (KBr): n˜ =

3318, 3153, 1646, 1574, 1426, 1246 cm^ꢂ1; MS (ESI) m/z (%): 173.0

(100) [M+H]⁺, 175.1 (100) [M+H+2]⁺; Anal. calcd for C₅H₅BrN₂: C

34.71, H 2.91, N 16.19, found: C 34.75, H 2.89, N 16.17.

3-Bromo-1,5-naphthyridine-1-oxide (17b): R_f=0.13 (CH₂Cl₂/EtOH,

96:4); mp: 153–1548C; ¹H NMR (400 MHz, [D₆]DMSO): d=9.12 (d,

J=4.3 Hz, 1H), 9.03 (s, 1H), 8.86 (d, J=7.4 Hz, 1H), 8.36 (s, 1H),

7.88 ppm (dd, J=7.4, 4.3 Hz, 1H); ¹³C NMR (100 MHz, [D₆]DMSO):

d=154.9, 145.4, 137.9 (2C), 129.4, 128.6, 126.2, 119.2 ppm; IR (KBr):

n˜ =3006, 1654, 1454, 1377, 1242, 1067 cm^ꢂ1; MS (ESI) m/z (%):

225.0 (100) [M+H]⁺, 227.0 (100) [M+H+2]⁺; Anal. calcd for

C₈H₅BrN₂O: C 42.70, H 2.24, N 12.45, found: C 42.75, H 2.22, N

12.42.

3-Bromo-8-chloro-1,5-naphthyridine (18a) and 7-bromo-2-

chloro-1,5-naphthyridine (18b): Method A: To a solution of

7-bromo-1,5-naphthyridine-1-oxide 17a (7.97 g, 35.4 mmol) in

CH₂Cl₂(600 mL) was added POCl₃(9.9 mL, 106.2 mmol). The reac-

tion mixture was heated at reflux for 2.5 h. CH₂Cl₂was partially

evaporated under reduced pressure. Then, the reaction mixture

was cooled in an ice bath and an aqueous solution of 1m NaOH

(200 mL) was carefully added. The aqueous layer was extracted

with CH₂Cl₂(500 mL), dried over anhyd Na₂SO₄, filtered, and the

solvent was removed under reduced pressure. The crude mixture

was separated by column chromatography on silica gel, eluting

with CH₂Cl₂to give compounds 18a as a white solid (4.65 g, 54%)

and 18b as a white solid (1.55 g, 18%).

3-Bromo-1,5-naphthyridine (16): In concentrated H₂SO₄(85 mL)

was successively added FeSO₄·7H₂O (3.58 g, 12.9 mmol), sodium

3-nitrobenzenesulfonate (44.11 g, 198.6 mmol) and B(OH)₃(9.69 g,

158.9 mmol). The reaction mixture was stirred at RT for 30 min.

Glycerol (42.96 g, 466.7 mmol), 3-amino-5-bromopyridine 15

(17.20 g, 99.3 mmol) and H₂O (85 mL) were added. The reaction

mixture was stirred at 1358C for 18 h and was allowed to cool to

RT. A solution of 8m NaOH was carefully added until the mixture

reached pH 14. The aqueous layer was extracted with EtOAc

(300 mL), the organic layer was dried over anhyd Na₂SO₄, filtered,

and then the solvent was removed under reduced pressure. The

crude product was purified by column chromatography on silica

gel, eluting with CH₂Cl₂to furnish compound 16 as a white solid

(10.38 g, 50%). R_f=0.77 (CH₂Cl₂/EtOH, 96:4); mp: 108–1098C (lit.^[45]

106–1078C); ¹H NMR (400 MHz, [D₆]DMSO): d=9.12 (d, J=2.0 Hz,

1H), 9.08 (dd, J=8.4, 2.4 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.50 (dd,

3-Bromo-8-chloro-1,5-naphthyridine (18a): R_f=0.75 (CH₂Cl₂/EtOH,

96:4); mp: 162–1638C (lit.^[27]163–1658C); ¹H NMR (400 MHz,

[D₆]DMSO): d=9.22 (d, J=2.1 Hz, 1H), 8.99 (d, J=4.5 Hz, 1H), 8.88

(d, J=2.1 Hz, 1H), 8.11 ppm (d, J=4.5 Hz, 1H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=152.8, 152.7, 144.8, 143.1, 139.1, 138.7, 125.4,

121.5 ppm; IR (KBr): n˜ =3031, 1646, 1467, 1312, 1220, 1104,

907 cm^ꢂ1; MS (ESI) m/z (%): 242.9 (73) [M+H]⁺, 245.0 (100) [M+

H+2]⁺, 247.0 (24) [M+H+4]⁺; Anal. calcd for C₈H₄BrClN₂: C 39.46,

H 1.66, N 11.51, found: C 39.59, H 1.65, N 11.48.

7-Bromo-2-chloro-1,5-naphthyridine (18b): R_f=0.82 (CH₂Cl₂/EtOH,

96:4); mp: 168–1698C; ¹H NMR (400 MHz, [D₆]DMSO): d=9.15 (d,

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J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.55 (d, J=8.8 Hz, 1H),

7.93 ppm (d, J=8.8 Hz, 1H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

152.5, 151.3, 143.2, 140.8, 140.7, 137.5, 126.6, 121.2 ppm; IR (KBr):

n˜ =3027, 1641, 1457, 1322, 1212, 1109, 905 cm^ꢂ1; MS (ESI) m/z (%):

242.9 (76) [M+H]⁺, 245.0 (100) [M+H+2]⁺, 246.9 (22) [M+H+

4]⁺; Anal. calcd for C₈H₄BrClN₂: C 39.46, H 1.66, N 11.51, found: C

39.51, H 1.69, N 11.43.

Na₂SO₄, filtered, and the solvent was removed under reduced pres-

sure. The crude mixture was purified by column chromatography

on silica gel, eluting with CH₂Cl₂, then CH₂Cl₂/EtOH 98:2 to give

compound 21 as a white solid (3.50 g, 76%); R_f=0.32 (CH₂Cl₂/

EtOH, 96:4); mp: 168–1698C; ¹H NMR (400 MHz, [D₆]DMSO): d=

8.82 (d, J=2.1 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.40 (d, J=5.5 Hz,

1H), 7.08 (brs, 2H), 6.79 ppm (d, J=5.5 Hz, 1H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=152.5, 151.9, 147.3, 144.3, 138.0, 133.3, 120.0,

104.4 ppm; IR (KBr): n˜ =3400, 3297, 1640 cm^ꢂ1; MS (ESI) m/z (%):

224.0 (100) [M+H]⁺, 226.1 (100) [M+H+2]⁺; Anal. calcd for

C₈H₆BrN₃: C 42.88, H 2.70, N 18.75, found: C 42.92, H 2.69, N 18.70.

3-Bromo-8-chloro-1,5-naphthyridine (18a). Method B: 7-Bromo-

1,5-naphthyridin-4-ol 20 (4.50 g, 20.0 mmol), described below, was

dissolved in POCl₃(9.3 mL, 100.0 mmol) under nitrogen atmos-

phere and held at reflux for 2 h. The mixture was then cooled and

concentrated under vacuo. The solid was taken up with H₂O

Method C. General method for the synthesis of ureas 22, 24, 26,

27, 31–33 using isocyanates: In a sealed reactor, a solution of

7-bromo-1,5-naphthyridin-4-amine 21 (500 mg, 2.23 mmol) and the

appropriate isocyanate (4.46 mmol) in pyridine (5 mL) was stirred

under argon atmosphere at 1408C for 24 h. The mixture was al-

lowed to reach RT, and the solvent was removed under reduced

pressure. The residue was purified by column chromatography on

silica gel, eluting with CH₂Cl₂/EtOH 99:1. The solvent was evaporat-

ed to dryness to afford the desired compounds 22, 24, 26, 27 and

31–33.

(100 mL), neutralized with

a saturated aqueous solution of

NaHCO₃, and extracted with CH₂Cl₂(300 mL). The solution was

dried over anhyd Na₂SO₄, filtered, and concentrated under reduced

pressure. The crude product was then purified by column chroma-

tography on silica gel, eluting with CH₂Cl₂to give compound 18a

as a white solid (4.53 g, 93%).

5-{[(5-Bromopyridin-3-yl)amino]methylidene}-2,2-dimethyl-1,3-

dioxane-4,6-dione (19): A mixture of triethyl orthoformate (2.9 mL,

17.3 mmol)

and

2,2-dimethyl-1,3-dioxane-4,6-dione

(9.60 g,

66.6 mmol) (Meldrum’s acid) was heated at 908C for 1.5 h and then

cooled to 708C. 3-Amino-5-bromopyridine 15 (10.00 g, 57.8 mol)

was slowly added over 10 min with an EtOH (20 mL) rinse while

maintaining the reaction temperature between 60 and 708C. The

reaction was then heated for an additional 30 min and allowed to

cool to RT. The precipitate was filtered, washed with EtOH (20 mL),

and dried to yield compound 19 as a light-yellow crystalline solid

(16.26 g, 86%). R_f=0.29 (CH₂Cl₂/EtOH, 95:5); mp: 199–2008C (lit.^[46]

200–2028C); ¹H NMR (400 MHz, CDCl₃): d=11.21 (d, J=13.5 Hz,

1H), 8.59 (d, J=13.5 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.52 (d, J=

2.4 Hz, 1H), 7.81 (t, J=2.1 Hz, 1H), 1.76 ppm (s, 6H); ¹³C NMR

(100 MHz, CDCl₃): d=165.4, 162.8, 152.4, 148.7, 138.5, 135.4, 127.3,

121.3, 105.7, 89.6, 27.2 ppm (2C); IR (KBr): n˜ =3150, 3053, 2986,

1722, 1668, 1612, 1557, 1471, 1408, 1377, 1263, 1222, 1196, 1103,

1001 cm^ꢂ1; MS (ESI) m/z (%): 327.1 (100) [M+H]⁺, 329.0 (100) [M+

H+2]⁺; Anal. calcd for C₁₂H₁₁BrN₂O₄: C 44.06, H 3.39, N 8.56,

found: C 44.22, H 3.40, N 8.60.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-ethylurea

(22):

Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with

ethyl isocyanate (350 mL, 4.46 mmol) to afford compound 22 as

a white powder (553 mg, 84%). R_f=0.44 (CH₂Cl₂/EtOH, 96:4); mp:

1

222–2238C; H NMR (400 MHz, [D₆]DMSO): d=9.69 (s, 1H), 9.01 (d,

J=2.1 Hz, 1H), 8.77 (d, J=4.8 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.44

(d, J=4.8 Hz, 1H), 7.67 (t, J=5.8 Hz, 1H), 3.25–3.14 (m, 2H),

1.13 ppm (t, J=7.0 Hz, 3H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

154.3, 153.5, 149.1, 144.3, 143.5, 138.7, 133.0, 120.6, 108.5, 34.2,

15.2 ppm; IR (KBr): n˜ =3281, 3031, 1651, 1515, 1230, 992 cm^ꢂ1; MS

(ESI) m/z (%): 295.1 (100) [M+H]⁺, 297.2 (100) [M+H+2]⁺; Anal.

calcd for C₁₁H₁₁BrN₄O: C 44.77, H 3.76, N 18.98, found: C 44.89, H

3.78, N 18.92.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-butylurea

(24):

Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with bu-

tylisocyanate (503 mL, 4.46 mmol) to afford compound 24 as

a beige powder (360 mg, 50%). R_f=0.24 (CH₂Cl₂/EtOH, 95:5); mp:

1

7-Bromo-1,5-naphthyridin-4-ol (20): 5-{[(5-Bromopyridin-3-yl)ami-

no]methylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione 19 (10.00 g,

30.6 mmol) was slowly added to Dowtherm A heat transfer fluid

(350 mL) over a period of 5 min at 235–2408C. Following addition,

the reaction was maintained for an additional 5 min and then al-

lowed to cool to 408C. A brown precipitate formed, which was fil-

tered and washed with petroleum ether (25 mL). The brown solid

was suspended in an EtOH/H₂O mixture (90:10, 250 mL), heated to

a boil for 30 min, isolated by filtration, and washed with EtOH

(30 mL) to yield compound 20 as a dark-brown powder (4.85 g,

70%). R_f=0.05 (CH₂Cl₂/EtOH, 95:5); mp: >3608C (lit.^[27]>3608C);

¹H NMR (400 MHz, [D₆]DMSO): d=12.25 (brs, 1H), 8.93 (s, 1H), 8.53

(s, 1H), 8.03 (dd, J=7.2, 6.0 Hz, 1H), 6.21 ppm (d, J=7.4 Hz, 1H);

compound 20 was not soluble enough in [D₆]DMSO for ¹³C NMR

analysis; IR (KBr): n˜ =3066–2550 (br), 1614, 1602, 1547, 1493, 1414,

1402, 1184, 1120 cm^ꢂ1; MS (ESI) m/z (%): 225.1 (100) [M+H]⁺,

227.0 (100) [M+H+2]⁺.

158–1608C; H NMR (400 MHz, [D₆]DMSO): d=9.73 (s, 1H), 9.00 (d,

J=2.0 Hz, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.40

(d, J=5.2 Hz, 1H), 7.67 (t, J=5.2 Hz, 1H), 3.18 (dt, J=7.2, 5.2 Hz,

2H), 1.51–1.36 (m, 4H), 0.93 ppm (t, J=7.2 Hz, 3H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=154.1, 153.2, 149.4, 144.8, 143.7, 138.1,

133.5, 121.0, 108.6, 42.1, 31.9, 19.6, 14.2 ppm; IR (KBr): n˜ =3256,

3041, 2942, 1657, 1519, 1220, 987 cm^ꢂ1; MS (ESI) m/z (%): 323.2

(100) [M+H]⁺, 325.3 (100) [M+H+2]⁺; Anal. calcd for

C₁₃H₁₅BrN₄O: C 48.31, H 4.68, N 17.34, found: C 48.48, H 4.70, N

17.31.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-isopropylurea (26): Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with iso-

propylisocyanate (438 mL, 4.46 mmol) to afford compound 26 as

a white powder (497 mg, 72%). R_f=0.43 (CH₂Cl₂/EtOH, 95:5); mp:

1

175–1778C; H NMR (400 MHz, [D₆]DMSO): d=9.63 (s, 1H), 9.00 (d,

J=2.4 Hz, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.43

(d, J=5.2 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 3.89–3.81 (m, 1H),

1.17 ppm (d, J=6.4 Hz, 6H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

154.3, 153.3, 149.1, 144.6, 143.9, 138.3, 133.4, 121.1, 108.7, 43.1,

22.6 ppm (2C); IR (KBr): n˜ =3223, 3025, 2964, 1645, 1510, 1221,

989 cm^ꢂ1; MS (ESI) m/z (%): 309.2 (100) [M+H]⁺, 311.3 (100) [M+

H+2]⁺; Anal. calcd for C₁₂H₁₃BrN₄O: C 46.62, H 4.24, N 18.12,

found: C 46.79, H 4.22, N 18.18.

7-Bromo-1,5-naphthyridin-4-amine (21): In a sealed tube, a mix-

ture

of

3-bromo-8-chloro-1,5-naphthyridine

18a

(5.00 g,

20.5 mmol) and 28% aqueous NH₃solution (120 mL) in dioxane

(120 mL) was heated at 1408C for 24 h. Then, the reaction mixture

was allowed to cool to RT and H₂O (200 mL) was added. The aque-

ous layer was extracted with EtOAc (400 mL), dried over anhyd

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1-(7-Bromo-1,5-naphthyridin-4-yl)-3-tert-butylurea (27): Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with tert-

butyl isocyanate (510 mL, 4.46 mmol) to afford compound 27 as

a white solid (541 mg, 75%). R_f=0.43 (CH₂Cl₂/EtOH, 96:4); mp:

tracted with CH₂Cl₂(150 mL). The organic layers were dried over

anhyd Na₂SO₄, filtered, and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel,

eluting with CH₂Cl₂/EtOH 96:4. The solvent was evaporated to dry-

ness to furnish the desired compounds 23, 25, 28–30, and 34–37.

1

192–1938C; H NMR (400 MHz, [D₆]DMSO): d=9.65 (s, 1H), 8.98 (d,

J=2.1 Hz, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.42

(d, J=5.2 Hz, 1H), 7.60 (s, 1H), 1.36 ppm (s, 9H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=153.5 (2C), 148.8, 144.9, 143.6, 138.7,

133.1, 120.4, 108.5, 50.0, 28.9 ppm (3C); IR (KBr): n˜ =3340, 3038,

2932, 1672, 1516, 1190, 990 cm^ꢂ1; MS (ESI) m/z (%): 323.2 (100)

[M+H]⁺, 325.3 (100) [M+H+2]⁺; Anal. calcd for C₁₃H₁₅BrN₄O: C

48.31, H 4.68, N 17.34, found: C 48.43, H 4.69, N 17.38.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-propylurea

(23):

Using

method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with pro-

pylamine (385 mL, 4.69 mmol) to afford compound 23 as a white

powder (359 mg, 52%). R_f=0.40 (CH₂Cl₂/EtOH, 96:4); mp: 173–

1

1748C; H NMR (400 MHz, [D₆]DMSO): d=9.72 (s, 1H), 8.99 (d, J=

2.0 Hz, 1H), 8.76 (d, J=5.6 Hz, 1H), 8.66 (d, J=2.0 Hz, 1H), 8.44 (d,

J=5.6 Hz, 1H), 7.68 (t, J=5.2 Hz, 1H), 3.15 (q, J=6.8 Hz, 2H), 1.57–

1.47 (m, 2H), 0.96 ppm (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=154.4, 153.5, 148.9, 144.1, 143.6, 138.8, 133.0, 120.4,

108.5, 40.1, 22.8, 11.5 ppm; IR (KBr): n˜ =3286, 2956, 1697, 1650,

1551, 1516, 1412, 1314, 1246, 1150, 1080 cm^ꢂ1; MS (ESI) m/z (%):

309.2 (100) [M+H]⁺, 311.3 (100) [M+H+2]⁺; Anal. calcd for

C₁₂H₁₃BrN₄O: C 46.62, H 4.24, N 18.12, found: C 46.74, H 4.25, N

18.09.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-cyclohexylurea (31): Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with

phenyl isocyanate (570 mL, 4.46 mmol) to afford compound 31 as

a white powder (429 mg, 55%). R_f=0.45 (CH₂Cl₂/EtOH, 96:4); mp:

1

179–1808C; H NMR (400 MHz, [D₆]DMSO): d=9.69 (s, 1H), 9.00 (d,

J=2.4 Hz, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.43

(d, J=5.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 3.59–3.57 (m, 1H), 1.91–

0.92 ppm (m, 10H); ¹³C NMR (100 MHz, [D₆]DMSO): d=153.6, 153.5,

148.9, 144.2, 143.6, 138.8, 133.1, 120.5, 108.5, 47.5, 33.5 (2C), 32.0,

24.6 ppm (2C); IR (KBr): n˜ =3260, 3025, 2928, 1695, 1525, 1246,

995 cm^ꢂ1; MS (ESI) m/z (%): 349.2 (100) [M+H]⁺, 351.3 (100) [M+

H+2]⁺; Anal. calcd for C₁₅H₁₇BrN₄O: C 51.59, H 4.91, N 16.04,

found: C 51.75, H 4.93, N 16.09.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-hexylurea

(25):

Using

method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with 1-

hexylamine (619 mL, 4.69 mmol) to afford compound 25 as a white

powder (486 mg, 62%). R_f=0.46 (CH₂Cl₂/EtOH, 96:4); mp: 186–

1

1878C; H NMR (400 MHz, [D₆]DMSO): d=9.72 (s, 1H), 9.00 (d, J=

2.2 Hz, 1H), 8.76 (d, J=5.2 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.44 (d,

J=5.2 Hz, 1H), 7.66 (t, J=5.4 Hz, 1H), 5.75 (dt, J=5.6, 5.4 Hz, 2H),

3.20–3.16 (m, 2H), 3.00–2.96 (m, 2H), 1.51–1.47 (m, 2H); 1.42–1.34

(m, 2H); 0.92 ppm (t, J=7.2 Hz, 3H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=154.5, 153.1, 149.3, 144.7, 143.7, 138.2, 133.6, 121.1,

108.6, 42.4, 31.7, 30.2, 27.2, 21.6, 14.4 ppm; IR (KBr): n˜ =3244, 3032,

2945, 1684, 1515, 1232, 992 cm^ꢂ1; MS (ESI) m/z (%): 351.3 (100)

[M+H]⁺, 353.4 (100) [M+H+2]⁺; Anal. calcd for C₁₅H₁₉BrN₄O: C

51.29, H 5.45, N 15.95, found: C 51.48, H 5.47, N 16.01.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-phenylurea

(32):

Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with

phenyl isocyanate (485 mL, 4.46 mmol) to afford compound 32 as

a white powder (505 mg, 66%). R_f=0.60 (CH₂Cl₂/EtOH, 96:4); mp:

1

195–1968C; H NMR (400 MHz, [D₆]DMSO): d=10.08 (s, 1H), 10.04

(s, 1H), 9.08 (d, J=2.4 Hz, 1H), 8.86 (d, J=5.2 Hz, 1H), 8.74 (d, J=

2.4 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 7.57 (d, J=7.6 Hz, 2H), 7.38

(dd, J=8.4, 7.6 Hz, 2H), 7.08 ppm (t, J=8.4 Hz, 1H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=153.7, 151.9, 149.3, 143.7, 143.5, 139.2,

139.0, 133.1, 129.1 (2C), 122.8, 120.6, 118.6 (2C), 109.0 ppm; IR

(KBr): n˜ =3273, 3015, 1708, 1515, 1422, 1210, 992 cm^ꢂ1; MS (ESI) m/

z (%): 343.2 (100) [M+H]⁺, 345.3 (100) [M+H+2]⁺; Anal. calcd for

C₁₅H₁₁BrN₄O: C 52.50, H 3.23, N 16.33, found: C 52.64, H 3.21, N

16.30.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-cyclopropylurea (28): Using

method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with cy-

clopropylamine (325 mL, 4.69 mmol) to afford compound 28 as

a white powder (446 mg, 65%). R_f=0.43 (CH₂Cl₂/EtOH, 95:5); mp:

1

205–2068C; H NMR (400 MHz, [D₆]DMSO): d=9.62 (s, 1H), 9.00 (d,

J=2.0 Hz, 1H), 8.78 (d, J=5.2 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.43

(d, J=5.2 Hz, 1H), 7.82 (s, 1H), 2.69–2.63 (m, 1H), 0.72 and

0.47 ppm (brs, 4H); ¹³C NMR (100 MHz, [D₆]DMSO): d=155.1,

153.6, 149.0, 143.6 (2C), 138.8, 133.0, 120.5, 108.5, 22.5, 6.3 ppm

(2C); IR (KBr): n˜ =3217, 3025, 2933, 1691, 1517, 1222, 990 cm^ꢂ1; MS

(ESI) m/z (%): 307.2 (100) [M+H]⁺, 309.3 (100) [M+H+2]⁺; Anal.

calcd for C₁₂H₁₁BrN₄O: C 46.93, H 3.61, N 18.24, found: C 46.81, H

3.63, N 18.29.

1-Benzyl-3-(7-bromo-1,5-naphthyridin-4-yl)urea

(33):

Using

method C, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with

benzyl isocyanate (551 mL, 4.46 mmol) to afford compound 33 as

a white powder (733 mg, 92%). R_f=0.28 (CH₂Cl₂/EtOH, 95:5); mp:

1

138–1408C; H NMR (400 MHz, [D₆]DMSO): d=9.87 (s, 1H), 9.01 (d,

J=2.0 Hz, 1H), 8.78 (d, J=5.4 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.46

(d, J=5.2 Hz, 1H), 8.16 (t, J=5.6 Hz, 1H), 7.39–7.27 (m, 5H),

4.35 ppm (d, J=5.6 Hz, 2H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

153.6, 151.8, 149.5, 143.4, 143.2, 139.3, 139.0, 133.5, 129.2 (2C),

128.1 (2C), 122.4, 120.4, 109.2, 45.1 ppm; IR (KBr): n˜ =3263, 3024,

1682, 1517, 1212, 995 cm^ꢂ1; MS (ESI) m/z (%): 357.2 (100) [M+H]⁺,

359.3 (100) [M+H+2]⁺; Anal. calcd for C₁₆H₁₃BrN₄O: C 53.80, H

3.67, N 15.68, found: C 54.01, H 3.68, N 15.72.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-cyclobutylurea (29): Using

method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with cy-

clobutylamine (400 mL, 4.69 mmol) to afford compound 29 as

a white powder (502 mg, 70%). R_f=0.40 (CH₂Cl₂/EtOH, 95:5); mp:

1

201–2028C; H NMR (400 MHz, [D₆]DMSO): d=9.62 (s, 1H), 9.01 (d,

J=2.4 Hz, 1H), 8.77 (d, J=5.2 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.41

(d, J=5.2 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 4.25–4.16 (m, 1H), 2.32–

2.44 and 1.95–1.84 (m, 4H), 1.75–1.64 ppm (m, 2H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=153.5, 153.2, 149.0, 143.9, 143.6, 138.8,

133.0, 120.4, 108.5, 44.6, 30.9 (2C), 14.7 ppm; IR (KBr): n˜ =3290,

3033, 2938, 1659, 1516, 1219, 995 cm^ꢂ1; MS (ESI) m/z (%): 321.2

(100) [M+H]⁺, 323.3 (100) [M+H+2]⁺; Anal. calcd for

C₁₃H₁₃BrN₄O: C 48.62, H 4.08, N 17.44, found: C 48.49, H 4.10, N

17.47.

Method D. General method for the synthesis of ureas 23, 25,

28–30, 34–37 using triphosgene and amines: Under argon at-

mosphere,

a solution of 7-bromo-1,5-naphthyridin-4-amine 21

(500 mg, 2.23 mmol) in CH₂Cl₂(40 mL) was added at 08C Et₃N

(8.4 mL, 60 mmol) and triphosgene (727 mg, 2.45 mmol). The mix-

ture was stirred at reflux for 1 h. The mixture was allowed to reach

RT, and the appropriate alkylamine (4.69 mmol) was added. The

mixture was stirred at reflux for 2 h. The mixture was allowed to

reach RT, and H₂O (100 mL) was added. The aqueous layer was ex-

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1-(7-Bromo-1,5-naphthyridin-4-yl)-3-cyclopentylurea (30): Using

method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted with cy-

clopentylamine (462 mL, 4.69 mmol) to afford compound 30 as

a brown powder (381 mg, 51%). R_f=0.34 (CH₂Cl₂/EtOH, 95:5); mp:

(d, J=5.2 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.41 (d, J=5.2 Hz, 1H),

8.23 (d, J=6.0 Hz, 1H), 4.11 (brs, 1H), 2.99–2.64 ppm (m, 2H);

¹³C NMR (100 MHz, [D₆]DMSO): d=155.2, 153.4, 149.2, 143.9, 143.1,

138.9, 133.1, 120.2, 108.2, 93.7 (t, 1C, J_CF=276 Hz), 32.5, 17.3 ppm

(t, 1C, J_CF=22 Hz); IR (KBr): n˜ =3221, 3028, 1662, 1517, 1224,

990 cm^ꢂ1; MS (ESI) m/z (%): 343.1 (100) [M+H]⁺, 345.2 (100) [M+

H+2]⁺; Anal. calcd for C₁₂H₉BrF₂N₄O: C 42.00, H 2.64, N 16.33,

found: C 42.15, H 2.65, N 16.39.

1

183–1858C; H NMR (400 MHz, [D₆]DMSO): d=9.65 (s, 1H), 9.00 (d,

J=2.4 Hz, 1H), 8.75 (d, J=5.2 Hz, 1H), 8.66 (d, J=2.4 Hz, 1H), 8.42

(d, J=5.2 Hz, 1H), 7.82 (d, J=7.3 Hz, 1H), 4.15–4.06 (m, 1H); 1.95–

1.24 ppm (m, 8H); ¹³C NMR (100 MHz, [D₆]DMSO): d=153.7, 153.3,

149.3, 143.5, 143.4, 138.5, 133.2, 120.4, 108.7, 51.2, 34.9 (2C),

25.3 ppm (2C); IR (KBr): n˜ =3256, 3041, 2938, 1665, 1515, 1223,

994 cm^ꢂ1; mp: 119–1218C; MS (ESI) m/z (%): 335.2 (100) [M+H]⁺,

337.3 (100) [M+H+2]⁺; Anal. calcd for C₁₄H₁₅BrN₄O: C 50.16, H

4.51, N 16.71, found: C 50.34, H 4.52, N 16.76.

Method E: General method for the synthesis of (7-aryl-1,5-naph-

thyridin-4-yl)ureas 38–60 by Suzuki–Miyaura cross-coupling:

Under argon atmosphere, 1-(7-bromo-1,5-naphthyridin-4-yl)urea

(0.70 mmol), arylboronic acid or ester (1.40 mmol), Na₂CO₃(220 mg,

2.10 mmol), and tetrakis(triphenylphosphine) palladium (80 mg,

0.07 mmol) were introduced in a mixture of DMF/H₂O 10:1 (22 mL).

The mixture was stirred at 808C for 2–16 h. The mixture was al-

lowed to reach RT, and H₂O (100 mL) was added. The aqueous

layer was extracted with EtOAc (150 mL). The organic layers were

dried over anhyd Na₂SO₄, filtered, and evaporated to dryness. The

residue was purified by column chromatography on silica gel, elut-

ing with CH₂Cl₂/EtOH 96:4. The solvent was evaporated to dryness

to afford, after trituration with (iPr)₂O, the desired compounds 38–

60.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-(2-phenylethyl)urea

(34):

Using method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted

with 2-phenylethylamine (589 mL, 4.69 mmol) to afford compound

34 as a brown powder (538 mg, 65%). R_f=0.33 (CH₂Cl₂/EtOH,

95:5); mp: 119–1218C; ¹H NMR (400 MHz, [D₆]DMSO): d=9.89 (s,

1H), 9.00 (d, J=2.2 Hz, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.67 (d, J=

2.2 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 7.85 (t, J=5.7 Hz, 1H), 7.35–

7.21 (m, 5H); 3.45 (dt, J=7.1, 5.7 Hz, 2H), 2.86 ppm (t, J=7.1 Hz,

2H); ¹³C NMR (100 MHz, [D₆]DMSO): d=153.3, 151.5, 149.4, 143.3,

143.0, 139.5, 139.0, 133.7, 129.2 (2C), 128.3 (2C), 122.5, 120.7, 109.1,

42.1, 35.7 ppm; IR (KBr): n˜ =3251, 3042, 1686, 1515, 1209,

1012 cm^ꢂ1; MS (ESI) m/z (%): 371.2 (100) [M+H]⁺, 373.3 (100) [M+

H+2]⁺; Anal. calcd for C₁₇H₁₅BrN₄O: C 55.00, H 4.07, N 15.09,

found: C 55.21, H 4.09, N 15.14.

1-[7-(3,4-Dimethoxyphenyl)-1,5-naphthyridin-4-yl]-3-ethylurea

(38): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-ethyl-

urea 22 (207 mg, 0.70 mmol) reacted for 16 h with 3,4-dimethoxy-

phenylboronic acid (255 mg, 1.40 mmol) to afford compound 38 as

a white powder (165 mg, 67%). R_f=0.31 (CH₂Cl₂/EtOH, 96:4); mp:

1

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-(4-phenylbutyl)urea

(35):

215–2168C; H NMR (400 MHz, [D₆]DMSO): d=9.69 (s, 1H), 9.23 (d,

Using method D, 7-bromo-1,5-naphthyridin-4-amine 21 reacted

with 4-phenylbutylamine (741 mL, 4.69 mmol) to afford compound

35 as a beige powder (535 mg, 60%). R_f=0.45 (CH₂Cl₂/EtOH, 96:4);

mp: 115–1168C; ¹H NMR (400 MHz, [D₆]DMSO): d=9.72 (s, 1H),

9.00 (d, J=2.4 Hz, 1H), 8.76 (d, J=5.2 Hz, 1H), 8.68 (d, J=2.4 Hz,

1H), 8.43 (d, J=5.2 Hz, 1H), 7.67 (t, J=5.2 Hz, 1H), 7.33–7.19 (m,

5H), 3.21 (q, J=6.4, 5.2 Hz, 2H), 2.64 (t, J=7.2 Hz, 2H), 1.69–1.61

(m, 2H), 1.55–1.49 ppm (m, 2H); ¹³C NMR (100 MHz, [D₆]DMSO):

d=154.4, 153.6, 148.9, 144.1, 143.6, 142.3, 138.8, 133.0, 128.5 (2C),

128.4 (2C), 125.8; 120.4, 108.5, 39.0, 35.0, 29.2, 28.6 ppm; IR (KBr):

n˜ =3493, 1651 cm^ꢂ1; MS (ESI) m/z (%): 399.3 (100) [M+H]⁺, 401.4

(100) [M+H+2]⁺; Anal. calcd for C₁₉H₁₉BrN₄O: C 57.15, H 4.80, N

14.03, found: C 57.11, H 4.81, N 14.06.

J=2.1 Hz, 1H), 8.77 (d, J=5.1 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.38

(d, J=5.1 Hz, 1H), 7.71 (t, J=5.1 Hz, 1H), 7.55–7.50 (m, 2H), 7.17

(d, J=9.1 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.29–3.16 (m, 2H),

1.14 ppm (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

154.4, 152.7, 149.7, 149.6, 147.2, 143.6, 143.1, 136.8, 133.2, 133.0,

129.0, 120.1, 112.5, 111.2, 107.7, 55.9, 55.8, 34.2, 15.2 ppm; IR (KBr):

n˜ =3442, 3288, 3032, 1656, 1567, 1517, 1258, 1143, 1020 cm^ꢂ1; MS

(ESI) m/z (%): 353.2 (100) [M+H]⁺; Anal. calcd for C₁₉H₂₀N₄O₃: C

64.76, H 5.72, N 15.90, found: C 64.70, H 5.73, N 15.94.

1-Ethyl-3-[7-(4-hydroxy-3-methoxyphenyl)-1,5-naphthyridin-4-

yl]urea (39): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

ethylurea 22 (207 mg, 0.70 mmol) reacted for 16 h with

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

(350 mg, 1.40 mmol) to afford compound 39 as a yellow powder

(111 mg, 47%). R_f=0.17 (CH₂Cl₂/EtOH, 96:4); mp: 202–2038C;

¹H NMR (400 MHz, [D₆]DMSO): d=9.88 (s, 1H), 9.49 (s, 1H), 9.26 (d,

J=1.5 Hz, 1H), 8.80 (d, J=5.5 Hz, 1H), 8.54 (d, J=1.5 Hz, 1H), 8.43

(d, J=5.5 Hz, 1H), 7.77 (t, J=5.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=

7.9 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 3.95 (s, 3H), 3.28–3.18 (m, 2H),

1.14 ppm (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

153.5, 152.2, 148.5, 147.6, 147.0, 143.7, 143.2, 137.0, 132.9, 132.6,

127.4, 120.4, 116.3, 111.5, 107.7, 56.2, 34.4, 15.4 ppm; IR (KBr): n˜ =

3369, 3025, 1702, 1521, 1252, 1123, 1022 cm^ꢂ1; MS (ESI) m/z (%):

339.1 [(M+H), 100]; Anal. calcd for C₁₈H₁₈N₄O₃: C 63.89, H 5.36, N

16.56, found: C 63.99, H 5.37, N 16.53.

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-(2,2,2-trifluoroethyl)urea

(36): Using method D, 7-bromo-1,5-naphthyridin-4-amine 21 react-

ed with 2,2,2-trifluoroethylamine hydrochloride (635 mg,

4.69 mmol) to afford compound 36 as a brown powder (436 mg,

56%). R_f=0.42 (CH₂Cl₂/EtOH, 96:4); mp: 181–1828C; ¹H NMR

(400 MHz, [D₆]DMSO): d=9.99 (s, 1H), 9.04 (d, J=2.0 Hz, 1H), 8.82

(d, J=5.2 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H),

8.30 (t, J=6.0 Hz, 1H), 4.13–4.03 ppm (m, 2H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=154.9, 154.2, 150.1, 144.0, 143.9, 139.1, 133.4, 125.6

(q, 1C, J_CF=278 Hz), 121.4, 109.6, 41.3 ppm (q, 1C, J_CF=33 Hz); IR

(KBr): n˜ =3261, 3022, 1686, 1509, 1222, 996 cm^ꢂ1; MS (ESI) m/z (%):

349.1 (100) [M+H]⁺, 351.2 (100) [M+H+2]⁺; Anal. calcd for

C₁₁H₈BrF₃N₄O: C 37.84, H 2.31, N 16.05, found: C 37.89, H 2.32, N

15.99.

1-[7-(3,5-Dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]-3-eth-

ylurea (40): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

ethylurea 22 (207 mg, 0.70 mmol) reacted for 16 h with 2,6-di-

1-(7-Bromo-1,5-naphthyridin-4-yl)-3-(2,2-difluorocyclopropyl)-

urea (37): Using method D, 7-bromo-1,5-naphthyridin-4-amine 21

reacted with 2,2-difluorocyclopropylamine hydrochloride (607 mg,

4.69 mmol) to afford compound 37 as a white powder (590 mg,

77%). R_f=0.45 (CH₂Cl₂/EtOH, 96:4); mp: 184–1858C; ¹H NMR

(400 MHz, [D₆]DMSO): d=9.70 (s, 1H), 9.03 (d, J=2.4 Hz, 1H), 8.80

chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol

(385 mg,

1.40 mmol) to afford compound 40 as an orange powder (53 mg,

20%). R_f=0.22 (CH₂Cl₂/EtOH, 96:4); mp: >3008C; ¹H NMR

(400 MHz, [D₆]DMSO): d=10.59 (s, 1H), 9.69 (s, 1H), 9.23 (d, J=

2.4 Hz, 1H), 8.78 (d, J=5.2 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.40 (d,

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J=5.2 Hz, 1H), 8.05 (s, 2H), 7.73 (t, J=5.6 Hz, 1H), 3.25–3.17 (m,

2H), 1.14 ppm (t, J=7.2 Hz, 3H); ¹³C NMR (100 MHz, [D₆]DMSO):

d=154.4, 151.3, 149.6, 149.2, 148.2, 137.0, 133.2, 132.8, 126.8 (2C),

126.2 (2C), 123.4, 115.5, 107.3, 34.5, 15.5 ppm; IR (KBr): n˜ =3453,

3339, 3041, 1657, 1567, 1246, 1143 cm^ꢂ1; MS (ESI) m/z (%): 377.1

[(M+H), 100], 379.1 [(M+H)+2, 71], 381.1 [(M+H)+4, 12]; Anal.

calcd for C₁₇H₁₄Cl₂N₄O₂: C 54.13, H, 3.74, N 14.85, found: C 54.02, H

3.73, N 14.88.

1H), 8.78 (d, J=5.2 Hz, 1H), 8.55 (s, 1H), 8.34 (d, J=5.2 Hz, 1H),

7.85 (s, 1H), 7.51 (s, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.98 (d, J=7.2 Hz,

1H), 3.95 (s, 3H), 2.72–2.64 (m, 1H), 0.74 and 0.50 ppm (brs, 4H);

¹³C NMR (100 MHz, [D₆]DMSO): d=153.4, 152.2, 148.6, 147.6, 147.0,

143.6, 143.1, 137.0, 132.8, 132.6, 127.4, 120.2, 116.3, 111.6, 107.5,

55.9, 22.7, 6.8 ppm (2C); IR (KBr): n˜ =3349, 3236, 2976, 1708, 1579,

1519, 1317, 1124, 1026 cm^ꢂ1; MS (ESI) m/z (%): 351.1 [(M+H), 100];

Anal. calcd for C₁₉H₁₈N₄O₃: C 65.13, H 5.18, N 15.99, found: C 65.19,

H 5.19, N 15.94.

1-tert-Butyl-3-[7-(3,4-dimethoxyphenyl)-1,5-naphthyridin-4-yl]-

urea (41): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

tert-butylurea 27 (226 mg, 0.70 mmol) reacted for 16 h with 3,4-di-

methoxyphenylboronic acid (255 mg, 1.40 mmol) to afford com-

pound 41 as a white powder (138 mg, 52%). R_f=0.29 (CH₂Cl₂/

EtOH, 96:4); mp: 215–2168C; ¹H NMR (400 MHz, [D₆]DMSO): d=

9.67 (s, 1H), 9.21 (d, J=2.1 Hz, 1H), 8.72 (d, J=5.5 Hz, 1H), 8.57 (d,

J=2.1 Hz, 1H), 8.36 (d, J=5.5 Hz, 1H), 7.63 (s, 1H), 7.55–7.50 (m,

2H), 7.17 (d, J=9.1 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 1.14 ppm (s,

9H); ¹³C NMR (100 MHz, [D₆]DMSO): d=154.4, 152.7, 149.7, 149.6,

147.2, 143.6, 143.1, 136.8, 133.2, 133.0, 129.0, 120.1, 112.5, 111.2,

107.7, 55.9, 55.8, 34.2, 15.2 ppm (3C); IR (KBr): n˜ =3442, 3256, 3032,

1662, 1558, 1512, 1268, 1135, 1018 cm^ꢂ1; MS (ESI) m/z (%): 381.1

[(M+H), 100]; Anal. calcd for C₂₁H₂₄N₄O₃: C 66.30, H 6.36, N 14.73,

found: C 66.24, H 6.35, N 14.77.

1-Ethyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-

yl]urea (45): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

ethylurea 22 (207 mg, 0.70 mmol) reacted for 5 h with 1-methyl-4-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg,

1.40 mmol) to afford compound 45 as a white powder (116 mg,

56%). R_f=0.10 (CH₂Cl₂/EtOH, 95:5); mp: 215–2168C; ¹H NMR

(400 MHz, [D₆]DMSO): d=9.64 (s, 1H), 9.18 (d, J=2.1 Hz, 1H), 8.71

(d, J=5.1 Hz, 1H), 8.56 (s,1H), 8.49 (d, J=2.1 Hz, 1H), 8.32 (d, J=

5.1 Hz, 1H), 8.26 (s, 1H), 7.68 (t, J=5.1 Hz, 1H), 3.96 (s, 3H), 3.23–

3.19 (m, 2H), 1.14 ppm (t, J=7.2 Hz, 3H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=154.5, 152.7, 146.4, 143.6, 143.4, 137.2, 132.5, 130.7,

130.0, 129.4, 118.2, 107.4, 39.7, 34.2, 15.3 ppm; IR (KBr): n˜ =3331,

3205, 2972, 1698, 1562, 1258, 1200, 1132 cm^ꢂ1; MS (ESI) m/z (%):

297.1 [(M+H), 100]; Anal. calcd for C₁₅H₁₆N₆O: C 60.80, H 5.44, N

28.36, found: C 60.72, H 5.45, N 28.40.

1-tert-Butyl-3-[7-(4-hydroxy-3-methoxyphenyl)-1,5-naphthyridin-

4-yl]urea (42): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-

3-tert-butylurea 27 (226 mg, 0.70 mmol) reacted for 16 h with

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

(350 mg, 1.40 mmol) to afford compound 42 as a yellow powder

(159 mg, 62%). R_f=0.21 (CH₂Cl₂/EtOH, 96:4); mp: 158–1598C;

¹H NMR (400 MHz, [D₆]DMSO): d=9.66 (s, 1H), 9.41 (s, 1H), 9.19 (d,

J=2.0 Hz, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.35

(d, J=5.2 Hz, 1H), 7.62 (s, 1H), 7.50 (d, J=1.6 Hz, 1H), 7.40 (dd, J=

8.0, 1.6 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 3.95 (s, 3H), 1.14 ppm (s,

9H); ¹³C NMR (100 MHz, [D₆]DMSO): d=153.7, 152.6, 148.5, 147.7,

147.1, 143.8, 143.2, 137.0, 132.9, 132.8, 127.5, 120.4, 116.3, 111.7,

107.7, 56.1, 49.9, 29.0 ppm (3C); IR (KBr): n˜ =3339, 2968, 1683,

1519, 1267, 1128, 1030 cm^ꢂ1; MS (ESI) m/z (%): 367.2 [(M+H), 100];

Anal. calcd for C₂₀H₂₂N₄O₃: C 65.56, H 6.05, N 15.29, found: C 65.69,

H 6.03, N 15.24.

1-[7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-3-propyl-

urea (46): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

propylurea 23 (216 mg, 0.70 mmol) reacted for 16 h with 1-methyl-

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg,

1.40 mmol) to afford compound 46 as a white powder (152 mg,

70%). R_f=0.08 (CH₂Cl₂/EtOH, 96:4); mp: 216–2178C; ¹H NMR

(400 MHz, [D₆]DMSO): d=9.68 (s, 1H), 9.18 (s, 1H), 8.72 (d, J=

4.8 Hz, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.33 (d, J=4.8 Hz, 1H), 8.25

(s, 1H), 7.07 (brs, 1H), 3.96 (s, 3H), 3.15 (q, J=6.4 Hz, 2H), 1.56–

1.49 (m, 2H), 0.96 ppm (t, J=7.0 Hz, 3H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=154.6, 152.6, 146.4, 143.6, 143.4, 137.2, 132.5, 130.6,

130.0, 129.4, 118.2, 107.4, 41.1, 39.0, 22.8, 11.6 ppm; IR (KBr): n˜ =

3349, 3254, 3030, 2937, 1699, 1560, 1251 cm^ꢂ1; MS (ESI) m/z (%):

311.1 [(M+H), 100]; Anal. calcd for C₁₆H₁₈N₆O: C 61.92, H 5.85, N

27.08, found: C 61.98, H 5.84, N 27.02.

1-tert-Butyl-3-[7-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyri-

din-4-yl]urea (43): Using method E, 1-(7-bromo-1,5-naphthyridin-4-

yl)-3-tert-butylurea 27 (226 mg, 0.70 mmol) reacted for 16 h with

2,6-dichloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol

1-Butyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-

urea (47): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-bu-

tylurea 24 (226 mg, 0.70 mmol) reacted for 5 h with 1-methyl-4-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg,

1.40 mmol) to afford compound 47 as a pale-yellow powder

(54 mg, 24%). R_f=0.15 (CH₂Cl₂/EtOH, 95:5); mp: 219–2208C;

¹H NMR (400 MHz, CDCl₃): d=10.12 (s, 1H), 8.86 (d, J=2.3 Hz, 1H),

8.64 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J=2.3 Hz, 1H), 7.97 (d,

J=5.1 Hz, 1H), 7.87 (s, 1H), 7.60 (t, J=5.1 Hz, 1H), 3.95 (s, 3H),

3.42–3.40 (m, 2H), 1.68–1.65, 1.50–1.47 and 1.00–0.96 ppm (m,

7H); ¹³C NMR (100 MHz, [D₆]DMSO): d=154.5, 152.7, 146.3, 143.6,

143.2, 137.2, 132.5, 130.7, 130.1, 129.4, 118.1, 107.4, 39.9, 42.3, 31.8,

19.4, 14.3 ppm; IR (KBr): n˜ =3351, 3245, 2942, 2913, 1663, 1538,

1522, 1203 cm^ꢂ1; MS (ESI) m/z (%): 325.1 [(M+H), 100]; Anal. calcd

for C₁₇H₂₀N₆O: C 62.95, H 6.21, N 25.91, found: C 63.18, H 6.19, N

25.99.

(385 mg, 1.40 mmol) to afford compound 43 as a yellow powder

1

(116 mg, 41%). R_f=0.31 (CH₂Cl₂/EtOH, 96:4); mp >3008C; H NMR

(400 MHz, [D₆]DMSO): d=10.57 (s, 1H), 9.67 (s, 1H), 9.21 (d, J=

2.4 Hz, 1H), 8.75 (d, J=9.2 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.38 (d,

J=9.2 Hz, 1H), 8.06 (s, 2H), 7.65 (s, 1H), 1.38 ppm (s, 9H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=154.5, 151.3, 149.6, 149.1, 148.2, 137.1,

133.2, 132.8, 126.8 (2C), 126.1 (2C), 123.4, 115.5, 107.4, 49.4,

29.0 ppm (3C); IR (KBr): n˜ =3442, 3354, 2947, 1675, 1522, 1456,

1267, 1128 cm^ꢂ1; MS (ESI) m/z (%): 405.1 [(M+H), 100], 407.1 [(M+

2)+H, 69], 409.1 [(M+4)+H, 11]; Anal. calcd for C₁₉H₁₈Cl₂N₄O₂: C

56.31, H 4.48, N 13.82, found: C 56.38, H 4.50, N 13.74.

1-Cyclopropyl-3-[7-(4-hydroxy-3-methoxyphenyl)-1,5-naphthyri-

din-4-yl]urea (44): Using method E, 1-(7-bromo-1,5-naphthyridin-4-

yl)-3-cyclopropylurea 28 (215 mg, 0.70 mmol) reacted for 16 h with

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

(350 mg, 1.40 mmol) to afford compound 44 as a yellow powder

(42 mg, 17%). R_f=0.22 (CH₂Cl₂/EtOH, 95:5); mp: 235–2368C;

¹H NMR (400 MHz, [D₆]DMSO): d=9.63 (s, 1H), 9.42 (s, 1H), 9.21 (s,

1-Hexyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-

urea (48): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

hexylurea 25 (246 mg, 0.70 mmol) reacted for 16 h with 1-methyl-

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg,

1.40 mmol) to afford compound 48 as a white powder (79 mg,

32%). R_f=0.03 (CH₂Cl₂/EtOH, 96:4); mp: 188–1898C; ¹H NMR

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(400 MHz, [D₆]DMSO): d=9.67 (s, 1H), 9.18 (d, J=2.4 Hz, 1H), 8.71

(d, J=9.2 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.32 (d, J=

9.2 Hz, 1H), 8.25 (s, 1H), 7.68 (t, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.18

(dt, J=6.8, 5.6 Hz, 2H), 1.53–1.46 (m, 2H), 1.40–1.32 (m, 6H),

0.91 ppm (t, J=6.8 Hz, 3H); ¹³C NMR (100 MHz, [D₆]DMSO): d=

154.6, 152.6, 146.4, 143.6, 143.4, 137.2, 132.5, 130.7, 130.0, 129.4,

118.2, 107.5, 39.0, 31.1, 29.5, 26.2, 23.0, 22.3, 14.1 ppm; IR (KBr): n˜ =

3451, 3320, 2947, 1674, 1558, 1523, 1302, 1268 cm^ꢂ1; MS (ESI) m/z

(%): 353.2 [(M+H), 100]; Anal. calcd for C₁₉H₂₄N₆O: C 64.75, H 6.86,

N 23.85, found: C 64.99, H 6.88, N 23.93.

(291 mg, 1.40 mmol) to afford compound 52 as a beige powder

(74 mg, 30%). R_f=0.03 (CH₂Cl₂/EtOH, 96:4); mp: 200–2018C;

¹H NMR (400 MHz, [D₆]DMSO): d=9.64 (s, 1H), 9.18 (d, J=2.0 Hz,

1H), 8.71 (d, J=5.2 Hz, 1H), 8.57 (s, 1H), 8.49 (d, J=2.0 Hz, 1H),

8.32 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7,69 (d, J=7.6 Hz, 1H), 3.60–

3.58 (m, 1H), 1.21–1.94 (m, 10H), 3.97 ppm (s, 3H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=154.4, 152.4, 147.4, 145.2, 142.8, 137.7,

132.8, 131.0, 130.1, 129.9, 118.6, 108.0, 48.6, 40.0, 33.2 (2C), 25.9,

24.8 ppm (2C); IR (KBr): n˜ =3432, 3312, 2946, 1684, 1542, 1516,

1224, 1212 cm^ꢂ1; MS (ESI) m/z (%): 351.2 [(M+H), 100]; Anal. calcd

for C₁₉H₂₂N₆O: C 65.12, H 6.33, N 23.98, found: C 65.29, H 6.35, N

24.05.

1-Cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-

4-yl]urea (49): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-

3-cyclopropylurea 28 (215 mg, 0.70 mmol) reacted for 16 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 49 as a white powder

(125 mg, 58%). R_f=0.10 (CH₂Cl₂/EtOH, 96:4); mp: 223–2248C;

¹H NMR (400 MHz, [D₆]DMSO): d=9.59 (s, 1H), 9.18 (d, J=1.6 Hz,

1H), 8.74 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J=1.6 Hz, 1H),

8.32 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.83 (brs, 1H), 3.96 (s, 3H),

2.71–2.64 (m, 1H), 0.73 and 0.49 ppm (brs, 4H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=155.3, 152.7, 146.5, 143.6, 143.4, 137.2, 132.4, 130.7,

130.0, 129.4, 118.2, 107.4, 39.7, 22.5, 6.4 ppm (2C); IR (KBr): n˜ =

3353, 3267, 3040, 2917, 1708, 1553, 1515, 1265, 1195 cm^ꢂ1; MS (ESI)

m/z (%): 309.1 [(M+H), 100]; Anal. calcd for C₁₆H₁₆N₆O: C 62.32, H

5.23, N 27.26, found: C 62.47, H 5.22, N 27.30.

1-Isopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-

yl]urea (53): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

isopropylurea 26 (216 mg, 0.70 mmol) reacted for 5 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 53 as a pale-yellow

powder (65 mg, 30%). R_f=0.12 (CH₂Cl₂/EtOH, 95:5); mp: 229–

1

2308C; H NMR (400 MHz, [D₆]DMSO): d=9.58 (s, 1H), 9.18 (d, J=

1.9 Hz, 1H), 8.71 (d, J=5.2 Hz, 1H), 8.56 (s,1H), 8.49 (d, J=1.9 Hz,

1H), 8.32 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.65 (t, J=7.2 Hz, 1H),

3.96 (s, 3H), 3.23–3.19 (m, 1H), 1.71 ppm (d, J=6.5 Hz, 6H);

¹³C NMR (100 MHz, [D₆]DMSO): d=153.6, 152.4, 146.2, 143.4, 143.1,

136.9, 132.2, 130.3, 129.8, 129.2, 118.0, 107.2, 41.1, 38.8, 22.7 ppm

(2C); IR (KBr): n˜ =3324, 3213, 2967, 2927, 1669, 1548, 1521, 1251,

1126 cm^ꢂ1; MS (ESI) m/z (%): 311.2 [(M+H), 100]; Anal. calcd for

C₁₆H₁₈N₆O: C 61.92, H 5.85, N 27.08, found: C 62.01, H 5.84, N

27.16.

1-Cyclobutyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-

yl]urea (50): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

cyclobutylurea 29 (225 mg, 0.70 mmol) reacted for 16 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 50 as a pale-yellow

powder (120 mg, 53%). R_f=0.10 (CH₂Cl₂/EtOH, 96:4); mp: 215–

1-tert-Butyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-

yl]urea (54): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

tert-butylurea 27 (226 mg, 0.70 mmol) reacted for 16 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 54 as a pale-yellow

powder (118 mg, 52%). R_f=0.15 (CH₂Cl₂/EtOH, 96:4); mp: 215–

1

2168C; H NMR (400 MHz, [D₆]DMSO): d=9.57 (s, 1H), 9.19 (d, J=

2.4 Hz, 1H), 8.71 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J=2.4 Hz,

1H), 8.30 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 8.00 (d, J=7.6 Hz, 1H),

4.26–4.18 (m, 1H), 3.96 (s, 3H), 2.33–2.24 and 1.95–1.86 (m, 4H),

1.75–1.64 ppm (m, 2H); ¹³C NMR (100 MHz, [D₆]DMSO): d=153.4,

152.6, 146.4, 143.5, 143.4, 137.2, 132.5, 130.7, 130.0, 129.4, 118.2,

107.4, 44.7, 39.0, 30.9 (2C), 14.6 ppm; IR (KBr): n˜ =3452, 3320, 2935,

1696, 1555, 1515, 1254, 1200 cm^ꢂ1; MS (ESI) m/z (%): 323.1 [(M+H),

100]; Anal. calcd for C₁₇H₁₈N₆O: C 63.34, H 5.63, N 26.07, found: C

63.45, H 5.65, N 26.01.

1

2168C; H NMR (400 MHz, [D₆]DMSO): d=9.61 (s, 1H), 9.16 (d, J=

2.1 Hz, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.56 (s,1H), 8.48 (d, J=2.1 Hz,

1H), 8.31 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.61 (s, 1H), 3.96 (s, 3H),

1.37 ppm (s, 9H); ¹³C NMR (100 MHz, [D₆]DMSO): d=153.6, 152.6,

146.3, 143.8, 143.4, 137.2, 132.6, 130.6, 129.9, 129.4, 118.2, 107.4,

49.9, 29.0 (3C), 23.0 ppm; IR (KBr): n˜ =3452, 3359, 2969, 1700, 1517,

1263, 1199, 1130 cm^ꢂ1; MS (ESI) m/z (%): 325.1 [(M+H), 100]; Anal.

calcd for C₁₇H₂₀N₆O: C 62.95, H 6.21, N 25.91, found: C 63.07, H

6.23, N 25.86.

1-Cyclopentyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-

4-yl]urea (51): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-

3-cyclopentylurea 30 (235 mg, 0.70 mmol) reacted for 5 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 51 as a white powder

(101 mg, 43%). R_f=0.21 (CH₂Cl₂/EtOH, 95:5); mp: 207–2088C;

¹H NMR (400 MHz, [D₆]DMSO): d=9.60 (s, 1H), 9.18 (d, J=1.9 Hz,

1H), 8.71 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.48 (d, J=1.9 Hz, 1H),

8.32 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.75 (d, J=6.8 Hz, 1H), 4.10–

4.02 (m, 1H), 3.97 (s, 3H), 1.92–1.26 ppm (m, 8H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=153.4, 152.6, 146.3, 143.5, 143.4, 137.1,

132.5, 130.7, 130.0, 129.4, 118.1, 107.4, 51.3, 40.0, 34.5 (2C),

25.5 ppm (2C); IR (KBr): n˜ =3425, 3342, 2972, 2935, 1675, 1551,

1515, 1244, 1163 cm^ꢂ1; MS (ESI) m/z (%): 337.1 [(M+H), 100]; Anal.

calcd for C₁₈H₂₀N₆O: C 64.27, H 5.99, N 24.98, found: C 64.50, H

6.01, N 25.06.

1-[7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-3-phenyl-

urea (55): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

phenylurea 32 (240 mg, 0.70 mmol) reacted for 16 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 55 as a yellow powder

(80 mg, 33%). R_f=0.63 (CH₂Cl₂/EtOH, 96:4); mp: 294–2958C;

¹H NMR (400 MHz, [D₆]DMSO): d=10.10 (s, 1H), 10.00 (s, 1H), 9.25

(d, J=2.4 Hz, 1H), 8.80 (d, J=5.2 Hz, 1H), 8.59 (s, 1H), 8.55 (d, J=

2.4 Hz, 1H), 8.39 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.58 (d, J=7.6 Hz,

2H), 7.38 (dd, J=8.4, 7.6 Hz, 2H), 7.08 (t, J=7.2 Hz, 1H), 3.99 ppm

(s, 3H); ¹³C NMR (100 MHz, [D₆]DMSO): d=154.3, 152.5, 146.4,

143.4, 143.1, 138.9, 137.2, 132.5, 130.6, 130.0, 129.5, 129.1 (2C),

122.7, 118.6 (2C), 118.1, 107.4, 39.2 ppm; IR (KBr): n˜ =3452, 3351,

1717, 1625, 1158, 1525, 1310, 1246, 1184 cm^ꢂ1; MS (ESI) m/z (%):

345.1 [(M+H), 100]; Anal. calcd for C₁₉H₁₆N₆O: C 66.27, H 4.61, N

24.40, found: C 66.20, H 4.63, N 24.45.

1-Cyclohexyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-

yl]urea (52): Using method E, 1-(7-bromo-1,5-naphthyridin-4-yl)-3-

cyclohexylurea 31 (244 mg, 0.70 mmol) reacted for 16 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

1-Benzyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-

urea (56): Using method E, 1-benzyl-3-(7-bromo-1,5-naphthyridin-

ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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4-yl)urea 33 (250 mg, 0.70 mmol) reacted for 5 h with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

(291 mg, 1.40 mmol) to afford compound 56 as a pale-yellow

powder (95 mg, 38%). R_f=0.12 (CH₂Cl₂/EtOH, 95:5); mp: 237–

Anal. calcd for C₁₅H₁₃F₃N₆O: C 51.43, H 3.74, N 23.99, found: C

51.54, H 3.73, N 24.05.

1-(2,2-Difluorocyclopropyl)-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-

naphthyridin-4-yl]urea (60): Using method E, 1-(7-bromo-1,5-

1

2388C; H NMR (400 MHz, [D₆]DMSO): d=9.81 (s, 1H), 9.19 (d, J=

naphthyridin-4-yl)-3-(2,2-difluorocyclopropyl)urea

37

(240 mg,

1.6 Hz, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J=1.6 Hz,

1H), 8.35 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 8.18 (t, J=5.6 Hz, 1H),

7.42–7.29 (m, 5H), 4.42 (d, J=5.6 Hz, 2H), 3.97 ppm (s, 3H);

¹³C NMR (100 MHz, [D₆]DMSO): d=154.5, 152.4, 146.3, 143.3, 143.1,

139.5, 136.9, 132.3, 130.4, 129.8, 129.2, 128.4 (2C); 127.2 (2C);

126.9, 117.9, 107.4, 42.7, 38.8 ppm; IR (KBr): n˜ =3359, 3251, 3070,

1697, 1560, 1517, 1251, 1204 cm^ꢂ1; MS (ESI) m/z (%): 359.1 [(M+H),

100]; Anal. calcd for C₂₀H₁₈N₆O: C 67.02, H 5.06, N 23.45, found: C

67.21, H 5.08, N 23.51.

0.70 mmol) reacted for 16 h with 1-methyl-4-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-1H-pyrazole (291 mg, 1.40 mmol) to afford

compound 60 as a white powder (104 mg, 43%). R_f=0.10 (CH₂Cl₂/

EtOH, 95:5); mp: 229–2308C; ¹H NMR (400 MHz, [D₆]DMSO): d=

9.65 (s, 1H), 9.20 (d, J=2.0 Hz, 1H), 8.73 (d, J=9.2 Hz, 1H), 8.57 (s,

1H), 8.50 (d, J=2.0 Hz, 1H), 8.30 (d, J=9.2 Hz, 1H), 8.26 (s, 1H),

8.24 (d, J=7.2 Hz, 1H), 4.12 (bs, 1H), 3.96 (s, 3H), 3.07–2.91 ppm

(m, 2H); ¹³C NMR (100 MHz, [D₆]DMSO): d=154.1, 152.6, 146.6,

143.4, 143.2, 137.3, 132.4, 130.7, 130.1, 129.4, 118.2, 107.5, 96.2 (t,

1C, J_CF=276 Hz), 39.0, 35.1, 19.5 ppm (t, 1C, J_CF=22 Hz); IR (KBr):

n˜ =3445, 3319, 1638, 1585, 1301, 1267, 1159, 1052 cm^ꢂ1; MS (ESI)

m/z (%): 345.1 [(M+H), 100]; Anal. calcd for C₁₆H₁₄F₂N₆O: C 55.81,

H 4.10, N 24.41, found: C 56.01, H 4.12, N 24.49.

1-[7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-3-(2-phe-

nylethyl)urea (57): Using method E, 1-(7-bromo-1,5-naphthyridin-

4-yl)-3-(2-phenylethyl)urea 34 (260 mg, 0.70 mmol) reacted for 5 h

with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-

pyrazole (291 mg, 1.40 mmol) to afford compound 57 as a white

powder (182 mg, 70%). R_f=0.11 (CH₂Cl₂/EtOH, 95:5); mp: 222–

1

Biological assays

2238C; H NMR (400 MHz, [D₆]DMSO): d=9.71 (s, 1H), 9.17 (d, J=

2.0 Hz, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J=1.6 Hz,

1H), 8.34 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.75 (t, J=5.6 Hz, 1H),

7.38–7.24 (m, 5H), 3.96 (s, 3H), 3.48–3.43 (m, 2H), 2.84 ppm (t, J=

7.1 Hz, 2H); ¹³C NMR (100 MHz, [D₆]DMSO): d=154.3, 152.4, 146.4,

143.4, 142.8, 139.2, 136.9, 132.2, 130.1, 129.8, 129.2, 128.6 (2C);

128.3 (2C); 126.2, 117.9, 107.4, 40.5, 38.7, 35.2 ppm; IR (KBr): n˜ =

3359, 3287, 3064, 2930, 1701, 1556, 1517, 1252, 1202 cm^ꢂ1; MS

(ESI) m/z (%): 373.1 [(M+H), 100]; Anal. calcd for C₂₁H₂₀N₆O: C

67.73, H 5.41, N 22.57, found: C 67.98, H 5.42, N 22.63.

In vitro kinase inhibition assay: Recombinant kinases were pur-

chased from Millipore or ProQinase. An AlphaScreen Protein-A De-

tection Kit (PerkinElmer) was used to quantify kinase activity. For

the assessment of IC₅₀values, compounds were tested at ten final

concentrations between 3.16 nm and 100 mm. Each kinase, 10 mm

ATP, kinase substrate, and the test compound were incubated for

1 h on a 384-well Optiplate in a final volume of 15 mL. The kinase

reaction was stopped by adding 10 mL Alpha Beadmix. The readout

was performed the following morning using an Envision reader

(PerkinElmer). IC₅₀values were calculated with GraphPad Prism

software. Kinase testing was performed by the Target Lab

(Dr. Seipelt, Preclinical Development) at Æterna Zentaris GmbH,

Frankfurt/Main (Germany).

1-[7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-3-(4-phe-

nylbutyl)urea (58): Using method E, 1-(7-bromo-1,5-naphthyridin-

4-yl)-3-(4-phenylbutyl)urea 35 (279 mg, 0.70 mmol) reacted for 16 h

with

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-

pyrazole (291 mg, 1.40 mmol) to afford compound 58 as a white

powder (168 mg, 60%). R_f=0.03 (CH₂Cl₂/EtOH, 96:4); mp: 185–

1868C; H NMR (400 MHz, [D₆]DMSO): d=9.66 (s, 1H), 9.18 (d, J=

In vitro antiproliferative assay: Cytotoxicity assessments were con-

ducted with five diverse tumor cell lines, namely HCT116 (colon),

MDA-MB468 (breast), PC3 (prostate), A549 (NSCLC), and U87MG

(CNS). The tumor cell lines used were acquired from ATCC. Tumor

cells were plated on 96-well plates and allowed to attach over-

night; 48 h after cell seeding, test compounds were added at ten

final concentrations from 0.0158 to 50 mm in duplicate. After test

substance incubations for 48 h, cell proliferation was determined

by XTT-PMS methodology.^[47]The XTT assay quantifies cellular met-

abolic activity, which correlates with cellular viability and/or cell

number. IC₅₀values were calculated using GraphPad Prism soft-

ware. Cell cultures were carried out according to the supplier’s in-

structions. XTT testing was performed by the Target Lab

(Dr. Seipelt, Preclinical Development) at Æterna Zentaris GmbH,

Frankfurt/Main (Germany).

1

2.0 Hz, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J=2.0 Hz,

1H), 8.32 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.69 (t, J=6.8 Hz, 1H),

7.34–7.19 (m, 5H), 3.96 (s, 3H), 3.22 (q, J=6.8, 6.4 Hz, 2H), 2.65 (t,

J=7.6 Hz, 2H), 1.72–1.64 (m, 2H), 1.56–1.49 ppm (m, 2H); ¹³C NMR

(100 MHz, [D₆]DMSO): d=154.6, 152.6, 146.4, 143.6, 143.4, 142.3,

137.2, 132.5, 130.7, 130.0, 129.4, 128.5 (2C), 128.4 (2C), 125.9, 118.2,

107.5, 55.1, 39.0, 35.0, 29.3, 28.6 ppm; IR (KBr): n˜ =3462, 3296,

2931, 1695, 1651, 1553, 1516, 1252, 1205 cm^ꢂ1; MS (ESI) m/z (%):

401.1 [(M+H), 100]; Anal. calcd for C₂₃H₂₄N₆O: C 68.98, H 6.04, N

20.99, found: C 69.09, H 6.03, N 20.94.

1-[7-(1-Methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]-3-(2,2,2-tri-

fluoroethyl)urea (59): Using method E, 1-(7-bromo-1,5-naphthyri-

din-4-yl)-3-(2,2,2-trifluoroethyl)urea 36 (244 mg, 0.70 mmol) reacted

for 16 h with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)-1H-pyrazole (291 mg, 1.40 mmol) to afford compound 59 as

a white powder (154 mg, 63%). R_f=0.05 (CH₂Cl₂/EtOH, 96:4); mp

>3008C; ¹H NMR (400 MHz, [D₆]DMSO): d=9.95 (s, 1H), 9.22 (d,

J=2.0 Hz, 1H), 8.76 (d, J=5.2 Hz, 1H), 8.57 (s, 1H), 8.52 (d, J=

2.0 Hz, 1H), 8.33 (t, J=6.4 Hz, 1H), 8.32 (d, J=5.2 Hz, 1H), 8.27 (s,

1H), 4.13–4.02 (m, 2H), 3.96 ppm (s, 3H); ¹³C NMR (100 MHz,

[D₆]DMSO): d=154.5, 152.7, 146.8, 143.4, 143.1, 137.3, 132.4, 130.6,

130.2, 129.5, 128.2 (q, 1C, J_CF=277 Hz), 118.2, 107.9, 40.4 (q, 1C,

RP-UPLC method for lipophilicity determination: To determine the

lipophilicity profile of the (7-aryl-1,5-naphthyridin-4-yl)ureas 45–60,

chromatographic hydrophobicity indices (CHI) were determined ac-

cording to an original procedure, based on a reversed-phase UPLC

gradient. First, ten reference compounds with known CHI values

(Table 3) were injected onto the UPLC system to generate a calibra-

tion line from their retention time (CHI=45.99ꢂt_Rꢂ48.25, R²=

0.966). The concentration was 0.2 mgmL^ꢂ1in MeOH for each com-

pound, and the injected volume was 2 mL. The ureas were analyzed

on the same system. The calibration line equation was used to de-

termine the CHI values of ureas. As CHI correlates closely with

logD_7.4octanol/water partition coefficients, we estimated logD_7.4

values for the 16 ureas. For that we used a correlation equation

J

_CF=22 Hz), 39.0 ppm; IR (KBr): n˜ =3462, 3323, 2962, 1716, 1564,

1516, 1401, 1246, 1146 cm^ꢂ1; MS (ESI) m/z (%): 351.1 [(M+H), 100];

ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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MeCN). Precipitation was completed by a 15 min incubation period

at RT, after which the samples were centrifuged for 15 min at

13000 rpm (swinging-bucket rotor), and the particle-free superna-

tant was transferred into glass vials for HPLC analysis. Metabolic

stability assessments were performed by the ADME laboratory

(Dr. Blumenstein, Preclinical Development) at Æterna Zentaris

GmbH, Frankfurt/Main (Germany).

Table 3. CHI and logD_7.4values for reference compounds.

Compd

CHI

LogD_7.4

theophylline

paracetamol

benzimidazole

colchicine

15.76

18.77

30.71

41.37

49.0

ꢂ0.33

0.47

1.31

1.07

1.54

1.67

2.59

2.18

2.69

3.20

phenol

CYP inhibition: Direct inhibition of CYP3A4/5 was assessed with

midazolam (16 mm) as marker substrates by an HPLC-based UV de-

tection method in pooled human liver microsomes. Incubations

were carried out as doublets with final concentrations ranging

from 0.01 to 200 mm (30 min, 378C). Percent inhibition was plotted

against concentration to calculate or extrapolate IC₅₀values form

the sigmoid curve. Control incubations were performed according-

ly, but the reaction mix was precipitated before the addition of

NADPH. Negative controls were performed by omission of test

compound at the same time points. All reactions were started by

addition of NADPH and terminated by precipitation with stop re-

agent (43% MeCN). Samples were centrifuged for 10 min at

10200 rpm (swinging-bucket rotor), and the particle-free superna-

tant was transferred into glass vials for HPLC analysis. CYP450 in-

hibition studies were performed by the ADME laboratory

(Dr. Blumenstein, Preclinical Development) at Æterna Zentaris

GmbH, Frankfurt/Main (Germany).

acetophenone

indole

propiophenone

butyrophenone

valerophenone

64.9

69.15

78.41

88.49

97.67

obtained from the ten reference compounds (logD_7.4=0.031ꢂ

CHIꢂ0.004, R²=0.902). The UPLC column used was an Acquity

UPLC T3 (2.1 mm i.d., 50 mm length, 1.8 mm particle size) from

Waters. A linear mobile-phase gradient was used with a mobile

phase A as 100% of NH₄OAc 50 mm in H₂O (adjusted to pH 7.4

with NH₄OH) and mobile phase B as 100% MeCN. The gradient

table was: 0–0.5 min, 0% B; 0.5–4.0 min, 0!100% B; 4.0–5.5 min,

100% B; 5.5–5.7 min, 100!0% B; 5.7–7.5 min, 0% B at a flow rate

of 0.5 mLmin^ꢂ1and a column temperature at 358C. The detection

wavelength was 254 nm. LC–MS analyses were performed using

a Waters UPLC and Waters ZQ mass spectrometer system with

electrospray ionization and alternating positive and negative ion

quadrupole mass spectrometry and scanning m/z 100–900 each

second.

Chromatography: The test compound samples resulting from the

metabolic stability or CYP inhibition experiments were analyzed

with a Shimadzu Prominence HPLC system with respect to the loss

of peak area of parent compound using a Merck Chromolith Per-

formance column and a Primus Phenomenex Gemini C₁₈pre-

column. The analytical parameters were as follows: mobile phase A

(10% MeOH, 90% ddH₂0, 0.09% formic acid, 0.01% TFA, pH 4.0),

mobile phase B (90% MeOH, 10% ddH₂0, 0.09% formic acid,

0.01% TFA, pH 4.0), flow rate: 2.5 mLmin^ꢂ1, gradient: 15% B (0–

Kinetic solubility: Kinetic solubility was determined by an HPLC-

based UV detection method. Kinetic solubility was assessed in the

ADME laboratory (Dr. Blumenstein, Preclinical Development) at

Æterna Zentaris GmbH, Frankfurt/Main (Germany).

1.00 min), 15!100%

B

(1.01–10.00 min), 100%

B

(10.01–

Microsomal stability: Metabolic stability in pooled mouse liver mi-

crosomes (in the presence of an NADPH-regenerating system,

1 mgmL^ꢂ1microsomal protein) was evaluated at 378C over time

(60 min in liver microsomes) in triplicates at a test concentration of

10 mm. The remaining relative amount of test compound (reflected

by integrated peak area) was analyzed at time points 0, 5, 10, 30,

and 60 min by an HPLC-based UV detection method. Control incu-

bations were performed with 10 mm testosterone as marker sub-

strate for 15 min at 378C in order to demonstrate that the micro-

somes are fully functional. Negative controls were performed in

duplicates by incubation of test compound without NADPH at the

same time points. All reactions were started by the addition of

NADPH and terminated by precipitation with stop reagent (43%

MeCN). Samples were centrifuged for 10 min at 10200 rpm (swing-

ing-bucket rotor), and the particle-free supernatant was transferred

into glass vials for HPLC analysis.

11.30 min), 15% B (11.31–13.00 min), stop time: 13.01 min. To meet

the requirements of peak detectability, selection, as well as sensi-

tivity at concentrations used, even with test compounds with low

extinction coefficients, adequate wavelengths were used, as select-

ed from the UV spectra of the analyte (usually the spectral maxi-

mum). Integration of peaks was performed automatically by Shi-

madzu LCsolution software (Version 1.11 SP1). Peaks with intensi-

ties too low to be integrated were set at zero.

CaCo-2 permeability assay: To generate a cell monolayer, 80000

Caco-2 cells (ATCC, HTB-37) were seeded in DMEM supplemented

with 10% FCS, 1% penicillin/streptomycin and 1% nonessential

amino acids per 24-well transwell plate (Corning #3397) and were

grown for 21 days by changing the media every second day. On

day 21 the medium was replaced by HBSS buffer (Invitrogen

#14065) supplemented with 0.25 and 1% BSA for the donor and

acceptor compartments, respectively. The compounds were added

to the respective donor compartment at a concentration of 3 mm

and were incubated for 2 h at 378C in duplicates. The respective

compound concentrations were determined by LC–MS/MS analysis

employing an Agilent 1100 Series system with G1312A pumps and

a G1367A autosampler. Mass spectrometry was performed on an

API 2000 triple quadrupole mass spectrometer (AB Sciex Instru-

ments, Darmstadt, Germany) with a TurboIonSpray ion source con-

nected to a PC running the standard software, Analyst 1.3.2. Com-

pound concentrations were calculated relative to a calibration

standard. Before LC–MS/MS measurement, all samples were cleared

from protein and cell debris by precipitation with MeCN at a 1:4

ratio. The rate of permeation of the drug across the cells, dQ/dt,

Plasma stability: Stability in mouse plasma was determined after in-

cubation of test compounds at 378C in triplicates at a test concen-

tration of 10 mm. The remaining relative amount of test compound

(reflected by integrated peak area) was analyzed at time points 0,

1, 2, 4, and 6 h by an HPLC-based UV detection method. Control

incubations were performed accordingly with an internal standard

as marker in order to demonstrate that the plasma is fully function-

al. Duplicates were carried out and stopped after 15 min of incuba-

tion with the stop reagent (see below). Negative controls were per-

formed in duplicates by incubation of test compound in phos-

phate buffer at the same time points. All reactions were terminat-

ed by precipitation in a 1:4 ratio with ice-cold stop reagent (75%

ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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was calculated by using standard procedures^[48,49]based on mea-

surement at time points of 0 and 2 h.

Ikeda, G. Bianchi, Y. Hu, D. Cirstea, L. Santo, Y.-T. Tai, S. Nahar, M. Zheng,

M. Bandi, R. D. Carrasco, N. Raje, N. Munshi, P. Richardson, K. C. Ander-

son, Blood 2010, 115, 5202–5213.

hERG assay: The Predictor hERG assay (Invitrogen #PV 5365) uses

a membrane fraction containing hERG channel protein (Predictor

hERG Membrane) and a high-affinity red fluorescent hERG channel

ligand, or “tracer” (Predictor hERG Tracer Red), in a homogenous,

fluorescence polarization (FP)-based format.^[50]The assay was per-

formed according to the guidelines of the manufacturer. The data

were calculated in percent inhibition according to cells treated

with saturating concentrations of the hERG inhibitor E-4031 (Invi-

trogen #PV 5365) as positive, and non-treated samples as negative

controls. IC₅₀values were determined by using the GraphPad Prism

analysis program (GraphPad Software).

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Acknowledgements

We are grateful to Dr. Maud Antoine (AtlanChim Pharma) for

lipophilicity determinations.

Keywords: 1,5-naphthyridines · aurora kinases · heterocycles ·

inhibitors · ureas

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Received: September 26, 2013

Revised: November 4, 2013

Published online on November 24, 2013

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Article Doi

Discovery of 7-aryl-substituted (1,5-naphthyridin-4-yl)ureas as Aurora kinase inhibitors

DOI: 10.1002/cmdc.201300384

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