Synthesis and biological activity of imidazopyridine anticoccidial agents: Part II

Available online at www.sciencedirect.com

European Journal of Medicinal Chemistry 43 (2008) 1123e1151

http://www.elsevier.com/locate/ejmech

Original article

Synthesis and biological activity of imidazopyridine

anticoccidial agents: Part II

a

Andrew Scribner ^a,, Richard Dennis , Shuliang Lee , Gilles Ouvry , David Perrey ,

Michael Fisher ^b, Matthew Wyvratt ^b, Penny Leavitt ^c, Paul Liberator ^c, Anne Gurnett ^c,

Chris Brown ^c, John Mathew ^c, Donald Thompson ^c, Dennis Schmatz ^c, Tesfaye Biftu ^b

*

^aSCYNEXIS, Inc., Discovery Chemistry, P.O. Box 12878, Research Triangle Park, NC 27709-2878, USA

^bDepartment of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA

^cDepartment of Human and Animal Infectious Disease Research, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA

Received 9 July 2007; received in revised form 15 September 2007; accepted 18 September 2007

Available online 26 September 2007

Abstract

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the in-

testinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials

has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis

and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite speciﬁc

cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds,

focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar

in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further

development.

Keywords: Coccidiosis; Antiparasitic; Antiprotozoal; Kinase; Imidazopyridine

1. Introduction

Genetic studies in Toxoplasma gondii, a protozoan parasite

closely related to Eimeria, demonstrate that cGMP-dependent

protein kinase (PKG) is essential for survival and represents

a desirable therapeutic target [2]. It was reported recently

that inhibition of a novel PKG, isolated from these parasites,

stops the parasite proliferation by blocking parasite invasion

[2,3]. High throughput screening of known kinase inhibitors

resulted in the discovery of imidazopyridine analogs as PKG

inhibitors and broad spectrum anticoccidial agents [4]. Re-

cently, we reported the synthesis and biological activity of imi-

dazo[1,2-a]pyridines with diversity introduced at the 2-aryl

and 3-aryl rings [4,5]. Herein, we report PKG inhibition, syn-

thesis, evaluation, optimization, and in vivo anticoccidial ac-

tivities of imidazopyridines possessing optimal functionality

at the 2-aryl and 3-aryl rings, and with diversity introduced

at the amine side chain of the imidazopyridine 7-position.

Coccidiosis is a parasitic disease which is the major cause

of morbidity and mortality in the poultry industry. It is a dis-

ease of the avian intestinal lining due to invasion by protozoan

parasites of the genus Eimeria [1]. Some of the most signiﬁ-

cant Eimeria species in poultry are Eimeria tenella, Eimeria

acervulina, Eimeria necartrix, Eimeria brunetti, Eimeria mitis,

and Eimeria maxima. Over 35 billion chickens are raised an-

nually worldwide, and all major poultry operations use anti-

coccidial agents prophylactically. Resistance to current

coccidiostats is becoming widespread, and new broad spec-

trum drugs directed at novel biochemical targets are needed.

* Corresponding author. Tel.: þ919 544 8610; fax: þ919 544 8697.

E-mail address: andrew.scribner@scynexis.com (A. Scribner).

doi:10.1016/j.ejmech.2007.09.013

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A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

2. Results and discussions

2.1. Chemistry

chloride gave Weinreb amide 13 [12]. Oxidation of the sulﬁde

group of 13 with OXONE^Òafforded sulfone 14, which was

treated with ammonia to give 2-aminopyrimidine 15 [13]. The

reaction of Weinreb amide 15 with ethylmagnesium bromide

gave both the expected ethyl ketone 16 [12], and 7-carboxylic

acid methyl amide 17, which likely arises from deprotonation

of the Weinreb amide methoxy group by the Grignard reagent

followed by E2 elimination of formaldehyde [14].

Introduction of functionality on a benzylic amine nitrogen

at the imidazopyridine 7-position was accomplished as shown

in Scheme 1. The synthesis of sulﬁde 1 is presented in a com-

panion publication [5]. Oxidation of sulﬁde 1 with OXONE^Ò

gave sulfone 2. Subsequent treatment with ammonia afforded

2-aminopyrimidine 3. Oxidation of the benzylic alcohol with

manganese(IV) oxide yielded aldehyde 4 [6]. Treatment of 4

with various amines and sodium triacetoxyborohydride ulti-

mately yielded benzylic amines 5aeg [7].

Syntheses of compounds bearing a carbonyl group bridging

the imidazopyridine 7-position to the benzylic amine are

shown in Schemes 2 and 3. In Scheme 2, treatment of alde-

hyde 4 with hydroxylamine and triﬂuoroacetic acid gave ni-

trile 6 [8], which was hydrolyzed with potassium hydroxide

to yield amide 7 [9]. Alternatively, nitrile 6 was converted to

imidate 8 when treated with ethanol and hydrochloric acid

[10]. Subsequent treatment of imidate 8 with dimethylamine

gave amidine 9 [10]. An unexpected byproduct of this reaction

was N,N-dimethylaniline 10, which presumably resulted from

elimination of ethanol from imidate 8 to give a 7-cyanoimida-

zopyridine, followed by dimethylamine displacement of the

cyano group.

Different pathways were used to introduce one or two alkyl

substituents at the benzylic carbon of a 7-(dimethylaminome-

thyl)imidazopyridine, shown in Schemes 4 and 5. Synthesis of

analogs in which this alkyl group is a single methyl or ethyl is

shown in Scheme 4. Oxidation of alcohol 1 with mangane-

se(IV) oxide gave aldehyde 18 [6], which was treated with

methylmagnesium bromide to give secondary alcohol 20a.

Similarly, treatment of Weinreb amide 13 with ethylmagne-

sium bromide gave ethyl ketone 19 [12], which was reduced

with sodium borohydride to give alcohol 20b. Esteriﬁcation

of alcohols 20a and 20b with methanesulfonyl chloride and

triethylamine yielded methanesulfonate esters 21a and 21b,

which was followed by treatment with dimethylamine and di-

isopropylethylamine to give benzylic dimethylamines 22a and

22b. Oxidation of sulﬁdes 22a and 22b to sulfones 23a and

23b was performed with either OXONE^Òor peracetic acid

and catalytic sodium tungstate hydrate, followed by treatment

with sulfur dioxide to reduce any tertiary amine oxide back to

the tertiary amine [15]. Subsequent displacement of sulfone by

ammonia then followed to ultimately yield 2-aminopyrimi-

dines [13] 24a and 24b. HPLC separation of enantiomers of

24a was conducted on a Chiralcel OJ (Diacel) column.

A slightly different approach was used to introduce either an

n-propyl chain or two geminal methyl groups onto the benzylic

Synthesis of the corresponding 7-carboxylic acid methyl

amide (17) is shown in Scheme 3. The synthesis of bromide

11 is presented in a companion publication [5]. Subsequent cy-

clization with 2-(amino)isonicotinic acid ethyl ester yielded

imidazopyridine 12 [11], which upon treatment with N,O-di-

methylhydroxylamine hydrochloride and isopropylmagnesium

NH₂

S

SO₂

N

a

b

N

OH

F

1

2

3

c

NH₂

N

H

O

N

d

N

R''

N

R'

N

F

5a-g

4

Scheme 1. Reagents: (a) OXONE^Ò; (b) NH₃; (c) MnO₂; (d) HNR⁰R⁰⁰, NaB(OAc)₃H where R⁰and R⁰⁰are deﬁned as part of the R substituent of compounds 5aeg in

Table 1.

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1125

NH₂

N

NH₂

N

O

N

b

a

CN

N

4

NH₂

F

7

6

c

NH₂

N

NH₂

N

NH₂

N

NH

O

NH

N

d

N

+

N

F

8

9

10

Scheme 2. Reagents: (a) NH₂OH, CF₃CO₂H; (b) KOH; (c) EtOH, HCl; (d) HNMe₂.

carbon(Scheme5).Methanesulfonate25(preparedinacompan-

ion publication) [5] was treated with tetra-n-butylammonium

cyanide to yield nitrile 26 [16], which was then alkylated with

1-bromopropane to give a-n-propylnitrile 27a [17], or excess io-

domethane to give gem-dimethylnitrile 27b [18]. Subsequent

hydrolysis with concentrated sulfuric acid yielded amides 28a

and 28b, which underwent Hofmann rearrangement with bis(tri-

ﬂuoroacetoxy)iodobenzene to afford primary amines 29a and

29b [19]. Reductive amination with formaldehyde and sodium

cyanoborohydride with catalytic acetic acid afforded dimethyl-

amines 30a and 30b [20]. Functionalization of the pyrimidine 2-

position ensued as described earlier, entailing oxidation of

sulﬁdes 30a and 30b to sulfone 31a and 31b with OXONE^Òfol-

lowed by back-reduction of any N-oxide with sulfur dioxide

[15], and ammonia displacement of this sulfone to ultimately

yield 2-aminopyrimidines 32a and 32b [13].

An alternative pathway to introduce two geminal methyl

groups onto the benzylic carbon is shown in Scheme 6. Treat-

ment of ester 12 with excess methylmagnesium bromide gave

tertiary alcohol 33 [21]. Functionalization of the pyrimidine 2-

position followed, as treatment of sulﬁde 33 with OXONE^Ò

gave sulfone 34, which was then treated with ammonia to

yield 2-aminopyrimidine 35 [13]. Treatment of tertiary alcohol

35 with Ritter conditions (sodium cyanide, acetic acid, and

sulfuric acid) gave a mixture of formamides 36a and 36b,

which was hydrolyzed with sodium hydroxide to ultimately

yield gem-dimethyl primary amine 37 [22].

explored for each substrate. Nitriles 39a and 39b were ﬁrst re-

duced via hydrogenation with catalytic platinum(IV) oxide

[23] to give primary amines 40a and 40b. Displacement of

the sulfones with ammonia gave 2-aminopyrimidines 41a

and 41b [13]. Alternatively, sulfone 39c was ﬁrst treated

with ammonia to give 2-aminopyrimidine 40c, whose nitrile

was then reduced via lithium aluminum hydride [24] to give

primary amine 41c; both of these routes towards intermediates

41aec proved viable. Subsequent reductive amination with

formaldehyde, sodium cyanoborohydride, and catalytic acetic

acid ultimately yielded 7-(dimethylamino)ethylimidazopyri-

dines 42aec [20].

The synthesis of a 7-(dimethylamino)ethylimidazopyridine

bearing a ﬂuorine at the benzylic carbon is shown in Scheme 8.

Reﬂuxing aldehyde 18 with sarcosine and paraformaldehyde

resulted in a [3 þ 2] cycloaddition to give aminal 43, which

was then cleaved open upon treatment with sodium borohy-

dride to give the benzylic alcohol 44 [25]. Subsequent treat-

ment with DAST gave ﬂuoride 45 [26]. Oxidation of sulﬁde

45 with OXONE^Òfollowed by back-reduction with sulfur

dioxide to give sulfone 46 [15]. Treatment with ammonia ulti-

mately yielded 2-aminopyrimidine 47 [13].

The synthesis of 7-(dimethylamino)-n-propylimidazopyri-

dine 55 is shown in Scheme 9. Treatment of 2-chloro-4⁰-ﬂuoroa-

cetophenone with O-methylhydroxylamine hydrochloride gave

a-chloro-O-methyloxime 48 [27], which upon treatment with

lithium bromide yielded a-bromo-O-methyloxime 49. Subse-

quent reaction of 4-propanolpyridine with 49 under basic con-

ditions afforded imidazopyridine 50 [27]. Esteriﬁcation with

methanesulfonyl chloride gave methanesulfonate ester 51, and

subsequent treatment with dimethylamine and diisopropyle-

thylamine yielded dimethylamine 52. Acylation then occurred

with acetic anhydride and catalytic sulfuric acid to give ketone

53 [28], which was activated with N,N-dimethylformamide

The synthesis of 7-(dimethylamino)ethylimidazopyridines

is shown in Schemes 7 and 8. Scheme 7 shows the synthesis

of 7-(dimethylamino)ethylimidazopyridines 42aec. Alkyl-

ation of nitrile 26 with ethyl bromide and sodium hydride

yielded a-ethylnitrile 38 [17]. Oxidation of sulﬁdes 26, 38,

and 27b to sulfones 39aec, respectively, was achieved with

OXONE^Ò. At this point, different routes and reagents were

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A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

S

N

O

N

N O

O

a

b

Br

O

N

O

F

11

12

13

c

NH₂

N

NH₂

N

SO₂

N

N O

O

N

N O

O

e

d

N

O

N

F

16

15

14

+

NH₂

H

N

O

F

17

Scheme 3. Reagents: (a) 2-(amino)isonicotinic acid ethyl ester; (b) Me(MeO)NH$HCl, i-PrMgCl; (c) OXONE^Ò; (d) NH₃; (e) CH₃CH₂MgBr.

dimethyl acetal (DMFDMA) to afford enone 54 [29]. Treatment

with guanidine hydrochloride and sodium methoxide ultimately

yielded 2-aminopyrimidine 55 [29].

followed by treatment with guanidine hydrochloride and so-

dium methoxide to afford 2-aminopyrimidine 66 [29]. Treat-

ment of 7-chloroimidazopyridine 66 with palladium(II) acetate,

2-(di-tert-butylphosphino)biphenyl, sodium tert-butoxide, and N-

methylpiperazine ultimately yielded 7-(N-Me-piperazin-4-yl)

imidazopyridine 67 [28,31].

The pathway used to prepare 7-(piperidinyl)imidazopyri-

dines is shown in Scheme 10. First, protection of the piperi-

dine nitrogen of 4-piperidin-4-ylpyridine occurred with

acetic anhydride to give acetamide 56. Subsequent treatment

with a-bromo-O-methyloxime 49 followed by base afforded

imidazopyridine 57 [27]. Acylation of the imidazopyridine

3-position occurred with acetic anhydride and catalytic sul-

furic acid to give ketone 58 [28]. Reaction of this with

DMFDMA then afforded enone 59 [29], which upon treatment

with guanidine hydrochloride and sodium methoxide yielded

2-aminopyrimidine 60 [29]. Subsequent hydrolysis of the acet-

amide protecting group with hydrochloric acid gave NH-

piperidine 61, which then underwent reductive amination

with appropriate aldehyde or alkylation with appropriate alkyl

halide under basic conditions to ultimately yield N-alkylpiper-

idines 62aek [20].

2.2. Biology

The title compounds were tested for in vitro efﬁcacy via the

Ten_K (Tenella Kinase) assay, and in vivo efﬁcacy via the Ex-

MAC (Expanded Mini-Assay Coccidiosis) assay. The Ten_K

assay measures inhibition of E. tenella PKG enzyme activity,

and is reported as the amount of compound required to inhibit

activity by 50% (IC₅₀, in nM). The ExMAC assay measures

antiparasitic activity after administration of compound to

infected chickens (ppm in feed). Birds are infected with

E. tenella (E_t), E. acervulina (E_a), E. mitis (E_mi), and E. max-

ima (E_ma), and efﬁcacy is reported using a score of 0 through 4

based on percent of oocyte reduction relative to an untreated

control. Treatments that provide 100% reduction of oocyte

production are scored with a ‘4’, those with 99% reduction

are scored ‘3þ’, those with 80e98% reduction are scored

‘3’, those with 50e79% reduction are scored ‘2’, and those

with <50% reduction are scored ‘0’. Details of these

Synthesis of 7-(piperazinyl)imidazopyridine 67 is shown in

Scheme 11. Treatment of 2-bromo-4⁰-ﬂuoroacetophenone with

2-amino-4-chloropyridine [30] afforded 7-chloroimidazopyri-

dine 63 [11] which was acylated to ketone 64 with acetic an-

hydride and catalytic sulfuric acid [28]. Reaction of this

ketone with DMFDMA gave enone 65 [29], which was

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1127

S

N

H

N

a

b

N

1

O

S

F

N

R

N

18

N

OH

d

S

F

R = CH₃(20a)

R = CH₂CH₃(20b)

N

c

N

13

O

e

F

19

SO₂

N

S

N

R

N

R

N

R

g

f

N

OSO₂CH₃

F

R = CH₃(21a)

R = CH₂CH₃(21b)

R = CH₃(23a)

R = CH₂CH₃(23b)

R = CH₃(22a)

R = CH₂CH₃(22b)

h

NH₂

N

R

N

F

R = CH₃(24a)

R = CH₂CH₃(24b)

Scheme 4. Reagents: (a) MnO₂; (b) CH₃MgBr; (c) CH₃CH₂MgBr; (d) NaBH₄; (e) CH₃SO₂Cl, Et₃N; (f) HNMe₂, i-Pr₂NEt; (g) i. OXONE^Òor 30% H₂O₂, AcOH,

Na₂WO₄$2H₂O; ii. SO₂; (h) NH₃.

procedures were published in earlier work [3]. In some cases,

not all four species of Eimeria were tested.

in these same compounds lacking a basic amine on the side

chain. In fact, only dimethylamine 68 and diethylamine 5f ex-

hibited signiﬁcant in vivo activity at 12.5 ppm, suggesting

that both basicity and minimal steric bulk at the amine nitrogen

are crucial for in vivo potency.

Table 2 shows the biological effect of varying the length of

the side chain tethering the imidazopyridine 7-postion to the

amine nitrogen. The in vitro data suggest that there is consid-

erable tolerance for amine side chains of different lengths,

with subnanomolar activity seen in compounds possessing

a chain of one, two, or three carbons (compounds 68, 42a,

The data presented in Table 1 summarize the effect on both in

vitro and in vivo activity of modifying substituents on the ben-

zylic amine at the imidazopyridine 7-position relative to our

benzylic dimethylamine lead compound (68), which we have

reported previously [4a]. Other than nitrile 5e and piperazine

5g, all compounds from this set showed subnanomolar in vitro

activity except for those lacking a basic nitrogen on the side

chain of the imidazopyridine 7-position (amides 7 and 17, and

amidine 9). Likewise, in vivo efﬁcacy was considerably weaker

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A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

S

R'

N

a

b

R''

CN

N

OSO₂CH₃

CN

F

25

26

R' = n-Pr; R'' = H (27a)

R', R'' = CH₃(27b)

c

S

R'

O

N

e

d

R''

NH₂

R''

NH₂

N

F

R' = n-Pr; R'' = H (30a)

R', R'' = CH₃(30b)

R' = n-Pr; R'' = H (29a)

R', R'' = CH₃(29b)

R' = n-Pr; R'' = H (28a)

R', R'' = CH₃(28b)

f

NH₂

SO₂

R'

N

R'

N

g

R''

N

F

R' = n-Pr; R'' = H (31a)

R', R'' = CH₃(31b)

R' = n-Pr; R'' = H (32a)

R', R'' = CH₃(32b)

Scheme 5. Reagents: (a) n-Bu₄NCN; (b) CH₃CH₂CH₂Br or CH₃I; NaH; (c) H₂SO₄; (d) PhI(OCO₂CF₃)₂; (e) H₂CO, NaBH₃CN, AcOH; (f) i. OXONE^Ò; ii. SO₂; (g) NH₃.

and 55, respectively). The N,N-dimethylaniline 10 may have

weaker in vitro activity due to the lack of a basic nitrogen,

as discussed for examples 7, 9, and 17 in Table 1. In vivo po-

tency was found to be optimal in the analogs possessing a one

or two carbon chain (compounds 68 and 42a).

case. In vivo activity was optimal with the unsubstituted ho-

mobenzylic amine 42a and the ﬂuoride 47. All other examples

with larger substituents on the side chain showed weaker in

vivo potency.

After observing promising activity with alkyl branching at

the benzylic carbon of the imidazopyridine 7-position, we then

explored the effect of combining this branching with an entro-

pically restricted side chain nitrogen. Table 4 shows the effect

of having a 6-membered amine-bearing ring (piperidine or pi-

perazine) at the imidazopyridine 7-position. All such com-

pounds tested showed subnanomolar in vitro potency, and in

several cases (61, 69, 62b, 62c, 62e, and 62k) showed an

IC₅₀< 0.1 nM. Although the straight-chain analog possessing

a 3-carbon tether (55, described in Table 2) exhibited rela-

tively weak in vivo potency, many of these piperidines showed

excellent activity in vivo, especially compounds in which the

N-substituent was methyl (69, previously published) [4], ethyl

(62a), hydroxyethyl (62b), isobutyl (62d), and cyclopropyl-

methyl (62e). Larger, more lipophilic N-substituents decreased

in vivo potency. The 7-N-methylpiperazine (67) showed

Table 3 shows the effect of substituents on the alkyl chain

tethering the imidazopyridine 7-position to the amine nitrogen.

Each benzylic amine (24a, 24b, 32a, 37, and 32b) exhibited

subnanomolar activity in vitro, and in some cases (24a, 32a)

showed an IC₅₀< 0.1 nM. Introducing one alkyl substituent

at the benzylic carbon increased in vivo activity when the sub-

stituent was methyl (24a, particularly enantiomer B, active vs.

all four Eimeria species in vivo down to 2 ppm) and ethyl

(24b). The n-propyl analog (32a) also showed strong in vitro

activity, but weaker in vivo potency. When two geminal

methyl groups were introduced at the benzylic carbon (37,

32b), the in vivo activity slightly increased in the case of the

tertiary dimethylamine (32b).

Regarding the homobenzylic amines (42a, 42b, 41c, 42c,

and 47), in vitro potency remained subnanomolar in each

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1129

S

SO₂

N

a

b

N

12

OH

F

33

34

c

NH₂

N

NH₂

N

NHR

N

d

N

e

N

NH₂

NH

O

OH

H

F

37

R = H (36a)

R = Ac (36b)

35

Scheme 6. Reagents: (a) CH₃MgBr; (b) OXONE^Ò; (c) NH₃; (d) NaCN, AcOH, H₂SO₄; (e) NaOH.

S

SO₂

N

R'

N

b

R''

CN

R''

CN

N

F

R', R'' = H (26)

R', R'' = H (39a)

a

R' = H; R'' = CH₂CH₃(39b)

R', R'' = CH₃(39c)

R' = H; R'' = CH₂CH₃(38)

R', R'' = CH₃(27b)

c

d

NH₂

N

SO₂

R'

N

R'

N

R''

CN

R''

NH₂

N

F

d

e

R', R'' = H (40a)

R' = H; R'' = CH₂CH₃(40b)

R', R'' = CH₃(40c)

NH₂

N

NH₂

N

R'

N

f

R''

N

R''

NH₂

N

F

R', R'' = H (42a)

R' = H; R'' = CH₂CH₃(42b)

R', R'' = CH₃(42c)

R', R'' = H (41a)

R' = H; R'' = CH₂CH₃(41b)

R', R'' = CH₃(41c)

Scheme 7. Reagents: (a) NaH, CH₃CH₂Br; (b) OXONE^Ò; (c) H₂, PtO₂; (d) NH₃; (e) LiAlH₄; (f) H₂CO, NaBH₃CN, AcOH.

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A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

S

a

b

N

OH

O

N

18

N

F

43

44

c

NH₂

N

SO₂

N

S

N

F

N

F

N

e

d

F

N

F

47

46

45

Scheme 8. Reagents: (a) H₃CN(H)CH₂CO₂H, (CH₂O)_n; (b) NaBH₄; (c) DAST; (d) i. OXONE^Ò; ii. SO₂; (e) NH₃.

greater in vivo activity that the other dialkylaniline tested (10)

which does not possess as basic a nitrogen in the side chain;

however, 67 was not as potent as the corresponding N-methyl-

piperidine (69).

performed using Isco RediSep cartridges on an Isco OptiX10

or Companion automated ﬂash chromatography system, or us-

ing EMD silica gel (230e400 mesh). HPLC puriﬁcation was

conducted on a Varian Dynamax HPLC Guard Column,

21.4 mm, Compression Module Microsorb Guard-8C-18 (P/N

1

R00083221G). H NMR spectra were recorded on a Varian

3. Conclusion

Unity INOVA 400 MHz spectrometer; the values of chemical

shifts (d) are given in parts per million relative to the central

peak of the solvent, and the values of coupling constants (J )

are given in hertz (Hz). Mass spectra were recorded on a Ther-

moFinnigan AQA spectrometer. HPLC traces were recorded

on an Agilent 1100 or Hewlett Packard 1050 instrument

with a Phenomenex Aqua C18 125A 5 mm column, 4.6 mm

i.d. ꢀ 50 mm length. All compounds tested biologically were

found to be ꢁ90% pure by HPLC at 254 nM.

We have prepared several 2-aryl-3-(2-aminopyrimidin-4-yl)

imidazopyridines with varying alkyl amine substitution on the

imidazopyridine 7-position as anticoccidial agents. We have

found that there is considerable tolerance for varying the chain

length between the imidazopyridine 7-position and the amine

from one to two to three carbons, and for introducing one or

two additional alkyl groups on the benzylic carbon. We have

also found tolerance in vitro for steric bulk at the 7-position, al-

though invivo efﬁcacy begins to decrease as the size and lipophi-

licity of the substituent increases. The most active compounds

from this series showing in vivo potency against all four species

of Eimeriaat orbelow 12.5 ppmincludemonoalkylatedbenzylic

amines 24a (enantiomeric mixture and enantiomer B) and 24b,

gem-dialkylated benzylic amine 32b, homobenzylic amines

42a and 47, and piperidines 62a, 62b, 62d, and 62e. However,

the potential genotoxicity of compounds in this series precluded

them from further development [4].

4.1.1. [2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]methanol (2)

Sulﬁde 1 (2.80 g, 7.64 mmol) was suspended in MeOH

(170 mL), acetone (140 mL), and an aqueous solution of

OXONE^Ò(14.1 g, 22.9 mmol, in 130 mL H₂O), and allowed

to stir for 12 h. The reaction was then concentrated under re-

duced pressure to approximately 100 mL, then diluted with

water (200 mL), ﬁltered, and dried in a vacuum oven at

40 ^ꢂC overnight. Yield of 2: 2.35 g (77%) of 5. ¹H NMR

(400 MHz, CDCl₃) d 3.20 (s, 3H), 4.83 (s, 2H), 7.04e7.44

(m, 4H), 7.53e7.76 (m, 2H), 7.87 (bs, 1H), 8.62 (d,

J ¼ 5.4 Hz, 1H), 9.82 (d, J ¼ 7.0 Hz, 1H). MS (ESIþ) 398.8.

4. Experimental sections

4.1. General

Reactions were monitored by thin-layer chromatography

(TLC) on precoated EMD silica gel (60 F₂₅₄) plates (250 mm

thickness) and visualized using UV light (254 nm), or by

LCMS using a ThermoFinnigan AQA spectrometer with UV

detection (254 nm). Flash chromatography puriﬁcation was

4.1.2. [3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-7-yl]methanol (3)

A mixture of sulfone 2 (14.4 g, 36.1 mmol) in THF

(200 mL) in a pressure reactor was chilled to less than

ꢃ70 ^ꢂC in a CO₂/IPA bath. Ammonia (33.1 g, 1.94 mol) was

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

Cl Cl Br

1131

a

b

O

N

F

48

49

OH

c

d

N

OH

OSO₂CH₃

F

N

50

51

e

O

g

N

f

N

F

N

F

54

53

52

h

NH₂

N

F

55

Scheme 9. Reagents: (a) H₂NOCH₃$HCl; (b) LiBr; (c) i. 49; ii. DBU; (d) CH₃SO₂Cl, Et₃N; (e) HNMe₂, i-Pr₂NEt; (f) Ac₂O, H₂SO₄; (g) DMFDMA; (h) guani-

dine$HCl, NaOMe.

then bubbled in over 15 min. The pressure reactor was then

sealed, and the reaction was allowed to warm to room temper-

ature and stirred for 12 h, during which the reaction pressure

reached 55 psi. The pressure was then released, and the reac-

tion was concentrated under reduced pressure, then chromato-

graphed on SiO₂using a gradient that started with CH₂Cl₂and

ended with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield

12 h, and was then ﬁltered through Celite, and the Celite ﬁl-

ter cake was then rinsed with 9:1 CH₂Cl₂:MeOH (9:1)

(500 mL). The ﬁltrates were combined, concentrated under

reduced pressure, and not puriﬁed further. Yield of 4: 7.8 g

1

(74%). H NMR (400 MHz, CDCl₃) d 5.22 (bs, 2H), 6.57

(d, J ¼ 5.3 Hz, 1H), 7.16 (t, J ¼ 8.7 Hz, 2H), 7.43 (dd,

J ¼ 7.2, 1.6 Hz, 1H), 7.67 (m, 2H), 8.17 (s, 1H), 8.22 (d,

J ¼ 5.3 Hz, 1H), 9.46 (d, J ¼ 7.2 Hz, 1H), 10.06 (s, 1H).

MS (ESIþ) 334.2.

1

of 3: 10.6 g (83%). H NMR (400 MHz, CDCl₃) d 4.74 (s,

2H), 5.06e5.25 (bs, 2H), 6.50 (d, J ¼ 5.4 Hz, 1H), 6.88 (dd,

J ¼ 7.2, 1.6 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.53e7.73 (m,

3H), 8.12 (d, J ¼ 5.4 Hz, 1H), 9.38 (d, J ¼ 7.2 Hz, 1H). MS

(ESIþ) 336.0.

4.1.4. General procedure for the synthesis of

tertiary amines 5aeg

A solution of aldehyde 4 in CH₂Cl₂was charged with appro-

priate amine and sodium triacetoxyborohydride. After stirring

at room temperature for 12 h, the reaction was concentrated

under reduced pressure, chromatographed on SiO₂using a gra-

dient that started with CH₂Cl₂and ended with 90:9:1

CH₂Cl₂:MeOH:concentrated NH₄OH, and then puriﬁed further

4.1.3. [3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridine-7-carbaldehyde (4)

A solution of alcohol 3 (10.7 g, 31.9 mmol) in CH₂Cl₂

(1.0 L) was charged with manganese(IV) oxide (69.4 g,

798 mmol). The reaction was stirred at room temperature for

1132

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

O

H

N

O

N

c

N

a

b

F

N

56

57

58

d

NH₂

N

O

N

e

f

N

NH

N

F

61

60

59

g

NH₂

N

R

N

F

62a-k

Scheme 10. Reagents: (a) Ac₂O; (b) i. 49; ii. t-BuOK; (c), Ac₂O, H₂SO₄; (d) DMFDMA; (e) guanidine$HCl, NaOMe; (f) HCl; (g) appropriate aldehyde,

NaBH₃CN, AcOH or RBr, K₂CO₃where R is deﬁned in Table 4.

O

Br

Cl

a

b

N

O

F

63

64

c

NH₂

N

NH₂

N

O

N

e

N

d

Cl

N

Cl

N

F

67

66

65

Scheme 11. Reagents: (a) i. 2-amino-4-chloropyridine; ii. t-BuOK; (b), Ac₂O, H₂SO₄; (c) DMFDMA; (d) guanidine$HCl, NaOMe; (e) Pd(OAc)₂, 2-(di-tert-bu-

tylphosphino)biphenyl, t-BuONa, N-Me-piperazine.

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1133

Table 1

Biological activity of 7-substituted imidazopyridines: benzylic amines

NH₂

N

R

N

F

Compound

R

Ten_K IC₅₀(nM)^a

ExMAC dose (ppm)

ExMAC rating

E_t

E_a

E_mi

E_ma

68

CH₂N(CH₃)₂

0.11

25

12.5

6.25

3

0

3

0

5a

5b

5c

5d

5e

5f

CH₂NHC(CH₃)₃

0.35; 0.68

0.5

ND

12.5

25

CH₂N(CH₃)CH₂CH₂OH

CH₂N(CH₃)CH₂CH₂OCH₃

CH₂N(CH₃)CH₂C^CH

CH₂N(CH₃)CH₂C^N

CH₂N(CH₂CH₃)₂

0

3

0

3

0

0.69

0.65

1.33

0.17; 0.42

25

12.5

6.25

3

0

2

0

3

0

2

3

0

5g

2.2

25

12.5

3

0

3

0

3

0

N

*

7

9

C(]O)NH₂

1.8

2.5

3.1

50

25

3

0

2

0

2

0

2

C(]NH)N(CH₃)₂

C(]O)NHCH₃

17

a

In cases where a compound was tested more than once, all values obtained are reported.

by HPLC using a MeOH/H₂O gradient, where the aqueous

phase was 98.9:1.0:0.1 H₂O:CH₃CN:Et₃N.

(t, J ¼ 8.7 Hz, 2H), 7.58 (bs, 1H), 7.61e7.71 (m, 2H), 8.13 (d,

J ¼ 5.3 Hz, 1H), 9.46 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 393.1.

4.1.4.1. 4-[7-tert-Butylaminomethyl)-2-(4-ﬂuorophenyl)imidazo-

[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (5a). Amine 5a was

prepared from aldehyde 4 (100 mg, 0.300 mmol), tert-butyl-

amine (33 mg, 47 mL, 0.45 mmol), and sodium triacetoxybor-

ohydride (95 mg, 0.45 mmol) in CH₂Cl₂(100 mL). Yield of

4.1.4.3. 4-(2-(4-Fluorophenyl)-7-{[(2-methoxyethyl)methyl-

amino]methyl}imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamine

(5c). Amine 5c was prepared from aldehyde 4 (100 mg,

0.300 mmol), N-(2-methoxyethyl)methylamine (40 mg, 48 mL,

0.45 mmol), and sodium triacetoxyborohydride (95 mg,

0.45 mmol) in CH₂Cl₂(100 mL). Yield of 5c: 44.6 mg (37%).

¹H NMR (400 MHz, CDCl₃) d 2.35 (s, 3H), 2.64e2.75 (m,

2H), 3.38 (s, 3H), 3.53e3.60 (m, 2H), 3.68 (bs, 2H), 5.10 (bs,

2H), 6.53 (d, J ¼ 5.4 Hz, 1H), 7.02e7.08 (m, 1H), 7.13 (t,

J ¼ 8.7 Hz, 2H), 7.58 (bs, 1H), 7.61e7.69 (m, 2H), 8.13 (d,

J ¼ 5.4 Hz, 1H), 9.42 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 407.4.

1

5a: 42.9 mg (37%). H NMR (400 MHz, CDCl₃) d 1.20 (s,

9H), 3.84 (s, 2H), 5.12 (bs, 2H), 6.52 (d, J ¼ 5.4 Hz, 1H),

7.00 (dd, J ¼ 7.2, 1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H),

7.59e7.70 (m, 3H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.42 (d,

J ¼ 7.2 Hz, 1H). MS (ESIþ) 391.1.

4.1.4.2. 2-{[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-7-ylmethyl]methylamino}ethanol (5b).

Amine 5b was prepared from aldehyde 4 (100 mg, 0.300 mmol),

2-(methylamino)ethanol (34 mg, 36 mL, 0.45 mmol), and sodium

triacetoxyborohydride (95 mg, 0.45 mmol) in CH₂Cl₂(100 mL).

Yield of 5b: 27.7 mg (23%). ¹H NMR (400 MHz, CDCl₃) d 2.33

(s, 3H), 2.69 (t, J ¼ 4.7 Hz, 2H), 3.62e3.76 (m, 4H), 5.13 (bs,

2H), 6.53 (d, J ¼ 5.3 Hz, 1H), 6.97e7.03 (m, 1H), 7.13

4.1.4.4. 4-{2-(4-Fluorophenyl)-7-[(methylprop-2-ynylamino)-

methyl]imidazo[1,2-a]pyridin-3-yl}pyrimidin-2-ylamine (5d).

Amine 5d was prepared from aldehyde 4 (100 mg, 0.300 mmol),

N-methylpropargylamine (31 mg, 37 mL, 0.45 mmol), and sodium

triacetoxyborohydride (95 mg, 0.45 mmol) in CH₂Cl₂(100 mL).

Yield of 5d: 48.3 mg (42%). ¹H NMR (400 MHz, CDCl₃) d 2.31

(t, J ¼ 2.2 Hz, 1H), 2.39 (s, 3H), 3.37 (d, J ¼ 2.2 Hz, 2H), 3.67

1134

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

Table 2

Biological activity of 7-substituted imidazopyridines: amine side chains of varying length

NH₂

N

R

N

F

Compound

R

Ten_K IC₅₀(nM)^a

ExMAC dose (ppm)

ExMAC rating

E_t

E_a

E_mi

E_ma

10

N(CH₃)₂

3

25

12.5

6.25

3

2

0

3

0

3

0

68

CH₂N(CH₃)₂

0.11

25

12.5

6.25

3

0

3

0

42a

CH₂CH₂N(CH₃)₂

CH₂CH₂CH₂N(CH₃)₂

0.46; 0.62

0.27

25

12.5

6.25

4

3

4

3

0

4

2

55

25

12.5

6.25

3

0

3

0

3

0

4

0

a

In cases where a compound was tested more than once, all values obtained are reported.

(s, 2H), 5.14 (bs, 2H), 6.53 (d, J ¼ 5.3 Hz, 1H), 7.01 (dd, J ¼ 7.2,

1.5 Hz, 1H), 7.13 (t, J ¼ 8.7 Hz, 2H), 7.62 (bs, 1H), 7.60e7.70 (m,

2H), 8.13(d, J ¼ 5.3 Hz, 1H), 9.42 (d, J ¼ 7.2 Hz, 1H). MS(ESIþ)

387.4.

triacetoxyborohydride (95 mg, 0.45 mmol) in CH₂Cl₂(100 mL).

Yield of 5g: 72.2 mg (58%). ¹H NMR (400 MHz, CDCl₃) d 2.32

(s, 3H), 2.40e2.69 (m, 8H), 3.60 (s, 2H), 5.12 (bs, 2H), 6.52 (d,

J ¼ 5.4 Hz, 1H), 7.00 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.12 (t, J ¼

8.7 Hz, 2H), 7.62 (bs, 1H), 7.63e7.76 (m, 2H), 8.13 (d,

J ¼ 5.4 Hz, 1H), 9.42 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 418.2.

4.1.4.5.

{[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)imi-

dazo[1,2-a]pyridin-7-ylmethyl]methylamino}acetonitrile (5e).

Amine 5e was prepared from aldehyde 4 (100 mg, 0.300 mmol),

methylaminoacetonitrile (32 mg, 34 mL, 0.45 mmol), and sodium

triacetoxyborohydride (95 mg, 0.45 mmol) in CH₂Cl₂(100 mL).

Yield of 5e: 19.5 mg (17%). ¹H NMR (400 MHz, CDCl₃) d 2.48

(s, 3H), 3.56 (s, 2H), 3.72 (s, 2H), 5.15 (bs, 2H), 6.53 (d,

J ¼ 5.3 Hz, 1H), 6.95 (dd, J ¼ 7.2, 1.5 Hz, 1H), 7.13 (t,

J ¼ 8.7 Hz, 2H), 7.61e7.68 (m, 2H), 7.64 (bs, 1H), 8.14 (d,

J ¼ 5.3 Hz, 1H), 9.45 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 388.3.

4.1.5. 3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridine-7-carbonitrile (6)

A solution of aldehyde 4 (1.20 g, 3.60 mmol) in triﬂuoroace-

tic acid (50 mL) was charged with hydroxylamine hydrochlo-

˚

ride (375 mg, 5.40 mmol) and 4 A molecular sieves, and

heated to 85 ^ꢂC for 15 h. The reaction was then cooled to

room temperature and neutralized with the slow addition of sat-

urated aqueous NaHCO₃solution (600 mL), then extracted into

9:1 CH₂Cl₂:MeOH (5 ꢀ 200 mL), dried over Na₂SO₄, concen-

trated under reduced pressure, and then chromatographed on

SiO₂using a gradient that started with CH₂Cl₂and ended

with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 6:

4.1.4.6. 4-[7-Diethylaminomethyl-2-(4-ﬂuorophenyl)imidazo-

[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (5f). Amine 5f was

prepared from aldehyde 4 (100 mg, 0.300 mmol), diethylamine

(33 mg, 47 mL, 0.45 mmol), and sodium triacetoxyborohydride

(95 mg, 0.45 mmol) in CH₂Cl₂(100 mL). Yield of 5f: 39.2 mg

(34%). ¹H NMR (400 MHz, CDCl₃) d 1.07 (t, J ¼ 7.0 Hz, 6H),

2.58 (q, J ¼ 7.0 Hz, 4H), 3.65 (s, 2H), 5.11 (bs, 2H), 6.53 (d,

J ¼ 5.4 Hz, 1H), 7.00e7.07 (m, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H),

7.62 (bs, 1H), 7.62e7.68 (m, 2H), 8.12 (d, J ¼ 5.4 Hz, 1H),

9.41 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 391.1.

1

590 mg (50%). H NMR (400 MHz, CDCl₃) d 5.19 (bs, 2H),

6.57 (d, J ¼ 5.3 Hz, 1H), 7.06 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.16

(t, J ¼ 8.7 Hz, 2H), 7.66e7.74 (m, 2H), 8.08 (bs, 1H), 8.22

(d, J ¼ 5.3 Hz, 1H), 9.54 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 331.1.

4.1.6. 3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridine-7-carboxylic acid amide (7)

Nitrile 6 (150 mg, 0.454 mmol) was slurried in 1-propanol

(25 mL), then charged with KOH (56.0 mg, 1.00 mmol) and

heated to 110 ^ꢂC for 12 h. The reaction was then concentrated

under reduced pressure, and then chromatographed on SiO₂us-

ing a gradient that started with CH₂Cl₂and ended with 90:9:1

4.1.4.7. 4-[2-(4-Fluorophenyl)-7-(4-methylpiperazin-1-ylmethyl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (5g). Amine

5g was prepared from aldehyde 4 (100 mg, 0.300 mmol),

N-methylpiperazine (45 mg, 60 mL, 0.45 mmol), and sodium

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1135

Table 3

Biological activity of 7-substituted imidazopyridines: branched amine side chains

NH₂

N

R

N

F

Compound

R

Ten_K IC₅₀(nM)^a

ExMAC dose (ppm)

ExMAC rating

E_t

E_a

E_mi

E_ma

68

CH₂N(CH₃)₂

0.11

25

12.5

6.25

3

0

3

0

24a

CH(CH₃)N(CH₃)₂

0.09

6.25

3.1

4

3

0

2

3

2

4

3

0

3

4

3

4

3

0

2

3

0

4

0

2

4

3

4

CH(CH₃)N(CH₃)₂enantiomer A

0.44; 0.28

2

1

CH(CH₃)N(CH₃)₂enantiomer B

0.087; 0.067

4

2

1

24b

32a

CH(CH₂CH₃)N(CH₃)₂

0.13; 0.3

0.065

12.5

8

4

2

4

3

4

0

4

2

CH(CH₂CH₂CH₃)N(CH₃)₂

25

12.5

6.25

4

0

4

3

4

0

4

0

4

37

C(CH₃)₂NH₂

0.145; 0.26

12

6

4

3

0

3

2

0

4

3

32b

42a

C(CH₃)₂N(CH₃)₂

CH₂CH₂N(CH₃)₂

0.11

8

6.25

4

0

3

4

3

0.46; 0.62

25

12.5

6.25

4

3

4

3

0

4

2

42b

41c

42c

CH(CH₂CH₃)CH₂N(CH₃)₂

C(CH₃)₂CH₂NH₂

0.4

25

4

2

0

2

4

0

0.26

0.2

C(CH₃)₂CH₂N(CH₃)₂

25

12.5

6.25

4

3

0

3

0

3

0

47

CHFCH₂N(CH₃)₂

0.59

25

12.5

6.25

4

3

4

3

0

4

2

0

4

a

In cases where a compound was tested more than once, all values obtained are reported.

CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 7: 42.0 mg

1

warm to room temperature while stirring for 12 h, and was

then concentrated under reduced pressure, and carried onto

the next step without further puriﬁcation. MS (ESIþ) 376.2.

(25%). H NMR (400 MHz, CDCl₃) d 6.47 (d, J ¼ 5.6 Hz,

1H), 7.15 (t, J ¼ 8.6 Hz, 2H), 7.53 (dd, J ¼ 7.3, 1.6 Hz, 1H),

7.56e7.64 (m, 2H), 8.06 (d, J ¼ 5.6 Hz, 1H), 8.16 (bs, 1H),

9.54 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 348.9.

4.1.8. 3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-N,N-

dimethylimidazo[1,2-a]pyridine-7-carboxamidine (9) and

3-(2-aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)imidazo[1,2-a]-

pyridin-7-yl]dimethylamine (10)

A solution of imidate 8 (theoretically 490 mg, 1.30 mmol)

was charged with EtOH (100 mL), then dimethylamine

(26.0 mL of a 2.0 M solution in THF, 52.0 mmol) and heated

4.1.7. 3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridine-7-carboximidic acid ethyl ester (8)

A solution of nitrile 6 (430 mg, 1.30 mmol) in EtOH

(200 mL) was cooled to 0 ^ꢂC in an ice water bath, then charged

with HCl gas for 30 min. The reaction was then allowed to

1136

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

Table 4

Biological activity of 7-substituted imidazopyridines: 6-membered amine side chains

NH₂

N

R

N

F

Compound

R

Ten_K IC₅₀(nM)

ExMAC dose (ppm)

ExMAC rating

E_tE_a

E_mi

E_ma

68

CH₂N(CH₃)₂

0.11

25

12.5

6.25

3

0

3

0

3

61

69

0.046

0.044

25

0

4

NH

*

25

12.5

10

8

4

3

4

3

4

N

6

62a

62b

0.12

25

12.5

10

8

4

3

0

4

3

4

0

*

6

0.044

25

12.5

6.25

3þ

2

0

3

0

2

3

0

OH

0

62c

62d

0.065

0.12

25

12.5

6.25

4

0

3

0

2

0

N

OH

*

25

12.5

6.25

4

2

4

3

4

3

0

4

3

62e

0.095

25

12.5

6.25

4

3

4

3

N

*

62f

0.13

0.11

12.5

3

0

N

*

62g

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1137

Table 4 (continued)

Compound

R

Ten_K IC₅₀(nM)

ExMAC dose (ppm)

ExMAC rating

E_tE_a

E_mi

0

E_ma

62h

0.12

12.5

3

0

N

*

62i

62j

0.13

0.11

12.5

2

0

N

*

25

12.5

6.25

3

0

3

0

4

3

62k

0.07

0.23

12.5

0

N

*

67

25

12.5

6.25

3

0

3

2

4

0

N

to 80 ^ꢂC for 2 h. The reaction was then concentrated under re-

duced pressure, and then chromatographed on SiO₂using

a gradient that started with CH₂Cl₂and ended with 90:9:1

CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 9: 210 mg

ﬁlter cake was rinsed with EtOH, and then dried in a vacuum

oven, yielding an additional 7.11 g (36%) of imidazopyridine

12. Total yield of 12: 14.9 g (76%). ¹H NMR (400 MHz,

CDCl₃) d 1.44 (t, J ¼ 7.2 Hz, 3H), 2.65 (s, 3H), 4.45

(q, J ¼ 7.2 Hz, 2H), 6.85 (d, J ¼ 5.0 Hz, 1H), 7.15 (t,

J ¼ 8.6 Hz, 2H), 7.58 (d, J ¼ 7.4 Hz, 1H), 7.60e7.68

(m, 2H), 8.36 (d, J ¼ 5.0 Hz, 1H), 8.45 (bs, 1H), 9.55

(d, J ¼ 7.4 Hz, 1H). MS (ESIþ) 409.3.

1

(43%). H NMR (400 MHz, CDCl₃) d 3.10 (s, 6H), 5.17 (bs,

2H), 6.54 (d, J ¼ 5.3 Hz, 1H), 6.98 (d, J ¼ 7.2 Hz, 1H), 7.14

(t, J ¼ 8.7 Hz, 2H), 7.61e7.69 (m, 2H), 7.73 (bs, 1H), 8.18

(d, J ¼ 5.3 Hz, 1H), 9.55 (d, J ¼ 7.2 Hz, 1H). Yield of 10:

1

70 mg (20%). H NMR (400 MHz, CDCl₃) d 3.49 (s, 6H),

5.21 (bs, 2H), 6.54 (d, J ¼ 5.3 Hz, 1H), 7.15 (t, J ¼ 8.7 Hz,

2H), 7.43 (d, J ¼ 7.4 Hz, 1H), 7.61e7.69 (m, 2H), 8.10 (bs,

1H), 8.19 (d, J ¼ 5.3 Hz, 1H), 9.50 (d, J ¼ 7.4 Hz, 1H). MS

(ESIþ) 349.1.

4.1.10. 2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridine-7-carboxylic acid

methoxymethylamide (13)

A solution of ester 12 (10.0 g, 24.5 mmol) in THF

(200 mL) was charged with N,O-dimethylhydroxylamine hy-

drochloride (7.20 g, 73.4 mmol), then cooled to 0 ^ꢂC in an

ice water bath. The reaction was then charged with the drop-

wise addition of isopropylmagnesium chloride (73.5 mL of

a 2.0 M solution in THF, 147 mmol), then allowed to warm

to room temperature and stir for 12 h, after which it was

quenched with saturated aqueous NH₄Cl solution (250 mL),

then extracted with CH₂Cl₂(2 ꢀ 250 mL). The organic frac-

tions were pooled, dried over Na₂SO₄, ﬁltered, and then chro-

matographed on SiO₂using a gradient that started with

heptane and ended with EtOAc. Yield of 13: 5.60 g (54%).

¹H NMR (500 MHz, CDCl₃) d 2.68 (s, 3H), 3.45 (s, 3H),

3.66 (s, 3H), 6.87 (d, J ¼ 5.5 Hz, 1H), 7.18 (t, J ¼ 8.5 Hz,

2H), 7.37 (dd, J ¼ 7.5, 2.0 Hz, 1H), 7.62e7.80 (m, 2H), 8.20

4.1.9. 2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-

imidazo[1,2-a]pyridine-7-carboxylic acid ethyl ester (12)

A solution of bromide 11 (16.2 g, 47.5 mmol) in EtOH

(100 mL) was charged with 2-(amino)isonicotinic acid ethyl

ester (7.89 g, 47.5 mmol), then heated to 60 ^ꢂC for 12 h, after

which it was concentrated under reduced pressure, then tritu-

rated with EtOH, then ﬁltered. The ﬁlter cake was rinsed

with EtOH and then dried in a vacuum oven, yielding 7.79 g

(40%) of imidazopyridine 12. The remaining ﬁltrate was

then concentrated under reduced pressure and suspended in

EtOH (100 mL), then charged with additional 2-(amino)isoni-

cotinic acid ethyl ester (5.40 g, 32.5 mmol), and heated to

90 ^ꢂC for 12 h, after which it was concentrated under reduced

pressure, and then triturated with EtOH, and then ﬁltered. The

1138

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

(bs, 1H), 8.36 (d, J ¼ 5.5 Hz, 1H), 9.58 (d, J ¼ 7.5 Hz, 1H).

MS (ESIþ) 424.2.

with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of

1

16: 220 mg (23%). H NMR (400 MHz, CDCl₃) d 1.26 (t,

J ¼ 7.2 Hz, 3H), 3.07 (q, J ¼ 7.2 Hz, 2H), 5.42 (bs, 2H), 6.50

(d, J ¼ 5.4 Hz, 1H), 7.13 (t, J ¼ 8.6 Hz, 2H), 7.49 (dd,

J ¼ 7.4, 1.5 Hz, 1H), 7.62 (m, 2H), 8.13 (d, J ¼ 5.4 Hz, 1H),

8.26 (bs, 1H), 9.43 (d, J ¼ 7.4 Hz, 1H). MS (ESIþ) 362.3. Yield

4.1.11. 2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-

4-yl)imidazo[1,2-a]pyridine-7-carboxylic acid

methoxymethylamide (14)

1

of 17: 260 mg (28%). H NMR (400 MHz, CDCl₃) d 2.99 (s,

A solution of sulﬁde 13 (2.00 g, 4.72 mmol) in 1:1 MeOH:

acetone (100 mL) was charged with a solution of OXONE^Ò

(8.70 g, 14.2 mmol) in H₂O (50 mL). The reaction was stirred

at room temperature for 12 h, and was then concentrated under

reduced pressure to remove as much of the organic solvent as

possible, then diluted with H₂O (100 mL) and ﬁltered. The ﬁl-

ter cake was dried in a vacuum oven at 60 ^ꢂC for 3 h. Yield of

14: 1.60 g (76%). ¹H NMR (400 MHz, CDCl₃) d 3.43 (s, 3H),

3.44 (s, 3H), 3.64 (s, 3H), 7.22 (t, J ¼ 8.5 Hz, 2H), 7.34 (d,

J ¼ 5.6 Hz, 1H), 7.48 (dd, J ¼ 7.4, 1.5 Hz, 1H), 7.60e7.68

(m, 2H), 8.19 (bs, 1H), 8.58 (d, J ¼ 5.5 Hz, 1H), 9.88 (d,

J ¼ 7.4 Hz, 1H). MS (ESIþ) 456.3.

3H), 5.51 (bs, 2H), 6.44 (d, J ¼ 5.4 Hz, 1H), 7.12 (t,

J ¼ 8.6 Hz, 2H), 7.47 (dd, J ¼ 7.3, 1.8 Hz, 1H), 7.54e7.60

(m, 2H), 7.99 (bs, 1H), 8.08 (d, J ¼ 5.4 Hz, 1H), 9.47 (d,

J ¼ 7.3 Hz, 1H). MS (ESIþ) 363.3.

4.1.14. 2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridine-7-carbaldehyde (18)

A solution of alcohol 1 (3.66 g, 9.99 mol) in CH₂Cl₂

(750 mL) was charged with manganese(IV) oxide (21.7 g,

250 mmol). The reaction was stirred at room temperature for

5 h, and was then ﬁltered through Celite, and the Celite ﬁlter

cake was then rinsed with CH₂Cl₂(750 mL) and EtOAc

(500 mL). The ﬁltrate was then concentrated under reduced

pressure and dried under vacuum, and not puriﬁed further.

Yield of 18: 2.39 g (66%). ¹H NMR (500 MHz, CDCl₃)

d 2.65 (s, 3H), 6.87 (d, J ¼ 5.5 Hz, 1H), 7.17 (t, J ¼ 9.0 Hz,

2H), 7.51 (d, J ¼ 7.5 Hz, 1H), 7.62e7.68 (m, 2H), 8.27 (bs,

1H), 8.40 (d, J ¼ 5.5 Hz, 1H), 9.54 (d, J ¼ 7.5 Hz, 1H),

10.08 (s, 1H). MS (ESIþ) 365.2.

4.1.12. 3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridine-7-carboxylic acid

methoxymethylamide (15)

A suspension of sulfone 14 (1.60 g, 3.51 mmol) in THF

(100 mL) was chilled in a pressure reactor to ꢃ70 ^ꢂC in

a CO₂/IPA bath. Ammonia (16 g, 0.94 mol) was then bubbled

in over 15 min, after which the pressure reactor was sealed,

and the reaction was allowed to warm to room temperature

with stirring for 12 h, during which the reaction pressure

reached 65 psi. The pressure was then released, and the reac-

tion was concentrated under reduced pressure, and then chro-

matographed on SiO₂using a gradient that started with

CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concentrated

NH₄OH. Yield of 15: 1.10 g (80%). ¹H NMR (400 MHz,

DMSO-d₆) d 3.32 (s, 3H), 3.62 (s, 3H), 6.37 (d, J ¼ 5.2 Hz,

1H), 6.90 (s, 2H), 7.22 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.30 (t,

J ¼ 8.8 Hz, 2H), 7.65e7.73 (m, 2H), 7.96 (bs, 1H), 8.17

(d, J ¼ 5.2 Hz, 1H), 9.52 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ)

393.3.

4.1.15. 1-[2-(4-Fluorophenyl)-3-(2-methanesulfanylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]propan-1-one (19)

A solution of Weinreb amide 13 (5.60 g, 13.2 mmol) and

THF (100 mL) was cooled to ꢃ70 ^ꢂC in a CO₂/IPA bath,

then charged with the dropwise addition of ethylmagnesium

bromide (15 mL of a 1.0 M solution in THF, 15.0 mmol). Ad-

ditional aliquots of ethylmagnesium bromide (15 mL of

a 1.0 M solution in THF, 15.0 mmol) were added at t ¼ 2 h

and t ¼ 12 h. After stirring for an additional 3 h, the reaction

was then quenched with a saturated aqueous NH₄Cl solution

(200 mL), and then extracted with CH₂Cl₂(3 ꢀ 200 mL).

The organic fractions were pooled, dried over Na₂SO₄, ﬁl-

tered, and concentrated under reduced pressure, and then chro-

matographed on SiO₂using a gradient that started with

CH₂Cl₂and ended with 96:3.6:0.4 CH₂Cl₂:MeOH:concen-

trated NH₄OH. Yield of 19: 1.50 g (29%). ¹H NMR

(400 MHz, CDCl₃) d 1.28 (t, J ¼ 7.3 Hz, 3H), 2.65 (s, 3H),

3.08 (q, J ¼ 7.3 Hz, 2H), 6.85 (d, J ¼ 5.2 Hz, 1H), 7.15 (t,

J ¼ 8.6 Hz, 2H), 7.56 (d, J ¼ 7.2 Hz, 1H), 7.59e7.67 (m,

2H), 8.30 (bs, 1H), 8.36 (d, J ¼ 5.2 Hz, 1H), 9.53 (d,

J ¼ 7.2 Hz, 1H). MS (ESIþ) 393.1.

4.1.13. 1-[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-7-yl]propan-1-one (16) and

3-(2-aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)imidazo-

[1,2-a]pyridine-7-carboxylic acid methyl amide (17)

A suspension of Weinreb amide 15 (1.02 g, 2.60 mmol) in

THF (175 mL) was charged with the dropwise addition of ethyl-

magnesium bromide (26.0 mL of a 1.0 M solution in THF,

26.0 mmol), and the reaction was stirred at room temperature

for 12 h, after which a second portion of ethylmagnesium bro-

mide (25.0 mL of a 1.0 M solution in THF, 25.0 mmol) was

added. After stirring at room temperature for an additional

2 h, the reaction was quenched with saturated aqueous NH₄Cl

solution (300 mL); the layers were separated, and the aqueous

layer was back-extracted with CH₂Cl₂(2 ꢀ 250 mL). The or-

ganic fractions were pooled, dried over Na₂SO₄, ﬁltered, con-

centrated under reduced pressure, and then chromatographed

on SiO₂using a gradient that started with CH₂Cl₂and ended

4.1.16. 1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]ethanol (20a)

A solution of aldehyde 18 (1.00 g, 2.74 mmol) in THF

(100 mL) was chilled to ꢃ70 ^ꢂC in a CO₂/IPA bath, then

charged with the dropwise addition of methylmagnesium bro-

mide (7.35 mL of a 1.4 M in 3:1 toluene:THF, 10.3 mmol).

After stirring at ꢃ70 ^ꢂC for 2 h, the reaction was quenched

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1139

with H₂O (50 mL) and extracted into EtOAc (3 ꢀ 200 mL).

The organic fractions were pooled, dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure, and then chromato-

graphed on SiO₂using a gradient that started with CH₂Cl₂

and ended with 97:2.7:0.3 CH₂Cl₂:MeOH:concentrated

J ¼ 8.6 Hz, 2H), 7.59e7.67 (m, 2H), 7.75 (bs, 1H), 8.33 (d,

J ¼ 5.4 Hz, 1H), 9.62 (d, J ¼ 7.4 Hz, 1H). MS (ESIþ) 394.9

(resulting from displacement of eOSO₂CH₃by eOCH₃in

the MS).

1

NH₄OH. Yield of 20a: 600 mg (58%). H NMR (400 MHz,

4.1.18.2. Methanesulfonic acid 1-[2-(4-ﬂuorophenyl)-3-(2-

methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]propyl

ester (21b). Mesylate 21b was prepared from alcohol 20b

(1.52 g, 3.82 mmol), Et₃N (1.16 g, 11.5 mmol at t ¼ 0 h and

t ¼ 12 h), and methanesulfonyl chloride (0.960 g, 8.40 mmol

at t ¼ 0 h and t ¼ 12 h) in THF (100 mL). After stirring for

12 h beyond the second addition of reagents, the reaction was

carried onto the next step (synthesis of dimethylamine 22b)

in the same reaction vessel without prior isolation of the

mesylate.

CDCl₃) d 1.56 (d, J ¼ 6.4 Hz, 3H), 2.70 (s, 3H), 4.97 (q,

J ¼ 6.4 Hz, 1H), 6.83 (d, J ¼ 5.5 Hz, 1H), 7.03 (dd, J ¼ 7.3,

1.5 Hz, 1H), 7.20 (t, J ¼ 8.7 Hz, 2H), 7.61e7.69 (m, 2H),

7.73 (bs, 1H), 8.34 (d, J ¼ 5.5 Hz, 1H), 9.52 (d, J ¼ 7.3 Hz,

1H). MS (ESIþ) 380.9.

4.1.17. 1-[2-(4-Fluorophenyl)-3-(2-methanesulfanylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]propan-1-ol (20b)

A solution of ketone 19 (1.50 g, 3.82 mmol) in EtOH

(100 mL) was charged with NaBH₄(174 mg, 4.60 mmol),

and the reaction was allowed to stir at room temperature for

12 h, and was then quenched with a saturated aqueous

NaHCO₃solution (150 mL) then extracted into CH₂Cl₂

(2 ꢀ 100 mL). The organic fractions were pooled, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure,

and not puriﬁed further. Yield of 20b: 1.52 g (100%). ¹H

NMR (400 MHz, CDCl₃) d 0.91 (t, J ¼ 7.4 Hz, 3H), 1.78

(m, 2H), 2.58 (s, 3H), 4.62e4.70 (m, 1H), 6.74 (d,

J ¼ 5.4 Hz, 1H), 6.95 (d, J ¼ 7.4 Hz, 1H), 7.07 (t,

J ¼ 8.6 Hz, 2H), 7.55 (m, 2H), 7.58 (bs, 1H), 8.22 (d,

J ¼ 5.4 Hz, 1H), 9.49 (d, J ¼ 7.4 Hz, 1H). MS (ESIþ)

395.2.

4.1.19. General procedure for the synthesis

of tertiary amines 22a and 22b

A solution of appropriate mesylate in THF was charged

with dimethylamine (2.0 M solution in THF), with addi-

tional portions added as indicated. The reaction was then

quenched with water and extracted into EtOAc, dried over

Na₂SO₄, ﬁltered, concentrated under reduced pressure, and

chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concen-

trated NH₄OH.

4.1.19.1. {1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimid-

in-4-yl)imidazo[1,2-a]pyridin-7-yl]ethyl}dimethylamine (22a).

Dimethylamine 22a was prepared from mesylate 21a (theo-

retically 422 mg, 0.920 mmol) and dimethylamine (920 mL

of a 2.0 M solution in THF, 1.84 mmol at t ¼ 0 h, t ¼ 2 h,

and t ¼ 4 h) in THF (10 mL). After stirring for 12 h beyond

the ﬁnal addition of dimethylamine solution, the reaction was

worked up and chromatographed as described in the general

procedure above. Yield of 22a: 110 mg (30% over two

steps). ¹H NMR (400 MHz, CDCl₃) d 1.40 (d, J ¼ 6.7 Hz,

3H), 2.25 (s, 6H), 2.63 (s, 3H), 3.38 (q, J ¼ 6.7 Hz, 1H),

6.80 (d, J ¼ 5.4 Hz, 1H), 7.09 (dd, J ¼ 7.4, 1.5 Hz, 1H),

7.13 (t, J ¼ 8.7 Hz, 2H), 7.56 (bs, 1H), 7.57e7.65 (m, 2H),

8.27 (d, J ¼ 5.4 Hz, 1H), 9.54 (d, J ¼ 7.4 Hz, 1H). MS

(ESIþ) 407.6.

4.1.18. General procedure for the synthesis

of mesylates 21a and 21b

A solution of appropriate alcohol in THF was cooled to

0 ^ꢂC in an ice water bath, charged with Et₃N and methanesul-

fonyl chloride, and then allowed to warm to room temperature

with stirring for 12 h. The reaction was cooled again to 0 ^ꢂC

and charged with additional portions of both Et₃N and metha-

nesulfonyl chloride as indicated, and allowed to warm to room

temperature again. Once starting material was consumed, the

product was then either isolated by aqueous workup (EtOAc,

H₂O), or carried directly onto the next step in the same reac-

tion vessel.

4.1.18.1. Methanesulfonic acid 1-[2-(4-ﬂuorophenyl)-3-(2-

methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]ethyl

ester (21a). Mesylate 21a was prepared from alcohol 20a

(1.00 g, 2.64 mmol), Et₃N (801 mg, 7.92 mmol at t ¼ 0 h

and t ¼ 12 h), and methanesulfonyl chloride (663 mg,

5.81 mmol at t ¼ 0 h and t ¼ 12 h) in THF (20 mL). After stir-

ring for 5 h beyond the second addition of reagents, the reac-

tion was then quenched with saturated aqueous NaHCO₃

solution (100 mL), and extracted into EtOAc (2 ꢀ 50 mL).

The organic fractions were pooled, dried over Na₂SO₄, ﬁl-

tered, and concentrated under reduced pressure. Crude mesy-

late 21a was then carried directly onto the next step. ¹H

NMR (400 MHz, CDCl₃) d 1.78 (d, J ¼ 6.6 Hz, 3H), 2.65 (s,

3H), 2.97 (s, 3H), 5.84 (q, J ¼ 6.6 Hz, 1H), 6.83 (d,

J ¼ 5.4 Hz, 1H), 7.06 (dd, J ¼ 7.4, 1.6 Hz, 1H), 7.16 (t,

4.1.19.2. {1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]propyl}dimethylamine (22b).

Dimethylamine 22b was prepared from mesylate 21b (theoret-

ically 1.81 g, 3.82 mmol) and dimethylamine (19.1 mL of

a 2.0 M solution in THF, 38.2 mmol at t ¼ 0 h and t ¼ 12 h)

in THF (100 mL). After stirring for 72 h beyond the ﬁnal addi-

tion of dimethylamine solution, the reaction was worked up

and chromatographed as described in the general procedure

1

above. Yield of 22b: 800 mg (50% over two steps). H NMR

(400 MHz, CDCl₃) d 0.77 (t, J ¼ 7.2 Hz, 3H), 1.69e1.77 (m,

1H), 1.93e2.01 (m, 1H), 2.23 (s, 6H), 2.63 (s, 3H), 3.12 (dd,

J ¼ 5.6, 0.8 Hz, 1H), 6.80 (d, J ¼ 5.2 Hz, 1H), 6.98 (dd,

J ¼ 7.2, 2.0 Hz, 1H), 7.08e7.16 (m, 2H), 7.50 (bs, 1H),

1140

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

7.57e7.65 (m, 2H), 8.26 (d, J ¼ 5.2 Hz, 1H), 9.53 (d,

J ¼ 7.2 Hz, 1H). MS (ESIþ) 422.1.

then chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concen-

trated NH₄OH.

4.1.20. {1-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]ethyl}-

dimethylamine (23a)

4.1.22.1. 4-[7-(1-Dimethylaminoethyl)-2-(4-ﬂuorophenyl)imi-

dazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (24a). 2-Amino-

pyrimidine 24a was prepared from sulfone 23a (theoretically

672 mg, 1.53 mmol) and ammonia (3.50 g, 205 mmol) in THF

(50 mL). Yield of 24a: 240 mg (42% over two steps). ¹H NMR

(400 MHz, CDCl₃) d 1.40 (d, J ¼ 6.6 Hz, 3H), 2.26 (s, 6H),

3.37 (q, J ¼ 6.6 Hz, 1H), 5.23 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz,

1H), 7.03 (dd, J ¼ 7.3, 1.3 Hz, 1H), 7.11 (t, J ¼ 8.7 Hz, 2H),

7.54 (bs, 1H), 7.60e7.68 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H),

9.41 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 376.8. The two enantiomers

of 24a were then separated on a ChiralCel OJ column (Diacel) by

eluting with 15% isopropyl alcohol and 85% heptane.

A solution of sulﬁde 22a (625 mg, 1.35 mmol) in MeOH

(25 mL) was charged with AcOH (919 mg, 876 mL,

15.3 mmol), hydrogen peroxide (730 mg of a 30% w/w aque-

ous solution, 658 mL, 6.43 mmol), and sodium tungstate dihy-

drate (152 mg, 0.461 mmol). After stirring for 4 h at room

temperature, second portions of AcOH (919 mg, 876 mL,

15.3 mmol) and hydrogen peroxide (730 mg of a 30% w/w

aqueous solution, 658 mL, 6.43 mmol) were added, and stir-

ring continued at room temperature for 12 h. The reaction

was then cooled to ꢃ70 ^ꢂC in a CO₂/IPA bath, and charged

with sulfur dioxide (22 g). The reaction was stirred at below

ꢃ20 ^ꢂC for 3 h, and then allowed to warm to room tempera-

ture, and was then quenched with a saturated aqueous

NaHCO₃solution (250 mL), and extracted into EtOAc

(3 ꢀ 100 mL). The organic fractions were pooled, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

Crude sulfone 23a was then carried onto the next step without

further puriﬁcation. MS (ESIþ) 394.9 (resulting from dis-

placement of eN(CH₃)₂by eOCH₃in the MS).

4.1.22.2. 4-[7-(1-Dimethylaminopropyl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (24b). 2-Ami-

nopyrimidine 24b was prepared from sulfone 23b (theoretical

quantity: 862 mg, 1.90 mmol) and ammonia (13.4 g, 787 mmol)

in THF (50 mL). Yield of 24b: 500 mg (68% over two steps).

¹H NMR (400 MHz, CDCl₃) d 0.77 (t, J ¼ 7.2 Hz, 3H), 1.70e

1.77 (m, 1H), 1.93e2.00 (m, 1H), 2.24 (s, 6H), 3.11 (dd,

J ¼ 5.6, 4.4 Hz, 1H), 5.12 (bs, 2H), 6.52 (d, J ¼ 5.6 Hz, 1H),

6.93 (dd, J ¼ 7.5, 1.4 Hz, 1H), 7.07e7.15 (m, 2H), 7.48 (bs,

1H), 7.59e7.67 (m, 2H), 8.11 (d, J ¼ 5.6 Hz, 1H), 9.41 (d,

J ¼ 7.5 Hz, 1H). MS (ESIþ) 391.3.

4.1.21. {1-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]propyl}-

dimethylamine (23b)

A solution of sulﬁde 22b (800 mg, 1.90 mmol) was charged

with MeOH (25 mL), then a solution of OXONE^Ò(3.5 g,

5.7 mmol) in H₂O (25 mL), then acetone (25 mL), and the re-

action was allowed to stir at room temperature for 12 h. The

reaction was then cooled to ꢃ50 ^ꢂC in a CO₂/IPA bath, and

charged with sulfur dioxide gas (6.6 g). The reaction was

then allowed to warm to room temperature for 3 h, after which

it was neutralized with a saturated aqueous NaHCO₃solution,

and extracted into CH₂Cl₂(2 ꢀ 250 mL). The organic extracts

were pooled, dried over Na₂SO₄, ﬁltered, and concentrated un-

der reduced pressure, and carried onto the next step without

4.1.23. [2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]acetonitrile (26)

A solution of mesylate 25 (7.40 g, 16.6 mmol) in CH₂Cl₂

(200 mL) was charged with tetra-n-butylammonium cyanide

(4.47 g, 16.6 mmol). After stirring at room temperature for

12 h, the reaction was concentrated under reduced pressure,

and then chromatographed on SiO₂using a gradient that started

with heptane and ended with EtOAc. Yield of 26: 4.20 g (67%).

¹H NMR (500 MHz, CDCl₃) d 2.65 (s, 3H), 3.88 (s, 2H), 6.83

(d, J ¼ 5.2 Hz, 1H), 6.95 (dd, J ¼ 7.5, 2.0 Hz, 1H), 7.15

(t, J ¼ 8.8 Hz, 2H), 7.58e7.66 (m, 2H), 7.69 (bs, 1H), 8.32 (d,

J ¼ 5.2 Hz, 1H), 9.61 (d, J ¼ 7.5 Hz, 1H). MS (ESIþ) 376.2.

1

further puriﬁcation. Crude yield of 23b: 886 mg (100%). H

NMR (400 MHz, CDCl₃) d 0.73 (t, J ¼ 7.2 Hz, 3H), 1.69e

1.74 (m, 1H), 1.89e1.95 (m, 1H), 2.19 (s, 6H), 3.09e3.17

(m, 1H), 3.33 (s, 3H), 7.06 (d, J ¼ 7.2 Hz, 1H), 7.14 (t,

J ¼ 8.4 Hz, 2H), 7.21 (d, J ¼ 5.6 Hz, 1H), 7.51 (bs, 1H),

7.52e7.60 (m, 2H), 8.43 (d, J ¼ 5.6 Hz, 1H), 9.79 (d,

J ¼ 7.2 Hz, 1H). MS (ESIþ) 454.2.

4.1.24. General procedure for the synthesis of a-alkylated

nitriles 27a and 27b

A solution of nitrile 26 in THF was cooled to 0 ^ꢂC in an ice

water bath, and then charged with NaH in portions. After stir-

ring for 5 min, appropriate alkyl halide was added. After

warming to room temperature and stirring for the indicated

length of time, then reaction was worked up (EtOAc, H₂O),

dried over Na₂SO₄, ﬁltered, concentrated under reduced pres-

sure, and chromatographed on SiO₂using a gradient that

started with heptane and ended with 50:50 EtOAc:heptane.

4.1.22. General procedure for the synthesis

of 2-aminopyrimidines 24a and 24b

A suspension of appropriate sulfone in THF was chilled in

a pressure reactor to ꢃ60 ^ꢂC to ꢃ70 ^ꢂC in a CO₂/IPA bath, and

charged with excess ammonia gas. The pressure reactor was

sealed, and the reaction was allowed to warm to room temper-

ature with stirring for 12 h, during which the reaction pressure

had reached 35e50 psi. The pressure was then released, and

the reaction was concentrated under reduced pressure, and

4.1.24.1. 2-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]pentanenitrile (27a). a-n-

Propylnitrile 27a was prepared from nitrile 26 (3.00 g,

7.99 mmol), NaH (352 mg of a 60% w/w suspension in

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1141

mineral oil, 8.79 mmol), and 1-bromopropane (2.95 g,

2.18 mL, 24.0 mmol) in THF (100 mL) with 12 h of stirring.

Yield of 27a: 1.77 g (53%). ¹H NMR (400 MHz, CDCl₃)

d 1.01 (t, J ¼ 7.3 Hz, 3H), 1.49e1.65 (m, 2H), 1.88e2.09

(m, 2H), 2.66 (s, 3H), 3.93 (dd, J ¼ 8.0, 6.4 Hz, 1H), 6.84

(d, J ¼ 5.5 Hz, 1H), 6.99 (dd, J ¼ 7.2, 1.9 Hz, 1H), 7.16 (t,

J ¼ 8.6 Hz, 2H), 7.59e7.67 (m, 2H), 7.68 (bs, 1H), 8.33 (d,

J ¼ 5.5 Hz, 1H), 9.63 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 418.1.

allowed to stir at room temperature for 12 h. The reaction

was then treated with the dropwise addition of concentrated

HCl and allowed to stir at room temperature for 15 min, after

which it was treated with 2 N NaOH solution until it became

basic to litmus paper. The mixture was then extracted repeat-

edly into EtOAc. The organic fractions were pooled, washed

with H₂O (2 ꢀ 100 mL), dried over Na₂SO₄, ﬁltered, concen-

trated under reduced pressure, and then chromatographed on

SiO₂using a gradient that started with CH₂Cl₂and ended

with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH.

4.1.24.2. 2-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-

yl)imidazo[1,2-a]pyridin-7-yl]-2-methylpropiontirile (27b). a,a-

Dimethylnitrile 27b was prepared from nitrile 26 (3.70 g,

9.85 mmol), NaH (1.18 g of 60% w/w suspension in mineral

oil, 29.6 mmol), and methyl iodide (3.08 g, 21.7 mmol) in

THF (200 mL) with 30 min of stirring. Yield of 27b: 3.21 g

4.1.26.1. 1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]butylamine (29a). Amine 29a

was prepared from amide 28a (460 mg, 1.05 mmol) and bis-

(triﬂuoroacetoxy)iodobenzene (454 mg, 1.05 mmol) in CH₃CN

1

(81%). H NMR 400 MHz, CDCl₃) d 1.80 (s, 6H), 2.64 (s,

(10 mL). Yield of 29a: 110 mg (26%). H NMR (400 MHz,

3H), 6.82 (d, J ¼ 5.6 Hz, 1H), 7.11 (d, J ¼ 7.3 Hz, 1H), 7.14

(t, J ¼ 8.6 Hz, 2H), 7.57e7.65 (m, 2H), 7.77 (bs, 1H), 8.31

(d, J ¼ 5.6 Hz, 1H), 9.61 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 404.2.

CDCl₃) d 0.94 (t, J ¼ 7.3 Hz, 3H), 1.23e1.46 (m, 2H), 1.70

(q, J ¼ 7.4 Hz, 2H), 2.65 (s, 3H), 4.03 (t, J ¼ 6.8 Hz, 1H),

6.81 (d, J ¼ 5.4 Hz, 1H), 7.03 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.14

(t, J ¼ 8.6 Hz, 2H), 7.61 (bs, 1H), 7.59e7.67 (m, 2H), 8.28

(d, J ¼ 5.4 Hz, 1H), 9.56 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ)

408.2.

4.1.25. General procedure for the synthesis of

amides 28a and 28b

Appropriate nitrile was chilled in an ice water bath and

treated with the dropwise addition of concentrated H₂SO₄.

The reaction was then heated to 100 ^ꢂC for 3 h, cooled to

room temperature, and then neutralized by the slow addition

of saturated aqueous NaHCO₃solution until basic to litmus

paper. The mixture was then extracted into EtOAc. The or-

ganic fractions were pooled, dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure, and not puriﬁed further.

4.1.26.2. 1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]-1-methylethylamine

(29b).

Amine 29b was prepared from amide 28b (400 mg,

0.949 mmol) and bis(triﬂuoroacetoxy)iodobenzene (410 mg,

0.953 mmol) in CH₃CN (40 mL). Yield of 29b: 202 mg

1

(54%). H NMR (500 MHz, CDCl₃) d 1.65 (s, 6H), 2.66 (s,

3H), 6.82 (d, J ¼ 5.5 Hz, 1H), 7.15 (t, J ¼ 8.8 Hz, 2H), 7.20

(d, J ¼ 6.0 Hz, 1H), 7.57e7.65 (m, 2H), 7.89 (bs, 1H), 8.30

(d, J ¼ 5.5 Hz, 1H), 9.52 (d, J ¼ 7.5 Hz, 1H). MS (ESIþ)

394.2.

4.1.25.1. 2-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]pentanoic acid amide (28a).

Amide 28a was prepared from nitrile 27a (1.67 g,

4.00 mmol) and concentrated H₂SO₄(20 mL). Yield of 28a:

1.48 g (85%). ¹H NMR (400 MHz, CDCl₃) d 0.94 (t,

J ¼ 7.3 Hz, 3H), 1.29e1.42 (m, 2H), 1.78e1.89 (m, 1H),

2.08e2.19 (m, 1H), 2.65 (s, 3H), 3.51 (t, J ¼ 7.6 Hz, 1H),

5.53 (bs, 1H), 5.79 (bs, 1H), 6.80 (d, J ¼ 5.4 Hz, 1H), 7.08

(dd, J ¼ 7.2, 1.7 Hz, 1H), 7.15 (t, J ¼ 8.7 Hz, 2H), 7.59 (bs,

1H), 7.59e7.66 (m, 2H), 8.30 (d, J ¼ 5.4 Hz, 1H), 9.56 (d,

J ¼ 7.2 Hz, 1H). MS (ESIþ) 436.2.

4.1.27. General procedure for the synthesis

of dimethylamines 30a and 30b

A solution of appropriate primary amine in CH₃OH was

charged with formaldehyde, AcOH, and sodium cyanoborohy-

dride. After stirring at room temperature for 3 h, the reaction

was worked up (EtOAc, saturated NaHCO₃solution), dried

over Na₂SO₄, ﬁltered, concentrated under reduced pressure,

and then chromatographed on SiO₂using a gradient that

started with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:-

concentrated NH₄OH.

4.1.25.2. 2-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]isobutyramide (28b). Amide

28b was prepared from nitrile 27b (1.85 g, 4.59 mmol) and

concentrated H₂SO₄(20 mL). Yield of 28b: 1.87 g (96%).

¹H NMR (500 MHz, CDCl₃) d 1.68 (s, 6H), 2.66 (s, 3H),

5.40 (m, 2H), 6.83 (d, J ¼ 5.2 Hz, 1H), 7.00 (d, J ¼ 7.5 Hz,

1H), 7.17 (t, J ¼ 8.8 Hz, 2H), 7.60e7.68 (m, 2H), 7.74 (bs,

1H), 8.32 (d, J ¼ 5.2 Hz, 1H), 9.54 (d, J ¼ 7.5 Hz, 1H). MS

(ESIþ) 422.2.

4.1.27.1. {1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]butyl}dimethylamine

(30a).

Dimethylamine 30a was prepared from primary amine 29a

(240 mg, 0.589 mmol), formaldehyde (143 mg of 37% w/w

solution in H₂O, 131 mL), AcOH (240 mL), and sodium cyano-

borohydride (2.94 mL of a 1.0 M solution in THF, 2.94 mmol)

in CH₃OH (5.0 mL). Crude yield of 30a: 310 mg (>100%). ¹H

NMR (400 MHz, CDCl₃) d 0.96 (t, J ¼ 7.3 Hz, 3H), 1.13e

1.34 (m, 2H), 2.10 (s, 3H), 2.17 (q, J ¼ 7.7 Hz, 1H), 2.67 (s,

3H), 2.79 (s, 3H), 3.50 (s, 1H), 4.08 (dd, J ¼ 9.1, 6.4 Hz,

1H), 6.83 (d, J ¼ 5.4 Hz, 1H), 7.17 (dd, J ¼ 7.2, 2.0 Hz, 1H),

7.17 (t, J ¼ 8.6 Hz, 2H), 7.57e7.65 (m, 2H), 7.77 (bs, 1H),

4.1.26. General procedure for the synthesis of primary

amines 29a and 29b

A solution of appropriate amide in CH₃CN was charged

with bis(triﬂuoroacetoxy)iodobenzene in portions, and

1142

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

8.37 (d, J ¼ 5.4 Hz, 1H), 9.69 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ)

charged with excess ammonia gas. The pressure reactor was

sealed, and the reaction was allowed to warm to room temper-

ature with stirring for 12 h, during which the reaction pressure

had reached 35e50 psi. The pressure was then released, and

the reaction was concentrated under reduced pressure, and

then chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concen-

trated NH₄OH.

436.7.

4.1.27.2. {1-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyrimi-

din-4-yl)imidazo[1,2-a]pyridin-7-yl]-1-methylethyl}dimethyl-

amine (30b). Dimethylamine 30b was prepared from amine

29b (643 mg, 1.63 mmol), formaldehyde (398 mg of a 37% w/

w aqueous solution, 4.90 mmol), AcOH (3.1 mL), and sodium

cyanoborohydride (8.17 mL of a 1.0 M solution in THF,

8.17 mmol) in MeOH (36 mL). Yield of 30b: 560 mg (82%).

¹H NMR (500 MHz, CDCl₃) d 1.80 (bs, 6H), 2.65 (bs, 6H),

2.70 (s, 3H), 6.85 (d, J ¼ 5.5 Hz, 1H), 7.18 (t, J ¼ 8.5 Hz, 2H),

7.48 (d, J ¼ 7.5 Hz, 1H), 7.60e7.68 (m, 2H), 7.78 (bs, 1H),

8.37 (bs, 1H), 9.67 (d, J ¼ 7.5 Hz, 1H). MS (ESIþ) 422.2.

4.1.29.1. 4-[7-(1-Dimethylaminobutyl)-2-(4-ﬂuorophenyl)imi-

dazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (32a). 2-Amino-

pyridimine 32a was prepared from sulfone 31a (224 mg,

0.479 mmol) and ammonia (12.9 g, 757 mmol) in THF

1

(20 mL). Yield of 32a: 125 mg (64%). H NMR (400 MHz,

CDCl₃) d 0.89 (t, J ¼ 7.3 Hz, 3H), 1.09e1.27 (m, 2H),

1.65e1.79 (m, 1H), 1.85e1.97 (m, 1H), 2.25 (s, 6H), 3.22

(dd, J ¼ 9.7, 4.6 Hz, 1H), 5.13 (bs, 2H), 6.54 (d, J ¼ 5.4 Hz,

1H), 6.94 (dd, J ¼ 7.2, 1.7 Hz, 1H), 7.13 (t, J ¼ 8.8 Hz, 2H),

7.50 (bs, 1H), 7.62e7.70 (m, 2H), 8.13 (d, J ¼ 5.4 Hz, 1H),

9.43 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 405.2.

4.1.28. General procedure for the synthesis of

sulfones 31a and 31b

A solution of appropriate sulﬁde in 1:1 MeOH:acetone was

charged with a solution of OXONE^Òin H₂O, and allowed to

stir at room temperature for 12 h. The reaction was then chilled

to ꢃ40 ^ꢂC in a CO₂/IPA bath. Excess sulfur dioxide gas was then

bubbled in over 5 min. After stirring at ꢃ40 ^ꢂC for an additional

15 min, the reaction was quenched with a saturated aqueous

NaHCO₃solution until basic to litmus paper, and then extracted

repeatedly into EtOAc. The organic fractions were pooled, dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

4.1.29.2. 4-[7-(1-Dimethylamino-1-methyl-ethyl)-2-(4-ﬂuorophe-

nyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (32b). 2-

Aminopyrimidine 32b was prepared from sulfone 31b

(354 mg, 0.780 mmol) and ammonia (28.0 g, 1.64 mmol) in

THF (150 mL). Yield of 32b: 168 mg (55%). ¹H NMR

(500 MHz, CDCl₃) d 1.40 (bs, 6H), 2.23 (bs, 6H), 5.11 (bs,

2H), 6.54 (d, J ¼ 5.5 Hz, 1H), 7.14 (t, J ¼ 8.8 Hz, 2H), 7.32

(d, J ¼ 6.8 Hz, 1H), 7.62e7.69 (m, 3H), 8.14 (d, J ¼ 5.5 Hz,

1H), 9.39 (d, J ¼ 6.8 Hz, 1H). MS (ESIþ) 391.2.

4.1.28.1. {1-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimi-

din-4-yl)imidazo[1,2-a]pyridin-7-yl]butyl}dimethylamine (31a).

Sulfone 31a was prepared from crude sulﬁde 30a (theoretically

257 mg, 0.589 mmol) and OXONE^Ò(1.08 g, 1.77 mol dissolved

in 10 mL H₂O) in 1:1 MeOH:acetone (20 mL), and subsequent

treatment with sulfur dioxide (12.9 g, 201 mmol). Yield of 31a:

4.1.30. 2-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]propan-2-ol (33)

A solution of ester 12 (327 mg, 0.828 mmol) in THF

(30 mL) was chilled to 0 ^ꢂC in an ice water bath, then charged

with methylmagnesium bromide (2.96 mL of a 1.4 M solution

in 3:1 toluene:THF, 4.14 mmol), and the reaction was allowed

to warm to room temperature and stir for 12 h, after which

a second portion of methylmagnesium bromide (2.96 mL of

a 1.4 M solution in 3:1 toluene:THF, 4.14 mmol) was added.

After stirring at room temperature for another 3 h, the reaction

was concentrated under reduced pressure, diluted with CH₂Cl₂

(800 mL), and then washed with H₂O (3 ꢀ 100 mL). The or-

ganic layer was dried with Na₂SO₄, ﬁltered, and concentrated

under reduced pressure, and not puriﬁed further. Yield of 33:

315 mg (96%). ¹H NMR (400 MHz, DMSO-d₆) d 1.50 (s,

6H), 2.60 (s, 3H), 6.88 (d, J ¼ 5.4 Hz, 1H), 7.23e7.30 (m,

1H), 7.32 (t, J ¼ 8.6 Hz, 2H), 7.62e7.70 (m, 2H), 7.73 (bs,

1H), 8.47 (d, J ¼ 5.4 Hz, 1H), 9.36 (d, J ¼ 7.4 Hz, 1H). MS

(ESIþ) 394.9.

1

234 mg (85% over two steps). H NMR (400 MHz, CDCl₃)

d 0.90 (t, J ¼ 7.2 Hz, 3H), 1.10e1.25 (m, 2H), 1.68e1.82 (m,

1H), 1.87e1.98 (m, 1H), 2.26 (s, 6H), 3.26e3.36 (m, 1H), 3.41

(s, 3H), 7.15 (dd, J ¼ 7.2, 1.7 Hz, 1H), 7.21 (t, J ¼ 8.8 Hz, 2H),

7.29 (d, J ¼ 5.7 Hz, 1H), 7.57 (bs, 1H), 7.60e7.67 (m, 2H),

8.51 (d, J ¼ 5.7 Hz, 1H), 9.87 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ)

468.0.

4.1.28.2. {1-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimi-

din-4-yl)imidazo[1,2-a]pyridin-7-yl]-1-methylethyl}dimethyl-

amine (31b). Sulfone 31a was prepared from sulﬁde 30b

(560 mg, 1.33 mmol) and OXONE^Ò(2.45 g, 3.99 mmol dis-

solved in 20 mL H₂O) in 1:1 MeOH:acetone (50 mL), and

subsequent treatment with sulfur dioxide (43 g, 670 mmol).

1

Yield of 31b: 354 mg (58%). H NMR (500 MHz, CDCl₃)

d 1.41 (bs, 6H), 2.25 (bs, 6H), 3.42 (s, 3H), 7.22 (t,

J ¼ 8.5 Hz, 2H), 7.30 (d, J ¼ 5.5 Hz, 1H), 7.55 (bs, 1H),

7.61e7.68 (m, 2H), 7.77 (bs, 1H), 8.52 (d, J ¼ 5.0 Hz, 1H),

9.83 (d, J ¼ 7.5 Hz, 1H). MS (ESIþ) 454.3.

4.1.31. 2-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]propan-2-ol (34)

A solution of sulﬁde 33 (1.45 g, 3.68 mmol) in MeOH/ac-

etone (7 mL þ 56 mL) was charged with a solution of OX-

ONE^Ò(6.78 g, 11.0 mmol) in H₂O (60 mL). The reaction

4.1.29. General procedure for the synthesis of

2-aminopyrimidines 32a and 32b

A suspension of appropriate sulfone in THF was chilled in

a pressure reactor to ꢃ60 ^ꢂC to ꢃ70 ^ꢂC in a CO₂/IPA bath, and

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1143

was allowed to stir at room temperature for 12 h, and was then

concentrated under reduced pressure to remove as much or-

ganic solvent as possible, then diluted with H₂O (200 mL),

and extracted into EtOAc (4 ꢀ 50 mL). The organic fractions

were pooled, washed with H₂O (2 ꢀ 50 mL), dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

started with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:

concentrated NH₄OH. Yield of 37: 50 mg (11% over two

1

steps). H NMR (400 MHz, CDCl₃) d 1.43e1.62 (m, 6H),

5.13 (bs, 2H), 6.52 (d, J ¼ 5.4 Hz, 1H), 7.05e7.17 (m, 1H),

7.12 (t, J ¼ 8.6 Hz, 2H), 7.60e7.68 (m, 2H), 7.77 (bs, 1H),

8.12 (d, J ¼ 5.4 Hz, 1H), 9.43 (d, J ¼ 7.5 Hz, 1H). MS

(ESIþ) 363.2.

1

Yield of 34: 1.12 g (72%). H NMR (400 MHz, DMSO-d₆)

d 1.51 (s, 6H), 3.48 (s, 3H), 7.28e7.41 (m, 4H), 7.67e7.75

(m, 2H), 7.79 (bs, 1H), 8.80 (d, J ¼ 5.6 Hz, 1H), 9.52 (d,

J ¼ 7.4 Hz, 1H). MS (ESIþ) 426.9.

4.1.34. 2-[2-(4-Fluorophenyl)-3-(2-methylsulfanylpyr-

imidin-4-yl)imidazo[1,2-a]pyridin-7-yl]butyrontirile (38)

A solution of nitrile 26 (2.00 g, 5.33 mmol) in THF

(100 mL) was charged with NaH (234 mg of a 60% w/w sus-

pension in mineral oil, 5.83 mmol), then bromoethane

(871 mg, 597 mL, 8.00 mmol), and the reaction was stirred at

room temperature for 12 h, and was then quenched with a sat-

urated aqueous NaHCO₃solution (200 mL) and extracted into

EtOAc (3 ꢀ 200 mL). The organic fractions were pooled,

dried over Na₂SO₄, ﬁltered, concentrated under reduced

pressure, and then chromatographed on SiO₂using a gradient

that started with CH₂Cl₂and ended with 97:2.7:0.3

CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 38: 660 mg

(31%). ¹H NMR (400 MHz, CDCl₃) d 1.16 (t, J ¼ 7.4 Hz,

3H), 2.00e2.11 (m, 2H), 2.66 (s, 3H), 3.88 (t, J ¼ 7.0 Hz,

1H), 6.84 (d, J ¼ 5.4 Hz, 1H), 6.98 (dd, J ¼ 7.3, 2.0 Hz, 1H),

7.16 (t, J ¼ 8.8 Hz, 2H), 7.60e7.67 (m, 2H), 7.67e7.72 (m,

1H), 8.33 (d, J ¼ 5.4 Hz, 1H), 9.63 (d, J ¼ 7.3 Hz, 1H). MS

(ESIþ) 404.1.

4.1.32. 2-[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-7-yl]propan-2-ol (35)

A suspension of sulfone 34 (237 mg, 0.555 mmol) in THF

(60 mL) in a pressure reactor was chilled to ꢃ78 ^ꢂC in a CO₂/

IPA bath, and ammonia (24.5 g, 144 mmol) was bubbled in

over 15 min. The pressure reactor was sealed, and the reaction

was allowed to warm to room temperature with stirring for

12 h, during which the reaction pressure reached 50 psi. The

pressure was then released, and the reaction was concentrated

under reduced pressure, and was then chromatographed on

SiO₂using a gradient that started with CH₂Cl₂and ended

with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of

1

35: 158 mg (78%). H NMR (400 MHz, DMSO-d₆) d 1.50

(s, 6H), 6.32 (d, J ¼ 5.3 Hz, 1H), 6.83 (s, 2H), 7.16 (dd,

J ¼ 7.4, 1.8 Hz, 1H), 7.29 (t, J ¼ 8.8 Hz, 2H), 7.56e7.73 (m,

3H), 8.11 (d, J ¼ 5.3 Hz, 1H), 9.47 (d, J ¼ 7.4 Hz, 1H). MS

(ESIþ) 363.9.

4.1.35. General procedure for the synthesis

of sulfones 39a, 39b, and 39c

4.1.33. 4-[7-(1-Amino-1-methyl-ethyl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (37)

A solution of appropriate sulﬁde in 1:1 MeOH:acetone was

charged with a solution of OXONE^Òin H₂O, and allowed to

stir at room temperature for 12 h. The reaction was then

chilled to ꢃ40 ^ꢂC in a CO₂/IPA bath. Excess sulfur dioxide

gas was then bubbled in over 5 min. After stirring at ꢃ40 ^ꢂC

for an additional 15 min, the reaction was quenched with a sat-

urated aqueous NaHCO₃solution until basic to litmus paper,

and then extracted repeatedly into EtOAc. The organic frac-

tions were pooled, dried over Na₂SO₄, ﬁltered, and concen-

trated under reduced pressure.

A mixture of alcohol 35 (440 mg, 1.21 mmol) and NaCN

(2.73 g, 55.9 mmol) was chilled to 0 ^ꢂC in an ice water bath,

then charged with the slow addition of AcOH (5.39 mL,

94.5 mmol), then allowed to stir for 10 min. A mixture of con-

centrated H₂SO₄(3.4 mL, 63 mmol) in AcOH (1.00 mL,

17.2 mmol) was then added, and the reaction was allowed to

warm to room temperature and stir for 1 h. The reaction was

then heated to 70 ^ꢂC for 2 h, then 90 ^ꢂC for 2 h. The reaction

was then diluted with EtOAc and poured into ice water, neu-

tralized with a saturated aqueous Na₂CO₃solution, and then

extracted repeatedly into EtOAc. The organic fractions were

pooled, dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure to yield 435 mg of a mixture of formamides

36a and 36b, which were carried onto the next step without

further puriﬁcation. This mixture of formamides 36a and

36b (435 mg) was charged with 1.0 N NaOH (30 mL), and

then heated to 70 ^ꢂC for 1 h, then 80 ^ꢂC for an additional

3 h, and then cooled to room temperature for 12 h. An addi-

tional portion of 1.0 N NaOH (30 mL) was added, and the re-

action was heated at 90 ^ꢂC for 3 h. The reaction was then

chilled in an ice water bath, then diluted with H₂O and ex-

tracted with EtOAc (3 ꢀ 250 mL). The organic fractions

were pooled, washed with H₂O (20 mL), dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure,

and then chromatographed on SiO₂using a gradient that

4.1.35.1. [2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-

4-yl)imidazo[1,2-a]pyridin-7-yl]acetonitrile

(39a). Sulfone

39a was prepared from sulﬁde 26 (1.00 g, 2.66 mmol) and

OXONE^Ò(10.0 g, 16.4 mmol dissolved in 150 mL H₂O) in

1:1 MeOH:acetone (300 mL). Yield of 39a: 980 mg (91%).

¹H NMR (400 MHz, CDCl₃) d 3.40 (s, 3H), 3.91 (s, 2H),

7.07 (d, J ¼ 7.6 Hz, 1H), 7.20 (t, J ¼ 8.2 Hz, 2H), 7.31 (d,

J ¼ 5.6 Hz, 1H), 7.57e7.65 (m, 2H), 7.77 (bs, 1H), 8.54

(d, J ¼ 5.6 Hz, 1H), 9.92 (d, J ¼ 7.6 Hz, 1H). MS (ESIþ)

408.2.

4.1.35.2. 2-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimi-

din-4-yl)imidazo[1,2-a]pyridin-7-yl]butyronitrile (39b). Sul-

fone 39b was prepared from sulﬁde 38 (660 mg, 1.64 mmol)

and OXONE^Ò(3.02 g, 4.92 mmol in 30 mL H₂O) in 1:1

1144

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

MeOH:acetone (60 mL). Yield of 39b: 630 mg (88%). MS

(ESIþ) 435.9.

7.62e7.70 (m, 2H), 7.77 (bs, 1H), 8.17 (d, J ¼ 5.5 Hz, 1H),

9.45 (d, J ¼ 7.5 Hz, 1H). MS (ESIþ) 373.4.

4.1.35.3. 2-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-

4.1.37.2. 4-[7-(2-Aminoethyl)-2-(4-ﬂuorophenyl)imidazo[1,2-

4-yl)imidazo[1,2-a]pyridin-7-yl]-2-methylpropiontirile

(39c).

a]pyridin-3-yl]pyrimidin-2-ylamine

(41a). 2-Aminopyrimi-

Sulfone 39c was prepared from sulﬁde 27b (2.20 g,

5.45 mmol) and OXONE^Ò(10.0 g, 16.4 mmol in 150 mL

H₂O) in 1:1 MeOH:acetone (200 mL). Yield of 39c: 2.10 g

dine 41a was prepared from sulfone 40a (theoretically

1.20 g, 2.41 mmol) and ammonia (19.1 g, 1.12 mol) in THF

(50 mL). Yield of 41a: 214 mg (26% over two steps). ¹H

NMR (500 MHz, CDCl₃) d 2.87 (t, J ¼ 7.0 Hz, 2H), 3.08 (t,

J ¼ 7.0 Hz, 2H), 5.14 (bs, 2H), 6.53 (d, J ¼ 5.2 Hz, 1H),

6.82 (dd, J ¼ 7.0, 1.5 Hz, 1H), 7.10e7.18 (m, 2H), 7.51 (bs,

1H), 7.61e7.69 (m, 2H), 8.13 (d, J ¼ 5.2 Hz, 1H), 9.45 (d,

J ¼ 7.0 Hz, 1H). MS (ESIþ) 349.3.

1

(89%). H NMR (500 MHz, CDCl₃) d 1.84 (s, 6H), 3.43 (s,

3H), 7.20e7.29 (m, 3H), 7.34 (d, J ¼ 5.5 Hz, 1H), 7.61e7.69

(m, 2H), 7.90 (bs, 1H), 8.57 (d, J ¼ 5.5 Hz, 1H), 9.97 (d,

J ¼ 7.5 Hz, 1H). MS (ESIþ) 436.2.

4.1.36. General procedure for the synthesis of primary

amines 40a and 40b

4.1.37.3. 4-[7-(2-Aminomethylpropyl)-2-(4-ﬂuorophenyl)imi-

dazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (41b). 2-Amino-

pyrimidine 41b was prepared from sulfone 40b (theoretically

636 mg, 1.45 mmol) and ammonia (16.0, 1.17 mol) in THF

A solution of appropriate nitrile in 9:1 EtOH:CHCl₃in

a pressure reactor was charged with platinum(IV) oxide, pres-

surized with hydrogen at 50 psi, and stirred at room tempera-

ture for 12 h. Additional platinum(IV) oxide was added as

noted. The reaction was then ﬁltered, concentrated under re-

duced pressure, and carried onto the next step without further

puriﬁcation.

1

(50 mL). Yield of 41b: 40.0 mg (7.3% over two steps). H

NMR (400 MHz, CDCl₃) d 0.89 (t, J ¼ 7.3 Hz, 3H), 1.49e

1.72 (m, 1H), 1.69e1.89 (m, 1H), 2.53e2.74 (m, 1H), 2.83e

3.15 (m, 2H), 5.10 (bs, 2H), 6.53 (d, J ¼ 5.4 Hz, 1H), 6.81 (d,

J ¼ 7.1Hz, 1H), 7.13 (t, J ¼ 8.4 Hz, 2H), 7.51 (bs, 1H), 7.61e

7.69 (m, 2H), 8.12 (d, J ¼ 5.4 Hz, 1H), 9.46 (d, J ¼ 7.1 Hz,

1H). MS (ESIþ) 377.2.

4.1.36.1. 2-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimi-

din-4-yl)imidazo[1,2-a]pyridin-7-yl]ethylamine (40a). Primary

amine 40a was prepared from nitrile 39a (980 mg, 2.41 mmol)

and platinum(IV) oxide (200 mg, 0.881 mmol at t ¼ 0 h, and

500 mg, 1.14 mmol at t ¼ 12 h) in 9:1 EtOH:CHCl₃(20 mL).

Crude yield of 40a: 1.20 g (>100%). MS (ESIþ) 412.2.

4.1.38. 4-[7-(2-Amino-1,1-dimethylethyl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (41c)

A solution of nitrile 40c (700 mg, 1.88 mmol) in THF

(25 mL) was charged with LiAlH₄(285 mg, 7.52 mmol). After

stirring at room temperature for 45 min, the reaction was diluted

with EtOAc (200 mL), treated with the slow addition of water

(10 mL), and then charged with excess of 2:1 Na_2-

SO₄$10H₂O:Celite. The mixture was ﬁltered, then concentrated

under reduced pressure, and then chromatographed on SiO₂us-

ing a gradient that started with CH₂Cl₂and ended with 90:9:1

CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 41c: 196 mg

4.1.36.2. 2-[2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimi-

din-4-yl)imidazo[1,2-a]pyridin-7-yl]butylamine (40b). Primary

amine 40b was prepared from nitrile 39b (630 mg, 1.45 mmol)

and platinum oxide (500 mg, 1.14 mmol) in 9:1 EtOH:CHCl₃

(50 mL). Crude yield of 40b: 740 mg (>100%). MS (ESIþ)

440.1.

1

4.1.37. General procedure for the synthesis

(28%). H NMR (500 MHz, CDCl₃) d 1.38 (s, 6H), 2.89 (s,

of 2-aminopyrimidines 40c, 41a, and 41b

2H), 5.14 (bs, 2H), 6.54 (d, J ¼ 5.5 Hz, 1H), 6.97 (dd, J ¼ 7.5,

2.0 Hz, 1H), 7.10e7.18 (m, 2H), 7.61e7.69 (m, 3H), 8.13 (d,

J ¼ 5.5 Hz, 1H), 9.46 (d, J ¼ 7.5 Hz, 1H). MS (ESIþ) 377.2.

A suspension of appropriate sulfone in THF was chilled in

a pressure reactor to ꢃ60 ^ꢂC to ꢃ70 ^ꢂC in a CO₂/IPA bath, and

charged with excess ammonia gas. The pressure reactor was

sealed, and the reaction was allowed to warm to room temper-

ature with stirring for 12 h, during which the reaction pressure

had reached 35e50 psi. The pressure was then released, and

the reaction was concentrated under reduced pressure, and

then chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concen-

trated NH₄OH.

4.1.39. General procedure for the synthesis

of tertiary amines 42a, 42b, and 42c

A solution of appropriate primary amine in CH₃OH was

charged with formaldehyde, AcOH, and sodium cyanoborohy-

dride. After stirring at room temperature for 3 h, the reaction

was worked up (EtOAc, saturated NaHCO₃solution), dried

over Na₂SO₄, ﬁltered, concentrated under reduced pressure,

and then chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concen-

trated NH₄OH.

4.1.37.1. 3-[2-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)imi-

dazo[1,2-a]pyridin-7-yl]-2-methylpropiontirile (40c). 2-Ami-

nopyrimidine 40c was prepared from sulfone 39c (1.10 g,

2.53 mmol) and ammonia (49.0 g, 2.88 mol) in THF

4.1.39.1. 4-[7-(2-Dimethylaminoethyl)-2-(4-ﬂuorophenyl)imi-

1

(100 mL). Yield of 40c: 750 mg (80%). H NMR 500 MHz,

CDCl₃) d 1.82 (s, 6H), 5.15 (bs, 2H), 6.56 (d, J ¼ 5.5 Hz,

dazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (42a). Dime-

thylamine 42a was prepared from primary amine 41a

(100 mg, 0.287 mmol), formaldehyde (93 mg of a 37% w/w/

1H), 7.09 (dd, J ¼ 7.5, 2.0 Hz, 1H), 7.15 (t, J ¼ 8.8 Hz, 2H),

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1145

solution in H₂O, 0.34 mmol), AcOH (100 mL), and sodium cy-

anoborohydride (1.43 mL of a 1.0 M solution in THF,

1.43 mmol) in MeOH (3.0 mL). After chromatography on

SiO₂, the product was puriﬁed further by HPLC using

a MeOH/H₂O gradient, where the aqueous phase was

98:9.1:0.1 H₂O:CH₃CN:Et₃N. Yield of 42a: 68.0 mg (63%).

¹H NMR (500 MHz, CDCl₃) d 2.33 (s, 6H), 2.64 (t,

J ¼ 7.8 Hz, 2H), 2.89 (t, J ¼ 7.8 Hz, 2H), 5.11 (bs, 2H), 6.52

(d, J ¼ 5.5 Hz, 1H), 6.83 (dd, J ¼ 7.0, 2.0 Hz, 1H), 7.10e

7.18 (m, 2H), 7.52 (bs, 1H), 7.61e7.69 (m, 2H), 8.12 (d,

J ¼ 5.5 Hz, 1H), 9.44 (dd, J ¼ 7.5, 0.5 Hz, 1H). MS (ESIþ)

377.4.

1H), 3.51e3.59 (m, 1H), 4.61e4.68 (m, 1H), 4.67e4.72 (m,

1H), 5.13e5.22 (m, 1H), 6.80 (d, J ¼ 5.4 Hz, 1H), 6.97 (d,

J ¼ 7.6 Hz, 1H), 7.13 (t, J ¼ 8.4 Hz, 2H), 7.57e7.64 (m,

2H), 7.69 (bs, 1H), 8.29 (d, J ¼ 5.4 Hz, 1H), 9.56 (d,

J ¼ 7.6 Hz, 1H). MS (ESIþ) 410.2 (under MS conditions,

the aminal bond is cleaved and instead an M þ 1 peak is ob-

served for the resulting 7-C(OH)HCH₂N(Me)H product).

4.1.41. 2-Dimethylamino-1-[2-(4-ﬂuorophenyl)-3-(2-methyl-

sulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]-

ethanol (44)

A solution of oxazolidine 43 (1.65 g, 3.91 mmol) in EtOH

(50 mL) was charged with NaBH₄(450 mg, 11.9 mmol), and

stirred at room temperature for 3 h. The reaction was then

quenched with a 20% w/v aqueous NH₄Cl solution (16 mL)

and concentrated under reduced pressure, then diluted with

H₂O and neutralized with an aqueous K₂CO₃solution, and

then extracted with CH₂Cl₂(3 ꢀ 50 mL). The organic extracts

were then pooled, dried over MgSO₄, ﬁltered, and concen-

trated under reduced pressure, and then chromatographed on

SiO₂using a gradient that started with CH₂Cl₂and ended

with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of

4.1.39.2.

4-[7-(1-Dimethylaminomethylpropyl)-2-(4-ﬂuoro-

phenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (42b).

Dimethylamine 42b was prepared from primary amine 41b

(40.0 mg, 0.106 mmol), formaldehyde (34 mg of a 37% w/w

solution in H₂O, 23 mL, 0.43 mmol), AcOH (35 mL), and so-

dium cyanoborohydride (531 mL of a 1.0 M in THF,

0.531 mmol) in MeOH (2.0 mL). Yield of 42b: 20.0 mg

1

(47%). H NMR (400 MHz, CDCl₃) d 0.60e0.90 (m, 1H),

0.85 (t, J ¼ 7.4 Hz, 3H), 1.47e1.68 (m, 1H), 1.70e1.93 (m,

1H), 2.25 (s, 6H), 2.62e2.75 (m, 1H), 2.73e2.90 (m, 1H),

5.09 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz, 1H), 6.81 (dd, J ¼ 7.3,

1.8 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.48 (bs, 1H), 7.60e

7.68 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.46 (d, J ¼ 7.3 Hz,

1H). MS (ESIþ) 405.2.

1

44: 1.01 g (60%). H NMR (400 MHz, DMSO-d₆) d 2.21 (s,

6H), 2.49 (m, 2H), 2.58 (s, 3H), 4.74e4.81 (m, 1H), 5.40

(bs, 1H), 6.86 (d, J ¼ 5.6 Hz, 1H), 7.16 (dd, J ¼ 7.2, 1.6 Hz,

1H), 7.29 (t, J ¼ 8.8 Hz, 2H), 7.60e7.68 (m, 3H), 8.45 (d,

J ¼ 5.6 Hz, 1H), 9.32 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 424.2.

4.1.39.3.

4-[7-(2-Dimethylamino-1,1-dimethylethyl)-2-(4-

4.1.42. {2-Fluoro-2-[2-(4-ﬂuorophenyl)-3-(2-methyl-

ﬂuorophenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine

(42c). Dimethylamine 42c was prepared from primary amine

41c (170 mg, 0.452 mmol), formaldehyde (110 mg of a 37%

aqueous solution, 1.35 mmol), AcOH (170 mL), and sodium

cyanoborohydride (2.26 mL of a 1.0 M solution in THF,

2.26 mmol) in MeOH (2.0 mL). After chromatography on

SiO₂, the product was puriﬁed further by HPLC using

a MeOH/H₂O gradient, where the aqueous phase was

98:9.1:0.1 H₂O:CH₃CN:Et₃N. Yield of 42c: 104 mg (57%).

¹H NMR (500 MHz, CDCl₃) d 1.39 (s, 6H), 2.15 (s, 6H),

2.54 (s, 2H), 5.11 (bs, 2H), 6.54 (d, J ¼ 5.5 Hz, 1H), 7.06

(dd, J ¼ 7.3, 2.0 Hz, 1H), 7.09e7.17 (m, 2H), 7.62e7.71 (m,

3H), 8.12 (d, J ¼ 5.5 Hz, 1H), 9.44 (d, J ¼ 7.3 Hz, 1H). MS

(ESIþ) 405.3.

sulfanylpyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]ethyl}-

dimethylamine (45)

A solution of alcohol 44 (134 mg, 0.316 mmol) in CH₂Cl₂

(5.0 mL) was cooled to ꢃ78 ^ꢂC in a CO₂/IPA bath, and then

charged with diethylaminosulfur triﬂuoride (51 mg, 42 mL,

0.32 mmol), then allowed to warm to room temperature and

stir for 2 h. The reaction was then washed with H₂O, dried

over MgSO₄, ﬁltered, and concentrated under reduced pres-

sure, and then chromatographed on SiO₂using a gradient

that started with CH₂Cl₂and ended with 90:9:1

CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 45: 44 mg

(32%). ¹H NMR (400 MHz, CDCl₃) d 2.46 (s, 6H), 2.64

(s, 3H), 2.74e3.01 (m, 2H), 5.70e5.88 (m, 1H), 6.82

(d, J ¼ 5.4 Hz, 1H), 7.00 (dd, J ¼ 7.3, 1.5 Hz, 1H), 7.14

(t, J ¼ 8.6 Hz, 2H), 7.58e7.66 (m, 2H), 7.69 (bs, 1H), 8.30

(d, J ¼ 5.4 Hz, 1H), 9.59 (d, J ¼ 7.3 Hz, 1H).

4.1.40. 2-(4-Fluorophenyl)-7-(3-methyloxazolidin-5-yl)-

3-(2-methylsulfanylpyrimidin-4-yl)imidazo-

[1,2-a]pyridine (43)

4.1.43. {2-Fluoro-2-[2-(4-ﬂuorophenyl)-3-(2-methane-

sulfonylpyrimidin-4-yl)imidazo[1,2-a]pyridin-7-yl]ethyl}-

dimethylamine (46)

A solution of aldehyde 18 (1.44 g, 3.95 mmol) in toluene

(120 mL) was charged with sarcosine (710 mg, 7.97 mmol)

and paraformaldehyde (600 mg, 20.0 mmol), and the reaction

was equipped with a Dean Stark trap and heated under reﬂux

for 12 h. The reaction was then concentrated under reduced

pressure, diluted with acetone, and then ﬁltered through

a 5 g SiO₂cartridge, which was then washed with acetone

(80 mL). The ﬁltrate was then concentrated under reduced

pressure, and not puriﬁed further. Yield of 43: 1.65 g (98%).

¹H NMR (400 MHz, CDCl₃) d 2.63 (bs, 6H), 2.90e2.98 (m,

A solution of sulﬁde 45 (59 mg, 0.14 mmol) in 1:1 MeO-

H:acetone (4.0 mL) was charged with a solution of OXONE^Ò

(256 mg, 0.417 mmol) in water (2.0 mL), and the reaction was

allowed to stir for 12 h at room temperature. The reaction was

then cooled to ꢃ78 ^ꢂC in a CO₂/IPA bath, and charged with

excess sulfur dioxide for 5 min. After stirring at room temper-

ature for an additional 2 h, the reaction was concentrated un-

der reduced pressure, diluted with H₂O, and treated with

1146

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

a saturated aqueous NaHCO₃solution until pH ¼ 8. The mix-

ture was then extracted with 9:1 CH₂Cl₂:MeOH (3 ꢀ 20 mL).

The organic fractions were pooled, dried over Na₂SO₄, ﬁl-

tered, and concentrated under reduced pressure, and not puri-

ﬁed further. Crude yield of 46: 102 mg (>100%). MS (ESIþ)

457.9.

d 1.76e1.86(m, 2H), 2.64(t, J ¼ 7.8 Hz, 2H), 3.59(t, J ¼ 6.3 Hz,

2H), 6.52 (d, J ¼ 6.9 Hz, 1H), 7.00 (t, J ¼ 8.7 Hz, 2H), 7.27 (bs,

1H), 7.59 (bs, 1H), 7.77 (m, 2H), 7.86 (d, J ¼ 6.9 Hz, 1H). MS

(ESIþ) 270.9.

4.1.47. Methanesulfonic acid 3-[2-(4-ﬂuorophenyl)imidazo-

[1,2-a]pyridin-7-yl]propyl ester (51)

A solution of alcohol 50 (600 mg, 2.22 mmol) in CH₂Cl₂

(20 mL) was chilled to 0 ^ꢂC in an ice water bath, then charged

with Et₃N (269 mg, 371 mL, 2.66 mmol) and methanesulfonyl

chloride (279 mg, 189 mL), then allowed to warm to room

temperature and stir for 2 h. The reaction was diluted with

9:1 CH₂Cl₂:MeOH and washed with H₂O, then dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

Crude methanesulfonate ester 51 was carried onto the next

step without further puriﬁcation.

4.1.44. 4-[7-(2-Dimethylamino-1-ﬂuoroethyl)-2-(4-ﬂuoro-

phenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (47)

A suspension of crude sulfone 46 (theoretically 64 mg,

0.14 mmol) in THF (20 mL) in a pressure reactor was chilled

to ꢃ78 ^ꢂC in a CO₂/IPA bath, and excess ammonia was bub-

bled in over 5 min. The pressure reactor was sealed, and the

reaction was allowed to warm to room temperature with stir-

ring for 12 h. The pressure was then released, and the reaction

was concentrated under reduced pressure, and then chromato-

graphed on SiO₂using a gradient that started with CH₂Cl₂and

ended with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield

of 47: 95 mg (44% over two steps). ¹H NMR (400 MHz,

CDCl₃) d 2.40 (s, 6H), 2.62e2.77 (m, 1H), 2.82e2.98 (m,

1H), 5.15 (bs, 2H), 5.58e5.78 (m, 1H), 6.53 (d, J ¼ 5.3 Hz,

1H), 6.93 (dd, J ¼ 7.3, 1.7 Hz, 1H), 7.13 (t, J ¼ 8.7 Hz, 2H),

7.61e7.70 (m, 3H), 8.15 (d, J ¼ 5.3 Hz, 1H), 9.49 (d,

J ¼ 7.3 Hz, 1H). MS (ESIþ) 395.2.

4.1.48. {3-[2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-

7-yl]propyl}dimethylamine (52)

A solution of crude methanesulfonate ester 51 (theoreti-

cally 773 mg, 2.22 mmol) in CH₂Cl₂(10 mL) was charged

with diisopropylethylamine (513 mg, 773 mL, 4.44 mmol)

and dimethylamine (773 mL of a 2.0 M in THF, 4.44 mmol).

After stirring at room temperature for 2 h, a second portion

of dimethylamine (773 mL of a 2.0 M in THF, 4.44 mmol)

was added, and the reaction was stirred at room temperature

for an additional 12 h. The reaction was then concentrated

under reduced pressure, and then chromatographed on SiO₂

using a gradient that started with CH₂Cl₂and ended with

90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 52:

4.1.45. 2-Chloro-1-(4-ﬂuorophenyl)ethanone O-methyl-

oxime (49) and 2-bromo-1-(4-ﬂuorophenyl)ethanone

O-methyloxime (49)

A solution of 4-ﬂuorophenacyl chloride (100 g, 579 mmol)

in MeOH (1.0 L) was charged with O-methylhydroxylamine

hydrochloride (96.8 g, 1.56 mol), and was then heated to

65 ^ꢂC for 2 h. The reaction with crude 48 was then concen-

trated under reduced pressure, then charged with acetone

(750 mL) and LiBr (252 g, 2.90 mol), and heated to 60 ^ꢂC

for 16 h. The reaction was then concentrated under reduced

pressure, suspended in CH₂Cl₂(1.0 L), and washed with

H₂O (3 ꢀ 200 mL). The organic extracts were then pooled,

dried over Na₂SO₄, ﬁltered, and concentrated under reduced

1

720 mg (78% over two steps). H NMR (400 MHz, CDCl₃)

d 1.67e1.77 (m, 2H), 2.11 (s, 6H), 2.21 (t, J ¼ 7.2 Hz,

2H), 2.56 (t, J ¼ 7.6 Hz, 2H), 6.54 (dd, J ¼ 6.9, 1.4 Hz,

1H), 6.99 (t, J ¼ 8.7 Hz, 2H), 7.27 (bs, 1H), 7.60 (bs, 1H),

7.72e7.81 (m, 2H), 7.89 (d, J ¼ 6.9 Hz, 1H). MS (ESIþ)

297.9.

4.1.49. 1-[7-(3-Dimethylaminopropyl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]ethanone (53)

1

pressure. Yield of 49: 118 g (83% over two steps). H NMR

(500 MHz, CDCl₃) d 4.10 (s, 3H), 4.35 (s, 2H), 7.11 (t,

J ¼ 8.8 Hz, 2H), 7.69e7.75 (m, 2H). MS (ESIþ) 246.0.

A solution of imidazopyridine 52 (170 mg, 0.572 mmol) in

acetic anhydride (10.0 mL) was charged with concentrated

H₂SO₄(four drops) and heated to 160 ^ꢂC for 12 h. The

reaction was then concentrated under reduced pressure, and

then chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concen-

trated NH₄OH. Yield of 53: 80.0 mg (41%). ¹H NMR

(400 MHz, CDCl₃) d 1.80e1.93 (m, 2H), 2.17 (s, 3H), 2.23

(s, 6H), 2.27e2.37 (m, 2H), 2.79 (t, J ¼ 7.6 Hz, 2H), 6.96

(dd, J ¼ 7.1, 1.6 Hz, 1H), 7.19 (t, J ¼ 8.7 Hz, 2H), 7.51

(bs, 1H), 7.57 (m, 2H), 9.65 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ)

340.1.

4.1.46. 3-[2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-

7-yl]propan-1-ol (50)

A solution of 3-(pyridin-4-yl)propan-1-ol (7.00 g, 51.0 mmol)

in acetone (250 mL) was charged with bromide 49 (12.5 g,

51.0 mmol), and the reaction was stirred at room temperature

for 12 h. The intermediate salt was ﬁltered, then dissolved in

THF (150 mL) and charged with DBU (5.96 g, 5.85 mL,

39.1 mmol), and the reaction was heated to reﬂux for 3 h. The re-

action was then concentrated under reduced pressure, diluted in

CH₂Cl₂, and washed with H₂O. The organic layer was dried

with Na₂SO₄, ﬁltered, and concentrated under reduced pressure,

and then chromatographed on SiO₂using a gradient that started

with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concentrated

NH₄OH. Yield of 50: 2.00 g (23%). ¹H NMR (400 MHz, CDCl₃)

4.1.50. 3-Dimethylamino-1-[7-(3-dimethylaminopropyl)-2-

(4-ﬂuorophenyl)imidazo[1,2-a]pyridin-3-yl]propenone (54)

A solution of ketone 53 (290 mg, 0.850 mmol) in

DMFDMA (509 mg, 567 mL, 4.27 mmol) was heated to

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1147

110 ^ꢂC for 12 h. The reaction was then concentrated under re-

duced pressure, and then chromatographed on SiO₂using

a gradient that started with CH₂Cl₂and ended with 90:9:1

CH₂Cl₂:MeOH:concentrated NH₄OH, and carried directly

onto the next step. Yield of 54: 100 mg (30%). MS (ESIþ)

395.2.

1H), 7.89e7.96 (m, 2H), 8.08 (d, J ¼ 7.1 Hz, 1H). MS

(ESIþ) 338.1.

4.1.54. 1-{4-[3-Acetyl-2-(4-ﬂuorophenyl)imidazo[1,2-a]-

pyridin-7-yl]piperidin-1-yl}ethanone (58)

A solution of imidazopyridine 57 (3.04 g, 9.01 mmol) in

acetic anhydride (100 mL) was charged with concentrated

H₂SO₄(three drops) and heated to 160 ^ꢂC for 12 h. The reac-

tion was then concentrated under reduced pressure, and then

chromatographed on SiO₂using a gradient that started with

CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:concentrated

NH₄OH. Yield of 58: 1.43 g (43%). ¹H NMR (400 MHz,

CDCl₃) d 1.61e1.77 (m, 2H), 1.96e2.06 (m, 2H), 2.17 (s,

3H), 2.20 (s, 3H), 2.64e2.73 (m, 1H), 2.86e2.95 (m, 1H),

3.18e3.28 (m, 1H), 4.01 (d, J ¼ 13.4 Hz, 1H), 4.86 (dd,

J ¼ 13.4, 1.6 Hz, 1H), 6.98 (dd, J ¼ 7.2, 1.4 Hz, 1H), 7.21

(t, J ¼ 8.6 Hz, 2H), 7.55e7.62 (m, 2H), 7.56 (s, 1H), 9.70

(d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 379.9.

4.1.51. 4-[7-(3-Dimethylaminopropyl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (55)

A solution of enone 54 (97 mg, 0.24 mmol) in DMF (6.0 mL)

was charged with guanidine hydrochloride (27 mg, 0.28 mmol)

and K₂CO₃(39 mg, 0.28 mmol), and the reaction was heated to

110 ^ꢂC for 12 h. The reaction was then diluted with 9:1

CH₂Cl₂:MeOH, and washed with a saturated aqueous NaHCO₃

solution, then saturated aqueous LiCl solution, then dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure,

and then chromatographed on SiO₂using a gradient that

started with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:

1

concentrated NH₄OH. Yield of 55: 27 mg (28%). H NMR

(400 MHz, CDCl₃) d 1.83e1.93 (m, 2H), 2.27 (s, 6H), 2.32e

2.39 (m, 2H), 2.77 (t, J ¼ 7.6 Hz, 2H), 5.09 (bs, 2H), 6.52

(d, J ¼ 5.5 Hz, 1H), 6.81 (dd, J ¼ 7.3, 1.8 Hz, 1H), 7.13

(t, J ¼ 8.9 Hz, 2H), 7.48 (bs, 1H), 7.60e7.67 (m, 2H), 8.12

(d, J ¼ 5.5 Hz, 1H), 9.43 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ)

391.3.

4.1.55. 1-[7-(1-Acetylpiperidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]-3-dimethylamino-

propenone (59)

A solution of ketone 58 (1.43 g, 3.77 mmol) in DMFDMA

(50 mL) was heated to 110 ^ꢂC for 12 h, then concentrated un-

der reduced pressure, and then chromatographed on SiO₂us-

ing a gradient that started with CH₂Cl₂and ended with

90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 59:

4.1.52. 1-(3,4,5,6-Tetrahydro-2H-[4,4⁰]bipyridin-1-yl)-

ethanone (56)

1

1.41 g (86%). H NMR (400 MHz, CDCl₃) d 1.58e1.78 (m,

A

solution of 1,2,3,4,5,6-hexahydro-[4,4⁰]bipyridinyl

2H), 1.99 (t, J ¼ 12.3 Hz, 2H), 2.16 (s, 3H), 2.48 (bs, 3H),

2.62e2.74 (m, 1H), 2.79e2.90 (m, 1H), 3.05 (bs, 3H),

3.16e3.27 (m, 1H), 3.99 (bd, J ¼ 13.4 Hz, 1H), 4.83 (bd,

J ¼ 13.4 Hz, 1H), 5.11 (d, J ¼ 12.5 Hz, 1H), 6.83 (dd,

J ¼ 7.3, 1.6 Hz, 1H), 7.14 (t, J ¼ 8.7 Hz, 2H), 7.45 (bs, 1H),

7.63 (d, J ¼ 12.5 Hz, 1H), 7.66e7.74 (m, 2H), 9.58 (d,

J ¼ 7.3 Hz, 1H). MS (ESIþ) 435.1.

(3.01 g, 18.6 mmol) in acetic anhydride was stirred at room

temperature for 12 h, and was then concentrated under re-

duced pressure, diluted with CH₂Cl₂(250 mL), washed with

a saturated aqueous NaHCO₃solution (3 ꢀ 50 mL), dried

over Na₂SO₄, ﬁltered, and concentrated under reduced pres-

sure. Yield of 56: 2.99 g (79%). ¹H NMR (400 MHz,

CDCl₃) d 1.54e1.72 (m, 2H), 1.92 (t, J ¼ 13.6 Hz, 2H), 2.14

(s, 3H), 2.58e2.70 (m, 1H), 2.70e2.83 (m, 1H), 3.14e3.25

(m, 1H), 3.91e4.02 (m, 1H), 4.75e4.88 (m, 1H), 7.15

(d, J ¼ 5.9 Hz, 2H), 8.55 (d, J ¼ 5.9 Hz, 2H). MS (ESIþ)

204.9.

4.1.56. 1-{4-[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-7-yl]piperidin-1-yl}ethanone (60)

A solution of enone 59 (1.41 g, 3.24 mmol) in 1-propanol

(100 mL) was charged with guanidine hydrochloride (465 mg,

4.87 mmol) and sodium methoxide (1.05 g of a 25% w/w solu-

tion in MeOH, 1.11 mL, 4.87 mmol), and the reaction was

heated to 100 ^ꢂC for 12 h. The reaction was then concentrated

under reduced pressure, suspended in H₂O (50 mL), and ex-

tracted into 4:1 CH₂Cl₂:MeOH (3 ꢀ 250 mL). The organic frac-

tions were pooled, dried over Na₂SO₄, ﬁltered, concentrated

under reduced pressure, and then chromatographed on SiO₂us-

ing a gradient that started with CH₂Cl₂and ended with 90:9:1

CH₂Cl₂:MeOH:concentrated NH₄OH. Yield of 60: 1.01 g

4.1.53.

1-{4-[2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-

7-yl]piperidin-1-yl}ethanone (57)

A solution of pyridine 56 (2.97 g, 14.5 mmol) in acetone

(100 mL) was charged with a-bromo-O-methyloxime 49

(3.57 g, 14.5 mmol), and the reaction was stirred at room tem-

perature for 12 h, then concentrated under reduced pressure,

diluted with MeOH (100 mL), charged with t-BuOK (1.95 g,

17.4 mmol), and heated to 80 ^ꢂC for 12 h. The reaction was

then concentrated under reduced pressure, and chromato-

graphed on SiO₂using a gradient that started with CH₂Cl₂

and ended with 90:9:1 CH₂Cl₂:MeOH:concentrated NH₄OH.

Yield of 57: 3.05 g (62%). ¹H NMR (400 MHz, CDCl₃)

d 1.57e1.73 (m, 2H), 1.92e2.04 (m, 2H), 2.16 (s, 3H),

2.62e2.72 (m, 1H), 2.76e2.86 (m, 1H), 3.17e3.27 (m, 1H),

3.94e4.04 (m, 1H), 4.79e4.88 (m, 1H), 6.69 (dd, J ¼ 7.1,

1.0 Hz, 1H), 7.13 (t, J ¼ 8.7 Hz, 2H), 7.46 (s, 1H), 7.77 (s,

1

(72%). H NMR (400 MHz, CDCl₃) d 1.57e1.74 (m, 2H),

1.98 (t, J ¼ 12.7 Hz, 2H), 2.15 (s, 3H), 2.63e2.73 (m, 1H),

2.79e2.89 (m, 1H), 3.17e3.28 (m, 1H), 3.98 (d, J ¼ 13.5 Hz,

1H), 4.83 (d, J ¼ 13.5 Hz, 1H), 5.22 (bs, 2H), 6.51 (d, J ¼

5.4 Hz, 1H), 6.78 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.12 (t,

J ¼ 8.7 Hz, 2H), 7.47 (bs, 1H), 7.59e7.67 (m, 2H), 8.11 (d,

J ¼ 5.4 Hz, 1H), 9.43 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 430.8.

1148

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

4.1.57. 4-[2-(4-Fluorophenyl)-7-piperidin-4-ylimidazo-

[1,2-a]pyridin-3-yl]piperidin-2-ylamine (61)

0.103 mmol), K₂CO₃(21.0 mg, 0.154 mmol), and 2-bromoe-

thanol (15 mg, 9.0 mL, 0.12 mmol). Yield of 62b: 23.4 mg

1

(53%). H NMR (400 MHz, CDCl₃) d 1.80e2.00 (m, 5H),

Amide 60 (990 mg, 2.30 mmol) was charged with 3 N HCl

(40 mL) and heated to 90 ^ꢂC for 12 h. The reaction was then

concentrated under reduced pressure, diluted to 10 mL in

MeOH, treated with concentrated NH₄OH until basic to litmus

paper, and then puriﬁed by HPLC using a MeOH/H₂O gradi-

ent, where the aqueous phase was 98.9:1.0:0.1 H₂O:CH₃C-

N:Et₃N. Yield of 61: 467 mg (52%). ¹H NMR (400 MHz,

CDCl₃) d 1.66e1.81 (m, 2H), 1.94 (bd, J ¼ 12.8 Hz, 2H),

2.69e2.80 (m, 1H), 2.77e2.87 (m, 2H), 3.28 (bd,

J ¼ 12.1 Hz, 2H), 5.12 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz, 1H),

6.85 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.50

(bs, 1H), 7.58e7.70 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.44

(d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 388.8.

2.28 (t, J ¼ 11.3 Hz, 2H), 2.64 (t, J ¼ 5.2 Hz, 2H), 3.12 (d,

J ¼ 11.3 Hz, 2H), 3.69 (t, J ¼ 5.2 Hz, 2H), 5.11 (bs, 2H), 6.52

(d, J ¼ 5.4 Hz, 1H), 6.85 (d, J ¼ 7.2 Hz, 1H), 7.13 (t,

J ¼ 8.5 Hz, 2H), 7.50 (bs, 1H), 7.60e7.68 (m, 2H), 8.12 (d,

J ¼ 5.4 Hz, 1H), 9.44 (d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 433.1.

4.1.59.3. 2-{4-[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-7-yl]piperidin-1-yl}propan-1-ol (62c).

Compound 62c was prepared by Method B from amine 61

(40.0 mg, 0.103 mmol), K₂CO₃(21.0 mg, 0.154 mmol), and

3-bromopropan-1-ol (15 mg, 9.0 mL, 0.12 mmol at t ¼ 0 h,

then an additional 11 mL at t ¼ 24 h, and 22 mL at t ¼ 48 h,

while heating at 90 ^ꢂC for a total of 72 h). Yield of 63c:

32.2 mg (70%). ¹H NMR (400 MHz, CDCl₃) d 1.61e1.86

(m, 4H), 1.75e2.00 (m, 2H), 2.11 (t, J ¼ 11.3 Hz, 2H),

2.55e2.70 (m, 1H), 2.67 (t, J ¼ 5.6 Hz, 2H), 3.23 (d,

J ¼ 11.3 Hz, 2H), 3.84 (t, J ¼ 5.1Hz, 2H), 5.14 (bs, 2H),

6.51 (d, J ¼ 5.3 Hz, 1H), 6.81 (d, J ¼ 7.3 Hz, 1H), 7.12 (t,

J ¼ 8.5 Hz, 2H), 7.48 (bs, 1H), 7.59e7.66 (m, 2H), 8.11 (d,

J ¼ 5.3 Hz, 1H), 9.42 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 447.2.

4.1.58. General procedure for the synthesis of N-substituted

piperidines 62a and 62dek (Method A)

A solution of secondary amine 61 in MeOH (8.0 mL) was

charged with AcOH, appropriate aldehyde, and sodium cyano-

borohydride (1.0 M solution in THF). After stirring at room

temperature for 6 h, additional aldehyde was added if the reac-

tion was not yet complete, and all reactions then stirred for an

additional 12 h at room temperature. Each reaction was then

treated with excess concentrated NH₄OH (500 mL), then puri-

ﬁed by HPLC using a MeOH/H₂O gradient, where the aqueous

phase was 98.9:1.0:0.1 H₂O:CH₃CN:Et₃N. Any modiﬁcations

to this procedure are noted below.

4.1.59.4. 4-[2-(4-Fluorophenyl)-7-(1-isobutylpiperidin-4-yl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62d). Com-

pound 62d was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), 2-methylpropionalde-

hyde (9.0 mg, 11 mL, 0.12 mmol at t ¼ 0 h, then an additional

2.0 mL at t ¼ 6 h), and sodium cyanoborohydride (113 mL of

a 1.0 M solution in THF, 0.113 mmol). Yield of 62d:

38.1 mg (69%). ¹H NMR (400 MHz, CDCl₃) d 0.94 (d,

J ¼ 6.5 Hz, 6H), 1.73e1.97 (m, 5H), 1.97e2.25 (m, 4H),

2.50e2.76 (m, 1H), 2.90e3.30 (m, 2H), 5.10 (bs, 2H), 6.51

(d, J ¼ 5.4 Hz, 1H), 6.87 (d, J ¼ 7.1 Hz, 1H), 7.12 (t,

J ¼ 8.7 Hz, 2H), 7.50 (bs, 1H), 7.60e7.68 (m, 2H), 8.11 (d,

J ¼ 5.4 Hz, 1H), 9.42 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 445.3.

4.1.59. General procedure for the synthesis of N-substituted

piperidines 62b and 62c (Method B)

A solution of secondary amine 61 in EtOH (10 mL) was

charged with K₂CO₃and appropriate alkyl bromide, and

heated to 90 ^ꢂC for 24 h. If necessary, additional alkyl halide

was then added, and heating continued for another 24 h. The

reaction was then puriﬁed by HPLC using a MeOH/H₂O gra-

dient, where the aqueous phase was 98.9:1.0:0.1 H₂O:CH₃C-

N:Et₃N. Any modiﬁcations to this procedure are noted below.

4.1.59.5. 4-[7-(1-Cyclopropylmethylpiperidin-4-yl)-2-(4-ﬂuoro-

phenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62e).

Compound 62e was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), cyclopropanecarbalde-

hyde (9.0 mg, 9.0 mL, 0.12 mmol), and sodium cyanoborohy-

dride (113 mL of a 1.0 M solution in THF, 0.113 mmol). Yield

of 62e: 34.3 mg (62%). ¹H NMR (400 MHz, CDCl₃) d 0.16 (q,

J ¼ 5.0 Hz, 2H), 0.57 (dd, J ¼ 12.8, 5.0 Hz, 2H), 0.81e1.09

(m, 1H), 1.80e2.00 (m, 4H), 2.14 (t, J ¼ 10.4 Hz, 2H), 2.35 (d,

J ¼ 6.4 Hz, 2H), 2.50e2.74 (m, 1H), 3.27 (d, J ¼ 11.1 Hz,

2H), 5.12 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz, 1H), 6.87 (dd, J ¼ 7.3,

1.5 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.51 (bs, 1H), 7.60e7.68

(m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.43 (d, J ¼ 7.3 Hz, 1H).

MS (ESIþ) 443.3.

4.1.59.1. 4-[7-(1-Ethylpiperidin-4-yl)-2-(4-ﬂuorophenyl)imidazo

[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62a). Compound 62a

was prepared by Method A from amine 61 (40.0 mg,

0.103 mmol), AcOH (40 mL), acetaldehyde (5.0 mg, 7.0 mL,

0.12 mmol at t ¼ 0 h, then an additional 3 mL at t ¼ 6 h), and so-

dium cyanoborohydride (113 mL of a 1.0 M solution in THF,

0.113 mmol). Yield of 62a: 27.5 mg (53%). ¹H NMR

(400 MHz, CDCl₃) d 1.14 (t, J ¼ 7.2 Hz, 3H), 1.71e2.13 (m,

6H), 2.48 (q, J ¼ 7.2 Hz, 2H), 2.55e2.66 (m, 1H), 3.05e3.20

(m, 2H), 5.14 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz, 1H), 6.84 (dd,

J ¼ 7.2, 1.9 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.50 (bs, 1H),

7.60e7.68 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.42 (d,

J ¼ 7.2 Hz, 1H). MS (ESIþ) 417.2.

4.1.59.6. 4-{2-(4-Fluorophenyl)-7-[1-(2-methylbutyl)piperid-

in-4-yl]imidazo[1,2-a]pyridin-3-yl}pyrimidin-2-ylamine (62f).

Compound 62f was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), 2-methylbutyraldehyde

4.1.59.2. 2-{4-[3-(2-Aminopyrimidin-4-yl)-2-(4-ﬂuorophenyl)i-

midazo[1,2-a]pyridin-7-yl]piperidin-1-yl}ethanol (62b). Com-

pound 62b was prepared by Method B from amine 61 (40.0 mg,

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

1149

(11 mg, 13 mL, 0.12 mmol at t ¼ 0 h, then an additional 2.0 mL at

t ¼ 6 h), and sodium cyanoborohydride (113 mL of a 1.0 M solu-

tion in THF, 0.113 mmol). Yield of 62f: 36.5 mg (64%). ¹H NMR

(400 MHz, CDCl₃) d 0.75e1.00 (m, 6H), 1.10e1.40 (m, 1H),

1.34e1.51 (m, 1H), 1.70e2.30 (m, 9H), 2.59 (t, J ¼ 9.8 Hz,

1H), 2.91e3.15 (m, 2H), 5.09 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz,

1H), 6.86 (d, J ¼ 7.1 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.50 (bs,

1H), 7.60e7.68 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.42 (d,

J ¼ 7.1 Hz, 1H). MS (ESIþ) 459.3.

(40.0 mg, 0.103 mmol), AcOH (40 mL), benzaldehyde

(13 mg, 13 mL, 0.12 mmol at t ¼ 0 h, then an additional

7.0 mL at t ¼ 6 h), and sodium cyanoborohydride (113 mL of

a 1.0 M solution in THF, 0.113 mmol). Yield of 62j:

35.4 mg (60%). ¹H NMR (400 MHz, CDCl₃) d 1.88 (q,

J ¼ 12.0 Hz, 4H), 2.15 (t, J ¼ 10.6 Hz, 2H), 2.53e2.69 (m,

1H), 3.07 (d, J ¼ 11.2 Hz, 2H), 3.59 (s, 2H), 5.10 (bs, 2H),

6.51 (d, J ¼ 5.4 Hz, 1H), 6.85 (dd, J ¼ 7.3, 1.5 Hz, 1H), 7.12

(t, J ¼ 8.7 Hz, 2H), 7.23e7.40 (m, 5H), 7.50 (bs, 1H), 7.63

(m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.42 (d, J ¼ 7.3 Hz, 1H).

MS (ESIþ) 479.4.

4.1.59.7. 4-[7-[1-(3,3-Dimethylbutyl)piperidin-4-yl)-2-(4-ﬂuoro-

phenyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62g).

Compound 62g was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), 3,3-dimethylbutyralde-

hyde (12 mg, 16 mL, 0.12 mmol), and sodium cyanoborohy-

dride (113 mL of a 1.0 M solution in THF, 0.113 mmol).

4.1.59.11. 4-[2-(4-Fluorophenyl)-7-(1-phenethylpiperidin-4-yl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62k). Com-

pound 62k was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), phenylacetaldehyde

(15 mg, 13 mL, 0.12 mmol at t ¼ 0 h, then an additional

2.0 mL at t ¼ 6 h), and sodium cyanoborohydride (113 mL of

a 1.0 M solution in THF, 0.113 mmol). Yield of 62k: 38.3 mg

1

Yield of 62g: 34.5 mg (58%). H NMR (400 MHz, CDCl₃)

d 0.94 (s, 9H), 1.40e1.55 (m, 2H), 1.73e1.98 (m, 4H),

2.00e2.19 (m, 2H), 2.28e2.47 (m, 2H), 2.52e2.70 (m, 1H),

3.13 (d, J ¼ 11.2 Hz, 2H), 5.10 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz,

1H), 6.86 (dd, J ¼ 7.2, 1.3 Hz, 1H), 7.12 (t, J ¼ 8.6 Hz, 2H),

7.51 (bs, 1H), 7.64 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.43

(d, J ¼ 7.2 Hz, 1H). MS (ESIþ) 473.3.

1

(63%). H NMR (400 MHz, CDCl₃) d 1.80e1.95 (m, 2H),

1.91e2.00 (m, 2H), 2.20 (bt, J ¼ 10.8 Hz, 2H), 2.57e2.74

(m, 3H), 2.82e2.94 (m, 2H), 3.20 (bd, J ¼ 11.3 Hz, 2H), 5.10

(bs, 2H), 6.51 (d, J ¼ 5.4 Hz, 1H), 6.85 (dd, J ¼ 7.3, 1.5 Hz,

1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.19e7.41 (m, 5H), 7.50 (bs,

1H), 7.59e7.67 (m, 2H), 8.11 (d, J ¼ 5.4 Hz, 1H), 9.42 (d,

J ¼ 7.3 Hz, 1H). MS (ESIþ) 493.3.

4.1.59.8. 4-{2-(4-Fluorophenyl)-7-[1-(2-methylpentyl)piperidin-

4-yl]imidazo[1,2-a]pyridin-3-yl}pyrimidin-2-ylamine

(62h).

Compound 62h was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), 2-methylpentanal

(12 mg, 15 mL, 0.12 mmol at t ¼ 0 h, then an additional

4.0 mL at t ¼ 6 h), and sodium cyanoborohydride (113 mL of

a 1.0 M solution in THF, 0.113 mmol). Yield of 62h:

38.8 mg (66%). ¹H NMR (400 MHz, CDCl₃) d 0.85e0.97

(m, 6H), 1.03e1.15 (m, 1H), 1.22e1.49 (m, 3H), 1.61e1.75

(m, 1H), 1.75e1.95 (m, 4H), 1.93e2.28 (m, 4H), 2.49e2.67

(m, 1H), 3.02 (t, J ¼ 11.5 Hz, 2H), 5.11 (bs, 2H), 6.51 (d,

J ¼ 5.4 Hz, 1H), 6.86 (dd, J ¼ 7.3, 1.6 Hz, 1H), 7.12 (t,

J ¼ 8.7 Hz, 2H), 7.50 (bs, 1H), 7.60e7.68 (m, 2H), 8.11 (d,

J ¼ 5.4 Hz, 1H), 9.42 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 473.4.

4.1.60. 7-Chloro-2-(4-ﬂuorophenyl)imidazo-

[1,2-a]pyridine (63)

A

solution of 2-amino-4-chloropyridine (2.00 g,

15.5 mmol) and 2-bromo-1-(4-ﬂuorophenyl)ethanone (3.36 g,

15.5 mmol) in EtOH (40 mL) was heated to 60 ^ꢂC for 12 h.

The reaction was then concentrated under reduced pressure,

and then chromatographed on SiO₂using a heptane/EtOAc

1

gradient. Yield of 63: 700 mg (18%). H NMR (400 MHz,

DMSO-d₆) d 6.98 (dd, J ¼ 7.1, 2.0 Hz, 1H), 7.28 (t,

J ¼ 8.6 Hz, 2H), 7.75 (bs, 1H), 7.95e8.05 (m, 2H), 8.41 (s,

1H), 8.57 (d, J ¼ 7.1 Hz, 1H). MS (ESIþ) 247.0.

4.1.59.9.

4-[2-(4-Fluorophenyl)-7-(1-hexylpiperidin-4-yl)-

4.1.61. 1-[7-Chloro-2-(4-ﬂuorophenyl)imidazo-

[1,2-a]pyridin-3-yl]ethanone (64)

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62i). Com-

pound 62i was prepared by Method A from amine 61

(40.0 mg, 0.103 mmol), AcOH (40 mL), hexanal (12 mg,

15 mL, 0.12 mmol at t ¼ 0 h, then an additional 4.0 mL at

t ¼ 6 h), and sodium cyanoborohydride (113 mL of a 1.0 M so-

A solution of imidazopyridine 63 (600 mg, 2.43 mmol) in

acetic anhydride (16 mL) was charged with concentrated

H₂SO₄(three drops) and heated to 160 ^ꢂC for 6 h. The reaction

was then concentrated under reduced pressure, and then chro-

matographed on SiO₂using a gradient that started with hep-

tane and ended with 30:70 EtOAc:heptane. Yield of 64:

1

lution in THF, 0.113 mmol). Yield of 62i: 38.6 mg (65%). H

NMR (400 MHz, CDCl₃) d 0.91 (t, J ¼ 6.6 Hz, 3H), 1.32 (bs,

6H), 1.50e1.63 (m, 2H), 1.75e1.98 (m, 4H), 1.98e2.14 (m,

2H), 2.33e2.45 (m, 2H), 2.54e2.71 (m, 1H), 3.12 (d,

J ¼ 10.1 Hz, 2H), 5.10 (bs, 2H), 6.51 (d, J ¼ 5.4 Hz, 1H),

6.86 (dd, J ¼ 7.3, 1.3 Hz, 1H), 7.12 (t, J ¼ 8.7 Hz, 2H), 7.51

(bs, 1H), 7.64 (dd, J ¼ 8.7, 5.5 Hz, 2H), 8.11 (d, J ¼ 5.4 Hz,

1H), 9.43 (d, J ¼ 7.3 Hz, 1H). MS (ESIþ) 473.4.

1

300 mg (42%). H NMR (400 MHz, CDCl₃) d 2.20 (s, 3H),

7.08 (dd, J ¼ 7.5, 1.9 Hz, 1H), 7.21 (t, J ¼ 8.6 Hz, 2H),

7.53e7.60 (m, 2H), 7.72 (d, J ¼ 1.9 Hz, 1H), 9.70 (d,

J ¼ 7.5 Hz, 1H). MS (ESIþ) 289.0.

4.1.62. 1-[7-Chloro-2-(4-ﬂuorophenyl)imidazo[1,2-a]-

pyridin-3-yl]-3-dimethylaminopropenone (65)

4.1.59.10.

4-[7-(1-Benzylpiperidin-4-yl)-2-(4-ﬂuorophenyl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (62j). Com-

pound 62j was prepared by Method A from amine 61

A mixture of ketone 64 (300 mg, 1.04 mmol) in DMF

(5.0 mL) was charged with DMFDMA (1.38 g, 10.4 mmol)

1150

A. Scribner et al. / European Journal of Medicinal Chemistry 43 (2008) 1123e1151

and heated to 110 ^ꢂC for 6 h. The reaction mixture with enone

65 was concentrated under reduced pressured, and then carried

onto the next step without further puriﬁcation. ¹H NMR

(400 MHz, CDCl₃) d 2.48 (bs, 3H), 3.07 (bs, 3H), 5.10 (d,

J ¼ 12.4 Hz, 1H), 6.93 (dd, J ¼ 7.5, 2.2 Hz, 1H), 7.14 (t,

J ¼ 8.7 Hz, 2H), 7.64 (d, J ¼ 12.4 Hz, 1H), 7.65 (d,

J ¼ 2.2 Hz, 1H), 7.65e7.73 (m, 2H), 9.59 (d, J ¼ 7.5 Hz,

1H). MS (ESIþ) 343.8.

D. Thompson, J. Mathew, A. Misura, S. Samaras, T. Tamas, J.F. Sina,

K.A. McNulty, C.G. McKnight, D.M. Schmatz, M. Wyvratt, Synthesis

and SAR studies of very potent imidazopyridine antiprotozoal agents,

Bioorg. Med. Chem. Lett. 16 (2006) 2479;

(b) D. Feng, M. Fisher, G.-B. Liang, X. Qian, C. Brown, A. Gurnett,

P.S. Leavitt, P.A. Liberator, J. Mathew, A. Misura, S. Samaras,

T. Tamas, D.M. Schmatz, M. Wyvratt, T. Biftu, Synthesis and SAR of

2-(4-ﬂuorophenyl)-3-pyrimidin-4-ylimidazo[1,2-a]pyridine derivatives

as anticoccidial agents, Bioorg. Med. Chem. Lett. 16 (2006) 5978.

[5] A. Scribner, R. Dennis, J. Hong, S. Lee, D. McIntyre, D. Perrey, D. Feng,

M. Fisher, M. Wyvratt, P. Leavitt, P. Liberator, A. Gurnett, C. Brown,

J. Mathew, D. Thompson, D. Schmatz, T. Biftu, Synthesis and biological

activity of imidazopyridine anticoccidial agents: part I, Eur, J. Med.

Chem. 42 (11e12) (2007) 1334.

4.1.63. 4-[7-Chloro-2-(4-ﬂuorophenyl)imidazo[1,2-a]-

pyridin-3-yl]pyrimidin-2-ylamine (66)

The reaction mixture described above with enone 65 (theo-

retically 357 mg, 1.04 mmol) in DMF (5.0 mL and DMFDMA

(1.38 g, 10.4 mmol) was charged with guanidine hydrochlo-

ride (496 mg, 5.19 mmol) and K₂CO₃(717 mg, 5.20 mmol).

The reaction was heated to 110 ^ꢂC for 12 h, and was then chro-

matographed on SiO₂using a heptane/EtOAc gradient. Yield

[6] E. Diez-Barra, J.C. Garcia-Martinez, S. Merino, R. del Ray,

J. Rodriguez-Lopez, P. Sanchez-Verdu, J. Tejeda, Synthesis, characteriza-

tion, and optical response of dipolar and non-dipolar poly(phenylenevi-

nylene) dendrimers, J. Org. Chem. 66 (2001) 5664.

[7] A.F. Abdel-Magid, K.G. Carson, B.D. Harris, C.A. Maryanoff,

R.D. Shah, Reductive amination of aldehydes and ketones with sodium

triacetoxyborohydride. Studies on direct and indirect reductive amination

procedures, J. Org. Chem. 61 (1996) 3849.

1

of 66: 147 mg (41% over two steps). H NMR (400 MHz,

CDCl₃) d 5.12 (bs, 2H), 6.53 (d, J ¼ 5.3 Hz, 1H), 6.92 (dd,

J ¼ 7.5, 1.9 Hz, 1H), 7.14 (t, J ¼ 8.7 Hz, 2H), 7.60e7.68 (m,

2H), 7.69 (d, J ¼ 1.9 Hz, 1H), 8.15 (d, J ¼ 5.3 Hz, 1H), 9.48

(d, J ¼ 7.5 Hz, 1H). MS (ESIþ) 339.8.

[8] A. Coelho, E. Sotelo, I. Estevez, E. Ravina, Pyridazines part XXIII: ef-

ﬁcient arylation at position 5 of the 6-phenyl-(2H )-pyridazin-3-one sys-

tem using a Suzuki cross-coupling reaction, Synthesis (2001) 871.

[9] J.H. Hall, M. Gisler, A simple method for converting nitriles to amides.

Hydrolysis with potassium hydroxide in tert-butyl alcohol, J. Org. Chem.

41 (1976) 3769.

[10] W.J. Guilford, K.J. Shaw, J.L. Dallas, S. Koovakkat, W. Lee, A. Liang,

D.R. Light, M.A. McCarrick, M. Whitlow, B. Ye, M.M. Morrissey, Syn-

thesis, characterization, and structureeactivity relationships of amidine-

substituted (bis)benzylidine-cycloketone oleﬁn isomers as potent and

selective factor Xa inhibitors, J. Med. Chem. 42 (1999) 5415.

[11] S.L. Colletti, J.L. Frie, E.C. Dixon, S.B. Singh, B.K. Choi, G. Scapin,

C.E. Fitzgerald, S. Kumar, E.A. Nichols, S.J. O’Keefe, E.A. O’Neill,

G. Porter, K. Samuel, D.M. Schmatz, C.D. Schwartz, W.L. Shoop,

C.M. Thompson, J.E. Thompson, R. Wang, A. Woods, D.M. Zaller,

J.B. Doherty, Hybrid-designed inhibitors of p38 MAP kinase utilizing

N-arylpyridazinones, J. Med. Chem. 46 (2003) 349.

4.1.64. 4-[2-(4-Fluorophenyl)-7-(4-methylpiperazin-1-yl)-

imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-ylamine (67)

Nitrogen was bubbled through a solution of imidazopyri-

dine 66 (62 mg, 0.18 mmol) in N-methylpiperazine (6.0 mL).

After 10 min, 2-(di-tert-butylphosphino)biphenyl (8.0 mg,

0.027 mmol), sodium tert-butoxide (26 mg, 0.27 mmol) and

palladium(II) acetate (4.0 mg, 0.018 mmol) were sequentially

added, and the reaction was heated to 100 ^ꢂC under nitrogen

for 12 h. The reaction was then concentrated under reduced

pressure, and chromatographed on SiO₂using a gradient that

started with CH₂Cl₂and ended with 90:9:1 CH₂Cl₂:MeOH:-

[12] J.M. Williams, R.B. Jobson, N. Yasunda, G. Marchesini, U.-H. Dolling,

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N-methylamides. Application in direct conversion of an ester to a ketone,

Tetrahedron Lett. 36 (1995) 5461.

1

concentrated NH₄OH. Yield of 67: 43 mg (58%). H NMR

(400 MHz, CDCl₃) d 2.38 (s, 3H), 2.60 (t, J ¼ 4.8 Hz, 4H),

3.35 (t, J ¼ 4.8 Hz, 4H), 5.01 (bs, 2H), 6.49 (d, J ¼ 5.5 Hz,

1H), 6.70 (dd, J ¼ 7.8, 2.7 Hz, 1H), 6.87 (bs, 1H), 7.12 (t,

J ¼ 8.8 Hz, 2H), 7.60e7.68 (m, 2H), 8.05 (d, J ¼ 5.5 Hz,

1H), 9.41 (d, J ¼ 7.8 Hz, 1H). MS (ESIþ) 404.2.

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synthesis of codeine labeled in the 3-methoxy group with C¹⁴, J. Org.

Chem. 15 (1950) 634;

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Article Doi

Synthesis and biological activity of imidazopyridine anticoccidial agents: Part II

DOI: 10.1016/j.ejmech.2007.09.013

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