1-METHYL-1H-PYRAZOLE-4-CARBOXAMIDES USEFUL AS CANCER CHEMOTHERAPEUTIC AGENTS

1-METHYL-1H-PYRAZOLE-4-CARBOXAMIDES UTILES COMME AGENTS CHIMIOTHERAPEUTIQUES ANTICANCEREUX

English Abstract

This invention relates to novel 1 -Methyl- lH-pyrazole-4-carboxamide
compounds, pharmaceutical compositions containing such compounds, and the use
of those compounds or compositions as cancer chemotherapeutic agents.

French Abstract

Cette invention porte sur de nouveaux composés de 1-méthyl-lH-pyrazole-4-carboxamide, sur des compositions pharmaceutiques contenant ces composés et sur l'utilisation de ces composés ou compositions comme agents chimiothérapeutiques anticancéreux.

Claims

CLAIMS:

We claim:


1. A compound of formula (I)

Image
wherein
Ar is selected from the group consisting of
Image

X is CH or N;
R1 is selected from the group consisting of
H,



99



halogen,
Image
wherein
R1-2 is selected from the group consisting of
.cndot. H,
.cndot. (C1-C4)alkoxy,
.cndot. (C1-C4)alkyl,
wherein said (C1-C4)alkyl can be substituted with 0, 1, or 2
groups independently selected from
- hydroxy,
- (C1-C4)alkylamino,
- (C1-C4)acyloxy,
- (Cl-C4)alkoxy, and
- (C2-C4)alkoxy substituted with 0,1 or 2(C1-C4)alkoxy
groups,
- wherein said (C1-C4)alkyl is independently optionally
substituted with F up to the perfluoro level,

.cndot. 5- or 6-membered heteroaryl,
or

.cndot. phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano;



100



R1-3 is H or (C1-C4)alkyl;
R1-4, R1-5 and R1-6 are independently selected from the group consisting of
.cndot. H,

.cndot. indan-5-yl,
.cndot. phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,

.cndot. 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups
selected from
- cyano,
- halo,
- nitro,
- (C1-C4)alkyl,
wherein said (C1-C4)alkyl is optionally substituted with 0, 1,
or 2 groups selected from
(C1-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-
C4)alkoxy groups,
.cndot. (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from
(C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo,
and
.cndot. (C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 0 or
1 group selected from
- NH2,
- (C1-C4)alkoxy,
- (C2-C4)alkoxy independently substituted with
0,1, 2 or 3 (C1-C4)alkoxy and OH groups,
and



101



independently optionally substituted with fluorine up to the
perfluoro level,
- carboxyl,
- (C1-C4)alkoxycarbonyl
- (C1-C4)alkylamino,
- aminocarbonyl,
- (C1-C4)alkylsulfonyl,
- phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and
cyano,
- 5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro
and
- heterocyclyl independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano,
and halo,
- and wherein said (C1-C6)alkyl is independently substituted
with 0, 1 or 2 OH or halo groups,
- and wherein said (C1-C6)alkyl is independently optionally
substituted with F up to the perfluoro level;
and
R1-3 and R1-4, R1-3 and R1-5, and R1-3 and R1-6, when attached to the same
nitrogen atom, may form, together with the N atom to which they
are attached, a 5- or 6-membered saturated heterocyclic ring
selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and
piperizinyl optionally substituted on N with (C1-C4)alkyl;

or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein



102



Ar is selected from the group consisting of
Image
X is CH or N;

R1 is selected from the group consisting of
Image



103



Image
wherein
R1-2 is selected from the group consisting of
.cndot. (C1-C4)alkyl,
wherein said (C1-C4)alkyl is substituted with 1 or 2 groups
independently selected from
- hydroxy,
- (C1-C4)alkylamino,
- (C1-C4)acyloxy,
- (C1-C4)alkoxy, and
- (C2-C4)alkoxy substituted with 0,1 or 2 (C1-C4)alkoxy
groups,
- wherein said (C1-C4)alkyl is independently optionally
substituted with F up to the perfluoro level,

.cndot. 5- or 6-membered heteroaryl,
or
.cndot. phenyl substituted with 1 or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano;
R1-3 is H or (C1-C4)alkyl;
R1-4 and R1-5 are independently selected from the group consisting of
.cndot. indan-5-yl,

.cndot. phenyl substituted with 1 or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,

.cndot. 5- or 6-membered heteroaryl substituted with 1 or 2 groups
selected from
- cyano,
- halo,
- nitro,
- (C1-C4)alkyl,



104



wherein said (C1-C4)alkyl is optionally substituted with 0, 1,
or 2 groups selected from
(C1-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-
C4)alkoxy groups,
.cndot. (C3-C6)cycloalkyl substituted with 1 or 2 groups selected from
(C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo,
and
.cndot. (C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 1
group selected from
- NH2,
- (C1-C4)alkoxy,
- (C2-C4)alkoxy independently substituted with
0,1, 2 or 3 (C1-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up to the
perfluoro level,
- carboxyl,
- (C1-C4)alkoxycarbonyl
- (C1-C4)alkylamino,
- aminocarbonyl,
- (C1-C4)alkylsulfonyl,
- phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and
cyano,
- 5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro
and



105



- heterocyclyl independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano,
and halo,
- and wherein said (C1-C6)alkyl is independently substituted
with 0, 1 or 2 OH or halo groups,
- and wherein said (C1-C6)alkyl is independently optionally
substituted with F up to the perfluoro level;
R1-6 is selected from the group consisting of
.cndot. H
.cndot. indan-5-yl,
.cndot. phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,
.cndot. 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups
selected from
- cyano,
- halo,
- nitro,
- (C1-C4)alkyl,
wherein said (C1-C4)alkyl is optionally substituted with 0, 1,
or 2 groups selected from
(C1-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-
C4)alkoxy groups,
.cndot. (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from
(C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo,

and
.cndot. (C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 0 or
1 group selected from



106



- NH2,
- (C1-C4)alkoxy,
- (C2-C4)alkoxy independently substituted with
0,1, 2 or 3 (C1-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up to the
perfluoro level,
- carboxyl,
- (C1-C4)alkoxycarbonyl
- (C1-C4)alkylamino,
- aminocarbonyl,
- (C1-C4)alkylsulfonyl,
- phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and
cyano,
- 5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro
and
- heterocyclyl independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (C1-C4)alkoxy, cyano,
and halo,
- and wherein said (C1-C6)alkyl is independently substituted
with 0, 1 or 2 OH or halo groups,
- and wherein said (C1-C6)alkyl is independently optionally
substituted with F up to the perfluoro level;
and
R1-3 and R1-4, R1-3 and R1-5, and R1-3 and R1-6, when attached to the same
nitrogen atom, may form, together with the N atom to which they
are attached, a 5- or 6-membered saturated heterocyclic ring
selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and
piperizinyl optionally substituted on N with (C1-C4)alkyl;



107



or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein

Ar is selected from the group consisting of
Image

X is CH;
R1 is selected from the group consisting of
Image
wherein
R1-3 is H or (C1-C4)alkyl,
R1-5 is selected from the group consisting of
indan-5-yl,



108



phenyl substituted with 1 or 2 groups independently selected from
(C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl substituted with 1 or 2 groups selected
from
cyano,
halo,
nitro,
(C1-C4)alkyl,
wherein said (C1-C4)alkyl is optionally substituted
with 0, 1, or 2 groups selected from
(C1-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2 (C1-C4)alkoxy
groups;
(C3-C6)cycloalkyl substituted with 1 or 2 groups selected from (C1-
C4)alkyl, (C1-C4)alkoxy, cyano, and halo;

and
(C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 1group
selected from
NH2,
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3 (C1-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up
to the perfluoro level,
carboxyl,
(C1-C4)alkoxycarbonyl
(C1-C4)alkylamino,
aminocarbonyl,



109




(C1-C4)alkylsulfonyl,
phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro,
(C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro

and
heterocyclyl is independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (C1-C4)alkoxy,
cyano, and halo,
and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (C1-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;

R1-6 is selected from the group consisting of
H,
indan-5-yl,
phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl substituted with 0, 1 or 2 groups
selected from
cyano,
halo,
nitro,
(C1-C4)alkyl,
wherein said (C1-C4)alkyl is optionally substituted
with 0, 1, or 2 groups selected from
(C1-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,



110




and
(C2-C4)alkoxy substituted with up to 0, 1 or 2(C1-C4)alkoxy
groups;
(C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from
(C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo;
and
(C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 0 or 1
group selected from

NH2,
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(C1-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up
to the perfluoro level,
carboxyl,
(C1-C4)alkoxycarbonyl
(C1-C4)alkylamino,
aminocarbonyl,
(C1-C4)alkylsulfonyl,
phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro,
(C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro

and
heterocyclyl is independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (C1-C4)alkoxy,
cyano, and halo,

and



111




wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,

and
wherein said (C1-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;

and
R1-3 and R1-5, and R1-3 and R16, when attached to the same nitrogen atom,
may form, together with the N atom to which they are attached, a 5-
or 6-membered saturated heterocyclic ring selected from
pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl
optionally substituted on N with (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein


Ar is selected from the group consisting of

Image


X is CH;
R1 is selected from the group consisting of

Image



112




and


Image

wherein
R1-3 is H,
R1-5 is (C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 1 group
selected from
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, or 2(C1-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up
to the perfluoro level,
and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (C1-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;
R1-6 is selected from the group
H,
and
(C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with
0 or 1 group selected from
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(C1-C4)alkoxy and OH groups,
and
independently optionally substituted with
fluorine up to the perfluoro level,



113




and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (C1-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;


or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein


Ar is selected from the group consisting of

Image


X is CH;
R1 is selected from the group consisting of

Image


wherein



114




R1-3 is H,
R1-6 is selected from the group
H,
and
(C1-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with
0 or 1 group selected from
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(C1-C4)alkoxy and OH groups,
and
independently optionally substituted with
fluorine up to the perfluoro level,
and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (C1-C6)alkyl is independently optionally substituted with F up to
the
perfluoro level;


or a pharmaceutically acceptable salt thereof.


6. A process for making a compound of claim 1, comprising


(A) reacting, with or without first hydrolizing the ester group -COOR', a
compound of
formula (VI)


Image



115




wherein X and R1 have the meaning described in claim 1, and R' is lower alkyl,


with a compound of formula Ar-NH2 (VIII),


wherein Ar has the meaning described in claim 1; or

(B) reacting a compound of formula (IX)


Image

wherein Ar has the meaning described in claim 1, with a compound of formula
(IV)


Image

wherein X and R1 have the meaning described in claim 1, and subsequently
reducing the resulting compound; or


(C) reacting a compound of formula (IX), wherein Ar has the meaning
described in claim 1, with a compound of formula (V)


Image

wherein lg represents a leaving group; or

(D) reacting a compound of formula (IIa)



116




Image

wherein X and R1 have the meaning described in claim 1, and R' is lower alkyl,

with a compound of formula (VIII)


ArNH2 (VIII),


wherein Ar has the meaning described in claim 1, in the presence of (R')3Al,
wherein R' is lower alkyl, or


(E) first hydrolizing the ester group -COOR' of a compound of formula (IIa) as

described above, and subsequently reacting the resulting compound with a
compound of formula (VIII) as described above.


7. A compound of claim 1 for the treatment or prevention of disorders.

8. A pharmaceutical composition comprising the compound of claim 1.


9. The pharmaceutical composition of claim 8, additionally comprising at least
one
pharmaceutically acceptable carrier or excipient.


10. A pharmaceutical composition of claim 8 or 9 for the treatment or
prevention of
cancer.


11. A process for preparing the pharmaceutical composition of claim 9,
comprising
combining at least one compound according to claim 1 with at least one



117


pharmaceutically acceptable carrier or excipient and bringing the resulting
combination into a form suitable for said pharmaceutical composition.

12. A use of a compound of claim 1 for manufacturing a pharmaceutical
composition
for the treatment or prevention of a disease.

13. The use of claim 12, wherein the disease is cancer.

14. A method of treating a disease or condition in a mammal, comprising
administering to a mammal in need thereof an effective amount of a compound of

claim 1.

15. The method of claim 14, wherein the disease or condition is cancer.
118

Description

CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
1-Methyl-lH-Pyrazole-4-Carboxamides Useful as Cancer Chemotherapeutic Agents
This invention relates to novel 1-Methyl-lH-pyrazole-4-carboxamide compounds,
pharmaceutical compositions containing such compounds, and the use of those
compounds
or compositions as cancer chemotherapeutic agents.

Many disease conditions are known to be associated with deregulated
angiogenesis. Among these are retinopathies; chronic inflammatory disorders
including
arthritis; arteriosclerosis; atherosclerosis; macular degeneration; and
neoplastic diseases
such as cancer. In recent years, much work has been carried out to find
inhibitors of
angiogenesis, in hopes of developing treatments for such disorders.

WO 2004/063330 discloses (2-carboxamido)(3-amino)thiophene compounds for
the treatment of cancer.

US patent 6,448,277 (Novartis) discloses and claims certain benzamide
derivatives
for inhibition of VEGF receptor tyrosine kinase, tumor growth, and VEGF-
dependent cell
proliferation.

Published PCT application WO 02/066470 (Amgen) broadly discloses
heterocycles containing amido and amino substituent groups, for prophylaxis
and
treatment of angiogenesis-mediated diseases. Published PCT application WO
2004/005279 (Amgen) discloses certain substituted anthranilic amide
derivatives for the
prophylaxis and treatment of angiogenesis-mediated diseases. Published PCT
application
WO 2004/007458 (Amgen) relates to substituted 2-alkylamine nicotinic amide
derivatives
and their uses in treatment of cancer and other disorders.

Published PCT application WO 00/27819 (Schering) discloses certain anthranilic
acid amides for treatment of diseases that are triggered by angiogenesis.
Published PCT
application WO 02/090352 (Schering) relates to selective anthranilamide
pyridine amides
as inhibitors of VEGFR-2 and VEGFR-3. Published PCT application WO 01/81311
(Schering) relates to substituted benzoic acid amides and use thereof for the
inhibition of
angiogenesis.
1


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
Anthranilamides as angiogenesis inhibitors have been discussed in a series of
research papers by scientists at Novartis and Schering. See Manley, et al., J.
Med. Chem.,
45, 5687-5693 (2002); Furet, et al., Bioorganic & Medicinal Chemistry Letters,
13, 2967-
2971 (2003); Manley, et al., Cell. Mol. Biol. Lett., 8, 532-533 (2003); and
Manley, et al.,
Biochimica et Biophysica Acta, 1697, 17-27 (2004).

EP-B-832 061 discloses benzamide derivatives and their use as vasopressin
antagonists.

The present invention relates to a compound of Formula (I)
0
N~ I H,Ar

N NH
H3C
H IX~R
wherein

Ar is selected from the group consisting of
x
O F
O F
F
xo
F
FF
~
):D;O
F F
Ol CF3

2


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
S, CF3

and

/
* ~ I O,CF3
X is CH or N;
Rl is selected from the group consisting of
H,
halogen,
O
*-NR1-2
R1-3
O
*AN ~R1-4
R1-3
*-N~R1-5

R1-3
and
O
R1-6
*_N N,

R1-3 R1-3

wherein
R1-2 is selected from the group consisting of
= H,

= (C1-C4)alkoxy,
= (Cl-C4)alkyl,
wherein said (Cl-C4)alkyl can be substituted with 0, 1, or 2
groups independently selected from
- hydroxy,
- (C1-C4)alkylamino,
- (Cl-C4)acyloxy,
- (C1-C4)alkoxy, and

3


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
-(Ca-C4)alkoxy substituted with 0,1 or 2(Cl-C4)alkoxy
groups,
- wherein said (Cl-C4)alkyl is independently optionally
substituted with F up to the perfluoro level,

= 5- or 6-membered heteroaryl,
or

= phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano;
R1"3 is H or (C1-C4)alkyl;
Rl"4, R1-5 and R1"6 are independently selected from the group consisting of
= H,

= indan-5-yl,

= phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano,

= 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups
selected from
- cyano,
- halo,
- nitro,
- (Cl-C4)alkyl,
wherein said (Cl-C4)alkyl is optionally substituted with 0, 1,
or 2 groups selected from
(Cl-Qalkylamino,
(C1-C4)acyloxy,
(Cl-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2(Cl-
C4)alkoxy groups,

= (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from
(C1-C4)alkyl, (C1-C4)alkoxy, cyano, and halo,
and
= (C1-C6)alkyl,

4


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
wherein said (Cl-C6)alkyl is independently substituted with 0 or
1 group selected from
- NH2,
- (C1-C4)alkoxy,
- (C2-C4)alkoxy independently substituted with
0,1, 2 or 3(Cl-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up to the
perfluoro level,
- carboxyl,
- (Cl-C4)alkoxycarbonyl
- (CI-C4)alkylamino,
- aminocarbonyl,
- (C1-C4)alkylsulfonyl,
- phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and
cyano,
- 5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (Cl-
C4)alkoxy, cyano, halo, and nitro
and
- heterocyclyl independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)a1ky1, (C1-C4)alkoxy, cyano,
and halo,
- and wherein said (Cl-C6)alkyl is independently substituted
with 0, 1 or 2 OH or halo groups,
- and wherein said (C1-C6)alkyl is independently optionally
substituted with F up to the perfluoro level;
and
R1"3 and Rl-4, Rl"3 and R1-5 , and R1"3 and Rl"6
, when attached to the same
nitrogen atom, may form, together with the N atom to which they
are attached, a 5- or 6-membered saturated heterocyclic ring



CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and
piperizinyl optionally substituted on N with (Cl-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions which comprise a
compound of Formula (I) as defined above plus a pharmaceutically acceptable
carrier.
In addition, the invention relates to a method of treating cancer coinprising
administering to a subject in need thereof an effective amount of a compound
of Formula
(I) as defined above.

Pharmaceutically acceptable salts of the compounds (1) include acid addition
salts of
mineral acids, carboxylic acids and sulphonic acids, for example salts of
hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic
acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic
acid, acetic acid,
propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric
acid, maleic acid and
benzoic acid.

Pharmaceutically acceptable salts of the compounds (1) also include salts of
customary bases, such as for example and preferably alkali metal salts (for
example sodium
and potassium salts, alkaline earth metal salts (for example calcium and
magnesium salts)
and ammonium salts derived from ammonia or organic amines having 1 to 16
carbon atoms,
such as illustratively and preferably ethylamine, diethylamine, triethylamine,
ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-
methylmorpholine,
dihydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.

Solvates for the puiposes of the invention are those forms of the compounds
that
coordinate with solvent molecules to form a complex in the solid or liquid
state. Hydrates are
a specific form of solvates, where the coordination is with water.

6


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For the purposes of the present invention, the substituents have the following
meanings, unless otherwise specified:

The terms "halogen" and "halo" mean Cl, Br, F and I, where Cl, Br and F are
preferred.

The terms "(C1-C4)alkyl" and "(C1-C6)alkyl" mean a linear or branched
saturated
carbon group having from about 1 to about 4 C atoms or from about 1 to about 6
C atoms,
respectively. Such groups include but are not limited to methyl, ethyl, n-
propyl, isopropyl,
n, butyl, isobutyl, sec-butyl, tert-butyl, and the like.

The term "(C3-C6)cycloalkyl" means a saturated carbocyclic ring group having
from about 3 to about 6 C atoms. Such groups include but are not limited to
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "(Cl-C4)alkoxy" means a linear or branched saturated carbon group
having from about 1 to about 4 C atoms, said carbon group being attached to an
0 atom.
The 0 atom is the point of attachment of the alkoxy substituent to the rest of
the molecule.
Such groups include but are not limited to methoxy, ethoxy, n-propoxy,
isopropoxy, and
the like.

The term "(Cl-C4)alkylamino" means an amino group having from one or two
(independently selected) (Cl-C4)alkyl substituents, illustratively
representing methylamino,
ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-
hexylamino,
N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylaniino, N-methyl-N-
n-propylamino, N-isopropyl-N n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-

n-pentylamino, N-n-hexyl N-methylamino and the like.

The term "(C1-C4)alkylsulfonyl" means a sulfonyl group having a(C1-C4)alkyl
substituent, illustratively representing methylsulfonyl, ethyl sulfonyl,
isopropylsulfonyl, t-
butylsulfonyl, and the like.

7


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The term "(Cl-C4)alkoxycarbonyl" means a(C1-C4)alkoxygroup bound to the C
atom of a carbonyl group[ -C(O) - ]said group being bound to the rest of the
molecule,
illustratively representing methoxycarbonyl, ethoxycarbonyl, fz-
propoxycarbonyol, i-
propoxycarbonyl, t-butoxycarbonyl, and the like

The term "(Cl-C4)acyloxy" means a(Cl-C4)group bound to the C atom of a
carboxyl group [-C(O)O- ], said group being bound by the oxygen atom to the
rest of the
molecule illustratively representing formyloxy, acetyloxy (acetoxy),
propanoyloxy,
butanoyloxy, t-butanoyloxy and the like

The term "5- or 6-membered heteroaryl" means, respectively,
(1) an aromatic ring made of 5 atoms and having 1, 2, 3 or 4 heteroatom(s)
each selected
independently from 0, N, and S, the rest being C atoms, with the proviso that
there
can be no more than 10 or S atom in the heteroaryl. This heteroaryl is
attached to the
core molecule at any available C or N atom and is optionally substituted at
any
available C or N atom with the recited substituents. Such groups include
pyrrole,
furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole,
isothiazole,
triazole, oxadiazole, thiadiazole, and tetrazole in all their possible
isomeric forms;
or
(2) an aromatic ring made of 6 atoms, 1, 2, or 3 of which are N atoms, the
rest being C,
where the heterocycle is attached to the core molecule at any available C atom
and is
optionally substituted at any available C atom with the recited substituents.
Such
groups include pyridine, pyrimidine, pyridazine and triazine in all their
possible
isomeric forms.

The term "heterocyclyl" means a 5-or 6- membered saturated or partially
saturated
heterocyclic ring containing 1-2 heteroatoms selected from 0, S or N, the
remaining atoms
being made up of C atoms, with the proviso that when there are 2 0 atoms they
must be
nonadjacent. This heterocycle is attached to the core molecule at any
available C or N
atom and is optionally substituted at any available C or N atom with the
recited
substituents. Such groups include pyrrolidine, tetrahydrofuryl,
tetrahydrothienyl,
piperidinyl, tetrahydropyranyl, tetrahydrothiopyrano, piperizinyl,
imidazolinyl,
pyrazolinyl, morpholinyl, thiomorpholinyl and the like in all their possible
isomeric forms.
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A * symbol next to a bond denotes the point of attachment in the molecule.

The compounds of this invention may contain one or more asymmetric centers,
depending upon the location and nature of the various substituents desired.
Asymmetric
carbon atoms may be present in the (R) or (S) configuration. It is intended
that all possible
stereoisomers (including enantiomers and diastereomers) are included within
the scope of
the present invention. Preferred compounds are those with the absolute
configuration of
the compound of this invention which exhibits the more desirable biological
activity.
Separated, pure or partially purified stereoisomers or racemic mixtures of the
compounds
of this invention are also included within the scope of the present invention.
The
purification of said isomers and the separation of said stereoisomeric
mixtures can be
accomplished by standard techniques known in the art.

In another embodiment, the invention relates to a compound of Formula (I),
wherein

Ar is selected from the group consisting of
x
p F
0 F
F
F
O F F
O
F F

/ I o'CF3

,
S, CF3

and

9


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
/

* ~ I O'CF3
X is CH or N;

Rl is selected from the group consisting of
O
*-N'k R1-2
R1-3
O
R1-4
* N
R1-3
*-N iR1-5
R1-3
and
O
R1-6
R1-3 R1-3

wherein
R1-2 is selected from the group consisting of
= (Cl-C4)alkyl,
wherein said (Cl-C4)alkyl is substituted with 1 or 2 groups
independently selected from
- hydroxy,
- (C1-C4)alkylamino,
- (Cl-C4)acyloxy,
- (Cl-C4)alkoxy, and
- (C2-C4)alkoxy substituted with 0,1 or 2(C1-C4)alkoxy
groups,
- wherein said (C1-C4)alkyl is independently optionally
substituted with F up to the perfluoro level,

= 5- or 6-membered heteroaryl,


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
or

= phenyl substituted with 1 or 2 groups independently selected
from (Cl-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and cyano;
R1"3 is H or (Cl-C4)alkyl;
R1-4 and R1-5 are independently selected from the group consisting of
= indan-5-yl,

= phenyl substituted with 1 or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,

= 5- or 6-membered heteroaryl substituted with 1 or 2 groups
selected from
- cyano,
- halo,
- nitro,
- (Cl-C4)alkyl,
wherein said (Cl-C4)alkyl is optionally substituted with 0, 1,
or 2 groups selected from
(C1-C4)alkylamino,
(C1-C4)acyloxy,
(Cl-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2(Cr-
C4)alkoxy groups,

=(C3-C6)cycloalkyl substituted with 1 or 2 groups selected from
(Cl-C4)alkyl, (C1-C4)alkoxy, cyano, and halo,
and
= (Cl-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with 1
group selected from
- NH2,
- (C1-C4)alkoxy,
- (C2-C4)alkoxy independently substituted with
0,1, 2 or 3(Cl-C4)alkoxy and OH groups,

11


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and

independently optionally substituted with fluorine up to the
perfluoro level,
- carboxyl,
- (Cl-C4)alkoxycarbonyl
- (Cl-C4)alkylamino,
- aminocarbonyl,
- (Cl-C4)alkylsulfonyl,
- phenyl substituted with 0, 1, or 2 groups independently
selected from (C1-C4)alkyl, halo, nitro, (Cl-C4)alkoxy and
cyano,

- 5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro
and
- heterocyclyl independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (Cl-C4)alkoxy, cyano,
and halo,
- and wherein said (Cl-C6)alkyl is independently substituted
with 0, 1 or 2 OH or halo groups,
- and wherein said (Cl-C6)alkyl is independently optionally
substituted with F up to the perfluoro level;
R1"6 is selected from the group consisting of
= H

= indan-5-yl,

= phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,

= 5- or 6-membered heteroaryl substituted with 0,1 or 2 groups
selected from
- cyano,
- halo,
- nitro,
- (Cl-C4)alkyl,
12


CA 02610509 2007-11-30
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wherein said (Cl-C4)alkyl is optionally substituted with 0, 1,
or 2 groups selected from
(C1-C4)alkylamino,
(Cl-C4)acyloxy,
(C1-C4)alkoxy,
and

(C2-C4)alkoxy substituted with up to 0, 1 or 2(C1-
C4)alkoxy groups,

= (C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from
(C1-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo,
and
= (C1-C6)alkyl,

wherein said (Cl-C6)alkyl is independently substituted with 0 or
1 group selected from
- NH2,
- (Cl-C4)alkoxy,
- (C2-C4)alkoxy independently substituted with
0,1, 2 or 3(C1-C4)alkoxy and OH groups,
and

independently optionally substituted with fluorine up to the
perfluoro level,
- carboxyl,
- (C1-C4)alkoxycarbonyl
- (C1-C4)alkylamino,
- aininocarbonyl,
- (C1-C4)alkylsulfonyl,
- phenyl substituted with 0, 1, or 2 groups independently
selected from (Cl-C4)alkyl, halo, nitro, (C1-C4)alkoxy and
cyano,

- 5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (C1-C4)alkyl, (C1-
C4)alkoxy, cyano, halo, and nitro
and
13


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- heterocyclyl independently substituted with 0, 1, 2 or 3
groups selected from (Cl-C4)alkyl, (Cl-C4)alkoxy, cyano,
and halo,

- and wherein said (C1-C6)alkyl is independently substituted
with 0, 1 or 2 OH or halo groups,
- and wherein said (C1-C6)alkyl is independently optionally
substituted with F up to the perfluoro level;
and
Rl 3 and Rl"4, Rl_3 and R1-5, and R1-3 and Rl 6, when attached to the same
nitrogen atom, may form, together with the N atom to which they
are attached, a 5- or 6-membered saturated heterocyclic ring
selected from pyrrolidinyl, morpholinyl, thiomorpholinyl and
piperizinyl optionally substituted on N with (Cl-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

In another einbodiment, the invention relates to a compound of Formula (I),
wherein

Ar is selected from the group consisting of
OcX

~ F
/ O F
~
F
o-f F F
O
F F

Ol CF3
and
14


CA 02610509 2007-11-30
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S, CF3
*~ =
X is CH;
Rl is selected from the group consisting of
* R1-5

R1-3
and
O
R1-6
*_N N,

R1-3 R1-3

wherein
R1-3 is H or (C1-C4)alkyl,
R1-5 is selected from the group consisting of
indan-5-yl,
phenyl substituted with 1 or 2 groups independently selected from
(C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl substituted with 1 or 2 groups selected
from
cyano,
halo,
nitro,
(C1-C4)alkyl,
wherein said (Cl-C4)alkyl is optionally substituted
with 0, 1, or 2 groups selected from
(Cl-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2(C1-C4)alkoxy
groups;
(C3-C6)cycloalkyl substituted with 1 or 2 groups selected from (Cl-
C4)alkyl, (C1-C4)alkoxy, cyano, and halo;



CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
and
(Cl-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with lgroup
selected from
NH2,
(Cl-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(C1-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up
to the perfluoro level,
carboxyl,
(C 1-C4) alkoxycarbonyl
(Cl-C4)alkylamino,
aminocarbonyl,
(Cl-C4)alkylsulfonyl,
phenyl substituted with 0, 1, or 2 groups independently
selected from (Cl-C4)alkyl, halo, nitro,
(C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (Cl-C4)a1ky1, (Cl-
C4)alkoxy, cyano, halo, and nitro
and
heterocyclyl is independently substituted with 0, 1, 2 or 3
groups selected from (Cl-C4)alkyl, (C1-C4)alkoxy,
cyano, and halo,
and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (C1-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;
Ri-6 is selected from the group consisting of
16


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
H,
indan-5-yl,
phenyl substituted with 0, 1, or 2 groups independently selected
from (C1-C4)alkyl, halo, nitro, (C1-C4)alkoxy and cyano,
5- or 6-membered heteroaryl substituted with 0, 1 or 2 groups
selected from
cyano,
halo,
nitro,
(C1-C4)alkyl,
wherein said (C1-C4)alkyl is optionally substituted
with 0, 1, or 2 groups selected from
(Cl-C4)alkylamino,
(C1-C4)acyloxy,
(C1-C4)alkoxy,
and
(C2-C4)alkoxy substituted with up to 0, 1 or 2(Cl-C4)alkoxy
groups;
(C3-C6)cycloalkyl substituted with 0,1 or 2 groups selected from
(Cl-C4)alkyl, (Cl-C4)alkoxy, cyano, and halo;
and
(Ci-C6)alkyl,
wherein said (Cl-C6)alkyl is independently substituted with 0 or 1
group selected from
NH2,
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(Cl-C4)alkoxy and OH groups,
and
independently optionally substituted with fluorine up
to the perfluoro level,
carboxyl,
(C 1-C4)alkoxycarbonyl
17


CA 02610509 2007-11-30
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(Cl-C4)alkylamino,
aminocarbonyl,
(Cl-C~)alkylsulfonyl,
phenyl substituted with 0, 1, or 2 groups independently
selected from (Cl-C4)alkyl, halo, nitro,
(Cl-C4)alkoxy and cyano,
5- or 6-membered heteroaryl independently substituted with
0, 1, 2 or 3 groups selected from (Cl-C4)alkyl, (Cl-
C4)alkoxy, cyano, halo, and nitro
and
heterocyclyl is independently substituted with 0, 1, 2 or 3
groups selected from (C1-C4)alkyl, (Cl-C4)alkoxy,
cyano, and halo,
and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (Cl-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;
and
R1-3 and R1-5, and Rl 3 and R1"6, when attached to the same nitrogen atom,
may form, together with the N atom to which they are attached, a 5-
or 6-membered saturated heterocyclic ring selected from
pyrrolidinyl, morpholinyl, thiomorpholinyl and piperizinyl
optionally substituted on N with (Cl-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of Formula (I)
Ar is selected from the group consisting of

18


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
F

iaoT O F
F
F

F F
/ IOt
* \ O

F F
O, CF3
and

S, CF3
*~ .
X is CH;
Rl is selected from the group consisting of
*_N"IR1-5

R1-3
and
O
R1-6
*_N N>

R1-3 R1-3

wherein
R1-3 is H,
R1-5 is (C1-C6)alkyl,

wherein said (C1-C6)alkyl is independently substituted with 1 group
selected from
(Cl-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, or 2(C1-C4)alkoxy and OH groups,
and

independently optionally substituted with fluorine up
to the perfluoro level,
and

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CA 02610509 2007-11-30
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wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (C1-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;
R1-6 is selected from the group
H,
and
(C1-C6)alkyl,
wherein said (Cl-C6)alkyl is independently substituted with
0 or 1 group selected from
(Cl-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(Cl-C4)alkoxy and OH groups,
and
independently optionally substituted with
fluorine up to the perfluoro level,
and
wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (Cl-C6)alkyl is independently optionally substituted
with F up to the perfluoro level;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of Formula (I)
Ar is selected from the group consisting of

::) CO xF



CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
/ O F
* ~ I F
O
F

O F F F

Ol CF3
and

Z1;t1F3.
X is CH;
Rl is selected from the group consisting of
O
R1-6
*_N N.

R1-3 R1-3

wherein
R1-3 is H,
R1-6 is selected from the group
H,
and
(Ci-C6)alkyl,
wherein said (C1-C6)alkyl is independently substituted with
0 or 1 group selected from
(C1-C4)alkoxy,
(C2-C4)alkoxy independently substituted with
0,1, 2 or 3(C1-C4)alkoxy and OH groups,
and
independently optionally substituted with
fluorine up to the perfluoro level,
and

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wherein said (C1-C6)alkyl is independently substituted with 0, 1 or 2
OH or halo groups,
and
wherein said (Cl-C6)alkyl is independently optionally substituted with F up to
the
perfluoro level;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a process for making a
compound
of formula (I), comprising

(A) reacting, with or without first hydrolizing the ester group -COOR', a
compound of
formula (VI)
O

ORI
N NH

H3C CH2 X R1
Y, Y
N (VI)
wherein X and Rl have the meaning described above, and R' is lower alkyl,
with a compound of formula Ar-NH2 (VIII),

wherein Ar has the meaning described above, for example in the presence of a
coupling agent such as PyBOP; or

(B) reacting a compound of formula (IX)
O
N~ I H,Ar
N N H2
H3C (IX)

wherein Ar has the meaning described above, with a compound of formula (IV)
22


CA 02610509 2007-11-30
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CHO

X
N~R1 (IV),

wherein X and Rl have the meaning described above, and subsequently reducing
the resulting compound; or

(C) reacting a compound of formula (IX), wherein Ar has the meaning
described above, with a compound of formula (V)
CH2Ig
X
N~Rl (V),
wherein lg represents a leaving group, such as halo, OTs or OMs; or
(D) reacting a compound of formula (IIa)
O
N//X OR'
N N O
H3C R
X
~-R1
_ N (Ra)

wherein X and Rl have the meaning described above, and R' is lower alkyl, with
a
compound of formula (VIII)

ArNH2 (VIII),

wherein Ar has the meaning described above, in the presence of (R')3A1,
wherein
R' is lower alkyl, or

(E) first hydrolizing the ester group -COOR' of a compound of formula (IIa) as
described above, and subsequently reacting the resulting compound with a

23


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compound of formula (VIII) as described above, for example in the presence of
a
coupling agent such as PyBOP.

General Methods of Preparation

Compounds of Formula (I) may be prepared by synthetic procedures known to
those skilled in the art or by methods analogous thereto. These methods are
summarized
below in Reaction Scheme 1.

Unless otherwise specifically defined, Rl and X have the same meanings as
defined hereinabove.

Reaction Scheme 1
24


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WO 2006/133006 PCT/US2006/021550
0
0
N~ ~ OR'
NH2 (BOC)20 Ni I OR'
H3C base N N(BOC)õ
H3C
(III) R' = lower alkyl (VII)
n=1 or 2
CHO

1 I~ X ArNH2 (VI II), (R')3AI
~ Ar-NH2 or
N R1 (VIII)
(IV) 1) hydrolysis
(R')3AI 2) ArNH2 (VIII),
2. reduction coupling agent, e.g.,
or PyBOP
Ig = leaving group, 3) TFA
CH21g e.g., halo, OTs
or OMs 0
I X
N~R1 N I H,Ar
(V) H H2
0 3C N (IX)

Ni I OR
N NH CHO
H3C CH2 X R1 1. X
~ N~R1
(VI) (IV)
2. reduction
Ar-NH2 or
(VIII),
(R')3AI CH21g
or

hydrolysis, 0
N~R1
Ar-NH2 (V)
(VIII) Ni H.Ar
coupling agent, ~N
e.g., PyBOP NH
H3C
H),T X
R1
H

(I)


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
As illustrated in Reaction Scheme 1, two general synthetic routes can be used
to
prepare the compounds of Formula (I).
In one route, the amino group of the compound of Formula (III), is subjected
to
either reductive amination using a pyridine or pyrimidine carboxaldehyde of
Formula (IV)
and a reducing agent, such as sodium triacetoxyborohydride, or to direct N-
alkylation
using a pyridine or pyrimidine methyl halide, tosylate or mesylate of Formula
(V) and a
optional base such as pyridine or K2C03, or a catalyst such as sodium iodide.
The product
formed, Formula (VI), is then allowed to react with an aromatic amine of
Formula (VIII)
in the presence of a coupling agent such as (R')3A1(where R' = lower alkyl)
giving the
compound of Formula (I), or alternatively, the ester of Formula (VI) is
hydrolyzed to the
acid which is then coupled to the amine (VIII) using a coupling agent such as
PyBOP.
In the second route, the compound of Formula (III) is converted to the
aminoamide
of Formula (IX) either directly by reaction with an aromatic amine of Formula
(VIII) as
described above, or by first protecting the amino function, e.g., as a BOC
derivative (VII),
and subsequent coupling with (VIII), either directly with (R')3A1, or via
hydrolysis, and
then coupling in the presence of PyBOP, followed by deprotection. The Formula
(IX)
compound is then converted to the Formula (I) compound using either the
reductive
amination method or direct N-alkylation as described above for preparation of
(VI).
An additional route shown below in Scheme la is also possible. The amino group
of the compound of formula (III) can be acylated using an acylating agent such
as acetic
anhydride and formic acid. N-alkylation of the acylated product Formula (II)
using a
pyridine or pyrimidine methyl halide, tosylate or mesylate of Formula (V) and
a base such
as DBU or K2CO3. The product formed, Formula (IIa), is then allowed to react
with an
aromatic amine of Formula (VIII) in the presence of a coupling agent such as
(R')3Al
(where R' = lower alkyl) giving the compound of Formula (I) after a basic work
up, or
alternatively, the ester of Formula (IIa) is hydrolyzed to the acid in which
the N-formyl
group is also removed which is then coupled to the amine (VIII) using a
coupling agent
such as PyBOP.

26


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Reaction Scheme la

0 0
(RCO)20
OR Base Ni I OR'
NH2 or N NH R
H3C RCOCI H3C ~ Base
(III) (II) O CH21g
I~ X Ig = leaving group,
'= lower alkyl
R
e.g., halo, OT
R1 or OMs

(V)

O
N~ OR'
~N O
,
H3C R
x
-N
(Ila) ZorArNH2 ~ ~~R1
VIII), (R')3AI
O 1) Hydr
olysis & PG removal (OH-)
Ar 2) ArNH2 (VIII),
N s N'
H coupling agent, e.g.,
N NH PyBOP
H3C
H ),,IX
H I
(I)

Starting materials of Formulae (III), (IV), (V) and (VIII) are commercially
available (e.g., Lanxess, Germany) or may be prepared by standard means well
known in
the art, or as described in Reaction Schemes 2-8.
Reaction Scheme 2
CI 0 CI
X CIxRi-2

N NH2 N" NR1_2
(X) (Va)
27


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Compounds of Formula (Va),
O
*-Nj~ R1-2
[Formula (V) where Rl is H and lg is Cl], may be prepared as shown in Reaction
Scheme 2 by reaction of an acid chloride with a chloromethyl heteroarylaniine
of Formula
(X), generally in the presence of a base such as triethylamine.

Reaction Scheme 3

OH Opg Opg
1-5
%~ X R~19
~
N NH2 N NH2 N- NHBOC
(XI) (XII) (XIII)
Opg OH Ig
X X X
-- _~
I N~NH
N~NBOC N~NH
(XIV) R 1-5 1 5 R1-5
l
(XV) R (Vb)
pg = protecting group, e.g., BOC

Ig = leaving group, e.g., halo, MsO, etc.

R1-5
Compounds of Formula (Vb) [Formula (V) where R' is H ], can be
prepared as shown in Reaction Scheme 3 from hydoxymethylheteroaryl amines of
Formula (XI). Protection of the alcohol and conversion to the BOC-derivative
of Formula
(XIII) is followed by N-alkylation to give the intermediate of Formula (XIV).
Deprotection of the alcohol and amine, followed by conversion of the hydroxy
group to a
leaving group, (for example, using SOC12, when lg is Cl) gives the
intermediate of
Formula (Vb).

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Reaction Scheme 4
O OR' OH

X LiBH4 X (R1-3)(R1-5)NH
N" CI N CI
(XVI) (XVII)
OH ig
X
-~ I X
NNR1-3R1-5 N111, NRi-3R1-5
(XVIII) (Vc)

R' = lower alkyl

Ig = leaving group, e.g., halo, MsO
Ri-5
*

Compounds of Formula (Vc) [Formula (V) where Rl is 1R1-3 ] can be prepared
by the route illustrated in Reaction Scheme 4. The chloroheteroarylcarboxylic
acid
derivative of Formula (XVI) is reduced to the chloroheteroaryl alcohol of
Formula (XVII)
with a standard reagent such as lithium borohydride. Reaction of the chloro
compound
with an amine of Formula (Rl-3)(R1-s)NH gives the intermediate alcohol of
Formula
(XVIlI). Conversion of this alcohol to a leaving group, e.g. mesylate,
completes the
synthesis of the compound of Formula (Vc)
Reaction Scheme 5
O OH O OH O OH
X H+ X NH4OAc X
~
NO R'OH N-~YO NH4CI N~O
OH OR' NH2
(XIX) (XX) (XXI)

O OMe OH Ig
Mel X NaBH4 X Ig-halo X
~ I I N O base N O
Na2CO3 N~ O
NH2 NH2 NH2
(XXII) (XXIII) (Vd)
29


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WO 2006/133006 PCT/US2006/021550
0
Compounds of Formula (Vd) [Formula (V) where Rl is *A NH2], can be
prepared as shown in Reaction Scheme 5 from the dicarboxylic acid of Formula
(XIX) by
conversion through the half acid ester (XX) to the acid amide of Formula
(XXI).
Esterification of (XXI) provides (XXII) which can be reduced with sodium
borohydride to
the alcohol (XXIII) and then converted to the Formula (Vd) compound, using for
example
MsCI and a base such as triethylamine.

Reaction Scheme 6
0 OEt O OEt
N N- O
NH2
(XXIV) (XXII)

An alternate method of preparing the pyridine amide ester of Formula (XXII) is
via
the Minisci reaction shown in Reaction Scheme 6 in which the pyridine
carboxylic acid
ester is stirred in formamide with cooling to 10 C in the presence of an
equivalent of
concentrated H2SO4, FeSO4 and H,,02.

Reaction Scheme 8
CI CI
I x R1-6NC0 X O

N NH or N N~N~R1-6
R13 R1-6R1-3NCOCI R1-3 R1-3
(X) (Vf)
O
R1-6
1- 1
Compounds of Formula (Vf) [Formula (V) where Rl is R1 3 R1-3 ] can be prepared
by
the route shown in Reaction Scheme 8. In the case that the R1-3 on the right
is H, the
intermediate of Formula (X) is allowed to react with an isocyanate of Formula
R1-6NC0 in
an aprotic solvent such as dichloromethane. In the case that the R1-3 on the
right is alkyl,
or that R1-3 and R1-6 are combined in a cyclic structure, the intermediate of
Formula (X) is
allowed to react with a carbamoyl chloride Formula R1-6 R1-3NCOC1 in an
aprotic solvent



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such as dichloromethane in the presence of a base such as triethylamine or
potassium
carbonate. The use of a starting material of Formula (X) in which the R1-3 on
the left is
O
R1-6
*_N N,

alkyl results in the preparation of a urea of structure (Vf) where Rl is R1 3
R1-3 in
which the R1-3 group on the left is alkyl.
In the cases that the isocyanate of Formula R1-6NC0 is not commercially
available
(and R1"3 is H on the right side), it can conveniently be prepared by
treatment of the amine
of Formula R1"6NH2, wherein Rl"6 is aryl or heteroaryl, with phosgene,
diphosgene or
triphosgene in a suitable solvent such as ethyl acetate. When R1-6 is alkyl or
substituted
alkyl, the preferred method is to treat the corresponding alkyl halide or
dialkyl sulfate with
inorganic cyanates. These methods, as well as others, are well known to those
skilled in
the art and examples are described in S. R. Sandler and W. Karo "Organic
Functional
Group Preparations," vol 12, 2"d ed., p 364-375, 1983, Academic Press and
references
cited therein.
In the cases that the carbamoyl chloride of Formula Rl"6 Rl-3NCOC1 is not
commercially available, it can conveniently be prepared by treatment of the
amine of
Formula Rl"6 Rl"3NH with phosgene, diphosgene or triphosgene in a suitable
solvent such
as dichloromethane at 0-4 C. Optionally, the N-benzyl protected amine of
Formula Rl"6
R1"3NCH2(C5H6) can be reacted with triphosgene as described by M.G. Banwell,
et al, J.
Org. Cheni. 2003, 68, 613-616.

A variety of compounds of Formula (I) can be prepared by elaboration of
compounds, also of Formula (I), prepared by the above schemes. These
elaboration
methods are illustrated below in Reaction Schemes 10-13.

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Reaction Scheme 10
O
Ns I H'Ar
N NH
H3C

X CH3
NN ~
~
NH2OH (Ij) H3C

O O
N, H'Ar O H'Ar
N NH CI11~ R1-2 N NH
H3C H3C

O
1-2
N" NH2 N" 'N R
H
(Ia) (Ib)

R1 6NCO
~IS-Ria

O 0
H'Ar N N,Ar
H
H C NH HCN NH
3 g
X X
~ 0 I 0
N N'SR1 7 NNN,R1 6
(Ic) H (Id) H H

For example, the dimethyl pyrrole compound of Formula (Ij) is made by coupling
[2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yl]methyl methanesulfonate with 5-
amino-N-
(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide as
shown in
Scheme 1. [2-(2,5-dimethyl-IH-pyrrol-1-yl)pyridin-4-yl]methyl methanesulfonate
is made
by coupling (2-aminopyridin-4-yl)methanol with hexane-2,5-dione using
catalytic acid
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and then mesylation of the alcohol produced. The dimethyl pyrrole compound of
Formula
(Ij), can be deprotected to give a compound of Formula (Ia).

The amine can then be converted to the amide compound of Formula (Ib), the
sulfonamide of Formula (Ic) or the urea of Formula (Id) as shown in Reaction
Scheme 10,
by reaction with an acid chloride, sulfonyl chloride or isocyanate,
respectively.

Reaction Scheme 11

O O
,Ar
N
11 N,Ar 200 OC 0:1
N I H Pyridine N H
' N sealed tube N N
H3C H3C
\X (R1-3)(R1-5)NH X
I I
i5
R
NCI N '
I
(le) Ri 3
(If)
Additionally, the chloro compound of Formula (Ie) can be converted to the
substituted amino compound of Formula (If) by reaction with an amine and a
base such as
pyridine in a sealed tube at elevated temperatures.

Reaction Scheme 12
O
O
N N.Ar
Ar
,N N~ I HAr I H
'N
NH
HsC H3C NH R1-4R1-aNH H3C HN
X DMF-DMA

N~ ~ O N
N
NH
2 NR1-3R1 4
OCH3
(19) (Ih) (I~)

Esters of Formula (Ih) and substituted amides of Formula (Ii) may be prepared
from the unsubstituted amide of Formula (Ig) by the sequence illustrated in
Reaction
Scheme 12. Reaction of the amide (Ig) with dimethylformamide-dimethylacetal
(DMF-
DMA) in methanol provides the ester of Formula (Ih); reaction of the ester
with a
substituted amine gives the amide of Formula (Ii).

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Generally, a desired salt of a compound of this invention can be prepared in
situ
during the final isolation and purification of a compound by means well known
in the art.
Or, a desired salt can be prepared by separately reacting the purified
compound in its free
base form with a suitable organic or inorganic acid and isolating the salt
thus formed.
These methods are conventional and would be readily apparent to one skilled in
the art.
Additionally, sensitive or reactive groups on the compound of this invention
may
need to be protected and deprotected during any of the above methods.
Protecting groups
in general may be added and removed by conventional methods well known in the
art (see,
for example, T. W. Greene and P.G.M. Wuts, Protective Groups in Organic
Synthesis;
Wiley: New York, (1999).

By using the general schemes illustrated above and choosing the appropriate
starting materials the compounds of the invention may be prepared. To further
illustrate
the invention, the following specific examples are provided, but are not meant
to limit the
scope of the invention in any way.

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A. Examples

Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure, they have
the following meaning:
bm broad multiplet
BOC t-butoxycarbonyl
bp boiling point
bs broad singlet
bt broad triplet
CD3CN acetonitrile-d3
CD3OD methanol-d4

Celite0 registered trademark of Celite Corp. brand of diatomaceous earth
d doublet
DMSO-d6 dimethylsulfoxide-d6
DMF N,N dimethylformamide
EtOAc ethyl acetate
h hour(s)
1H NMR proton nuclear magnetic resonance
HPLC high performance liquid chromatography
LCMS liquid chromatography / mass spectroscopy
.min minute(s)
ML inilliliter(s)
Ms methanesulfonyl
nilz mass to charge ratio
PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate
rt room temperature
RT retention time (HPLC or LCMS)
s singlet
t triplet
TFA trifluoroacetic acid
THF tetrahydrofuran



CA 02610509 2007-11-30
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TLC thin layer chromatography
Ts p-toluenesulfonyl
General Analytical Procedures

The stiucture of representative compounds of this invention were confirmed
using
the following procedures.

Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard
5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph
with a J & W DB-5 column (0.25 M coating; 30 m x 0.25 mm). The ion source is
maintained at 250 C and spectra were scanned from 50-800 amu at 2 sec per
scan.
High pressure liquid chromatography-electrospray mass spectra (LC-MS) were
obtained using either a:

(A) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable
wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A),
and a
Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra
were
scanned from 120-1200 amu using a variable ion time according to the number of
ions in
the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B:
2%
water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over
3.5 min
at a flowrate of 1.0 mL/min is used with an initial hold of 0.5 min and a
final hold at 95%
B of 0.5 min. Total run time is 6.5 min.
or
(B) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215
Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2 x 23 mm,
120 A),
and a Micromass LCZ single quadrupole mass spectrometer with z-spray
electrospray
ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD
(Evaporative Light Scattering Detector) data is also acquired as an analog
channel. The
eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in
acetonitrile
with 0.018% TFA. Gradient elution from 10% B to 90% over 3.5 min at a flowrate
of 1.5
mL/min is used with an initial hold of 0.5 rnin and a final hold at 90% B of
0.5 nzin. Total
run time is 4.8 min. An extra switching valve is used for colun-m switching
and
regeneration.

Routine one-dimensional NMR spectroscopy is performed on 400 MHz Varian
Mercury-plus spectrometers. The samples were dissolved in deuterated solvents
obtained
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WO 2006/133006 PCT/US2006/021550
from Cambridge Isotope Labs, and transferred to 5 mm ID Wilmad NMR tubes. The
spectra were acquired at 293 K. The chemical shifts were recorded on the ppm
scale and
were referenced to the appropriate solvent signals, such as 2.49 ppm for DMSO-
d6, 1.93
ppm for CD3CN, 3.30 ppm for CD3OD 5.32 ppm for CD2C12 and 7.26 ppm for CDC13
for
1H spectra.

Preparation of Intermediates

Intermediate A
Preparation of 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-
pyrazole-4-carboxamide
O XF
N~ ~ H O
N NH2
H3C
Step 1: Preparation of ethyl 5-fbis(tert-butoxycarbonyl)aminol-l-methyl-lH-
pyrazole-
4-carboxylate
0
~-CH3

N/ I oC CH
N N4 H
~G~3

H3C O~ C CH
0 C3

HH3
C3
Ethyl 5-amino-l-methyl-lH-pyrazole-4-carboxylate (4.7 g, 27.78) in
dichloromethane (100 mL) was stirred under nitrogen in a 500 mL flask as di-
tert-butyl
dicarbonate (7.88 g, 36.11 mmol) was added followed by N,N-dimethylpyridin-4-
amine
(339 mg, 2.78 mmol). The solution was stirred for 16 h. An additonal 5 g of di-
tert-butyl
dicarbonate was added and the solution was stirred for an additional 2 h. Very
little
starting material remained at this point and the solvents were evaporated to
give a residue
that was purified using silica gel. Products were eluted with a gradient from
0-80 % ethyl
acetate in hexane to yield 8.1 g (79%) of the title pure material.
1H NMR (300 MHz, CD2C12-d2) 8 7.85 (s, 1H), 4.25 (q, 2H), 2.68 (s, 3H), 1.40
(s,
18H), 1.30 (t, 3H); ES-MS nilz 370.0 [M+H]+, LCMS RT (min) 3.17.

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Step 2: Preparation of 5-[(tert-butox carbonyl)aminol-l-methyl-lH-Pyrazole-
4-carboxylic acid
O
N/ I OH
N H3 CONH
ZZ~ O CH3
CHH3
3
A solution of ethyl5-[bis(tert-butoxycarbonyl)amino]-1-methyl-lH-pyrazole-
4-carboxylate (8.0 g, 21.66 mmol) in ethanol (100 mL) was stirred under
nitrogen as
aqueous 1 N sodium hydroxide (108 mL) was added. The resulting mixture was
stirred at
50 C for 64 h, cooled to ambient temperature and then evaporated in vacuo.
The pH was
adjusted to 5-6 by slow addition of 2 N aqueous HCl. The product was extracted
with
ethyl acetate and then a 20% inixture of isopropanol in dichloromethane. The
combined
extracts were dried (Na2SO4) and evaporated in vacuo, and then toluene was
added to the
residue which was evaporated again to yield 3.5 g (67%) of pure dry product
ready for the
next step.

1H NMR (300 MHz, CD3OD-d4) b 7.82 (s, 1H), 3.75 (s, 3H), 1.5 (s, 9H); ES-MS
rn/z
241.9 [M+H]+, LCMS RT (min) 1.81.

Step 3: Preparation of 5-amino-N-(2 2-difluoro-1 3-benzodioxol-5- 1-1-methyl-
IH-
pyrazole-4-carboxamide
O XF
N H
O
O
D
N NH2
H3C

A solution of 5-[(tert-butoxycarbonyl)amino]-1-methyl-lH-pyrazole-
4-carboxylic acid (1 g , 4.15 mmol), 2,2-difluoro-1,3-benzodioxol-5-amine (861
mg, 4.97
rnmol), triethylamine (1.19 mL, 8.55 mmol) and (1H-1,2,3-benzotriazol-l-
yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP, 2.15 g, 4.15
mmol)
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in anhydrous dimethylformamide (20 mL) and dichloromethane (1 mL) was stirred
at 60
C for 12 h under nitrogen and then cooled. The resulting solution was diluted
with ethyl
acetate and washed with water and then saturated brine. The organic layer was
dried
(Na2SO4) and evaporated in vacuo. The resulting residue was chromatographed
using
silica gel with 0 - 100% ethyl acetate in hexane to yield tert-butyl (4-{
[(2,2-difluoro-l,3-
benzodioxol-5-yl)amino]carbonyl}-1-methyl-lH-pyrazol-5-yl)carbamate (500 mg,
>60%
in purity) which was dissolved in dichloromethane (5 mL) and trifluoroacetic
acid (3 mL)
and was stirred under nitrogen for 2 h and evaporated in vacuo. The residue
was dissolved
in ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase
was
dried (NkSO4), evaporated in vacuo and purified using silica gel with 0-80 %
ethyl
acetate in hexanes to yield 250 mg of the title compound.

1H NMR (300 MHz, CD3OD-d4) 8 7.85 (bs, 1H), 7.70 (s, 1H), 7.25 (dd, 1H),
7.10(dd,
1H), 3.60 (s, 3H); ES-MS nt/z 297.2 [M+H]+, LCMS RT (inin) 3.03.

Intermediate B
Preparation of 5-amino-l-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-l,4-
benzodioxin-6-yl)-1H-pyrazole-4-carboxaniide
F
0 / I O F
F
N~ ~ H ~ F
N NH2
H3C
This intermediate can be prepared by using the method described above for the
preparation of Intermediate A but using 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-
benzodioxin-
6-amine rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 3. The pure
product is
characterized by NMR and LCMS spectroscopy.

Intermediate B-2
Preparation of 5-amino-l-methyl-N-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-
6-yl)-1H-p_yrazole-4-carboxamide
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WO 2006/133006 PCT/US2006/021550
O ~ I O F
~
N/ H F F
NH2
H36
This intermediate can be prepared by using the method described above for the
preparation of Intermediate A but using 2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-
6-amine
rather than 2,2-difluoro-1,3-benzodioxol-5-amine in Step 3.

Intermediate B-3
Preparation of 5-amino-l-methyl-N-f4-(trifluoromethox )phenyll-4,5-dihydro-
1H-n_yrazole-4-carboxamide
F
O
j
N,/D H F
H C NH2
3

This intermediate can be prepared by using the method described above for the
preparation of Intermediate A but using 4-(trifluoromethoxy) aniline rather
than 2,2-
difluoro-1,3-benzodioxol-5-amine in Step 3.

Intermediate B-4
Preparation of 5-amino-l-methyl-N-r3-(trifluoromethoxv)phenyll-4,5-dihydro-
1H-u_yrazole-4-carboxamide
O F

N~ I H O F
H C NH2
3

This intermediate can be prepared by using the method described above for the
preparation of Intermediate A but using 3-(trifluoromethoxy)aniline rather
than 2,2-
difluoro-1,3-benzodioxol-5-amine in Step 3.

Intermediate B-5
Preparation of 5-amino-l-methvl-N-{4-f(trifluoromethvl)thiolphenyll-1H-
pyrazole-4-carboxamide


CA 02610509 2007-11-30
WO 2006/133006 PCT/US2006/021550
0 SF
F
N F
N, ~
N NH2
H3C

This intermediate can be prepared by using the method described above for the
preparation
of Intermediate A but using 4-[(trifluoromethyl)thio] rather than 2,2-difluoro-
1,3-
benzodioxol-5-amine in Step 4.

Intermediate C
Preparation of [2-(aminocarbonyl)pyridin-4-y11methyl methanesulfonate
CH
o ~ O 0
V~,N NH2 Step 1: Preparation of ethyl 2-(aminocarbonyl)isonicotinate

OCH3 0

O NH2
N
A solution of ethyl isonicotinate (25.2 mL, 165 mmol) in formamide (200 mL)
was
stirred with ice/methanol bath cooling as concentrated sulfuric acid (8.80 mL,
165 mmol)
was added. Ferrous sulfate heptahydrate (69 g, 248 mmol) and hydrogen peroxide
(25.6
mL of 30% in water) were added slowly over 25 min in alternating portions such
that the
temperature of the mixture was kept between 8-10.5 C. During this addition
small pieces
of dry ice were added to the bath to keep the reaction temperature in the
desired range.
After the addition was complete, the ice bath was removed and the dark mixture
was
stirred for 2 h without cooling. The mixture was then poured into a solution
of trisodium
citrate dihydrate (80.6 g) in water (700 mL) and then residues left in the
reaction flask
were washed out with a little methanol and water. The resulting mixture was
rapidly
stirred in a large flask as solid NaHCO3 was added slowly, portion-wise, until
the mixture
was basic. Some saturated aqueous NaHCO3 was added to make the mixture more
basic
and then it was vacuum filtered through Celite0 and the solids were washed
down with
three 200 mL portions of dichloromethane. The phases of the filtrate were
separated and

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the aqueous layer was extracted twice with dichloromethane. The combined
extract was
dried

(Na2SO4) and evaporated in vacuo. The resulting solid residue was washed with
ether/hexane (200 mL, 1:30) twice with warming and sonication followed by
cooling and
filtration to yield 13.9 g (44%) of pure title compound. The wash solutions,
which
contained some highly contaminated desired product, were discarded.

1H NMR (300 MHz, DMSO-d,) 5 8.83 (d, 1H), 8.39 (d, 1H, meta coupling), 8.24
(bs, 1H), 8.00 (d, 1H), 7.81 (bs, 1H), 4.39 (q, 2H) and 1.37 ppm (t, 3H); ES-
MS m/z 195.0
[M+H]+, HPLC RT (min) 1.83.

Step 2: Preparation of 4-(hydroxymeth yl)pyridine-2-carboxamide
OH O

I ~ NH2
~N

A slurry of ethyl2-(aminocarbonyl)isonicotinate (5.00 g, 25.8 mmol) in
absolute
ethanol (150 mL) was stirred under nitrogen as sodium borohydride (2.92 g,
77.2 mmol)
was added. After 22 h stirring at ambient temperature, the reaction was
carefully
quenched by addition of 17 mL of saturated aqueous ammonium chloride followed
by
stirring until the bubbling stopped and then evaporation in vacuo to leave a
white solid
residue. Saturated aqueous sodium chloride (80 mL) was added followed by five
extractions with 200 mL portions of ethyl acetate. Combined extracts were
dried
(Na2SO4) and evaporated in vacuo to yield 3.85 g (98%) of pure title compound
as a white
solid.

1H NMR (300 MHz, DMSO-d6) b 8.52 (d, 1H), 8.00 (s, 1H), 8.07 (bs, 1H), 7.46
(d,
1H), 7.60 (bs, 1H), 5.54 (t, 1H) and 4.60 ppm (d, 2H); ES-MS m/z 154.0 [M+H,
weak
signal]+, HPLC RT (min) 1.05.

Step 3: Preparation of [2-(aminocarbon~l)pyridin-4-yllmethyl methanesulfonate
CH
O~1
1O 0
I ~ NH2
~N

4-(hydroxymethyl)pyridine-2-carboxamide (1.00 g, 6.57 mmol) was dissolved in
ethyl acetate (80 mL) and then cooled to 0 C with stirring under nitrogen in
an ice bath
42


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before triethylamine (1.37 mL, 9.86 mmol) was added, followed by
methanesulfonyl
chloride (0.66 mL, 8.54 mmol, added dropwise over 7 min). The ice bath was
removed
and the resulting suspension was stirred 2 h, and then the reaction mixture
was poured into
60 mL water and stirred rapidly for 10 min. The phases were separated and the
aqueous
was extracted twice more with ethyl acetate. Each extract was washed with
brine and the
combined extracts were dried (Na2SO4) and evaporated in vacuo to yield 1.50 g
(99%) of
pure product as a fine white solid which turned pink on storage. Re-assay by
NMR after
such color change did not show significant decomposition.

1H NMR (300 MHz, DMSO-d6) 8 8.64 (d, 1H), 8.06 (s, 1H), 8.14 (bs, 1H), 7.6 (d,
1H), 7.70 (bs, 1H), 5.41 (s, 2H) and 3.33 ppm (s, overlaps with water in
solvent).
Intermediate D
Preparation of {2-[(methylamino)carbonyllpyridin-4-yl}methyl methanesulfonate
C H 3
O~O O
I H,CH3
iN

This compound was prepared by using the method described above for
Intermediate C but starting with methyl formamide rather than formamide in
step 1 and
methanesulfonic anhydride rather than methanesulfonyl chloride in step 3.

'H NMR (300 MHz, DMSO-d6) 8 8.80 (bs, 1H), 8.64 (d, 1H), 8.03 (s, 1H), 7.58
(d,
1H), 5.41 (s, 2H), 3.29 (s, 3H) and 2.80 ppm (d, 3H); ES-MS m/z 145.1 [M+H]+,
HPLC
RT (min) 1.43.

Intermediate E
Preparation of 2-{[4-(chloromethyl)pyridin-2-yllamino}-2-oxoethyl acetate
CI H O

I ~ N~OxCH3
N O

Step 1: Preparation of 4-(chlorometh~l)pyridin-2-amine
CI
I ~ NH2

43


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(2-Aminopyridin-4-yl)methanol (11.2 g, 90 mmol) was stirred in a flask with
ice
bath cooling as thionyl chloride (65.8 mL, 902 mmol) was slowly added. After
about 10
mL was added, the temperature increased suddenly to about 50 C and addition
was halted
as the mixture was broken up so that stirring could continue as the rest of
the thionyl
chloride was added. The cooling bath was then removed and the reaction was
stirred for 2
h at ambient temperature before it was evaporated in vacuo and then toluene
was added
twice and evaporated each time in vacuo to yield the hydrochloride salt of the
title
compound. A suspension of this material in dichloromethane (150 mL) was
stirred with
saturated aqueous sodium bicarbonate (150 mL) for 1.5 h. The phases were
separated and
the organic extract was washed twice with water, once with brine and then
dried (Na2SO4)
and evaporated in vacuo to yield 10.71 g (83%) of pure title compound.

'H NMR (300 MHz, DMSO-d6) 8 7.87 (d, 1H), 6.48 (d, 1H), 6.45 (s, 1H), 6.04 (s,
2H) and 4.60 ppm (s, 2H); ES-MS rn/z 143.2 [M+H]+, HPLC RT (min) 1.34.

Step 2: Preparation of 2- f f 4-(chloromethyl)pyridin-2-y11amino 1-2-oxoethyl
acetate
CI O
\ Ny'O'J~ CH3
I ~N O

A suspension of 4-(chloromethyl)pyridin-2-amine (2.50 g, 10 nunol) and
triethylamine (11.7 mL) in dichloroethane (10 mL) was stirred under nitrogen
with ice
bath cooling as acetoxyacetyl chloride (1.86 mL, 17 minol) was added slowly
over 10 min.
After 2 h stirring with cooling, TLC showed no starting material but three
major product
spots. The mixture was diluted with dichloromethane and washed with water and
then
brine. It was dried (Na2SO4) and evaporated in vacuo. The residue was purified
by
chromatography on silica gel using a gradient from 0-3% methanol in
dichloromethane to
yield 0.62 g(18%) of the correct and pure title compound.

1H NMR (300 MHz, DMSO-d6) b 10.75 (s, 1H), 8.30 (d, 1H), 8.10 (bs, 1H), 7.17
(d, 1H), 4.79 (s, 2H), 4.71 (s, 2H) and 2.13 ppm (s, 3H); ES-MS tn/z 243.1
[M+H]+, HPLC
RT (min) 1.87.

Intermediate F
Preparation of N-[4-(chloromethyl)pyridin-2-y11acetamide
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CI H

CN NuCH3
IOI
By using the methods described for preparation of Intermediate E and by
substituting acetyl chloride instead of acetoxyacetyl chloride in step 2,
Intermediate F was
prepared from 2.30 g of 4-(chloromethyl)pyridin-2-amine and proportional
amounts of
other reagents. The yield of title compound was 2.0 g (67%) after silica gel
chromatography. Even though examination of this material by NMR spectroscopy
indicated that it was a mixture of the desired compound and the diacylated
product N-
acetyl-N-[4-(chloromethyl)pyridin-2-yl]acetamide (about 45:55), it was used as
is in the
next reaction and side products were separated by chromatography after the
subsequent
reaction.

'H NMR (300 MHz, CD2C12) 8 8.33 (bs, 1H), 7.41 (d, 1H), 7.30 (s, 1H), 7.10 (d,
1H), 4.65 (s, 2H) and 2.20 ppm (s, 3H); ES-MS rn/z 185.0 [M+H]+, HPLC RT (min)
1.16.
Signals for the contaminating diacyl compound show at 1H NMR (300 MHz, CD2C12)
8
8.56 (d, 1H), 8.18 (s, 1H), 78.24 (d, 1H), 4.75 (s, 2H) and 2.25 ppm (s, 6H);
ES-MS m/z
no significant M+H+ion, HPLC RT (min) 0.97. Because of the closeness of the %
content
of the two compounds, it is possible that some of the NMR peak assignments
have been
switched between the desired material and the contaminant.

Intermediate G
Preparation of N-[4-(chloromethyl)pyridin-2-yll-2-methoxyacetamide
CI H
1I ~ NO,CH3
~N O

By using the methods described for preparation of Intermediate E and by
substituting 2-methoxyacetyl chloride instead of acetoxyacetyl chloride in
step 2,
Intermediate G was prepared from 731 mg of 4-(chloromethyl)pyridin-2-amine and
proportional amounts of other reagents. The yield of pure title compound was
397 mg
(45%) after silica gel chromatography using a gradient from 0-40% ethyl
acetate in
hexane.

1H NMR (300 MHz, CDC13) 8 9.00 (bs, 1H), 8.31 (d, 1H), 8.30 (s, 1H), 7.13 (d,
1H), 4.55 (s, 2H), 4.06 (s, 2H) and 3.51 ppm (s, 3H); ES-MS m/z 215.0 [M+H]+,
HPLC


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RT (min) 0.71.

Intermediate H
Preparation of N-[4-(chloromethyl)nyridin-2-yl1-2-(2-methoxyethoxy)acetamide
CI H

CN N~O~/O'CH3
O

By using the methods described for preparation of Intermediate E and by
substituting 2-(2-methoxyethoxy)acetyl chloride instead of acetoxyacetyl
chloride in step
2, Intermediate H was prepared from 599 mg of 4-(chloromethyl)pyridin-2-amine
and
proportional amounts of other reagents. The yield of pure title compound was
314 mg
(29%) after silica gel chromatography twice, first using a gradient from 2-3%
methanol in
dichloromethane, and then a second chromatography of the best fractions using
a gradient
from 0-40% ethyl acetate in hexane.

1H NMR (300 MHz, CD2Cla) 8 9.39 (bs, 1H), 8.30 (d, 1H), 8.29 (s, 1H), 7.13 (d,
1H), 4.59 (s, 2H), 4.14 (s, 2H), 3.76 (t, 2H), 3.60 (t, 2H) and 3.44 ppm (s,
3H); ES-MS m,/z
259.1 [M+H]+, HPLC RT (min) 1.46.

Intermediate I
Preparation of N-[4-(chloromethyl)pyridin-2-y11-2-methoxypropanamide
CI H H 3 C
NO,CH3
N O

Step 1: Preparation of 2-methoxypropanoic acid

H3C ~CH3
HOO
O

Sodium methoxide in methanol (25%, 16 mL) was added to a stirred solution of 2-

bromopropionic acid (19.6 mmol) in methanol (5 mL) under nitrogen. The
reaction was
heated at 50 C under nitrogen overnight. The reaction was then concentrated
under
vacuum. The residue was brouglit to pH 1 by the addition of 1 N aqueous HCl
and this
solution was then extracted with ethyl acetate three times (70 mL, 25 mL, 10
mL). The
combined organic layer was dried (Na2SO4) and then concentrated under vacuum
to yield
the title compound as a colorless oil 2.04 g (99%) which was of sufficient
purity to be
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used without purification. 'H NMR (CD3OD) S 3.67 (q, 1H), 3.33 (s, 3H), and
1.33 ppm
(d, 3H).

Step 2: Preparation of 2-methoxypropanoyl chloride
H3C
ClQ/CH3
Q

2-Methoxypropanoic acid (2.04 g, 19.2 mmol) was dissolved in dichloromethane
(3 mL) which was stirred under nitrogen as a drop of dimethylformamide was
added.
Thionyl chloride was added dropwise into the reaction over 3 min and then the
reaction
was stirred at room temperature overnight. The reaction solution was
concentrated in
vacuo and the resulting pale yellow oil was placed under high vacuum to remove
last
traces of thionyl chloride. The yield of pure title compound was 303 mg (13%).
1HNMR
(CDC13) 8 4.10 (q, 1H), 3.48 (s, 3H), and 1.56 ppm (d, 3H).

Step 3: Preparation of N-f4-(chloromethyl)pyridin-2-yll-2-methoxypropanamide
ci NH$C CH H \ Os 3

I ~N O

By using the methods described for preparation of Intermediate E (Step 2) and
by
substituting 2-methoxypropanoyl chloride instead of acetoxyacetyl chloride,
Intermediate I
was prepared from 352 mg of 4-(chloromethyl)pyridin-2-amine and proportional
amounts
of other reagents. The yield of pure title compound was 341 mg (60%) after
silica gel
chromatography using a gradient from 0-30% ethyl acetate in hexane.

'H NMR (300 MHz, DMSO-d6) b 10.2 (bs, 1H), 8.30 (d, 1H), 8.17 (s, 1H), 7.16
(d,
1H), 4.77 (s, 2H), 4.00 (q, 1H), 3.26 (s, 3H), and 1.27 ppm (d, 6H).

Intermediate J
Preparation of N-f4-(chloromethyl)pyridin-2-yll-2-methoxy-2-methylpropanamide
Ci H H3C CH3
\ N O~
N O CH3
Step 1: Preparation of 2-methoxy-2-methylpropanoic acid
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H3C CH3
HOO

CH3
O

The procedure of Weizmann, Sulzbacher, and Bergmann as written in JACS
70,1153 (1948), which is hereby incorporated by reference, was used as
follows: A
solution of potassium hydroxide (8.96 g, 159.7 mmol) in 5 mL of water and 20
mL of
methanol was stirred with ice batli cooling under nitrogen as 1,1,1-trichloro-
2-
methylpropan-2-ol (7.10 g, 40.0 mmol) was carefully added dropwise over ten
min.
Vigorous bubbling was observed as a white precipitate formed. The ice bath was
removed
after 15 min. The reaction was stirred at room temperature for 2 h then
refluxed for 3 h.
The reaction was cooled to room temperature and the solids were then removed
by
filtration and rinsed with methanol (350 mL). The filtrate was concentrated
under vacuum
to remove methanol and the remaining aqueous layer was brought to pH 0 by the
addition
of aqueous HC1 then extracted with ethyl acetate (300 mL). The extract was
dried
(Na2SO4) and concentrated in vacuo to yield 4.11 g of crude product, which was
purified
by vacuum distillation to yield 2.28 g (48%) of the pure title coinpound as a
colorless oil
which was distilled at 105 C (28 mm Hg). 1HNMR (CDC13) 6 9.65 (s, 1H), 3.20
(s, 3H)
and 1.32 ppm (s, 6H).
Step 2: Preparation of 2-methoxy-2-methylpropanoyl chloride
H3C CH3
C~~
O CH3

By following the procedure of Intermediate I (Step 2) but using 2-methoxy-2-
methylpropanoic acid (6.99 g, 59.2 mmol) rather than 2-methoxypropanoic acid
and
proportional amounts of other reagents the title compound was synthesized. The
crude
product was distilled in vacuo to yield 2.671 g (33%) of pure compound, bp 44-
48 C
(38 mm Hg).
1HNMR (CDC13) 6 3.33 (s, 3H) and 1.51 ppm (s, 6H).
Step 3: Preparation of N-f4-(chloromethyl)pyridin-2-yll-2-methoxy-2-
methylpropanamide
ci HH3C CH3
N O
CH3
I ~N O

By using the methods described for preparation of Intermediate E (Step 2) and
by
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substituting 2-methoxy-2-methylpropanoyl chloride instead of acetoxyacetyl
chloride,
Intermediate J was prepared from 1.04 g of 4-(chloromethyl)pyridin-2-amine and
proportional amounts of other reagents. The yield of title compound was 1.23 g
(69%)
after silica gel chromatography using 30% ethyl acetate in hexane.

1H NMR (300 MHz, DMSO-d6) 8 9.41 (bs, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 7.19
(d,
1H), 4.78 (s, 2H), 3.28 (s, 3H) and 1.36 ppm (s, 6H); ES-MS m/z 243.1 [M+H]+,
HPLC
RT (min) 2.12.

Intermediate K
Preparation of N-[4-(chloromethvl)uvridin-2-vllmethanesulfonamide
CI H
N'g ;CH3
I ~N O. 0

Step 1: Preparation of N-f4-(chlorometh y1)pyridin-2-yll-N-(methylsulfonyl)
methanesulfonamide

CH3
CI O~I

N'S;CH3
N O. .O

A solution of 4-(chloromethyl)pyridin-2-amine (500 mg, 3.51 mmol) and
triethylamine (1.47 mL, 10.5 mmol) in ethyl acetate (4 mL) was stirred under
nitrogen in a
flask with ice bath cooling as methanesulfonyl chloride (0.81 mL, 10.5 mmol)
was added
dropwise. The reaction was then allowed to stir without cooling for 1 h before
it was
diluted with additional ethyl acetate, washed with water, dried (Na2SO4) and
evaporated in
vacuo. The resulting residue was purified by chromatography on silica gel
using an ethyl
acetate/ hexane gradient to yield 860 mg (82%) of pure title compound.

1H NMR (300 Hz, CD2C12) 8 8.56 (d, 1H), 7.50 (d, 1H), 7.41 (s, 1H), 4.66 (s,
2H), and
3.55 ppm (s, 6H); ES-MS m/z 299.0 [M+H]+, HPLC RT (min) 2.08.
Step 2: Preparation of N-f4-(chloromethyl)pyridin-2-yllmethanesulfonamide
CI H
\ N'S;CH3
I /N 0 O

A suspension of N-[4-(chloromethyl)pyridin-2-yl]-N-(methylsulfonyl)-
methanesulfonamide (700 mg, 2.34 mmol) in methanol (10 mL) and aqueous sodium
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hydroxide (1 N, 11.7 mL, 11.7 nunol) was stirred at ambient temperature as the
starting
material dissolved over 10 min. After another 10 min the reaction was adjusted
to a pH
between 3 and 6 by addition of aqueous hydrochloric acid (2 N) to precipitate
the desired
product as a white solid that was collected by filtration, washed with
methanol and dried
in vacuo. The yield of title compound was 250 mg (48%).

1H NMR (300 MHz, DMSO-d6) b 10.93 (bs, 1H), 8.21 (d, 1H), 7.02 (m, 2H), 4.73
(s, 2H), and 3.23 ppm (s, 3H); ES-MS m/z 221.1 [M+H]+, HPLC RT (min) 1.45.
Intermediate L
Preparation of N-[4-(chlorometh 1)pyridin-2-yl]-N'-ethylurea
Ci H H
NuNCH3
N IOI

To 4-(chloromethyl)pyridin-2-amine (100mg, 0.70mmo1) in 3 mL DMF was added
ethyl isocyanate (59 mg, 0.84 mmol) and the resulting mixture was stirred
under nitrogen
for 16 h. The reaction was diluted with EtOAc (15 mL) and washed with H20
three times,
dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by
column
chromatography on silica gel using 25% EtOAc in hexane to give 110 mg of N-[4-
(chloromethyl)pyridin-2-yl]-N'-ethylurea (73 %).

1H NMR (DMSO-d6) S 9.22 (s, 1H), 8.14-8.16(m, 1H), 7.91-7.94 (m, 1H), 7.45 (d,
J=0.8Hz, 1H), 6.93-6.95 (m, 1H), 4.70 (s, 2H), 3.12-3.14(m, 2H), 1.01-1.09(m,
3H) ppm;
LCMS: 214.1 [M+H]+, RT 0.47 min.

Intermediate M
Preparation of N-[4-(chloromethyl)nyridin-2-yll-N'-nhenylurea
CI H H
NuN ~
~ N IOI ~ /

By using the methods described for preparation of Intermediate L and by
substituting phenyl isocyanate instead of ethyl isocyanate, Intermediate M was
prepared.
From 250 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of
other
reagents the yield of title compound was 218 mg (47%) after silica gel
chromatography
using a gradient from 0-40 % ethyl acetate in hexane. Though there was
evidence of


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contamination with the starting material 4-(chloromethyl)pyridin-2-amine in
the NMR
spectrum, this material was used without further purification and side
products were
separated by chromatography after the next step.

'H NMR (300 MHz, DMSO-d6) b 10.25 (bs, 1H), 9.50 (bs, 1H), 8.29 (d, 1H), 7.95
(s, 1H), 7.52 (d, 1H), 7.27-7.36 (m, 2H), 7.0-7.1 (m, 2H), and 4.79 ppm (s,
2H); LCMS:
262.2 [M+H]+, RT 2.65 min.
Intermediate N
Preparation of N-[4-(chloromethyl)pyridin-2-_ 1]-N'-methylurea
Ci H H
Ny N.CH3
N B
y using the methods described for preparation of Intermediate L and by
substituting methyl isocyanate instead of ethyl isocyanate, Intermediate N was
prepared.
From 180 mg of 4-(chloromethyl)pyridin-2-amine and proportional amounts of
other
reagents the yield of pure title compound was 42 mg (17%) after silica gel
chromatography using a gradient from 0-50 % ethyl acetate in hexane followed
by
trituration of the residue with ether to remove a contaminant.

1H NMR (DMSO-d6) S 9.31 (s, 1H), 8.16 (d, 1H), 7.92 (bm, 1H), 7.40 (s, 1H),
6.93
(d, 1H), 4.69 (s, 2H) and 2.70 ppm (d, 3H); LCMS: 200.1 [M+H]+, RT 1.17 min.
Intermediate NN
Preparation of N'-[4-(chloromethyl)pyridin-2-yl]-N,N-dimethylurea
CI H CH3
~ NuN.CH
N ICI s

By using the methods described for preparation of Intermediate K and by
substituting dimethylcarbamic chloride instead of methanesulfonyl chloride,
Intermediate
NN is prepared.
Intermediate 0
Preparation of 2,4-dichloro-6-(chloromethvl)pvrimidine
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CI
NYCI
IN
CI

This product was prepared similarly to the 5-methyl substituted analog
described in
Biorg. Med. Chena. 2002, 10, 525. A stirred suspension of 6-
(chloromethyl)pyrimidine-
2,4(1H,3H)-dione (5.2 g, 32.6 mmol) in POC13 (9.1 mL, 97.9 mmol) was refluxed
for 16 h
under nitrogen. The mixture was cooled and evaporated to leave a dark colored
oil. Ice
water was slowly added and the product was extracted into dichloromethane. The
organic
layer was washed with brine, dried over MgSO4, and concentrated under reduced
pressure
to give 2,4-dichloro-6-(chloromethyl)pyrimidine (5 g) as a yellow oil. Though
this
product could be used in the next step with out purification, another batch
prepared in the
same way was further purified by chromatography to show the following NMR.

1H NMR (DMSO-d6) b 7.90 (s, 1H) and 4.78 ppm (s, 2H).
Intermediate P
Preparation of 2-chloro-4-(chloromethyl)pyridine
CI
CI
~N

Step 1: Preparation of (2-chloropyridin-4-yl)methanol
OH
CI

I ~N

A sample of inethyl2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in
mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was
treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol)
and then
allowed to warm to room temp. After 4 h the solution was cooled to 0 C and
quenched
with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution,
and the
reaction mixture was extracted with EtOAc. The organic extracts were washed
with brine
and concentrated in vacuo yielding 2.96 g (70.8%) of product.
1H NMR (300 MHz, CD3CN) S 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62
(s,
2 H) and 3.53 ppm (bs, 1 H).
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Step 2: Preparation of 2-chloro-4-(chloromethvl)p ri~
CI
CI
I ~N

A sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved
in anhydrous THF (1.5 mL), treated with N,N-diisopropylethylamine (0.29 mL,
1.69
mmol) and cooled to -78 C. Methanesulfonyl chloride was added (0.07 mL, 0.84
mmol),
and the reaction mixture was allowed to slowly warm to room temperature
overnight. The
reaction mixture was then diluted with dichloromethane and washed with water.
The
organic layer was dried over NaZSO4 and concentrated in vacuo yielding the
title
compound (110.0 mg, 88.6%).

1H NMR (300 MHz, CD3CN) 8 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63
ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.

Intermediate PP
Preparation of f2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4- llXl
methanesulfonate
O11BO H3C
H3C.s.O 3

N
CH3
Step 1: Preparation of f2-(2 5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yllmethanol
H H3C
O
I ~ N

~ N CH3

(2-aminopyridin-4-yl)methanol (7.5 g, 60.41 mmol), hexane-2,5-dione (7.58 g,
66.46
mmol) and p-toluenesulfonic acid monohydrate(1.14 g, 6.04) was dissolved in
Toluene
(10 mL) in a flask fitted with a Dean Stark trap. The solution was heated to
reflux at 135
C for 16 h. The solvents were evaporated and ethyl acetate was added. The
organic
extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The
residue

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was purified using silica gel with a gradient elution from 10-50% ethyl
acetate in hexanes
to yield 10.2 g (83%) of product.

'H NMR (300 MHz, CD2C12-d2) 8 8.52 (dd, 1H), 7.30 (m, 1H), 7.22 (m, 1H),
5.85(s, 2H), 4.78 (s, 2H), 2.08 (s, 6H); ES-MS m/z 203.2[M+H]+, LCMS RT (min)
2.04.
Step 2: Preparation of f2-(2 5-dimethyl-lH-p rrol-1-yl)pyridin-4- 1lyI
methanesulfonate
O~ //o H C
H3C' S\C 3
I ~ N ~
~ N CH3

A sample of [2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4-yl]methanol (6.80 g,
33.62
mmol) was dissolved in anhydrous dichloromethane (30 mL), treated with
triethylamine
(14.06 mL, 100.9 mrnol) and cooled to 0 C. Methanesulfonyl chloride was added
(3.90
mL, 50.43 mmol), and the reaction inixture was allowed to slowly warm to room
temperature overnight. The reaction mixture was then diluted with
dichloromethane and
washed with water. The organic layer was dried over Na2SO4 and concentrated in
vacuo
and the residue was purified over silica gel using 10-60% ethylacetate in
hexanes as eluant
to yield the title compound (7.5 g, 80%).

'H NMR (300 MHz, CD2C12-d2) 8 8.65 (dd, 1H), 7.35 (m, 1H), 7.25 (m, 1H),
5.88(s, 2H), 5.30 (s, 2H), 3.10 (s, 3H), 2.12 (s, 6H); ES-MS m/z 281.1[M+H]+,
LCMS RT
(min) 2.67.

Intermediate 0
Preparation of 4-(chloromethvl)-N-(4-methyl-1,3-thiazol-2-yl)pyridin-2-amine
CI H
S
N N /
CH3
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Step 1: Preparation of 4-({ [tert-butyl(dimethyl)silylloxy}methyl)pyridin-2-
amine
CH3
H3C J<CH3
,Si CH3
0 CH3
NH2
A solution of (2-aminopyridin-4-yl)methanol (5.0 g, 40 mmol), tert-
butyldimethylsilyl chloride (6.07 g, 40 mmol), N-ethyl-N-isopropylpropan-2-
amine (7.0
mL, 40 mmol) and N,N-dimethylpyridin-4-amine (0.49 g, 4 mtnol) in
dichloromethane (50
mL) was stirred 2 days at ambient temperature under nitrogen. The resulting
reaction
mixture was washed in sequence with aqueous sodium hydroxide (1 N), water and
brine.
It was then dried (Na2SO4) and concentrated in vacuo. The residue was
chromatographed
on silica gel using 50 % ethyl acetate in hexane to yield pure title compound
(5.47 g).

1H NMR (300 MHz, CD3CN) $ 7.75 (m, 1H), 6.39 -6.48 (m, 2H), 4.70 (bs, 1H), 4.
50 (s, 2H), 0.83 (s, 9H) and 0.03 ppm (s, 6H); ES-MS m/z 239.3 [M+H]+, HPLC RT
(min) 2.35.

Step 2: Preparation of N-({ f4-({ ftef-t-butyl(dimethyl)sil ly lox
}~yl)pyridin-2-
yll amino }carbonothioyl)benzamide

H C CH3
3 ~--CH3
H3C-Si-CH3
0

4 ~ ~ O

N H H I \
/
A solution of 4-({ [tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-amine (2.00
g,
8.39 mmol) and benzoyl isothiocyanate (1.51 g, 9.23 mmol) in toluene (20 mL)
was
heated to 85 C for 12 h. The solvent was removed by evaporation in vacuo and
the
residue was purified by chromatography on silica gel using a gradient from 0-
10% ethyl
acetate in hexane to yield pure title coinpound as a yellow oil which
solidified on standing
(2.68 g, 79%).



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1H NMR (300 MHz, CD3OD) S 8.79 (bs, 1H), 8.18 (d, 1H), 7.83 (m, 2H), 7. 50
(m, 1H), 7.40 (m, 2H), 7.04 (m, 1H), 4.68 (s, 2H), 0.82 (s, 9H), and 0.03 ppm
(s, 6H); ES-
MS in/z 402.0 [M+H]+, HPLC RT (min) 4.24.

Step 3: Preparation of N-r4-( f(tert-butyl(dimeth ly )sil l~loxy}meth
~1)pyridin-2-yllthiourea
CH3
H3C\I/CH3
H3C-STI-CH3
O

N H 11 NH2

A solution of N-({ [4-({ [tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-
yl]amino}carbonothioyl)benzamide (1.00 g, 2.49 mmol) in absolute ethanol (15
mL) was
stirred with potassium carbonate (0.344 g, 2.49 mmol) and heated to reflux
under nitrogen
for 16 h,after which the reaction mixture was filtered and the filtrate was
evaporated
under vacuum to give crude title compound (670 mg, > 100%) as a white solid
which was
carried on to the next step without purification.

1H NMR (300 MHz, DMSO-d6) b 10.55 (bs, 2H), 8.75 (bs, 1H), 8.05 (d, 1H), 7.10
(s, 1H), 6.83 (d, 1H), 4. 60 (s, 2H), 0.83 (s, 9H) and 0.03 ppm (s, 6H); ES-MS
m/z 298.2
[M+H]+, HPLC RT (inin) 3.25.

Step 4: Preparation of { 2- f(4-methyl-1 3-thiazol-2-yl)aminolpyridin-4-yl }
methanol
OH H

N N N /
CH3
A solution of N-[4-({ [teyt-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-
yl]thiourea
(crude material, 650 mg) and 1-chloroacetone (0.18 mL, 2.18 mmol) in ethanol
(10 mL)
was refluxed under nitrogen for 16 h and cooled. A white/pink solid was
collected by
filtration and washed with ethanol. The filtrate was evaporated in vacuo to
yield a second
white/pink solid. Comparison of the NMR of the two solids indicated that they
were both

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the title compound and were pure enough (about 90%) to carry on to the next
step without
further purification (combined residue yield 516 mg, > 100 %).

1H NMR (300 MHz, DMSO-d6) S 8.13 (d, 1H), 7.05 (s, 1H), 6.83 (d, 1H), 6. 58
(s,
1H), 4.42 (s, 2H) and 2.18 ppm (s, 3H); ES-MS nz/z 222.2 [M+H]+, HPLC RT (min)
1.41.

Step 5: Preparation of 4-(chloromethyl)-N-(4-methyl-1,3-thiazol-2-yl)pyridin-2-
amine
CI H
N S
I N NII
CH3

A mixture of {2-[(4-methyl-1,3-thiazol-2-yl)arnino]pyridin-4-yl}methanol (200
mg, 0.9 mmol) and thionyl chloride (0.66 mL, 9.04 mmol) was stirred for 3 h
and then
evaporated in vacuo. The residue was dissolved in ethyl acetate and washed
with
saturated sodium bicarbonate. The aqueous layer was back extracted twice with
ethyl
acetate and then twice with a mixture of isopropanol, ethyl acetate and
dichloromethane
(1:8:1). The combined extracts were dried (Na2SO4) and concentrated in vacuo.
The
resulting residue was mixed with methanol, evaporated and then mixed with
ethyl acetate
and then evaporated again to yield the title compound as a light pink solid
(200 mg, 92%)
which was taken on to the next step as a crude solid.

1H NMR (300 MHz, CD2Cl2) 8 8.30 (m, 1H), 6.98 (s, 1H), 6.90 (m, 1H), 6. 50 (s,
1H), 4.55 (s, 2H) and 2.33 ppm (s, 3H); ES-MS rnJz 240.2 [M+H]+, HPLC RT (min)
1.14.
Intermediate R
Preparation of N-(f f 4-(chloromethyl)pyridin-2-yllaminolcarbonyl)benzamide
CI H ~
\ N~N \ I
I ~N IOI O

By using the methods described for preparation of Intermediate L and by
substituting benzoyl isocyanate instead of ethyl isocyanate and using
dichloromethane
rather than DMF as solvent, Intermediate R was prepared. The product, which
separated
from the reaction mixure as a solid, was collected by filtration and washed
with
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dichloromethane.

1H NMR (DMSO-d6) 8 11.01 (s, 1H), 10.98 (bs, 1H), 8.06 (d, 1H), 7.82 (s, 1H),
7.73 (d, 2H), 7.37 (t, 1H), 7.25 (t, 2H), 6.90 (d, 1H), and 4.52 (s, 2H).

Preparation of Compounds of the Invention
Example 1
Preparation of 4-f [(44 [(2,2-difluoro-1,3-benzodioxol-5-vl)aminol carbonyll-
1-methyl-lH-pyrazol-5-yl)aminolmethyl}-N-methylp_yridine-
2-carboxamide

0 XF
N O
N
H
N NH O
CH3 ~ N.CH3
~ ~N H

A solution 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-
pyrazole-4-carboxamide (Intermediate A, 280 mg, 0.95 mmol), sodium iodide (283
mg,
1.89 mmol), and 2,6-di(tert)butyl-4-methylphenol (10 mg) in dry
dimethylformamide (1.5
mL) was stirred under nitrogen as {2-[(methylamino)carbonyl]pyridin-4-
yl}methyl
methanesulfonate (Intermediate D, 461 mg, 1.89 mmol) was added. The resulting
solution
was stirred at 60 C in a foil wrapped flask for 20h. The resulting solution
was evaporated
and then diluted with 1 mL methanol and injected in two portions on a 150/20
mm C18
HPLC column using a gradient from 10-50 % acetonitrile in water (plus 0.05%
trifluoroacetic acid). The best fractions containing the desired material, as
identified by
LCMS, were combined, mixed with saturated NaHCO3, and extracted three times
with
dichloromethane. The combined extracts were dried (Na2SO4) and evaporated in
vacuo to
yield 90 mg (21%) of pure title compound.

1H NMR (300 MHz, CD3OD-d4) 8 8.50 (d, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.70
(m, 1H),
7.55 (d, 1H), 7.25 (m, 1H), 7.10 (m, 1H), 4.65 (s, 2H), 3.70 (s, 3H), 2.95
(s,3H); ES-MS
m1z 445.3 [M+H]+, LCMS RT (min) 2.87.

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Example 2
Preparation of 5-{[(2-chloropyridin-4-yl)methyllaminol-N-(2,2-diflnoro-
1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide
O OXF
F
N O
H
N NH
CHg Cl
N
Step 1: Preparation of ethyl 5-(foimylamino)-1-methyl-lH-pyrazole-4-
carboxylate
O
O---CH3
N

H3C NII
O
A solution of formic acid (4ml, 106.02mmo1) and acetic anhydride (6m1,
63.59mrnol) was added to a solution of ethyl5-amino-l-methyl-lH-pyrazole-4-
carboxylate (5.OOg, 29.55mmo1) in dry THF (30mL) and allowed to stir at room
temperature for 16 h. The reaction mixture was then diluted with EtOAc and
washed with
concentrated NaHCO3 solution, followed by water, and then brine. The organic
layer was
dried over Na2SO4 and concentrated ira vacuo yielding 4.16g (71.4 Io) crude
product. This
material was used without further purification.

1H NMR (300 MHz, CD3CN) 8 8.32 (bs, 1H), 7.78 (s, 1H), 4.23 (q, 2H), 3.68 (s,
3H), 1.25 (t, 3H); ES-MS m/z 198.0 [M+H]+, HPLC RT (min) 1.41.
Step 2: Preparation of ethyl5-f((2-chloroi2yridin-4-yl)methyll(formyl)aminol-l-

methyl-lH-pyrazole-4-carbox. ~~
O
O---CH3
N
H3C NO

CI
~N

A solution of crude ethyl5-(formylamino)-1-methyl-lH-pyrazole-4-carboxylate
(3.OOg, 15.21mmo1) from step 1 in dichloromethane (30m1) was treated with
diazabicyclo(5.4.0)undec-7-ene (3.41m1, 22.82mmo1) and allowed to stir at room

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temperature for 30 minutes. 2-Chloro-4-chloromethylpyridine (4.93g, 30.43mmol)
was
added, and the reaction mixture was allowed to stir at room temperature for 16
h. The
reaction mixture was then diluted with DCM and washed with concentrated NaHCO3
solution, followed by water, then brine. The organic layer was dried over
Na2SO4 and
concentrated in vacuo. The crude residue was washed with ether, and the ether
washings
were concentrated and triturated with hexanes. The residue was again
concentrated
yielding 3.93g (80.1%) product as a thin oil.

'H NMR (300 MHz, CD3CN) 8 8.30 (d, 1H), 8.23 (s, 1H), 7.85 (s, 1H), 7.33 (s,
1H), 7.22 (d, 1H), 4.80 (bs, 2H), 4.17 (q, 2H), 3.67 (s, 3H), 1.23 (t, 3H); ES-
MS m/z 323.1
[M+H]+, HPLC RT (min) 2.31.

Step 3: Preparation of 5-f r(2-chloropyridin-4-yl)methyllan-iinol-l-methyl-lH--
Dyrazole-
4-carboxvlic acid
O
N OH
N
CH3 NH

~ ~ CI
~N
A solution of ethyl 5-[[(2-chloropyridin-4-yl)methyl](formyl)amino]-1-
methyl-lH-pyrazole-4-carboxylate (3.93g, 12.18mmo1) in THF (25mL), MeOH (5mL),
and water (5mL) was treated with LiOH (2.91 g, 1221.77mmo1) and allowed to
stir at 80 C
overnight. The reaction mixture was then cooled to room temperature, and the
pH was
adjusted to three using 1N HC1. The reaction mixture was then diluted with
EtOAc and
washed with water, brine, and then dried over Na2SO4. Concentration of the
ethyl acetate
solution in vacuo gave crude product, which was triturated with ether yielding
2.Og
(61.6%) product.

1H NMR (300 MHz, CD3CN) 8 8.32 (d, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.28 (d,
1H), 6.18 (bm, 1H), 4.59 (d, 2H), 3.64 (s, 3H); ES-MS nz/z 267.1 [M+H]+, HPLC
RT
(min) 1.66.

Step 4: 5-f f(2-chloropyridin-4-yl)methyllaminoI -N-(2 2-difluoro-1 3-
benzodioxol-5-yl)-
1-methyl-1 H-pyrazole-4-carboxamide



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O O
F
NN N ~
% H O F
CH3 NH

~ ~ cl
~N
A solution of 5-{[(2-chloropyridin-4-yl)methyl]amino}-1-methyl-1H-pyrazole-
4-carboxylic acid (50.0mg, 0.19mmo1) in dry DMF (3mL) was treated with N,N-
diisopropylethylamine (0.l0mL, 0.56minol), followed by PyBOP (97.57mg,
0.19mmol)
and allowed to stir for 30 minutes. 5-Amino-2, 2-difluorobenzo-1,3-dioxole
(64.91mg,
0.37mmol) was added, and the reaction mixture was allowed to stir for 16 h at
60 C. The
reaction mixture was then diluted with EtOAc, and the organics were washed
with
concentrated NaHCO3 solution, followed by water, and then brine. The organics
were
then dried over Na2SO4 and concentrated in vacuo. The crude residue was
triturated with
hot hexanes yielding 55.0mg (68.6%) product.

1H NMR(300 MHz, CD3CN) S 8.43 (bs, 1H), 8.29 (d, 1H), 7.75 (d, 2H), 7.40 (s,
1H), 7.23-7.32 (m, 2H), 7.17 (d, 1H), 6.76 (bs, 1H), 4.53 (d, 2H), 3.68 (s,
3H); ES-MS
in/z 422.0 [M+H]+, HPLC RT (min) 3.12.

Example 3
Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-[(f2-r(2-hydroxyethyl)
aminolnyridin-4-yl}methyl)aminol-l-methyl-lH-pyrazole-4-
carboxamide

O O
F
N~ N
~\~
N H O r
CH3 NH
z/OH
~ ~
F H
~
F OH N
F
A solution of 5-{[(2-chloropyridin-4-yl)methyl]amino}-N-(2,2-difluoro-1,3-
benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (100.0mg, 0.24mmol) in
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pyridine (1mL) was treated with ethanolamine (0.50mL, 8.28mmol) and heated to
200 C
in a sealed tube for 6 h. The reaction mixture was then allowed to cool to
room
temperature overnight. It was then diluted with water and extracted with
EtOAc. The
organic extracts were washed with water, dried over Na2SO4, and concentrated
in vacuo.
Purification of the crude residue by HPLC (10-90% MeCN in water gradient
containing
0.1% TFA) gave 23.0 mg (17.3%) of the title compound as the TFA salt.

1H NMR (300 MHz, CD3CN) S 8.40 (bs, 1H), 7.67-7.78 (m, 3H), 7.27 (d, 1H),
7.18 (d, 1H), 7.02 (s, 1H), 6.78 (d, 1H), 4.57 (s, 2H), 3.6-3.71 (m, 4H), 3.38
(m, 2H);
ES-MS a/.z 447.2 [M+H]+, HPLC RT (min) 2.23.

Examples 3-a to 3-e in Table A were made using the procedure of Example 2
(step
4) and Example 3 by substituting the appropriate starting materials:

Table A

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Ex. Structure Name LC-MS LCMS
No [M+H]+ RT (min)
O
H \ ~ ~F
F
H3C N H
H 5-[({2-[(2-
N
hydroxyethyl)amino]pyridin-4-
N oH yl}methyl)amino]-1-methyl-N-
F F o [4-(trifluoromethoxy)phenyl]-
oH 1 H-pyrazole-4-carboxamide
3-a F trifluoroacetate (salt); 451.2 2.28
o _
p F
NH \ ) ~-F
H3C NH F
5-[({2-[(2,3-
/ \ N OH dihydroxypropyl)amino]pyridin
-N oH 4-yl}methyl)amino]-1-methyl-
F F o N-[4-(trifluoromethoxy)phenyl]
AoH 1 H-pyrazole-4-carboxamide
3-b o F trifluoroacetate (salt ; 481.2 2.27
~ O F
H \ ~ F
N N H o F ~F
H 3c 5-[({2-[(2-
hydroxyethyl)amino]pyridin-4-
/ \ rHV yI}methyl)amino]-1-methyl-N-
N ~oH (2,2,3,3-tetrafluoro-2,3-
F o dihydro-1,4-benzodioxin-6-yl)-
F~oH 1 H-pyrazole-4-carboxamide
3-c F trifluoroacetate (salt); 497.2 2.51
C ~ O F
NH \ ~ F
O~F
H3C NH F 5-[({2-[(2,3-
dihydroxypropyl)amino]pyridin
/ \ N OH 4-yl}methyl)amino]-1-methyl-
N o ~oH N-(2,2,3,3-tetrafluoro-2,3-
F F dihydro-1,4-benzodioxin-6-yl)-
oH 1 H-pyrazole-4-carboxamide
3-d 0 F trifluoroacetate (salt); 527.2 2.46
NH \/'~ F
~
'F
H3C NH
N-(2,2-difluoro-1,3-
/ \ N OH benzodioxoi-5-yi)-5-[({2-[(2,3-
N ~ OH dihydroxypropyl)amino]pyridin
F
o 4-yI}methyl)amino]-1-methyl-
F~oH 1 H-pyrazole-4-carboxamide
3-e F trifluoroacetate salt ; 477.1 2.2
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Example 4
Preparation of inethyl4-{[(4-{[(2,2-difluoro-l,3-benzodioxol-5-
yl)aminolcarbonyl}-1-
methyl-lH-pyrazol-5-yl)aminolmethyl}pyridine-2-carboxylate
O ~ I ~F
N~ I N O
H
N NH O
CH3 I ~ O,Me

~N
Step 1: Preparation of 4-{r(4-{r(2,2-difluoro-1,3-benzodioxol-5-
yl)amino1carbonylL-
1-methyl-IH-pyrazol-5-yl)aminolmethyllpyridine-2-carboxamide

O :I ~F
N~ I N O
, H
N NH O
CH3
V~, NH2
Th
e title compound can be prepared by the following method. A solution of 5-
amino-N-
(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxainide
(Intermediate
A), sodium iodide, and 2,6-di(tef t)butyl-4-methylphenol in dry
dimethylformamide can
be stirred under nitrogen as [2-(aminocarbonyl)pyridin-4-yl]methyl
methanesulfonate
(Intermediate C) added. The resulting solution isstirred at 60 C in a foil
wrapped flask
for 20h. The resulting solution evaporated and then diluted with methanol and
injected on
a 150/20 mm C 18 HPLC column using a gradient from 10-50 % acetonitrile in
water (plus
0.05% trifluoroacetic acid). The best fractions containing the desired
material, as
identified by LCMS, are combined, mixed with saturated NaHCO3, and extracted
three
times with dichloromethane. The combined extracts are dried (Na2SO4) and
evaporated in
vacuo to yield pure title compound.

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Step 2 Preparation of methyl 4-{ [(4-{ f(2 2-difluoro-1 3-benzodioxol-5-
yl)aminolcarbonyl i methyl-1 H-pyrazol-5-yl)aminolmethyllpyridine-2-
carboxylate

0 ~ ~ XF
N~ I N O
, H
N NH O
,
e
CH3 V~, O,M

A suspension of 4-{[(4-{[(2,2-difluoro-l,3-benzodioxol-5-yl)amino]carbonyl}-
1-methyl-lH-pyrazol-5-yl)amino]methyl}pyridine-2-carboxamide in 1.2 mL
methanol and
N,N'-dimethylformamide dimethylacetal is heated with stirring in a sealed vial
at 50 C.
After 2 h heating the solution is evaporated in vacuo and the residue is
chromatographed
on silica gel with a gradient from 0-1% methanol in dichloromethane to yield
pure title
compound.

Example 5
Preparation of 4-f[(4-{[(2,2-difluoro-1,3-benzodioxol-5-vl aminolcarbonyl}-1-
methyl-
1H-pyrazol-5-yl)aminolmethyl}-N-(4-pyrrolidin-l-ylbutyl)pyridine-2-carboxamide
O C C~F
N~ I N O
H
N NH O
H3C \ N
I
~ ~N H

A slurry of 4-{ [(4-{ [(2,2-difluoro-1,3-benzodioxol-5-yl)amino]carbonyl}-
1-methyl-lH-pyrazol-5-yl)amino]methyl}pyridine-2-carboxamide (Product from
example
4 step 1) (95 mg, 0.21 mmol) in methanol (0.60 mL) is treated as in Example 4,
step 2 to
prepare a solution of inethyl4-{ [(4-{ [(2,2-difluoro-1,3-benzodioxol-5-
yl)amino]carbonyl }-1-methyl-lH-pyrazol-5-yl)amino]methyl }pyridine-2-
carboxylate,
which isused directly and addition of 4-pyrrolidin-1-ylbutan-l-amine (266 mg,
1.87
mmol) and stirring at 65 C for 16 h. The reaction solution is purified by
HPLC using
direct injection, in three portions, on a YMC-Pack Pro C 18 column (150 x 20
mm) and is
eluted at 20 mL/min with a gradient from 10-50 % acetonitrile in water plus
0.05% TFA.



CA 02610509 2007-11-30
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Pure fractions from each injection are combined, made basic by addition of
sodium
bicarbonate and extracted with ethyl acetate. Combined extracts are dried
(NkSO4) and
evaporated in vacuo to yield pure title compound

Example 6
Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-vl)-5-
F({2r(methox.yacetyl)aminol
pyridin-4-yl}meth_yl)aminol-l-methyl-lH-pvrazole-4-carboxamide
O a ><F
N~ N O
H
N NH H
CH3 \ N OCH3
I ~N O~

This material is prepared using the same method described for Example 1 but
starting with 4-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1,3-thiazole-5-
carboxamide
(Intermediate A) and proportionate amounts of Intermediate G rather than
Intermediate D
and also proportional amounts of the other reaction components. The reaction
mixture is
heated to 60 C in a foil wrapped flask overnight before crude product
isolated. This
material is purified by chromatography on silica gel using a gradient from 0-
60 % ethyl
acetate in hexane to yield final product.

Example 7
Preparation of 1-methyl-5- f({2- f(methylsulfonyl)aminolnyridin-4-
yl}methyl)aminol-
N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-
carboxamide
F
O a~:F
O N F

N NH H
CH3 N, CH3
tN pO'S

The title compound is prepared using the same method described for Example 1
but starting with 5-amino-l-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-
benzodioxin-6-
yl)-1H-pyrazole-4-carboxamide (Intermediate B) rather than 5-amino-N-(2,2-
difluoro-1,3-
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benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (Intermediate A) and
proportionate amounts of N-[4-(chloromethyl)pyridin-2-yl]methanesulfonamide
(Intermediate K) rather than Intermediate D and also proportional amounts of
the other

reaction components. The reaction mixture is heated to 60 C in a foil wrapped
flask for
16 h and then cooled. The reaction mixture is diluted with ethyl acetate,
washed with
water, dried (Na2SO4) and evaporated in vacuo. The crude product is purified
by
preparative HPLC to yield pure title compound.

Example 8
Preparation of 5-{ f (2-{[(ethylamino)carbonyllamino}pyridin-4-
yl)methyllamino}-
1-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-l,4-benzodioxin-
6-yl)-1H-pyrazole-4-carboxamide
F
O / I O F
iF
N ~ N O F
, H
N NH H H
CH3 N~r N,_,-CH3
N O

Step 1 Preparation of 5-({[2-(2,5-dimethyl-lH-Ryrrol-l-yl)pyridin-4-
yllmethyl}amino)-1-
inethyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-

carboxami.de
F
0 / I O F
:t-F
N// I NH Me O F
N NH
I --
Me N ~
I , N Me

The title compound was prepared using the saine method described for Example 2
using steps 1, 2, 3, and 4. In Step 2, intermediate PP was used in place of
intermediate P.
1H NMR (300 MHz, CD3OD-d4) Fi 8.45 (d, 1H), 7.85 (s, 1H), 7.62 (m, 2H), 7.45
(m, 1H), 7.35 (m, 1H), 7.20 (m, 2H), 5.75 (s, 1H), 4.70 (s, 2H), 3.75 (s, 3H),
1.93 (s, 6H);
ES-MS rrzlz 485.1 [M+H]+, LCMS RT (min) 3.45.

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Step 2 Preparation of 5-{f(2-aminopyridin-4- 1)methyllamino}-1-methyl-N-(2 2 3
3-
tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-y1)-1 H-pyrazole-
4-carboxamide
F
O O IF
N~ ~ N O F
F
H
N NH
CH3 NH2
I ~N

To a solution of 5-({[2-(2,5-dimethyl-lH-pyrrol-1-yl)pyridin-4-
yl]methyl}amino)-
1-methyl-N-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1 H-pyrazole-
4-
carboxamide (340 mg, 0.64 mmol) in ethanol (3 mL) was added water (1 mL),
hydroxylamine hydrochloride (445 mg, 6.41mmol), followed by triethyl amine
(0.18 mL).
The mixture was heated to reflux for 5 h and then cooled. The mixture was
diluted with
EtOAc and extracted with saturated NaHCO3. The organic layer was dried,
evaporated and
purified over silica gel using a 0-10% MeOH in DCM as a gradient to yield 222
mg (77%)
of white solid.

1H NMR (300 MHz, CD3OD-d4) 8 7.85 (s, 1H), 7.79 (m, 2H), 7.42 (m, 1H), 7.20
(d, 1H), 6.58 (m,2H), 4.44 (s,2H), 3.74 (s,3H); ES-MS m1z 453.0 [M+H]+, LCMS
RT
(min) 2.50.
Step 3 Preparation of 5-{f(2-{r(ethylamino)carbonyllaminolpyridin-4-
l)~yl1aminol-
1-methyl-N-(2,2,3,3 -tetrafluoro-2,3-dihydro-1,4-benzodioxin-
6- l)-1 pyrazole-4-carboxamide
F
O / I O F
IF
N ~ N O F
H
N NH H H
CH3 Ny N,,_,CH3
N 0

To a solution of 5-{[(2-aminopyridin-4-yl)methyl]amino}-1-methyl-N-(2,2,3,3-
tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-4-carboxamide (100
mg, 0.22
mmol) in dichloroethane (1 mL) was added ethyl isocyanate (0.3 mL, 3.33
rnmol). The
mixture was stirred at room temperature for 72 h. The solid precipitated out
as the
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reaction proceeded. Ether (2mL) was added to the reaction mixture and the
solid was
filtered. The solid was washed with methanol (1 mL to remove any remaining
starting
material) and again with ether (2 mL) before evaporation to give the desired
product (62
mg, 53%).
1H NMR (300 MHz, DMSO-d6) 8 9.80 (s, 1H), 9.12 (s, 1H), 8.05 (m, 2H), 7.88
(m, 1H), 7.82 (s, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.30 (bs, 1H), 6.98 (t,
1H), 6.80 (d, 1H),
4.54 (d, 2H), 6.05 (s, 3H), 3.15 (m, 2H), 1.02 (t, 3H); ES-MS n2/z 524.1
[M+H]+, LCMS
RT (min) 2.71.
The compounds of examples 13, 14, and 15 as shown in Table B were made
according to this method substituting the appropriate starting materials.

Example 9
Preparation of 1-methyl-5-1[(2-{ [(methylamino)carbonyllaminolpyridin-4-
yl methyllaminol-N-(2 2 4,4-tetrafluoro-4H-1,3-benzodioxin-
6-yl)-1H=pyrazole-4-carboxamide

p O F I--F

N I C
N ~ H F F
N NH H H
CH3 I ~ N~N,CH

~N O 3

The title compound was prepared using the same method described for Example 2
using steps 1, 2, 3, and 4. In Step 2, intermediate N was used in place of 2-
Chloro-4-
chloromethylpyridine. In Step 4, the appropriate aniline was also substituted
to give the
title compound.
1H NMR (300 MHz, CD3OD-d4) S 8.25 (s, 1H), 8.15 (m, 1H), 7.90-7.97 (m, 2H),
7.32-7.37 (m, 1H), 7.12 (s, 1H), 6.94-6.97 (m, 1H), 4.60 (s, 2H under the
water peak), 3.75
(s, 3H), 2.88 (s, 3H), ES-MS m/z 510.0 [M+H]+, LCMS RT (min) 2.67.
Examples 17, 18, and 19 as shown in Table B were made according to this method
substituting the appropriate starting materials.

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Examnle 10
Preparation of 5-r({2-[(aminocarbonyl)aminolRyridin-4-yl}methyl)aminol-
N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pray zole-
4-carboxamide

O O ,F
O~F
N'/ ~ H
N NH H
CH3 Ny NH2
N O

The title compound was prepared using the same method described for Example 2
using steps 1, 2, 3, and 4. In Step 2, intermediate R was used in place of 2-
Chloro-4-
chloromethylpyridine. In Step 3, the hydrolysis also removes the benzoyl group
along
with the formyl group and hydrolysis of the ester.

1H NMR (300 MHz, CD3OD-d4) S 8.18 (d, 1H), 7.85 (s, 1H), 7.70 (m, 1H), 7.38
(m, 1H), 7.32 (m, 1H), 7.20 (m, 1H), 7.13 (m, 1H), 4.75 (s, 2H), 3.74 (s, 3H);
ES-MS m1z
446.0 [M+H]+, LCMS RT (min) 2.34.
Example 16 as shown in Table B was made according to this method substituting
the appropriate starting materials.

Example 11
Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-{ f(2-{ f(ethylamino)
carbonyllamino}Ryridin-4- 1)~yllaminol-l-methyl- 1 H-pyrazole-
4-carboxamide trifluoroacetate

O \ I O~F
(J1 H
N NH H H
CH3 NuN~CH3
O iN IOI
F
OH
F F



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The title compound was prepared using the same method described for Example 1.
The intermediate L was used in place of intermediate D and the concentrated
HPLC
fractions were analyzed without free-basing with NaHCO3.

1H NMR (300 MHz, CD3CN) S 8.45 (s, 1H), 8.30 (s, 1H), 8.02 (d, 1H), 7.77 (s,
1H), 7.73 (s, 1H), 7.34 (s, 1H), 7.26 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H),
4.65 (s, 2H), 3.68
(s, 3H), 3.28 (q, 2H), 1.15 (t, 3H); ES-MS nz/z 474.3 [M+H]+, LCMS RT (min)
2.53.

Example 12
Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{ f (2-
{f(methylarnino)carbonyllaminolpyridin-4- 1)methyllaminol-
1 H-pyrazole-4-carboxamide trifluoroacetate
O F
~ ~
O F
N/ H
N NH H H
CH3 t'N NuN.CH
II 3
0 0
F
OH
F F

Step 1: Preparation of ethyl5-f f(2-aminopyridin-4- 1)rnethyll(formyl)aminol-l-
methyl-
1 H-pyrazole-4-carb oxylate

O
O---CHa
N
H3C N 0

~ ~ NH2
~N

A solution of crude ethyl 5-(formylamino)-1-methyl-lH-pyrazole-4-carboxylate
(500.00mg, 2.54mmo1) from Example 2, step 1, in THF (7.5ml) was treated with
diazabicyclo(5.4.0)undec-7-ene (0.57m1, 3.80mmo1) and allowed to stir at room
temperature for 30 minutes. 2-Amino-4-chloromethylpyridine (723.09mg,
5.07mmo1) was
added, and the reaction mixture was heated to 60 C for one hour, then allowed
to stir at
room temperature for 16 h. The reaction mixture was then diluted with ethyl
acetate and
washed with saturated NaHCO3 solution, followed by water, then brine. The
organic layer
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was dried over NaaSO4 and concentrated in vacuo, yielding 440mg (57.1%,
impure)
product as a 2:1 mixture of product to deformylated product.
ES-MS rrz/z 304.1 [M+H]+, HPLC RT (min) 1.08.
Step 2: Preparation of ethyl5-f({2-f(tert-butoxycarbonyl)aminolpyridin-4-
yl 1 methyl)(formyl)aminol-l-methyl-lH-pyrazole-4-carboxylate

O
O--~CH3
N
H3C N~O
N
~ N ~-O
0
A solution of crude ethyl5-[[(2-aminopyridin-4-yl)methyl](formyl)amino]-1-
methyl-

1H-pyrazole-4-carboxylate (500.OOmg, 1.651nmol) in THF (5m1) was treated with
N,N-
diisopropylethylamine (0.32m1, 1.81mmo1) and 4-dimethylaminopyridine (20.14mg,
0.16mmo1). Di-tert-butyl dicarbonate (1.81m1 of 1M solution in THF) was added
to the
reaction mixture and allowed to stir at room temperature for 16 h. The
reaction mixture
was then diluted with ethyl acetate and washed with concentrated NH4C1
solution,
followed by water, then brine. The organic layer was dried over Na2SO4 and
concentrated
in vacuo. The crude residue was triturated with ether, and the solvent was
again
evaporated yielding 600mg (90.1%, impure) product. The product was used
without
purification.

Step 3: Preparation of 5-f({2-f (tert-butoxycarbonyl)aminolpyridin-4-
l~thyl)aminol-
1-methyl-1 H-pyrazole-4-carboxylic acid

O
N OH
% N
CH3 NH

/ ~ N
~N O~- O
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The title compound (130.0mg, 25.1 Io) was prepared in a similar fashion to
Example 2, step 3, using ethyl5-[({2-[(tert-butoxycarbonyl)amino]pyridin-4-
yl}methyl)(formyl)amino]-1-methyl-lH-pyrazole-4-carboxylate (600.0mg,
1.49mmol) as
starting material.

1H NMR (300 MHz, CD3CN) 8 8.28 (bs, 1H), 8.18 (d, 1H), 7.89 (s, 1H), 7.55 (d,
1H),
6.98 (m, 1H), 4.59 (m, 2H), 3.64 (s, 3H), 1.50 (s, 9H).
Step 4: Preparation of tert-butyl (4-f f(4- { f(2 2-difluoro-1 3-benzodioxol-
5-yl)arninolcarbonyl l-1-methyl-lH-Ryrazol-5-yl)aminol
methyl I pyridin-2-yl)carbamate
O O F
N~ N ~
N H O F
CH3 NH

NH y-
'ON O~ - 0

The title compound (90.0mg, 48.4%) was prepared in a similar fashion to
Example
2, step 4, using 5-[({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}methyl)amino]-
1-methyl-
1H-pyrazole-4-carboxylic acid (130.0mg, 0.37mmol) as starting material. This
material
was used without purification.
ES-MS nz/z 502.8 [M+H]+, HPLC RT (min) 2.83.

Step 5: Preparation of 5-f f(2-aminopyridin-4-yl)methyllaminoI -N-(2 2-
difluoro-1 3-
benzodioxol-5-yl)-1-methyl-1 H-pyrazole-4-carboxamide

O ~
\ ~ F
N x
N H O F
CH3 NH

~ ~ NH2
~N

A solution of tert-butyl (4-{ [(4-{ [(2,2-difluoro-l,3-benzodioxol-5-
yl)amino]carbonyl } -1-methyl-1 H-pyrazol-5-yl)amino]methyl }pyridin-2-
yl)carbamate
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(66.15mg, 0.13mmol) in dichloromethane (1.5m1) was treated with
trifluoroacetic acid
(1.4m1, 18.12mmo1) and allowed to stir at room temperature for 16 hours. The
reaction
mixture was then diluted with ethyl acetate and washed with 1N NaOH solution.
The
aqueous layer was extracted with EtOAc, and the organic extracts were combined
and
dried over MgSO4. Concentration of the EtOAc solution in, vacuo gave 60.0mg
(>99%)
crude product estimated 50% pure by 1H NMR. The product was used without
purification.
ES-MS rn/z 403.1 [M+H]+, HPLC RT (min) 0.99.

Step 6: Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{ f(2-
j f (methylamino)carbonyllamino lpyridin-4-yl)meth_yllamino l-
1 H-pyrazole-4-carboxarnide trifluoroacetate
O \ I O 'F

O~F
N// ~ H
N NH H H
CH3 NuN.CH
II 3
0 N O
F
OH
F F

The title compound was prepared using the same method described for Example 8
step 3. In Step 3, methyl isocyanate was used in place of ethyl isocyanate.
The worlcup for
the final step was different in that the concentrated HPLC fractions were
analyzed without
free-basing with NaHCO3.

1H NMR (300 MHz, CD3CN) 812.10 (s, 1H), 8.40 (s, 1H), 8.06 (bd, 2H), 7.72 (d,
2H), 7.32 (s, 1H), 7.20-7.27 (m, 2H), 7.15 (d, 1H), 4.63 (s, 2H), 3.63 (s,
3H), 2.80 (d, 3H);
ES-MS in/z 460.3 [M+H]+, LCMS RT (min) 2.37.

Table B

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LCMS
Entry Structure Chemical Name LC-MS RT
No. [M+H]+
min
N
H3c-N~' '~o 1-methyl-5-{[(2-
{[(methylamino)carbonyl]a
HN HN O F mino}pyridin-4-
N ~F yI)methyl]amino}-N-
NH O F F (2,2,3,3-tetrafluoro-2,3-
dihyd ro-1,4-benzodioxin-6-
oNH yI)-1 H-pyrazole-4-
13 H 3 c carboxamide; 532 2.63
H3C-N O

HN HN 1-methyl-5-{[(2-
\ ~ ~ {[(methylamino)carbonyl]a
N / mino}pyridin-4-
O yl)methyl]amino}-N-[4-
NH F
(trifluoromethoxy)phenyl]-
ONH F F 1 H-pyrazole-4-
14 Hs6 carboxamide; 464.1 2.4
H3C-N O
5-{[(2-
HN HN {[(ethylamino)carbonyl]ami
, iao no}pyridin-4-
N yl)methyl]amino}-1-methyl-
o~ H kF N-[4-
NH F F (trifluoromethoxy)phenyl]-
1 H-pyrazole-4-
15 ~H3 carboxamide; 478 2.5
H30-NN~ O F
OI
HN N F F 5-[({2-
H [(aminocarbonyl)amino]pyr
i ~ idin-4-yI}methyl)amino]-1-
N ~ methyl-N-[4-
HN (trifluoromethoxy)phenyl]-
> NH2 1 H-pyrazole-4-
16 carboxamide; 450 2.4
O F 1-methyl-5-{[(2-
N~ N o~GF {[(methylamino)carbonyl]a
H H mino}pyridin-4-
N NHH ~-N O yl)methyl]amino}-N-[3-
H3~ 3 N (trifluoromethoxy)phenyl]-
1 H-pyrazole-4-
17 N carboxamide; 464 2.48


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1"~F
H3C-NN~ p ~ S\
HN N F F 1-methyl-5-{[(2-
H {[(methylamino)carbonyl]a
N ~ mino}pyridin-4-
yl)methyl]amino}-N-{4-
HN H [(trifluoromethyi)thio]phen
N yl}-1 H-pyrazole-4-11
18 0 CH3 carboxamide; 480.1 2.64
H3C-NN~-p I a"~z p F N-(3-chloro-2,2,3-trifluoro-
F 2,3-dihydro-1,4-
HN
p~
CI F benzodioxin-6-yI)-1-methyl
5-{[(2-
N ~ {[(methylamino)carbonyl]a
HN H mino}pyridin-4-
N yl)methyl]amino}-1 H-
19 p cH3 pyrazole-4-carboxamide; 526 2.73
Example 20-a
Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-
{ [(2{methyl[(methylamino)carbonyllaminolpyridin-4-yl)methyllamino}-1H-
pyrazole
4-carboxamide

0 ~ ~ ~ F
~ I N O
N
H
N NH CH3 H
H3C I ~ Ny N'CH
3
~N 0

Step 1: Preparation of [2-(methylamino)pyridin-4-yllmethanol
OH CH3
NH

N
A solution of (2-chloropyridine-4-yl)methanol (from the preparation of
Intermediate P, Step 1) and methylamine hydrochloride in pyridine is heated at
200 C in
a sealed tube for about 16 h. The solvent is removed by evaporation in vacuo
and the
crude product residue is purified by chromatography on silica gel using a
gradient from
dichloromethane to about 10 % methanol in dichloromethane.

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Step 2 Preparation of 4-(chloromethyl)-N-methylpyridin-2-amine
CI CH3
~ NH
I ~N

By using the general method of preparation of Intermediate E, Step 1 but
substituting [2-(methylamino)pyridin-4-yl]methanol for (2-aminopyridin-4-
yl)methanol,
the Title compound is prepared.

Step 3. Preparation of N-f4-(chloromethyl)pyridin-2-_yll-N,N'-dimeth. l
CI CH3 H

tTN Ny N'CH3
O
The step is carried out using the method described for the preparation of
Intermediate L but using the product of Step 2 above rather than 4-
(chloromethyl)pyridin-
2-amine and methyl isocyanate rather than ethyl isocyanate.

Step 4: Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-5-{r(2-
{ methyl((methylamino)carbonyll amino }pyridin-4-yl)methyllamino } -1H-
p_yrazole-4-
carboxamide

0 ~ ~ ~ F
N, I N O
H
N NH CH3 H

H3C ~ Ny N'CH3
I
,N 0

The title compound can be prepared using the same method described for Example
1 but
starting with 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-
pyrazole-4-carboxamide (Intermediate A) and a proportionate amount of N-[4-
(chloromethyl)pyridin-2-yl]-N,N'-dimethylurea (from Step 3) rather than
Intermediate D.
The reaction mixture is heated at 60 C in a foil wrapped flask under nitrogen
for between
2 and 24 h until an LCMS analysis of the reaction mixture shows substantial
conversion to
products. The resulting final crude mixture is diluted with saturated aqueous
sodium
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bicarbonate and extracted 3 times with ethyl acetate. The combined extracts
are dried
(Na2SO4) and evaporated in vacuo to yield a residue that is purified by
preparative C18
HPLC using water to acetonitrile gradient (usually 10-50%) with added 0.05-0.1
% TFA.
The free base is prepared from the TFA salt by addition of saturated aqueous
NaHCO3 to
the fractions containing the product and extraction with dichloromethane
followed by
drying of the extract (Na2SO4) and concentration in vacuo to yield pure title
compound.

Examples 20-b to 20-x
O
H,Ar
N% N NH H R13
H3C \ N~N,R1-6

I ~N O

Step 1: Preparation of various N-(4-(chloromethyl)p~idin-2-y11ureas with other
N-
substituents
CI H R1-a
N~N,R16
N 0

By using the methods described for the preparation of Intermediate L but
substituting the appropriate alkyl or aryl isocyanate rather than ethyl
isocyanate, (using
either DMF or dichloromethane) the intermediates which lead to examples 20-b
to 20-g,
20-i, and 20-o to 20-w of Table C are prepared. By using the methods described
for the
preparation of Intermediate E, step 2 but using the appropriate carbamoyl
chloride rather
than acetoxyacetyl chloride, the intermediates which lead to Examples 21-k to
21-n of
Table C can be prepared. In all cases the appropriate isocyanate or carbamoyl
chloride is
either comrnercially available or the synthesis is straightforward to one
skilled in the art
and is reported in the general literature.

Step 2: Preparation of the Title Compounds (Table C)
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O
N~ I H,Ar

,N NH H Ri s
H3C N-Tr N, Ri-6
N 0

The title compounds can be prepared using the same method described for
Example 1 but starting with 5-amino-N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-
methyl-lH-
pyrazole-4-carboxainide (Intermediate A) or another material from the list of
Intermediates B, B-2, B-3, B-4 or B-5 instead of hitermediate A and
proportionate
amounts of the appropriate Intermediate from Step 1 above rather than
Intermediate D and
also proportional amounts of the other reaction components. The reaction
mixture is
heated at 60 C in a foil wrapped flask for between 2 and 24 h until an LCMS
analysis of
the reaction mixture shows substantial conversion to products. The resulting
final crude
mixture is diluted with saturated aqueous sodium bicarbonate and extracted 3
times with
ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in
vacuo to yield
a residue that is purified by preparative C 18 HPLC using water to
acetonitrile gradient
(usually 10-50%) with added 0.05-0.1 % TFA. The free base is prepared from the
TFA
salt by addition of saturated aqueous NaHCO3 to the fractions containing the
product and
extraction with dichloromethane followed by drying of the extract (Na2SO4) and
concentration in vacuo to yield pure title compound. In the case of Title
compounds 20-h
and 20-j, the initial blocked products 20-g and 20-i respectively are
converted to the final
Title compounds by treatment with potassium carbonate in methanol or ethanol.
Structures and names of the Title Compounds 20-a to 20-x are shown in Table C

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Table C
Example Structure Name
Number
20-a O CC ~F N-(2,2-difluoro-1,3-benzodioxol-5-
1 -1-meth 1-5- 2-
0 Y ) Y { [(
N N I H {methyl[(methylamino)carbonyl]a
, N H CH3 H
H3C rN.CH mino}pyridin-4-yl)methyl]amino}-
3
N 0 1H-pyrazole-4-carboxamide
20-b , O F 1-methyl-5-{ [(2-{ [(pyridin-4-
0 ~ ~
Nr I N~ O F ylamino)carbonyl]amino}pyridin-
H F 4-yl)methyl]amino}-N-(2,2,3,3-
N NH
H3C Nu H tetrafluoro-2,3-dihydro-1,4-
N 0 N benzodioxin-6-yl)-1H-pyrazole-4-
\ II
carboxamide
20-c O OF 1-methyl-N-(2,2,4,4-tetrafluoro-
0 4H-1,3-benzodioxin-6-yl)-
N H F F 5-{[(2-{[(1,3-thiazol-2-
N NH
H3C H N S ylamino)carbonyl]amino}pyridin-
N O N~ 4-yl)methyl] amino }-1 H-pyrazole-
4-carboxamide

20-d O , O~F 5-({[2-({[(4-cyano-2-methyl-l,3-
~ ~ F oxazol5-
N ( , H N yl)amino]carbonyl}amino)pyridin-
N NH t H H
H3C N N 4-yl]methyl}amino)-1-methyl-N-
N O O i N [4-(trifluoromethoxy)phenyl]-1H-
~ H3 pyrazole-4-carboxamide

s0


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20-e 0 F 5-{ [(2-
F
N i I N O~ F {[(cyclopropylamino)carbonyl] ami
N H no}pyridin-4-
, NH H H
Hsc Ny N yl)methyl]amino}-1-methyl-N-[3-
N O (trifluoromethoxy)phenyl]-
1 H-pyrazole-4-carboxamide

20-f 0 vF N-(2,2-difluoro-1,3-benzodioxol-5-
F
1 -1-meth 1-5- 2-
O Y) Y {[(
N
N,N NH H H {[(pyrimidin-2-
HsC Ny N'Ti" N\ ylamino)carbonyl] amino } pyridin-
N 0 N J 4-yl)
methyl] amino } -1 H-pyrazole-4-
carboxamide

20-g 0 O F 5-{[(2-
~ ~F {[(benzoylamino)carbonyl]amino}
Ni N O
H F pyridin-4-yl)methyl] amino }-1-
N NH /
H3C N N ~ ~ methyl-N-(2,2,3,3-tetrafluoro-2,3-
~
I N O O dihydro-1,4-benzodioxin-6-yl)-1H-
pyrazole-4-carboxamide
e

20-h O , O F 5-[({2-
~ ~ ~F [(aminocarbonyl)amino]pyridin-4-
N/ ~ H O F yl } methyl)amino]-
N NH H
H3C NuNH2 1-methyl-N=(2,2,3,3-tetrafluoro-
II
I ~ N O 2,3-dihydro 1,4 benzodioxin
6-yl)-1 H-pyrazole-4-carboxamide
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20-i o I 0~F 2-[({ [4-({ [1-methyl-4-({ [4-

~ F (trifluoromethoxy)phenyl]
N~ x N O
N H amino}carbonyl)-1H-pyrazol-5-
H3C NH H H O CH3
N J yl] amino } methyl)pyridin-2-
~N 0 yl]amino}carbonyl)amino]ethyl
acetate
20-j o , pF 5-({ [2-({ [(2-

~ I F hydroxyethyl)amino]carbonyl}ami
N N ~ H no)pyridin-4-
, NH H H OH
H3C N N J yl]inethyl}amino)-1-methyl-N-[4-
~ ~ N ~ (trifluoromethoxy)phenyl]-
1 H-pyrazole-4-carboxamide
20-k 0 F F 5- {[(2-

N~ I H F {[(dirnethylamino)carbonyl] amino }
N NH H CH3 pyridin-4-yl)
H3C ~ N y N. CH3 methyl]amino}-1-methyl-N-[3-
I ~ N 0 (trifluoromethoxy)phenyl]-1H-
pyrazole-4-carboxamide

20-1 0 \ I O ~ F 5-( {[2-( {[(2-chloropyridin-3-
N O/~ yl)(methyl)amino]carbonyl}amino)
N% I H
N NH H CH3 CI pyridin-4-yl]methyl}amino)-N-
H3C N~ N N (2,2-difluoro-1,3-benzodioxol-
~ N 0 i 5-yl)-1-methyl-lH-pyrazole-4-
carboxamide

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O F 4-methyl-N-(4-{ [(1-methyl-4-
20-m O a-,
{ [(2,2,3,3-tetrafluoro-2,3-dihydro-
~F
N~ ~ H O F
1,4-benzodioxin-6-
IN NH H r'N.CH3
H3C N N J yl)amino]carbonyl}-1H-pyrazol-5-
N O yl)amino]methyl}pyridin-2-
yl)piperazine-l-carboxamide
N-(4-{ [(I-methyl-4-1[(2,2,4,4-
Oj
20-n O ic,
N 0 tetrafluoro-4H-1,3-benzodioxin-
N/ ~ H F F 6-yl)amino]carbonyl}-1H-pyrazol-
N NH H r'O
H3C N N J 5-yl)arnino]methyl}pyridin-
C,, N O 2-yl)morpholine-4-carboxamide
20-o O , Of ',F 1-methyl-5-{ [(2-
~ ~ 0 {[(methylamino)carbonyl]amino}p
N~ N
~ H F F yridin-4-
N NH
H3C N N yl)methyl]amino}-N-(2,2,4,4-
~ CH3
N y tetrafluoro-4H-1,3-benzodioxin-
6-yl)-1 H-pyrazole-4-carboxamide
1-methyl-5-{ [(2-
O
20-p 0 J:Dr
F {[(methylamino)carbonyl]amino}p
N~ N
, ~ H yridin-4-
N
NH
H
H3C N N,CH yl)methyl]amino}-N-[4-
~ N ~ 3 (trifluoromethoxy)phenyl]-1H-
pyrazole-
4-carboxamide
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20-q p ao F /F 1-methyl-5-{[(2-

N r N =~F {[(methylamino)carbonyl]arnino }p
'N NH H H yridin-4-
HsC NyN-CH3 yl)methyl]amino}-N-[3-
N O (trifluoromethoxy)phenyl]-1H-
pyrazole-
4-carboxam.ide

O F N-(2,2-difluoro-1,3-benzodioxol-5-
20-r 0 J::)c
Nr HO F yl)-1-methyl-5 {[(2-{[(pyridin-
N NH H H 3-
H3C I~ NN I~N ylamino)carbonyl]aznino}pyridin-
~ N O 4-y1)methyl]amino}-1H-
pyrazole-4-carboxamide
20-s O F
5-({[2-({[(2-furylmethyl)
~F amino]carbonyl } amino)pyridin-4-
Nr I N F
~N H yl]methyl } amino)-1-methyl-N-
,
H3C NH H N ~ ~ (2,2,3,3-tetrafluoro-2,3-dihydro-
~
( N N 0 1,4-benzodioxin-6-y1)-1H-
pyrazole-4-carboxamide
20-t 0 JIj1_O<F 1-methyl-5-({ [2-({ [(pyridin-4-
F ylmefihyl)amino]carbonyl}amino)
N
t'N NH H H IN pyridin-4-yl]methyl}amino)-N-[4-
H3C N N (trifluoromethoxY)PhenY1]-
I ~ N O~'
~ O 1H-pyrazole-4-carboxamide
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20-u O ~ F N-(2,2-difluoro-l,3-benzodioxol-5-
~ 1 -1-meth 1-5- 2-
~ I N O
N% Y) Y ({L
H ({ [(pyridin-2-
N NH H H N- H3C N N ~ I ylmethyl)amino]carbonyl}amino)p

N 0 yridin-
4-yl]methyl } amino)-1H-pyrazole-
4-carboxanude

20-v O o ~F YN-(2,2-difluoro-1,3-benzodioxol-5-
j::) 1)-1-methY1-5-({[2-
N'N I N NH H H O ({ [(tetrahydrofuran-2-
HsC N y N ylmethyl)amino]carbonyl } amino)p
N 0 yridin-
4-yl] methyl } amino)-1 H-pyrazole-
4-carboxamide

20-w o , o F 1 -methyl-5-({ [2-({ [(2-pyridin-2-
~ I ~F ylethyl)amino]carbonyl}amino)
N N o F
N H H H pyridin-4-yl]inethyl } amino)-N-
NH
H3C ~ NuN N\ (2,2,3,3-tetrafluoro-2,3-dihydro-
I~ N IOI 1,4-benzodioxin-6-yl)-1H-
pyrazole-4-carboxamide

20-x 0 JSF 1-methyl-5-{ [(2-
~ F {[(methylamino)carbonyl]amino}p
Ni N
H yridin-4-
N NH
H3C N N,CH yl)methyl]amino}-N-{4-
~ N ~ 3 [(trifluoromethyl)thio]phenyl}-1H-
pyrazole-4-carboxamide


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Example 21
Preparation of N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-meth.yl-5-({[2-
(methylamino)pyrimidin-4-yllmethyllamino)-1H-pyrazole-4-
carboxamide

0 \ ~ XF
N~ I N O
H
N NH H
CH3 N~N,
CH
I 3
oN

Step 1. Preparation of 5-{f(2 6-dichloropyrimidin-4-yl)methyllamino}-N-(2,2-
difluoro-
1,3-benzodioxol-5-yl)-1-meth 1-1H-pyrazole-4-carboxamide

XF
0 \ J::DCO
N~ I N , H
N NH
HsC NCI
oN
CI
A mixture of 2,4-dichloro-6-(chloromethyl)pyrimidine (Intermediate 0, 99 mg,
0.5
mmol) and sodium iodide (75 mg, 0.5 mmol) in anhydrous DMF (0.5 mL) is stirred
under
nitrogen until a solution forms and then 5-amino-N-(2,2-difluoro-1,3-
benzodioxol-5-yl)-1-
methyl-lH-pyrazole-4-carboxamide (Intermediate A, 100 mg, 0.33 nrnmol) is
added. The
resulting mixture is heated and stirred under nitrogen at 40 C for 4 h and
then at 59 C
overnight. If after TLC analysis some remaining pyrazole starting materials
are present,
additional 2,4-dichloro-6-(chloromethyl)pyrimidine (30 mg) is added and the
reaction
rnixture is again heated at 59 C for another 2 h. The resulting final crude
mixture is
diluted with saturated aqueous sodium bicarbonate and extracted 3 times with
ethyl
acetate. The combined extracts is dried (Na2S04) and evaporated in vacuo to
yield a
residue that is purified by chromatography on silica gel using a gradient from
10-40 %
ethyl acetate in hexane.
Step 2. Preparation of 5-( { f 6-chloro-2-(methylamino)pyrimidin-4-yllmethyl I
amino)-
N-(2 2-difluoro-1 3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide and 5-
({ f2-
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chloro-6-(methylamino)pyrimidin-4- ll~methyl}amino)-N-(2 2-difluoro-1 3-
benzodioxol-
5-yl)-1-meth 1-1H-pyrazole-4-carboxamide

O \ o~~ p o,F
OJ~ ~O~ F
H H
N NH H N NH
CH3 NN,CH3 CH3 I N~CI
iN ~N
CI H3CNH
A solution of 5-{[(2,6-dichloropyrimidin-4-yl)methyl]amino}-N-(2,2-difluoro-
1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (the product of step
1, 0.2
minol) and methylamine (0.4 mmol) in methanol (1.2 mL) can be stirred in a
sealed tube
for -5h. The products can be purified by direct injection on a preparative
HPLC to yield
purified isomers wherein the 6-(methylamino)pyrimidin-4-yl isomer is expected
to be the
major product.
Step 3. Preparation of the Title Compound

A mixture of 5-( {[6-chloro-2-(methylamino)pyrimidin-4-yl]methyl } amino)-
N-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide (the
minor
product of step 2, 0.18 mmol) plus palladium (II) hydroxide (0.36 mmol) and
ammonium
formate (1.76 mmol) in ethyl acetate (15 mL) and methanol (15 mL) can be
stirred with
heating at reflux for 16 h. The product solution can be filtered using Celite0
filter aid and
evaporated in vacuo. The residue can be purified by preparative C 18 HPLC
using a
gradient from 5 to 45% acetonitrile in water plus 0.1% TFA. Evaporation of
product
containing fractions can yield pure compounds as TFA salts. Alternatively, the
fractions
containing the product can be mixed with saturated aqueous NaHCO3 and
extracted with
dichloromethane. The extracts are dried (Na2SO4) and evaporated in vacuo to
yield pure
free base title compound.

Example 22
Preparation of 5-{[(2-aminopyridin-4-vl)methyllamino}-1-methyl-N-(2,2,3,3-
tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1H-pyrazole-
4-carboxamide

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O O F F
IF
N/ ~ H O F
N NH
CH3 ~ NH2
I ~N

This compound was prepared as shown in Example 8 and is the product of Step 2.
Example 23
Preparation of tert-butyl (4-jr(4-{ f (2,2-difluoro-1,3-benzodioxol-
5-yl)aminolcarbonyll-l-methyl-lH-p_yrazol-5-yl)aminol
methyllpyridin-2-_yl)carbamate

F
N~ N x
,N ~ H O F
CH3 NH

~ ~ NH
~ N O~--0

This compound was prepared as shown in Example 12 and is the product of Step
4.
Example 24
Preparation of 5-{ f (2-aminopyridin-4-yl)methyllaminol-N-(2,2-difluoro-1,3-
benzodioxol-5-yl)-1-methyl-lH-pyrazole-4-carboxamide
O O
F
N ~ A
N H CH3 NH

~ ~ NH2
~N
This compound was prepared as shown in Example 12 and is the product of Step
5.
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B. Evaluation of physiological activity

The utility of the compounds of the present invention can be illustrated, for
example, by
their activity in the P-AKT/PKB Cytoblot Assay described below.
The involvement of the P-AKT/PKB[ PI3K/AKt] pathway as a target for cancer
chemotherapy has been recognized in the art. For example, see F. Chang et al,
Iizvolvement
of PI3K1Akt pathway in cell cycle progression, apoptosis, and neoplastic
transformation:
a target for carzcer chem,otherapy, Leukemia, 2003, 17: p. 590-603; K. A. West
et al,
Activation of the PI3K/Akt pathway and chemotlzerapeutic resistance, Drug
Resistance
Updates, 2002, 5: p. 234-248; and P. Sen et al, Involvefnent of the Akt/PKB
signaling
pathway with disease processes, Molecular and Cellular Biochemistry, 2003,
253: p. 241-
246.

P-AKT/PKB Cytoblot Assay Protocol with H209 Cells
H209 small cell lung carcinoma cells in log phase were plated at 50,000
cells/well in 96-
well poly-lysine coated, clear bottom/ black-sided plates (Becton-Dickinson,
USA Cat #
354640) in 100 l RPMI medium containing 0.1% (w/v) BSA, and incubated
overnight at
37 C in 5% CO2 incubator. The following day, compounds (10 mM stock solutions
in
DMSO) were added to the plates to generate final concentrations of 0.0, 0.01,
0.03, 0.1,
0.3, 1.0, 3.0 and 10 M for IC50 determinations and incubated for 1 hour at 37
C. Cells
were then left untreated or stimulated with Stem Cell Factor (SCF: Biosource
Cat #
PHC2116) at a final concentration of 25 ng/mL for 5 minutes at 37 C in 5% CO2
incubator. The media was then removed using a vacuum manifold and the cells
were
washed once with Tris Buffered Saline (TBS). Cells were then fixed by adding
200 l of
cold 3.7% (v/v) formaldehyde in TBS to each well for 15 minutes at 4 C. After
removal
of the formaldehyde, the cells were treated with the addition of 50 l of
methanol (at -

20 C) to each well for 5 minutes. After removal of the methanol, 200 l of 1%
(w/v) BSA
in TBS was added to each well to block non-specific antibody binding sites and
the plate
was incubated at room temperature for 30 minutes.
After removal of the blocking buffer, 50 1 of p-(S473) AKT rabbit polyclonal
antibody (Cell Signaling, USA Cat # 9277S) was added at a dilution of 1:250 in
0.1%
(w/v) BSA in TBS, and the plate was incubated at room temperature for 1 hour.
Plates
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were then washed 3 times with cold TBS containing 0.05% (v/v) Tween 20 (TBS-T)
and
100 l of Horseradish peroxidase (HRP)-conjugated goat-anti-rabbit antibody
(Amersham,
USA Cat # NA934V) at a dilution of 1:250 in TBS-T was added and the plate was
incubated at room temperature for lh. After washing with ice-cold TBS-T four
times, 100
l of Enhanced Chemiluminescence (ECL) reagent (Amersham, USA Cat# RPN2209)
was added to each well and mixed on a mini-orbital shaker for 1 min. The plate
was then
read on a Perkin Elmer Victor 5 Multilabel Counter (#1420-0421).
Compounds of examples 1, 3-a, 3-b, 3-c, 3-d, 8, 9, 10,11, 12, 13, 14, 15, 16,
16, 17, 18, 19.
were tested in the above P-AKT/PKB Cytoblot assay, with the result that these
examples
exhibited IC50 values of less than 500 nM. In one embodiment, the present
invention
relates to a compound which exhibits an IC50 value of less than 500 nM in this
assay.

The utility of the compounds of the present invention can also be illustrated,
for example,
by their activity in the phosph-ERK Assay described below.
Growth-factor induction of the RAS/MEK/ERK signaling pathway leads to the
induction
of phosphorylation of a number of proteins including phospho-ERK (See C. J.
Marshall,
MAP kinase kinase kinase, MAP kinase kinase and MAP kinase, Current Opinions
in
Genetic Development, 1994, 4: p. 82-89). The importance of this pathway in
cancer
biology has been recognized in the art. Activation of the RAS signaling
pathway is an
important mechanism by which cancer develops (R. Herrera, et al, Unr aveling
the
conaplexities of the Raf/MAP kinase pathway for pharmacological intervetztion,
Trends
Mol. Med., 2002, 8: p. S27-3 1). Mutational activation of RAS or downstream
effectors as
well as growth factor induction of this pathway leads to increased tumor cell
proliferation
and survival (A. A. Adjei, Blockifzg oncogenic RAS sigyzaling for cancet=
therapy, J. Natl.
Cancer Inst., 2001, 93(14): p. 1062-1074; J Schlessinger, Cell signaling by
receptor
tyrosine kinases, Cell, 2000, 103: p. 211-225).

Phospho-ERK Cytoblot Assay Protocol with MDA-MB 231 Cells
MDA-MB-231 cells in log phase were plated at 25,000 cells/well in 96-well
opaque plates
(Falcon, USA Cat # 353296) in 100 L RPMI medium containing 10% (w/v) FBS, and
incubated overnight at 37 C in 5% CO2 incubator. The following day, the growth
medium
was removed from the plate by aspiration and replaced with RPMI medium
containing


CA 02610509 2007-11-30
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0.1% BSA and example compounds diluted to generate final concentrations of
0.0, 0.001,
0.003, 0.01, 0.03, 0.1, 0.3, 1 and 3 M. Cells were incubated with compound
for 1 hour
at 37 C in a 5% CO2 incubator. The media was then removed from the plate by
aspiration
and the cells were washed once with 180 ,L/well cold Tris Buffered Saline
(TBS). After
removal of the wash buffer, the cells were fixed by adding 180 L of cold 3.7%
(v/v)
formaldehyde in TBS to each well for 1 hour at 4 C. After removal of the
formaldehyde,
the cells were treated with the addition of 60 L of -20 C methanol to each
well for 5
ininutes at 4 C. The methanol was removed and the cells were washed with 180
L/well
of 5% (w/v) BSA in TBS. To block non-specific antibody binding sites, each
well was
treated with 180 L/well 5% BSA (w/v) in TBS for thirty minutes at room
temperature.
After removal of the blocking buffer, 50 L of an anti-phospho-p44/42 MAP
kinase
(Thr202/Tyr204) rabbit polyclonal antibody (Cell Signaling, USA Cat # 9101)
was added
to each well at a dilution of 1:1000 in 5% (w/v) BSA in TBS, and the plate was
incubated
at 4 C overnight. Plates were then washed three times with 300 L/well TBS at
room
temperature. The plates were then incubated with 50 gL of Horseradish
peroxidase
(HRP)-conjugated goat-anti-rabbit antibody (Amersham, USA Cat. # NA934V) at a
dilution of 1:1000 in 5% BSA-TBS at room temperature for 1 hr. After washing
the plate
three times with 300 L/well TBS, 60 L of Enhanced Chemiluminescence (ECL)
reagent
(Amersham, USA Cat# RPN2209) was added to each well and incubated at room
temperature for five minutes. The plate was then read on a Perkin Elmer Victor
5
Multilabel Counter (#1420-0421).
The compounds of examples 1, 10, 11, 12, 13, 14, 15, 17, 18, 19, were tested
and showed
an IC50 value of less than 3 M in this assay. In one embodiment, the present
invention
relates to a compound which exhibits an IC50 value of less than 3 M.

The utility of the compounds of the present invention can also be illustrated,
for example,
by their activity in the flk-1(murine VEGFR2) Assay described below.
The VEGF-VEGFR2 signaling pathway has been extensively characterized as an
important regulator of angiogenesis and tumor angiogeneisis (See G.
Yancopoulos et al,
Vascula.r-specific growth factors afid blood vessel forizzatiofz, Nature,
2000, 407: p.. 242-
248; D. Shweiki et al, Ifzductiofz of vascular efidotl2elial growth factor
expression by
lzypoxia afzd by glucose deficiezzcy ifzinulticell spheroids: Ifzzplicatioyzs
for tufnor=

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angiogenesis, Proc. Natl. Acad. Sci, 1995, 92: p. 768-772). Inhibition of
tumor cell growth
by blocking this pathway has been well documented in the art. Administration
of soluble
VEGFR2 receptors inhibits the growth of a wide variety of tumors (See C. Bruns
et al,
Vascular endothelial growt7a factor is an in vivo survival factor for tumor
endotlieliunz in a
murine ntodel of colorectal liver metastases, Cancer, 2000, 89: p. 495-499; B.
Millauer et
al, Glioblastoina growtlz inhibited in vivo by a dominant-negative FLK-1
mutant, Nature,
1994, 367: p. 576-579). Neutralizing antibodies to VEGF or VEGFR2 and VEGF
antisense suppress tumor growth in vivo (See K. Kim et al, Inhibition of
vascular
endotlteli.al growth factor-induced angiogenest's suppresses tumor growtlz in
vivo, Nature,
1993, 362: p. 841-844; M. Prewett et al, Antivascular erzdothelial growth
factor receptor
(fetal liver kinase 1) monoclonal antibody iithibits tuntor angiogenesis and
growth of
several mouse and human tutnors, Cancer Research, 1999, 59: p. 5209-5218; M.
Saleh et
al, Inhibition of growth of C6 glioma cells in- vivo by expression of
antisense vascular
endotlzelial growth factor sequence, Cancer Research, 1996, 56: p. 393-401).

Flk-1 (murine VEGFR-2) Biochemical AssaX
This assay was performed in 96-well opaque plates (Costar, USA Cat #3915) in
the TR-
FRET format. Reaction conditions were as follows: 10 M ATP, 25 nM poly
(Glu,Tyr)-
biotin (CIS BIO International, USA Cat#61GTOBLD), 2 nM Eu-labelled phospho-Tyr
Ab
(Perkin Elmer, USA Cat#AD0067), 10 nM Strepavidin-APC (Perkin Elmer, USA
Cat#CR 130-100), 7 nM Flk-1 (kinase domain), 1% DMSO, 50 mM HEPES pH 7.5, 10
mM MgC12, 0.1 mM EDTA, 0.015% BRIJ, 0.1 mg/mL BSA, 0.1% mercapto-ethanol.
Prior to the addition of enzyme, compounds were added to final concentrations
ranging
from 10 M to 4.56 nM in 1% DMSO. The reaction was initiated upon addition of
enzyme. Final reaction volume in each well was 100 L. Time-resolved
fluorescence was
read after excitation at 340 nM. Emission readings were taken at both 665 and
615 nM on
a Perkin Elmer Victor V Multilabel counter at 1.5 - 2.0 hrs after reaction
initiation. Signal
was calculated as follows: Emission 665 nm/ Emission 615 nM x 10000 for each
well.

The compounds of examples 10,13, 16, 17, 18, 19, were tested and showed an
IC50 value
of less than 500 nM in this assay. In one embodiment, the present invention
relates to a
compound which exhibits an IC50 value of less than 500 nM.

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Method of Treating
Another embodiment of the present invention thus relates to a method of using
the
compounds described above, including salts thereof and corresponding
compositions
thereof, as cancer chemotherapeutic agents . This method comprises
administering to a
patient an amount of a compound of this invention, or a pharmaceutically
acceptable salt
thereof, which is effective to treat the patient's cancer. A patient, for the
purpose of this
invention, is a mammal, including a human, in need of treatment for a
particular cancer.
Cancers include but are not limited to solid tumors, such as cancers of the
breast,
respiratory tract, brain, reproductive organs, digestive tract, urinary tract,
eye, liver, skin,
head and neck, thyroid, parathyroid and their distant metastases. Those
disorders also
include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal
carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular
carcinoma in
situ.
Examples of cancers of the respiratory tract include, but are not limited to
small-
cell and non-small-cell lung carcinoma, as well as bronchial adenoma and
pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and
hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma,
ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to
prostate and
testicular cancer. Tuinors of the female reproductive organs include, but are
not limited to
endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma
of the
uterus.
Tumors of the digestive tract include, but are not limited to anal, colon,
colorectal,
esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and
salivary gland
cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile,
kidney,
renal pelvis, ureter, and urethral cancers.
Eye cancers include, but are not limited to intraocular melanoma and
retinoblastoma.

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Examples of liver cancers include, but are not limited to hepatocellular
carcinoma
(liver cell carcinomas with or without fibrolamellar variant),
cholangiocarcinoma
(intrahepatic bile duct carcinoma), and mixed hepatocellular
cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's
sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin
cancer.
Head-and-neck cancers include, but are not limited to laryngeal /
hypopharyngeal /
nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-
Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma
of
the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue,
osteosarcoma,
malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous
leukemia,
and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a
similar etiology in other mainmals, and can be treated by administering
pharmaceutical
compositions of the present invention.

The compounds of this invention can be administered as the sole pharmaceutical
agent or in combination with one or more other pharmaceutical agents where the
combination causes no unacceptable adverse effects. For example, the compounds
of this
invention can be combined with known anti-hyper-proliferative,
chemotherapeutic, or
other indication agents, and the like, as well as with admixtures and
combinations thereof.
Optional anti-hyper-proliferative agents which can be added to the composition
include but are not limited to compounds listed on the cancer chemotherapy
drug regimens
in the 1 lth Edition of the Merck Index, (1996), such as cisplatin.
Other anti-hyper-proliferative agents suitable for use with this invention
include
but are not limited to those compounds acknowledged to be used in the
treatment of
neoplastic diseases in Goodman and Gilnz.an.'s The Phaf=nzacological Basis of
Tlzerapeutics
(Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-
1287, (1996)
such as idarubicin.

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C. Operative examples relating to pharmaceutical compositions

The active compound can act systemically, locally or both. For this purpose it
can
be administered in a suitable manner, such as for example by oral, parenteral,
pulmonary,
nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival
or aural
administration or in the form of an implant or stent. The active compound can
be
administered in forms suitable for these modes of administration.

Suitable forms of oral administration are those according to the prior art
which
function by releasing the active compound rapidly or in a modified or
controlled manner
and which contain the active coinpound in a crystalline, amorphous, or
dissolved form, for
example tablets (which can be uncoated or coated, for example with enteric
coatings or
coatings which dissolve after a delay in time or insoluble coatings which
control the
release of the active compound), tablets or films (wafers), which disintegrate
rapidly in the
oral cavity, films/lyophilisates, capsules (e.g. hard or soft gelatin
capsules), dragees,
pellets, powders, emulsions, suspensions and solutions. An overview of
application forms
is given in Remington's Pharmaceutical Sciences, 18th ed. 1990, Mack
Publishing Group,
Enolo.

Parenteral administration can be carried out by avoiding an absorption step
(e.g. by
intravenous, intraarterial, intracardial, intraspinal or intralumbar
administration) or by
including absoiption (e.g. by intramuscular, subcutaneous, intracutaneous or
intraperitoneal administration). Suitable parenteral administration forms are
for example
injection and infusion formulations in the form of solutions, suspensions,
einulsions,
lyophilisates and sterile powders. Such parenteral pharmaceutical compositions
are
described in Part 8, Chapter 84 of Remington's Pharmaceutical Sciences, 18th
ed. 1990,
Mack Publishing Group, Enolo.

Suitable forms of administration for the other modes of administration are for
example inhalation devices (such as for example powder inhalers, nebulizers),
nasal drops,
solutions and sprays; tablets or films/wafers for lingual, sublingual or
buccal
administration or capsules, suppositories, ear and eye preparations, vaginal
capsules,
aqueous suspensions (lotions or shaking mixtures), lipophilic suspensions,
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creams, transdermal therapeutic systems, milky lotions, pastes, foams, dusting
powders,
implants or stents.

The active compounds can be converted into the abovementioned forms of
administration in a manner known to the skilled man and in accordance with the
prior art
using inert, non-toxic, pharmaceutically suitable auxiliaries. The latter
include for
example excipients (e.g. microcrystalline cellulose, lactose, mannitol, etc.),
solvents (e.g.
liquid polyethylene glycols), emulsifiers and dispersants or wetting agents
(e.g. sodium
dodecyl sulfate, polyoxysorbitan oleate etc.), binders (e.g. polyvinyl
pyrrolidone),
synthetic and/or natural polymers (e.g. albumin), stabilizers (e.g.
antioxidants, such as, for
example, ascorbic acid), dyes (e.g. inorganic pigments such as iron oxides) or
taste-
and/or odour-corrective agents.

The total amount of the active ingredient to be administered will generally
range from
about 0.01 mg/kg to about 200 mg/kg, and preferably from about 0.1 mg/kg to
about 20
mg/kg body weight per day. A unit dosage may contain from about 0.5 mg to
about 1500
mg of active ingredient, and can be administered one or more times per day.
The daily
dosage for administration by injection, including intravenous, intramuscular,
subcutaneous
and parenteral injections, and use of infusion techniques will preferably be
from 0.01 to
200 mg/kg of total body weight. The daily oral dosage regimen will preferably
be from
0.01 to 200 mg/kg of total body weight.

It may however be necessary to deviate from the abovementioned quantities,
depending on the body weight, mode of administration, the individual patient
response to
the active compound, the type of preparation and the time or interval of
administration.

If used as active compounds, the compounds according to the invention are
preferably isolated in more or less pure form, that is more or less free from
residues from
the synthetic procedure. The degree of purity can be determined by methods
known to the
chemist or pharmacist (see Remington's Pharmaceutical Sciences, 18t" ed. 1990,
Mack
Publishing Group, Enolo). Preferably the compounds are greater than 99% pure
(w/w),
while purities of greater than 95%, 90% or 85% can be employed if necessary.

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The compounds according to the invention can be converted into pharmaceutical
preparations as follows:

Tablet:
Composition:
100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of
maize
starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF,
Ludwigshafen,
Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.
Preparation:

The mixture of active component, lactose and starch is granulated with a 5%
solution
(m/m) of the PVP in water. After drying, the granules are mixed with magnesium
stearate
for 5 min. This mixture is moulded using a customary tablet press (tablet
format, see
above). The moulding force applied is typically 15 kN.

Orally administrable suspension:
Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of
Rhodigel
(xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of the compound according to the invention is provided
by 10 ml
of oral suspension.

Preparation:
The Rhodigel is suspended in ethanol and the active component is added to the
suspension. The water is added with-stirring. Stirring is continued for about
6h until the
swelling of the Rhodigel is complete.

It is believed that one skilled in the art, using the preceding information,
can utilize
the present invention to its fullest extent. It should be apparent to one of
ordinary skill in
the art that changes and modifications can be made to this invention without
departing
from the spirit or scope of the invention as it is set forth herein. Other
embodiments of the
invention will be apparent to the skilled in the art from a consideration of
this specification
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or practice of the invention disclosed herein. It is intended that the
specification and
examples be considered as exemplary only, with the true scope and spirit of
the invention
being indicated by the following claims.

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