CA2622725A1

CA2622725A1 - 5-oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of c-fms kinase

Info

Publication number: CA2622725A1
Application number: CA002622725A
Authority: CA
Inventors: Mark R. Player; Hui Huang; Daniel Hutta
Original assignee: Individual
Current assignee: Janssen Pharmaceutica NV
Priority date: 2005-09-14
Filing date: 2006-09-13
Publication date: 2007-03-22
Also published as: CN101305000A; JP2009507924A; KR20080045279A; BRPI0615838A2; AU2006291007A1; EP1937681A1; WO2007033232A1; CN101300258A

Abstract

The invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase. The invention is directed to the novel compounds of Formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: W, A, Y, Z, R101 and R200 are described in the specification.

Description

5-OXO-5,8-DIHYDRO-PYRIDO-PYRIMIDINES AS INHIBITORS OF C-FMS KINASE
CROSS REFERENCE TO RELATED APPLICATIONS

This present application claims benefit of U.S. Provisional Patent Application Serial No. 60/714,527, filed September 14, 2005, which is incorporated herein by reference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION

The invention relates to novel compounds that function as protein tyrosine kinase inhibitors. The family of 5-oxo-5,8-dihydro-pyrido-pyrimidines has exhibited promising pharmaceutical properties in the past; United States Patent 4,556,709, JP
09221424 and DE
19532235 are indicative of recent investigations. More particularly, the invention relates to novel compounds that function as inhibitors of c-fms kinase.

c-Fms is a type III receptor tyrosine kinase selectively expressed on macrophages and their progenitors. The extracellular Ig domain of c-fms binds macrophage colony stimulating factor (M-CSF), also known as colony stimulating factor-1 (CSF-1).
Binding of CSF-1 induces receptor dimerization and trans-phosphorylation of the intracellular c-fms kinase domain on Y723 and other tyrosine residues. Once phosphorylated, c-fms efficiently phosphorylates several cytoplasmic signaling molecules that lead to de novo gene expression and proliferation. Small molecule inhibitors of the kinase catalytic site of c-fms are expected to prevent CSF- 1 induced cellular responses.

Macrophages are a predominant source of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in the destructive pannus of rheumatoid arthritis. TNF
and IL-1 activate stromal expression of hematopoietic factors including CSF-1. In turn, recruits monocytes and promotes macrophage survival, functional activation, and in some settings, proliferation. Thus, TNF and CSF-1 interact in a perpetuating cycle that leads to inflammation and joint destruction. The exclusive receptor for CSF-1 is c-fms, and the disclosed invention is a c-fms inhibitor designed to interrupt this cycle.

Macrophages are abundant at sites of chronic inflammation where they are are often the most important source of TNF, IL-1, and other cytokines. Moreover, macrophages can be an important source of factors that function in tissue remodeling such as plasminogen activators, matrix metalloproteases, vascular endothelial growth factor, and transforming growth factor -(3. The numbers of macrophages present within.
target tissues have strongly correlated with disease severity in rheumatoid arthritis (Ann'Rheum Dis'53 (1994) pp 39-44), immune nephritis (Kidney Int 54 (1998) pp 143-151), and graft rejection (Transpl Int 7 Suppl 1 (1994) pp 577-579). Macrophage numbers are also elevated in atherosclerotic plaque (Arch Pathol Lab Med 109 (1985) pp 445-449), adipose tissue in obesity (J Clin Invest 112 (2003) pp 1796-1898), diabetic nephropathy.(Kidney Int 65 (2004) pp 116-128), cardiac hypertrophy (Hypertension 25 (1999) pp132-138), and in many solid tumors (Trends in Immunology 23 (2002) pp 549-555), particularly breast cancer (J. Experimental Medicine 193 (2001) pp 727-739), where they are thought to' contribute to disease progression. Modulation of macrophage functionthr-ough inhibition of c-fms thus is expected to be useful in treating inflammatory mediated diseases and conditions.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: rheumatoid arthritis, graft rejection, atherosclerosis, obesity, diabetic nephropathy, cardiac hypertrophy and solid tumor diseases, especially breast cancer, in a subject in need of such treatment.

Preclinical data suggest CSF-1/FMS is a particularly viable therapeutic target for rheumatoid arthritis. Recent work has shown that neutralizing antibodies to CSF-1 reduce substantially the severity of collagen-induced arthritis in mice (J Leukoc Bio168 (2000) pp 144-150). The authors additionally demonstrated that recombinant CSF-1 exacerbated the disease progress in this model. Therefore, a preferred use for the invention is the treatment of rheumatoid arthritis.

SUMMARY OF THE INVENTION

The invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase.

The invention is directed to the novel compounds of Formula I:

R1o1 0 R200 U N ~
.
N~W N
H A\Y

or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein W, A, Y, Z, Rlol and R200 are as defined herein.

The invention is also directed to a method of using a compound of Formula I
for inhibiting protein tyrosine kinase activity comprising administering an effective amount of at least one compound of Formula I.

The invention is directed to a method of inhibiting c-fms kinase activity in a subject in need thereof comprising administering to the subject an effective amount of at least one compound of Formula I.

The invention is also directed to a method of treating or ameliorating a c-fms kinase mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of at least one compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to a compound of Formula I:

N ~ Z
II /

NJ~W N
H A
, Y
or a form thereof, wherein:

WisNorCH;
A is absent or alkyl;

Y is a ring selected from cycloalkyl, bicycloalkyl, aryl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

Rlol is hydrogen, hydroxyl, methyl, halogen, -CF3, or methoxy;

R200 is halogen, alkoxy optionally substituted with -CH(OH)-CH2-NR203R204~
alkyl optionally substituted with R201, heterocyclyl optionally substituted with one alkyl and optionally substituted with one R202, amino, alkylamino, dialkylamino, -C(O)(CH2)nNR203R204, heteroaryl, or R300_R4oo; wherein n is 0, 1, 2, 3, or 4;
R201 is hydroxyl, methyl, lialogen, -CF3, amino, alkylamino, dialkylamino or methoxy;
R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)nNR203R204' or -CON-alkyl-NR203R204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

Ra Ra Rd j-~N ~ R -N~N
Ra O ~j ~. -Ra Ra 0 RN-~- ~0- O SN ~N + CN1-, and S~N: ~ , I I ~ ~

wherein Ra, Rc and Ra are independently hydrogen or alkyl;
R3o0 is alkyl;

R400 iS -NR403R404, -SO2NR405R4061 oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R401, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R4oi;

wherein R401 is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R404 are independently hydrogen, alkyl, or R403 and R404 may be taken together to form a ring selected from the following:

a Ra R Rd O N-~- ~- ~ O~ CN g aY R -N N O, 3- 0= S~N#'- ~-R ~ > > , , Ra O
Ra 0 RN-3- O CN ~N 3 O;S~N 3 and S~N3 =
. ~/
wherein Ra, R and Rd are independently hydrogen or alkyl;

R 405 and R406 are independently hydrogen, alkyl, or R4os and R406 may be taken together to form a ring selected from the following:

Ra Ra Rd 0N O.
N"~- S N O=S Nf- S N"y-, Ra ~/ O
Ra/
N~
Ra O~S-\N O' ,\N O' S'\
and N-~- .
~ ~/ ~ O N ~ ~
~
wherein Ra, R and Rd are independently hydrogen or alkyl; and Z is CO2H, CO2alkyl, or CONR1R2; wherein Rl is hydrogen or alkyl; and R 2 is hydrogen, alkyl, cycloalkyl, or alkoxy.

An example of the present invention is a compound of Formula I or a form thereof, wherein:

W is N or CH;

A is absent or alkyl;

Y is a ring selected from cycloalkyl, bicycloalkyl, aryl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

Rlol is hydrogen, hydroxyl, methyl, halogen, -CF3, or methoxy;

20 is halogen, alkoxy optionally substituted with -CH(OH)-CH2-NR2o3R2oa R , alkyl optionally substituted with R201, heterocyclyl optionally substituted with one alkyl , and optionally substituted with one R20z, dialkylamino, -C(O)(CH2)õNR203R204 heteroar l, or -R3oo-Raoo y ; wherein n is 0, 1, 2, 3, or 4;

R201 is hydroxyl, methyl, halogen, -CF3, dialkylamino or methoxy;

R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)NR203R204, or -CON-alkyl-NR2 3R204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

Ra Ra ~ Rd tN- 0 N + RC_ N_~- 0, N 0= "N-~ S N=1-Ra Q
Ra Ra N O SN j" ~N-- p ~N=~- and S L ~N-~- .

wherein Ra, R and Rd are independently hydrogen or alkyl;
R30o is alkyl;

R400 iS -NR403R404, -S02NW05R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R401, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R401;

wherein R401 is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R4o4 are independently hydrogen, alkyl, or R 403 and R404 may be taken together to form a ring selected from the following:

Ra Ra Rd YN ~ Rc- N_~_ ~ S N~ 0= N~- S N'~-~--/ Ra ~ , 0 Ra a R O O
rO N 3 ' CN 3 jN+
O~ CNf, and S--\N-~- , wherein Ra, R and Ra are independently hydrogen or alkyl;

R405 and R4o6 are independently hydrogen, alkyl, or R405 and R406 may be taken together to form a ring selected from the following:

Ra Ra Rd Nf ~-~N I R - N ~ Oi N"~- 0- ~~N~ ~S N=~-a R a >.-! O / , Ra N~
Ra N~ O'S~N ~ O' \N_1_~~CNI, : S
O and N-~- .
~
wherein Ra, R'and Rd are independently hydrogen or alkyl; and Z is CO2H, CO2alkyl, or CONR1R2; wherein Rl is hydrogen or alkyl; and R2 is hydrogen, alkyl, cycloalkyl, or alkoxy.

Examples of the present invention iriclude those compounds of Formula I or a form thereof wherein one or more of the following limitations are present:

WisNorCH;
A is absent;

Y is a ring selected from cycloalkyl, bicycloalkyl, phenyl, 'alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

Rlo1 is hydrogen, hydroxyl, methyl, halogen, -CF3, or methoxy;

R200 is halogen, C(l.4)alkoxy optionally substituted with -CH(OH)-CH2-NR203R204, C(i-4)alkyl optionally substituted with R?ol, heterocyclyl optionally substituted with one C(l-4)alkyl and optionally substituted with one R202, dialkylamino, -C(O)(CH2)nNR203R204, heteroaryl, or -R30 -R40o; wherein n is 0, 1; 2, 3, or 4;

R2oi is hydroxyl, methyl, halogen, -CF3, dialkylamino or methoxy;
R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)nNR203R204, -C(O)N(CH2)nNR203R204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, C(1-4)alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

Ra Ra Rd bNf O N-1- Ra N~
Ra~ ~ ~ and Ra wherein Ra, R' and Ra are independently hydrogen or alkyl;

R30o is C(l_4)alkyl; and R400 is -NR403R404, -S02NR405R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R4o1, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R401;

wherein R4o1 is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R404 are independently hydrogen, C(1.4)alkyl, or R403 and iZ404 may be taken together to form a ring selected from the following:

Ra ~ a N R
Ra C)N-j- d R
'~- ~--~ R -N N-~ ~~~///~N-~
Ra ~ >--/ ' and Ra wherein Ra, R and Rd are independently hydrogen or alkyl;

R405 and R406 are independently hydrogen, C(l4)alkyl, or R405 and R406 may be taken together to form a ring selected from the following:

Ra Ra Rd a tN-~- ~N_~- R - ~N + R N-~-, Ra ~ \ / , and ~
Ra/

wherein Ra, R and Rd are independently hydrogen or alkyl; and Z is COZalkyl, or CONR1R2; wherein Rl is hydrogen or C(1-4)alkyl; and R2 is hydrogen, C(1.4)alkyl, cycloalkyl, or C(1-4)alkoxy.

In another embodiment of the invention one or more of the following limitations are present:

WisN;
A is absent;

Y is a ring selected from cycloalkyl or arylcycloalkyl;
Rlol is hydrogen;

R2oo, is -R3oo_R4oo; and Z is CO2alkyl, or CONRIR2; wherein Rl and R2 are independently hydrogen, or C(l-4)alkyl.
Examples of the present invention include those compounds of Formula I or a forxn thereof wherein one or more of the following limitations are present:

WisN;
A is absent;

Y is a ring selected from cycloalkyl or arylcycloalkyl;
Rlol is hydroxyl, methyl, halogen, -CF3, or methoxy;

R200 is piperazine optionally substituted with one or two methyl substituents, piperidine optionally substituted with one or two methyl substituents, morpholine or _R30o_R400 wherein R3oo is methyl or ethyl and R4oo is piperazine optionally substituted with one or two methyl substituents; and Z is CO2alkyl, or CONR1R2; wherein Rl is hydrogen or C(l-4)alkyl; and R2 is hydrogen, C(l-4)alkyl, or cycloalkyl.

Examples of the present invention include those compounds of Formula I or a form thereof wherein one or more of the following limitations are present:

Wis N;

A is absent;

Y is a ring selected from cyclohexyl, cyclopentyl, bicyclo[2.2.ljheptyl, indanyl, phenyl or 1,2,3,4-tetrahydronaphthalenyl;

Rlol is hydrogen, hydroxyl, methyl, halogen, -CF3, or methoxy;

R200 is heterocyclyl (preferably tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 4-methyl piperazin-l-yl, piperazinyl, morpholinyl, or thiomorpholino), dialkylamino, _R300-R400' ' or C(l-4)alkyl wherein said C(1.4)alkyl is optionally substituted with one or both substituents selected from hydroxyl and dialkylamino;

R300 is C(1_4)alkyl;

R400 iS _NR 403R404, _S02p&05R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R4o1, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R401;

wherein Raol is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R404 are independently hydrogen, C(l-4)alkyl, or R403 and R404 may, be taken together to form a ring selected from the following:

a Ra R Rd 3 Ra tNf ~N 3 R - ~N-~ and N-~-, Ra >--/ ~ ~
Ra wherein Ra, Rc and Ra are independently hydrogen or alkyl;

-4)alkyl, or Raos and R4o6 may be taken R4os and R4o6 are independently hydrogen, C(1' together to form a ring selected from the following:
Ra Ra Rd Ra N1- O N~ Rc- N-1- and R>--/
Ra and wherein Ra, R and Rd are independently hydrogen or alkyl;

Z is C02alkyl, or CONR1R2; wherein Rl is hydrogen or C(l-4)alkyl; and RZ is hydrogen, C(I-4)alkyl, cycloalkyl, or C(l-4)alkoxy.

Examples of the present invention include those compounds of Formula I or a form thereof wherein one or more of the following limitations are present:

W is N or CH;

A is absent or alkyl;

Y is a ring selected from indan-5-yl, phenyl, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptyl or adamantan-2-yl;

Rlol is hydrogen or hydroxyl;

R200 is fluorine, alkoxy substituted with -CH(OH)-CH2-N(CH3)2, alkyl optionally substituted with R201, morpholinyl, piperazinyl optionally substituted with R202, 3,5-dimethyl piperazinyl, piperidinyl, piperidinyl substituted with -C(O)-alkyl-N(CH3)2, -C(O)-alkyl-piperazinyl (optionally substituted on piperazinyl with alkyl), dimethylamino, -C(O)N(CH3)2, heteroaryl, or -R300-R400;
R201 is hydroxyl or dimethylamino;

R202 is -CH3;
R310 is alkyl; and R4o0 is -N(CH3)2, morpholinyl, -SO2NR405R406, piperazinyl optionally substituted with R202 or oxazolidinonyl;

R405 and R406 are independently hydrogen, alkyl, or R405 and R4 6 may be taken together to form the following ring. 'and Z is CO2alkyl, or CONR1R2; wherein Rl is hydrogen or alkyl; and R2 is hydrogen, alkyl, cycloalkyl, or alkoxy.

An example of the present invention includes compounds of Formula I or a form thereof wherein:

W is N or CH;
A is absent;

Y is a ring selected from cycloalkyl, bicycloalkyl, phenyl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

Rlol is hydrogen, hydroxyl, methyl; halogen, -CF3, or methoxy;

R200 is halogen, C(l~.)alkoxy optionally substituted with -CH(OH)-CH2-NR203R204~
C(l-4)alkyl optionally substituted with R201, heterocyclyl optionally substituted with one C(l-4)alkyl and optionally substituted with one R202, dialkylamino, -C(O)(CH2)nNR203R204, heteroaryl, or -R300-R400; wherein n is 0, 1, 2, 3, or 4;

R201 is hydroxyl, methyl, halogen, -CF3, dialkylamino or methoxy;
R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)õNR203R204, -C(O)N(CH2)nNR203 R 204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, C(l-4)alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

a =
Ra R Rd O N-1- ~a tN-~- ~ --~ Rc-N N-~ and Ra , ~

Ra wherein Ra, R and Rd are independently hydrogen or alkyl;
R300 is C(1_4)alkyl; and R400 iS -p&03R404, -S02 NR405R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R401, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R4oi;

wherein R401 is methyl, -C(O)-CH3, or -CH2-C(O)-C H3;

wherein R403 and R404 are independently hydrogen, C(1-4)alkyl, or R4o3 and R404 may be taken together to form a ring selected from the following:

Ra Ra Rd 3 Ra ~/N 3 RO-~N+ N-~- .
Ra , ~--~ , and ~
Ra wherein Ra, R and Rd are independently hydrogen or alkyl;

R405 and R406 are independently hydrogen, C(1~)alkyl, or R405 ~d Ra06 may be taken together to form a ring selected from the following:

Ra Ra Rd 0--~N__ Ra ~N'~- Rc-NN-l- N-~
, and ~
Ra wherein Ra, Rc and Rd are independently hydrogen or alkyl; and Z is CO2H.

An example of the present invention is a compound of Formula I'selected from the group consisting of:

O O 0 Oi 0 Oj N ~ 0 0 N ~ 0 HN N N HN N N HN N N

N O (N
N XH 'O
Cpd 1 -Cpd 2 Cpd 3 O OH
O O O O~ Nll~ O
. ~- ~
N O ~. O HN N N
HN N N HN N N

' N
N N f' J
N

Cpd 4 Cpd 5 Cpd,6 O O O O O O
N~ NH2 ~/ N~ N~ N~ N~
~ H H
~
HN' N N HN N N HN N N
(rJ) ') N N

Cpd 7 Cpd 8 Cpd 9 O O O O O O

~ ~ ( NH2 H/ H
HN N N HN N N HN N N

O O O
XH XH XH
Cpd 10 Cpd 11 Cpd 12 O O O O O O
~\ NH2 ~\ I NH2 N NH2 = /\~~
HN N N HN N= N HN' N, N
N~ CN
N O
Cpd 13 Cpd 14 Cpd 15 -0 O ) HN" , N N N ~ O N O
HN N N HN N N
N
~ ' (NJ oN\
N
I
Cpd16 Cpd17 Cpd18 O O
N~ ~ NH2 0 O 0 O"
HN,' N N 1 O NNt I O
HN N N HN N N

N O
N OH F
Cpd 19 Cpd 20 Cpd 21 O O N NH2 N~~NH2 N ''. I ~' HN N N HN N N
HN~N N

N,N N (0) NN Cpd 22 Cpd 23 Cpd 24 O O O O O O
N~ NH2 N% I NH2 N~ I NH2 HN N N HN N HN N N
HO ~~ 0 6 1 N N
'N) N N
I V CO) Cpd 25 Cpd 26 Cpd 27 O O O O I O O
N N- N~ NH1 N~ NH2 ~ H A
HN N N HN N N HN N N

N HN(N) ~

Cpd 28 Cpd 29 Cpd 30 O O o O O o J~' H ~' H/
HN N N HN N N HN N N

O o HN-J HN~ 02S~NH
O 0 Cpd 31 Cpd 32 Cpd 33 ~~ H H ~. ~ H
HN N N HN N N HN N N

02S~NH 02S~l N'~ 02S~Oo ~ ~O Cpd 34 Cpd 35 Cpd 36 O O O O O O
NNt NH2 N~ N
JH A
HN N N HN N N HN N N

~ ~~ '~
Cpd 37 Cpd 38 Cpd 39 NH2 NN/ N/\J~N
HN' N N I HN''N N H HNj ' N N I H
lNJ lNJ N
N N N
H H H
Cpd 40 Cpd 41 Cpd 42 O O O O O O
N NH2 N N~ N~ N~
~~ H '~ ~ H
HN N N HN N N HN N N

N~ N N
N~ N
H H H
Cpd 43 Cpd 44 Cpd 45 O O O O O O
NH2 N~ NJ
J:~ H ~. ~ H
HN N N HN N N HN N N

N N N
CN NJl 'N~
I I I

Cpd 46 Cpd 47 Cpd 48 IN\ ~ . : NH2 H N I H
HN N N HN N N HN N N

N N N
H H H
Cpd 49 Cpd 50 Cpd 51 O O O O O O

N~~ I N N~ I
H
'~ ~ <J'H
HN N N HN N N HN' N N
6 \ ~
~
~~H \ ~H (\,NH
Cpd 52 Cpd 534 Cpd 54 O O O O O O

~ NH2 ~ \ ~ H ~ \ I NH2 HN N N HN N N HN N N

N-~ N--~
)--NH ~NH N
/ O~

Cpd 55 Cpd 56 Cpd 57 O O O O O O
~~ H/ NH N\ NH2 HN N N HN N N HN N N
\I \I \I ' N
N N N
OJ O~
Cpd 58 Cpd 59 Cpd 60 O, O O O O O
NNk N N~ N N NH2 H ( H ~ = ~
HN N N HN N N HN N N
N N N
r 1 ~~\
'NJ N
I I
Cpd 61 Cpd 62 Cpd 63 O O O O O O

N~ N 7NH2~~ H ~~ H ~. ~
HN N N HN N N HN N N
/
' N
N\ N;
O2S~NH
Cpd 64 Cpd 65 Cpd 66 NH2 NH2 ' . NH2 HN' N N HN N N HN NA N

02S~ L"p N
~,O Ol~~

Cpd 67 Cpd 68 Cpd 69 ~~ NH2 NH2 NH2 HN N N HN N N HN N N

\/ N O

N N
O ~ O
N~
OeNll N' lNJ

Cpd 70 Cpd 71 Cpd 72 O O O O O O
~ ~ I NH2 N NH2 N H 2 HN N N HN N N HN N N

N
N O ON, ~ ON

Cpd 73 Cpd 74 Cpd 75 O O O O O O
N\ I NH2 N\T I N' N I N
\~~ JL/\H A/\~H
HN N N HN N N HN N N

iN= . iN. iN. ' Cpd 76 Cpd 77 Cpd 78 O O O O O O
H H
N\ I NH2 N~ \ I N' N\ I N
HN N N HN N N HN NN~
O
--N ~-N\ N

Cpd 79 Cpd 80 Cpd 81 O O O O O fl ~\ ( NH2 HN N N HN N N HN N N
N) N N
N N L,,N, i I

Cpd 82 Cpd 83 Cpd 84 O O
~
N
~ j H
HN N N

N
N
Cpd 85 Examples of the present invention include those compounds of Formula I or a form thereof selected from, but not limited to, the following:

1 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 2 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 3 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 4 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 6 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylainino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid, 7 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8 8-indan-5-yl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylaniide, 9 '8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-y1=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 11 2- [4-(3 -dimethylamino-2-hydroxy-propoxy)-phenylamino] -8-indan-5-y1=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide 12 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid =ethylamide, 13 2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 14 8-indan-5-y1-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3--d]pyrimidine-6-carboxylic acid amide, 16 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido{2,3-d]pyrimidine-6-carboxylic acid amide;
.17 8-cyclohexyl-2-[4-(4-methyl-pipexazin-1-yl)-phenylamino]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 18 8-cyclohexyl-2-(4-dimethylamino-phenylamino)=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 19, 8-cyclopentyl-2- [4-(4-methyl-piperazin-1-yl)-phenyl amino] -5-oxo=5;8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-hydroxymethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 21 2-(4-fluoro-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid ethyl ester, 22 8-indan-5-yl-5-oxo-2-(4-pyrazol-1-yl-phenylamino)=5,8-dihydro-pyridn[2,3-d]pyrimidine-6-carboxylic acid amide, 23 8-indan-5-yl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 24 8-indan-5-yl-2-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo=5,8-dihydro-pyrido.[2,3-d]pyrimidine-6-carboxyiic acid amide, 26 1-indan-5 -yl-7,[4-(4-methyl-piperazin-1-yl)-phenylamino] -4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid amide, 27 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 28. 8-Indan-5-y1-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino] -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 29 8-Indan-S-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 30 (4S)-8-Indan-S-yl-S-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 31 (4S)-B-Indan-S-yl-S-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 32 (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 33 8-Indan-S-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 34 8-Indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine=6-carboxylic acid ethyl amide, 35 8-Indan-5-yl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5;8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 36 8-Indan-5-yl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 37 8-Indan-5-y1-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-' pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 38 8-Indan-S-yl-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 39 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 40 8-Indan-S-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3--d]pyrimidine-6-carboxylic acid amide, 41 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5, 87dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methyl amide, 42 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 43 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-y1=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 44 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 45 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 46 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)=ethyl]-phenylamino}=5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 47 8-Indan-5-y1-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 48 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino }=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 49 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 50 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 51 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 52 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 53 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 54 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 55 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 56 - 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine=6-carboxylic acid methyl amide, 57 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 58 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 59 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 60 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 61 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 62 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 63 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 64 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 65 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 66 8-Cyclohexyl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 67 8-Cyclohexyl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 68 8-Cyclohexyl-2-{4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylainino}-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 69 8-Indan-5-y1-2-(4-morpholin-4-ylmethyl-phenylamino)-5-0X0-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 70 2-{4-[l-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-y1-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid arnide, 71 2-{ 3-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino }-8-indan-5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 72 8-Indan-5-yl-2-(4-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4=yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 73 8-Indan-5-yl-2-(3-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxyli'c acid arnide, 74 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxp=5,8--dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 75 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 76 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo=5,8-dihydxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 77 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 78 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo=5,8-dihydro=
pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 79 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-y1=5-oxo-5,8-dihydro-.
pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 80 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 81 2-(3 -Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 82 8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 83 8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 84 8-Indan-S-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5;8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, and 85 8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxn-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide:
The most preferred compounds are those having a c-fms IC50 < 25 iun.

The invention also relates to methods of inhibiting protein tyrosine kinase activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I. A preferred tyrosine kinase is c-fms.

The compounds of the present invention are further useful as markers for the c-fnis receptor. Compounds of formula (I) when used as markers are for example radio-labeled by for example, substituting at least one hydrogen atom with a tritium atom.
Other labeling techniques known in the arts can also be used.

An aspect of the use for a compound of Formula (I) includes use of an instant compound as a marker, wherein the compound is labeled with a ligand such as a radioligand (selected from deuterium, tritium and the like).

Cornpound Forms The term "form" means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form. The present invention encompasses all such compound forms and mixtures thereof.

The term "isolated form" means, in reference to compounds of the present invention, such may exist in an essentially pure state such as, without limitation, an enantiomer, a racemic mixture, a geometric isomer (such as a cis or trans stereoisomer), a mixture of geometric isomers, and the like. The present invention encompasses all such compound forms and mixtures thereof.

Certain compounds of Formula (I) may exist in various stereoisomeric or tautomeric forms and mixtures thereof. The invention encompasses all such compounds, including active compounds in the form of essentially pure enantiomers, racemic mixtures and tautomers.

The compounds of the present invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the "pharmaceutically acceptable salts" of the compounds of this invention refer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a soiution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Furthermore when the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, -e.g.
sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Thus, representative pharmaceutically acceptable salts include the following:
acetate, =_ benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate (or camphosulphonate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate, glutamate, hydrabamine, hydrobromine, hydrochloride, iodide, isothionate, lactate, malate, maleate, mandelate, mesylate, nitrate, oleate, pamoate, palmitate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tartrate, tosylate.

The invention includes compounds of various isomers and mixtures thereof. The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or in an ability to rotate the plane of polarized light (stereoisomers).

The term "optical isomer" means isomers of identical constitution that differ only in the spatial arrangement of their groups. Optical isomers rotate the plane of polarized light in different directions. The term "optical activity" means the degree to which an optical isomer rotates the plane of polarized light.

The term "racemate" or "racemic mixture" means an equimolar mixture of two enantiomeric species, wherein each of the isolated species rotates the plane of polarized light in the opposite direction such that the mixture is devoid of optical activity.

The term "enantiomer" means an isomer having a nonsuperimposable mirror image. The term "diastereomer" means stereoisomers that are not enantiomers.

The term "chiral" means a molecule which, in a given configuration, cannot be superimposed on its mirror image. This is in contrast to achiral molecules which can be superimposed on their mirror images.

The invention is considered to include the tautomeric forms of all compounds of Formula I. In addition, for chiral embodiments of the invention, the invention is considered to include pure enantiomers, racemic mixtures, as well as mixtures of enantiomers having 0.001% to 99.99% enantiomeric excess. In addition, some of the compounds represented by Formula I may be prodrugs, i.e., derivatives of a diug that possess superior delivery capabilities and therapeutic value as compared to the active drug.
Prodrugs are transformed into active drugs by in vivo enzymatic or chemical processes.

The two distinct mirror image versions of the chiral molecule are also known as levo (left-handed), abbreviated L, or dextro (right handed), abbreviated D, depending on which way they rotate polarized light. The symbols "R" and "S" represent the configuration of groups around a stereogenic carbon atom(s):

An example of an enantiomerically enriched form isolated from a racemic mixture includes a dextrorotatory enantiomer, wherein the mixture is substantially free of the levorotatory isomer. In this context, substantially free means the levorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10 %, less than 5 %, less than 2 % or less than 1 % of the mixture according to the formula;

%alevorotatory = (jnassleyorotatory) X100 (mass dextrorotatory) + (mass levorotatory) Similarly, an example of an enantiomerically enriched form isolated from a racemic mixture includes a levorotatory enantiomer, wherein the mixture is substantially free of the dextrorotatory isomer. In this context, substantially free means the dextrorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10 %, less than 5 %, less than 2 % or less than 1% of the mixture according to the formula:

(ritass dextrorotatory) % dextrorotatory = X100 (nzass dextrorotatory) + (mass levorotatory) "Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or,to a bridged bicyclic system. Substituent atoms (other than hydrogen) on each side of a carbon-carbon double bond may be in ari E or Z configuration. In the "E" configuration, the substituents are on opposite sides in relationship to the carbon- carbon double bond.. In the "Z"
configuration, the substituents are oriented on the same 5ide in relationship to the carbon-carbon double bond.

Substituent atoms (other than hydrogen) attached to a ring system may be in a cis or trans configuration. In the "cis" configuration, the substituents are on the same 'side in relationship to the plane of the ring; in the "trans" configuration, the substituents are on opposite sides in relationship to the plane of the ring. Compounds having a mixture of "cis" and "trans" species are designated "cis/trans".

The isomeric descriptors ("R," "S," "E," and "Z") indicate atom configurations relative to a core molecule and are intended to be used as defined in the literature.
Furthermore, compounds of the present invention may have at least one crystalline, polymorph or amorphous form. The plurality of such forms are included in the scope of the invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like).
The plurality of such solvates are also intended to be encompassed within the scope of this invention.

CheTiaical Nomenclature afid Definitions Bond lines drawn into a ring system from a substituent variable indicate that the substituent may be attached to any of the substitutable ring atoms.

As used herein, the following terms are intended to have the following meanings (additional definitions are provided where needed throughout the Specification). The definitions herein may specify that a chemical term has an indicated formula.
The particular formula provided is not intended to limit the scope of the invention, but is provided as an illustration of the term. The scope of the per se definition of the term is intended to include the plurality of variations expected to be included by one of ordinary skill in the art.

Definitions The term "alkyl" refers to both linear and branched chain radicals of up to 8 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl. The term "C(,,_y)alkyl" refers to an alkyl chain of length not less than x carbons and not more than y carbons. For example, the term C(1-4)alkyl refers to both linear and branched chain radicals of up to 4. carbon atoms. Alkyl radicals or linking groups may be attached to a core molecule via a terminal carbon atom or via a carbon atom within the chain. Similarly, substituent variables may be attached to an alkyl linking group when allowed by available valences.

The term "amino" means an amine group of the formula: -NH2.

The term "alkylamino or dialkylamino" refers to an amino with one or two alkyl substituents, respectively, wherein the amino group is the point of attachment to the rest of the molecule.

The term "aryl" refers to monocyclic or bicyclic aromatic ring systems containing from 6 to 12 carbons in the ring. Alkyl substituents may optionally be present on the ring.
Examples include benzene, biphenyl, naphthalene (also referred toas naphthalenyl), azulenyl, anthracenyl and the like. Aryl radicals may be attached to a core molecule and further substituted on any atom when allowed by available valences.

The term "aromatic" refers to a cycloalkylic hydrocarbon ring system having an unsaturated, conjugated 7E electron system.

The term "aralkyl" refers to a CI_6 alkyl group containing an aryl substituent, in which the point of attachment is the alkyl group. Examples include benzyl, phenylethyl or 2-naphthylmethyl. It is possible that both the alkyl and aryl portion may be substituted, and in that case, it is intended that the alkyl group is closer to the core ring structure.

The term "alkylaryl" refers to a C1_6 alkyl group containing an aryl substituent, in which the point of attachment is the aryl group. It is possible that both the alkyl and aryl portion may be siubstituted, and in that case, it is intended that the aryl group is closer to the core ring structure.

The term "alkoxy" refers to a saturated branched or straight chain monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen substituent on a parent alkane, as in the formula: -O-CI_$alkyl.
Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy. The term "C(,_ y)alkoxy" refers to an alkoxy chain of length not less than x carbons and not more than y carbons. For example, the term C(l-4)alkoxy refers to both linear and branched alkoxy chain radicals of up to 4 carbon atoms. An alkoxy radical may be attached to acore molecule and further substituted when allowed by available valences.

The term "arylcycloalkyl" refers to a C8_10 fused bicyclic ring system comprising an aryl group and a cycloalkyl group in which the point of attachment is the aryl group, as in a benzofused C3_14cycloalkyl ring system defined below. Examples include, but are not limited to 1H-indenyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl and the like.

The term "cycloalkyl" refers to a saturated or partially unsaturated ring composed of from 3 to 14 carbon atoms. Up to four alkyl substituents may optionally be present on the ring. The term also includes a C3_$cycloalkyl, C3_1ocycloalkyl, C5-6cycloalkyl, C5_8cycloalkyl, C5_12cycloalkyl, C$_locycloalkyl, C9_13cycloalkyl, C3_14cycloalkyl or benzofused C3_14cycloalkyl ring system. Examples include 1,1-dimethyl cyclobutyl, 1,2,3-trimethylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indenyl, indanyl, 9H-fluorenyl, 1,2,3;4-tetrahydro-naphthalenyl, acenaphthenyl, bicyclo[2.2.1]heptenyl and the like.
C3_14cycloalkyl radicals may be attached to a core molecule and further substituted on any atom when allowed by available valences.

The term "cycloalkylaryl" refers to a C8_10 fused bicyclic ring system comprising an aryl group and a cycloalkyl group in which the point of attachment is the cycloalkyl group, as in a benzofused C3_14cycloalkyl ring system defined above, such as 1H-indenyl, indanyl, 1,2,3,4-tetrahydro-naphthalenyl and the like.

The term "bicycloalkyl" refers to a saturated or partially unsaturated fused ixng pair composed of from 8 to 10 carbon atoms. Up to four alkyl substituents may optionally be present on the ring. Examples include adamantyl, bicyclo[2.2.1]heptenyl, decahydronaphthalenyl and 1,2,3,4 tetrahydropentalenyl and the like.

The term "hetero" used as a prefix for a ring system refers to the replacement of at least one ring carbon atom with one or more heteroatoms independently selected from N, S, or O. Examples include rings wherein 1, 2, 3 or 4 ring members are a nitrogen atom; or, 0, 1, 2 or 3 ring 'members are nitrogen atoms and 1 member is, an oxygen or 'sulfur atom.
When allowed by available valences, up to two adjacent ring members may be heteroatoms; wherein one heteroatom is nitrogen and the other is one heteroatom selected from N, S or O.

The term "heterocyclyl" refers to a nonaromatic (i.e. saturated or partially unsaturated) ring composed of from 3 to 7 carbon atoms and at least one heteroatom selected from N, 0 or S. Alkyl substituents and/or carbonyl substituents may optionally be present on the ring.. Examples include tetrahydrofuranyl, dihydropyranyl, piperidinyl, 2,5-dimethypiperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 2H-pyrrole, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, imidazolinyl (also referred to as 4,5-dihydro-lH-imidazolyl), 1,3-dioxolanyl, tetrazolinyl, tetrazolidinyl, 1,4-dioxanyl, 1,4-dithianyl, azetidinyl, azepanyl, hexahydro-1,4-diazepinyl, hexahydro-1,4-oxazepanyl, tetrahydro-thienyl, tetrahydro-pyranyl, tetrahydro-pyridazinyl, 1,3-benzodioxolyl (also referred to as,benzo[1,3]dioxolyl), 2,3 -dihydro- 1,4-benzodioxinyl (also referred to as 2,3-dihydro-benzo[1,4]dioxinyl) and the like.
Heterocyclyl radicals may be attached to a core molecule and further substituted on any atom when allowed by available valences.

The term "heteroaryl" refers to 5- to 7-membered mono- or 8- to 10-membered bicyclic aromatic ring systems, any ring of which may consist of from one to four heteroatoms selected from N, 0, S, S(O) or SOZ where the nitrogen and sulfur atoms can exist in any allowed oxidation state. Examples include benzoimidazolyl, benzothiazo]yl, benzothienyl, benzoxazolyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl, thienyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, indolizinyl, indolyl, azaindolyl, isoindolyl, benzofuranyl, indazolyl, azaindazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl and the like. Heteroaryl radicals may be attached to a core molecule and further substituted on any atom when allowed by available valences..

The term "heteroatom" refers to a nitrogen atom, an oxygen atom or a sulfur atom wherein the nitrogen and sulfur atoms can exist in any allowed oxidation states.

The term "sulfonyl" refers to the group -S(O)2RZ, where RZ is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl; aralkyl, heteroaryl and heterocyclyl.

The term "halogen" or "halo" means the,group fluoro, chloro, bromo or iodo.
The term "substituted," refers to a core molecule on which one or more hydrogen atoms have been replaced with one or more functional radical moieties. The number that is allowed by available valences limits the amount of substituents. Substitution is riot limited to the core molecule, but may also occur on a substituent radical, whereby the substituent radical becomes a linking group.

Therapeutic Uses The compounds of Formula I represent novel potent inhibitors of protein tyrosine kinases, such as c-fms, and may be useful in the prevention and treatment of disorders resulting from actions of these kinases.

The invention also provides methods of inhibiting a protein tyrosine kinase comprising contacting the protein tyrosine kinase with an effective inhibitory amount of at least one of the compounds of Formula I. A preferred tyrosine kinase is c-fms.
In one embodiment of inhibiting a protein tyrosine kinase, at least one of the compounds of Formula I is combined with a known tyrosine kinase inhibitor.

In various embodiments of the invention, the protein tyrosine kinases inhibited by the compounds of Formula I are located in cells, in a mammal or in vitro. In the case of mammals, which includes humans, a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I
is administered.

The invention further provides methods of treating cancer in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable composition of least one compound of Formula I. Exemplary cancers include, but are not limited to, ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma. In one embodiment of the invention, an,effective amount of at least one compound of Formula I is administered in combination with an effective amount of a chemotherapeutic agent.

The invention also provides methods of treating cardiovascular and inflammatory diseases in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Foxmula 1. Examples of diseases that may be effectively treated include atherosclerosis, cardiac hypertrophy, glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia and Alzheimer's dementia.

When employed as protein tyrosine kinase inhibitors, the compounds of the invention may be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g, in single or divided daily doses. A preferred dosage is 5 mg/kg, delivered orally. The dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments. ' The compounds of Formula I may be formulated into phaimaceutical compositions comprising any known pharmaceutically acceptable carriers. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents. Exemplary excipients that may also be components of the forinulation include fillers, binders, disintegrating agents and lubricants.

The pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts and salts with aniino acids such as arginine. Also, the basic nitrogen-containing groups may be quaternized with, for example; alkyl halides.

The pharmaceutical compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.

A representative compound of Formula (I) or a form thereof for use in the therapeutic methods and pharmaceutical compositions, medicines or medicaments described herein includes a compound selected from the group consisting of:

7 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 9 8-indan-5-yl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 11 2-[4-(3-dimethylamino-2-hydroxy- propoxy)-phenylamino]-8-indan-5-yl-5=oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide 12 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]=8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 14 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido,[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 16 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 19 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 23 8-indan-5-yl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 24 8-indan-5-yl-2-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 25 2-[2-hydroxy=4-(4-methyl-piperazin-1-yl)-phenylamino]-8-indan-5-y1-5-oxo-5,-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 26 1-indan-5-yl-7-[4-(4-methyl-piperazin-1-yl)-phenylamino]-4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid amide, 27 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 28 8-Indan-5=y1-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 29 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 30 (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 31 (4S)-8-Indan-5-yl-5-oxo-2-[4=(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine=6-carboxylic acid methyl amide, 32 (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 33 8-Indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 35 8-Indan-5-yl-2-{4-[2-(morpholine-4-sulfonyl)=ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 37 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 38 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 39 8-Indan-5-y1-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 40 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydto-pyrido{2,3-d]pyrimidine-6-carboxylic acid amide, 41 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methyl amide, 42 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 43 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-y1=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 44 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 45. 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino] -8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 46 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 47 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 48 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 49 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyridol2,3-d]pyrimidine-6-carboxylic acid amide, 50 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3=
d]pyrimidine-6-carboxylic acid methyl amide, 51 8-Indan-5 -y1-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 52 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 53 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5;8=dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 54 8-Indan-S-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 55 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 56 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 57 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro=
pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 60 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 63 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 64 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 69 8-Indan-5-y1-2-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 74 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 75 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydi-o-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 76 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 79 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 80 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-S,B-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 82 8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperaziri-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, and 84 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide.

General Synthetic Methods The compounds of Formula I can be prepared by methods known to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to limit the invention.

The following general reaction schemes display various methods of reaching the compounds of Formula I. It is recognized by those skilled in the art that some compounds of Formula I may be further derivatized to provide additional embodiments of the invention. Representative further derivitizations appear in schemes I, II, and V.

A typical preparation of compounds of the present invention is shown in Scheme I, wherein Ph is phenyl, which may be optionally further substituted witli Rlol An amine was reacted with ethyl3-chloropropionate at elevated temperature at the presence of an inorganic base and a catalytic amount of tetrabutylammonium bromide to afford the aminopropionate ester 1-1.

The amine was reacted with ethyl4-chloro-2-methylthio=5-pyrimidinecarboxylate to produce the corresponding 4-substituted aminopyrimidine 1-2. Cyclization of this diester under Dieckmann conditions afforded the bicyclic compound 1-3.

Subsequent halogenation with bromine followed by dehydrohalogenation gave the unsaturated 1-4 (Eur J Med Chem 9 (2000) pp 585-590). The methylthio group was oxidized to the sulfone 1-5, which was subsequently replaced with an amine by nucleophilic substitution.

The resulting carboxylic ester 1-6 was converted to the carboxylic acid 1-7 via basic hydrolysis. Decarboxylation to give 1-8 occured when the carboxylic acid was heated in DMSO in the presence of sodium cyanide (Tet Lett 35 (1994) pp 8303-8306).

The carboxylic acid 1-7 was.reacted with an amine under normal coupling conditions to form the corresponding amide 1-9. The amide 1-9 "could also be prepared directly from the ester 1-6 when the amine Rl-NH2 was ammonia, or an alkylamine:

Scheme 1 C02Et Cl C02Et y ---~COZEt INIS'N Cl K2C03, 100 C A Et3N
Bu4NBr (cat.) y n-BuOH

N C02Et rj C02Et t BuONa \ ~ 1) Br2 ---- S N N~,COZEt S N N 2) Et3N
1-2 A.Y 1-3 q C02Et O
C02Et I\ mCPBA rj R2o-Ph-NH2 \S~N N -> ~ /I
A ~~ N A i-PrOH, 90 C
1-4 I' 1-5 y C02Et O
N CO-NH-RI
\
Ph, N~N NI Rl-NH2 Ph\ I ~
R2oo H 1 Rzoo H N N

1-9 y NaOH Rl-NH2 N COOH N Ph DMSO / NaCN Ph _j'I 26 N N N
R2oo H N N R H AI
A ~Y
1-7 y 1-8 The synthesis was further extended to include the preparation of 5,8-dihydro-pyrido[2,3-d]pyrimidines with a carbonitrile functional group at the C6 position. The method of preparation was identical with that used for preparing the esters (Scheme I) except that suitably 3-substituted aminopropionitriles 2-1 were used in the first step (Scheme II).

Hydrolysis of 2-5 under basic conditions provided the corresponding primary amide 2-6, wherein Ph is phenyl, which inay be optionally further substituted with Rl 1 Scheme II

N
HN
~A 2-1 N \ CO2Et N COZEt y ~$~ N J~ Iji~CN
~
S N C1 Et3N
n-BuOH 2-2 y O O
CN CN
t-BuONa N 1) Br2 \ II ~ I
I
S N i 2) Et3N S N i 2-3 A~ 2-4 Ay O O O
1) mCPBA CN
-~ \ KOH N , I NH2 2) R2oo-Ph-NHZ HNN N I t-BuOH HN- ~

i-PrOH, A I 1 2-6 gp C Ph '-R200 y Ph'-'R 200 A--Y

When 6-amide was the desired product, the intermediate 3-1 was converted to the primary amide 3-2 using liquid ammonia in a pressure bottle (Scheme III).
Subsequent oxidation to methyl sulfone and nuclear substitution by an amine provided the desired 6-amide analogs 3-3, wherein Ph is phenyl, which may be optionally further substituted with Rioi Scheme III

N CO2Et 1 N
\ CONH2 J~ I I -> ~ I I
S N N IN 2. nz-CPBA O~\ N N
3-1 A, y O 3-2 A, y N \ ~2 R2oo_Ph-NH2 ~rN N
( 3-3 Ph A
~Rzoo y Compounds of formula (I) wherein W is CH were prepared by methods shown in Scheme IV, wherein Ph is phenyl, which may be optionally further substituted with Rlol.
4,6-Dihydroxy-nicotinic acid ethyl ester 4-1 was obtained via two steps from diethyl 1,3-acetonedicarboxylate. Treatment of 4-1 with POC13 gave 4,6-dichloio-nicotinic acid ethyl ester 4-2. The following nucleophilic substitution and Dieckmann cyclization reactions were similar to the methods outfined in Scheme I. The intermediate 4-5 was treated with au amine in N-methyl pyrrolidinone (NMP) under microwave conditions to afford the ester 4-6, which was subsequently converted to the amide 4-7.

Scheme IV

1) Trimethylorthoformate O ACZO ~~CO2Et PCI ~
EtO,C"~/CO2Et ~'l\
2) NH4OH HO OH

COZEt HN 1-1 CO2Et N \ COZEt y%~' N \
Cl N'~/CO2Et t-BuONa C1 ~ C1 0 A -~
4-2 4-3 y C02Et CO Et R2ooPh-NH2 N 1) Br2 N JY
Cl A 2) Et3N Cl ~NMP
\Y -5 \Y

N O
C02Et CONH2 NH3 N \
200 Ph'N I J Ph I
R H N CH30H R2oo ~ N
H ll 1-6 AY 2-6 Ay Where R200 is heterocyclyl, alkoxy or dialkylairiino, anilines of the form R2 phenyl-NH2 were prepared using SNAr reactions as shown in Scheme V (A) followed by hydrogenation converting the nitro group to the amino group. The phenyl portion of the compounds depicted in Scheme V may be optionally substituted with Riol Where R300 is alkyl, anilines of the form R 400-alkyl-phenyl-NH2 were prepared using SN2 reactions as shown in Scheme V (B) followed by hydrogenation converting the nitro group to the amino group.

Where R200 is -C(O)(CH2)nNR203R204, re aration of the aniline R2oo p p -phenyl-NH2 may be accomplished using SN2 reactions as shown in Scheme V (C) followed by hydrogenation converting the nitro group to the amino group. It is recognized by those skilled in the art that where n=O, the desired product may be obtained from nitrobenzoic acid, nitrobenzoyl chloride and other starting materials.

Alternatively, anilines where R200 is piperidinyl substituted with -C(O)-alkyl-NR203R204, may be obtained according to Scheme V (D and E).

Ketones of formula 5-1 can be converted to a vinyl triflate of formula 5-2 by treatment with a non-nucleophilic base such as LDA and then trapping of the resulting enolate with a triflating reagent such as trifluoromethanesulfonic anhydride or preferably N-phenyltrifluoromethanesulfonimide.

Suzuki coupling of boronic acids or boronate esters of formula 5-3 (prepared by palladium catalyzed borylation, see for example J. Org. Chein., 60: 7508 (1995)) to vinyl triflates of formula 5-2 provided compounds of formula 5-4 (see, for example, Synthesis, 993 (1991)). Reduction of the olefin with hydrogen over palladium on carbon gave the aniline 5-5. N-Boc protected anilines of formula 5-6 can be converted to amides of formula 5-7 through normal amide formation reactions (Scheme V, E). Anilines of formula 5-8 were obtained upon acidic deprotection of the Boc group. It is recognized by those skilled in the art that the same procedure described for Scheme V(E) can al'so be used to generate ureas wherein the R2 piperidine is substituted with -C(O)N-a1ky1=NR203R204 When R300 is alkyl, anilines of the form Rao7Ra0sNS02-alkyl-phenyl-NH2 were prepared as described in Scheme V (F). Thioacetate of formula 5-9 was obtained from nucleophilic replacement of bromide with potassium thioacetate. Hydrolysis followed by treatment with thionyl chloride afforded sulfonyl chloride of formula 5-10, which was subsequently converted to sulfonamides of formula 5-11 when treated with various amines.
The final nitro reduction provided the anilines of formula 5-12.

Scheme V

H (1NO2 H2 (\~2 ia NO2 R200 A).
/ 200 ~
F K2C03, DMF R200 Pd/C R

Br 01NO:400 Ra00 N02 ~2 B) ~
Raoo x{, /n ~
base, DMF Pd/C

C). Br O 203R204RN O 203RRN 0 NO 2 R203R2o4NH n br- N02 NHH n - base, DMF Pd/C

0 F3CO2S"0 -D). LDA, I/ 10% Pd/C I./
PhNTf2 5-3 0 / ' N \
N NH2 H2, MeOH
5-1 Boc 5-2 1 Pd(PPh3)a Boc 2M Na2CO3 Boc 4 Boc -5 tol/EtOH

O~
)n NHBoc ~2 or ~203R204 I I \
' -NHBoc OH
E). 01~ ~ 5-7 TFA 5-8 n ~203R204 N
O O
5-6 )n )n NH
NR 203R204 ~203R204 Br AcS ~S0 n n n Fl)= NO2 KSAc N02 1) AcOH; H2O2 Cl \ NO2 -~ -~
DMSO 2) SOC12 '5-9 5-10 Ra07\ 00 Rao \ ~S~
S
F2). 408N R40s%j n Rao7R4os_~ R n NO H2 ~2 2 5-11 I Pd/C 5-12 Example 1 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 1) ON CO2Et \ I J~ ~ I
N N N
H

A. 3-(Indan-5-ylamino)-propionic acid ethyl ester Tetrabutylammonium bromide (200 rrig) was added to a mixture of 5-aminoindan (5 g, 37.6 mmol), ethyl3-chloropropionate (4.7 mL, 37.6 mmol) and potassium caibonate (5.2 g, 37.6 mmol). The mixture was stirred at 100 C for 16 hours. After cooling to room temperature (rt), the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:20-1:10, v/v), gave 6.2 g(71%) of the title compound. 1H NMR (300MHz, CDC13) S(ppm): 7.03 (d, J = 7.6Hz, 1H), 6.55 (s, 1H), 6.43 (d, J= 7.6Hz, 1H), 4.15 (q, 2H), 3.86 (br, 1H), 3.43 (t, 2H), 2.82 (m, 4H), 2.60 (t, 2H), 2.06 (m, 2H), 1.27 (t, 3H).

B. 4- [(2-Ethoxycarbonyl-ethyl)-indan-5-yl-amino] -2-methylsulfanyl-pyrimidine=5-carboxylic acid ethyl ester To a solution of 3-(indan-5-ylamino)-propionic acid ethyl ester (5 g, 21.4 mmol) and ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (5 g, 21.4 mmol) in 40 mL of n-butanol was added triethylamine (3 mL, 21.4 mmol). The solution was stirr-ed at rt for 2 days. The solvent was removed under vacuum. The residue was extracted into EtOAc, washed with, water, brine and then dried with NaZSO4. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:10-1:6, v/v), gave 8.2 b(90%) of the titled compound as a white solid. 'H NMR (300MHz, CDC13) S(ppm): 8.22 (s, 1H), 7.16 (d, J = 7.6Hz, 1H), 6.95 (s, 1H), 6.87 (d, J= 7.6Hz, 1H), 4.35 (t, 214), 4.06 (q, 2H), 3.55 (q, 2H), 2.82 (m, 411), 2.69 (t, 2H), 2.58 (s, 3H), 2.06(m, 2H), 1.20 (t, 3H), 1.02 (t, 3H).

C. 8-Indan-S-yl-2-methylsulfanyl-5-oxo-5,6,7, 8-tetrahydro-pyrido[2,3 -d]pyrimidine 6-carboxylic acid ethyl ester To sodium (25 wt% dispersion in paraffin wax, 1.6 g, 16.9 mmol) was added t-butanol (30 mL) under stirring and N2. After 10 minutes, a solution of 4-[(2-ethoxycarbonyl-ethyl)-indan-5-yl-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6.6 g, 15.4 mmol) in 40 mL of toluene was added to the sodium t-butoxide solution. The mixture was then heated at 90 C for 30 minutes. The solution was cooled and poured into crushed ice. The solution was adjusted to pH 7 using HCl solution. The precipitates were extracted into EtOAc twice. The solvent was evaporated under vacuum and the product (bright yellow solid, 4 g, 62%) was recrystallized from isopropanol. 'H
NMR (300MHz, CDC13) indicated that the presence of both enol and keto forms in a 4:1 ratio.

D. 8-lndan-5-yl-2-methylsulfanyl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester To a solution of 8-indan-5-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.32 g, 0.84 mmol) in 5 mL of methylene chloride (CH2C12) was added bromine (43 L, 0.84 mmol) slowly under N2.
The solution was stirred at room temperature for 2 hours (or to completion).
The solvent was removed under vacuum without heating. The residue was redissolved in 2 mLof CH2C12, and was added triethylamine (234 L, 1.68 mmol) in 1 mL of CHaC12. The solution was stirred at rt for 4 hours. The progress of the reaction was monitored by LC-MS. The solvent was evaporated and the residue was applied onto a silica gel column. The product was eluted with EtOAc/hexanes (1:5-1:2.5, v/v) and ob#ained as a white solid (0.30 g, 94%). iH NMR (300MHz, CDC13) S(ppm): 9.42 (s, 1H), 8:59 (s, 1H), 7.37 (d, J
7.8Hz, 1H), 7.24 (s, 1H), 7.16 (d, J= 7.8Hz, 1H), 4.40 (q, 2H), 3.00 (m, 4H), 2.35 (s, 3H), 2.10(m, 2H), 1.40 (t, 3H).

E. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester To a solution of 8-indan-5-yl-2-methylsulfazryl-5-oxo-5,8-dihydro-pyridot2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.3 g, 0.79 mmol) in 5 inL of CH2C12, was added 3-chloroperoxybenzoic acid (m-CPBA, 69.5%, 431 mg, 1.73 mmol) portionwise.
The solution was stirred at room temperature for 3 hours. An aqueous solution of 10%
sodium thiosulfate was added to quench the reaction. After 30 minutes saturated sodium bicarbonate solution was added, and the aqueous solution was extracted by CH2C12. The combined CH2C12 solution was washed with brine and dried over Na2S04. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:3-1:1.6, v/v) gave '0.22 g (67%) of the title compound as an off-white solid. 1H NMR (300MHz, CDC13) S
(ppm): 9.75 (s, 1H), 8.70 (s, 1H), 7.39 (d, J= 7.8Hz, 1H), 7.24 (s, 1H), 7.16 (d, J= 7.8Hz, 1H), 4.38 (q, 2H), 3.19 (s, 3H), 3.00 (m, 4H), 2.10(m, 2H), 1.40 (t, 3H).

F. 4-(4-Methyl-piperazin-1-yl)-phenylamine Potassium carbonate (1.9 g, 14.2 nunol) was added to a mixture of 1-fluoro-4-nitrobenzene (1 g, 7.1 mmol) and 1-methyl-piperazine (0.94 mL, 8.5 mmol) in methyl sulfoxide (DMSO, 5 mL). The mixture was stirred at 80 C for 3 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na2SO4. Removal of the solvent in vacuo yielded an orange solid. The solid was dissolved in 25 mL of methanol and palladium on carbon (1.0% Pd/C, 50 mg) was added slowly. The system was sealed and blanketed with hydrogen.
The mixture was stirred at rt for 16 hours under hydrogen. The catalyst was filtered through a celite pad and the solvent was evaporated to leave a dark purple solid (1.3 g, 80%). iH
NMR (300MHz, CD3OD) 8(ppm): 6.90 (m, 2H), 6.81 (m, 2H), 3.38 (m, 4H), 3.26 (m, 4H), 2.93 (s, 3H).

G. 8-Indan-5-yl-2- [4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 1) The mixture of 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (11.2 mg, 0.027 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (5.2 mg, 0.027 mmol) in 1 mL of isopropanol was heated to 90 C for 1 hour. The solvent was evaporated and the residue was re-dissolved in a mixture of methanol and CH2C12 (1: l, v/v) and applied onto a prep=TLC plate (2000 micro). The plate was developed in NH4OH/MeOH/CH2CI2 (1:9:90, v/v). 8-Indan=5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 1) was obtained as a yellow solid (8.6 rng, 6 1%). 'H NMR
(300MHz, CDC13) 8 (ppm): 9.38 (s, 1H), 8.52 (s, 1H), 7.44 (m, 2H), 7.28 (s, 1H), 7.19 (m, 3H), 6.66 (m, 2H), 4.40 (q, 2H), 3.00-3.18 (m, 8H), 2.60 (m, 4H), 2.35 (s, 3H), 2.22 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N603:
525.25 (M +
H), Found: 525.4.

Example 2 2-[4-(3-Dimethylamino-2-hydroxy.-propoxy)-phenylamino] -8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 2) iN 0 C02Et.
HO I
N N N
H

A. 2-(4-Nitro-phenoxymethyl)-oxirane Potassium carbonate (1.3 g, 9.6 mmol) was added to a mixture of 4-nitrophenol (1.11 g, 8 mmol) and epibromohydrin,(1.37 mL, 16 mmol) The mixture was stirred at 100 C for 18 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na2SO4. Removal of the solvent in vacuo gave an orange residue, which was purified chromatographically on silica eluting with EtOAc/ hexanes (1:10, v/v). The product was obtained as a yellow solid (0.8 g, 51%).
'H NMR (300MHz, CDC13) 8(ppm): 8.21 (m, 2H), 6.98 (m, 2H), 4.37 (dd, J =
2.8Hz, 11.1Hz, 1H), 4.00 (dd, J= 5.9Hz, 11.1Hz, 1H), 3.90 (m, 1H), 2.93 (t, J= 4.8Hz, 1H), 2.77 (dd, J = 2.8Hz, 4.8Hz, 1H).

B. 1-(4-Amino-phenoxy)-3-dimethylamino-prop an-2-ol To a solution of 2-(4-nitro-phenoxymethyl)-oxirane (0.2 g, 1 mmol) in 2 mL of ethanol was added a solution of dimethylamine (2 M in methanol, 2.5 mL). The solution was stirred at 80 C for 2 hours in a capped vial. The solvent was removed in vacuo.
Hydrogenation of the residue using the procedure described in Example 1 (f) gave the title compound as a brown solid. 1H NMR (300MHz, CD3OD) S(ppm): 6.76 =(m, 2H), 6.71 (m, 2H), 4.20 (m, 1H), 3.88 (d, 2H), 3.04 (m, 2H), 2.71 (s, 6H).

C. 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5, dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 1-(4-amino-phenoxy)-3-dimethylamino-propan-2-ol (18 mg, 0.083 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 34 mg, 0.083 mmol). 3.1 mg of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H
NMR (300MHz, CDC13) S(ppm): 9.38 (s, 1H), 8.52 (s, 1H), 7.50 (br, 1H), 7:40 (d, 2H), 7.28 (m, 311), 7.19 (d, 1H), 6.66 (br, 2H), 4.40 (q, 2H), 4.05 (m, 1H), 3.90 (d, 2H), 3.10 (m, 4H), 2.52 (dd, 1H), 2.33 (m, 7H), 2.22 (m, 2H), 1.40 (t, 3H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C30H33N505: 544.25 (M + H), Found: 544.4.

Example 3 8-Indan-5-yl-2-(4-morpholin-4-yl-phenylamino) -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 3) , N ~ CO2Et \ I~ ~
N N N
H

Using the procedure outlined in Example 1(g) the title compound was prepared from 4-morpholin-4-yl-phenylamine (6.5 mg, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol). 11.9 mg of 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (400MHz, CDC13) S(ppm): 9.38 (br, 111), 8.53 (s, 1H), 7.69 (br, 1H), 7.43 (d, 1H), 7.23 (m, 4H), 6.64(br, 2H), 4.36 (q, 2H), 3.87 (m, 4H), 3.04 (m, 8H), 2.22 (m, 2H), 1.39 (t, 311). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C29H29N504: 512.24 (M + H), Found: 512.4.

Example 4 2-(4-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 4) I
~N \ I N~ I COZEt NN N
H

Using the procedure outlined in Example 1(g) the title compound was prepared from 4-dimethylaminoaniline (5 gL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol). 7.9 mg of 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (400MHz, CDC13) 8(ppm): 9.31 (br, 1H), 8.53 (s, IH), 7.82 (d, 1H), 7.61 (br, 1H), 7.41 (d, 1H), 7.29 (s, 1H), 7.17 (d, 1H), 6.76 (d, IH), 6.46 (br, 2H), 4.39 (q, 2H), 3.03 (m, 4H), 2.89 (s, 611), 2.22 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H27N503: 470.21 (M + H), Found: 470.4.

Example 5 2-(3-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 5) CO2Et / I N i I
N N N N
I H
Ii Using the procedure outlined in Example 1(g) the title compound was prepared from 3-dimethylaminoaniline dihydrochloride (7.6 mg, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol) at the presence of triethylainine (11 L, 0.072 mmol). 6.6 mg of 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. IH NMR (300MHz, CDC13) S(ppm): 9.41 (br, 1H), 8.53 (s, 1H), 7.47'(br, 1H), 7.40 (d, 1H), 7.29 (s, 1H), 7.18 (d, 1H), 6.90 (m, 2H), 6.50 (m, 2H), 4.39 (q, 2H), 3.00 (m, 4H), 2.80 (s, 6H), 2.21 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Ca1cd. For C27H27N503: 470.21 (M + H), Found: 470.4.

Example 6 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid (Cpd 6) ON COOH N N, N

H
Hydrolysis of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1(Exa.mple 1(g), 50 mg) in a mixture of tetrahydrofuran (THF) and 1 N sodium hydroxide solution at an elevated temperature gave 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid Cpd 6, which was purified using preparative HPLC, resulting in a formic acid salt form (28 mg, yellow solid). 1H
NMR (300MHz, CDC13) S(ppm): 9.38 (s, 1H), 8.80 (s, 1H), 8.35 (br, 1H), 7.83 (br, 1H), 7.42 (m, 2H), 7.20 (m, 4H), 6.65 (br, 2H), 3.20 (m, 4H), 3.03 (m, 4H), 2.88(m, 4H), 2.60(m, 4H), 2.50 (s, 3H), 2.20 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C28H28N603: 497.22 (M + H), Found: 497.5.

Example 7 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid amide (Cpd 7) I~ 0 0 N\ I N~ NH2 NN N
H

To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1(Example 1(g), mg) in 1 mL of methanol was bubbled ammonia at -78 C for 5 minutes in a pressure bottle (10 mL). The bottle was capped and warmed up to room temperature and stirred for 16 hours. The solvent was evaporated to leave 8-Indan-5-yl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Cpd 7 as a yellow solid (8.1 mg). I H NMR (400MHz, DMSO-d6) 8(ppm): 10.24 (s, 1H), 9.17 (s, 1H), 9.03 (s, 1H), 8.52 (s, 1H), 7.62 (d, 1H), 7.44 (m, 2H), 7.33 (d, 1H), 7.27 (m, 2H), 6.57 (m, 2H), 3.00 (m, 4H), 2.93 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H), 2.13 (m, 2H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H29N702: 496.24 ~M + H), Found:
496.4.

Example 8 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methylamide (Cpd 8) ~'N~ 0 0 N \ I ~ % H/
N N N
H
= I ~ .

To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1{Example 1,(g), 5 mg) in 1 mL of methanol was added 1 mL of methylamine (40 wt.% in water). The solution was stirred at 70 C for 30 minutes. The solvent was evaporated and the product was purified by preparative HPLC. 1.7 mg of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide Cpd 8 was obtained as yellow solid. 1H NMR (400MHz, CDC13) S(ppm): 9.65 (s, 1H), 9.36 (s, 1H), 8.84 (s, 1H), 7.42 (d, 1H), 7.23 (m, 3H), 7.17 (d, 1H), 6.67 (br, 2H), 3.14 (m, 4H), 3.02 (m, 7H), 2.59 (m, 4H), 2.37 (s, 3H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C29H31N702: 510.25 (M + H), Found: 510.2.

Example 9 8-Indan-S-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethylamide (Cpd 9) "IN O p N \ I ~ H
N N N
H

To a solution of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1(Example 1(g), 5 mg) in 1 mL of methanol was added 1 mL of ethylamine (2 M in methanol). The solution was stirred at 70 C for 30 minutes. The solvent was evaporated arid the product was purified by preparative HPLC as the formic acid salt (1 mg, yellow solid). 'H
NMR
(400MHz, CDC13) S(ppm): 9.71 (m, 1H), 9.35 (s, 1H), 8.83 (s, 1H), 8.24 (br, 1H), 7.69 (br, 1H), 7.42 (d, 1H), 7.27 (m, 3H), 7.17 (d, 1H), 6.67 (br, 2H), 3.50 (m, 2H), 3.25 (m, 4H), 3.03 (m, 4H), 2.92 (m, 414), 2.55 (s, 3I1), 2.22 (m, 2H), 1.27 (t, 3H):
Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N702: 524.27 (M + H), Found: 524.3.

Example 10 2- [4-( 3 -Dimethylamino-2-hydroxy-propoxy)-.
phenylamino] -8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid amide (Cpd 10) iN O
HOO ~ NI CONH2 ' N N
H
I
Using the procedure outlined in Example 7 the title compound was prepared from 2-[4-(3 -dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 2(c), 5 mg).
4.3 mg of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6) S(ppm): 10.32 (br, 1H), 9.20 (s, 1H),9.02 (br, 1H), 8.52 (s, 1H), 7.63 (d, 1H), 7.45 (m, 2H), 7.32 (m, 3H), 6.59 (br, 2H), 4.89 (br, IH), 3.88 (m, 2H), 3.75 (m, 1H), 3.00 (m, 4H), 2.37 (m, 2H), 2.23 (s, 6H), 2.14 (m, 2H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H30N604: 515.23 (M + H), Found: 515.3.

Example 11 2- [4-(3 -Dimethylamino-2-hydroxy-propoxy)-phenylamino] -8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methylamide (Cpd 11) iN O O
HO Oa ~ H
N N N H

To a solution of 2-[4-(3-dimethylarnino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 2(c), 8 mg). in 1 mL of inetlianol was added 1 mL of methylamine (40 wt.% in water). The solution was stirred at 70 C for 30 minutes. The solvent was evaporated to yield a yellow solid (6.6 mg). 1H NMR (400MHz, CDC13) S(ppm): 9.64 (m, 1H), 9.35 (s, 1H), 8.82 (s,,1H), 7.39 (m, 2H), 7.27 (m, 1H), 7.15 (m, 2H), 6.66 (br, 2H), 4.06 (m, 1H), 3.93 (m, 2H), 3.02 (m, 5H), 2.89 (m, 4H), 2.56 (dd, 1H), 2.35 (m, 7H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H32N604: 529.25 (M + H), Found: 529.2.

Example 12 2- [4-(3-Dimethylamino-2-hydroxy-propoxy)-phenylamino] -8 -indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethylamide (Cpd 12) N O O
HO),,, O 01 N~ I H\
N N N
H

To a solution of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]=8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 2(c), 8 mg). in 1 mL of methanol was added 1 mL of ethylamine (2M in methanol). The solution was stirred at 70 C for 30 minutes. The solvent was evaporated and 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide was purified by preparative HPLC as the trifluoroacetic acid salt (2.7 mg, brown solid). 1H NMR,(400MHz, CD3OD) 8 (ppm): 10.07 (br, 1H), 9.27 (s, 1H), 8.69 (s, 1H), 7.46 (m, 1H), 7.34 (m, 4H), 7.26 (m, .1H), 6.64 (br, 2H), 4.34 (m, 1H), 3.94 (m, 2H), 3.46 (m, 2H), 3.00 (m, 12H),. 2.23 (m, 2H), 1.25 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H34N604: 543.26 (M + H), Found: 543.2. -Example 13 2-[4-(4-Methyl-piperazin-l-yl)-phenylamino]-5-oxo-8-phenyl-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid amide (Cpd 13) ~N~ 0 0 IN / i ~NH2 \ I
NN N
H

A. 4-[(2-Cyano-ethyl)-phenyl-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester.

The title compound was prepared from ethyl4-chloro-2-methylthio=5-pyrimidinecarboxylate (3.7 g, 15.8 mmol) and 3-phenylamino-propionitrile (2.3 g, 15.8 mmol) according to the procedure outlined in Example 1 (B). The product was purified chromatographically (silica, EtOAc/ hexanes 1:20-1:2, v/v). A white solid was obtained (3.5 g, 65%). IH NMR (300MHz, CDC13) 8(ppm): 8.32 (s, 1H), 7.34(m, 2H), 7.20 (m, 1H), 7.13 (m, 2H), 4.32 (t, J= 7.1Hz, 2H), 3.56 (q, J= 7. iHz, 2H), 2.75 (t, J= 7.1Hz, 2H), 2.55 (s, 3H), 1.00 (t, J= 7.2Hz, 3H).

B . 2-Methylsulfanyl-5-oxo-8-phenyl-5,6,7, 8-tetrahydro-pyrido [2, 3-d]pyrimidine-6-carbonitrile.

The title compound was prepared from 4-[(2-cyano-ethyl)-phenyl-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (0.78 g, 2.27 mmol) according to the procedure outlined in Example 1 (C). The product was purified chromatographically (silica, EtOAc/ hexanes 1:1-1:0, v/v).. A yellow solid was obtained (0.39 g, 58%). 1H NMR
(300MHz, CDC13) indicated that the presence of both enol and keto forms in a 1:1 ratio.

C. 2-Methylsulfanyl-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine 6-carbonitrile The title compound was prepared from 2-methylsulfanyl-5-oxo-8-phenyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (0.83 g, 2.8 mmol) according to the procedure outlined in Example 1 (D). The product was purified chromatographically (silica, EtOAc/ hexanes (1:5-1:2.5, v/v) and obtained as a white solid (0.73 g, 89%). 1H
NMR (300MHz, CDC13) S(ppm): 9.42 (s, 1H), 8.59 (s, 1H), 7.37 (m, 2H), 7.24 (m, 1H), 7.14 (m, 2H), 2.37 (s, 3H).

D. 2-Methanesulfonyl-5-oxo-8-phenyl-5, 8-dihydro-pyrido [2, 3-d] pyrimidine-6-carbonitrile The title compound was prepared from 2-methylsulfanyl-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (0.73 g, 2.5 mmol) according to the procedure outlined in Example 1 (E). The product was obtained as an off-white solid (0.77 g, 95%). 1H NMR (300MHz, CDC13) S(ppm): 9.51 (s, 1H), 8.62 (s, 1H), 7.38 (m, 2H), 7.24 (m, 1H), 7.14 (m, 2H), 3.20 (s, 3H).

E. 2- [4-(4-Methyl-pip erazin-1-yl)-phenyl amino] -5-oxo- 8-phenyl-5, 8-dihydro-pyrido[2,3 -d]pyrimidine-6-carbonitrile Using the procedure outlined in Example 1(G) the title compound was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (32 mg, 0.16 mmol) and 2-methanesulfonyl-5-oxo-8-phenyl-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carbonitrile (Example 13 (D) above, 50 mg, 0.15 mmol). The product was obtained as a yellow solid (17.1 mg). 'H NMR (300MHz, CDC13) 8(ppm): 9.34 (s, 1H), 8.55 (br, 1H), 7.61 (m, 3H), 7.41 (d, 2H), 7.24 (m, 2H), 6.55 (d, 2H), 3.00 (m, 4H), 2.55 ~m, 4H), 2.35 (s, 3H)..1V,[ass Spectrum (LCMS, ESI pos.) Calcd. For C25H23N70: 438.20 (M + H), Found:.438.5.

F. 2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide To a solution of 2-[4-(4-Methyl-piperazin-l-yl)-phenylamino]-5-oxo-8-phenyl=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (Example 13 F, 9 mg) in 1 mL of t-butanol was added potassium hydroxide (ground, 5 mg). The mixture was stirred atS5 C
for 1 hour. After cooling to rt, water was added and the precipitates were extracted into EtOAc.
The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to leave 2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide as a yellow solid (7.2 mg, 79%). 1H NMR (300MHz, CDC13) b(ppm): 10.64 (br, 1H), 10.30 (s, 1H), 9.17 (s, 111), 7.71 (m, 3H), 7.53 (br, 1H), 7.43 (m, 2H), 6.94 (br, 2H), 6.35 ~br, 2H), 5.06 (br, 1H), 3.12 (m, 4H), 2.59 (m, 4H), 2.37 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H25N702: 456.51 (M + H), Found: 456.6.

Example 14 8-Indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 14) N N
H

Using the procedure outlined in Example 7, the title compound was prepared from 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5 -oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 3 above, 9 mg, 0.017 mmol). 8-Indan-5-y1-2-(4-morpholin-4-yl-phenylamino)-5 -oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid (8.6 mg, 100%). IH
NMR (400MHz, CD2C12/CD3OD (20:1 v/v)) S(ppm): 9.22 (br, 1H), 8.68 (br, 1H), 7.35 (br, 1H), 7.10-7.26 (m, 4H), 6.57 (br, 2H), 3.75 (m; 4H), 2.96 (m, 8H), 2.11 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H26N603: 483.21(M + H), Found: 483.2.

Example 15 2-(4-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 15) ~N / I i\ I CONH2 N N N
H

Using the procedure outlined in Example 7, the title compound was prepared from 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 4 above, 4.9 mg, 0.010 mmol).
2-(4-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid (3.8 mg, 83%). IH
NMR (400MHz, CD2C12/CD3OD (20:1 v/v)) S(ppm): 9.19 (br, 1H), 8.68 (s, 1H), 7.66 (d, J= 9.2 Hz,. 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.22 (s, 1H), 7.11 (d, J= 7:9 Hz, IH), 6.68 (d, J
= 9.2 Hz, 1H), 6.3'8 (br, 1H), 2.94 (m, 4H), 2.79 (s, 6H), 1.96 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H24N602: 4441.20 (M + H), Found: 441.2.

Example 16 2-(3-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 16) N N N
H
Using the procedure outlined in Example 7 the title compound was prepared from 2-(3-dimethylamino-phenylamino)-8-indan-5-y1-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 5 above, 3.3 mg, 0.007 mmol).
2-(3 -Dimethylamino-phenylamino)-8-indan-5-y1-5 -oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid (2.7 mg, 88%). 1H
NMR (400MHz, CD2C12/CD3OD (20:1 v/v)) 8(ppm): 9.26 (s, 1H), 8.68 (s, 1H), 7.33.(d, J, = 7.5 Hz, 1H), 7.22 (s, 1H), 7.18 (d, J= 7.5 Hz, 1H), 6.84 (br, 1H), 6.80 (d, J= 7.7 Hz, 1H), 6.54 (br, 1H), 6.36 (d, J = 7.7 Hz, 1H), 2.96 (m, 4H), 2.71 (s, 6H), 2.10 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H24N602: 441.20 (M + H), Found: 441.2.

Example 17 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 17) N C02Et zt~' A, I
N N N
H

A. 3-Cyclohexylamino-propionic acid ethyl ester Cyclohexylamine (0.86 g, 8.7 mmol) and 3-chloro-propionic acid ethyl ester (1.18 g, 8.67 mmol) were combined neat and K2C03 (1.2 g, 8.7 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 5 mg) was added. The mixture was heated at 80 C
overnight. The resulting mixture was then partitioned between water and DCM.
The organic layer was dried (MgS04) and concentrated to afford 1.25 g (72%) of the title compound. 1H-NMR (400 MHz, CDC13) b ppm 4.14 (q, 2H, J = 7.2Hz), 2.90 (t, 2H, J
6.6Hz), 2.50 (t, 2H, J= 6.6Hz), 1.86-1.89 (m, 211), 1.70- 1.75 (m, 2H), 1.58-1.62 (m, 2H), 1.25 (t, 1H, J = 7.2Hz).

B. 4-[Cyclohexyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 3-Cyclohexylamino-propionic acid ethyl ester (1.0 g, 5.0 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.17 g, 5.02 mmol) were combined in DCM (15 mL) and diisopropylethylamine (0.81 g, 6.3 mmol) was added.
After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO~) and concentrated. Chromatography (0-20 % EtOAc/ hexanes gradient) provided 1.63 g (84%) of the title compound. 'H-NMR (400 MHz, CDC13) S ppm 8.39 (s, 1H) 5.30 (s, 1H), 4.30 (q, 2H, J=7.lHz), 4.14 (q, 1H, J=7.lHz), 3.76-3.80 (m, 2H), 2.65-2.69 (m, 2H), 2.49 (s, 3H), 1.81-1.84 (m, 2H), 1.34-1.40,(m, 7H), 1.12-1.27 {m, 7H).

C. 8-Cyclohexyl-2-methylsulfanyl-5-oxo-5,6,7, 8-tetrahydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester Sodium (25 wt % dispersion in paraffm wax, 0.lOg, 3.8 mmol) was added to t-butanol (1.8 mL) at rt. After 10 minutes, a solution of 4-[cyclohexyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester.(1.0 g, 2.5 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90 C for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2 X 20 mL) and the organic layer was dried (MgS04) and concentrated to provide 0.55 g, (42%) of the title compound. 1H NMR indicated the presence of both enol and keto.
forms in a 1:1.75 ratio.'H-NMR (400 MHz, CDC13) 8 ppm 8.63 (s, 1H), 8.18 (s, 1H), 4.76-4.82 (m), 4.58-4.68 (m), 4.16-4.36 (m), 3.91-3.96 (m), 3.60-3.64 (m), 3.46-3:49 (m), 2.53 (s, 3H), 2.50 (s, 5.25H), 1.86-1.89 (m)', 1.71-1.73 (m), 1.32-1.56 (m), 1.26 (t, J=7.2Hz), 1.10-1.21 (m).

D. 8-Cyclohexyl-2-methylsulfanyl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Bromine (0.15 g, 0.94 mmol) was added to a solution of 8-cyclohexyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.28 g, 0.79 mmol) in DCM (10 mL). After 5 min, the solution was concentrated and the crude residue was redissolved in DCM (10 mL) and diisopropylethylamine (0.42 mL, 2.4 mmol) was added. After 15 h, the reaction mixture was partitioned between water and DCM, the organic layer was separated, dried (MgSO4) and concentrated to provide 0.28 g (87%) of the title compound. ). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C17H21N303S: 347.13, found: (M + H) 348.3.

E. 8-Cyclohexyl-2-methanesulfonyl=5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidirie-carboxylic acid ethyl ester a-CPBA (0.33 g, 1.5 mmol of a 70% w/w mixture) was added to a solution of 8-cyclohexyl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3 -d]pyrimidine-6-carboxylic acid ethyl ester (0.206 g, 0.59 mmol) in DCM (15 mL). After 2 hours, a 10%
solution of Na2SO3 (1 mL) was added and the mixture was partitioned between sat. NaHCO3 and DCM. The organic layer was dried (MgSO4) and concentrated to provide 0.22 g of the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C17H21N3Os'S:
379.12, found: (M + H) 3 80.1.

F. 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,$-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Cyclohexyl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido[2, 3 -d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.051 mmol) and 4-(4-methyl-piperazin-1-yi)-phenylamine (10 mg, 0.051 mmol) were combined in i-PrOH (2 mL) and heated to 80 C:
After 14 h, the solution was concentrated and purified by preparative HPLC (30 mLJ min 0-100% H20/ MeCN gradient over 10 min) to provide 7.2 mg (29%) of 8-cyclohexyl-2-{4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDC13:) S ppm 9.32 (s, 1 H), 8.31 (s, 1 H), 7.57 (d, 2 H, J=9.OHz), 6.96 (d, 1H, J=8.9Hz), 4.40 (q, 2 H, J=7.lHz), 3.25-3.46 (m, 8 H), 2.82-2.84 (m, 3 H), 1.49-2.0 (m, 8 H), 1.41 (t, 3 H, J=7.1Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H34N603: 490.27, found: (M + H) 491.3.

Example 18 8-Cyclohexyl-2-(4-dimethylamino-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 18) N CO2Et A
N N N
H

8-Cyclohexyl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 17E) (20 mg, 0.051 mmol) and 4-N,N-dimethylaminoaniline (7.8 mg, 0.057 mmol) were combined in i-PrOH (1 mL) and heated to 80 C. After 14 h, the solution was concentrated and purified by preparative HPLC (30 mL/ min 0-100% H20/ MeCN gradient over 10 min) to provide 3.4 mg of 8-cyclohexyl-2-(4-dimethylamino-phenylamino)-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDC13;) 8 ppm 9.34 (s, 1 H), 8.53 (s, 1 H), 7.73 (m, 1 H), 6.79-6.84 (m, 1 H), 6.62-6.64 (m, 1 H), 5.10-5.17 (m, 1 H), 4A0 (q, 2 H, J=7.OHz), 3.01 (s, 6 H), 2.46-2.07 (m, 10 H), 1.41 (t, 1H, J=7.OHz). Mass Spectrum (LCMS, ESI
pos:) Calcd. For C24H29N503: .435.23, found: (M + H) 436.3.

Example 19 8 -Cyclopentyl-2- [4-(4-methyl-p iperazin-1-yl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido{2, 3-d]pyrimidine-6-carboxylic acid amide (Cpd 19) \~ ~.1 ~
N N N
H b A. 3-Cyclopentylamino-propionic acid ethyl ester Cyclopentylamine (1.72 g, 17.5 mmol) and 3-chloro-propionic acid ethyl ester (2.4 g, 18 mmol) were combined neat and K2C03 (2.4 g, 18 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 5 mg) was added. The mixture was heated at 80 C
overnight. The resulting mixture was then partitioned between water and DCM.
The organic layer was dried (MgSO4) and concentrated to provide 2.68 g (83%) of the title compound. 1H-NMR (400 MHz, CDC13:) S ppm 4.13 (p, 2H, J=7.OHz), 3.07 (p, 1H, J=6.7Hz), 2.81-2.94 (m, 4 H), 2.51 (t, 1H, J=6.5Hz), 2.44 (t, 1H, J=7.4Hz), 1.29-1.88 (m, 6 H), 1.25 (t, 3H, J=7.lHz) B. 8-Cyclopentyl-2-methylsulfanyl-5-oxo-5,6,7, 8-tetrahydro-pyrido [2,3-djpyriinidine-6-carboxylic acid ethyl ester 3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added.
After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO~) and concentrated. Chromatography (0-20 % EtOAc/ hexanes gradient) provided the title compound that was directly carried on to the next step.
Sodium ~25 wt%
dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol- (5.0 mL) at rt. After minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90 C for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2 X 20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDC13:) S ppm 12.0 (br s, 1 H), 8.20 (s, 1 H), 5.10-5.18 (m, 1 H), 4.26-4.31 (m, 3 H), 3.72 (q, 2H, J=7.OHz), 2.50 (s, 3 H), 1.63-1.86'(m, 5 H), 1.20-1.35 (m, 5 H).

C. 8-Cyclopentyl-2-methylsulfanyl-5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-carboxylic acid ethyl ester Bromine (0.13 g, 0.82 mmol) was added to a solution of 8-Cyclopentyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.34 g, 0.82 mmol) in DCM (5 mL). After 15 min, the solution was =concentrated and the crude residue was redissolved in DCM (5 mL) and triethylamine (0.16 mL, 0.24 mmol) was added. After 15 h, the reaction mixture was partitioned between water and DCM, the organic layer was separated, dried (MgSO4) and concentrated to provide the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C16H19N303S: 333.11, found:
(M+H) 334.1.

D. 8-Cyclopentyl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido[2,3 -d]
pyrimidine-6-carboxylic acid ethyl ester rn-CPBA (0.45 g, 2.05 mmol of a 77% powder) was added to a solution of 8-cyclopentyl-2-methylsulfanyl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.27 g, 0.82 mmol) in DCM (5 mL). After 2 hours, a 10%
solution of Na2SO3 (2 mL) was added and the mixture was partitioned between sat. NaHCO3 and DCM. The organic layer was dried (MgSO4) and concentrated to provide the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. For C16H1qN305S: 365.10, found:
(M+H) 366.1.

E. 8-Cyclopentyl-2- [4-(4-methyl-piperazin-1-yl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 8-Cyclopentyl-2-methanesulfonyl=5-oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-carboxylic acid ethyl ester (45 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (23 mg, 0.12 mmol) were combined in i-PrOH (1 mL) and heated to 80 C.
After 14 h, the solution was concentrated and purified by preparative HPLC (30 mL/ min 0-100% H20/ MeCN gradient over 10 min) to provide 19.8 mg of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-carboxylic acid ethyl ester. The ester was dissolved in MeOH (2 mL) and cooled to -78 C
in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated to provide 5.4 mg of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylainino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 'H-NMR (400 MHz, CDC13:) 8 ppm 9.30 (s, 1 H), 8.51 (s, 1 H), 8.34 (s, 1 H), 7.53 (d, 2 H, J=8.9Hz), 6.94 (d, 2 H, J=9.OHz), 5.23-5.52 (m, 4 H), 4.38 (q, 2 H, J=7.1Hz), 3.34-3.36 (m, 4 H), 3.00-3.01 (m, 4 H), 2.60 (s, 3 H), 2.21-2.28 (m, 2 H), 1.80-1.93 ( m, 6 H), 1.40 (t, 3 H, J=7.lHz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H32N603: 476.25, found:
(M + H) 477.3.

Example 20 2-(3-Hydroxymethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 20) HO O
CO2Et N
A
N N N
H

Using the procedure outlined in Example 1(g) the title compound was prepared from (3-amino-phenyl)-methanol (3.2 mg, 0.026 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 10 mg, 0.026 mmol). 2-(3-Hydroxy"methyl-phenylarnino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide was obtained as a white solid. 1H NMR (400MHz, CDC13) S(ppm): 9.37 (br s, 1 H), 8.50 (s, 1 H), 7.35-7.45 (m, 3H), 7.02-7.21 (m, 3H), 5.30 (s, 2H), 4.43 (br s, 111), 4.39 (dd, 2H, J=7.lHz, J=14.3Hz), 3.05 (td, 4H, J=7.5Hz, J=28.2Hz), 2.20-2.27 (m, 2H), 1.39 (t, 3H, J=7.lHz). Mass Spectrum (LCMS, ESI pos.) Calcd. For Ca4H21N503: 427.16, found:
(M +
H) 428.1. Example 21 2-(4-Fluoro-phenyl amino)-8-indan-5-yl-5 -oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Cpd 21) F aN)~'N'!: CO2Et N
H ~
I~
Using the procedure outlined in Example 1(g) 2-(4-fluoro-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was prepared from 4-fluoroaniline (6 mg, 0.05 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 21 mg, 0.050 mmol). Purification by preparative HPLC (30 mL/ min 0-100%

MeCN gradient over 10 min) provided 2-(4-fluoro-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (3.6 mg). 'H NMR
(400MHz, CDC13) 8(ppm): 9.21 (s, 1H), 8.44 (s, 1H), 7.84-7.94 (m, IH), 7.10-7.48 (m, 6H), 4.23 (dd, 1H, J=7.2Hz, J=14.5Hz), 2.96 (td, 1H, J=7.3Hz, J=25.1Hz), 2.10-2.18 (m, 2H), 1.18-1.40 (m, 7H). ). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H21FN403:
444.16.14, found: (M + H) 445.1.

Example 22 8-Indan-5-yl-5-oxo-2-(4-pyrazol-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 22) ~N , N ~ CO2~Et ~
N N N
H

Using the procedure outlined in Example 1(g) 8-indan-5-y1-5-oxo-2-(4-pyrazol-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide was prepared from 4-pyrazol-1-yl-phenylamine (8.0 mg, 0.053 mmol) and 8-indan-5-yl-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 20 mg, 0.053 mmol). 8-Indan-5-yl-5-oxo-2-(4-pyrazol-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide was obtained as a white solid. 'H NMR (400MHz, CDC13) S(ppm): 9.30(br s, 1H), 8.48 (s, IH), 7.75 (s, 111), 7.64 (s, 1H), 7.13-7.23 (m, 5H), 6.39 (s, 1H), 4.31 (q, 1H, J=7.lHz), 3.02 (t, 1H, J=7.3Hz), 2.94 (t, 1H, J=7.3Hz), 2.17 (p, 1H, J=7.5Hz), 1.32 (t, 1H, J=7.lHz).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H21N702: 463.18, found: (M + H) 464.1.

Example 23 8-Indan-S-yl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl amino] -5 -oxo-5, 8-dihydro-pyrido [2, 3-d] pyrimidine-6-carboxylic acid amide (Cpd 23) ~ ~ ~ ~
~ N N N
H ~ I~

A. 3 -(4-Methyl-p iperazin-1-ylmethyl)-phenyl amine in-Nitrobenzyl bromide (500 mg, 2.31 mmol) was added to a mixture of 1-methylpiperazine (277 mg, 2.77 mmol) and potassium carbonate (414 g, 3. 0 mmol) in 5 mL of DMF. The mixture was stirred at 90 C for 16 hours. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave:510 mg of 1-methyl-4-(3-nitro-benzyl)-piperazine, which was converted to the title compound under normal hydrogenation conditions. The titled compound was obtained as a yellow solid (450 mg, 95%). 1H NMR (400MHz, CDC13) S(ppm): 7.02 (t, J = 7.6Hz, 1H), 6.62 (s, 1H), 6.60 (d, J = 7.6Hz, 1H), 6.54 (d, J = 7.6Hz, 1H), 3.43 (s, 2H), 2.76 (br, 4H), 2.65 (br, 4H), 2.82 (m, 4H), 2.46 (s, 3H).

B. 8-Indan-5-yl-2-methanesulfonyl-5 -oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid amide 8-Indan-S-yl-2-methylsulfanyl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(d), 200 mg, 0.52 mmol) was di'ssolved in 2 mL of CH3OH. To the solution was bubbled ammonia at -78 C for 5 minutes in a pressure bottle (15 mL). The bottle was capped and warmed up to room temperature and stirred for 16 hours. The solvent was evaporated to leave an off-white solid.
The solid was suspended in 50 mL of CHZC12. To the mixture was added m-CPBA (69.5%, 325 mg, 1.3 mmol). The mixture was stirred at r.t. for 4 hrs. An aqueous solution of 10%
sodium thiosulfate was added to quench the reaction. After 30 minutes saturated sodium bicarbonate solution was added, and the aqueous solution was extracted by CH2C12. The combined CH2Cl2 solution was washed with brine and dried over NaZS04. Removal of the solvent and chromatography on silica, eluting with EtOAc/hexanes (1:1-2:1, v/v) gave 0.18 g (90%) of the title compound as an off-white solid.1H NMR (400MHz, DMSO-d6) 8 (ppm): 9.75 (s, 1H), 8.75 (s, 1H), 8.69 (d, J= 3.3 Hz, 1H), 7.87 (d, J= 3.3 Hz, 1H), 7.49 (s, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 3.19 (s, 3H), 2.93 (m, 4H), 2.10(m, 2H).

C. 8-Indan-5-yl-2-[3-(4-methyl-piperazin-l-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide To a suspension of 8-indan-5-yl-2-methanesulfonyl-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg) in 1 mL of i-PrOH was added 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (5 mg). The mixture was stirred at 90 C for 1 hr. After cooling down, the solvent was evaporated and the product was purified chromatographically (CH2C12/CH3OH/NH4OH (10:1:0.1, v/v)). The title compound was obtained as white solid (2.7 mg, 29%). 1H NMR (400MHz, CDC13) 5 (ppm): 9.39 (br, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 7.48 (br, 1H), 7.35 (d, J=
8.0 Hz, 1H), 7.29 (br, 1H), 7.17 (s, 1H), 7.12 (d, J= 8.0 Hz, 1H), 6.94 (br, 2H), 5.67 (br, 1H), 3.29 (br, 2H), 3.00 (t, J= 7.3 Hz, 2H), 2.92 (t, J= 7.3 Hz, 2H), 2.49 (br, 7H), 2.33 (br, 4H), 2.15 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N702: 510.25 (M + H), Found:
510.1.

Example 24 8-Indan-5-yl-2-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 24) O

O 1 ~I ~~ I
N. N N
H

Using the procedure outlined in Example 23 (a and c), the title compound was prepared from 3-morpholin-4-ylmethyl-phenylamine (5 mg) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/ min, 5-100%
H20/ MeCN (0.01% TFA, v/v) gradient over 10 min) gave the title compound as a white solid (3.9 mg, 35%). 1H NMR (400MHz, CDC13) S(ppm): 9.55 (br, 1H), 9.42 (s, 1H), 8.83 (s, 1H), 7.60 (br, 1H), 7.50 (br, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (br, 2H), 6.23 (br, 1H), 4.00 (br, 4H), 3.32 (br, 2H), 3.08 (t, J= 7.3 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H), 2.72 (br, 2H), 2.23 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H28N603: 497.22 (M + H), Found: 497.1.

Example 25 2-[2-Hydroxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 25) '/ CONHz N ~ N \ O
~N~N N
OH H

Using the procedure outlined in Example 23 (c), the title compound was prepared from 2-amino-5-(4-methyl-piperazin-l-yl)-phenol (5 mg, prepared using the procedure outlined in Example 1 (F) from 1-fluoro-2-hydroxy-4-nitrobenzene and 1-methyl-piperazine)and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/ min, 5-100% H20/ MeCN (0.01% TFA, v/v) gradient over niin) followed by a basic aqueous work-up gave the title compound as a yellow solid (3.7 mg, 40%). 'H NMR (406MHz, CD3OD) S(ppm): 9.25 (br, 1H), 8.73 (s, 1H), 7.44 (d, J
8.4 Hz, 2H), 7.36 (s, 1H), 7.25 (d, J= 7.1 Hz, 1H), 6.45 (s, 1H), 6.02 (br, 1H), 3.20 (br, 2H), 3.03 (m, 6H), 2.65 (s, 3H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C28H29N703: 512.23 (M + H), Found: 512.1.

Example 26 1-Indan-5 -yl-7- [4-(4-methyl-pip erazin-1-yl)-phenylamino] -4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid amide (Cpd 26) \ 1 N /
O

/
N N
H

A. 4,6-Dichloro-nicotinic acid ethyl ester Diethyl 1,3-acetonedicarboxylate (10 mL, 49.5 mmol) was taken in 10 mL of acetic anhydride. To the solution was added trimethylorthoformate (8.2 mL, 49.5 mmol). The mixture was heated to 120 C for 3 hours. The reaction was then cooled and 10 mL of NH4OH (30%) was added. After stirring for additional 1 hour, the solution was triturated for 3 times in CH2Cl2 to afford 7.3 g of an off-white solid. The solid was suspended in 10 mL of POC13 and the mixture was heated at 100 C for 6 hours. The reaction was cooled, quenched with water, and extracted 3 times with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography=(EtOAc/Hexanes, 1:10 v/v) afforded the title compound as a white solid (6g, 68%). 1H NMR (400MHz, CDC13) (ppm): 8.79 (s, 1H), 7.42 (s, 1H), 4.3.8 (q, J= 7.1 Hz, 2H), 1.37 (t, J= 7.1 Hz, 3H).

B. 6-Chloro-4-[(2-ethoxycarbonyl-ethyl)-indan-5-yl-amino] -nicotinic acid ethyl ester To a solution of 4,6-dichloro-nicotinic acid ethyl ester (2 g, 9 mmol) and 3-(indan-5-ylamino)-propionic acid ethyl ester (from Example 1 (A), 2.3 g, 10 mmol) in 5 mL of DMF was added triethylamine (2 g, 20 mmol). The mixture was stirred at 100 C
for 48 hours. The reaction was cooled, quenched with water, and extracted 3 times with EtOAc.
The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc/Hexanes, 2:10 v/v) afforded the title compound as a white solid (1.6 g, 44%). 'H NMR (400MHz, CDC13) 8(ppm): 8.22 (s, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.92 (s, 1H), 6.85 (m, 2H), 4.03-4.15 (m, 4H), 3.74 (q, J= 7.1Hz, 2H), 2.85 (t, J= 7.4Hz, 4H), 2.64 (m, 2H), 2.07 (m, 2H), 1.23 (t, J= 7.1Hz, 3H), 1.08 (t, J= 7.1Hz, 3H).

C. 7-Chloro-l-indan-5-yl-4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic kid ethyl ester Using the procedures outlined in Example 1 (C and D), the title compound was prepared from 6-chloro-4-[(2-ethoxycarbonyl-ethyl)-indan-5-yl-amino]-nicotinic acid ethyl ester (1.6 g, 4 mmol). A white solid was obtained (500 mg,34%). 'H NMR
(300MHz, CDC13) S(ppm): 9.38 (s, 1H), 8.46 (s, 1H), 7.47 (d, J= 7.8 Hz, 1H), 7.23 (s, 1H), 7.14 (dd, J = 2.2 Hz, J = 7.8 Hz, 1H), 6.88 (s, 1H), 4.36 (q, J= 7.1Hz, 2H), 3.04 (m, 4H), 2.22 (m, 2H), 1.38 (t, J= 7.1Hz, 3H).

D. 1-Indan-5 -yl-7- [4-(4-methyl-piperazin-1-yl)-phenylamino] -4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid amide To a solution of 7-chloro-l-indan-5-yl-4-oxo-1,4-dihydro-[1,6]naphthyridine=3-carboxylic acid ethyl ester (40 mg, 0.11 mmol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (45 mg, 0.23 mmol) in 1 mL of NMP was added triethylamine (24 mg, 0.24 mmol). The reaction was heated in a microwave reactor at 200 C for 2 hours.
The solvent was evaporated under vacuo and the product was purified by preparative HPLC
(32 mL/
min, 5-100% H20/ MeCN (0.01% TFA, v/v) gradient over 15 min). The title compound, was obtained as a yellow solid (6.9 mg, 10%).1H NMR (400MHz, CD3OD) S(ppm):
9.11 (s, 1H), 8.57 (s, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.35 (m, 3H), 7.25 (dd, J= 1.9 Hz, J= 7.9 Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.13 (s, 1H), 3.40-3.80 (br, 8H), 3.01 {m, 4H), 2.96 (s, 3H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H3QN602:
495.24 (M +
H), Found: 495.1.

Example 27 8-Indan-S-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carb oxylic acid amide (Cpd 27) '1 ~N / N ~ CONHZ
~ ~
N N' N
H

A. 4-(2-Morpholin-4-yl-ethyl)-phenylamine 1-(2-Bromo-ethyl)-4-nitro-benzene (1 g, 4.3 mmol) was added to a mixture of morpholine (435 L, 5 mmol) and potassium carbonate (690 mg, 5.0 mmol) in 5 mL
of DMSO. The mixture was stirred at 100 C for 1 hour. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na2SO4). Removal of the solvent and chromatography on silica,.
eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 950 mg of 4-[2-(4-nitro-phenyl)-ethyl] -morpholine, which was converted to the title compound under noimal hydrogenation conditions. The title compound was obtained as a yellow solid (880 mg, 99 %). 1H NMR (400MHz, CDC13) 8(ppm): 6.98 (d, J 8.2 Hz, 2H), 6.61 (d, J = 8.2 Hz, 2H), 3.73 (t, J= 4.5 Hz, 4H), 3.57 (br, 2H), 2.64-2.71 (m, 2H), 2.45-2.56 {m, 6H).

B. 8-Indan-5-yl-2- [4-(2-morpholin-4=yl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-moipholin-4-yl-ethyl)-phenylamine (49 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-py'rido[2,3-d]pyrimidine-6.-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 1H NMR (400MHz, CDC13) S(ppm): 9.29 (s, 1H), 8.45 (s, 1H), 7.50 (br, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.21 (m, 3H), 7.13 (d, J= 7.8 Hz, 1H), 6.87 (br, 2H), 4.31 (q, J= 7.0 Hz, 2H), 3.69 (br, 4H), 2.96 (t, J= 7.4 Hz, 2H), 2.91 (t, J= 7.4 Hz, 2H), 2.67 (br, 2H), 2.46 (br, 6 H), 2.17 (m, 2H), 1.30 (t, J= 7.1 Hz, 3H).

C. 8-Indan-5-yl-2- [4-(2-morpholin-4-yl-ethyl)-phenylamino] -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-2- [4-(2-morpholin-4-yl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.037 mmol). A yellow solid was obtained (15.8 mg, 84%). 1H NMR (400MHz, DMSO-d6) S(ppm): 10.37 ~br, 1H), 9.22 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 7.64 (m, 1H), 7.47 (m, 211), 7.32 (m, 2H), 6.87 (br, 2H), 3.55 (m, 4H), 3.01 (t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.61 (in, 2H), 2.37 (m, 6H), 2.14 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H3oN603: 511.24 (M
+ H), Found 511Ø

Example 28 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methyl amide (Cpd 28) 0'1 0 0 ~N

NJ~N N
H

To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamirio]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg,, 0.037 mmol) in 1 mL methanol was added a solution of methylamine in THF (2N,, 2mL).
The mixture was stirred at 80 C for 4 hours. The solvent was removed by vacuum to leave a yellow solid (17mg, 87%). IH NMR (400MHz, CDC13) 8(ppm): 10.60 (br, 1H), 9.29 (s, 111), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J= 7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J= 7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.01 (t, J= 7.3 Hz, 2H), 2.94 (m, 5H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N603: 525.25 (M + H), Found 525Ø

Example 29 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 29) 0'1 0 0 ~N

N N
H

To a solution of 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 27 (b), 20 mg, 0.037 mmol) in 1 mL methanol was added a solution of ethylamine in THF (2N, 2mL).
The mixture was stirred at 80 C for 16 hours. The solvent was removed by vacuum to leave a yellow solid (12.7mg, 64%). 1H NMR (400MHz, CDC13) S(ppm): 10.60 (br, 1H), 9.29 (s, 1H), 8.78 (s, 1H), 7.75 (s, 1H), 7.60 (br, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.20 (m, 2H), 7.12 (d, J= 7.6 Hz, 1H), 6.87 (br, 2H), 3.69 (br, 4H), 3.42(q, J= 7.1 Hz, 2H), 3.1)1(t, J= 7.3 Hz, 2H), 2.93 (t, J= 7.4 Hz, 2H), 2.65 (br, 2H), 2.49 (br, 6H), 2.17 {m, 2H). 1.08 ~t, 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H34N603: 539.27 (M +
H), Found 539Ø

Example 30 (4S)-8-Indan-5-yl-5 -oxo-2- [4-(2 -oxo-oxazolidin-4-ylmethyl)-phenylamino] -5, 8-dihydro-pyrido[2,3 -d]pyrimidine-6-carboxylic acid amide ~Cpd 30) 0 0, HN N N
\' \I
HN-~

A. (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidiri-4-ylmethyl)-phenylalnino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from (4S)-4-(4-amino-beazyl)-1,3-oxazolidin-2-one (46 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (56 mg, 44%). 1H NMR (400MHz, CDC13) S(ppm): 9.00 (br, 1H), 8.42 (s, 1H), 7.50 (br, 1H), 7.33 (d, J= 7.9 Hz, 1H), 7.28 (br, 2H), 7.18 (s, 1H), 7.08 (d, J= 7.8 Iiz, 1H), 6.81 (br, 2H), 5.88 (s, 1H), 4.41 (t, J= 8.2 Hz, 1H), 4.31 (q, J= 7.0 Hz, 2H), 4.05 (m, 1H), 3.98 (m, 1H), 2.99 (t, J = 7.4 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.79-2.66 (ni, 2H), 2.15 (m, 2H), 1.31 (t, J= 7.1 Hz, 3H).

B. (4,S')-B-Indan-S-yl-S-oxo-2-{4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepar=ed from (4S)-8-indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.028 mmol). A
white solid was obtained (9.9 mg, 71%) after a preparative HPLC (32 mL/ min 5-100% MeCN/

gradient over 10 min) purification. 'H NMR (400MHz, DMSO-d6) S(ppm): 10.41 (br, 1H), 9.24 (s, 1H), 9.01 (d, J = 3.6 Hz, 1H), 8.54 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 3.9 Hz, 1H), 7.45 (m, 2H), 7.36 (m, 3H), 6.89 (br, 2H), 5.72 (s, 1H), 4.21 (t, J
7.8Hz, 1H), 3.92 (m, 2H), 3.02 (t, J = 7.4 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.73-2.60 (m, 2H), 2.14 (m, 2H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H24N604: 497. 10 {M + H), Found 497Ø

Example 31 (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenyl amino] -5, 8-dihydi o-p yrido [2, 3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 31) O O

H N
HN N N

O
HN-~
Using the procedure outlined in Example 28 the title compound was prepared from (45)-8-indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.038 mmol). A
white solid was obtained (17.3 mg, 89%) after a preparative HPLC (32 mL/ min 5-100% MeCN/

gradient over 10 min) purification. 1H NMR (400MHz, CDC13) S(ppm): 9.58 (t, J
= 5.6 Hz, 1H), 9.20 (br, 1H), 8.76 (s, 1H), 7.95 (br, 1H), 7.75 (s, 1H), 7.34 (d, J=
7.9 Hz, 1H), 7.29 (br, 2H), 7.18 (s,1H), 7.09 (d, J= 7.8 Hz, 1H), 6.85 (br, 2H), 5.22 {s, 1H), 4.42 (t, J=
8.2 Hz, 1H), 4.06 (m, 1H), 3.96 (m, 1H), 3.22 (s, 3H), 3.00 (t, J = 7.4 Hz, 2H), 2.93 (t, J

7.4 Hz, 2H), 2.80-2.66 (m, 2H), 2.16 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C28H26N604: 511.20 (M + H), Found 511Ø

Example 32 (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenyl amino] -5, 8-dihydro-p yrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 32) 11 , u I N
H
HN N N
\I ,\I
HN~
O
Using the procedure outlined in Example 29 the title compound was prepared from (4S)-8-indan-5-yl-5-oxo-2- [4-(2=oxo-oxazolidin-4-ylmethyl)-phenylamino] -5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.038 mmol). A
white solid was obtained (13.5 mg, 68 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/

gradient over 10 min) purification. iH NMR (400MHz, CDC13) 8(ppm): 9.58 (t, J
= 5.6 Hz, 1H), 9.20 (br, 1H), 8.76 (s, 1H), 7.95 (br, 1H), 7.75 (s, 1H), 7.34 (d, J=
7.9 Hz, 1H), 7.29 (br, 2H), 7.18 (s, 1H), 7.09 (d, J= 7.8 Hz, 1H), 6.85 (br, 2H), 5.22 (s, 1H), 4.42 (t, J=
8.2 Hz, 1H), 4.06 (m, 1H), 3.96 (m, 1H), 3.44 (m, 2H), 3.00 (t, J= 7.4 Hz, 2H), 2.93,(t, J=
7.4 Hz, 2H), 2.80-2.66 (m, 2H), 2.16 (m, 2H), 1.21 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H28N604: 525.22 (M + H), Found 525Ø

Example 33 8-Indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenyl amino] -5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 33) o Q
N ~
N H
H
N N
H

A. 2-(4-Nitro-phenyl)-ethanesulfonyl chloride 1-(2-Bromo-ethyl)-4-nitro-benzene (3 g, 13 mmol) an d potassium thioacetate (3 g, 26 mmol) in DMSO (10 mL) were stirred at r.t. for 3 hours. EtOAc was used to dilute the reaction. The organic layer was washed with water twice (2X 100 mL), brine and dried over Na2SO4. The solvent was evaporated under vacuum to give a brown solid (-3 g), which was taken in 50 mL of acetic acid. To the stirring solution was added 20 mL of hydrogen peroxide (30% in water). The resulting yellow solution was stirred at r.t.
overnight. Water (50 mL) was added and the solvent was evaporated in vacuum with minimal heating. The yellow residue was dried on high vacuum for two days.
Then it was suspended in thionyl chloride (18 mL) and the mixture was heated to reflux (80 C) for 6 hours. The volatiles were evaporated to leave a yellow solid, which was used for next step without purification.

B. 2-(4-Amino-phenyl)-ethanesulfonic acid isopropylamide 2-(4-Nitro-phenyl)-ethanesulfonyl chloride (300 mg) was suspended in 5 mL of THF. To the stirring solution was added isopropylamine (600 L) dropwise at r.t: After 5 hours the solvent was evaporated. The nitro product was purified by flash chromatography (CHZC12/ CH3OH 10:1 v/v) and was converted to the title compound under nonnal hydrogenation conditions. The title compound was obtained as a yellow solid (182 mg, 54 %). 'H NMR (300MHz, CD3OD) 8(ppm): 6.96 (d, 'J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H), 3.53 (m, 1H), 3.19 (m, 2H), 2.91 (m, 2H), 1.20 (s, 3H), 1.18 (s, 3H).

C. 8-Indan-5-yl-2- [4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-57oxo-5,-8-dihydi=o-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 2-(4-amino-phenyl)-ethanesulfonic acid isopropylamide (58 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5 -oxo-5, 8-dihydro-pyri do [2,3 -d] pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (50 mg, 36%). 'H NMR (400MHz, CDC13) 8(ppm): 9.34 (s, 1H), 8.53 (s, 1H), 7.88 (br, 1H), 7.42 (d, J= 7.9 Hz, 1H), 7.27 (m, 3H), 7.18 (d, J= 7.9 Hz, 1H), 6.94 (br, 2H), 5.88 (s, 1H), 4.37 (q, J= 7.1 Hz, 2H), 3.61 (m, 1H), 3.22=(m, 2H), 3.10-2.96 (m, 6H), 2.23 (m, 2H), 1.38 (t, J= 7.1 Hz, 3H), 1.25 (s, 3H), 1.22 (s, 3H).

D. 8-Indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide Using the procedure outlined in Example 28 the title compound was prepared fiom 8-indan-5-yl-2- [4-(2-isopropylsulf amoyl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.034 mmol). A
yellow solid was obtained (13.9 mg, 70%). IH NMR (400MHz, CDC13) S(ppm): 9:59~br, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 7.52(br, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.24 (m, 3H), 7.09 ~d, J
7.9 Hz, 1H), 6.88 (br, 2H), 3.88 (d, J= 7.7 Hz, 1H), 3.60 (s, 3H), 3:55 (m, 1H), 3.14 (m, 2H), 3.03-2.90 (m, 6H), 2.16 (m, 2H), 1.15 (s, 3H), 1.13 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H32N604S: 561.22 (M + H), Found 561Ø

Example 34 8-Indan-5-yl-2- [4-(2-isopropylsulfamoyl-ethyl)-phenyl amino] -5 -oxo-5, 8-dihydro-pyrido [2, 3-d] p yrimidine-6-carboxylic acid ethyl amide (Cpd 34) \\S:~,o 0 0 H' H
N N
H

Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.026 mmol). A
yellow solid was obtained (7.5 mg, 50%). 1H NMR (400MHz, CDC13) S(ppm): 9.59 ~br, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 7.52 (br, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.24 (m, 3H), 7.09 (d, J
7.9 Hz, 1H), 6.88 (br, 2H), 3.88 (d, J= 7.7 Hz, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 3.14 (m, 2H); 3.03-2.90 (m, 6H), 2.16 (m, 2H), 1.20 (t, J= 7.3 Hz, 3H), 1.15 (s, 3H), 1.13 (s, 3H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H34N60~S: 575.24 {M + H), Found 575Ø

Example 35 8-Indan-5-yl-2- { 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 35) 0 N N I& N
as?i~ITr H

A. 4-[2-(Morpholine-4-sulfonyl)-ethyl]-phenylamine 2-(4-Nitro-phenyl)-ethanesulfonyl chloride (from Example 33 (A), 300 mg) was suspended in 5 mL of THF. To the stirring solution was added morpholine (1 mL) dropwise at r.t. After 5 hours the solvent was evaporated. The nitro product was purified by flash chromatography (CH2C12/ CH3OH 10:1 v/v) and was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (167 mg, 52 %). 1H NMR (400MHz, CD3OD) b(ppm): 7.01(d, J 8.4 Hz, 2H), 6.65 (d, J= 8.4 Hz, 2H), 3.72 (t, J= 4.7 Hz, 4H), 3.23 (t, J= 4.7 Hz, 4H), 3:11 (m;
2H), 2.98 (m, 2H).

B. 8-Indan-5-yl-2- { 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino }-5-oxo-5,8-dihydro-pyrido[2,3=d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (65 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (42 mg, 29%). IH NMR (400MHz, CDC13) S(ppm): 9.35 (s, 1H), 8.53 (s, 1H), 8.01 (br, 1H), 7.42 (d, J= 7.8 Hz, 1H), 7.30 (m, 3H), 7.19 ~d, J= 7.8 Hz, 1H), 6.94 (br, 2H), 4.37 (q, J= 7.1 Hz, 2H), 3.72 (t, J= 4.5 Hz, 4H), 3.25 (t, J= 4.7 Hz, 4H), 3.08 (m, 6H), 3.01 (t, J= 7.4 Hz, 2H), 2.24 (m, 2H), 1.38 (t, J= 7.1 Hz, 3H).

C. 8-Indan-5-yl-2- { 4- [2-(morpholine-4-sulfonyl)-ethyl] -phenylamino } -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-2- { 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino } -5-oxo=5,B-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (12 mg, 0.020 mmol). A
yellow solid was obtained (6.4 mg, 54%). 1H NMR (400MHz, CDC13) 8(ppm): 9.59 (br, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 8.25 (br, 1H), 7.36 (d, J= 7.9 Hz, 1H), 7.26 (br, 2H), 7.19 (s, 1H), 7.10 (d, J= 7.9 Hz, 1H), 6.89 (br, 2H), 3.67 (t, J= 4.7 Hz, 4H), 3.22 {s, 3H), 3.18 (t, J
= 4.7 Hz, 4H), 3.01 (m, 6H), 2.94 (t, J= 7.4 Hz, 2H), 2.17 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N605S: 589.22 (M + H), Found 589Ø

Example 36 8 -Ind an-5 -yl-2- { 4- [2-(morpholine-4-sulfonyl)-ethyl] -phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 36) o;S o N) H
N
N N
pJ
H
. ~~

Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2-{ 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 35 (B), 12 mg, 0.020 mmol). A yellow solid was obtained (7.6 mg, 63%). 1H NMR (400MHz, CDC13) 8(ppm):
9.59 (br, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 8.25 (br, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.26 (br, 2H), 7.19 (s, 1H), 7.10 (d, J= 7.9 Hz, 1H), 6.89 (br, 2H), 3.67 (t, J= 4.7 Hz, 4H), 3.43 (m, 2H), 3.18 (t, J = 4.7 Hz, 4H), 3.01 (m, 6H), 2.94 (t, J = 7.4 Hz, 2H), 2.17 (m, 2H), 1.20 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H34N605S: 603.23 (M +
H), Found 602.9 Example 37 8 -Indan-5 -y1-2- [ 3 -(4-methyl-pip erazin-1-yl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid amide (Cpd 37) rNN N N
,NJ H

A. 3-(4-Methyl-piperazin-1-yl)-phenylamine To a suspension of 1-fluoro-3-nitrobenzene (3.77 mL, 35.4 mmol) and potassium carbonate (lOg, 71 mmol) in DMSO (30 mL) was added 1-methyl piperazine (59 mL, 53.2 mmol). The mixture was stirred at 122 C for 24 hours. After cooing down, the mixture was diluted with water (100 mL) and extracted with EtOAc (3x 100 mL). The Combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford an orange oil. Recrystallization from EtOAc/hexanes gave 4.2 g of 1-(4-methyl-piperazin-1-yl)-3-nitrobenzene, which was reduced via hydrogenation to give the title compound (beige solid, 3 g). 1H NMR (400MHz, CDC13) 5(ppm):
7.04 (t, J = 8.0 Hz, 1H), 6.38 (dd, J = 2.3, 8.2 Hz, 1H), 6.26 (t, J= 2.2 Hz, 1H), 6.22,(dd, J= 2.3, 8.2 Hz, 1H), 3.60 (br, 2H), 3.18 (t, J = 4.9 Hz, 4H), 2.55 (t, J= 4.9 Hz, 4H), 2.34 (s, 3H).
B. 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 3-(4-methyl-piperazin-1-yl)-phenylamine (50 mg, 0.27 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 'H NMR (400MHz, CDC13) 8(ppm): 9.29 (s, 1H), 8.44 (s, 1H), 7.49 (br, 1H), 7.31 (d, J= 7.9 Hz, 1H), 7.20 (m, 2H), 7.09 (d, J= 7.8 Hz, iH), 6.94 (d, J= 7.9 Hz, 1H), 6.87 (br, 1H), 6.52 (d, J= 7.9 Hz, 1H), 4.32 (q, J= 7.1 Hz, 2H), 3.02-2.90 (m, 8H), 2.45 (m, 4H), 2.26 (s, 3H), 2.14 (nl, 2H), 1.32 (t, J= 7.1 Hz, 3H).

C. 8-Indan-5-y1-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from B above, 20 mg, 0:038 mmol).
A yellow solid was obtained (8.3 mg, 44%). 1H NMR (400MHz,CD2C12) $(ppm): 9.35 (br, iH), 9.27 (s, 1H), 8.69 (s, 1H), 7.34 (d, J= 8.1 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J=
8.1 Hz, 1H), 6.97 (d, J= 7.9 Hz, 1H), 6.86 (br, 1H), 6.65 (br, 1H), 6.53 (d, J= 7.9 Hz, 1H), 5.91 (br, 1H), 3.00-2.84 (m, 8H), 2.43 (br, 4H), 2.22 (s, 3H), 2.12 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2$H29N702: 496.24 (M + H), Found 496.1.

Example 38 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-.
5-oxo-5; 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 38) \ I N \ I NI-I
H
r'N Nll N N

,NJ H Using the procedure outlined in Example 28 the title compound was prepared fTom 8 -indan-5 -yl-2- [ 3 -(4-methyl-p iperazin-1-y1)-phenyl amino] -5 -ox o-5, 8 -dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid ethyl ester (from Example 37(B) above, 15 mg, 0.028 mmol). A yellow solid was obtained (8.8 mg, 62%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 1H NMR (400MHz,CDC13) 8 (ppm): 9.55 (br, 1H), 9.31 (s, 1H), 8.75 (s, 1H), 7.46 (br, 1H), 7.30 (d, J=
8.1 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J= 8.1 Hz, 1H), 6.98 (d, J= 7.9 Hz, 1H), 6.88 (br, 1H), 6.60 (br, 1H), 6.54 (d, J= 7.9 Hz, 1H), 3.06-2.89 (m, 11H), 2.45 (m, 4H), 2.27 (s, 3H), 2.12 (m, 2H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N702: 510.25 (M + H), Found 510.1.

Example 39 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 39) / H
N ~ N N N
~
/N,) H

Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2-[3-(4-methyl-piperazin- l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 37(B) above, 15 mg, 0.028 mmol). A yellow solid was obtained (8.6 mg, 59%) after a preparative HPLC (32 mL/ inin 5-100% MeCN/ H20 gradient over 10 min) purification. 1H NMR (400MHz,CDC13) 8 (ppm): 9.62 (br, 1H), 9.31 (s, 1H), 8.75 (s, 1H), 7.46 (br, 1H), 7.30 (d, J=
8.1 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J= 8.1 Hz, 1H), 6.98 (d, J= 7.9 Hz, 1H), 6.88 (br, 1H), 6.64 (br, 1H), 6.56 (d, J = 7.9 Hz, 1H), 3.43 (m, 2H), 3.06-2.86 (m, 8H), 2.45 (m, 4H), 2.27 (s, 3H), 2.13 (m, 2H), 1.20 (t, J = 7.3 Hz, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C3oH33N702: 524.27 (M + H), Found 524.1.

Example 40 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 4) HON ~
\ IN~ I NH2 N N
H

A. 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester To a suspension of 1-fluoro-4-nitrobenzene (1.4 mL, 13 mmol) and potassium carbonate (2.5 g, 18 mmol) in DMSO (10 mL) was added 1-Boc-piperazine (2.75 g, 14.8 mmol). The mixture was stirred at 100 C for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (NaZSO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAC/hexanes gave 4.0 g of 1-(4-Boc-piperazin-1-yl)-4-nitrobenzene, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 'H NMR (400MHz, CDC13) S(ppm): 6.68 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 3.56 (t, J = 5.0 Hz, 4H), 2.96 (t, J = 5.0 Hz, 4H), 1.46 (s, 9H).

B. 8-Indan-5-yl-5-oxo-2-(4-piperazin-l-yl-phenylamino)-5, 8-dihydro-pyridol2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-amino-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (52 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 70 mg, 0.17 mmol). A
yellow solid was obtained (75 mg, 86 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/

gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CHZC12 0:1 v/v) to give the title compound. 'H NMR (400MHz, CDC13) 6 (ppm):
9.25 (s, 1H), 8.45 (s, 1H), 7.61 (br, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.21 (s, 1H), 7.14 (br, 2H), 7.10 (d, J= 7.9 Hz, 1H), 6.57 (br, 2H), 4.30 (q, J= 7.1 Hz, 2H), 3.02-2.90 (m, 12H), 2.15 (m, 2H), 1.30 (t, J= 7.1 Hz, 3H).

C. 8 -Indan-5 -yl-5-oxo-2-(4-piperazin-l-yl-phenylamino)-5,8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester (from B above, 20 mg, 0.038 mmol).
The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5-100%
MeCN/ H20 gradient over 10 min) purification (12.8 mg, 52%). 'H NMR (400MHz, CD2C12/CD3OD 10:1 v/v) 8(ppm): 9.23 (s, 1H), 8.70 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.27 (br, 2H), 7.23 (s, 1 H), 7.14 (d, J= 7.9 Hz, 1 H), 6.63 (br, 2H), 3.25 (m, 12H), 2.96 (m, 4H), 2.13 (m, 214). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H27N702:
482.22 (M +
H), Found 482Ø

Example 41 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 41) H~I o 0 NOIN
N N
H

Using the procedure outlined in Example 28 the title compound was prepared fivm 8-indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido.[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 40(B) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 12.2 mg, 51%) after a preparative HPLC
(32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification: 'H NMR
(400MHz, CDC13/CD3OD 10:1 v/v) 8(ppm): 9.67 (br,111), 9.26 (s, 1H), 8.71 (s, 1H), 7.37 (d, J 7.9 Hz, 114), 7.25 (br, 2H), 7.20 (s, 1H), 7.11 (d, J= 7.9 Hz, 111), 6.58 (br, 2H), 3.24 (m, 8H), 2.97-2.93 (m, 7H), 2.15 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H29N702: 496.24 (M + H), Found 496Ø

Example 42 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 42) N----H
N N N
H
I~
Using the procedure outlined in Example 29 the title compound was 'prepared from 8-indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 40(B) above, 20 mg, '0.039 mmol). A yellow solid was obtained (TFA salt, 4.4 mg, 22%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 'H NMR (400MHz, CDC13/CD3OD 10:1 v/v) 8(ppm): 9.67 (br,1H), 9.26 (s, 1H), 8.71 (s, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.25 (br, 2H), 7.20 (s, 1H), 7.11 (d, J= 7.9 Hz, 1H), 6.58 (br, 2H), 3.42 .(m, 2H), 3.25 (m, 8H), 2.91-3.00 (m, 4H), 2.15 (m, 2H), 1.20 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N702: 510.25 (M + H), Found 510Ø

Example 43 2- [4-(3, 5 -Dimethyl-piperazin-1-yl)-phenylamino] -8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid amide (Cpd 43) N' N N
H

A. 4-(3,5-Dimethyl-piperazin-1-yl)-phenylamine To a suspension of 1-fluoro-4-nitrobenzene (2.12 mL, 20 mmol) and potassium carbonate (3.5 g, 25 mmol) in DMSO (10 mL) was added 3,5-dimethyl-piperazine (2.5 g, 22 mmol). The mixture was stirred at 100 C for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAc/hexanes gave '3.9 g of 3,5-dimethyl-l-(4-nitro-phenyl)-piperazine, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400MHz, CDC13) S(ppm):
6.80 (d, J= 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 3.40 (br, 2H), 3.32 (d, J = 9,5 Hz, 2H), 3.05 (m, 2H), 2.19 (t, J= 10.5 Hz, 2H), 1.12 (s, 3H), 1.10 (s, 3H).

B. 2- [4-(3, 5 -Dimethyl-piperazin-1-yl)-phenylamino] -8-indan-5 -yl-5 -oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(3,5-dimethyl-piperazin-1-yl)-phenylamine (from the previous step, 27 mg, 0.13 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 50 mg, 0.12 mmol). A
yellow solid was obtained (40 mg, 62 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/

gradient over 10 min) purification. 1H NMR (400MHz, CDC13) 8(ppm): 9.31 (s, 1H), 8.52 (s, 1H), 7.83 (br, 1H), 7.40 (d, J= 7.9 Hz, 1H), 7.27 (s, 1H), 7.20 (br, 2H), 7.17 (d, J= 7.9 Hz, 1H), 6.63. (br, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.38 (d, J = 10.5 Hz, 2H), 3.03 (m, 6H), 2.24 (m, 4H), 1.38 (t, J= 7.1 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H).

C. 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 2-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from B above, 15 mg, 0.028 mmol).
The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/
min 5-100% MeCN/ H20 gradient over 10 min) purification (10.5 mg; 60%). 1H NMR
(400MHz, CD2C12/CD3OD 10:1 v/v) 8(ppm): 9.24 (s, 111), 8.70 (s, 1H), 7.38 (d J= 7.9,Hz, .1H), 7.27 (br, 2H), 7.23 (s, 1H), 7.14 (d, J= 7.9 Hz, 1H), 6.62 (br, 2H), 3.49 (d, J= 10.5 Hz,.
2H), 3.37 (in, 2H), 2.96 (m,,4H), 2.65 (t, J= 11.5 Hz, 2H), 2.13 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N702: 510.25 (M + H), Found 510Ø

Example 44 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8 -dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methyl amide (Cpd 44) HN~ 0 0 ,),,N \ I N ~ I H~

NN N
H

Using the procedure outlined in Example 28 the title compound was prepared from 2-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 43(B) above, 15 mg, 0.028 mmol). A yellow solid was obtained (TFA salt, 9.6 mg, 54%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. IH NMR
(400MHz, CDC13) 8(ppm): 10.14 (br, 1H), 9.62 (m, 1H), 9.26 (s, 1H), 8.98 (br, 1H), 8.75 (s, 1H), 7.35 (d, J 7.9 Hz, 1H), 7.22 (m, 3H), 7.09 (d, J = 7.9 Hz, 1H), 6.60 (br, 2H), 3.46-3.38 (m, 4H), 3.00-2.82 (m, 9H), 2.14 (m, 2H), 1.32 (s, 3H), 1.30 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N702: 524.27 (M + H), Found 524Ø

Example 45 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 45) HN O O
C(N N N
H ~

Using the procedure outlined in Example 29, the title compound was prepared from 2-[4-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 43(B) above, 10 mg, 0.018 mmol). A yellow solid was obtained (TFA salt, 5.2mg, 44%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 'H NMR
(400MHz, CDC13) 8(ppm): 10.14 (br, 1H), 9.62 (m, 1H), 9.26 (s, 1H), 8.98 (br, 1H), 8.75 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.22 (m, 3H), 7.09 (d, J= 7.9 Hz, 1H), 6.60 (br, 2H), 3.46-3.38 (m, 4H), 3.00-2.82 (m, 6H), 2.66 (br, 2H), 2.14 (m, 2H), 1.32 (s, 3H), 1.30 (s, 3H), 1.19 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H35N702:
538.27 (M + H), Found 538.1.

Example 46 8-Indan-5-yl-2- { 4- [2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino { -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 46) N~
O
~N CONH2 N ~-N H

A. 4-[2-(4-Methyl-piperazin-1-y1)-ethyl]-phenylamine 1-(2-Bromo-ethyl)-4-nitro-benzene (0.9 g, 3.9 mmol) was added to a mixture of methyl-piperazine (520 L, 4.7 mmol) and potassium carbonate (1 g, 4.7 mmol) in 5 mL of DMSO. The mixture was stirred at 100 C for 2 hour. After cooling to room temperature, the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (NaZSO4). Removal of the solvent and chromatography on silica, eluting with EtOAc/CH3OH/NH4OH (10:1:0.1, v/v), gave 850 mg of 1-methyl-4-[2=(4-nitro-phenyl)-ethyl]-piperazine, which was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (780 mg, 91 %). 1H NMR (400MHz, CDC13) 8(ppm): 6.98 (d, J= 8.3 Hz, 2H), 6.61 {d, J = 8.3 Hz, 2H), 3.57 (br, 2H), 2.71 (br, 12H), 2.43 (br, 3H).

B. 8-Indan-5 -y1-2- { 4- [2-(4-methyl-piperazin-1-yl)-ethyl] -phenylamino } -5-vxo-5; 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamine (53 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (70 mg, 53%). 1H NMR (400MHz, CDC13) 8(ppm): 9.28 (s, 1H), 8.46 (s, 1H), 7.60 (br, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.21 (s, 1H), 7.16 (br, 2H), 7.12 (d, J = 7.9 Hz, 1H), 6.86 (br, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.99 .(t, J =
7.4 Hz, 2H), 2.93 (t,.
J= 7.4 Hz, 2H), 2.64 (m, 2H), 2.47 (m, 10H), 2.34 (s, 3H), 2.16 (m, 2H), 1.32 (t, J= 7.1 Hz, 3H).

C. 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino }-5=oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-2- { 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid etliyl ester (20 mg, 0.036 mmol). A
yellow solid was obtained (5.8 mg, 30%). 'H NMR (400MHz, DMSO-d6) 8(ppm): 10.48 (br, 1H), 9.31 (s, 1H), 9.10 (s, 1H), 8.62 (s, 1H), 7.75 (m, 1H), 7.54 (m, 2H), 7.41 (m, 2H), 6.97 (br, 2H), 3.55 (m, 4H), 3.09 (t, J = 7.3 Hz, 2H); 3.01 (t, J 7.4 Hz, 2H), 2.71 (m, 2H), 2.57 (m, 13H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N702:
524.27 (M
+ H), Found 524.1.

Example 47 8-Indan-5 -yl-2- { 4- [2-(4-methyl-piperazin-1-yl)-ethyl] -phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 47) \N~ 0 0 N ~
~ \ I N / I H/

NN N
H

Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-2- { 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 46(B) above, 20 mg, 0.036 mmol). A yellow solid was obtained (5.1 mg, 26%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 1H NMR (400MHz, CDC13/CD3OD 20:1 v/v) 8 (ppm): 9.61 (m, 1H), 9.29 (s, 1H), 8.75 (s, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.19 (m, 3H), 7.09 (d, J= 7.9 Hz, 1H), 6.84 (br, 2H), 3.00-2.90 (m, 7H), 2.64 (m, 2H), 2.47 (m, 10H), 2.24 (s, 3H), 2.15 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C31H35N702: 538.29 (M + H), Found 538.1.

Example 48 8-Indan-5-yl-2- { 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino }-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 48) \~.1 0 0 N \ i~ I N/\
NN N H
H
I~
Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2- { 4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 46(B) above; 20 nig, 0.036 mmol). A yellow solid was obtained (7.1 mg, 36%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification.1H NMR (400MHz, CDC13/CD3OD 20:1 v/v) S(ppm): 9.61 (m, 1H), 9.29 (s, 1H), 8.75 (s, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.19 (m, 3H), 7.09 (d, J= 7.9 Hz, 1H), 6.84 (br, 2H), 3.50 (m,' 2H), 3.06 (t, J=
7.4 Hz, 211), 2.99 (t, J = 7.4 Hz, 2H), 2.73 (m, 2H), 2.53 (m, 10H), 2.31(s, 3H), 2.22 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C32H37N702:
552.30 (M + H), Found 552.1.

Example 49 8-Indan-5 -yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (CPd 49) HN p O
i N'I\ NH2 \ I J~ ~ I
N N N
H

A. 4-(4-Amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester The title compound was prepared by Suzuki coupling of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (Synthesis, 993, (1991)). Mass spectrum (ESI, m/z): Calcd. for C16H22N202, 275.2 (M+H), found 275.1.

B. 4-(4-Amino-phenyl)-piperidine-l-carboxylic acid tert-butyl ester A solution of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.35 g, 1.2 nunol) (as prepared in the previous step) in methanol was hydrogenated over 10 % Pd/C at 20 psi for 1 h. The solution was filtered and concentrated to give 0.35 g (100 %) of the title compound as a yellow solid. 'H NMR
(400MHz, DMSO-d6) 8(ppm): 6.85 (d, J= 8.3 Hz, 2H), 6.50 (d, J= 8.3 Hz, 2H), 4.81 (s, 2H), 4.012 (m, 2H), 3.85 (br, 2H), 2.44 (m, 1H), 2.66 (m, 2H), 1.42 (m, 11H).

C. 8-Indan-5 -yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)=5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-amino-phenyl)-piperidine-l-carboxylic acid tert-butyl ester (from the previous step, 66 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e), 100 mg, 0.24 mmol). A yellow solid was obtained (75 mg, 51 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. The $oc ,group was removed by treatment with TFA in CH2C12 (1:1 v/v) to give the title compound. 'H NMR
(440MHz, CDC13) 8(ppm): 9.31 (s, 1H), 8.54 (s, 1H), 7.42 (d, J= 7.9 Hz, 1H), 7.29 (br, 2H), 7.27 (s, 1H), 7.18 (d, J= 7.9 Hz, 1H), 6.91 (br, 2H), 4.35 (q, J= 7.1 Hz, 2H), 3.52 (m, 2H), 3.16 (br, 2H), 2.97 (m, 4H), 2.68 (m, 1H), 2.22 (m, 2H), 1.95 (m, 2H), 1.35 (t, J=
7.1 Hz, 3H).
D. 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5, 8 -dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5, 8-dihydro-pyrido [2,3-d]pyrimidin6-6-carboxylic acid ethyl ester (27 mg, 0.053 mmol). A yellow solid was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (24 mg, 76 %). 1H NMR (400MHz, DMSO-d6) S(ppm):
10.48 (br, 1H); 9.31 (s, 1H), 9.10 (s, 1H), 8.62 (s, 1H), 7.75 (m, 1H), 7.54 (m, 2H), 7.41 (m, 2H), 6.97 (br, 2H), 3.55 (m, 4H), 3.09 (t, J= 7.3 Hz, 2H), 3.01 (t, J= 7.4 Hz, 2H), 2.81 (m, 1H), 2.22 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C28H28N602: 481.23 (M + H), Found 481.1.

Example 50 8-Indan-5-y1-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl.
amide (Cpd 50) ' \ d H
N N H

Using the procedure outlined in Example 28 the title compound.was prepared from 8-indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 48(C) above, 20 mg;
0.039 mmol). A yellow solid was obtained (TFA salt, 8.9 mg, 37%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H2O gradient over 10 min) purification. 1H NMR (400MHz, CDC13/CD3OD 20:1 v/v) 8(ppm): 9.30 (s, 1H), 8.75 (s, 1H), 7.35 (d, J= 7.9 Hz, 1H); 7.19 (m, 3H), 7.09 (d, J = 7.9 Hz, 1H), 6.84 (br, 2H), 3.48 (m, 211), 2.97 (m, 11H), 2.62 (m, IH), 2.16 (m, 2H), 1.88 (m, 21-1). Mass Spectrum (LCMS, ESI pos.) Cal=cd. For C29H30N602: 495.24 (M + H), Found 495.1.

Example 51 8-Indan-5 -yl-5 -oxo-2-(4-piperidin-4-yl-phenylamino)-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 51) ~
HN
~
\ I II \ I H
NN N
N N
H

Using the procedure outlined in Example 29 the title compound was prepared from 8 -indan-5 -y1-5-oxo-2-(4-piperidin-4-yl-phenyl amino)-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethyl ester (from Example 48(C) above, 20 mg, '0.039 mmol). A yellow solid was obtained (TFA salt, 7.3 mg, 30%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 'H NMR (400MHz, CDC13/CD3OD 20:1 v/v) 8(ppm): 9.30 (s, 1H), 8.75 (s, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.19 (m, 3H), 7.09 (d, J = 7.9 Hz, 1H), 6.84 (br, 2H), 3.48 (m, 4H), 2.97 (m, 8H), 2.64 (m, 1H), 2.20 (m, 2H), 1.90 (m, 2H), 1.26 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C30H32N602: 509.26 (M + H), Found 509.1.

Example 52 8-Indan-5-yl-5-oxo-2-(3 -piperazin-1-yl-phenyl amino)=5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 52) o 0 \ I ~~ NH2 ON N N
H H

A. 4-(3-Amino-phenyl)-piperazine-l-carboxylic acid tert-butyl ester Using the procedure outlined in Example 37 (A), the title compound was prepared from 1-fluoro-3-nitrobenzene (1g, 7 mmol) and 1-Boc-piperazine (1.9 g, 10 mmol) 1H
NMR (400MHz, CDC13) 8(ppm): 7.03 (t, J = 8.0 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 6.23 (m, 2H), 3.62 (br, 2H), 3.53 (m, 4H), 3.07 (m, 2H), 1.47 (s, 9H).

B. 8-Indan-5-yl-5-oxo-2-(3 -piperazin-1-yl-phenylamino)-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Exasnple 1(g) the title compound was prepared from 4-(3-amino-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (from the previous step, 54 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 80 mg, 0.19 mmol). A yellow solid was obtained (60 mg, 62 %) after a preparative HPLC
(32 mL/
min 5-100% MeCN/ H20 gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CH2C12 (1:1 v/v) to give the title compound. 'H NMR
(400MHz, CDC13/CD3OD 10:1 v/v) 8(ppm): 9.26 (br, 1H), 8.49 (s, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.20 (s, 1H), 7.11 (m, 2H), 6.78 (br, 2H), 6.54 (m, 1H), 4.24 (q, J=
7.1 Hz, 2H), 3.98 (m, 4H), 2.29 (m, 4H), 2.96 (m, 4H), 2.14 (m, 2H), 1.27 (t, J= 7.1 Hz, 3H).

C. 8-Indan-5-y1-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.038 mmol).
The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/
min 5-100% MeCN/ H20 gradient over 10 min) purification (6.9 mg, 30%). 1H NMR
(400MHz, DMSO-d6) b(ppm): 10.21 (br, 1H), 9.20 (s, 1H), 8.96 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.41(m, 2H), 7.30 (d, J = 8.1 Hz, 1H), 7.10 (d, J=
7.7 Hz, 1H), 6.81 (br, 1H), 6.57 (d, J= 8.5 Hz, 1H), 3.14 (m, 4H), 2.90 (m, 4H), 2.05 (m, 2H):1Vlass Spectrum (LCMS, ESI- pos.) Calcd. For C27H27N702: 482.22 (M + H), Found 482.1r=

Example 53 8-Indan-5-yl-5-oxo-2-(3 -piperazin-1-yl-phenylamino)-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 53) /
H
r'NN/ N N

NN,,J H 'Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Exainple 52(B) above, '20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 13.2 mg, 56%) after a preparative HPLC
(32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 1H N1VIR
(400MHz, CDC13/CD3OD 10:1 v/v) 8(ppm): 9.67 (br,1H), 9.35 (s, 1H), 8.77 (s, 1H), 7.36 (d, J= 7.9 Hz, 1H), 7.23 (s, 1H), 7.17 (br, 1H), 7.13 (d, J= 7.9 Hz, 1H), 6.87 (br, 1H), 6.67 (br, 1H), 6.57 (m, 1H), 3.27 (m, 4H), 2.97 (m, 7H), 2.44 (br, 4H), 2.16 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H29N7OZ: 496.24 (M + H), Found 496Ø

Example 54 8-Indan-5-yl-5-oxo-2-(3-piperazin-.l-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 54) cyrf HrNN/N N
HN J H

Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido.[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 52(B) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 8.5 mg, 35%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 1H NMR (400MHz, CDC13/CD3OD 10:1 v/v) 8(ppm): 9.30 (s, 1H), 8.72 (s, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.19 (s, 1H), 7.15 (br, 1H), 7.10 (d, J= 7.9 Hz, 1H), 6.84 (br, 1H), 6.61 (br, 1H), 6.54 (m, 1H), 3.41 (m, 2H), 3.22 (m, 4H), 2.96 (m, 4H), 2.77 (br, 4H), 2.14 (m, 2H), 1.18 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N702: 510.25 (M + H), Found 510.1.

Example 55 2- [3 -(3, 5-Dimethyl-piperazin-1-yl)-phenylamino] - 8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2, 3 -d] pyrimidine-6-carboxylic acid amide (Cpd 55) ~ NHZ
~NN N N
HN' J H

A. 3-(3,5-Dimethyl-piperazin-1-yl)-phenylamine Using the procedure outlined in Example 37 (A), the title compound was prepared from 1-fluoro-3-nitrobenzene (lg, 7 mmol) and 3,5-dimethyl-piperazine (1.14 g, mmol). 1 H NMR (400MHz, CDC13) S(ppm): 7.00 (t, J = 8.0 Hz, 1H), 6.33 (d, J =
8.2 Hz, 1H), 6.21 (m, 1H), 6.15 (d, J= 8.2 Hz, 1H), 3.60 (br, 2H), 3.45 (d, J= 9.8Hz, 2H), 2.98 (m, 1H), 2.22 (t, J= 11.3 Hz, 2H), 1.10 (s, 311), 1.08 (s, 3H).

B. 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8 -indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 3-(3,5-dimethyl=piperazin-1-yl)-phenylamine (from the previous step, 52 mg, 0.25 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24.mmo1). A
yellow solid was obtained (67 mg, 52 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/

gradient over 10 min) purification. IH NMR (400MHz, CDC13) S(ppm): 9.29 (s, 111), 8.44 (s, 1H), 7.49 (br, 1H), 7.31 (d, J= 7.9 Hz, 111), 7.20 (m, 211), 7:09.(d, J=
7.8 Hz, 1H), 6.94 (d, J= 7.9 Hz, 111), 6.87 (br, 1H), 6.52 (d, J= 7.9 Hz, 1H), 4.32 (q, J= 7.1 H7, 2H), 3.38 (d, J= 10.5 Hz, 211), 3.03 (m, 6H), 2.25 (m, 2H), 2.12 (m, 2H), 1.32 (t, J=
7.1 Hz, 3H), 1.10 (s, 311), 1.08 (s, 3H).

C. 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6=carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 2-[3-(3,5-dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-y1-5-oxo-5,8-dihydxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 15 mg, 0.028 mmol). The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (10.8 mg, 62%). IH
NMR (400MHz, CDC13/CD30D 5:1 v/v) 8(ppm): 9.67 (br, 1H), 9.35 (s, 1H), 8.77 (s, 1H), 7.36 (d, J= 7.9 Hz, 1H), 7.23 (s, 1H), 7.17 (br, 1H), 7.13 (d, J= 7.9 Hz, 1H), 6.87 (br, 1H), 6.67 (br, 1H), 6.57 (m, 1H), 3.49 (d, J = 10.5 Hz, 2H), 3.37 (m, 2H), 2.96 (m, 4H), 2.65 (t, J= 11.5 Hz, 2H), 2.13 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H). Mass Spectrum (LCMS, ESI
pos.) Calcd. For C29H31N702: 510.25 (M + H), Found 510.1.

Example 56 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5, 8 -dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid methyl amide (Cpd 56) H
N N N
HN~ H

Using the procedure outlined in Example 28 the title compound was prepar=ed from 2-[3 -(3,5-dimethyl-piperazin-l-yl)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 55(B), 15 mg, 0.028 mmol). A yellow solid was obtained (TFA salt, 5.3 mg, 30%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification. 'H NMR'(400MHz, CDC13) S(ppm): 9.67 (br, 114); 9.34 (s, 1H), 8.77 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 7.17 (br, 1H), 7.13 (d, J= 7.9 Hz, 1H), 6.85 (br, 1H), 6.67 (br, 1H), 6.55 (m, 1H), 3.49 (d, J= 10.5 Hz, 2H), 3.37 (m, 2H), 2.97 (m, 7H), 2.74 (m, 4H), 2.13 (m, 2H), 1.33 (s, 3H), 1.31 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N702:
524.27 (M +
H), Found 524.1.

Example 57 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 57) '1 ~N CONH2 N N N
H ~

A. 8-Cyclohexyl-2- [4-(2-morpholin-4-yl-ethyl)-phenyl amino] -5 -oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title conlpound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (from Example 27(A), 54 mg, 0.26 mniol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. (from Example 17(e) above, 100 mg, 0.26 mmol).
The title compound was obtained as a white solid (77 mg, 59%). 'H NMR (400MHz, CDC13) 5 (ppm): 9.28 (s; 1H), 8.46 (s, 1H), 7.98 (br, 1H), 7.50 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz, 2H), 5.04 (m, 1H), 4.32 (q, J= 7.1 Hz, 2H), 3.67 (t, J= 4.6 Hz, 4H), 2.76 (m, 2H), 2.54 (m, 2H), 2.47 (m, 4 H), 1.99 (m, 4H), 1.78 (m, 1H), 1.61 (m, 2H), 1.46 {m, 2H), 1.34 (t, J= 7.1 Hz, 3H), 1.23 (m, 1H).

B . 8-Cyclohexyl-2- [4-(2-morpholin-4-yl-ethyl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dih_vdro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step; 20 mg, 0.039 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min.5-100% MeCN/ H20 gradient over 10 min) purification (10.7,mg, 56%). 'H NMR
(400MHz, CDC13) 8(ppm): 9.42 (br, 1H), 9.31 (s, 1H), 8.78 (s, 1H), 7.50 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz, 2H), 5.10 (m, 1H), 3.67 (t, J= 4.6 Hz, 4H), 2.76 (m, 2H), 2.54 (m, 2H), 2.46 (m, 4H), 1.99 (m, 4H), 1.78-1.19 (m, 10H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H32N603: 477.25 (M + H), Found 477.1.

Example 58 8-Cyclohexyl-2- [4-(2-morpholin-4-yl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid methyl amide (Cpd 58) 0'1 0 0 I
L,N \ I , ~ H-N N

Using the procedure outlined in Example 28 the title compound was prepared from 8 -cyclohexyl-2- [4-(2-morpholin-4-yl-ethyl)-phenyl amino] -5 -oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 57(A), 20 mg, 0:039 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (13.4 mg, 70%). 'H NM3'.
(400MHz, CDC13) 8(ppm): 9.57 (m, 1H), 9.30 (s, IH), 8.78 (s, 1H), 7.70 (br, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.16 (d, J= 8.5 Hz, 2H), 5.09 (m, 114), 3.67 (t, J = 4.6 Hz, 4H), 2.94 (d, J= 4.9 Hz, 3H), 2.76 (m, 2H), 2.54 (m, 2H), 2.46 (m, 4H), 1.97 (m, 4H), 1.71 (m, 3H), 1.44 (m, 2H), 1.23 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H34N603:
491.27 (M +
H), Found 491Ø

Example 59 8-Cyclohexyl-2- [4-(2-morpholin-4-yl-ethyl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl amide (Cpd 59) 0'1 o c ~N N
"
N N N
" b Using the procedure outlined in Example 29, the title compound was prepared from 8-cyclohexyl-2- [4-(2-morpholin-4-yl-ethyl)-phenylamino] -S-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 57(A), 20 mg, 0.039 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (11.9 mg, 60%). 1H NMR
(400MHz, CDC13) 8(ppm): 9.64 (m, 1H), 9.30(s, 1H), 8.78 (s, 1H), 7.70 (br, 1H), 7.50 (d, J= 8.5 Hz, 2H), 7.16 (d, J = 8.5 Hz, 211), 5.07 (m, 1H), 3.67 (t, J 4.6 Hz, 4H), 3.42 (m, 2I-i), 2.76 (m, 2H), 2.54 (m, 2H), 2.46 (m, 4H), 1.97 (m, 4H), 1.71 (m, 3H), 1.44 (m, 211), 1.18 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H36N603: 505.28 (M + H), Found 505Ø

Example 60 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl amino] -5 -ox o-5, 8-dihydro-pyrido [2, 3-d] p yrimi dine-6-carboxylic acid amide (Cpd 60) \N O

~~~I~
N N N
H ~

A. 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (50 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, Ø26 mmol). The title compound was obtained as a yellow solid (80 mg, 63%). 1H NMR (400MHz, CDC13) S(ppm): 9.25 (s, 1H), 8.44 a(s,1H), (br, 1H), 7.43 (d, J= 8.9 Hz, 2H), 6.87 (d, J= 9.0 Hz, 2H), 5.00 (m, 1H), 4.32 (.q, J= 7.1 Hz, 2H), 3.16 (t, J= 4.9 Hz, 4H), 2.55 (t, J= 4.9 Hz, 4H), 2.30 (s, 3H), 1.94 ~.~(m, 4H), 1.76 (m, 1H), 1.62 (m, 2H), 1.42 (m, 2H), 1.34 (t, J= 7.1 Hz, 3H), 1.21 (m, 1H).

B . 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Usirig the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg,.
0.040 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (9.9 mg, 54%). 'H NMR
(400MHz, DMSO-d6) 8(ppm): 10.27 (br, 1H), 9.15 (s, 1H), 9.05 (m, 1H), 8.68 (s, 1H), 7.60 (m, 3H), 6.92 (d, J= 9.0 Hz, 2H), 4.99 (m, 1H), 3.09 (m, 4H), 2.44 (m, 4H), 2.20 (s, 3H), 1.92 (m, 4H), 1.71 (m, 3H), 1.42 (m, 2H), 1.30 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd.
For C25H31N702: 462.25 (M + H), Found 462Ø

Example 61 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenyl amino] -5 -oxo-5, 8-dihydro-pyrido [2, 3-d] p yrimidine-6-carboxylic acid methyl amide (Cpd 61) ~N'l O O
\

N N
H ~

Using the procedure outlined in Example 28 the title compound was prepared fi-om 8-cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamirio]=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 60(A), 20 mg, 0.040 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (9.0 mg, 47%). 'H NMR
(400MHz, CDC13) S(ppm): 9.60 (m, 1H), 9.27 (s, 1H), 8.76 (s, 1H), 7.50 (br, 1H), 7.44 (d, J = 8.6 Hz, 2H), 6.88 (d, J= 9.0 Hz, 2H), 5.05 (m, 1H), 3.14 (m, 4H), 2.92 (d, J= 4.9 Hz, 3H), 2.54 (m, 4H), 2.30 (s, 3H), 1.95 (m, 4H), 1.66 (m, 3H), 1.44 (m, 2H), 1.20 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H33N702: 476.27 (M + H), Found 476Ø

Example 62 8-Cyclohexyl-2-[4-(4-methyl-piperazin-l-yl)-phenyl amino] -5 -oxo-5, 8-dihydro-p yrido [2, 3-d] p yrimidine-6-carboxylic acid ethyl amide (Cpd 62) o 0 \ I II / I H
DN

N N
H ~

Using the procedure outlined in Example 29 the title compound was prepared from 8-cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 60(A), 20 mg, 0.040 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (8.3 mg, 42%). 'H NMR
(400MHz, CDC13) b(ppm): 9.60 (m, 1H), 9.27 (s, 1H), 8.76 (s, 1H), 7.50 (br, 1H), 7.44 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.05 (m, 1H), 3.42 (m, 2H), 3.14 (m, 4H), 2.54 (m, 4H), 2.30 (s, 3H), 1.95 (m, 4H), 1.66 (m, 3H), 1.44 (m, 2H), 1.23 (m, 1H), 1.18 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H35N702: 490.29 ~M + H), Found 490Ø

Example 63 8-Cyclohexyl-2-[3-(4-methyl-piperazin-l-yl)-phenyl amino] -5-ox o-5, 8- dihydro-pyrido [2, 3-d] p yrimidine-6-carboxylic acid amide (Cpd 63) / N ~ CONH2 N \ IN N N

N-) H

A. 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 3-(4-methyl-piperazin-1-yl)-phenylamine (from Example 37(A), 55 mg, 0.29 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (72 mg, 56%). 1H NMR (400MHz, CDC13) S(ppm):
9.27 (s, 1H), 8.46 (s, 1H), 7.75 (br, 1H), 7.29 (m, 1H), 7.22 (d, J= 8.5 Hz, 1H), 6.86 (m, 1H), 6.66 (d, J= 8.5 Hz, 1 H), 5.05 (m, 1 H), 4.31 (q, J= 7.1 Hz, 2H), 3.17 (t, J=
4.9 Hz, 4H), 2.51 (t, J 4.9 Hz, 4H), 2.28 (s, 3H), 1.94 (m, 4H), 1.76-1.19 (m, 6H); 1.34 (t, J= 7.1 Hz, 3H).

B. 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared fi=om 8-cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3=
d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.040 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (2.3 mg, 12%). 1H NMR
(400MHz, CDC13) 8(ppm): 9.44 (br, 1H), 9.32 (s, 1H), 8.77 (s, 1H), 7.50 (br, 1H), 7.29 (br, 1H), 7.22 (m, 1H), 6.86 (br, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.67 (br, 1H), 5.11 (m, 1H), 3.18 (m, 4H), 2.52 (m, 4H), 2.29 (s, 3H), 1.95 (m, 4H), 1.69 (m, 3H), 1.44 (m, 2H), 1.20 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H3i N702: 462.25 (M + H), Found 462.1.

Example 64 8-Cyclohexyl,-2-[3-(4-methyl-piperazin-l-yl)-phenyl amino] -5-ox o-5, 8-dihydro-pyrido [2, 3-d] p yrimidine-6-carboxylic acid methyl amide (Cpd 64) \ I
~ H/
N
H

Using the procedure outlined in Example 28 the title compound was prepared from 8-cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 63(A), 20 mg, 0.040 mmol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (8.9 mg, 47%). 1H NMR
(400MHz;
CDC13) b(ppm): 9.59 (m, 1H), 9.31 (s, 1H), 8.78 (s, 1H), 7.50 (br, 1H), 7.29 (m, 1H), 7.22 (d; J = 8.5 Hz, 1H), 6.87 (m, 1H), 6.68 (d, J= 8.5 Hz, 1H), 5.09 (m, 1H), 3.14 (m, 4H), 2.92 (d, J = 4.9 Hz, 3H), 2.54 (m, 4H), 2.30 (s, 3H), 1.95 (in, 4H), 1.66 (m, 3H), 1.44 (m, 2H), 1.20 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H33N702:
476.27 (M +
H), Found 476.1.

Example 65 8-Cyclohexyl-2- [3 -(4-methyl-piperazin-1-yl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido [2, 3-d] pyrimidine-6-carboxylic acid ethyl amide (Cpd 65) jj H
N\/ HN N
b Using the procedure outlined in Example 29 the title compound was prepared froiii 8-cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 63(A), 20 mg, 0.040 mniol).
The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (7.5 mg, 38%). 'H NMR
(400MHz, CDC13) S(ppm): 9.65 (m, 1H), 9.30 (s, 1H), 8.78 (s, 1H), 7.47 (br, 1H), 7.29 (m, 1H), 7.22 (d, J= 8.5 Hz, 1H), 6.87 (m, 1H), 6.68 (d, J= 8.5 Hz, 1H), 5.09(m, 1H), 3.42 (m, 2H), 3.14 (m, 4H), 2.54 (m, 4H), 2.30 (s, 3H), 1.95 (m, 4H), 1.66 (m, 3H), 1.44 (m, 2H), 1.23 (m, 1H), 1.18 (t, J= 7.3 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H35N702: 490.29 (M + H), Found 490.1.
Example 66 8-Cyclohexyl-2- [4-(2-isopropylsulfamoyl-ethyl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid amide (Cpd 66) ~ \S/O 0 0 N' \ I N~ I Ny2 H
N N N
H ~

A. 8-Cyclohexyl-2- [4-(2-i sopropylsulfamoyl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 2-(4-amino-phenyl)-ethanesulfonic acid isopropylamide (from Example 33(B), 68 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mnlol). The title compound was obtained as a yellow solid (50 mg, 35%). 1H NMR (400MHz, CDC13) 8(ppm): 9.34 (s, 1H), 8.54 (s, 1H), 7.88 (br, 1H), 7.61 (d, J= 8.3 Hz, 2H), 7.25 (d, J= 8.3 Hz, 2H), 5.10 (m, 1H), 4.40 (q, J= 7.1 Hz, 2H), 4.17 (m, 1H), 3.66 (m, 1H), 3.29 (m, 2H), 3.14 (m, 2H), 2.06 (m, 4 H), 1.86 (m, 1H), 1.68 (m, 2H), 1.51 (m, 2H), 1.41 (t, J= 7.1 Hz, 3H), 1.31(m, 1H), 1.24 (s, 3H), 1.23 (s, 3H).

B. 8-Cyclohexyl-2- [4-(2-isopropylsulfamoyl-ethyl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared fiom 8-cyclohexyl-2- [4-(2-isopropylsulfamoyl-ethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.037 mmol). The title compound was obtained as yellow solid after a preparative HPLC
(32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (6.6 mg, 35%).
'H

NMR (400MHz, DMSO-d6) 8(ppm): 10.45 (br, 1H), 9.20 (s, 1H), 9.103 (m, 1H), 8.71 {s, 1H), 7.72 (d, J= 7.6 Hz, 2H), 7.58 (m, 111), 7.26 (d, J= 8:3 Hz, 1H), 7.04 (d, J= 7.5 Hz, 1H), 5.01 (br, 1H), 3.47 (m, 1H), 3.23 (m, 2H), 2.92 (m, 2H), 1.93 (m, 4H), 1.43 (m, 3H), 130 (m, 2H), 1.12 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H).1Vlass Spectrum (LCMS, ESI pos.)"
Calcd. For C25H32N604S: 513.22 (M + H), Found 513Ø

Example 67 8-Cyclohexyl-2- { 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 67) o; 0 ~N \ I II / . I NH2 pJ H N N
~

A. '8-Cyclohexyl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) tlie title compound was prepared from 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (from Example 35(A), 75 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (57 mg, 38%). 1H NMR (400MHz, CDC13) 8 (ppm): 9.26 (s, 1H), 8.46 (s, 1H), 7.65 (br, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 5.04 (m, 1H), 4.32 (q, J= 7.1 Hz, 2H), 3.68 (m, 4H), 3.22 (m, 4H), 3.10 (m, 4H), 2.00 (m, 41 H), 1.80 (m, 1H), 1.62 (m, 2H), 1.48 (m, 2H), 1.34 (t, J= 7.1 Hz, 3H), 1.31(m, 1H).

B. 8-Cyclohexyl-2-{ 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title coinpound was prepared from 8-cyclohexyl-2- { 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 nig, 0.035 mmol). The title compound was obtained as yellow solid after a preparative HPLC

(32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (9.2 mg, 49%).
'H
NMR (400MHz, CD2C12) S(ppm): 9.26 (br, 1H), 8.76 (s, 111), 7.62 (d, J= 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.08 (br, 1H), 3.64 (m, 4H), 3.18 (m, 8H), 1.97 (m, 4H), 1.71 (m, 3H), 1.45 (m, 2H), 1.27 (m, 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H32N605S: 541.22 (M + H), Found 541Ø

Example 68 8-Cyclohexyl-2- { 4-[ 1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamino }-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 68) I o \ NH2 N N
H

A. 8-Cyclohexyl-2- { 4- [ 1-(2-dimethyl amino-acetyl)-piperidin-4-yl] -phenylamino }-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamine (from Example 70(B)), 73 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5;8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a white solid (40 mg, 25%). 'H NMR (4fl0MHz, CDC13) $
(ppm): 9.21 (s, 1H), 8.99 (s, 1H), 8.41 (s, 1H), 7.47 (d, J= 8.5 Hz, 2H), .7.13 (d, J= 8.5 Hz, 2H), 4.96 (m, 3H), 4.31 (q, J= 7.1 Hz, 2H), 3.00 (m, 4H), 2.77 (m, 1H), 2.30 (s, 6H), 1.93 (m, 6 H), 1.64 (m, 5H), 1.42 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.18(m, 1H).

B. 8-Cyclohexyl-2- { 4-[ l -(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2- { 4-[ 1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamino }
-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.036 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H20 gradient over 10 min) purification (16 mg, 84%).

1H NMR (400MHz, CDC13) S(ppm): 9.58 (m, 1H), 9.30 (s, 1H), 9.05 (s, 1H), 8.78 ~s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.20 (d, J 8.5 Hz, 2H), 5.08 (m, 3H), 3.06 (m, 4H), 2.86 (m, 1H), 2.37 (s, 6H), 1.99 (m, 6 H), 1.72 (m, 5H), 1.41 (m, 3H), 1.18(m, 1H).
Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H37N703: 532.30 (M + H), Found 532.1.

Example 69 8-Indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 69) O N ~ i CONH2 ~
J N N N
H
A. 8-Indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5 -oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5 -yl-2-methanesulfonyl-5 -oxo-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-carboxylic acid ethyl ester (0.28 g, 0.068 nunol) and 4-morpholin-4-ylmethyl-phenylamine (0.013 g, 0.068 mmol) were combined in i-PrOH ( 1 mL) and heated to 90 C .
After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/
min 5-100% MeCN/ H20 gradient over 10 min) and lyophilized to provide 22 mg (62%) of indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5-ox o-5, 8-dihydro-pyrido [2, 3 -d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (300MHz, CDC13) 8(ppm):
9.38 {br s, 1H), 8.55 (s, 1H), 7.44 (d, 2H, J=7.6Hz), 7.05-7.30 (m, 5H), 4.40 (q, 2H, J=7.lHz), 3.71 (br s, 4H), 3.43 (s, 2H), 3.09 (t, 2H, J=7.5Hz), 3.02 (t, 2H, J=7.2Hz), 2.42 (br s, 4H), 2.21-2.31 (m, 2H), 1.40 (t, 3H, J=7.lHz).

B. 8-Indan-5 -yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5 -oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 8-Indan-5-yl-2-(4-moipholin-4-ylmethyl-phenylamino)-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (18 mg, 0.034 mmol) was dissolved in'MeOH (2 mL) and cooled to -78 C in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 11.6 mg of 8-Indan-5-yl-2-(4-morpholin-4-ylmethyl-phenyl amino)-5-oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid amide. 1H NMR (400MHz, CDC13) S(ppm): 9.31 (s, 1H), 8.77 (s, 1H), 7.35 (d, 2H, J=7.9Hz), 7.10 (d, 2H, J=7.3Hz), 6.91-7.01 (m, 3H), 3.62-3.64 (m, 4H), 3.35 (s, 2H), 3.01 (t, 2H, J=7.2Hz), 2.92 (t, 2H, J=7.3Hz), 2.43 (br s, 4H), 2.15-2.19 (rn; 2H).
Mass Spectrum (LCMS, ESI pos.) Calcd. for C31H34N603: 538.27, Found: 539.2 {M
+ H).

Example 70 2- { 4-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 70) I O'J
N, 0 N N= N H
i l A. {4-[l-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-carbamic acid tert-butyl ester Dimethylamino-acetyl chloride (0.14 g, 0.86 mmol) and (4-piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol) were combined in CH2C12 ( 5 mL) and triethylamine (0.21 g, 2.2 mmol) was added. After 6 h, water ( 5 mL) was added. The reaction mixture was extracted with CH2C12 (3 x 5 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The compound was found to be unstable on silica and therefore carried on without further purification. 'H NMR (400MHz, CDC13) S(ppm):
9.04 (s, 1H), 7.52 (d, 2H, J=8.5Hz), 7.16 (d, 2H, J=8.5Hz), 3.06 ( s 2H), 2.76-2.82 ( m, 2H), 2.59-2.65 (m, 1H), 2.37 (s, 6H), 1.78-1.81 (m, 2H), 1.54-1.64 (m, 2H), 1.48 (s, 9H), 1.30 (br s, 2H).

B. 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone {4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2C12 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.11 g) (59%) of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone. 'H NMR (TFA salt) (4001VIHz, CDC13) (ppm): 10.54 (s, 1H), 7.52 (d, 211, J=8.5Hz), 7.20 (d, 2H, J=8:5Hz), 4.10 (s, 2H), 3.34-3.37 (m, 2H), 2.97-3.12 (m, 3H), 2.85 (s, 6H), 1.88-1.91 (m, 2H), 1.69-1.78 (m, 2H).

C. 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino }-8-inrlan-:5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5-yl-2-methanesulfonyl-5-oxo=5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethyl ester (20.5 mg, 0.050 mmol) and 1-[4-(4-amino-phenyl)-piperidin-l-yl]-2-dimethylamino-ethanne di-TFA salt (24 mg g, 0.050 mmol) were combined in i-PrOH ( 1 mL) and TEA (10.6 mg, 0.11 mmol) was added and the mixture was heated to 90 C . After 3 h, the reaction mixture was concentrated and purified by preparative HPLC
(30 mL/ min 5-100% MeCN/ H20 gradient over 10 min) and lyophilized to provide 24 mg (80%) of 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR
(300MHz, CDC13) 8(ppm): 9.31 (s, 1H), 9.10 (br s, 1H), 8.48 (s, 1H), 7.51 (d, 2H, J=8.lHz), 7.22-7.34 (21-1), 7.13-7.16 (m 3H), 4.38 (q, 2H, J=7.OHz), 3.09 (br s, 2H), 2.95-3.02 (m, 6H), 2.71-2.80 (m, 211), 2.39 (s, 6H), 2.11-2.22 (m, 2H), 1.55-1.93 (m, 411), 1.39 (t, 3H, J=7.2Hz).

D. 2-{ 4-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 2- { 4-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.034 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel.
Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added; the solution frozen and lyophilized to provide 15 mg of 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl] -phenylamino } -8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. IH NMR (400MHz, CDC13) S,(ppm):
9.24 (s, 1H), 8.68 (s, 1H), 7.43 (d, 2H, J=8.4Hz),7.16-7.25 (m, 3H), 7.07 (d;
2H, J=8.5Hz), 3.01 (s, 2H), 2.87-2.93 (m, 4H), 2.30 (s, 6H), 2.04-2.12 (m, 2H), 1.73-1.85 (m, 2H), 1.61 (br s, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C32H35N703: 565.28, Found:
566.3 (M + H).

Example 71 2- { 3 - [ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl] -phenylamino }-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 71) CONH

N N N
N-~y N H

A 1-[3-(4-Amino-phenyl)-piperidin-1-yl]-2-dimethylamino-ethanone Dimethylamino-acetyl chloride (0.14 g, 0.86 mmol) and (3-piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol) were combined in CH2Cla ( 5 mL) and triethylamine (0.21 g, 2.2 mmol) was added. After 6 h, water (5 mL) was added.
The reaction mixture was extracted with CH2CI2 (3 x 5 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The compound was found to be unstable on silica and therefore carried on without further purification. (3-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.090 g) (48%) of 1-[4-(3-amino-phenyl)-piperidin-l-yl]-2-dimethylamino-ethanone.

B. 2-{ 3-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan=5-yl-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5-yl-2-methanesulfonyl-5 -oxo-5, 8-dihydro-pyrido [2, 3-d]pyr.imidine-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[3-(4-amino-phenyl)-piperidin-l-yl] -2-dimethylamino-ethanone di-TFA salt (38.5 mg g, 0.079 mmol) were combined in i-PrOH ( 1 mL) and TEA (17 mg, .16 mmol) was added and the mixture was heated to C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC
(30 mL/ min 5-100% MeCN/ H20 gradient over 10 min) and lyophilized to provide 16.5 mg of 2-{3-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan=5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR
(400MHz, CDC13) 8(ppm): 9.23 (s, 1H), 9.08 (br s, 1H), 8.40 (s, IH), 7.44 (s, 1H), 7.17-7.29 (m, 4H), 7.08 (dd, 111, J=1.9Hz, J=7.9Hz), 6.85 (d, 1H, J=7.6Hz), 4.29 (q, 2H, J=7.1Hz), 3.02 (br s, 2H), 2.88-2.93 (m, 5H), 2.66-2.73 (m, 2H), 2.32 (s, 6H), 2.05-2.12 (m, 2H), 1.75-1.84 (m, 211), 1.55 (br s, 2H), 1.31 (t, 3H, J=7.1Hz).

C. 2- { 3-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 2- { 4- [ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl] -phenylamino } -8-indan-5-yl-5 -oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (16 mg, 0.027 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel.
Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 13.6 mg of 2-{3-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. IH NMR (400MHz, CDC13) 8 (ppm): 9.49 (br s, 1H), 9.25 (s, 1H), 9.04 (br s, 1H), 8.69 (s, 1H), 7.47 (s, 1H), 7.15-7.27 (m, 2H), 7.07 (d, 211, J=7.8Hz), 6.85 (d, 1H, J=7.5Hz), 5.80 (br s, 1H), 3.00 (s, 214), 2.87-2.92 (m, 411), 2.30 (s, 6H), 2.04-2.12 (m, 211), 1.76-1.87 (m, 2H), 1.57 (br s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C32H35N703: 565.28, Found: 566.3 (M + H).

Exarnple 72 8-Indan-5-yl-2-(4-{ 1-[2-(4-methyl-piperazin-1-y1)-acetyl]-piperidin-4-yl } -phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 72).
N~
N
~aaN 0 N N
H

A. 8-Indan-5-yl-2-(4-{ I-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-.
phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4=
methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI
(0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL)..
After 16 h, water (10 mL) and CH2C12 (10 mL) were added. The organic layer was washed with water (3 x 10 mL), dried (MgSO4) and concentrated. Chromatography (0-15%
EtOAc/ hexanes gradient) provided 0.24 g(83%) of (4-{ 1-[2-(4-methyl-piperazin-l-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{ 1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2C12 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1- [4-(4-Amino-phenyl)-piperidin- 1 -yl] -2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmoi) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA
salt (52 mg g, 0.079 mmol) were combined in i-PrOH ( 1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90 C . After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100% MeCN/ H20 gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl } -phenylamino)-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR (400MHz, CDC13) S(ppm):
9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.lHz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 211), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.lHz).

B. 8-Indan-5-yl-2-(4-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6--carboxylic acid amide 8-Indan-5-y1-2-(4-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6=carboxylic acid ethyl ester (15 mg, 0.024 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After l4 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 11.6 mg of 8-Indan-5-yl-2-(4-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-, yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6=carboxylic acid amide.
'H NMR (400MHz, CDC13) b(ppm): 9.46 (br s, 1H), 9.25 (s, 1H), 8.80 (br s, 1H), 8.69 (s, 1H), 7.40 (d, 2H, J=8.3Hz), 7.15-7.24 (m, 3H), 7.07 (d, 2H, J=8.3Hz), 5.70 (br s, 1H), 3.10' (s, 2H), 2.86-2.92 (m, 6H), 2.68 (br s, 12H), 2.41 (br s, 2H), 2.04-2.12 (m, 2H), 1.74-1.86 (m, 2HO, 1.50 (br s, 211). Mass Spectrum (LCMS, ESI pos.) Calcd. for C351i4oNg03.
620.32, Found: 621.3 (M + H).

Example 73 8-Indan-5-yl-2-(3-{ 1-[2-(4-methyl-piperazin-l-yl)-acetyl]-piperidin-4-yl } -phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 73) , N ~ CONH2 \ ( N N N
~N=~N H
"INJ O

A. 2- { 3-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-y1=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (3-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI
(0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF ('5 mL).
After 16 h, water (10 mL) and CH2C12 (10 mL) were added. The organic layer was,washed with water (3 x 10 mL), dried (MgSO4) and concentrated. Chromatography (0715%
EtOAc/ hexanes gradient) provided 0.22 g (73%) of 1-[4-(3-Amino-phenyl)-piperidxn-l-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. (3-{ 1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl }-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CHZCl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated.
Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.18 g) (81%) of 1-[4-(3-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5 -yl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[3-(4-amino-phenyl)-piperidin-l-yl]-2-dimethylamino-ethanone di-TFA salt (38.5 mg g, 0.079 mmol) were combined in z-PrOH ( 1 mL) and TEA (17 mg, 0.16 mmol) was added and the mixture was heated to 90 C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC
(30 mL/ min 5-100% MeCN/ H20 gradient over 10 min) and lyophilized to provide 16.5 mg of 2-{3-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-y1=5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR
(400MHz, CDC13) 8(ppm): 9.23 (s, 1H), 9.08 (br s, 1H), 8.40 (s, 1H), 7.44 (s, 1H), 7.17-7.29 (m, 4H), 7.08 (dd, 1H, J=1.9Hz, J=7.9Hz), 6.85 (d, 1H, J=7.6Hz), 4.29 (q, 2H, J=7.lHz), 3.02 (br s, 2H), 2.88-2.93 (m, 5H), 2.66-2.73 (m, 2H), 2.32 (s, 6H), 2.05-2.12 (m, 2H), 1.75-1.84 (m, 2H), 1.55 (br s, 2H), 1.31 (t, 3H, J=7.lHz).

B. 2- { 3-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 2- { 4-[ 1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino } -8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (16 mg,-0:027 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel.

Ammonia was bubbled into the solution for 1 min and'the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 13.6 mg of 8-indan-5-yl-2-(3-{ 1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl)-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 'H NMR
(400MHz, CDC13) S(ppm): 9.49 (br s, 1H), 9.25 (s, 1H), 9.04 (br s, 1H), 8.69 (s, 1H), 7.47 (s, 1H), 7.15-7.27 (m, 2H), 7.07 (d, 2H, J=7.8Hz), 6.85 (d, 1H, J=7.5Hz), 5.80 (br s, 1H), 3.00 (s, 2H), 2.87-2.92 (m, 4H), 2.30 (s, 6H), 2.04-2.12 (m, 2H), 1.76-1.87 (m, 2H), 1.57 (br s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C35H40N803:620.32, Found: 621.3 {M+->-H).

Example 74 8-Indan-5-yl-2- [4-(4-methyl-piperazin-1-ylmethyl)-phenyl amino] -5 -oxo-5, 8-dihydro-pyrido [2, 3-d] p yrimidine-6-carboxylic acid amide (Cpd 74) J \ I N i I
/N A
NN N
H

A. 8-Indaii-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.098 g, 0.24 mmol) and 4-(4-methyl-piperazin-l-ylmethyl)-phenylamine (0.049 g, 0.24 mmol) were combined in i-PrOH ( 2 mL) and heated to 90 C.
After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100 Io MeCN/ H20 gradient over 10 min) and lyophilized to provide 20 mg of 8 -Indan-5 -yl-2- [4- (4-methyl-piperazin- 1 -ylmethyl) -phenyl amino] -5 -oxo-5,8 -dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR (400MHz, CDC13) b (ppm): 9.36 (s, 1H), 8.54 (s, 1H), 7.43 (d, 2H, J=7.9Hz), 7.29 (m, 2H), 7.18 (dd, 2H, J=2.OHz, J=7.9Hz), 7.03-7.05 (m, 1H), 4.38 (q, 2H, J=7.lHz), 3.44 (s, 2H), 3.08 (t, 2H, J=7.4Hz), 3.01 (t, 2H, J=7.5Hz), 2.52 (br s, 8H), 2.36 (s, 3H), 2.19-2.29 (m, 2H), 1.39 (t, 3H, J=7.1Hz).

B. 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester{10 mg, 0.020 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel.
Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt.
After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN
(1 mL) was added, the solution frozen and lyophilized to provide 6.3 mg of 8-indan-5-yl-2, [4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 'H NMR (400MHz, CDC13) b(ppm): 9.39 (s, 1H), 9.32 (s, 1H);
8.78 (s, 1H), 7.34 (d, 2H, J=7.8Hz), 7.10 (d, 2H, J=7.9Hz), 6.97-6.99 (m, 3H), 5.68 ~br s, 1H), 3.37 (s, 2H), 3.00 (t, 2H, J=7.4Hz), 2.92 (t, 2H, J=7.5Hz), 2.81 (s, 3H), 2:44 (br s, 4H), 2.28 (br s, 4H), 2.13-2.15 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd.
for C29H38N603: 518.30, Found: 519.2 (M + H).

Example 75 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 75) N a~:-j NCONH2 N N N

H
i I

A. 2-(4-Dimethyl aminomethyl-phenyl amino)-8-indan-5-yl-5 -oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (87 mg, 0.21 mmol) and 4-dimethylaminomethyl-phenylamine (32 mg, 0.21 mmol) were combined in i-PrOH ( 2 mL) and heated to 90 C . After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100%
MeCN/ H20 gradient over 10 min) and lyophilized to provide 66 mg of 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR (400MHz, CDC13) 5 (ppm):
9.38 (s, 1H), 8.54 (s, 1H), 7.09-7.43 (m, 7H), 4.35-4.42 (m, 2H), 3.57 (s, 2H), 2:90-3.08 (m, 4H), 2.35 (s, 6H), 2.16-2.26 (m, 2H), 1.39 (t, 3H, J=7.lHz).

B. 2-(4-Dimethylaminomethyl-phenyl amino)-8-indan-5-yl-5-oxo-5, 8-dihydro=
pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (30 mg, 0.062 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 3.5 mg of 2-(4-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 1H NMR (400MHz, CDC13) S(ppm): 9.39 (br s, 1H), 9.35 (s, 1H), 8.79 (s, 1H), 7.03-7.45 (m, 7H), 3.01 (t, 214, J=7.3Hz), 2.93 (t, 2H, J=7.8Hz), 2.37 (br s, 2H), 2.10-2.18 (m, 2H), 1.19 (s, 6H). Mass Spectrum (LCMS, ESI
pos.) Calcd. for C26H26N602; 454.21, Found: 455.2 (M + H).

Example 76 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 76) CONHZ
N ~
N N N
H
i I
~

A. 2-(3 -Dimethylaminomethyl-phenyl amino)-8-indan-5-y1-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (105 mg, 0.25 mmol) and 3-dimethylaminomethyl-pheriylamine (38 mg, 0.25 mmol) were combined in iPrOH ( 2 mL) and heated to 90 C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC .(30 mL/
min 5-100%
MeCN/ H20 gradient over 10 min) and lyophilized to provide 56 mg of 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5 -y1-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR (400MHz; CDC13) S(ppm):
9.31 (br s, 1H), 8.98 (br s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 7.00-7.53 (m, 7H), 4.28-4.40 ~m, 2H), 3.64 (br s, 2H), 2.88-3.09 (m, 4H), 2.40 (s, 6H), 2.05-2.25 (m, 2H), 1.32-1.40 (m, 3H).

B. 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 2-( 3-Dimethylaminomethyl-phenyl amino)-8-indan-5-yl-5-oxo-5, 8-dihydi o-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.041 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 2.5 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 1H NMR (400MHz, CDC13) S(ppm): 9.36 (s, 2H), 8.77 (s, 1H), 6.97-4.45 (m, 7H), 3.00 (t, 2H, J=7.6Hz), 2.93 (t, 2H, J=7.4Hz), 2.13-2.21 (m, 2H), 1.47 (br s, 2H), 1.19 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H26N602; 454.21, Found: 455.2 (M + H).

Example 77 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide (Cpd 77) N
N H
N N N
H
2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo=5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 ing, 0.032 mmol) was dissolved in MeOH (1, ml.) and methylainine (1 mL of 1.0 M solution in THF,1.0 mmol) was added and the reaction mixture was heated at 80 C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100% MeCN/ H20 gradient over 15 min) and lyophilized to provide 2.3 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. iH NMR (TFA salt) (400MHz, CDC13) S(ppm): 9.51 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 7.01-7.50 (m, 7H), 3.90 (br s, 211), 2.90-3.02 (m, 7H), 2.60 (s, 611), 2.11-2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H2$N602:468.23, Found:
469.1 (M+H).

Example 78 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide (Cpd 78) 'IN N~N N H
H
i I
2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.032 mniol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80 C. After 16 h, the solution was cooled to it and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100% MeCN/'H20 gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide. 1H NMR (TFA salt) (400MHz, CDC13) S(ppm): 9.57 (s, 1H), 9.34 =(s, 1H), 8.74 (s, 1H), 6.99-7.37 (m, 7H), 3.89 (br s, 2H), 3.39-3.46 (m, 2H), 2:89-3.02 (m, 4H), 2.60 (s, 6H), 2.13-2.17 (m, 2H), 1.19 (t, 1H, J=7.3Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H30N602:482.24, Found: 483.2 (M + H).

Example 79 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (Cpd 79) N N
O H

A. 2-(3-Dimethylcarbamoyl-phenylainino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.048 minol) and 3-amino-N,N-dimethyl-benzamide (8 mg, 0.05 mmol) were combined in i-PrOH ( 2 mL) and heated to 90 C. After 15 h, the reaction mixture was concentrated and purified by preparative HPLC'(C-18 colurnn, 32 mL/ min 5-100% MeCN/ H20 gradient over 15 min) and lyophilized to provide 15.6 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-y1-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR (400MHz, CDC13) 8(ppm):
9.31 (s, 1H), 1.13 (s, 1H), 7.46 (br s, 1H), 7.33 (d, 1H, J=7.9Hz), 7.16-7.21 (m, 2H), 7.10 (d, 1H, J=7.6Hz), 6.96 (br s, 211), 4.29 (q, 2H, J=7.lHz), 2.97-3.04 (m, 5H), 2.85-2.93 (m, 5H), 2.14 (p, 2H, J=7.4Hz), 1.29 (t, 3H, J=7.lHz) B 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-.5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 2-(3 -Dimethylcarbamoyl-phenyl amino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0.010 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel. Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt. After 14 h;
the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN (1 mL) was added, the solution frozen and lyophilized to provide 4.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 'H NMR (400MHz, CDC13) b(ppm): 9.42 (s, 1H), 9.29 (s, 1H), 8.88 (s, 1H), 7.49 (m, 4H), 6.88-6.90 (m, 3H), 3.29 (br s, 2H), 2.44-2.93 (m), 1.94-2.15 (m), 1.19-1.76 (m).
Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H24N603:.468.19, Found: 469.2 (M
+ H).

Example 80 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide (Cpd 80) O O
N, N YN
H
N N
O H
2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0:010 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80 C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100% MeCN/ H20 gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide.
IH NMR (TFA salt) (400MHz, CDC13) 8(ppm): 9.56 (br. S, 1H), 9.33 (s, 1H), 8.77 (s, 1H), 7.51 (dd, 1H, J=2.3Hz, J=9.3Hz), 7.34 (d, 1H, J=7.9Hz), 7.11 (dd, iH, J=1.7Hz, J=7.8Hz), 6.99 (br. S, 1H), 2.86-3.05 (m, 13H), 2.12-2.19 fm, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H26N603: 482.21, Found: 483.2 (M + H).

Example 81 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide (Cpd 81) o O
N N
N ~ H
N N N
O H

2-(3 -Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0.010 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80 C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100% MeCN/ H20 gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylanlide. 1H
NMR (TFA salt) (400MHz, CDC13) S(ppm): 9.64 (s, 1H), 9.32 (s, 1H), 8.77 (s, 1H), 7.51 (dd, 1H, J=2.3Hz, J=9.3Hz), 7.34 (d, 1H, J=7.8Hz), 7.17-7.19 (m, 3H), 7.11 (dd, 1H, J=2.OHz, J=8.OHz), 6.99 (br. S, 1H), 3.44 (dq, 2H, J=5.8Hz, J=7.3Hz), 2.86-3.05 (m, 10H), 2.11-2.19 (m, 2H), 1.21 (t, 1H, J=7.3Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H28N603; 496.22, Found: 497.2 (M + H).

Example 82 8-B icyclo [2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido [2, 3 -d].pyrimidine-6-carboxylic acid amide (Cpd 82) HN N N

(N) N
A. 3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester Bicyclo[2.2.1]hept-2-ylamine (2.0 g, 18.0 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.45 g, 18.0 mmol) were combined neat and K2C03 (3.72 g, 27.0 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 2 mg) was added. The mixture was heated at 80 C overnight. The resulting mixture was then partitioned between water and DCM. The organic layer was dried (MgSO4) and concentrated to provide 1.5 g of 3-(bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester. 1H NMR (400MHz, CDC13) 8(ppm): 5.29 (s, 1H), 4.13 (q, 2H, J=7.1Hz), 2.77-2.92 (m, 2H), 2.57 (dd, 1H, J=3.lHz, J=7.3Hz), 2.50 (t, 211, J=6.6Hz), 2.16-2.20 (m, 2H), 1.57 (ddd, 1H, J=2.2Hz, J=7.5Hz, J=12.3Hz), 1.41-1.49 (m, 3H), 1.25 (t, 311, J=7.2Hz), 1.01-1.10(m,4H).

B. 8-B icyclo [2.2.1 ] hept-2-yl-2- [4-(4-methyl-piperazin-1-yl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester 3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-inethylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2C12 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/ hexanes gradient) provided 1.8 g of 4-[bicyclo [2.2.1 ]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino] -2-methylsulfanyl-pyrimidine-5 -carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4-[bicyclo [2.2.1 ]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino] -2-methylsulfanyl-pyrimidine=5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90 C for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2 X 20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH.provided 0.51 g of 8-bicyclo[2.2.1 ]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7, 8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8=dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH ( 2 mL) and heated to 90 C . After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100% MeCN/ H20 gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-inethyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400MHz, CDC13) 8(ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9Hz), 6.87 (d, 2H, J=9.OHz), 4.31 (q, 2H, J=7.lHz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).

C. 8 -B icyclo [2.2.1 ]hept-2 -y1-2- [4-(4-methyl-piperazin-1-yl)-phenylamino]
-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide 8-B icyclo [2.2.1 ]hept-2-y1-2- [4-(4-methyl-piperazin-l-yl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.7 mg, 0.11 mmol) was dissolved in MeOH (2 mL) and cooled to -78 C in a high pressure vessel.
Ammonia was bubbled into the solution for 1 min and the vessel was sealed and allowed to warm to rt.
After 14 h, the solution was cooled to -78 C, the vessel was opened and the solution was allowed to warm to rt. The solution was concentrated and water (2 mL) and MeCN
(1 mL) was added, the solution frozen and lyophilized to provide 3.2 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide. 'H NMR (TFA salt) (400MHz, CDC13) S(ppm):
9.36-9.39 (m, 2H), 8.78 (s, 1H), 7.52 (d, 1H, J=7.2Hz), 7.33 (d, 1H, J=7.9Hz), 7.12 (d, 1H, J=8.OHz), 6.98 (br s, 1H), 5.69 (br s, 1H), 2.86-3.04 (m, .11H), 2.13-2.17 (m, 2H), 1.52 (br s, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H31N702:473.25, Found:
474.3 (M+H).

Example 83 8-Bicyclo [2.2.1 ]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenyl amino] -5 -ox o-5, 8-dihydro-pyrido [2, 3-d] pyrimidine-6-carboxylic acid ethylamide (Cpd 83) N' H
HN N N

' ~
N

8-B icyclo [2.2.1 ] hept-2-yl-2- [4-(4-methyl-piperazin-1-yl)-phenylamino] -5-oxo-5,$-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.7 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 inL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80 C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 colunm, 32 mL/ min 5-100%
MeCN/
H20 gradient over 15 min) and lyophilized to provide 3.7 of 8 -bicyclo [2.2. 1 ]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. . 1H NMR (TFA salt) (400MHz, CDC13) 8(ppm): 9.62 (s, 1H), 9.26 (s, 1H), 8.90 (s, 1H), 7.54 (d, 2H, J=8.8Hz), 6.89 (d, 2H, J=8.9Hz), 4.85-4.88 (m, 1H), 3.26-3.64 (m, 9H), 2.91-2.94 (m, 2H), 2.82 (s, 3H), 2.55 (s, 1H), 2.44 (s, IH), 2.03 (br s, 8H), 1.59-1.61 (m, 4H), 1.35-1.41 (m, 2H), 1.19 (t, 1H, J=7.3Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H35N702: 501.29, Found: 502.3 (M + H).

Example 84 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl amino] -5-oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethylamide (Cpd 84) cio H
H
i I
8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (9.2 mg, 0.017 miimol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 nunol) was added and the reaction mixture was heated at 80 C. After 16 h,the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100%
MeCN/
H20 gradient over 15 min) and lyophilized to provide 5.2 mg of 8-indan-5-yl-2-[4-(4-inethyl-piperazin-1-ylmethyl)-phenylamino] -5-oxo-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid ethylamide. 'H NMR TFA salt (400MHz, CDC13) S(ppm): 9.38 (br s, 1H), 9.37 (s, 1H), 8.84 (s, 111), 7.58-7.60 (m,1H), 7.40-7.47 (m, 2H), 7.16 (dd, 2H, J=2.OHz, J=7.9Hz), 7.05 (br s, 2H), 3.43-3.55 (m, 4H), 3.07 (t, 2H, J=7.3Hz), 2.99 (t, 211, J=7.4Hz), 2.53 (br s, 8H), 2.36 (s, 3H), 2.18-2.27 (m, 2H), 1.15-1.39 (m, 3H).
Mass Spectrum (LCMS, ESI pos.) Calcd. for C31H35N702: 537.29, Found: 538.3 (M + H).

Example 85 8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide (Cpd 85) N) 0 0 i I N N N-NN N H
H

A. 4-[Benzyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 3-Benzylamino-propionic acid ethyl ester (2.0 g, 9.6 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.2 g, 9.6 mmol) were combined in DCM (50 mL) and triethylamine (1.5 g, 14.5 mmol) was added. After 14 h, water (25 mL) was added and the organic layer was separated, dried (MgSO4), and concentrated.
Chromatography on silica (0-30% EtOAc/ hexanes gradient) provided 2.91 g of 4-[benzyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. 1H NMR (400MHz, CDC13) 8(ppm): 8.46 (s, 1H), 7.23-7.33 (m, 5H), 4.75 (s, 2H), 4.21 (q, 2H, J=7.2Hz), 4.06-4.15 (m, 2H), 3.77 (t, 2H, J=7.2Hz), 2.66-2.70(app t, 2H), 2.45 (s, 3H), 1.19-1.29 (m, 6H).

B. 8-Benzyl-2-methylsulfanyl-5-oxo-5,6,7; 8-tetrahydro-pyrido[2,3-d]pyrimidine-carboxylic acid ethyl ester Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4-[benzyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.9 g, 7.2 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90 C for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2 X 20 mL) and the organic layer was dried (MgSO~), and concentrated.
Recrystallization from i-PrOH provided 1.53 g of 8-benzyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 'H NMR mixture of tautomers in a 2.3 : 1 ratio, (400MHz, CDC13) b(ppm): 8.65 (s, 1H), 8.25 (s, 1H), 7.24-7.36 (m, 511), 5.07 (d, 1H, J=14.9Hz), 4.83 (d, 1H, J=14.9Hz), 4.79 (s, 2H),4.17-4.22 (m, 2H), 2.51 (s, 1.3H), 2.46 (s, 3H), 0.85-0.89 (m, 3H).

C. 8-B enzyl-2-methylsulfanyl-5-oxo-5, 8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester Bromine (0.68 g, 4.3 mmol) was added to a solution of 8-benzyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1.53 g, 4.28 mmol) in DCM (20 mL). After 30 minutes, the reaction mixture was concentrated.
The residue was redissolved in DCM (20 mL) and triethylamine (1.08 g, 10.7 mmol) was added. After 15 h, water (10 mL) was added, the organic layer separated, dried (MgSO4), and concentrated. Chromatography on silica (0-50% EtOAc/ hexanes gradient) provided 0.39 g 8-benzyl-2-methylsulfanyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400MHz, CDC13) S(ppm): 9.26 (s, 1H), 8..51 fs, 1H), 7.21-7.29 (m, 5H), 5.45 (s, 2H), 4.27 (q, 2H, J=7.1Hz), 2.48 (s, 3H), 1.30 (t, 3H, J=7.1Hz).', D. 8-B enzyl-2-meth anesulfonyl-5-oxo-5, 8-dihydro-pyrido [2,3 -d]pyrimidine-6-carboxylic acid ethyl ester 8-B enzyl-2-methylsulfanyl-5-oxo-5, 6,7, 8-tetrahydro-pyrido[2,3 -d]
pyrimidine-6-carboxylic acid ethyl ester (0.39 g, 1.1 mmol) and fn-CPBA (0.61 g(77% w/w), 2.7 mmol) were combined in DCM (20 mL). After 2 hours, a 10% solution of Na2SO3 (5 mL) was added and the mixture was partitioned between sat. NaHCO3 and DCM. The organic layer was dried (MgSO4) and concentrated. Chromatography on silica (25-100% EtOAc/
hexanes gradient) provided 0.21 g of 8-benzyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400MHz, CDC13) b (ppm): 9.70 (s, 1H), 8.72 (s, 1H), 7.38-7.41 (m, 5H), 5.57 (s, 2H), 4.40 (q, 2H, J=7.1Hz), 3.38 (s, 3H), 1.40 (t, 3H, J=7.lHz).

E. 8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide 8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (7.6 mg, 0.015 mmol) was dissolved in MeOH (1 mL) and methylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80 C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/ min 5-100% MeCN/ H20 gradient over 15 min) and lyophilized to provide 1.3 mg of 8-benzyl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbbxylic acid methylamide. 'H NMR (TFA salt) (400MHz, CDC13) S(ppm): 9.54 (br s, 1H), 9.25 (s, 1H), 8.70 (s, 1H), 7.23-7.30 (m, 5H), 7.13-7.15 (m, 2H), 6.83 (d, 2H, J=8.9Hz), 5.35 (s, 2H), 3.13 (br s, 4H), 2.91 (s, 3H), 2.53 (br s, 4H), 2.30 (br s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H29N702; 483.24, Found: 484.3 (M + H).

Biological Examples Example 1 Autophosphorylation, Fluorescence Polarization Competition Imrnunoassay An autophosphorylation, fluorescence polarization competition immunoassay was used to determine the potency for c-fms inhibition exhibited by selected compounds of Formula I. The assay was performed in black 96-well microplates (LJL
BioSystems). The assay buffer used was 100 mM 4-(2-hydroxyethyl)piperazine 1-ethanesulfonic acid (HEPES), pH 7.5, 1 mM 1,4-dithio-DL-threitol (DTT), 0.01 % (v/v) Tween-20.
Compounds were diluted in assay buffer containing 4 % dimethylsulfoxide (DMSO) just prior to the assay. To each well, 5 L of compound were added followed by the addition of 3 L of a mix containing 33 nM c-fms and 16.7 mM MgC12 (Sigma) in assay buffer. The kinase reaction was initiated by adding 2 L of 5 mM ATP (Sigma) in assay buffer. The final concentrations in the assay were 10 nM c-fms, 1 mM ATP, 5 mM MgCl2, 2 %
DMSO. Control reactions were ran in each plate: in positive and negative control wells, assay buffer (made 4 % in DMSO) was substituted for the compound; in addition, positive control wells received 1.2 L of 50 mM ethylenediaminetetraaceticacid (EDTA).

The plates were incubated at room temperature for 45 min. At the end of the incubation, the reaction was quenched with 1.2 gL of 50 mM EDTA (EDTA was not added to the positive control wells at this point; see above). Following a 5-min incubation, each well received 10 gL of a 1:1:3 mixture of anti-phosphotyrosine antibody, lOX, PTK
green tracer, 10X (vortexed), FP dilution buffer, respectively (all from PanVera, =cat. #
P2837). The plate was covered, incubated for 30 min at room temperature and the fluorescence polarization was read on the Analyst. The instrument settings were: 485 nm excitation filter; 530 nm emission filter; Z height: middle of well; G factor:
0.93. Under these conditions, the fluorescence polarization values for positive and negative controls were approximately 300 and 150, respectively, and were used to define the 100 % and 0 %
inhibition of the c-fms reaction.

The IC50 values shown in Table 1 are averages of three independent measurements.
Table 1 c-fms Autophosphorylation IC50 Values Cpd IC50 (IJM) Cpd IC50 ( M) Cpd IC50 ( M) 1 0.28 30 0.012 58 0.12 2 0.44 31 0.02 59 0.19 3 2.9 32 0.033 60 0.035 4 >10 33 0.1 61 0.16 0.59 34 >1 62 0.19 6 1.1 35 0.08 63 0.021 7. 0.013 36 1.0 '64 0.05 8 0.031 37 0.008 65 0.11 9 0.068 38 0.009 66 0.12 0.013 39 0.013 67 0.12 11 0.046 40 0.005 68 0.13 12 0.077 41 0.011 69 0.018 13 0.73 42 0.016 70 1.1 14 0.019 43 0.007 71 7.4 0.07 44 0.008 72 4.1 16 0.012 45 0.012 73 > 1 17 1.7 46 0.008 74 0.032 18 10 47 0.015 75 0.021 19 0.056 48 0.032 76 0.018 1.4 49 0.008 77 0.15 21 10 50 0.015 78 0.14 22 >10 51 0.025 79 0.062 23 0.014 52 0.005 80 0.074 24 0.018 53 0.008 81 0.11 0.093 54 0.011 82 0.081 26 0.056 55 0.006 83 0.3 27 0.01 56 0.01 84 0.032 28 0.03 57 0.026 85 0.42 29 0.033 Example 2 Peptide (Non-Phosphorylated) Assay A fluorescence polarization competition immunoassay was used to measure compound inhibition of CSF-1R phosphorylation of tyrosine on a synthetic CSF-1R555=568 peptide (SYEGNSYTFIDPTQ). The assay was performed in black 96-well microplates (Cat # 42-000-0117, Molecular Devices, Sunnyvale, CA). To each well, 5 L of compound (in 4% DMSO) were mixed with 2 L of 3.5 nM CSF-1R, 25 mM MgCl2 in assay buffer (100 mM HEPES, pH 7.5, 1 mM DTT, 0.01% Tween-20), and 2 L of 1540 M peptide in assay buffer. The kinase reaction was initiated by adding 1 L of 10 mM ATP in assay buffer. The final concentrations in the 10 uL reaction mixture were 100 mM
HEPES, pH
7.5, 1 mM DTT, 0.01% Tween-20, 2% DMSO, 308 M SYEGNSYTFIDPTQ, 1 mM
ATP, 5 mM Mg02, and 0.7 nM CSF-1R. Positive and negative control wells were included on each plate, where 4% DMSO in assay buffer, was substituted for the compound; in addition, positive control wells received 1.2 L of 50 mM EDTA
before the start of the reaction.

The plates were covered and incubated at room temperature for 80 min.
Reactions were stopped by addition of 1.2 L of 50 mM EDTA. Each well then received 10 L of a 1:1:3 mixture of lOX anti-phosphotyrosine antibody, lOX PTK green tracer, and FP
dilution buffer, respectively (Cat. # P2837, Invitrogen, Carlsbad, CA). The plates were covered, incubated for 30 min at room temperature, and the fluorescence polarization was read on an Analyst plate reader (Molecular Devices). Instrument settings were:
485 nm excitation, 530 nm emission, with a 505 nm cut-off filter; Z height: middle of well; G
factor: 0.93: Under these conditions, the fluorescence polarization values for positive and negative controls were approximately 290 and 160, respectively, and were used to define 100% and 0% inhibition of the CSF-1R reaction.

The IC50 values reported in Table 2 are the mean of at least three determinations.

Table 2 c-fms Peptide IC50 Values Cpd IC50 ( M) Cpd IC50 ( M) Cpd IC50 ( M) 7 0.0039 43 0.00058 53 0.00046 0.0027 44 0.00053 54 0.0011 11 0.0056 46 0.00074 55 0.00051 16 0.0043 47 0.0013 56 0.0011 23 0.0015 49 0.00049 28 0.0016 50 0.00097 40 0.00024 52 0.00042 While the foregoing specification teaches the principles'o.f the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

All publications disclosed in the above specification are hereby incorporated by reference in full.

Claims

1. A compound of Formula I:

or a form thereof, wherein:

W is N or CH;

A is absent or alkyl;

Y is a ring selected from cycloalkyl, bicycloalkyl, aryl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

R101 is hydrogen, hydroxyl, methyl, halogen, -CF3, or methoxy;

R200 is halogen, alkoxy optionally substituted with -CH(OH)-CH2-NR203R204, alkyl optionally substituted with R201, heterocyclyl optionally substituted with one alkyl and optionally substituted with one R202, amino, alkylamino, dialkylamino, -C(O)(CH2)n NR203R204, heteroaryl, or -R300-R400; wherein n is 0, 1, 2, 3, or 4;

R201 is hydroxyl, methyl, halogen, -CF3, amino, alkylamino, dialkylamino or methoxy;
R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)n NR203R204, or -CON-alkyl-NR203R204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl;
R300 is alkyl;

R400 is -NR403R404, -SO2NR405R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R401, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R401;

wherein R401 is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R404 are independently hydrogen, alkyl, or R403 and R404 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl;

R405 and R406 are independently hydrogen, alkyl, or R405 and R406 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl; and Z is CO2H, CO2alkyl, or CONR1R2; wherein R1 is hydrogen or alkyl; and R2 is hydrogen, alkyl, cycloalkyl, or alkoxy.

2. The compound of Claim 1 wherein:
A is absent;

Y is a ring selected from cycloalkyl, bicycloalkyl, phenyl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

R200 is halogen, C(1-4)alkoxy optionally substituted with -CH(OH)-CH2-C(1-4)alkyl optionally substituted with R201, heterocyclyl optionally substituted with one C(1-4)alkyl and optionally substituted with one R202, dialkylamino, -C(O)(CH2)n NR203R204, heteroaryl, or R300-R400; wherein n is 0, 1, 2, 3, or 4;

R201 is hydroxyl, methyl, halogen, -CF3, dialkylamino or methoxy;
R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)n R203R204, -C(O)N(CH2)n NR203R204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, C(1-4)alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl;
R300 is C(1-4)alkyl; and R400 is -NR403R404, -SO2NR405R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R401, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R 401;

wherein R401 is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R404 are independently hydrogen, C(1-4)alkyl, or R403 and R404 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl;

R405 and R406 are independently hydrogen, C(1-4)alkyl, or R405 and R406 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl; and Z is CO2alkyl, or CONR1R2; wherein R1 is hydrogen or C(1-4)alkyl; and R2 is hydrogen, C(1-4)alkyl, cycloalkyl, or C(1-4)alkoxy.

3. The compound of Claim 1 wherein:

Y is a ring selected from indan-5-yl, phenyl, cyclohexyl, cyclopentyl;
cbicyclo[2.2.1]heptyl or adamantan-2-yl;

R101 is hydrogen or hydroxyl;

R200 is fluorine, alkoxy substituted with -CH(OH)-CH2-N(CH3)2, alkyl optionally substituted with R201, morpholinyl, piperazinyl optionally substituted with 3,5-dimethyl piperazinyl, piperidinyl, piperidinyl substituted with -CO-alkyl-N(CH3)2, -C(O)-alkyl-piperazinyl (optionally substituted on piperazinyl with alkyl), dimethylamino, -C(O)N(CH3)2, heteroaryl, or -R300-R400;

R201 is hydroxyl or dimethylamino;
R202 is -CH3;

R300 is alkyl; and R400 is -N(CH3)2, morpholinyl, -SO2NR405R406, piperazinyl optionally substituted with R202 or oxazolidinonyl;

R405 and R406 are independently hydrogen, alkyl, or R405 and R406 may be taken together to form the following ring: .

4. The compounds of Claim 1 wherein:
W is N;

A is absent;

Y is a ring selected from cycloalkyl or arylcycloalkyl;

R200 is piperazine optionally substituted with one or two methyl substituents, piperidine optionally substituted with one or two methyl substituents, morpholine or -R300-R400 wherein R300 is methyl or ethyl and R400 is piperazine optionally substituted with one or two methyl substituents.

Z is CO2alkyl, or CONR1R2; wherein R1 is hydrogen or C(1-4)alkyl; and R2 is hydrogen, C(1-4)alkyl, or cycloalkyl.

5. A compound of Formula I wherein:
W is N or CH;

A is absent;

Y is a ring selected from cycloalkyl, bicycloalkyl, phenyl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;

R101 is hydrogen, hydroxyl, methyl, halogen, -CF3, or methoxy;

R200 is halogen, C(1-4)alkoxy optionally substituted with -CH(OH)-CH2-NR203R204, C(1-4)alkyl optionally substituted with R201, heterocyclyl optionally substituted with one C(1-4)alkyl and optionally substituted with one R202, dialkylamino, -C(O)(CH2)n NR203R204 , heteroaryl, or -R300-R400; wherein n is 0, 1, 2, 3, or 4;

R201 is hydroxyl, methyl, halogen, -CF3, dialkylamino or methoxy;
R202 is alkyl, -C(O)-CH3, -CH2-C(O)-CH3, -C(O)(CH2)n NR203R204, -C(O)N(CH2)n NR203R204; wherein n is 0, 1, 2, 3, or 4;

R203 and R204 are independently hydrogen, C(1-4)alkyl, or R203 and R204 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl;

R300 is C(1-4)alkyl; and R400 is -NR403R404, -SO2NR405R406, oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R401, piperazinyl wherein said piperazinyl is optionally substituted with R202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R401;

wherein R401 is methyl, -C(O)-CH3, or -CH2-C(O)-CH3;

wherein R403 and R404 are independently hydrogen, C(1-4)alkyl, or R403 and R404 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl;

R405 and R406 are independently hydrogen, C(1-4)alkyl, or R405 and R406 may be taken together to form a ring selected from the following:

wherein R a, R c and R d are independently hydrogen or alkyl; and Z is CO2H.

6. A compound selected from the group consisting of:
8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid, 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 8-cyclohexyl-2-(4-dimethylamino-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 8-cyclopentyl-2- [4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-hydroxymethyl-phenylamino)-8-indan-5-yl-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-fluoro-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester, 8-indan-5-yl-5 -oxo-2-(4-pyrazol-1-yl-phenylamino)-5, 8-dihydro-pyrido [2, 3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid amide, 2-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 1-indan-5-yl-7-[4-(4-methyl-piperazin-1-yl)-phenylamino]-4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid amide, 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5 -yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-2- [4-(2-isopropylsulfamoyl-ethyl)-phenyl amino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2- [4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 2-[4-(3, 5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Cyclohexyl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-{4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-{4-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-{3-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino}-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-(3-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, and 8-Benzyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid methylamide.

7. A compound selected from the group consisting of:

8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide, 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide, 8-indan-5-yl-2-(4-morpholin-4-yl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-indan-5-yl-2-(3-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 1-indan-5-yl-7-[4-(4-methyl-piperazin-1-yl)-phenylamino]-4-oxo-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid amide, 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, (4S)-8-Indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, (4S)-8-Indan-5-y1-5-oxo-2- [4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino] -5, 8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, (4S)-8-Indan-5-yl-5-oxo-2- [4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-{4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-[3-(4-methyl-piperazin-1=yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 2-[4-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenylamino}-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-5-oxo-2-(3-piperazin-1-yl-phenylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl amide, 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-[3-(3,5-Dimethyl-piperazin-1-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-[3-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Cyclohexyl-2-[3 -(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methyl amide, 8-Indan-5-yl-2-(4-morpholin-4-ylmethyl-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(4-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, 2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido [2,3-d]pyrimidine-6-carboxylic acid methylamide, 8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide, and 8-Indan-5-yl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide.

8. A pharmaceutical composition, comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.

9. A method for inhibiting protein tyrosine kinase activity, comprising contacting the kinase with an effective inhibitory amount of at least one compound of Claim 1.

10. A method according to claim 9, wherein the protein tyrosine kinase is c-fms.

11. A method of treating inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of at. least one compound of Claim 1.

12. A method of treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of Claim 1.

13. A method of treating cardiovascular disease in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of Claim 1.

14. A method of treating glomerulonephritis, rheumatoid arthritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, pancreatitis, HIV infection, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia or Alzheimer's dementia in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound of Claim 1.

15. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of Claim 1.

16. A dosage form according to Claim 15 adapted for parenteral or oral administration.

17. The use of a compound as in Claim 1 for the preparation of a medicament for the treatment of: rheumatoid arthritis, graft rejection, atherosclerosis, obesiy, diabetic nephropathy, cardiac hypertrophy and solid tumor diseases, especially breast cancer, in a subject in need of such treatment.